Organic Reaction Mechanisms: An Annual Survey of Literature, 1995

ORGANIC REACTION MECHANISMS - 1995

ORGANIC REACTION MECHANISMS 1995 An annual survey covering the literature dated December 1994 to November 1995

Ediied by

A. C. Knipe and W. E. Watts University of Ulster Northern Ireland

An Intersciencea Publication

JOHN WILEY & SONS Chichester . New York . Weinheim . Singapore . Toronto

copyright

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Contributors 1. I. BILKlS

Institute of Biochemistry, Food Science and Nutrition, Faculty of Agriculture, The Hebrew University of Jerusalem, Rehovot 76 1 00, Israel Department of Chemistry, University of Warwick, Coventry, A. J. CLARK CV4 7AL, UK Department of Chemistry, Brunel University, Uxbridge, R. G. COOMBES Middlesex, UB8 3PH, UK Department of Chemistry, University of Toronto, 80 St. R. A. COX George Street, Toronto, Ontario M5S IAl, Canada M. R. CRAMPTON Department of Chemistry, University of Durham, Durham, DHl 3LE, UK N. DENNIS Australian Commercial Research and Development Ltd, GPO Box 248 1, Brisbane, Queensland 4001, Australia Dyson Perrins Laboratory, University of Oxford, South Parks G. W. J. FLEET Road, Oxford, OX1 3QY, UK Department of Chemistry, California State University, Fresno, J. R. GANDLER CA 97740-0070, USA Department of Chemistry, University of Newcastle upon Tyne, J. G. KNIGHT Newcastle upon Tyne, NEl 7RU, UK School of Applied Biological and Chemical Sciences, A. C. KNIPE University of Ulster, Coleraine, Co Londonderry, BT.52 ISA, UK Department of Chemistry, University of Leicester, Leicester, P. KOCOVSKY LEI 7RH, UK Departmcnt of Chemistry, University of Dundee, Dundee, A. W. MURRAY DD14HN, UK Department of Applied Science, RTC Tallaght, Dublin 24, B. A. MURRAY Ireland Department of Chemistry, University of Warwick, Coventry, S. M. ROOKE CV4 7AL, UK School of Chemistry, University of Hull, Hull, HU6 7RX, UK J. SHORTER Department of Chemistry, University College, Galway, Ireland W. J. SPILLANE

V

The present volume, the thirty-first in the series, surveys research on organic reaction mechanisms described in the literature dated December 1994 to November 1995. In order to limit the size of the volume, we must necessarily exclude or restrict overlap with other publications which review specialist areas (e.g. photochemical reactions, biosynthesis, electrochemistry, organometallic chemistry, surface chemistry and hetcrogeneous catalysis). In order to minimize duplication, while ensuring a comprehensive coverage, the editors conduct a survey of all relevant literature and allocate publications to appropriate chapters. While a particular reference may be allocated to more than one chapter, we do assume that readers will be aware of the alternative chapters to which a borderline topic of interest may have been preferentially assigned. There have been several changes of authorship since last year. We say farewell to Prof M. I. Page, Dr W. R. Bowman, Dr D. R. Coghlan, Dr S. W. Ginn and Dr J. H. Stewart, with thanks for their contributions over several years. Their places have becn filled by four authors who are new to the series: Dr B. Murray, Dr A. Clark, Dr S. M. Rooke and Prof I. Bilkis are welcomed as experts on ‘Reactions of Aldehydes and Ketones’, and on ‘Radical Reactions: Parts 1 and 2’, respectively. We regret that late arrival of a chapter caused some delay in publication, but once again wish to thank the production staff of John Wiley & Sons and our team of experienced contributors for their efforts to ensure that the standards of this series are sustained. We are also indebted to Dr N. Cully, who compiled the subject index. A.C.K.

w.w. w.

vii

CONTENTS

.

1

Reactions of Aldehydes and Ketones and their Derivatives byB.A.Murray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Reactions of Acids and their Derivatives by W. J. Spillane . . . . . . . 3 Radical Reactions Part 1 by A . J. Clark and S. M. Rooke. . . . . . . . 4. Radical Reactions Part 2 by I . I. Bilkis . . . . . . . . . . . . . . . . . . . . 5 Oxidation and Reduction by G . W. J. Fleet . . . . . . . . . . . . . . . . . . 6 Carbenes and Nitrenes by J. G . Knight . . . . . . . . . . . . . . . . . . . . 7. Nucleophilic Aromatic Substitution by M . R . Crampton . . . . . . . . . 8. Electrophilic Aromatic Substitution by R . G . Coombes . . . . . . . . . 9. Carbocations by R . A . Cox . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Nucleophilic Aliphatic Substitution by J. Shorter. . . . . . . . . . . . . . 11 Carbanions and Electrophilic Aliphatic Substitution by A . C . Knipe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12. Elimination Reactions by J. R . Gandler . . . . . . . . . . . . . . . . . . . . 13. Addition Reactions: Polar Addition by l? KoEovskf . . . . . . . . . . . 14 Addition Reactions: Cycloaddition by N . Dennis . . . . . . . . . . . . . 15 Molecular Rearrangements by A . W. Murray . . . . . . . . . . . . . . . . Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. .

. . .

. .

ix

1 35 91 123 181 213 231 249 259 279 303 337 363 399 439 555 593

CHAPTER 1

Reactions of Aldehydes and Ketones and their Derivatives B. A . MURRAY Department of Applied Sciences. Regional Technical College Tallught. Dublin. Irelund Formation and Reactions of Acetals and Related Species . . . . . . . . . . . . . . . Hydrolysis of Glucosides and Nucleosides . . . . . . . . . . . . . . . . . . . . . . . . . Formation. Hydration. and Hydrolysis of Ketenes . . . . . . . . . . . . . . . . . . . . Formation and Reactions of Nitrogen Derivatives . . . . . . . . . . . . . . . . . . . .

Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . lminium Ions and Related Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oximes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydrazones, Semicarbazones, and Related Species . . . . . . . . . . . . . . . . . . . C-C Bond Formation and Fission: Aldol and Related Reactions . . . . . . . . . . Aldol Rcactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tntramolecuiar Aldols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mukaiyama (Enolsilane) Aldol Reactions . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Aldol-type Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Benzoin Condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Addition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . General and Theoretical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Addition of Organometallics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Addition of Carbon Nucleophiles Containing N, Si, P, or S Substituents . . . . . . Addition of Amine Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Addition of Phosphorus Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enolization and Related Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hydrolysis and Reactions of Vinyl Ethers and Related Compounds . . . . . . . . Oxidation and Reduction of Carbonyl Compounds . . . . . . . . . . . . . . . . . . . Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 2 3 4 4 6 1 8 8 8

10 11

12 13 15 15 16 17

18 19

20 20 21 25 26 28 31

Formation and Reactions of Acetals and Related Species An a-diketonc acetal (1a) (cis- 1,6-dimethyl-2,5,7,l0-tetraoxabicyclo[4.4.0]dccanc) undergoes titanium chloride-mediated addition of allyltrimethylsilane diastereoselectively to give the corresponding meso.2,3.diallyl.2,3.dimethyl.l, 4.dioxane (1 b); the two successive substitutions involved are proposed to occur via SN2-like inversions stabilized through an anomeric effect in each case.’ Diastereoselective ring opening of cyclic acetals with hindered Grignards appears to depend on complexation of the magnesium to a remote substrate oxygen.2 Organic Reuctiun Mechanisms 1995. Edited by A . C . Knipe and W. E . Watts 0 1997 John Wiley & Sons Ltd

1

Organic Reaction Mechanisms 1995

2

Dipole repulsions-and not hyperconjugation-have been claimed as the cause of the anomeric effect in 2-methoxyazacyclohexanes,3abut this has been disputed in a theoretical conformational analysis:3bthe effects observed can be explained in terms of back-donation from lone pairs. A wide variety of ‘dimeric’ ring systems (2) have been synthesized from 2-naphthol and various dials, using Friedel-Crafts-type condensations and intramolecular acetali~ations.~ Examples include naphthofuronaphthofuran (rn = n = 0), the corresponding pyranopyran, methano- and propano-dinaphtho[ I ,3]dioxocins (m= 0; n = I , 3), and spiropyrans. Six- and seven-membered hemiperacetals (3; R = R’ = H, n = 2, 3) in HCI-MeOH yield peroxidic products with one, two, or three rings, while the corresponding peracctals (R = Me, R’ = H) give non-peroxidic products, as do persubstituted peracetals (R = R’ =Me), the latter showing skeletal fragmentati~n.~ The results are interpreted in terms of the competing protonation sites in the intermediates arising from each class. Cyclic aryl thioacetals (4) are hydrolysed in a silver-promoted reaction: with electronwithdrawing substituents, this occurs via a 1 : 1 complex, but the p-methoxy compound reacts via a species with two silver ions.6 Hydrolysis rates are > 104-fold slower than with the analogous open-chain species, partly due to lower basicity towards Ag+; the bchaviour is compared with the H+ catalysis. Hydrolyses of cyclic thioacetals of benzophenone and also of its cyclic and open-chain 0,O-acetals are all believed to proceed via an ASE2 me~hanism.~” In contrast, diethyl and diary1 thioacetals, Ph2C(SEt/Ar)2, react via A 1.7b The chemistry of the cr-thio carbocations involved, Ph,C+-SEt and Ph2-SAr, is described.

Fo

Me

OMe

(cH2$A R’ OR

%

CT

CONHL

\

R

HO

Het+

HO X

Hydrolysis of Glucosides and Nucleosides Enzymatic cleavage of glycosides often involves the formation of an enzyme-substrate complex, which is then hydrolyscd via an oxocarbenium ion-like transition state with

I Reactions of Aldehydes und Ketones and their Derivatives

3

acid-base catalysis. Thus, elucidation of the mechanism requires the identification of an active-site nucleophile and the appropriate acid-base residue(s). New methods are described for these tasks, involving a mechanism-based inactivator, and kinetic analysis of candidate acid-base amino acids chosen on the basis of sequence similarities, respectively.' Hydrolyses of (2-deoxy-/?-~-glucopyranosyl)-pyrid~nium and 4soquinolinium salts ( 5 ) in water show first-order rate constants which are independent of pH from 4.4 to 10.1.9aBased on measurements with acetate, halide, and azide, the reaction shows no sensitivity to the nature of the anion. The possible mechanisms are discussed in detail and evidence for the glucopyranosyloxocarbenium ion as a viable intermediate is presented. Its lifetime in water is calculated at > 2.5 x s, slightly higher than the estimate of I x s extrapolated from experimentally measured lifetimes of acyclic oxocarbenium ions.9b The effects of 2'-substitution of the ribofuranosyl ring on the chemical and enzymatic cleavage of the nicotinamide-ribosyl bond for a series of P-NADf analogues (6; X = H, NH2, OH, N3, F; R = H , ADP, 1,p-etheno-ADP) suggest the involvement of the functional equivalent of a diol anion."

Formation, Hydration, and Hydrolysis of Ketenes Rapid, shock wave-induced heating of acetonitrile to 1400-1700 K under pressure gives ketene imine, H2C=C=NH." Ab initio calculations suggest that the ratedetermining step for the reverse reaction is a 1,2-hydrogen transfer from nitrogen to produce vinylnitrene. Acid-catalysed hydration of bisketene (721) shows two steps: rate-determining protonation of Cg, to give an acylium ion, which then reacts with water to give the (monoketeny1)acetic acid (7b),'2a previously proposed as an intermediate in the neutral hydrolysis of (7a). '2b Ring closure then gives cis- and truns-2,3-bis(trimethylsilyl)succinic anhydride (7c). Ab initio calculations for (7a) and the unsubstituted bisketenc clarify the role of the silyl groups in favouring electrophilic attack at C,, as opposed to C,.

The question of the reversibility of the hydration of ketenes to carboxylic acids appears to have been settled by diarylketenes incorporating "0-label from solvent, as shown by NMR, IR, and MS.13 A symmetrical species (with respect to the oxygens) is formed: it is presumed to be the 1,l-enediol; build-up of the acid follows: Ar2C=C=O

Ar2C=C(OH),

4

--t

Ar2CHC02H

Organic Reaction Mechanisms I995

4

Reversibility is seen not only with bulky aryl groups (Me.& 2,4,6-PGC6H2)which stabilize the two ene species relative to the acid, but also for diphenylketene. Inductive and steric effects in hydrolysis of monoalkylketenes have been quantitatively estimated; increasing length and branching of the alkyl group decrease the rate. l4 Kinetics of spontaneous hydrolysis of dialkylketenes in water-acetonitrile shows a sharp decrease in hydration rate connected with a significant non-additivity of substituent effects.'' Formation and Reactions of Nitrogen Derivatives Imines Formation of Schiff bases of pyridoxal 5'-phosphate and polyallylamine proceeds via an ionized carbinolamine which is deprotonated in the rate-determining step, followed by dehydration.16 2-Acetylcycloalkanones of ring size from 5 to 8 have been condensed with simple diamines to examine the preference for Schiff bases with a ring vs a sidechain carbonyl;17 the results are explained on the basis of whether the product enaminone has an endo-double bond (six-membered ring) or two exo-double bonds (five-, seven-, and eight-membered rings). A novel Mannich-type reaction for synthesis of p-amino ketones involves combination of an aldehyde, amine, and vinyl ether in aqueous solution by the action of a lanthanide triflate." The mechanism is proposed to involve initial imine formation followed by combination with the vinyl ether and subsequent hydration to give a pamino hemiacetal. Lithium and zinc dienolates of 3,4-unsaturated carboxylic acid esters give two reactions with imines R'CH=NR2 (R' = 2-Py, Me3SiC-C, R2 = Ph, CHMePh): (i) a kinetically controlled a-coupling (at - 78 "C) to give P,y-unsaturated-$-amino esters, and (ii) a thermodynamically controlled y-coupling (at - 20 "C) to give (E/Z)-a,Punsaturated-E-amino esters.'' The a-coupling product can cyclize to give a P-lactam with a pendant alkene, while the (Z)-y-product can cyclize to a 5,6-dihydropyridin-2one; some of the reactions show high asymmetric inductions. Six-membered cyclic transition states involving a zinc enolate or allylzinc species, respectively, are proposed. 1,2-Asymmetric induction in the addition of n-butyllithium to imine (8; R = SiMe3) (to give the syn- and anti-amines) shows large solvent and temperature dependences, e.g. a switch from a ratio of 28 : 72 at - 90 'C to 78 : 22 at 54 "C, in hexane.20An extension of existing models to incorporate such effects is proposed. At least two selection steps are involved. At low temperature, the stereoselectivitymay be controlled by lithium chelation. N-Substituted lactaldehyde imines (8; R = alkyl) are cyanosilylated to a-aminonitriles (9a, 9b) with syn-diastereoselectivity, regardless of the nature

? OSiBu'Me2

NR

OSiBu'Mel &CN

-

NHR

1 Reactions of Aldehydes and Ketones and their Derivatives

5

(or presence) of Lewis acid catalyst;” it is suggested that silicon coordinates the imine nitrogen. 2-Methyl(benzylimino)cyclohexane (10a) reacts with a$-ethylenic carbonyl compounds to give cyclized adducts with excellent diastereoselectivities.22The reaction is a Michael-type addition via the enamine tautomer (lob), with a chair-like transition state. Use of the (a-1-phenethylamine imine (11) makes it enantioselective as well.23

Schiff bases of 1-tetralone (12a) react with acid chlorides to give spiro-annulated blactams (12b) stere~selectively.’~ N-Benzylideneamino-ethanolsand -propanols undergo a cyclization via an N-bromoiminium cation (13a) to give oxazoles/oxazines (13b).25On lithiation, heteroarylchloromethanes add cleanly and diastereoselectively to imines to give heteroarylaziridines via a Darzens-type reaction.26

R

Ar

Asymmetric hydrogenation of imines catalysed by a chiral titanocene” involves the imine reacting with a titanium hydride in a fast 1,2-insertion step to give titanium amide, which is then slowly hydrogenolysed to amine and regenerated hydride. Mechanisms for the hydrolyses of methyl derivatives of salicylanil in acidic, neutral, and basic media are discussed in terms of steric, electronic, and pK, effeck2* Hydrolysis of N-(2/4-hydroxy)benzylidene-2-aminobenzothiazoles in micro-emulsions has been studied over a wide pH and the rate of acidic hydrolysis of diimines, (RPhCH=N)2(CH2),, in micelles depends markedly on the value of n and the position of the cetyloxy R group.3o Thermochromic reactions of salicylideneaniline and related compounds involve proton transfer between hydroxyl oxygen and imine nitrogen via a six-membered transition state.31

6

Organic Reaction Mechanisms 1995

Iminium Ions and Related Species f

A series of N-aryliminium ions, ArN(Me)=CH2 (Ar = C6H4X), has been generated in aqueous solution from the solvolysis of the corresponding anilinothioethers, ArN(Me)CH2SR.32Exploiting common-ion inhibition, rate constants for the hydration of the iminium ions were measured, thus affording lifetimes for the cations, varying from 10 ns (X=p-nitro) to 320 ns (X=p-chloro). The dependence of the solvolysis rate on the pK, of the thiolate leaving group yields a value of - 0.93 f0.09 for &, indicating a very late transition state, consistent with a diffusion-controlled cationanion encounter in the reverse direction. The late transition state for cleavage of the C-S bond also involves a large amount of donation from nitrogen: Pdg,= - 0.79 -f 0.06. The significance of the results for the possible intermediacy of an iminium cation (14) in the reaction of N5,N1'-methylenetetrahydrofolate with dUMP to give dTMP is discussed. The method has been extended to produce a simple f alkyliminium cation: CF3CH2N(Me)=CH2 has a lifetime of 55 ns in water.33

+

The lifetime of an a-phenyl-N-nitrosiminium cation, PhCH=N(NO)Me, and its selectivity towards various nucleophiles have been measured directly in aqueous solution.34 Laser flash photolysis of the a-(4-cyanophenyl) ether was used to generate the cation, which has a half-life of about 600 ns in aqueous solution (pH 11, 25 "C). The second-order rate constants for reaction of the species with azide and thiolate nucleophiles are just below the diffusion limit; other values (dm3 mol- s- ') include 2 x 10' (hydrazine), 2 x lo7 (cyanide), 2 x lo7 and 2 x lo6 (hydrogen- and dihydrogen-phosphate), and lo4 (water). Diastereoselective addition of trimethylsilyl cyanide to nitrone (15a) yields syn-ccaminonitrile (15b), useful for making a-amino acids;35 Et2A1CN may be an intermediate. The Westphal condensation of an a-methylcycloiminium ion (16a; X = e.g. C-C02Et or N) with (typically) a symmetrical diketone, RCOCOR, gives a quaternary ammonium bridgehead system (16b). Using the unsymmetrical 1-arylpropane-l,2diones, the regioselectivities are explained in terms of kinetic vs thermodynamic control.36 The latter has the more conjugated intermediate, and is favoured by nexcessive aryls in the diketone. The stereochemical course of the reduction of iminium ions at a bridgehead position, e.g. (17), is examined in terms of its conformational preferences and of the relative steric demands of the two reagents used viz. sodium cyano- and triacetoxyborohydride~.~

'

'

1 Reactions of Aldehydes and Ketones and their Derivatives

7

The use of an iminium chloride to aminomethylate furan has been compared with the conventional Mannich reaction between ammonia, formaldehyde, and furan, the latter under both neutral and acidic conditions (i.e. H2NCH20Hand H2NCH: as immediate reactant).38 The first two proceed through activated complexes with a four-membered ring structure, with calculated activation energies of 205 and 342 kJ mol-', respectively. In contrast, the acid-catalysed route involves a pronounced product-like transition state which is non-cyclic and has the lowest activation energy (1 13 kJ mol- '), apparently arising from a favourable orbital match on the bondforming carbons. If h a n is replaced with ethylene as the pseudo-acid component, similar results with the same energy order are obtained.39 Oximes

Thermolysis of aryl ketoxime arenesulfonates in refluxing tetralin yields a wide range of products arising predominantly from radicals formed via homolyses of the N-0 and S-0 bonds.40 The substrates also undergo isomerization to imidosulfonates: PhC(R)=NOSOxAr

-+

PhN=C(R)OSOzAr

This proceeds via a 1,2-phenyl migration followed by rearrangement, and leads to amide products. Photolysis gives results similar to thermolysis. A new catalytic method for carrying out Beckmann rearrangements in solution uses tetrabutylammonium perrhenate and trifluoromethanesulfonic acid in a variety of solvents under azeotropic reflux:' the oxime perrhenate (18a) is proposed as intermediate. The optimum solvent is nitromethane, which may favour the reaction by formation of an aci-nitro derivative (18b). Using hydroxylamine hydrochloride, the method has been extended to a one-pot synthesis of lactams and amides from ketones. An unusual ring-opening reaction of tropone' oxime tosylate (19a) by a range of N-, 0-,and C-nucleophiles gives exclusively and stereoselectively 6-substituted (Z,Z,Z)0+/ H;?C N

0 II ,0-Re=O II 0

.

(18a)

d \

-

(18b)

Tsol

Organic Reaction Mechanisms 1995

8

1,3,5-hexatriene~arbonitriles~~ (19b). Labelling and substitution experiments show that the nucleophile attacks the a-carbon anti to the tosylate. A nitrene intermediate (i.e. N-0 fission before C-C fission) appears to be ruled out by the failure to trap it, and reaction-path calculations favour a concerted route much lower in energy than reaction via the nitrene. Kinetics of aminolyses of N-(2,4-dinitrophenyl)camphor oxime by cyclohexylamine and piperidine have been measured in aqueous a~etonitrile.~~ Mechanisms of cyclo-condensations of aldehydes or ketones with o-aminophenyl ketoximes and aldoximes to yield a variety of quinazolines, oxadiazolines, and aminoindoles have been analysed by molecular-orbital calculation^.^^

Hydrazones, Semicarbazones, and Related Species Reaction of phenylhydrazine with 5-substituted furfurals shows familiar ratedetermining carbinolamine formation at pH < 5, with a switch-over to dehydration of the carbinolamine at higher pH.45 Base-catalysed dehydration is reported for the 5nitrohhral derivative. Acid hydrolysis of phenylhydrazono esters derived from diethyl malonate and ethyl aceto- and cyano-acetates yield half ester, diacid, and reactant, re~pectively.~~ 4-Aminopent-3-en-2-one and its N-aryl analogues (20) couple with benzenediazonium salts at C(3);47 in some cases, the kinetics are independent of both pH and buffer. Substitution in both rings gives linear Yukawa-Tsuno plots. The rate-limiting step is either reactant combination, or else proton loss from C(3) of the intermediate. The possible tautomers and isomers (hydrazo vs azo; intramolecularly hydrogen-bonded species) are also discussed.

p% fA --r

X 0

Me N-N L N H A r '

-

Me Ar

H O

N-N

I

Ar'

Benzaldehyde semicarbazones (21a) are selectively cyclized to 1,2,4-triazolin-5-ones (21b) by copper(I1):' the corresponding oxadiazole system is not formed. The reaction is accelerated by electron-donating substituents, and mechanistic alternatives are discussed. A 1 : 1 substrate-oxidant complex is proposed to account for the kinetics of the oxidation of acetophenone semicarbazones by peroxodisulfate in aqueous acetic acid.49

C-C Bond Formation and Fission: Aldol and Related Reactions Aldol Reactions The use of an 'ansa chain' across a pyridine ring to bring about chiral induction in a pyridoxal/pyridoxamine model has been known for some time: (22a; X = CH2NH2,

1 Reuctions o j Aldehydes and Ketones and their Derivatives

9

R = H) enantioselectively transaminates keto acids in the presence of zinc(II).So"'h Surprisingly, the enantioselective C-protonation to give the amino acid took place from the apparently more hindered side-chain side of the pyridine. The intermediacy of a zinc dimer with the open faces mutually blocking each other was invoked. This type of model has now been used for the enantioselective aldol condensation of glycine with acetaldehyde to give threonine and allo-threonine, using a pyridoxal with pendant amino groups in the chain (2223; X = CHO, R = SCH2C6H4CH2NMe2).50c At low pH the catalyst is enantioselective,with protonation again coming from the bulkier side, but not apparently due to zinc complexation on the open side. And at high pH, the enantioselectivity reverses as the pendant ammoniums deprotonate. The reaction on the (apparently) bulkier side is explained by a stereochemical argument involving puckering of the pyridine ring (22b).

A number of studies of asymmetric aldol reactions involving en01 borinates are reported. A computer model combines an a b initio transition state 'core' (where bonds are being made and broken) with a molecular-mechanics treatment of the rest of the system, i.e. the parts which provide the steric and electronic effects necessary for stereo~electivity.~'This has then been used to develop chiral boron enolates which diastereoselectively add to chiral a-amin~aldehydes.~' Ethyl N-benzyl-N-methylglycinate, PhCH2N(Me)CH2C02Et,gives moderate to good syn-selectivity in reaction with aldehydes to give a-amino-B-hydroxy esters.53 When complexed with boron [i.e. PhCH2h(Me)(BH3-)CH2CO2Et], good to excellent anti-selectivity is achieved. The cause of this complementarity appears to be an equilibration in the boron adduct case (to give the most stable product) vs chelation control (in the lithium enolate) in the case of the free amine, which prevents equilibration. The development of an aldol reaction between lithium enolates of difluoro ketones and non-enolizable aldehydes, to give difluoro aldol adducts in one step, depended on the recognition of the effect of the low nucleophilicity of the difluoro e n ~ l a t e s . ~ ~ 3-Methylpiperazine-2,5-dione derivatives (23a; R = Me) and (23b; R = CH'Ph) participate in stereoselective aldol reaction^;^"^^ (23a) also undergoes stereoselective acy~ations.~' A conference report describes the use of chiral chelated lithium aniides, e.g. (R)-(24), for deprotonation of prochiral cyclic ketones in a variety of reaction types. Stereochemical mechanisms have been developed based on the solid and solution stn~ctures.~~

Organic Reaction Mechanisms 1995

10

(23a b)

(24)

Aldol reactions are included in reviews of tin(I1) enolates5*(220 references) and of lanthanide and scandium triflate catalysis in aqueous solution59(38 references).

Intramolecular Aldols The absolute and relative electrophilicities of the carbonyl group towards an enolate have been determined.60a Substituted benzaldehyde (25a) has a pendant acetone function which can form an enolate anion (25b), setting up formation of the aldol(25c); subsequent fast steps yield P-naphthol. C-Protonation of the enolate to give back (25a) competes with the cyclization, and was measured by deuterium exchange. Exploiting saturation kinetics with a quinuclidine buffer (due to a switch in rate-determining step from bufler-catalysed enolization to uncatalysed cyclization), the rate constant, k,, for cyclization was found to be 1.6 x lo6 s-'. This compares with a recent estimate of 1.4 x lo6 s-l for aldol adduct formation from benzaldehyde and acetone enolate.60b The carbonyl group of (25b) is a stronger electrophile than water, but weaker than tertiary ammonium ions of pKBH< 13.2.

Evidence for bifunctional acid-base catalysis of an intramolecular aldol condensation by P-cyclodextrins bearing two imidazole groups is seen in a modest rate increase over the control monoimidazolyl or unsubstituted cyclodextrins.61a The reaction is stereoselective, but with only slight enantio-induction: apparently the imidazoles are not optimally placed, compared with other reactions61b3c for which this catalyst has been used. The 1,4-dicarbonyl sugar (26a) has been converted into the enone (26b) via an intramolecular cyclopenta-annulation;" an X-ray crystal structure of the enone is reported.

1 Reactions of Aldehydes and Ketones and their Derivatives

11

A stereo- and regio-selective synthesis of the A-ring of taxol has been achieved by means of an intermolecular aldol addition and an intramolecular aldol condensation.h3

Mukaiyama (Enolsilane) Aldol Reactions In the Lewis acid-catalysed Mukaiyama aldol and Sakurai allylation reactions, silyl enol ethers and allylic silanes, respectively, couple with aldehydes or ketones (see Scheme 1) to give p-hydroxy ketones and y-hydroxyalkenes, respectively (in silylated form). Acetals and orthoesters can replace carbonyl substrates in both reactions.

SCHEME 1

A possible solution to several conhsing and contradictory claims of enantioselective catalysis is provided by a careful study of three new ‘catalysts:’ T ~ ( C P ) ~ ( O T ~ ) ~ , Ph3COTf, and Ph3CC104.64Trace amounts of water hydrolyse them to produce acids which in turn react with silyl reactant to produce ‘Me3Si+’species, i.e. Me3SiOTf and Mc3SiC1O4. These are the actual catalysts, and the rate and stereoselectivity is dependent on counterion concentration; it is also suggested that this situation pertains in many other systems, as dehydration of the solvent or quenching of the acid produced does not necessarily prevent the formation of these catalysts. Ways of obviating the presence of such species are discussed; many of the successful catalysts and strategies in the literature, it is claimed, work because they contain features which prevent or minimize the incursion of Me3SiX catalysis. A ‘supersilylating agent,’ R3SiB(OTf)4,65aprepared from trimethylsilyl and boron triflates, has been used to achieve high levels of Cram-type stereoselectivitybShin the aldol addition of acetophenone silyl enol ether, PhC(OSiR3)=CH2, to 2-phenylpropanal (27) and 3-phenyl-2-methylpropanal(28). A bulky R group on the silicon is essential for selectivity, though whether it extrts its effect in the silyl ether itself, or in the likely silyloxonium intermediate, R’CH=O-SiR3, derived from combination of catalyst and somewhat hindered silyl triflate, Pr‘’ SiOTf, is interesting in the light of the catalysis by MeXSiOTf reported above.64 The simplest case of the uncatalysed Mukaiyama aldol, addition of enol silane (29a) to formaldehyde to give 3-(silyloxy)propanal, has been studied by ab initio methods.6h

12

Organic Reaction Mechanisms 1995

The s-cis conformation of (29a) with silicon overlying the double bond is the most stable. A boat-like transition state (29b) was located: the new C-C bond is substantially formed with Si-0 bond breaking and making proceeding asynchronously. The driving force is suggested to be the nucleophilicity of the enol, rather than carbonyl activation by silicon. While an a-stereogenic centre is typically the major determinant of enantioselectivity in nucleophilic addition to carbonyl groups, a series of aldol and allylstannane addition reactions show significant (and sometimes dominant) effects from fi-alkoxy s ~ b s t i t u e n t s ;the ~ ~ cases involved do not arise due to chelate organization. In an attempt to combine the Felkin-Ahn model for a-alkyl substituents with the corresponding 1,3-asymmetric induction model, it is proposed that additions to aldehydes are highly stereo-regular if the a-alkyl and P-alkoxy substituents are in the anti-diastereomeric relationship (i.e. they are mutually reinforcing in their effects), while syn-aldehydes will undergo anti-Felkin addition with dominant stereo-control emanating from the more remote fi-heteroatom substituent. Aldol reaction of (a-0-silylketene-0,s-acetal (30a) (derived from 2-pyridyl thioesters) with benzaldehyde gives enantiomeric fi-hydroxy thioesters6' (30b). The 2-mercaptopyridyl group has several advantages: it is a good leaving group and the sterically demanding pyridine can also coordinate to Lewis acids to give stereo-control. The latter indeed appears to be realized in the switchover from mti- to syn-selectivity on changing from BF3 to Tic& mediation of the reaction, and a switch back occurs when phenyl replaces pyridyl.

Miscellaneous Aldol-type Reactions Molecular-orbital calculations are used to assess an aza-aldof9 (a nitrogen analogue of the boron-mediated aldol reaction) in which an enaminyl borinate forms an ate complex with the aldehyde, which then rearranges to form the new C-C bond via a cyclic transition state. Theory and experiment give disappointing results, apparently because the nitrogen lone pair reduces the Lewis acidity of the boron, a conclusion which should facilitate improvements.

I Reactions of Aldehydes and Ketones and their Derivatives

13

Enantio- and diastereo-selective aldol addition of boron enolates of substituted acetic acids [i.e. R1(R2)C=C(OBL,*)2; L* = isocaranyl] to benzaldehyde yields the corresponding j-hydroxycarboxylic acids,70 PhCH(OH)CR'(R2)C02H. Titaniummediated aldol-type reactions of acetate thioimide enolates with aldehydes proceed with .n-facial differentiation via chelation control to give enantio-pure P-hydroxycarboxylic acids.71 The asymmetric aldolization of the acetate enolate of a chiral carbonyl compound with aldehydes has been achieved with an achiral Lewis acid.72 aSubstituted serines have been prepared dia~tereoselectively.~~ Modifications of mesoporous sieve MCM-41 have been used as acid-base catalysts of aldol and Knoevenagel condensations, Michael addition, and an acetali~ation.~~ Cyclic j-keto esters (31) are converted stereoselectively into cycloalkenones (32) by a y-arylidenation with aldehydes.75 Requiring DBU (1,8-diazabicyclo[5.4.O]undec-7-ene)and methanol, the reaction is initiated by a reversible a-aldol process to give an enolate anion, which reacts irreversibly with aldehyde, followed by dehydration.

6-Aminocaproic acid catalysis of ethyl 2-cyanoacrylate formation from formaldehyde and ethyl cyanoacetate involves rate-determining dehydration of HOCH2NH(CH& CO~H.~~ The Benzoin Condensation In an investigation of antihydrophobic effects, the proportion of aromatic surface shielded from the solvent in the transition state (relative to the totally exposed reactants) has been probed by correlating the effects of co-solvent on rates and s o l ~ b i l i t i e sWith .~~ water as solvent, ethanol lowers the free energy of reactants more than that of the partially stacked transition state, slowing the reaction. The results are related by log(k0lk) = hXlog(S/So), where the subscript refers to pure solvent, S is the solubility, and h is a function of the hydrophobic surface which becomes inaccessible in the transition state. The value of h was found to be ca 0.15-0.20 for 10-20% addition of small alcohols/diols, corresponding to a 3 0 4 0 % coverage of a face of each phenyl group. The mechanism of benzoin condensation catalysed by 3-benzyl- and 3-methylthiazolium ions has been studied in KOBu'-DMSO.'* 2-(a-Hydroxybenzyl)thiazolium ion (33) forms and is stable for long periods, but is converted into benzoin on addition of a trace of protic solvent. The role of this species in the mechanism (together with additional information from '3C-labelled thiazolium and 'H-labelled aldehyde) is discussed. The bis(thiazo1in-2-ylidene) (34) was virtually ruled out as the reactive species which condenses with the aldehyde. However, a kinetic study in the same

Organic Reaction Mechanisms 1995

14

medium79aclaims that (34) is the authentic catalytic species; it is implicated by the finding that the kinetics are second order in both benzaldehyde and thiazolium cation, contrary to the original Breslow proposal.79b

Thiamine (35) promotes reactions occurring via acyl carbanion equivalents through the formation of (33); in weakly alkaline solutions, (33) can revert to (35) and benzaldehyde. However, under neutral or acidic conditions, the intermediate is 'diverted from catalysis' into an irreversible fragmentation to a pyrimidine (36a) and a phenyl thiazolyl ketone (36b). As the conditions implicate pyrimidine protonation, the N"methyl analogue of the intermediate was prepared and found to hydrolise at all pH values; in D20, the newly formed methyl group in pyrimidine product (36a) had incorporated a deuteron.80 The mechanism involves C(2a)-deprotonation of the substrate to give an enolimine, which tautomerizes to the ylide-like enolate (37), which finally undergoes C -N fission with proton transfer across the (breaking) bond. Me

Me

y 3 2

(35)

.OH

I Reactions of Aldehydes and Ketones and their Derivatives

15

N,”-Disubstituted o-phenylenediamines catalyse the benzoin condensations of Nalkylbenzimidazolyl- and benzothiazolyl-aldehydes and hrfiual, via a radical mechanism.81

Other Addition Reactions General and Theoretical In an ub initio calculation of the intrinsic (gas-phase) hydride affinities of carbonyl compounds,82XYCO (X,Y = H, Me, NH2, OH, F), relative hydride affinities, AHRHA represent the enthalpy difference between the following reactions:

XYCO H2CO

+ H+ H-

XYCHO-+ CH30-

--+

Alternatively, they can be viewed as the difference between the isodesmic reaction: XYCO 2CH3 -H HzCO CH3 -X CH3 -Y AHco

+

-+

+

+

and the corresponding reaction for the alkoxide (AHCHO). Significant findings include the following: (i) isodesmic enthalpies are additive: i.e. A f f ~ o ( x Y C 0 = ) AHo(HC0X) AHo(HC0Y)

+

except when both substituents are from the set (NH2, OH, F); (ii) the alkoxides all show such additive behaviour; (iii) electron-withdrawing substituents stabilize both carbonyl groups and alkoxide ions, but stabilize the latter more: this observation conflicts with the more simplistic statement that ‘electronegative atoms activate carbonyl toward nucleophilic attack‘ found in many introductory textbooks; (iv) AHco correlates with charge on oxygen, and the charge on the alkoxide carbon correlates with AHCHO, the latter in an additive fashion; and (v) AHco does not correlate with the bond length of the carbonyl. Other carbonyl systems (a$-unsaturated, cycloalkanones, Lewis acidcomplexed formaldehyde) are also studied. Calculations of nucleophilic additions involving intramolecular proton transfer have been compared and contrasted in the gas phase and solution.83 To rationalize a number of apparently contradictory results in 1,2-asymmetric induction reactions, three rules, supported by model calculations, have been proposed.84 First, in weakly interacting systems the best transition state derives fiom the most stable ground-state conformation of the reactants (rule 1). Second, the best transition state for frontier-controlled reactions has the strongest acceptor anti to the incoming nucleophile (rule 2). Third, the best late transition state derives from the most stable conformation of the product (rule 3). Thus rule 1 requires that the substituents are poor acceptors, while rule 2 may not be obeyed in charge-controlled reactions. If the ‘best’ acceptor is not a sufficiently good electrophile, rule 2 may also be violated: for example, when a methyl competes with hydrogen for the anti position, the results sometimes suggest that the methyl is the ‘smaller’ substituent. The influence of hyperconjugation of allylic bonds, torsional strain, diaxial steric repulsion, and ring deformation on the x-facial selectivity of addition of boron or methyllithium to cyclohexanone has been investigated through calculation of transitionstate geometries and kinetic and equilibrium isotope effects.R5

16

Organic Reaction Mechanisms 1995

Cram’s rule for predicting the stereochemical course of 1,2-asymmetric additions86a has been incorporated86b into the CAMEO interactive computer program.86c Substituents are designated as small, medium, or large, using an algorithm which calculates Taft E, values. Using sample sequences, the scope and limitations of this predictive tool are discussed. A review (79 references) covers the design of N,N-dialkylnorephedrines as asymmetric catalysts and ligands for use in enantioselective addition reaction^.'^

Addition of Orgunometullics Substituted chloromethyloxiranes (epichlorohydrins) and allylic alcohols have been prepared with high diastereoselectivity from chloro- or iodo-methyllithium and achloro- or a-bromo-ketones or -aldehydes.88In each case, the organometallic reagent is added across the carbonyl group, followed by ring closure with loss of LiX. In the case of the allylic alcohols, the oxirane undergoes iodine-for-chlorine exchange (or lithiumfor-chlorine, depending on reagent), followed by a ring-opening p-elimination. The degree of aggregation in solution of alkyllithiums bearing Lewis base groups, LiCH2Si(Me)2CH2N(CH2X)CH2Y(X,Y = H and/or CH2NMe2), has been correlated with their chemoselectivity (enolate anion formation vs addition) with ketones:89those which exist as monomers deprotonate, whereas the more aggregated ones add. 1Bromo- 1-1ithioalk-1-enes, acting as carbenoids equivalent to -CH20H and -CHO, add to O-protected a- and fi-hydro~yaldehydes.’~Reaction of organolithiums with 1,2dicarbonyl compounds leads to products derived from homolytic C-C bond cleavage induced by electrostatic repulsion of the negatively charged oxygen atoms.91 Enantioselective auto-induction has been observed in the addition of phenyl- or n-butyl-lithium to isob~tyraldehyde.~~ 4,4-Disubstituted cyclohexadienones (38) have been selected as test cases for the study of n-facial selectivity in nucleophilic addition reaction^.'^ Given the distance equivalence of the substituents from the reaction centre and the lack of steric or electronic effects, electrostatic interactions can be studied by varying the combined effects of the substituents on p l , the component of the dipole moment which is perpendicular to the dienone system. The results suggest that dipolar control is dominant, with hyperconjugative orbital stabilization and orbital distortion effects of secondary importance: p I correlates linearly with the logarithm of the selectivity. The point is emphasized by the reversal of selectivity accompanying a reversal of p I achieved by changing R’ from methyl to CF2CF3.

1 Reactions of Aldehydes and Ketones and their Derivatives

17

Only the E-isomer of 2-(2-methylpropylidene)cyclohexanone reacts with MeMgT.94 Although a homogeneous catalyst’s interaction with the solvent is typically subjected to considerable scrutiny, multiple catalysts present in solution are typically treated independently. For example, an impure enantioselective catalyst is usually assumed to catalyse at the same rate as either pure isomer, and to give an enantiomeric excess corresponding to the linear cancellation of some of the effect of the major isomer by the minor. However, in the fl-amino alcohol-promoted enantioselective addition of dialkylzincs to aldehydes, significant non-linear effects are observed, and are explained in terms of the association of the catalysts, with crucial contributions from both ‘self‘ and ‘non-self’ recognition^.^' An ab initio study of the simplest from of the reaction (addition of dimethylzinc to formaldehyde, with 2-aminoethanol as catalyst) has been carried An amino alcohol with two types of chiral phenethyl substituent (39), with 1,4stereogenic centres, catalyses the enantioselective addition of diethylzinc to aromatic aldehydes.97It is proposed to involve formation of an ethylzinc alkoxide of the catalyst hydroxyl, with the metal also complexing the nitrogen and carbonyl group of the substrate, leading to rate-determining ethyl transfer from a second zinc tethered to the alkoxide. Syn-selective addition of diethylzinc to trans-a,@-epoxyaldehydeshas been achieved via chelation control.98 Stereoselective addition of various zinc species, generated by Pd(0)-catalysed reaction of ally1 esters and diethylzinc, to benzaldehyde occurs via an umpolung of n-allylpalladium involving syn addition with inversion of the allylic stereo-centre.99 Enantioselective addition of methyltitanium and diethylzinc to benzaldehyde has been investigated with new ljgands based on TADDOL (a,a,a’,a’tetraaryl-l,3-dioxolane-4,5-dimethanol). loo Results are correlated with X-ray data and molecular mechanics to identify the precise features for optimum catalysis/enantioselectivity and to refine the mechanism. A stereoselective synthesis of trisubstituted alkenes from ketones uses a tungsten or molybdenum alkylidene initially coordinating to a directing Lewis base (ideally hydroxy) or y to the keto function, followed by intramolecular addition to the carbonyl to give a four-membered oxametallacycle intermediate. lo’ Addition of (E)- and (4-crotyltri-n-butylstannanes to several aldehyde types, mediated by various Lewis acids, gives subtle changes in the degree and direction of enantioselectivity,’” due to the inherent closeness in energy of the synclinal vs antiperiplanar transition states. BF3-promoted additions of chiral y-oxygenated allylic stannanes to diastereomeric enals exhibit a facial bias at the carbonyl group due to conformational effects in the enal.”? Allylstannanes have been added to aldehydes via a bis(n-ally1)palladium complex to give homoallylic alcohols. lo4 Addition of Carbon Nucleophiles Containing N, Si,

or S Suhstituents

Optically active cyanohydrins are valuable starting materials for a variety of asubstituted aldehydes and acids. (R)-Oxynitrilase catalyses an enantioselective transcyanation from racemic ketone cyanohydrins to w-bromoaldehydes.’05 Starting from Br(CH*),CHO (n = 3, 4) and the racemate, (R)-o-bromocyanohydrin,

18

Organic Reaction Mechanisms I995

Br(CH,),CH(CN)OH, and the (9-debrominated ketone cyanohydrin, H(CH2), - C(CN)OHCH3, are produced (plus ketone by-product). With BF3, (9-crotylsilanes add selectively to a-alkoxyaldehydes to give homoallylic alcohols.Io6 Diastereoselectivity reverses with TiC14, due to chelation (as in 30a discussed earlier6*),as shown by the use of the non-chelating t-butyldiphenylsilyloxy substituent as a control. The insertion of aldehydes into the C-Si bonds of siliranes (silacyclopropanes) to give oxasilacyclopentanes [e.g. (40) from hexamethylsilirane and benzaldehyde] undergoes a reversal of regio- and stereo-selectivity between thermal and K0Bu'catalysed reactions. lo7 Various silylated nucleophiles form C-C bonds with aldehydes, ketones, and acetals with tetracyanoethylene catalysis, proceeding via a single-electron-transfer mechanism. l o x Wittig reaction of 3-pyridyl X-substituted phenyl ketones with a simple 'nonstabilized' ylid, Ph3P+ -CH(CH2),C02H, typically gives predominantly (3-alkene, but switches dramatically to the E-isomer when a phenylsulfonamido substituent is used.'o9 This is ascribed to interaction between the carboxy and sulfonamide sidechains (either through a hydrogen bond or a salt bridge) in the oxaphosphetane intermediate (41). Removing or N-methylating the sulfonamide, or removing the ylid's o-carboxylate, reverses the selectivity.

n

Me I Me .si-o Me

Ph

Me

Me

O,\'

Y s'o

Ph

trans- 1,3-Dithiane 1,3-dioxide (pK, = 25) adds cleanly and enantioselectively to aromatic aldehydes to give adduct (42) as long as it is delivered as its sodium salt, i.e. under equilibrium control.' l o The adducts show strong hydrogen bonding in the solid state. Addition of Amine Nucleophiles C-Hydroxylation of N-methylanilines by hexafluoroacetone and other polyfluorocarbonyls has been the subject of AM1 calculations."' 9-Aryloxy derivatives, e.g. (43a), of the highly reactive 1,lO-anthraquinone nucleus have been isolated by irreversible photo-isomerization of the 1-phenoxyanthraquinones, and their reactions with methanol and alkyl- and aryl-amines investigated.' l 2 Methanol

1 Reactions of Aldehydes and Ketones and their Derivatives

19

reacts by I ,Caddition to give an acetal (43b; R = Ar), followed by substitution of the aryloxy group to give another (43b; R = Me). Amines, in contrast, add with immediate elimination of phenol, resulting in an equilibrium mixture of the expected enamin(quin)one, 9-amino-1,lO-anthraquinone (44a), and its enolimine tautomer (44b). This equilibrium, and the influence of the nature of the quinone, and solvent, have been extensively studied by IR, UV, ‘H, 13C and I5N NMR spectroscopy and by quantum-mechanical methods.

Addition of Phosphorus Nucleophiles The presence of two nucleophiles in the synthesis of aminophosphonates by nucleophilic addition of an amine to a carbonyl group and addition of phosphite to the resulting imine sometimes leads to phosphite interception of the carbonyl to give hydroxyphosphonate. The balance of the two routes has been correlated with the hardsoft acid-base properties of the substrates: hard amines react preferentially with hard aliphatic carbonyl electrophiles, while the softer phosphite is more llkely to react with the aryl aldehydes and ketones.’ l4 Diastereoselective phosphonylation of aldehydes using diazaphospholidine reagents, e.g. (45) based on the N,N-bis[ 1-(a-phenylethyllethylene- 1,2-diamine auxiliary, has been achieved in both the Abramov [addition of organophosphoms(II1) ester] and Pudovik [addition of H-phosphonate(V) ester] procedures. l 5

’

H

20

Organic Reaction Mechanisms 1995

Hydration

A comprehensive ah initio study of the uncatalysed hydration of formaldehyde has yielded thermochemical parameters, vibrational frequencies, solvent isotope effects, and proton inventories for the reaction with a single water molecule, and for clusters containing two, three, and four water molecules.116aIn both the gas phase and aqueous solution, the reaction flux is almost exclusively via an eight-membered ring species containing three water molecules (46), with asynchronous proton transfers. While clearly entropically disfavoured, an enthalpic gain arises from the extra hydrogen bonds achieved relative to, say, the previously proposed' 16b six-membered ring containing two water molecules. In particular, the eight-membered ring allows near-linear proton transfer.116b'c The calculations reproduce accurately a number of experimental parameters, and confirm long-standing theoretical proposals about this reaction. I 16d The kinetics and equilibria of protonation and hydration of 9-acridinecarboxaldehyde (47) have been measured in aqueous solution.'17 It has ca 6% hydrate, vs 70% for the protonated form. The behaviour is similar to 4-pyridinecarboxaldehyde, but both hydration constants are ca 20 times lower, presumably due to crowding. Rateequilibrium relationships for the hydration of both heterocyclic cations match those of neutral benzaldehydes. Hydration of 9-formylfluorene (50; R = H) is discussed later under Enolization and Related Reactions. CHO

Miscellaneous

Benzaldehyde undergoes a Friedel-Crafts-type reaction with benzene in the presence of strong acids to give, inter alia, di- and tri-phenylmethane and triphenylmethanol.1'8The obvious intermediate, 0-protonated benzaldehyde, is, however, a weak electrophile with very low reactivity towards benzene: it has predominantly carboxonium rather than hydroxycarbenium character.' I 9 Instead a super-electrophile, diprotonated benzaldehyde (with both protons on the oxygen) is proposed;"* lack of exchange apparently rules out protonation of the tertiary aromatic or aldehydic carbons, and lack of CO"' or products derived from protonated formyl dication' * tends to rule out @so-protonation. However, ub initio calculations favour C-protonation: relative energies (kcal mol- '1 are 0.0 (ortho- and meta-), 5.1 (para-) and 13.7 (ipso-), vs 20.6 for both the protons being on oxygen."' The o-, m-, and p-structures also show a substantially longer ex0 C-C bond, probably due to the decrease in 71-conjugation between the carbonyl group and the cyclohexadienyl ring: this is also consistent with the greatly increased reactivity in superacid solution.

'

f Reactions of Aldehydes and Ketones and their Derivatives

21

The intramolecular Schmidt reaction, in which azidoalkyl-acyclic and -monocyclic ketones give mono- and bi-cyclic lactams, respectively, has been demonstrated.‘’O It is proposed to occur via initial attack of a ketone activated by a protic or Lewis acid to give an azidohydrin (48), which directly rearranges to product amide and molecular nitrogen. Improvements in the synthetic utility of n-cyclizations of alkenyl- and alkynylcyclopentane-l,3-diones to form a variety of bicyclic ketones have been developed.”’ Contrary to an earlier report, ‘22a the reaction of hydroxide with 2,4-dinitrobenzaldehyde to give 2-nitro-4-nitrosophenol is jirst order in substrate, with the order in hydroxide changing from one to two at high concentrations.’12b The immediate reactant is the hydrate anion, and a mechanism involving a Meisenheimer adduct at the 1position, with subsequent loss of the aldehyde carbon as formate, is proposed. The pseudo-first-order rate constant for reaction of morpholine with carbon disulfide follows the rate law k,,,i,,[amine]2 kw[amine][H20],which is compatible with either a zwitterion mechanism, or a termolecular mechanism previously proposed for C 0 2 and

+

c0s.1~3

Enolization and Related Reactions 3-Hydroxyindene (49a) has been generated by Norrish type I1 photo-elimination of 2methoxyindan-1-one, and the kinetics of its ketonization to indan-1-one (49b) have been studied in aqueous s~lution.’’~ Combination with measurements of rates of the enolization reaction (using halogen scavenging) gives the ketowmol constant (pKE= 7.48) and pK, values of the enol (9.48) and ketone (16.96). Compared with acetophenone (7.96, 10.34 and 18.31), the enol acidity is higher, with the co-planar phenyl better able to stabilize the enolate anion.

OH

0

The enol contents of acetic acid and its methyl ester have both been estimated, coincidentally, as 1 part in 2.5 x using a combination of gas-phase thermodynamic data and calculated free energies of transfer to aqueous solution, together with hydrolysis and vaporization measurements, and the assumption that the free-energy change for the hypothetical hydrolysis of a simple enol ether to its enol is independent of The estimate for the acid agrees with two previous estimates by independent methods. 125b The fluorenyl group dramatically increases enol stability and ketone acidity in 9acylfluorenes (50): values of pKE, p e and p e H for R = Ph in water are 1.91, 9.44

Organic Reaction Mechanisms 1995

22

and 7.53, respectively.'26 Thus the benzoyl compound has a 106-fold higher enol content than benzoylmethane (i.e. acetophenone; see values above), and is lo9 times more acidic. For the aldehyde, 9-fonnylfluorene (50; R=H), the enol is the predominant tautomer (7 1%), and destabilization of the carbonyl by electron withdrawal also gives a high hydrate content (24%). Trapping with hydrogen bisulfite was used to measure ketonization, while kinetics of enolization required generation of an excess of aldehyde from its hemithioacetal. The tautomeric constant of 2-phenylacetylhran (51a) in water is 5.88 Its pK, value is 14.38, giving p e H = 8.50. Relative to deoxybenzoin ('phenylacetylbenzene' pKE 5.15, pKfiH 9.6), furan enhances enol acidity, but stabilizes the ketone. The former is explained by electron withdrawal by oxygen, whereas the latter (an effect on a neutral equilibrium) is ascribed to resonance (51a) cf (51b).

The precise mechanism of proton transfer in the interconversion of dihydroxyacetone and glyceraldehyde phosphates catalysed by triose phosphate isomerase is discussedI2*" in terms of the putative advantage of an 'internal pK, balance"2Rh in enzyme active sites. A polyazacleft (52) has been designed to recognize enolates of 1,3-dioxo compounds, e.g. cyclohexane-l,3-dione enolate (53), via the formation of four hydrogen bonds as in complex (54).'29 Binding constants of 102-104 dm3 mol-' have been found in acetonitrile. Complementarity is the dominant factor, but for shape-similar enolates, binding correlates with guest basicity. Binding-induced pK, changes are small: (53) is 1 .O unit more acidic in the presence of host. The relevance of the results to enolases and racemases is discussed.

Et02C

+

-b

t

Et02C

0

I

I

H

EtO,C

(53)

(54)

1 Reactions of Aldehydes and Ketones and their Derivatives

23

Protonation of o,o-dimethylacetophenonesin sulfuric acid is much more sensitive to variation of the para-substituent than the unhindered analogues: p = 5.3 vs l.2.130 a-Heterocyclic ketones such as 2-phenacylpyridine (55a; X = CH), in addition to having an enol tautomer (55b), can also exist as an enaminone (5%): the predominant tautomer varies considerably with solvent. Whereas the keto tautomer is readily identifiable, the other two are difficult to distinguish by UV, IR or 'H NMR spectroscopy. Studies of seven different heterocycles show that the 13Cchemical shift of the 'carbonyl' carbon is more reliably diagn~stic.'~'"Why a particular tautomer predominates with particular heterocycles is discussed.

In contrast to 2-phenacylpyridine, stability in phenacylpyrazine follows keto(imine) (55a; X = N) > enol(imine) (55b) > enaminone (5%); in water the ratio is 99 : 0.89 : 0.004.'32Enolization of the ketone does not occur via the 0-protonation route, but rather by N-protonation followed by proton loss from carbon to give (55c),

which rapidly e n o l i ~ e s . ' ~The ' ~ mechanism depends on binding and activation components of the N- and 0-catalyses, the former being measured by pK, values and the latter by proton-activating factors derived from kinetics: 0-protonation typically activates C-H bond breaking more, but the nitrogen atom generally has an even greater basicity advantage, even in this case x 0.4). N-(5-Methyl-4-isoxazolyl)-4-amino-1,2-naphthoquinone (56a) can enolize to (56b) in what is essentially an enaminone-to-enolimine tautomeri~ation;'~~ subsequent degradation gives 2-hydroxy-1,4-naphthoquinone. Kinetic and thermodynamic parameters have been determined in aqueous alkaline solution at 35 "C;the tautomeric constant is 0.40. Kinetic and thermodynamic acid-strengthening effects of a 0-nitroxyl group have been studied for conformationally restricted ketones.134 Relative rates of deuterium

5

HN

N

(56a)

Organic Reaction Mechanisms I995

24

exchange in dioxme-DZ0 for cyclohexanones (57; X = CH2, NOH, NO) are 1.O, 7.0 and 170, and these correlate with (relative) gas-phase ionization enthalpies of 0.0, - 3.6 and - 11.0 kcal mol-'. Hyperconjugation is suggested to play only a minor role in stabilizing the nitroxyl enolates.

The isomeric cycloheptatrienols (58a, b, and c) ketonize by a-protonation in all cases to the corresponding cycloheptadienones (59a, b, and c).13' However, (59c) is unstable relative to (59a): conversion takes place through enol (58a). Rate constants for diazo coupling of the enols (58a and c) (to give a-mono- and a,a'-bis-phenylhydrazones) have been measured; the reactive form in each case is the enolate, which reacts at close to the diffusion limit. In contrast, (58b) isomerizes to norcaradienol(60), which then diazo couples. The results suggest that homoaromatic stabilization in cycloheptatriene must be insignificant, and that the 2-hydroxy group provides a small but effective stabilizing effect on norcaradienol (60).

OH

0

OH

The kinetics of the a-enolization of ketones (61), (62), and (63) have been measured by deuterium exchange to establish the relative roles of homoconjugation and polar effects due to a second carbonyl group.'36 The rate ratio of 76 : 1 for (61) vs (63) is not surprising, but the equivalent value for (62) of 0.0027 is difficult to explain, but may arise from a through-space interaction of the n-systems, and from angle strain. AM1 calculations suggest that only the kinetic acidity of (62) is anomalous. Polar effects are believed to be much more important than homoconjugation, as (61) and (62) show negligible exo- vs endo-selectivity.

I Reactions of Aldehydes and Ketones and their Derivatives

O m o

25

Qo

Chiral binaphthalenes (64) have been designed to protonate enolates selectively: one side of the phenolic group is protected by the second na~htha1ene.l~~ In the protonation of metal enolates of 2-alkyltetralones (65), good to excellent enantioselectivities result with magnesium if the counterion is bromide or iodide (but not chloride), whereas with lithium the selectivities are poor, and often with the opposite stereochemistry. These unusual effects may be due to aggregation, or a ‘steering’ effect of a carbamatecomplexed magnesium.

a-Alkoxy and -acetoxy substitution of ketones has been achieved using the appropriate alcohol or acetic acid in an a-umpolung based on the inversion of the thermochemical stability of the keto-enol system upon one-electron oxidation. 38b Enolization is rate determining, followed by oxidation (to the enol radical cation), deprotonation, a second oxidation (to the a-cation of the ketone), and finally attack of the nucleophile. The synthesis relies on the much higher rate of acidcatalysed enolization in ‘ acetonitrile compared with water ( > 1000-fold faster), and indeed the monitoring system used [the oxidant/indicator, iron(II1) phenanthroline] is proposed as part of a novel strategy to measure rates of enolization in anhydrous solvents.

’

Hydrolysis and Reactions of Vinyl Ethers and Related Compounds The a-umpolung of ketones above’38ahas been modified by the use of the silyl enol ether as reactant, allowing a wider range of nucleophiles to be successfully substituted.139 Enantioselective preparation of silyl enol ethers of 3-methylcyclohexanone and related compounds using chiral lithium amide bases involves ‘regiodivergent resolution.”40 An antibody raised against a quaternary ammonium ion, acting as a transition-state analogue modelled on the oxocarbonium intermediate of enol ether hydrolysis, gives high enantioselectivity. I 4 l The best substrates are alkyl enol ethers with a P-alkyl

26

Organic Reaction Mechanisms 1995

substituent and a 2-double bond. The rate-determining protonation occurs on the re face, giving an S-configured carbonyl product. The enantioselective catalysis includes a contribution from general acid catalysis by a protein side-chain site of pK, 5.2. As part of a search for widely applicable methods for preparing seven- and eightmembered ring systems, [3 41 and [3 51 annulations of bis(trimethylsily1)enolethers with acylsilane dicarbonyl dielectrophiles have been found to proceed with good regioand stereo-chemical control, via a mechanism involving neighbouring-group participation.142 The methoxy group of the trichloroacetyl-activated vinyl ether (66a) is substituted by amines to give (2)-alkyl (or aryl) aminovinyl ketones (66b); the kinetics are first order in amine in polar solvents, but second order in hexane and t01uene.l~~Stepwise addition-elimination mechanisms are proposed, with a zwitterionic enolate (67a) or enol (67b) as intermediate in the respective solvent types.

+

+

OMe

OMe

Oxidation and Reduction of Carbonyl Compounds Hydrogen formation from formaldehyde in basic aqueous solutions is first order in formaldehyde, and tends towards second order in hydroxide at low formaldehyde concentration^.'^^ The role of formaldehyde hydrate and its mono- and di-anion, and the Cannizzaro reactions arising from these species, are discussed. Oxidation of substituted benzaldehydes by peroxodisulfate is first order in reagent, and independent of silver(1).145 Autoxidation oscillating reactions of substituted benzaldehydes and aliphatic aldehydes in aqueous acetic acid are catalysed by cobalt(I1) and bromide;'46 kinetic constraints on the oscillation period were studied, and a mechanism involving 14 elementary reactions proposed. Oxidation of cinnamaldehyde by chromium(V1) in a similar medium involves the chromic acid ester of the hydrated aldehyde.147 Oxidation of ketones by vanadium(V), cerium(IV), chromium(VI), and related reagents has been reviewed (80 reference^).'^' Reduction of formaldehyde by general acid-catalysed hydride transfer has been studied, using three combinations of hydride and proton donor: dihydropyridine-imidazolium, dihydropyridine-ammonium, and methylamine-ammonium. 149 All give similar conclusions with both ab initio and

I Reactions of Aldehydes and Ketones and their Derivatives

27

semiempirical methods: (i) proton and hydride transfer occur in roughly perpendicular planes; and (ii) the processes are kinetically coupled (i.e. concerted) but dynamically uncoupled (with proton transfer more advanced in the transition state). The basic geometry seems to be fairly robust: these simple pairs are consistent with more sophisticated models of, e.g., lactate dehydrogenase (see later). The reduction of pyruvate to lactate, catalysed by lactate dehydrogenase, has been modelled semiempirically using NADH as reductant, and two moieties based on relevant amino acids: an imidazole (for His195) and a guanidine (for Arg171).’’0 The starting point (which corresponds to an X-ray structure) consists of a protonated imidazole within hydrogen-bonding distance of the pyruvate carbonyl group, the pyruvate carboxylate itself hydrogen-bonded to the guanidine, and the nicotinamide adjacent to the carbonyl carbon. At the transition state, the proton from imidazole has already been transferred to oxygen along the pre-existing hydrogen bond, and the hydride is almost half-way transferred: the proton and hydride transfers are approximately perpendicular. The stereochemistry of delivery of hydride anion in the reduction of 5fluoroadamantan-2-one (68) switches over from Cieplak-’ ’la to Anh-hyperconjugdtion”lb when the identities of all hydrogen and fluorine atoms are reversed.151CIt is suggested that the periplanar bonds can no longer stabilize the transition state by electron donation, and instead do so by accepting electron density from the incipient bond into the CT* orbitals. These substrates appear to be well suited to this type of study because of their rigidity, and because the substituent, while allowing distinction of the faces, does not obstruct either of them. Ab initio and semiempirical calculations on the transition states for the reduction of 5+ substituted adamantan-2-ones (69; X =N, N-0-, or C-substituent) by aluminium hydride show evidence for hyperconjugative delocalization.lS2 The C(a)-C(p) bond which is antiperiplanar to the incoming nucleophile is lengthened.

Norbornan-7-one (70) has often been used as an isosteric probe of z-facial selectivity. Electrostatic effects appear to dominate in borohydride reduction of 2-endo-substituted and 2,3-endo,endo-disubstitutednorbornan-7-ones, as shown by polar-field susceptibility parameters, and a 13CNMR probe based on the transmission of polar substituent effects.IS3 The diastereo- and regio-selectivity of reduction of bicyclo[3.3.l]nonane-2,9-dione (71) by various hydride reagents has been determined via the product distribution of the four possible hydroxy ketones and four possible diastereomeric diols; steric, stereoelectronic and electrostatic factors are probed by molecular mechanics. lS4

28

Organic Reaction Mechanisms 1995

Borane complexes of chiral 1-phenethylamines reduce aromatic ketones with moderate to good enantioselectivity in the presence of boron trifluoride etherate; the transition state is proposed to involve hydride transfer from an amine-BF3-BH3 c0mp1ex.I~~ Acetophenone has been reduced enantioselectively with borane using chiral oxazaborolidine catalysts.156 A chiral bis(phospho1ano)ethaneruthenium catalyst brings about highly enantioselective hydrogenation of p-keto esters under mild conditions; the P-hydroxy ester products can in turn be used to make ligand for the catalyst, i.e. the reaction ‘breeds its own chirality.”57 LiBuS,H reduces an acyclic y-sulfenyl-substituted a-enone with 1,4-diastereoselectivity by exploiting conjugation: X-ray analysis shows the sulfbr is approximately orthogonal to the enone plane, and the hydride attacks fiom the opposite side.‘5x Similar results are seen in the corresponding enals, and with y-alkoxy and -siloxy a-enones. Metal hydride reduction of a-seleno ketone, ArCOCH(R)SeR’ (R = alkyl, R’ = Ph, Me), yields mainly threo-8-aryl-P-hydroxyalkyl phenyl (or methyl) selenides,’59 in contrast to the elythro-products found for most other a-heteroatoms: NR2, OH, OR, P(0)Ph2, SR, etc. Cyclopropyl ketones have been reduced diastereoselectively with hydride reagents.160

Other Reactions 8,y-Unsaturated aldehydes typically decarbonylate on photo-irradiation: the formation of a cyclopropyl aldehyde via an oxa-di-n-methane rearrangement has previously only been reported for a rigid aldehyde161aor one with sterically hindered rotation.161bNow aldehydes as simple as (72) undergo the reaction effectively; the phenyl group probably stabilizes the bridging 1,4-biradical intermediate.l 6 l C Although P,y-unsaturated oximes are usually photochemically inert, appropriately substituted acyclic aldoximes (73a) can cyclize in a stereoselective aza-di-n-methane rearrangement to cyclopropyl aldoximes’62 (73b). The reaction has also been extended to an oxime ether and to ketones. The chiral (Z)-oxazolone (74) has been cyclopropanated at the alkene (with modest selectivities) using oxosulfonium methylides, to give four isomeric spiro compounds.‘63 Biphenyls, which are twisted in the ground state, tend to become planar upon electronic excitation. Direct evidence that the singlet (S,) state is extensively polarized in simple substituted biphenyls is seen in the observation that, while 4-phenylphenol (75) undergoes thermal deuterium exchange (in acid) at the 2-position, exchange under irradiation takes place in the 2’- and 4’-positi0ns.l~~ This suggests the intermediacy of quinone methide species, and evidence for them was obtained by irradiating benzylic alcohols (76a) and (77a). Using laser flash photolysis at 266 nm in aqueous solution, both lose hydroxide to give quinone methides, (76b; d,,,=570 nm) and (77b; A, = 525 m). The gas-phase reactions of the hydroxyl radical with P-methyl-substituted ketones have been studied in the presence of NO,; evidence for isomerization of alkoxy radicals, particularly those to the carbonyl, is presented.I6’ When a-alkylcyclohex-

1 Reactions of Aldehydes and Ketones and their Derivatives

29

Me CH=CH2

Ph

(73a)

Ph

R = H. COMe, COCF3

CH=NOR (73b)

anones such as (78) bear a hydrogen in the y-position (in the side-chain), Norrish type I1 cleavage causes loss of the side-chain, to give (80) as major product. However, with a p-silyl substituent (R2= SiR,Ar,), the reaction switches over to the generally more useful Norrish type I products (79a and b), presumably due to silyl stabilization of a radical intermediate.'66 Carbonylation of chloral (trichloroacetaldehyde) in concentrated sulfuric acid gives cis- and trans-2,5-bis(trichloromethyl)-l,3-dioxolan-4-ones(81), with the ratio

Organic Reaction Mechanisms I995

30

dependent on the acid concentration.'67a This in turn depends on the stability of the anti-form o f the protonated aldehyde (82; R = CC13), which predominates in strongly acidic media.167b

When propanedinitrile is reacted in base with an a$-unsaturated carbonyl compound such as (Q-4-phenylbut-3-ene-2-one (83a), a 2-aminobenzene-l,3-dicarbonitrile (83b) is ~btained.'~' This appears to arise from reaction o f three molecules o f dinitrile with enone to give an iminobicyclooctene, which eliminates NaC(CN)3 en route to product (83b). 0

CN

The catalysis o f the thermal spiropyran-to-merocyanine isomerization (84a) + (84b) by a-, /3-, and y-cyclodextrins has been studied at high pressures, yielding data on the volumes o f activation and of reaction and on the nature of the 1 : 1 inclusion complex formed.'69

Halogenation o f aldehydes and ketones by selenium(1V) oxyhalides (generated from SeOz and Me3SiX) involves P-keto selenenyl halides; polyhalogenation is suppressed.170

1 Reactions of Aldehydes and Ketones and their Derivatives

31

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2o

” 22

23 24 25

26

’*

27

29

3o

31

32 33

34

35

36 37 38 39 4o 4’

42

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Organic Reaction Mechanisms 1995

Battachajee, G., Singh, A. K., and Gairola, F'., Indian J ; Chem., 34B, 129 (1995); Chem. Abs., 122, 105060 (1995). 44 Lessel, J., Arch. Phurm. (Weinheim, Ger:), 328, 397 (1995). 45 Do Amaral, L., An. Assoc. Bras. Quzm., 43, 125 (1994); Chem. A h . , 122, 238976 (1 995). 46 Prasad, N., Prasad, R. M., Sahay, A., Srivastava, A. K., and Prasad, J., Asian 1 Chem., 6, 901 (1994); Chem. Abs., 122, 213346 (1995). 47 Machacek, V, Cegan, A,, Halama, A., Roznavska, O., and Sterba, V, Collect. Czech. Chem. Commun., 60, 1367 (1995). 48 Noto, R., Gruttadauria, M., Lo Meo, P., Frenna, V, and Werber, G., 1 Heterocycl. Chem., 32, 1277 (1995). 49 Meenal, Kr. and Bai, T. S. J., 1 Indian Chem. Soc., 71, 117 (1994); Chrm. Abs., 121, 300325 (1994). (a) Kuzuhara, H., Iwata, M., and Emoto, S.,J Am. Chem. Soc., 99,4173 (1977); (b) Tachibana, Y , Ando, M., and Kuzuhara, H., Chem. Lett., 1982, 1769; (c) Koh, J. T., Delaude, L., and Breslow, R., 1 Am. Chem. SOC., 116, 11234 (1994). 51 Bernardi, A., Gennari, C., Goodman, J. M., and Paterson, I., Etruhedron: Asymmetry,6, 2613 (1995). 52 Gennari, C., Pain, G., and Moresca, D., 1Org. Chem., 60, 6248 (1995). 53 Ferey, V, Le Gall, T., and Mioskowski, C., 1 Chem. Soc., Chem. Commun., 1995, 487. 54 Chem. Commun., 1995, 757. Howarth, J. A., Owton, W. M., and Percy, J. M., 1 Chem. SOC., 55 D'Arrigo, M. C., Porzi, G., Rossetti, M., and Sandri, S., J ; Chem. Rex (S), 1995, 162. 56 D'Arrigo, M. C., Porzi, G., and Sandri, S., 1 Chem. Res. (s), 1995, 430. 57 Koga, K., New Aspects Org. Chem. /I, Proc. Int. Kyoto Conj, 5th, 1991 (Pub. 1992); Chem. A h . , 122, I8658 1 (I995). 58 Mukaiyama, T. and Kobayashi, S., Org. Reuct. ( N Y ) ) ,46, 1 (1994); Chem. Abs., 122, 186541 (1995). 59 Kobayashi, S. and Hachiya, I., Yuki Gosei Kagaku Kyokaishi, 53, 370 (1995); Chem. Abs., 123, 8823 (1995). (a) Nagorski, R. W., Mizerski, T., and Richard, J. P., 1 Am. Chem. Soc., 117,4718 (1995); (b) Guthrie, J. F'., 1 Am. Chem. Soc., 113, 7249 (1991). (a) Desper, J. M. and Breslow, R., 1 Am. Chem. Soc., 116, 12081 (1994); (b) Anslyn, E. and Breslow, R., 1 Am. Chem. Soc., 111, 5972 (1989); (c) Breslow, R. and Graff, A., 1 Am. Chem. Soc., 115, 10988 (1 993). Wood A. J., Jenkins, P. R., Fawcett, J., and Russell, D. R., .I Chem. Soc., Chem. Commun., 1995, 1567. 63 Ding, Y. and Jiang, X.-R., 1 Chem. Soc., Chem. Commun., 1995, 1693. '4 Hollis, T. K. and Bosnich, B., 1 Am. Chem. Soc., 117, 4570 (1995). 65 (a) Davis, A. P. and Plunkett, S. J., 1 Chem. Soc., Chem. Commun., 1995, 2173; (b) Cram, D. J. and Elhafez, F. A. A,, 1Am. Chem. Soc., 74, 5828 (1952). 66 Gung, B. W., Zhu, Z., and Fouch, R. A., 1 Org. Chem., 60, 2860 (1995). 67 Evans, D. A,, Dart, M. J., DufFy, J. L., Yang, M. G., and Livingston, A. B., 1 Am. Chem. Soc., 117,6619 (1995). " Suh, K.-H. and Choo, D.-J., Tetrahedron Lett., 36, 6109 (1995). " Bernardi, A,, Gennari, C., Goodman, J. M., Leue, V, and Paterson, I., Tetrahedron, 51, 4853 (1995). Fringuelli, F., Piermatti, O., and Pizzo, F.. .I Org. Chem., 60, 7006 (1995). 71 Yan, T.-H., Hung, A.-W., Lee, H.-C., Chang, C.-S., and Liu, W.-H., 1 Org. Chem., 60, 3301 (1995). 7 2 Yan, T.-H., Hung, A,-W, Lee, H.-C., and Chang, C.-S., 1 Org. Chem., 59, 8187 (1994). 73 Sano, S., Liu, X.-K., Takebayashi, M., Kobayashi, Y., Tabata, K., Shiro, M., and Nagao, Y., Tetrahedron Lett., 36, 4101 (1995). 74 Kloetstra, K. R. and van Bekkum, H., 1 Chem. Soc., Chem. Commun., 1995, 1005. 75 Filippini, M.-H. and Rodriguez, J., 1 Chem. Sue., Chem. Commun., 1995, 33. " Voitekunas, Yu. B. and Pirig, Ya. N., Kinet. Katul., 35, 554 (1994); Chem. Abs., 122, 186889 (1995). 77 Breslow, R. and Connors, R. V, 1 Am. Chem. Soc., 117, 6601 (1995). " Chen, Y.-T., Barletta, G. L., Haghjoo, K., Cheng, J. T., and Jordan, F., 1 Org. Chem., 59, 7714 (1994). 79 (a) Lopez-Calahorra, F. and Rubires, R., Tetrahedron, 51, 9713 (1995); (b) Breslow, R., 1Am. Chem. Soc., 80, 3719 (1958). Kluger, R., Lam, J. F., Pezacki, J. P., and Yang, C.-M., 1 Am. Chem. Soc., 117, 113x3 (1995). * I Morkovnik, A. S., Kbrustalev, V N., Lindeman, S. V, Struchkov, Yu. T., and Morkovnik, Z. S., Mendeleev Commun., 1995, 11. " Rosenberg, R. E., 1 Am. Chrtn. Soc., 117, 10358 (1995). 83 Tsaev, A. N., Izu A h d . Nauk, Ser: Khim., 1994, 227; Chem. Abs., 123, 8897 (1995). 84 Anh, N. T., Maurel, F., and Lefour, J.-M., New 1 Chem., 19, 353 (1995). Yamataka, H., 1 Phys. Org. Chem., 8, 445 (1995). ' 6 (a) Cram, D. J. and Elhafez, F. A. A., 1Am. Chem. Soc., 74, 3210 (1952); (b) Fleischcr, J. M., Gushurst, A. J., and Jorgensen, W. L., 1Org. Chem., 60,490 (1995); (c) for a review of CAMEO, see Jorgensen, W. 43

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L., Laird, E. R., Paderes, G. D., and Sinclair, S., Pure Appl. Chem., 62, 192 1 ( I 990). Kenso, S. and Hayase, T., Yuki Gosei Kagaku Kyokuishi, 53, 138 (1995); Chem. A h . , 122, 186552 (1995). " Concellon. J. M.. Llavona. L.. and Bemad P. L. Tetrahedron. 51. 5573 (19951. \ , 89 Luitjes, H:,Schakel, M., Schmitz, R. F., and Klumpp, G. W., Angav. Chem., Int. Ed. Engl., 34, 2152 I1 995). ,90 Braun, M. and Mahler, H., Liebigs Ann. Chem., 1995, 29. 91 Varea, T., Medio, M., Ballesteros, R., Oniga, O., and Asensio, G., Tetrahedron, 51, 10093 (1995). y2 Yang, Z. Y., Fan, X., and Jiang, X. Y., Chin. Chem. Lett., 5, 931 (1995); Chem. Abs., 122, 55463 (1995). 93 Wipf, P. and Kim, Y., 1 Am. Chem. SOC., 116, 11678 (1994). y4 Cuza, O., Caravaniez, D., and Zavoianu, D., Rev. Chim. (Bucharest), 45, 368 (1994); Chem. Abs., 122, 80508 (1995). " Kitainura, M., Suga, S., Niwa, M., and Noyori, R., 1 Am. Chem. SOC., 117, 4832 (1995). " Yamakawa, M. and Noyori, R., 1 Am. Chem. SOC.,117, 6327 (1995). 97 Iuliano, A., Phi, D., and Salvadori, P., Tetrahedron; Asymmetry,6, 739 (1995). 98 Urabe, H., Evin, 0. O., and Sato, F., 1 Org. Chem., 60, 2660 (1995). 99 Tamaru, Y., Tanaka, A., Yasui, K., Goto, S., and Tanaka, S., Angew Chem., Int. Ed. Engl., 34, 787 (1995). l o o Ito, Y.N., Ariza, X., Beck, A. K., Bohac, A,, Ganter, C., Gawley, R. E., Kuhnle, F. N.M., Tuleja, J., Wang, Y. M., and Siebach, D., Helv. Chim. Acra, 77, 2071 (1994). lo' Fujimura, O., Fu, G. C., Rothemund, P. W. K., and Grubbs, R. H., 1 Am. Chem. SOC.,117, 2355 (1995). In2 Keck, G. E., Savin, K. A., Cressman, E. N.K., and Abbott, D. A,, 1 Org. Chem., 59, 7889 (1994). Io3 Marshall, J. A. and Beaudoin, S., 1 Org. Chem., 59, 7833 (1994). Io4 Nakamura, H., Asao, N., and Yamamoto, Y., 1 Chem. SOC.,Chem. Commun., 1995, 1273. lo' Menendez, E.. Brieva, R.,Rebolledo, F., and Gotor, V, 1 Chem. Soc.. Chem. Commun., 1995, 989. lo' Jain, N.F., Cirillo, I? F., Pelletier, R., and Panek, J. S., Tetrahedron Lelt., 36, 8727 (1995). lo' Bodnar, P. M., Palmer, W. S., Shaw, J. T., Smitrovich, J. H., Sonnenberg, J. D., Presley, A. L., and Woerpel, K. A,, 1 Am. Chem. SOC.,117, 10575 (1995). 'Ox Miura, T. and Masaki, Y., J Chem. SOC., Perkin Trans. I , 1995, 2155. Iny Takeuchi, K., Paschal, J. W., and Loncharich, R. J., 1 Org. Chem., 60, 156 (1995). 110 Agganval, V. K., Franklin, R., Maddock, J., Evans, G. R., Thomas, A,, Mahon, M. F., Molloy, K. C., and Rice, M. J., 1 Org. Chem., 60, 2174 (1995). I I Borisov, Yu. A,, Chkanikov, N. D., Kolomiets, A. F., and Fokin, A. V, I , . Akad. Nuuk, Srr: Khim., 1993, 1883; Chenz. Abs., 123, 255928 (1995). I I2 Gritsan, N.P., Klimenko, L. S., Leonenko, 2. V, Mainagashev, I. Ya., Mamatyuk, V I., and Vetchinov, V P., Tetrahedron, 51, 3061 ( 1 995). 1 I? Leonenko, Z. V, Gritsan, N. F!, and Klimenko, L. S., In?Akad. NauS Srr Khim., 1995,255; Chem. A h . , 123, 143087 (1995). ' I 4 Gancarz, R., Tetrahedron, 51, 10627 (1995). ' I 5 Devitt, P. G. and Kee, T. P., Tetrahedron, 51, 10987 (1995). ' I 6 (a) Wolfc, S., Kim, C.-K., Yang, K., Weinberg, N., and Shi, Z., 1 Am. Chem. SOC., 117, 4240 (1995); (b) Gandour, R. D., Tetrahedron Lett., 1974, 295; (c) Williams, I. H., Spangler, D., Femec, D. A,, Maggiora, G. M., and Schowen, R. L., 1 Am. Chem. SOC., 105, 31 (1983); Scheiner, S., Acc. Chem lies., 27, 402 (1994); (d) Bell, R. P., Rand, M. H., and Wynne-Jones, K. M. A,, Truns. Furuday SOC.,52, 1093 (1956); 39, 7 (1965); Bell, R. P. and Sorensen, P. E., 1 Chem. SOC., Perkin Eigen, M., Discuss. Faruday SOC., Trans. 2, 1972, 1740. I17 McClelland, R. A,, Sukhai, P., Engell, K. M., and Sorensen, P. E., Can. 1 Chem., 72, 2333 (1994). Saito, S., Ohwada, T., and Shudo, K., 1 Am. Chem. SOC.,117, 11081 (1995). ' I 9 Olah, G. A., Rasul, G., York, C., and S u v a Prakash, G. K., 1 Am. Chem. Soc., 117, 11211 (1995). I2O Milligan, G. L., Mossman, C. J., and Aube, I., 1 Am. Chem. Soc., 117, 10449 (1995). 121 Balog, A., Geib, S. J., and Curran, D. I?, 1 Org. Chem., 60, 345 (1995). I22 (a) Forbes, E. J. and Grcgory, M. J., J Chem. SOC.B, 1968,207; (b) Machacek, V , Manova, J., Sedlak, M., and Sterba, V, Collect. Czech. Chem. Commun., 59, 2262 ( I 994). Alper, E. and Bouhamra, W., Chem. Eng. Technol., 17, 138 (1994); Chem. A h . , 122, 55549 (1995). 124 Jefferson, E. A., Keeffe, J. R., and Kresge, A. J., 1 Chem. Sac., Perkin Truns. 2, 1995, 2041. 125 (a) Guthrie, J. P.and Liu, Z., Can. 1 Chem., 73, 1395 (1995); (b) Guthrie, J. P., Can. 1 Chem., 71, 2123 (1 993). Iz6 Harcourt, M. F! and More O'Ferrall, R. A., 1 Chem. SOC.,Perkin Truns. 2, 1995, 1415. I27 Fontana, A. and More O'Ferrall, R. A., 1 Chem. SOC.,Perkin Trans. 2, 1994, 2453. 12' (a) Alagona, G., Ghio, C., and Kollman, I? A., 1 Am. Chem. SOC., 117, 9855 (1995); (b) Gerlt, J. A. and Gassman, P. G., 1 Am. Chem. Soc., 115, 11552 (1993). - I

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Kelly-Rowley, A. M., Lynch, V. M., and Anslyn, E. V., 1 Am. Chem. SOC.,117, 3438 (1995). Chimichi, S., Dell'Erba, C., Gruttadauria, M., Noto, R., Novi, M., Petrillo, G., Sancassan, F., and Spinelli, D., 1 Chem. SOC., Perkin Trans. 2,1995, 1021. 131 (a) More O'Fcrrall, R. A. and Murray, B. A., 1 Chem. Soc., Perkin Trans. 2 1994, 2461;(b) Argile, A., Carey, A. R. E., More O'Ferrall, R. A,, Murray, B. A,, and Murphy, M. G., I Chem. SOC., Chem. Commun., 1987, 1847. 132 Carey, A. R. E., More O'Ferrall, R. A., Murphy, M. G., and Murray, B. A,, 1 Chem. Soc., Perkin Trans. 2, 1994, 2471. 1 3 3 Ortiz, C. S. and de Bertorello, M. M., 1 Pharm. Sci., 84, 783 (1995). 1 3 4 Werstiuk, N. H. and Roy, C. D., Can. 1 Chem., 72, 2348 (1994). I35 Lew, C. S. Q., Tang, T.-H., Csizmadia, I. G., and Capon, B., 1 Chem. Soc.. Chem. Commun., 1995, 175. I36 Werstiuk, N. 11. and Roy, C. D., Can. 1 Chcm., 73, 460 (1995). Fuji, K., Kawabata, T., Kuroda, A,, and Taga, T., 1 Org. Chem., 60, 1914 (1995). (a) Schmittel, M.and Levis, M., Chem. Lett., 1994, 1935;Chem. Abs., 122, 105085 (1995); (b) Schmittel, M. and Baumann, U., Angew. Chem., Int. Ed. Engl., 29, 541 (1990); Schmittel, M., Abufarag, A,, Luche, O., and Levis, M., Angew Chem., Int. Ed. Engl., 29, 1 144 (1 990). I39 Schmittel, M.and Levis, M., Chem. Lett., 1994, 1939. I40 Bambridge, K., Clark, B. P., and Simpkins, N. S . , 1 Chem. Soc., Perkin Trans. I , 1995, 2535. 14' Jahanagiri, G. K. and Reymond, J.-L., I Am. Chem. Soc., 116, 11264 (1994). '41 Moiander, G.A. and Siedem, C. S . , J. Org. Chem., 60, 130 (1995). 143 Gesser, J. C., Zucco, C., and Nome, F., 1 Phys. Org. Chem., 8, 97 (1995). I44 Kapoor, S., Barnabas, F. A,, Sauer, M. C., Meisel, D., and Jonah, C. D., 1 Phys. Chem., 99,6857(1995). 145 Hiran, B.L., Jain, S. L., and Joshi, S. N., Asian I Chem., 6, 830 (1994); Chem. Abs., 122, 9323 (1995). 146 Song, X.-Y., Zhang, Y. X., Jiao, N.-X., Cui, J.-X., Yang, X.-P., Shang, Z.-F., Ma, K.-Q., Zhao, H.-X., Zang, Y.-R., and Zhao, X.-Z., Gaodeng Xuexiao Huaxue Xuebao, 15, 840 (1994); Chem. Abs., 122, 129 13"

55451 (1995).

Chellamani, A., Alhaji, N. M. I., and Selvarijan, S . , Asian 1 Chem. Rev., 7, 365 (1995);Chem. Ahs., 122, 29017I (1995). I 48 Sharma, K., Sharma, V. K., and Pandey, A,, Asian 1 Cham. Rrv., 5, 1 (1994); Chem. Ahs., 122, 186622 (I 995). I49 Wilkie, J. and Williams, I. H., J: Chem. SOC.,Perkin Trans. 2,1995, 1559. Is" Andres, J., Moliner, V, Krechl, J., and Silla, E., 1 Chem. SOC., Perkin Trans. 2,1995, 1551 . (a)Cieplak,A.S.,IAm. Chem.Soc.,103,4540(1981);(b)Anh,N.T.,Top. Cum Chem.,88,145(198O);(c) Kaselj, M., Adcock, J. L., Luo, H., Zhang,H., Li, H., andleNoble, W. J.,JAm. Chem. SOC., 117,7088 (1995). 1 5 2 Coxon, J. M., Houk, K. N., and Luibrand, R. T., 1 Org. Chem., 60, 418 (1995). 153 Mehta, G., Khan, E A., and Adcock, W., 1 Chem. SOC.,Perkin Trans. 2, 1995, 2189. 154 Berg, U., Butkus, E., and Stoncius, A., 1 Chem. Suc., Perkin Trans. 2,1995, 97. 1 5 5 Pcriasamy, M., Kanth, J. V B., and Reddy, Ch. K., J. Chem. SOC.,Perkin Trans. I , 1995, 427. 156 Dubois, L., Fiaud, J.-C., and Kagan, H. B., Tetrahedron: Asymmetry, 6, 1097 (1995). 157 Burk, M. J., Harper, T. G. P.,and Kalberg, C. S., 1 Am. Chem. SOC., 117, 4423 (1995). Is' Sato, T., Kido, M., and Otera, J., Angew Chem., Int. Ed. Engl., 34,2254 (1995). 159 Aoki, I., Nishibayashi, Y., and Uemura, S . , Bull. Chem. Soc. Jpn, 68, 337 (1995). Delanghe, P. H. M. and Lautens, M., Tetrahedron Lett., 35, 9513 (1994). (a) Pfenninger, E., Poel, D. E., Berse, C., Wehrli, H., Schafher, K., and Jeger, O., Helv. Chim. Acfu, 51, 772 (1968); (b) Zimmermann, H. E. and Cassel, O., 1 Org. Chem., 92, 4906 (1970);( c ) Armesto, D., Ortiz, M. J., and Romano, S., Tetrahedron Lett., 36, 965 (1995). 162 Armesto, D., Ortiz, M. J., Ramos, A,, Horspool, W. M., and Mayoral, E. P.,1 Org. Chem., 59, 8115 (1994);Chem. Abs., 122, 213344 (1995). 163 Cativiela, C., Diaz-de-Villegas, M. D., and Jimenez, A. I., Tetrahedron, 51, 3025 (1995). 164 Shi, Y.and Wan, P.. 1 Chem. Soc.. Chem. Commun., 1995, 1217. Atkinson, R. and Aschmann, S. M., Int. 1 Chem. Kinef., 27, 261 (1995). I66 Hwu, J. R.,Chen, B.-L., Huang, L. W., and Yang, T.-H., 1 Chem. Soc.. Chem. Commun., 1995, 299. 16' (a) Mod, S., Emura, K., Kano, M., Kudo, K., Komatsu, K., and Sugita, N., Tetrahedron, 51, 8977 (1995); (b) Olah, G. A., O'Brien, D. H., and Calin, M., I .4m. Chem. SOC.,80, 3719 (1958);Olah, G. A., Surya Prakash, G. K., and Somnier, J., Superucid.s, Wiley, New York, 1985,p. 116. Victory, P., Alvarez-Larena, A., Germain, G., Kessels, R., Piniella, J. E, and Vidal-Ferran, A,, Tetrahedron, 51, 235 (1995). '69 Sueishi, Y. and Nishimura, T., 1 Phys. Org. Chem., 8, 335 (1995). Lee, J. G., Park, I. S., and Seo, J. W, Bull. Korean Chem. Suc., 16, 349 (1995);Chem. A h , 123, 255833 14'

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(1995).

CHAPTER 2

Reactions of Acids and their Derivatives W. J . SPILLANE

Chemistry Department. University College. Galway. Ireland CARBOXYLICACIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tetrahedral Intermediates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intermolecular Catalysis and Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions in Hydroxylic Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (a) General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (b)Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (i) Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (ii) Transesterification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (iii) Other reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (c) Lactones and derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (d) Acids and anhydrides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (e) Acid halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (0 Ureas, carbamates. hydroxylamine, and derivatives. . . . . . . . . . . . . . . . (g) Amides. anilides. lactams. and lactims . . . . . . . . . . . . . . . . . . . . . . . (h) Non-heterocyclic nitrogen centres . . . . . . . . . . . . . . . . . . . . . . . . . . (i) Other heterocyclic nitrogen centres . . . . . . . . . . . . . . . . . . . . . . . . . Reactions in Aprotic Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intramolecular Catalysis and Neighbouring-group Participation . . . . . . . . . . Association-prefaced Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metal-ion Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Decarboxylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enzymic Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Serine Proteinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lipases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Penicillin Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . O ~ e r E n z y m e.s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NON-CARBOXYLIC ACIDS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phosphorus-containing Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-enzymic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (a) Phosphates. phosphoryl transfer, phosphonates . . . . . . . . . . . . . . . . . . @) Other phosphorus functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enzymic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sulfur-containing Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (a) Sulfur-oxygen compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (b) Sulfur-nitrogen compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (c) Other sulfur compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ReEerences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Organic Reaction Mechanism.y 1995 . Edited by A . C . Knipe and W. E . Wans 6 1997 John Wiley & Sons I.td

35

36 36 38 38 38 39 39 40 41 45 45 48 48 50 53 54 56 60 61 67 67 69 69 69 70 70 70 71 71 71 71 75 75 78 78 80 81 84 84

Organic Reaction Mechanisms 1995

36

CARBOXYLIC ACIDS

Tetrahedral Intermediates Semiempirical molecular orbital (PM3) calculations have been reported for the reactions of m-nitro-, p-nitro-, and 3,4-dinitro-phenyl formates (1) with 18 phenolate anions in the gas phase and in solution (Scheme l).' The mechanistic changeover from rate-limiting formation to breakdown of the anionic tetrahedral adduct (T-) can occur at approximately equal proton affinities (i.e. @A = 0) of the leaving-group phenolates and the nucleophile in the gas phase, particularly for the m-nitro compound. The low stability of T- in solution and stabilization by solvation of the transition state for the breakdown step result in all three formates reacting by a concerted mechanism. Recent evidence from l 8 0 exchange studies in H 2 0 and DzO on the basic hydrolysis of ethyl toluate and isopropyl toluate suggests that the anionic tetrahedral intermediates (2) produced in these hydrolyses equilibriate very rapidly compared with C-OH or C-OR cleavage (Scheme 2).* Oxygen-18 isotope effect studies in the carbonyl oxygen of p nitrophenyl acetate and in the phenolic oxygen atom of the leaving group, together with "N isotope effects in the leaving group indicate that the acyl-transfer reactions of this substrate with various nucleophiles are concerted and do not involve an inte~mediate.~ For the reaction with methoxyethylamine, a stepwise mechanism involving the

XC6H40-

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I

XC6H40-C-OC6H4Z

I

H

1

T-

O II XCbH40-CH

+ -OC6H4Z

SCHEME1

0-

~-M~C~HC-(!-OR

I

OH

__ (2) R = Et, Pr' Scmm 2

OH

I

4-MeC6H4-C-OR

I

0-

2 Reactions of Acids and their Derivatives

37

0

SS II EtO-C-SAr

(7)

II

EtO-C-SAr I+ -NH-

(8)

zwitterionic tetrahedral intermediate (3), with its breakdown rate-determining, is taking place as the crucial step. Cross-interaction constants pxx pyz, and pxz (where X, Y, and Z axe substituents in the attacking nucleophile, the substrate, and the leaving group, respectively) have for some years proved very useful in examining the nature of the transition states in concerted SN2 reactions where pxy < 0, pyz > 0, and pxz > 0 or < 0. Now the crossinteraction constants expected for stepwise carbonyl addition reactions involving ratelimiting breakdown or formation of a tetrahedral intermediate are proposed as p x y > 0, ~ Y 0 and pxY < 0, pyz x 0, and pxz > 0 or < 0, re~pectively.~ Hydrolysis of the major alkaloid securinine (4) from the genus Securinegu, which as its nitrate salt is a stimulant to the central nervous system, involves lactone ring opening and may involve tetrahedral intermediates such as ( 5 ) and (6).5 The aminolysis (secondary alicyclic amines) reactions of 0-ethyl S-aryldithiocarbonates (7) in aqueous ethanol have been r e p ~ r t e d .For ~ ’ ~0-ethyl S-phenyl dithiocarbonate (7; Ar = Ph), plots of kobs (excess amine) vs [amine] showed some upward curvature, but plots of [amine]/k,b, vs l/[amine] were linear. When the amine was 1formylpiperazine, plots of kobs vs [aminel* were linear. A mechanism involving zwitterionic and anionic tetrahedral intermediates is proposed where the aminecatalysed proton transfer from TSto T- is partially rate-determining normally and hlly rate-limiting for l-formylpiperazine.6 Aminolysis of 4-nitrophenyl (7; Ar = 4-02NC6H4)and 2,4-dinitrophenyl [7; Ar = 2,4-(02N)2C6H3]0-ethyl dithiocarbonates gave Brernsted plots which were biphasic with P I = 0.3 (high pK,), p2 = 0.95 (low pK,) for the 4-nitro substrate, and /I1 =0.3 and B2=0.80 for the 2,4-dinitro substrate, respectively. These reactions are seen as being stepwise with the formation of a zwitterionic tetrahedral intermediate (tQ7 The breakdown of a neutral tetrahedral intermediate (9) has been proposed for hydrolysis of methylthiazolium ions8 and the same authors’ now propose that such an intermediate (9) is involved in the hydrolysis of several 3-R-4-methyl- and 3-R-2,4dimethyl-thiazolium ions leading to the enethiolate products (10). Breakdown of (9) is again rate determining.

Organic Reaction Mechanisms I995

38

See also references 37, 39, 41, 48, 73, 80, 84, 94, 104, 105, 110 and 11 1.

Intermolecular Catalysis and Reactions

Reactions in Hydroxylic Solvents (a) General A new set of steric parameters developed by the use of the AM1 semiempirical MO method incorporation MOPAC have been derived using calculated proton affinities (Ap) and methyl ion affinities (AMe).The new parameters, designated 6, have been tested in various ways including the use of kinetic data for the Menschutkin reaction in Scheme 4. For 22 pyridines, the following equation shown was followed: log (k/kH) = 0.656

+ 0.43 PK, - 2.26

with Y = 0.942, s = 0.048, and F= 74.55. This approach is expected to be useful in QSAR studies in biochemistry and medicine. The coefficients in the equation are interpreted as indicating 65% hindrance for the methyl group compared with what it experiences in the methylpyridinium ion; in the transition state, the nitrogen atom is seen as having an effective charge of +0.43."

SCHEME 4

Lee" has reviewed (ca 40 references) the more important aspects of secondary adeuterium kinetic isotope effects involving deuteriated nucleophiles, especially in relation to mechanistic criteria based on cross-interaction constants. Williams'2 examines the topic 'the diagnosis of concerted organic mechanisms' in a short review (ca 35 references). He looks at the energy considerations involved, the exclusion of stepwise mechanisms, and finally some systems under current study. The latter include examples of phosphoryl, sulfonate, and carbonyl group transfer, and a brief look at substitutions at carbon and cyclical and elimination reactions.

2 Reactions of Acids and their Derivatives

39

For reactions involving [2.1. Ilcryptates of organolithium compounds (1 1) as metallating agents during transmetallation, acidity scales of a series of CH acids in a range of solvents have been developed at 25 OC.13 The pK, values lie in the range 10-33. A thermodynamic analysis of the effect of the various solvation interactions on acidity has been undertaken. The energetics of the enol form of acetic acid (12) in aqueous media have been exarnined.I4 The acidities of N-H bonds in 15 carboxamides in DMSO, and the homolytic bond dissociation enthalpies for these bonds, have been derived by Bordwell’s group.’’ The average pKHAfor five aliphatic carboxamides is 25.5, and the average bond dissociation enthalpy is 45 1 kJ mol - I . The use of ethyl trifluoroacetate (13) to protect selectively primary arnines in the presence of secondary arnines, and for mono-hctionalization of diamines, has been described.I6 Intramolecular catalysis is supported by several competition experiments carried out with various secondary mines.

(b) Esters (i) Formation The kinetics of esterification of mono-5-methylheptyl phthalate (14) with 5methylheptanol to give bis(5-methylheptyl) phthalate in the presence of sulfuric acid have been investigated in an isothermal semi-batch reactor. The reaction appears to be first order with respect to (14).” Benzoyl chloride or benzoic anhydnde acylates p nitrophenol in the presence of hexachlorocyclotriphosphazatrieneand triethylamine. * The kinetics of the esterification of terephthalic acid (15) with isooctanol over SnC12type non-acid catalysts were studied.’’ The activation energy for the process was 40.22 kJ mol Scandium trifluoromethanesulfonate, Sc(OTQ3, is a new highly effective acylation catalyst.20It has been shown to be highly effective in the acetylation of octan-2-01 with acetic anhydride to give the ester (16). The acetylation and benzoylation of menthol (17) are greatly facilitated with Sc(0TQ3. Alcohols were protected by esterification with

’

’.

Organic Reaction Mechanisms I995

40

C02H

I

Me

I

Me(CH2)s -CH-OAc

acids of the type (18) and the resulting esters could be chemoselectively deprotected.” A review (1 1 references) on the use of iron(II1) chloride in esterification has appeared.22 (ii) Transesterijcation Lipase-catalysed transesterification of w-phenylalkan-1-01s (19) with vinyl acetate (Scheme 5) in organic solvents gives the products (20). R may be phenyl or cyclohexyl and n = 1 4 or 5 for R = phenyl. The most reactive substrate is (19; R = Ph, n = l).23 Transacylation (0-+N acyl transfer) in 1-isopropylamino-3-(1-naphthoxy)propan-2-01 (21; R1 = OAc, R2 =NHPri) to give [21; R’ =OH, R’ = N(Ac)Pr’] proceeds via an anionic tetrahedral intermediate of the type (22). Hydrolysis competes with tran~acylation.~~ The application of iron(II1) chloride in transesterification reactions has been reviewed.*‘ 0 II R(CH2),0H + CH2=CH-O-C-Me

0

__f

II R(CH2),0-C-Me (20)

SCHEME 5

The effectiveness of a series of alkylguanidinium ions containing appended nitrogen bases (23;R = H, CH2CH2NMe2,etc.) and (24) in the transesterification of the RNA model 2-hydroxypropyl p-nitrophenyl phosphate (25) has recently been examined.25 The phosphoryl transfer reaction of (25) gave p-nitrophenol and the cyclic phosphate ester (26). Phosphorus oxychloride-mediated transesterification of alkyl carbamates to aryl carbamates gives reasonable

41

2 Reactions of Acids and their Derivatives R’ I OCH2CHCH2R2 I

H

NHR

NHR (23)

\c””

cNH

MeNHC02R

+ POC13

ArOH

MeNHC02Ar

SCHEME 6

(iii) Other reactions

AM1 semiempirical quantum mechanical calculations using the Langevin dipole solvent model have been made for reaction pathways in the gas phase and in polar solution for the cleavage of phenyl acetate by hydroxide ion and by b-cyclodextrin. Experimental results can be reported using the solvent The question of concerted or stepwise mechanisms in the acyl-transfer reactions of p-nitrophenyl acetate was examined using isotope effects as indicated earlier.3 A mechanistic change from ElcB to BAc2 in the alkaline hydrolysis of aryl 2hydroxycinnamates (27)has been detected from a biphasic Brsnsted type plot with PI = - 1.11 and p2= -0.25 for various phenolate leaving groups in (27). These esters with good leaving groups gave a P value of - 1.11 , consistent with ElcB hydrolysis; at pK,, > 6, the lower Brarnsted slope is ascribed to a BAc2 process.28A kinetic study of the saponification of methyl 2-chloro-4(dimethylaminosulfonyl)phenoxyacetate (28) has been rep~rted.’~ Some saponification studies of industrially important diesters have been rep~rted.~’ The alkaline hydrolysis of ethyl 2-(2’-benzimidazoly1)acetateand ethyl 3-(2’-benzimidazolyl)propionate has been assessed in DMSO-H20 and dioxane-H20

mixture^.^'

The hydrolysis of the a-benzoyloxystyrenes (29; X =Me, H, C1, NOz) in strong acids proceeds by an AAc2 mechanism up to 5.5 M HC104. The evidence includes a Bunnett w parameter of f7.6 and a Bunnett and Olson 4 parameter of + 0 ~ 4 The . ~ k~E 2 o / k D 2 0 ratio is 0.72 and p = -0.6 using CT+ constants. Above 5.5 M HC104, ktr,o/ku,o is 3.32, p is - 1.60, the rate is linear with the Ho function, and the mechanism changes to

Organic Reaction Mechanisms I995

42

involve slow olefin protonation. Acid hydrolysis of n-amyl formate, HC02(CH2)4Me, in aqueous DMSO, aqueous propan-2-01, aqueous acetone, aqueous dioxane, and aqueous ethanol has been studied.33 The kinetics and mechanism of acidic, basic, and neutral hydrolysis of 1-aryloxyethyl alkanoates (30) have been examined.34 An AALl mechanism involving an alkoxy carbocation (31) is indicated in acidic media, whereas in basic media attack of HO- at the carbonyl carbon gives a B ~ c mechanism. 2 In neutral media (PH 2.5-8.8), attack of a water molecule on the acyl carbon is rate-determining. Protonated methyl acetate undergoes slow acyl-oxygen cleavage even at - 78 "C (much faster at -20 "C) in FS03H-SbF5-S02 solution to give acetyl cation and methyloxonium ion35 (Scheme 7). The formation of a gitonic dication (32) from 1,ldimethoxyethyl cation (33) is proposed based on studies in deuteriated media. Theoretical calculations at the MP4(SDTQ)/6-3 lG*//MP 2/6-3 1G* level were performed on these mono- and di-activated ester systems.

0 11 RC-OCH(Me)OAr

'OH

II

MeC-OMe

H+

H+

'OH II +

MeC-OMe

H

0 I1 + RC-OCH(Me)

-

SCHEME I

c

MeCO+ + MeOH2

2 Reactions of Acids and their Derivatives

43

The hydrolysis of p-nitrophenyl acetate in aqueous solution (PH 3-8) is accelerated by two orders of magnitude by ultrasonic irradiation. The role of supercritical water in the sonolytic hydrolysis has been assessed and a dynamic heat-transfer model presented.36 The first step in the neutral hydrolysis of bis(4-nitrophenyl) oxalate (34) in aqueous acetonitrile proceeds by a BAc3 mechanism judging from solvent isotope effects and the effects of solvent on rate.37The second step, involving reaction of (35), is much slower owing to the retarding inductive effect of the carboxylate group. Imidazole-catalysed reaction of (34) proceeds with successive release of the two p-nitrophenyl groups and involves the formation and breakup of 1,l'-oxalyl diimidazole (ImCOCOIm) and the tetrahedral intermediate (36). Solvent and substituent effects for the hydrolysis of methyl salicylate and methyl 0-,m-, and p-methoxybenzoates in aqueous organic solvents have been studied.38 Semiempirical MO calculations using the PM3 method have been performed for the reactions of acetate esters with phenolate anions. The mechanistic change from breakdown to formation of the anionic tetrahedral intermediates on the reaction pathway have been examined for the acetates and for formate esters.39 The rates of reaction of the esters 4-nitrophenylbenzoate (37; X = Y =O), S-(4nitropheny1)thiobenzoate (37; X = 0, Y = S), and 0-(4-nitrophenyl)thiobenzoate (37; X = S, Y =0)with alkoxides, aryloxides and thioaryloxides in ethanol at 25 "C have been mea~ured.~' Replacement of Y =O by Y = S in the substrates (37) had little effect, but replacement of X = 0 by X = S in (37) reduced the rate by a factor of 10. Reactivity differences are attributed to polarizability effects. The same workers have recently reported some aminolysis studies (using secondary cyclic amines) with (37; X = 0, Y =0) and (37; X = S , Y=O). The slow step for reaction of (37; X = S , Y=O) depends on the basicity and concentration of amine; it changes from loss of proton from tetrahedral intermediate (38) to give T- (39), to formation of (38) when the amine concentration of becomes high.4'

(35)

(34)

0 0I1 I ArO-C -C -0Ar If ImH

(36)

(37)

Using Hammett, Bransted and cross-interaction constants, novel mechanistic criteria have been derived for various S, reactions including SNl, diss-SN2,concert-SN2,SAN and a ~ s - S ~The 2 . ~same ~ group has looked at the aminolysis (piperidine, Et,NH, and

Organic Reaction Mechanisms 1995

44

Et3N) of benzoate esters in acetonitrile and propose an enforced SAN mechanism.43 Reaction of diethyl 5-X-2-furoylmalonates (40) with secondary amines (EtZNH, piperidine, pyrrolidine, morpholine and 1-phenylpiperazine) gave products of type (41). No nucleophilic substitution of X by the amines occurred.44 The kinetics of the reaction of imidazole (Im) with 4-nitrophenyl chloroacetate and dichloroacetate (42) in acetonitrile, and acetonitrile with 0.56 mol dmp3 added water, show terms that are first and second order in [Im]. The first term represents nucleophilic reaction by Im and the second is due to general base-catalysed nucleophilic reaction by I ~ . ~ ~ Neutral and anionic forms of hydroxylamine are the strongest known acyl-group acceptors. This conclusion was drawn from a study of the reaction of hydroxylamine

S-

I

S-

+/

I

/

I

\

Ph-C-N

Ph-C-NH I \ OAr

OAr

(38)

(39)

CH2=CHCH2CH(CO*Et)2

(43)

@*&do 0

CH2 =CHCH2C(Me)(CO*Et)PO(OEt)2

1-0

0H

(44)

(45)

0

0

II RC-C(=NOAc)C02Et I R

(46)

(47)

0-

2 Reactions of Acids and their Derivatives

45

with 4-nitrophenyl acetate, p-toluenesulfonate, diethyl phosphate, and diethyl ph~sphonate.~~ The iodo-lactonization of unsaturated carboxylic esters containing a-ethoxycarbonyl and a-diethoxyphosphoryl groups, i.e. (43) and (44), has been studied.47 The oiodosobenzoate (45)-catalysed hydrolysis of a series of benzoate esters occurs by a nucleophilic mechanism in which the rate-limiting step is the collapse of the tetrahedral intermediate (46) which forms by attack of (45) on the ester. FT-IR has been used to detect the presence of the reaction intermediate formed between (45) and the ester.4x Acylium ions form in the decomposition in neat polyphosphoric acid of the aacetoximino keto esters (47; R = Me, Ph, phenylalkyl, cyclopropyl, 3,4,5-trimethoxyphenyl, e t ~ . ) . ~ ~ (c) Lactones and derivatives Di-y-lactone dihydrocanadensolide (48) ring opens in base to give the monolactones (49), (50), and (51) by parallel routes involving hydrolysis to (49) and (50) and a fielimination perhaps via an ElcB mechanism to give (Sl).” The hydrolysis rates are much faster than predicted by models, and an unusual intramolecular interaction which arises froin steric effects is suggested. Further hydrolysis of (50) is normal giving (52) and the hydrolysis of (49) probably proceeds via the &lactone (53). Irradiation in TFE of carboxyalkyl-substituted pyran-4-ones (54) gave reactive oxyallyl zwitterions and cyclization of the pendant carboxyl onto the electrophilic terminus of the oxyallyl system gave the fused bicyclic cyclopentenone lactones (55).5’ The complete mechanistic course of the atropo-selective ring opening of the axially prostereogenic biaryl lactone (56) by a chiral oxazaborolidine-BH3 reagent was investigated by semiempirical AM1 calculation^.^^ The reactions of soft (thiols, acetic acid, bromide) and hard (alcohols, benzylamine) nucleophiles with the 2,3-aziridino-y-lactones (57) and (58) have been studied and the reactivities compared with those of aziridine-2-carboxylic esters with the same nucleophiles. MNDO calculations can predict the regioselectivity of nucleophilic attack on (57) and (58).’? (d) Acids and anhydrides A reasonable correlation exists between gas-phase acidities, calculated by MNDO for 15 aliphatic carboxylic acids, the net atomic charges on the acidic hydrogens in the neutral form, and the net atomic charges and ionization potentials of the anions. There was no correlation between the gas-phase acidities and HOMO and band gaps.54 Theorctical linear solvation energy relationship descriptions have been used to model solute-solvent interactions that influence the acidity of substituted acetic acids [59; X = H , simple alkyl, branched alkyl, OMe, SMe, Ada, %Me3, CbFs, C1, NMe2, CI(CH&, C6H5, CF3, F, Br, CN, CH2=CH, SC6H5, OC6H5, etc.] in different solvents.55 A multilinear regression (MLR) analysis approach is used to generate an equation with the descriptors V,, n,,cB, q - , EA, and q+. Predicted and experimental acidities show good agreement for 25 acids in seven solvents (H20, MeOH, EtOH, iPrOH, DME, EG, t-BuOH). Six monocarboxylic acids (60), (61), and (62) have been

Organic Reaction Mechanisms 1995

46 Bu I H

H02C

<

-

Me

(49)

Bu

Me

(53)

cr

Me0 \ /

Me (56)

N Cbz

AC

(57)

prepared with I3C isotopic enrichment in the carboxylic acid groups and their pK, values were then determined at low concentrations ( 5 M) in H 2 0 and H20(CD3)2S0 mixtures by analysis of pH-dependent chemical shifts. The pK, values were all in the range 4.14.8. The xanthobilirubic acid (62; n = 2) and the nomanthobilirubic acid (62; n = 1) are bilirubic analogue^.^^ Two papers from the same group have examined the reactivity of cc,P-unsaturated In the first paper, the kinetics of the reactions of 2-substituted cyclohex-lenylacetic acids (63) with diazodiphenylmethane in 11 alcohols were correlated using the Hammett equation and op constants. These results have been compared with those for ortho-substituted phenylacetic acids.57 The same reaction in 10 different alcohols with 2-phenylcyclohex-1-enylcarboxylic acid (64) was investigated in the second paper.58A multiple linear correlation of log k with the Kirkwood function of relative permittivity, f(E,), the Taft o* for the alkyl group of the alcohol and the number of y-hydrogen atoms was successful.

2 Reactions of Acids and their Derivatives

47

n=1,2

The kinetics of chlorination in a semi-batch reactor of propanoic acid with chlorosulfonic acid have been investigated at 70-130 "C. 2-Chloropropanoic acid was the main product and the 2,2- and 2,3-dichloro acids were by-products. Propanoyl chloride is the key intermediate and the rate-determining steps are the acid-catalysed enolization of the chloride and the Chlorination of the enol form.59 In the presence of a tin-lead solder, the thermolytic decomposition of citric acid leads to 2-hydroxyglutaric, citraconic, itaconic, and aconitic acids and anhydndes as products. Products were examined by solid-state 13CNMR and by solution I3C NMR.60 The acid-catalysed hydrolysis of phenyldiazoacetic acid (65) has been examined at 25 "C and a wide range of acidities. Reaction occurs through both (65) and its ionized form (66) with the latter reacting 650 times as fast as (65).61 The mechanism involves rate-determining proton transfer to the diazo carbon atom of the substrate. A pK, value of 3.70 has been derived from the kinetics for (65). Thus the diazo group (by comparison with the pK, of 4.32 for phenylacetic acid) has a slight acid-strengthening effect. Potassium phenolate ions, solubilized in chlorobenzene by 18-crown-6, react with acetic anhydride to yield phenyl acetates (Scheme 8). In the same way, potassium acetate displaces the phenolate ion from phenyl acetate. Thus both forward and reverse stages of Scheme 8 can be studied. The rate constants for each process could be correlated in Brmsted equations in which pK, values for phenols in water were used.

Organic Reaction Mechanisms 1995

48 ArO-

+ Ac20

-4

ArOCOMe

+ AcO-

SCHEME 8

The equilibrium constant for the transfer of the acetyl group between phenolate ions and acetic anhydride has a Brmsted Peqvalue (chlorobenzene) of 2.6. Comparison of this value with the beqvalue of 1.7 for the same equilibrium in water shows that there is a greater development of effective charge in chlorobenzene, consistent with its weaker solvating power.62 Leffler (a) indices of 0.33 and 0.62 for the reaction of phenolates with acetic anhydride in water and chlorobenzene, respectively, indicate more advanced bond formation in the transition state of the reaction of the latter, although the reactions are faster in water. Conversion of the 2-(t-butyldimethylsilyloxy)phenylacetic acid (67) into its 3 3 dinitrobenzoyl mixed anhydride (68), followed by reaction with a-azido esters and trialkylphosphines, afforded a strategy for obtaining good yields of peptides without much epimer formation for reactions involving Phe-Val and Val-Val linkages.63

(e) Acid halides A number of papers dealing with acid halide reactivity have been more appropriately placed in the later section Reactions in Aprotic Solvents.

(f) Ureas, carbamates, hydroxylamine, and derivatives

The AM1 method has been used to calculate the dynamics of hydrolysis of nitrourea (NH2CONHN02)in neutral, acidic and alkaline media. In neutral and acidic hydrolysis, the activated complexes have a four-membered ring structure.64EROS 6 (Elaboration of Reactions for Organic Synthesis) is a computer program system for the prediction of organic reactions. This system has now been employed to allow quantitative predictions for the hydrolysis of benzoylphenylureas (69) and amides under acidic and basic condition^.^^ It has been possible to predict half-lives for hydrolysis of some benzoylphenylureas including some that are important agrochemicals. Building on work reviewed66ahere last year, German workers have subjected the reactions of organic isocyanates with alcohols and phenols, giving carbamates,

OSiBu'MeZ

2 Reactions of Acids and their Derivatives

49

allophanates (70), and isocyanurates (71), to further scrutiny.66b At equimolar isocyanate : alcohol (phenol) ratios, carbamates are favoured. At high ratios of isocyanate to alcohol (phenol), the isocyanurates (71) are the only final products formed via carbamate and allophanate as detectable intermediates. The transesterification of alkyl to aryl carbamates (Scheme 6)was discussed earlier.26 Using the extended two-term Grunwald-Winstein equation: log klko = IN

+my +c

the solvolysis of N,N-diphenylcarbamoyl chloride (72) has been investigated. An 1 value of 0.23 and an m value of 0.58 support an SNl pathway for the solvolysis, with extensive internal nucleophilic assistance and weak nucleophilic solvation of the developing carbocation. Sensitivity to changes in solvent nucleophilicity and product selectivities in aqueous ethanol and methanol closely follow those for the solvolysis of p-methoxybenzoyl chloride (73), which has been established as reacting by an SNl mechanism.67

RNHCON(R)COzR’ (70)

RN

K

ANX0

0

R

Ph2NCOCI

(72)

(71)

3

COCl

I

OMe

0 II ArS02NHC -0Ar’

(74)

ArS02NHCON (75)

A detailed study of the hydrolysis of aryl N-(substituted phenylsulfony1)carbamates (74) at 50 “C in the pH range 0-13.5 has been made by French workers.68The products are benzenesulfonamides and phenols. Reaction at pH > 5 shows no change with pH and the authors favour an ElcB elimination-addition mechanism involving the anien of (74) and the sulfonylisocyanate ArS02N=C=0, which was trapped with piperidine to give N-(piperidinocarbony1)benzenesulfonamide (75). In the acidic pH region, general acid catalysis (a = 0.46) is observed. Two papers from McClelland’s group on the rearrangement69and hydrolysis7oof Uaroyl-N-acetyl-N-(2,6-dimethylphenyl)hydroxylamines (76) have appeared. Rearrangement of (76) leads initially to 1,5-dimethyl-5-aroyloxy-6-N-acetyliminocyclohexa-l,3-

Organic Reaction Mechanisms I995

50

dienes, which react in aqueous solution producing m-aroyloxy- and m-hydroxy-2,6dimethylacetanilides (77) in an acid-catalysed reaction, while non-catalysed reaction gives the corresponding para products (77).69The cyclohexadienes are seen as model intermediates that may form during the metabolism of certain carcinogenic amines; (76) hydrolyses in aqueous solution by slow ionization to a nitrenium-carboxylate ion-pair intermediate (78). These intermediates then react by various paths.7o

(77)

(78)

Four papers have appeared on hydroxamic acids. An Indian group has continued its studies on the hydrolysis of hydroxamic The application of the excess acidity method to the hydrolysis of N-benzylbenzohydroxamic acids (79; X = H, Me, NOz, F) in HCl solutions in dioxane-H20 (10 : 90, v/v) indicates that an A2 mechanism is f ~ l l o w e d . ~Kinetics studies on the alkaline hydrolysis of N-phenylbenzohydroxamic acid have been carried out in various solvents and solvent mixtures.72 The kinetics of alkaline hydrolysis of N-phenylfurohydroxamic acid in the same medium at 65 “C was studied. Rate-limiting formation of a tetrahedral intermediate is the critical step.73 0Alkylhydroxamic acids (80; R = R’ = H; R = Ph, R’ = H; R = R’ = Me) readily give good yields of phenylseleno-substituted 1,4,2-dioxazines (81) or N-acylisoxazolidines (82) in acetonitrile in organoselenium-induced cyclizations in which the oxygen atom of the carbonyl group or the nitrogen atom acts as nucleophile leading to the two ringclosure reactions. The formation of these products is kinetically and thermodynamically controlled, respective~y.~~

’

(g) Amides, anilides, lactams, and lactims The EROS 6 computer program has been used to make predictions for the hydrolysis of amides and benzoylphenylureas (see earlier).64Ab initio MO calculations at the RHF/63 1 G(d) level have been made for the base hydrolysis of N-methylformamide. The tetrahedral intermediate formed has to undergo conformational transitions before the reaction can proceed with the elimination step. The preferred elimination mechanism leads to methylamine and formate ion.75 Sonication (50 kHz) of argon-saturated aqueous mixtures of N,N-dimethylformamide was investigated by spin trapping using 3,5-dibromo-4-nitrosobenzenesulfonateand EPR dete~tion.’~ Both methyl radicals and N,N-dimethylformamide radicals (83) were spin-trapped over a wide range of substrate concentration.

+

2 Reactions of Acids and their Derivatives

51

The hydrolysis of acrylamide (84) and methacrylamide (85) in aqueous sulfuric acid (up to 46%) has been studied over the temperature range 65-85 "C; (85) hydrolyses more rapidly than (84).77The kinetics of the oxidation with trichloroisocyanuric acid of formamide, acetamide, benzamide, and 4-nitrobenzamide are first order in the oxidant and show a fractional order in the amide. The medium was acetic acid-sodium acetate buffer. The reaction is pH-dependent and the rate increases linearly with increase in concentration of acetate The gas-phase elimination reactions of N-benzoyl- and N-acetyl-propanamide (86) and N-benzoyl- and N-acetyl-2-methylpropanamide(87) are unimolecular first-order processes. Polar factors are more important than steric in these p y r ~ l y s e sStudies . ~ ~ on the acid-catalysed cyclization of N-phenyl-2-methyl-2-(2-aminophenyl)propanamides (88) suggest that reaction occurs via slow concerted attack of the neutral amine and proton transfer from a general acid to the amide oxygen leading to the tetrahedral intermediate (89) and finally to the cyclized product (90)." Water hydrolysis of several activated amides (91; R' = R2 = Ph; R' = Et, R2 = Bu'; R' = Ph, R2 = H) in aqueous solution is significantly retarded by a-phenylalanine whereas other a-amino acids not containing a benzyl group in their side-chain produce rate accelerations. The large hydropholicity of a-phenylalanine is responsible for this difference and these results are of importance in understanding protein folding and molecular recognition processes.81 Benzoylthioamide (92) can be formed by reaction of (N,N-dimethylthiocarbamoy1)lithium, Me2NC(S)Li, with methyl benzoate or b e n d On reaction with LDA at -78 'C, (92) cyclizes to the P-thiolactam (93) which, on reaction with ozone, gives good yields of p-lactam (94). This is an important new route to ,0-lactams.R2 The maleic anhydride acylation of substituted anilines in various solvents has been studied kineti~ally.~~ BAc2 hydrolysis of penicillanic acid (95) under basic conditions at 25 "C is supported by b-secondary and solvent deuterium isotope effects. The slow step is formation of the tetrahedral intermediate (96). An AAC1 mechanism is supported for acidic hydrolysis with unimolecular fission of the protonated lactam ring as the slow step.84Acylation of the amine nitrogen of 6-aminopenicillanic acid (6-APA) has led to the preparation of a spin-labelled penicillin (97) with the nitroxy spin label, 2,2,5,5-tetramethyl-loxypyrro~ine-3-carboxy~ic acid. From use of electron nuclear double resonance (ENDOR) it has been possible to determine the principal hyperfine component of specific protons in the two rings. The ENDOR-assigned conformation of the spinlabelled penicillin is almost the same as the X-ray-defined structure of amoxycillin. Some light has also been thrown on the mechanism of a-lactam hydrolysis from the ENDOR ~pectra.'~A three-step reaction mechanism has been proposed in the perfluoroalkylation of 2-pyrrolidinone (98) by 2-(perfluoroalkyl) 1-iodoethanes (99) giving 2-(perfluoroalkyl)ethanols (100) in 95% yield. The steps are (i) O-alkylation of (98) to give a lactim salt, (ii) N-substitution of salt by another molecule of lactam to form a tetrahedral adduct, and (iii) breakdown of this adduct to (100) and an iminolactarn saht.% The reactions of arylimines (Schiff bases) (101) of l-tetralone with substituted acetyl chlorides (102; R=CI, PhO, PhCH20, MeO, EtO) in the presence of triethylamine gives p-lactams of type (103). The reactions are highly stereo~elective.~~

Organic Reaction Mechanisms I995

52

0

CH2N(Me)CH0

II CH2=CH-C-NH2

0 11 CH2=C(Me)-C-NH

0 0 II II EtC-NH-CR

0

0

II

Me2CHC-NH-CR

II

(87)

R = Ac, Ph

H I’.”-!y”aOMe \

-

OH

(89)

0 s

II I1 PhC-CNMe2 (92)

p Sh j i \ Me

(93)

C0,-

phj3A\ (94) Me

53

2 Reactions of Acids and their Derivatives

Two competing pathways control regioselectivity in the reaction of a-lactams with nucleophiles. With good nucleophiles (unhindered primary or secondary amines) attack at the carbonyl group occurs leading to the rearranged a-aminoamides (104). Poor nucleophiles (Cl-, N;, H20, hindered secondary amines) result in ring opening to give an azaoxallyl cation ion pair (105) which then reacts at C(2) with nucleophiles to give 2-substituted amides (106); C(2) substituents which can stabilize positive charge speed up ion-pair formation favouring the latter mechanism, but electron-withdrawing substituents encourage ring opening and carbonyl addition. Several unsymmetrical urea peptide mimetics have been prepared with regiochemical control by taking account of these factors.88

Me+=gp:' l00-lSO"C

R F C H ~ C H ~+I

Me

Me 0

co*-

(98)

I

6

H I

0

5-60 h

RFCH~CH~OH

(100)

(99)

(97)

n

+ RCH2COCl

Et3N

&-Ar

(104) SCHEME 9

(h) Non-heterocyclic nitrogen centres The reaction ofpara- and meta-substituted benzoic acids with dicyclohexylcarbodimide (107) gives initially in a slow step the highly reactive intermediate (not isolated)

Organic Reaction Mechanisms 1995

54

0-acylisourea (108). Benzoate ion attacks the carbonyl carbon of protonated (108) giving the anhydride (109) and urea (110). A curved Hammett plot from the reaction has been rationalized in terms of the acid strength of the benzoic acids and the amount of anion present.89

0

Arc-0-CAr

I1

0

II

+

II

c - C ~ HINHCNHC~HI I 1-c

0

Thermal decomposition of 2-dimethylamino-3-methylbenzoyl azide (111) unexpectedly produced the isomeric cyclized product 1,1,7-trimethylindazol-3-yliooxide (112) instead of an isocyanate.” The electronic structures of the aryl isocyanates (113; X = H , Me, C1, Br, NH2, CN NO2) were calculated by the EHMO method. The nucleophilic reactivity of these compounds could be linked to the positive change on the C atom in the NCO group. The nucleophilic addition of HNCO and H 2 0 was also studied theoretically.” MINDO/3 MO calculations have been used to study the mechanism of the consecutive addition of HCN to propionitrile. The results indicate that the first of five steps is rate-determining and that the reaction is ex other mi^.'^

Q NCO

I

x

(i) Other heterocyclic nitrogen centres Ammonolysis and pyrrolidinolysis of phthalimide (114) in buffered solutions have been studied; the former reaction was found to include a second-order term in the kinetics while the latter showed second- and third-order terms. Both nucleophiles showed

2 Reactions of Acids and their Derivatives

55

reactivity towards ionized phthalimide only within the pH range of the reported study. Intramolecular general base-acid catalysis occurs.93 In other work by the same group, the hydrazinolysis of (114) was found not to follow linear kinetics; plots of kobs vs [total hydrazine buffer] were downward curved at pH 7.85-9.06. The mechanism is stepwise, involving the zwitterionic and anionic tetrahedral intermediates shown in Scheme 10.~~

The acid hydrolysis of diazepam (11S), used in various psychiatric treatments, gives principally 2-(N-methylamino)-5-chlorobenzophenone (1 16) and the hydrolysis in MeOH-H20/HCI of (1 16) has now been studied.” The kinetics of enolization and of degradation of N-(5-methyl-4-isoxazolyl)-4-amino-l,2-naphthoquinone (117) have been examined at 35 “C in the alkaline pH region at constant ionic strength. The experimental points fitted a theoretical pH-rate profile fairly well, based on a rate equation which includes terms for the spontaneous (water) catalysis rate constant, the tautomerization constant, the specific basic catalysis rate constant, and the fraction of (117) existing as the enolate anion. The main product is 2-hydroxy-l,4-naphthoquinone.96 The HO--catalysed hydrolysis of securinine (118), a major alkaloid from Securinega, involves lactone ring opening. The hydroxycarboxylate product (1 19) undergoes cyclization in acidic medium to give (118) again.97The HO- hydrolysis of (118) involves a tetrahedral intermediate (120) and acid cyclisation back to (118) involves the intermediate (121). Ceftazidime (122), a semi-synthetic broad-spectrum cephalosporin, has been studied under hydrolytic conditions in the pH range 0.5-8.5 at temperatures from 45 to 65 0C.98 The mechanism of the general acid-catalysed thiolytic cleavage of 9anilinoacridinc (123) with 2-mercaptoethanol (HSCH2CHZOH) has been probed. A Brarnsted slope (a)of 0.93 has been obtained and a slow step involving proton transfer

56

Organic Reaction Mechanisms I995 0 II

Me

MP

is therefore suggested.99 Hydrolysis of N-[CI-benzotriazol-1-yl)benzyl]aniline derivatives (124) proceeds via an A-SN2 mechanism based on kinetics, solvent, substituent, and salt effects, observation of general base catalysis, and product analysis. Above pH 13 the mechanism becomes simply S N loo ~ . Intramolecular double Michael reaction of the amide esters (125) gave, via a stepwise mechanism, indole[2,3a]quinolizines stereoselectively. They form a common fiamework of indole alkaloids.lo' Engberts, Blandamer and co-workers have been able to describe the effects of added salts and alcohols (ethanol, propanol) on the hydrolysis in aqueous solution of 1benzoyl-l,2,4-triazole (126) in terms of painvise and triplet Gibbs interaction parameters (Scheme 11).Io2 The isomerization and kinetics of acid hydrolysis of 9(1 -methoxy-2-hydroxypropyl)carbazole(127) diastereomers have been investigated.lo3 Hydrolysis proceeds by an A1 mechanism with the formation of a fi-hydroxycarbenium-immonium ion in the slow step. The threo isomer was thermodynamically more stable than the erythro isomer because of intramolecular hydrogen bonding. The kinetics and mechanism of hydrolysis at 25 "C in H 2 0 over a wide pH range of 5,6dihydro- 1,4-thiazine derivatives (128) have been examined.lo4 The final hydrolytic product was the enol(l29). Electron-donating substituents (X) in (128) accelerated the formation of (129). Reactions in Aprotic Solvents Some papers that might be appropriately placed here have already been discussed earlier. Thus, the reactions in acetonitrile of the bis(4-nitropheny1)oxalate (34),37the aminolysis of benzoate esters in a ~e toni tril e ,~~ the reaction of imidazole with the chloroacetates (42) in a~etonitrile,4~ the derivation of Brmsted Peq for the reaction of

2 Reactions of Acids and their Derivatives

57

NHPh

I

SCHEME 11

I

H

CH2CH(OH)CH20Me

(127)

Ac

58

Organic Reaction Mechanisms 1995

phenolate ions with acetic anhydride in chlorobenzene (Scheme 8),62rearrangement of hydroxylamines in a~etonitrile,~'and formation of dioxazines (81) and isoxazolidines (82) in acetonitrile have been dealt The n-butylaminolysis of substituted phenyl acetates in chlorobenzene in the presence of crown ethers obeys the rate law

+

rate = k, [BuNH2I2[ester] k2[BuNH2][crown][ester] the individual rate constants k, and k2 give negative PIgvalues of - 0.75 and ca - 0.60, respectively, when plotted against pK, for the ionization of phenols in H2O.Io5"These /Ieqvalues can now be calibrated using the peqvalue from reference 62. The data for the kl reaction is consistent with slow proton transfer from a zwitterion-crown ether adduct (130) to base and, for k2, rate-determining formation of this adduct with fast ArO-C bond fission is occurring. The mechanism of reaction of phenyl dithiobenzoates (131) with anilines (XC6H4NH2)in acetonitrile at 55 "C has been examined by Lee and cow o r k e r ~ .A ' ~Px(finuc) ~~ value of ca 0.9 and the signs of the various cross-interaction constants (pxy > 0, p y z < 0, and pxz > 0) are consistent with rate-limiting breakdown of a zwitterionic tetrahedral intermediate (132) in which amine expulsion is favoured. Aminolysis of the thiophenes (133) with n-butylamine, benzylamine, pyrrolidine, and piperidine in benzene at 20 "C has been studied.'06 The tetrahedral intermediate (134) is involved. The kinetics of the aminolysis of 9-isothiocyanatoacridine (135) in acetonitrile, dioxane, and ethyl acetate with a series of 12 aromatic and five aliphatic/ alicyclic amines, giving (136), have been studied. The acridine undergoes reaction about two orders of magnitude faster than phenyl isothiocyanate. Steric effects are important in the reaction of the aliphatic/alicyclic amines. lo7 The kinetics of aminolysis of benzoyl fluorides in dioxane, CC14, cyclohexane, isooctane, diethyl ether, CHC13, THF, and acetonitrile have been studied by Satchell's group."' The kinetic behaviour is different to that found for aqueous solution. Tetrahedral intermediates such as (137) may be involved and their breakdown is ratedetermining. The aminolysis of benzoic anhydrides (138; X = H, C1, MeO) in dioxane at 25 "C with various amines has also been studied by this group. The effects of twelve salts on the aminolysis by 4-dimethylaminopyridine in y-butyrolactone and propylene carbonate of N-(4-~hlorophenyl)benzirnidoyl chloride (139) were studied."' All salts accelerated reactions except chlorides which retarded it. 18-Crown-6 suppressed completely the accelerating effect of NaBr. In acetonitrile solution, the aminolysis (morpholine, pyrrolidine, azetidine) of (2)-0-methylbenzohydroximoyl chlorides (140) to give the corresponding (2)-aldoximes (141) occurs via an addition-elimination mechanism with rate-determining loss of chloride ion (AN&,& from the tetrahedral intermediate (142)."" The kinetics of solvolysis in MeOH-MeCN and aminolysis (anilines) in MeCN of cinnamoyl chlorides (143) at 25 "C have been studied by Lee's group."' For methanolysis, an SN2-like dissociative mechanism is supported by py+ = - 0.9 to - 1.5. For aminolysis py values are in the range +0.52 to t-1.64 and p x values (X in anilines) range from - 1.68 to -2.51; PX = 0.6-0.9 and pxy = 0.88. The mechanism involves a slow breakdown of the tetrahedral intermediate (144).

2 Reuctions of Acids and their Derivatives

59

N=C=S

ArC(Cl)=NOMe

(140) 0-

I

Y C6H4CH=CH-C-C1 YChH4CH=CHCOCl

I

H2N+C6H4X

R I R ~ N C O ~H-& R I R ~

(143)

Reaction of various carbamate anions (145) in acetonitrile with alkyl chlorides to give R'R2NC02R3 has been examined.'" This is an important new route to urethanes that avoids the phosgenelisocyanate technology. The reactions of the dipent-4-enyl acetals (146) with Br+ or I+ leads to the oxocarbenium ions (147); if these are captured by a diol, the mixed acetal(148), which could in firther reaction give the cyclic acetal (149), results. Acetonitrile was used as solvent for these reactions.

60

Organic Reaction Mechanisms 1995

Intramolecular Catalysis and Neighbouring-group Participation The alkaline hydrolysis kinetics of ethyl 2-(2'-benzimidazolyl) acetate (150; n = 1) and of ethyl 3-(2'-benzimidazolyl)propionate (150; n = 2) in DMSO- and 1,4-dioxanewater have been e~amined.~' With an increase in DMSO content the observed rate constants go through an irregular bell-shaped curve. Intramolecular general base catalysis by the benzimidazolyl group and intermolecular specific base catalysis by HO- occur. In further studies by the same group,''4 intramolecular general base catalysis is observed in the hydrolysis of ethyl 3-(2'-benzimidazolyl)-3-hydroxypropionate. Intramolecular nucleophilic substitution of the tetrapeptide (151) gives cyclization to (152) which can ring open to (153) or revert back to (151) (Scheme 1 31 1'5 ILJ.

Neighbouring-group participation by the amide group in (154) facilitates the acid hydrolysis of the methyl ether linkage by a factor of at least 1.7 x 103-fold compared with the reference compound (155) where such an opportunity does not exist. An A2 mechanism is supported by the ASf value of -32.6 J mol- IS-',the kinetic isotope ratio for the acid hydrolysis ranges from 0.55 to 0.72, and the Bunnett and Olsen 0 parameter is 0.78.'16 The effect of the cationic micelles CTABr on the intramolecular general basecatalysed hydrolysis of ionized phenyl salicylate has been examined at different temperatures.' l 7 Simultaneous carboxylate and carboxyl group participation in the hydrolysis in water (pH 2-7) of the phosphate diester (156) has been demonstrated by Bruice et ~ 1 . " The ~ rate enhancement of (156) over (157) is lo9. The 0-CO; group acts as an intramolecular nucleophile and the role of o-C02H group is as a general acid. Several possibilities are discussed for the mechanism and comparisons made with various types of phosphate diester analogues. In another example of rate enhancement in phosphate

2 Reactions of Acids and their Derivatives

61

SCHEME 12

chemistry, intramolecular nucleophilic attack by a metal-bound hydroxide ion enhances the rate of hydrolysis of the phosphotriester (158) by factors of 6.0 x 105;I19 1 : 1 complexes of (158) with the divalent metal ions (Zn2+, Cu2+, Co2+, and Ni2+) were prepared and reacted at 25 “C at pH 8.0 and reaction was monitored by the release of 4-nitrophenolate ion accompanied by (159).

Association-prefaced Catalysis ‘Cystomimetic organic chemistry: early developments’ is the title of a review article (50 references) by Menger and Gabrielson. 120 The review deals with aspects of supramolecular chemistry vesicles. A new 1 1-volume series’2’ entitled ‘Comprehensive Supramolecular Chemistry,’ with Lehn as Chief Editor, has been announced. The topics covered will be molecular recognition receptors for cationic and molecular guests, supramolecular reactivity and transport in bioorganic and bioinorganic systems, solidstate supramolecular chemistry, crystal engineering and two- and three-dimensional inorganic networks, cyclodextrins, physical methods in supramolecular chemistry,

62

Organic Reaction Mechanisms 1995

templating, self-assembly and self-organization, and molecular devices and applications of supramolecular technology. Several nucleophilic (&2, SNAr)processes achieved with HOP, N;, and CI-/Br have been examined in the presence of the cetyltrimethylammonium surfactants CTABr, CTACl and CTAOMs. The results have been analysed in terms of both coulombic and specific interactions of ions with aqueous ionic micelles using the Poisson-Boltzmann equation. This model differs in several ways from the more generally employed pseudophase model and some advantages of the present approach are pointed out. The three bimolecular processes studied were (i) alkaline hydrolysis of the benzoates (160; R = 2-naphthyl, Bu'O) giving ROH, (ii) Cl-, Br-, and N; attack on n-butyl-4-nitro-, 4-bromo- and 4-methyl-benzenesulfonates (161; X = NO2, Br, Me) giving the appropriate benzenesulfonate ion and n-butyl chloride, bromide and azide, and (iii) substitution by HO- and N; of 2-chlor0-3,5-dinitropyridine.'~~ The effect of CTABr on the hydrolysis of ionized phenyl salicylate, which reacts via intramolecular general base catalysis, has been examined. Raising the micelle concentration from 0 to 0.12 mol d r K 3causes the rate to decrease 5-6-fold, but raising the temperature from 20 to 58 "C increases the rate from 7.1 x 10K5 to 123 x lop5 s-' in addition to decreasing the salicylate anion-micelle binding constants from 7100 to 5000 dm3 mol-'. In the hydroxide-catalysed hydrolysis of acetyl salicylate ion in the presence of sodium dodecyl sulfate (SDA) micelles at a constant [HO-1, the observed rate constants follow the empirical relationship /cobs = C+ F [SDSIT where [SDSIT is the total micelle concentration. The magnitudes of C and F increase with increase in ~

''

2 Reactions of Acids and their Derivatives

63

The effect of hexadecylpyridinium chloride on the hydrolysis of p-nitrophenyl acetate, propionate, and butyrate (162; R = H, Me, Et) have been treated in terms of the pseudophase model.'24 Compounds (162; R = H, Me) have also been hydrolysed by HO- in the presence of CTABr and differing catalytic effects, even inhibition, have been noted. An ammonolysis reaction hitherto overlooked has been 0 b ~ e r v e d . The l~~ effects of the micelles DTAB, TTAB, CTAB, SDS, Brij-35, and Triton X-100 on the alkaline hydrolysis of aromatic and aliphatic acid esters have been reported. 126 The rate of hydrolysis of 2-nitro-4-trimethylammoniophenyl2-picolinate (163; 2substitution) is enhanced remarkably when catalysed by a Cu2+ complex of surfactant imidazole ligand [(164), (165), (166), and (167)] possessing 2-hydroxymethyl and anionic charged groups in the co-micelles of SDS. A reactive ternary complex of structure (168) is proposed as the critical intermediate. The 3- and 4-picolinates (163) react much slower than the 2-picolinate.127 Both cationic and anionic surfactants gave rate inhibitions in the acid-catalysed hydrolysis of N-p-chlorophenylbenzohydroxamicacid (169).12*The activity of 5(6)-nalkyl-2-(mercaptomethyl)benzimidazoles (170) towards p-nitrophenyl esters has been investigated in the presence of CTABr.'29 Esterolytic activity was also displayed by a novel polymer catalyst, imprinted by a transition-state analogue, in the esterolysis of p nitrophenyl N-(benzyloxycarbony1)-L-leucinate (171) in 10% v/v dimethyl ether-Tris buffer (PH 7.15) at 20-35 "C. The catalyst, represented in (172), was imprinted from the phosphonate (173).13" Dodecyl(dimethy1)phosphine oxide, a non-ionic surfactant, when added to aqueous CTABr inhibits the micellar-mediated reaction of bromide ion with fully bound methyl naphthalene-2-sulfonate (174). The results were analysed in terms of the pseudophase model. Interactions between the surfactants were examined using 'H and 31PNMR.13' The rate of the spontaneous hydrolysis of 2,4-dinitrophenylphosphate dianion (1 75) is

"i

64

Organic Reaction Mechanisms 1995

65

2 Reactions of Acids and their Derivatives

strongly increased by cetyltrialkylammonium bromides and tetraquinuclinium bromide. Betaine sulfonate micelle (176) also speeds hydrolysis. 13’ The hydrolysis of p-nitrophenyl diphenyl phosphate by dichloroisocyanuric acid sodium salt in borate buffer at pH 8.9 micellar phase has been reported.’33 The acid hydrolysis of 1-phenylethyl nitrite (177) has been studied in water and in aqueous micellar solutions of SDS. The effect of various ureas in both environments has also been probed.134 Use of AM1 semiempirical calculations to examine reactions of phenyl acetate in water were mentioned p r e v i o u ~ l y .These ~ ~ calculations were also used to study the reaction of the alkoxide ion of P-cyclodextrin (p-CD) with bound phenyl acetate. Large acceleration effects have been observed in the cleavage of p-nitrophenyl amethoxyphenylacetate (178) by mono-6-(alkylamino)-~-cyclodextrins.The meta isomers in p-CD are more reactive than the para isomers in p-CD rnedia.l3’ A cyclization study of L, D- and L,L-0-methyltyrosyl-p-nitrophenylalaninemethyl esters in the presence of P-CD showed that only the L,L-isomer reacted.’36

r-NHOH

A series of modified p-CDs has been prepared using the a-nucleophiles hydrazine, hydroxylamine, oxime, and hydroperoxide functionalities. Transacylation studies using p-nitrophneyl acetate have shown that the primary side hydroxylamine (179) shows the highest reactivity with a 1900-fold increase in rate compared with p-CD it~e1f.I~’ Amino-substituted a- and p-CDs have been prepared in related work and found to have significant acceleratory effects in the hydrolysis of p-nitrophenyl acetate but not in the hydrolysis of the m-nitro isomer.’38 Tee’s group has published four papers on CD work during the period of this review. Substrate binding and transition-state binding with P-CDs in the cleavage of m- and pnitrophenyl alkanoates in basic media has been looked at. ‘39The meta compounds react through a transition state involving aryl group interaction (180), while many of the para isomers react with acyl group inclusion (181). Additives such as ROH, RCO-, and RSO, catalyse the basic hydrolysis of p-nitrophenyl alkanoates by fl-CD.’B, The reactions of 1- and 2-naphthyl acetates (182) with a-, p-, and y-CD and hydroxypropyl-

Organic Reaction Mechanisms 1995

66

8-CD (Hp-P-CD) in basic solution all show saturation kinetics. Differences in behaviour are examined in terms of the relative importance of transition-state and initial-state binding and structural variations in the CDs used.'41 In cognate work, CI-, b-, and Hp-b-CD have been used in the basic hydrolysis ofp-nitrophenyl alkanoates (up to Clo) in trifluoroethanol.142 Differential scanning calorimetry (DSC) has been used to examine mixtures of esters of benzoic and 4-hydroxybenzoic acid with heptakis(2,6-di-O-methyl)-~-cyclodextrin (DMBCD). Two endothermic peaks were observed on the DSC curves.143p-CD forms 1 : 1 and 1 : 2 inclusion complexes to catalyse the hydrolysis of thep-nitroanilides of the peduoroalkanoic acids (183; n = 1-3, 5-7). For the 1 : 1 complexes, the peduoroalkyl chain inserts into the CD cone while for the 1 : 2 complexes the aryl unit is inserted.'44

HNCO(CFZ)~CF~

I

In an interesting paper from Tee's group, it is proposed that two different CDs, dimethyl-P-CD (dm-8-CD) and pCD, cooperate by bimodal recognition of different parts of m- and p-nitrophenyl alkanoates and 1- and 2-naphthyl acetates. When allowance is made for reaction with each of the CDs including a cooperative third-order process, which may have the termolecular transition state shown (184), the calculated rate constants give a straight-line plot against the observed values, thus vindicating

2 Reactions of Acids and their Derivatives

67

Tee’s treatment of this interesting phenomenon. A similar plot, which ignores cooperation of the pair of CDs, deviates substantially from a straight line.’45 Reactions of three methylfluorophosphonates with CL-, ,!?-,and y-CDs in hydrolysis reactions have been i n~e st iga te d.’~~ Metal-ion Catalysis The kinetics of the alkali metal ion-catalysed nucleophilic displacement of p nitrophenyl benzoate with ethoxide ion in ethanol have been reported. The rates decreased on addition of a metal ion-complexing agent such as a crown ether.’47 The rate of hydrolysis of the 2-picolinate (163) is remarkably enhanced by a Cu2+ complex as discussed earlier. A ternary complex (168) has been proposed.’27 Use of a chelating amine, N-benzyl-N’,N’-dimethylethylenediamine, yields acrylamide and acrylate ester adducts, demonstrating significant hydrolysis (up to 1.5 x lo4fold) by Cu2+ at pH 7.5 at room temperature.I4* A polyamine-zinc(I1) complex (185) with an alcohol pendant group promotes the hydrolysis of diethyl (4-nitropheny1)phosphate (186) via transfer of the diethylphosphate groups to its alkoxy pendant; see (187).’49 The hydrolysis of uridylyl(3’,5’)uridine (188), promoted by Zn2+, Mg2+ and Zn2+[12]aneN3, ([ 12]aneN3 = 1,5,9-triazacyclododecane) has been studied in imidazole, N-(2-hydroxyethyl)piperazine-N’-(ethane-2-sulfonicacid), and 2,2’,2-nitrilotriethanolbuffers. A bifunctional mechanism occurs15oin which there is coordination of the metal ion to the anionic phosphodiester and intracomplex general base or nucleophilic catalysis by its hydroxy ligand. The dinuclear zinc(I1) complex with N,N,N’,N’-tetrakis(2-pyridyl)methyl-2hydroxy-l,3-diaminopropane (189) is an efficient hydrolysis catalyst for adenylyl(3’,5’)adenosine at pH 7 and 50 “C. This complex is much more efficient than the corresponding mononuclear analogue. It can be looked upon as a good artificial ribonuclease which can mimic the active centres of enzymes and act as a guide for the design of active sites of artificial ribonucleosides.15’ The hydrolysis of 4-nitrophenyl phosphate (190) is catalysed by lanthanide(III)(2.2.l)cryptate complexes (191). There is a good correlation between the pH dependence of the rate constants and the concentration of the lanthanide(2.2.l)hydroxides pointing to its involvement as a nucleophile. About a 104-foldrate enhancement was achieved.152 Cooperative catalysis by lanthanum(II1) ion and non-lanthanide metals ions (Fe3+, Mn3+, Sn4+, In3+ and Ga3+) has been observed in the hydrolysis of bis(4-nitropheny1)phosphate (1 92).’53 This work throws some light on the reaction mechanism of natural phosphodiesterases and phosphomonoesterases. The stereochemical course of tungsten-promoted cyclocarbonylations to give five- to seven-membered lactone rings has been examined;‘54see also reference I 8 1. Decarboxylation

MNDO-PM3 calculations have been performed to probe the decarboxylation of 2methyl-2-ethyl-(2’-pyridyl)acetic acid (193). The transition-state geometry of the reaction possesses the following key features: (i) the activation enthalpy is 6.0 kcal mol-’; (ii) the dihedral angle C(S)-C(7)-C(2)-N is 50.2 ”; and (iii) the

Organic Reaction Mechanisms 1995

68

0

II

~ - 0 2 N C h H 4 0-P-OEt

I OEt

0 OH I

O=P-0I

o v OH OH

n

Co c1wowN

co 0 1 Ln’iO’)

3

u (191)

(192

interatomic distances 0-(9)-H(1’) and C(7)-C(8) increase by 11 1% and 124%, re~pectively.’~~ There have been two reports on the decarboylation of benzisoxazole-3carboxylic acid (194). Ab initio MO calculations, which have included one or two water molecules in the transition state, have been carried out. The decarboxylation and ringopening steps are concerted, giving COZ and (195).’56 In other work, what is effectively an automated procedure for simulating chemical reactions in solution has been developed using a Monte Carlo quantum mechanical and molecular mechanical (QMi MM) simulation method and this has been tested on the decarboxylation of (194).lS7 The predicted free energy of activation is virtually in agreement with the experimental value of 109.9 kJ mol-’.

2 Reactions of Acids and their Derivatives

69

The kinetics of the pyrolysis of acids (196), (197), and 2-, 3- and 4-chlorobutyric acids in the presence of a free-radical inhibitor (cyclohexene or toluene) have been investigated. Reactions are first order and unimolecular. In this study, the mechanisms of pyrolyses occumng when the chlorine atom is at different positions along the carbon chain of aliphatic acids has been studied.'58 Decarboxylation and decarbonylation processes took place. The decarboxylation of oxalic acid in sulfuric and phosphoric acid has been studied using I3C and I4C kinetic isotope effects.'59 The oxidative decarboxylation of cyciohexanecarboxylic acid was initiated by H202. The process is a non-branching chain reaction. Cyclohexanone and cyclohexanol form in termination reactions.16' The stereochemical course of malonate decarboxylation in Malonomonas rubra has been researched.I6' Malonate is decarboxylated by malonate decarboxylase with retention of configuration and this agrees with the stereochemistry observed for other biotin-containing decarboxylases. Enzymic Catalysis General

A review (170 references) in French on enzymic catalysis in organic media has appeared. The current and future potential applications of biocatalysis in organic media are discussed.'62 Breslow has written an account of 'biomimetric chemistry and artificial enzymes: catalysis by design' (75 reference^).'^^ Serine Proteinases

A perfect enantioselective catalysis for the hydrolytic cleavage of p-nitrophenyl Ndodecanoyl-D(L)-phenylalaninates has been achieved using the modified enzyme decanoyl-a-chymotrypsin (198). 64 The enzymatic activity of a-chymotrypsin, modified with monomethoxypolyethylene glycol, has been examined in the reactions of esters different from the natural substrates of the enzyme. Information on the subsites of the enzyme has been obtained from these reaction^.'^^

'

Organic Reaction Mechanisms I995

70

A general model for enantio-recognition by esterases, based on some new crystalstructure data, has been proposed recently. Esterases carry out nucleophilic attack on the si face of the ester bond in all cases.166 The regioselectivity of N-nucleophilc addition to N-carbonyl-protected dehydroalanines (199) can be totally controlled by varying the N-protecting groups or the carboxy protecting groups.'67 Lipases Lipase-catalysed transesterification (Scheme 5) was discussed earlier.23 Monoaminolysis of diesters (200) by amino alcohols (201) is catalysed by lipase from Candidu anturcticu.'68 The main product is the amido ester (202).

Penicillin Enzymes The structure of isopenicillin N-synthase, an enzyme that catalyses the key step in penicillin biosynthesis, has been determined. 169 This enzyme catalyses the critical stage in penicillin biosynthesis, i.e. the oxidative reaction in which the p-lactam and thiazolidine rings are made from a linear tripeptide precursor. A detailed reaction mechanism has been proposed for the enzyme. Phenoxymethylpenicillin 3-aldehyde (203) is a good substrate for E. cloacae P99 plactamase, despite lacking a 3-carboxylate group.'7o A short review of the reactivity of fi-lactams with phosphonamidates and the reactions with 8-lactamase has appeared (25 references).

'

Other Enzymes Some in vitro studies of the mode of action of the thioesterase of the erythiomycinproducing polyketide synthase show that it cleaves ester groups by forming acylenzyme intermediates. '72 This enzyme has a wide substrate specificity. Urease, the first nickel-containing metalloenzyme, which catalyses urea hydrolysis, has had its crystal structure determined. The active site of the enzyme contains two nickel atoms 3.5 A apart from one coordinated with three ligands and the other with five. The catalytic mechanism is believed to involve reaction of urea with one nickel atom and subsequent attack on the urea's carbonyl group by HOP ligand of the second nickel atom.'73 O-(a-Acylamino-2-styrylacryloyl)-~-fi-phenyllactates (204) and (205) have been examined as substrates for carboxy peptidase A. They are regarded as the link connecting non-specific and specific esters. The k,,, value for (204), (205), and the various non-specific and specific esters are independent of pH and this common kinetic feature indicates that rate-determining breakdown of an anhydride intermediate is occ~rring.'~~ A series of esters (206) and amides (207) undergo oxidative cleavage in the presence of purified isoforms of liver microsomal cytochrome P450 in a reconstituted enzyme system.'75

2 Reactions of Acids and their Derivatives

71

The stereochemical course of the Malonomonas rubra malonate decarboxylase decarboxylation of malonate was briefly mentioned earlier.161The decarboxylase is a biotin-containing acetyl-enzyme. The malonate exchanges with the enzyme-bound malonyl thioester which undergoes decarboxylation regenerating the acetyl-enzyme. The increased consumption of the carboxylates (208) in the presence of the protein avidin is due to a specific bimolecular acyl-transfer reaction. 76 Lerner's group has reported antibody-catalysed phosphate triester hydrolysis. A series of antibodies were screened for their catalytic ability to hydrolyse the triesters (209) and (210). Five antibodies to each hapten were catalytic. Antibody Txl-4C6, though limited in its substrate range, was particularly effective with (209) and (210).'77

NON-CARBOXYLIC ACIDS Phosphorus-containing Acids Non-enzymic Reactions

(a) Phosphates, phosphoryl transfer; phosphonates The involvement of substrate-cation complexes is indicated in the acid-catalysed hydrolysis of diethyl2-pyridyl phosphate (21 1) and the basic hydrolysis of N-methyl-8(dimethylphosphory1oxy)quinolinium ion (212), since the observed rates depend on the nature of and quantity of cation present in the buffer.I7' The transesterification of the RNA model 2-hydroxypropyl-p-nitrophenylphosphate (25) has been discussed earlier.25 Simultaneous carboxylate and carboxyl-group participation in the hydrolysis of the phosphate diester (156) has also been mentioned earlier.' The metal-catalysed hydrolysis of the phosphotriester (158) which experiences ca 6 x 105-fold acceleration was dealt with earlier."' Three other examples of metal-catalysed hydrolysis of phosphates have been discussed earlier, namely diethyl 4-nitrophenyl phosphate (1 86),'49 4-nitrophenyl phosphate (190),"* and bis(4-nitrophenyl) phosphate (192).'j3 Micellar catalysis was observed with the substrates 2,4-dinitrophenylphosphate dianion (175)132and p-nitrophenyl diphenyl phosphate. 1 3 3 The use of hydroxylamine anion as an effective a-nucleophile has been illustrated in reactions with 4-nitrophenyl diethyl phosphate (186) and 4-nitrophenyl diethyl phosphonate (213).46 The iodo-lactonization of the phosphonate (44) was described earlier.47 Heavy-atom KIEs have been utilized to study the transition states for phosphoryl transfer for the phosphodiestersp-t-butylphenyl p-nitrophenyl phosphate (214) and 3,3dimethylbutyl p-nitrophenyl phosphate (215).179The " 0 and "N isotope data indicate early transition-state structures for the aqueous hydrolysis of the two compounds, with little bond cleavage to the leaving group. With phosphodiesterase I from snake venom, significant differences in the transition states for reactions of (214) and (215) were noted. The effects of fluoride ion on the hydrolysis of the three dialkyl aryl phosphates (216), (217), and (218) and on dimethyl phosphorofluoridate (219) have been assessed.'" Fluoride can act in three ways: (i) as a powerful nucleophile, it catalyses the

72

Organic Reaction Mechanisms 1995

wx

PhOCH2CONH

0

CHO

(203)

1.11

Ph

1

Ph

0

11 RC-OEt

(206) R = H, alkyl

2 Reactions of Acids and their Derivatives

I

0

73

0

reaction with the substrate giving a reactive phosphorofluoridate intermediate; (ii) for substrates where leaving-group departure is acid-catalysed, fluoride acts as an inhibitor by diminishing the medium acidity; and (iii) the metallic ion (accompanying F-) can enhance the electrophilicity of the phosphorus atom via complexation to the phosphoryl group. A truly remarkable rate enhancement of ca 1013 in phosphonate ester hydrolysis catalysed by two metal ions has been observed by Tsubouchi and Bruice.lgl The bis(2quinolyl) phosphonate (220) ligates two La3+ ions. This 1 : 2 complex of (216) and La3+ has the ideal geometry for intra-complex catalysis of the hydrolysis of the ester P-0 bond, judging from X-ray data and theoretical calculations. One lanthanum ion is associated with both the negative charge on the PO; group, and the departing CH20'leaving group, while the second La3+ is complexed to the PO; and an HO-, which is in alignment for an in-line nucleophilic attack on phosphorus. The product of the hydrolysis is 8-hydroxy-2-quinolylmethanol. The hydrolysis of (220) in the absence of ~ a was ~ so + slow that it was necessary to estimate it at ca 5 x s-' at p~ 8, whereas the catalysed reaction gave a rate constant of 1.36 x l o p 3 s-I, hence the outstanding enhancement of ca A fuller paper on this and related work from the same group has since appeared. Interestingly, the 'mono' compound, i.e. (X-hydroxy2-quinoly1)methyl methyl phosphonate (221), forms hydrolytically inert 1 : 1 complexes with Ida3+.Free La3+ ions will, however, catalyse its reaction. Strong imbalances in the transition states of the reaction of substituted phenoxide ions with bis(4-nitrophenyl) phenyl phosphonate (222) in aqueous and aqueous DMSO solvent mixtures, due to solvation effects, are believed to be the cause of the curvature of Brransted plots for the reactions in various solvent mixtures. Those plots are linear (PnucM 0.7) using pKa values for the leaving phenolates, but then at high pKa values they suddenly display strong downward curvature and more or less plateau. The changeover point does not correspond to the pKa value of the departing p nitrophenolate, suggesting that the explanation for the break is not the usual one; i.e. a change in the rate-determining step of a two-step process involving a Ppentacoordinate intermediate.ls3 The Buncel strategy was used in this study.lS4 The reaction of three methylfluorophosphonates (isopropyl, 1,2,2-trimethyl, and cyclohexyl) (223) with a-,p-, and y-cyclodextrins has been in~estigated.'~'

Organic Reaction Mechanisms 1995

74

0

0 E

W

~-O

-

LI O

-

I

To-P-0-

0 I

O 2 N OO - P ( O MII e ) 2

0

R I

MeO-P=O

I

F

(223)

75

2 Reactions of Acids and their Derivatives

(b) Other phosphorus functions Evidence for a three-coordinate intermediate, the fluoroenylidineoxophosphorane (224), has emerged from a study of the nucleophilic reaction of the phosphonamidic chloride (225; R2CH = 9-fluorenyl) with Et2NH. The substitution at oxygen is very fast and discriminates less than is usual with competing Me2NH. The mechanism involves loss of proton on the fluoroenyl a-carbon and elimination to give the phosphene intermediate (224), and there is a subsequent fast reaction with Et2NH as nucleophile to give the phosphonic diamide (226; R2CH = 9-fl~oroenyl).'~~ The thermolysis of 0-ethyl N-mesityl- (227) and 0-ethyl N-phenyl-phosphoramidates (228) in anhydrous ethanol at 80 "C involve proton transfer from the OH group to the nitrogen moiety. A metaphosphate-like transition state or 'exploded' SN2(P) transition state is proposed for the solvolysis of (227). Being less bulky, an earlier transition state in the unimolecular process or a change to an AIE mechanism is likely for (228). These conclusions were drawn from solvent kinetic isotope effects and I4N/l5N KIEs for these reactions.'86 The phenoxy-substituted phospholidine (229) reacts with p-anisidine to give the salts (230) and (231), showing that only ammoniolysis takes place. Aminolysis products such as (232) and (233) did not form. The mechanism is seen as being A/E with deprotonation of the zwitterionic intermediate (234) as the critical step. 87 The rate of reaction of p-nitrophenyl diphenylphosphinate (235) with the anucleophile butane-2,3-dione monoximate (236) and a 'normal' nucleophile, 4chlorophenoxide (Scheme 13), has been studied at 25 "C in aqueous DMSO. The magnitude of the a-effect k ~ 2 3 6 ) l k 4 - c ~ cshows 6 ~ o - a bell-shaped dependence on solvent composition and goes through a maximum of ca 40 at 50 mol% DMSO. The observation of the bell-shaped dependence is attributed to the effect of advanced desolvation of the oximate (236). Tarkka and B u n ~ e l used ' ~ ~ their own strategy (see below) to analyse the data. A kinetic study, using 'H NMR, has been made of the reaction (Scheme 14) between ethyl pyruvate (237) and diethyl phosphite, yielding 2-diethoxyphosphonyl-2hydroxypropionic acid ethyl ester (238); AS' was ca - 135 J mol-' K-', suggesting a bimolecular r n e cha ni~m.'~~

'

Enzymic reactions Stereochemical, mechanistic, and structural features of enzyme-catalysed phosphate monoester hydrolysis have been recently reviewed (35 references)."* The sub-headings of the review reflect the coverage: enzyme models and the role of metal ions; alkaline phosphatase; acid phosphatase; purple acid phosphatase; inositol monophosphatase; Dfructose 1,6-bisphosphate 1-phosphatase; 5'-nucleotidase; and protein tyrosine and protein serine threonine phosphatases. The kinetics of hydrolysis and interconversion of 5'-0-pivaloyluridine-2' and -3'dimethyl phosphates (239) and (240), respectively, over the pH range 0-9 have been studied."' Mono-cationic and mono-anionic phosphorane intermediates are proposed on the reaction paths. The metal ion-promoted hydrolysis of uridylyl(3/,5/)uridine(188) was considered earlier. 50 The hydrolysis of isomeric cytidylyl-(3',5')5'-C-methylur-

'

Organic Reaction Mechanisms 1995

76

Me+NH-!-OH

7

OEt I

Ph-NH-P-OH I OEt

Me

(227)

NOH 0 I II MeCH--C -Me

(236) OH

I

MeCOC02Et + (Et0)2P(0)H4 (EtO),P(O) -C -C02Et

I

Me

(237)

(238) SCHEME 14

idines (241; R’ = H, R2 = Me; R’ =Me, R2 = H), promoted by H30f, HO-, Znzf, Gd3+, and various macrocyclic tri- (242) and tetra- (243)/(244) aza-chelates of Zn2+ has been reported. 192 An alternative mechanism, that reproduces the experimental data for the hydrolysis and isomerization of 3’J’uridyluridine and related dialkyl phosphates in aqueous

2 Reactions of Acids and their Derivatives

0

OH

77

HO

I O=P-OMe I

0

I

O=P-OMe I OMe

OMe

(240)

(239)

SCHEME 15

0

I O=P-0I

OH

B’ = cytosine B2 = uracil

F?

CHzOH U

0\p/o 0 -’

1

‘0OR

(245)

78

Organic Reaction Mechanisms 1995

morpholine buffers, has been proposed by Perrin.lY3A key feature of this mechanism is the involvement of a dianionic phosphorane (245). Recently, the classical general acidbase mechanism, rather than the triester-like mechanism, for ribonuclease A has been supported.lY4 In current work, the importance of medium effects in Breslow's mechanism for the hydrolysis of RNA and various derivatives has been highlighted, based on measurements with the acetal ester of uridine-3'-phosphate (246), whose leaving group, p-02NC6H4CH20H,has a pK, value near to that of the 5'-OH of a ribose derivative and which breaks down rapidly to release p-nitrophenol. IY5 The non-existence of a proton-transfer process in the cleavage of RNA by hammerhead ribozyme is supported from kinetic evidence, based on solvent isotope effects. The substitution reactions of amines with phosphoimidazolide-activated derivatives of guanosine and cytidine occur by replacement of the imidazole group. This process has been studied with a series of primary and secondary aliphatic amines; Brarnsted plots for the aminolysis have been c o n s t r ~ c t e d . ' ~ ~ The reactivity of four-membered cyclic phosphonamidates such as (247), and the inhibition of p-lactamase by them, has been reviewed briefly by Page et ~ 1 . ' ~ '

Sulfur-containing Acids (a) Sulfur-oxygen compounds Ab initio MO calculations have been performed on the gas-phase hydrolysis and methanolysis of methanesulfonyl chloride. A concerted Sp~2process with a trigonal bipyramidal transition state is supported. The role of solvent molecules is assessed.'" Molecular-mechanism calculations on several benzenesulfonyl chlorides have been r e ~ 0 r t e d . IThe ~ ~ main reaction of 2-methyl-2-propanesulfonylchloride (248) in H20 (PH 3.5-13), or in MeOH-CDC13, is ionization to the t-butyl cation and chlorosulfite anion ClSO;, followed by hrther reactions of these.*" Later products include t-butyl chloride and alcohol, isobutene (249) and, at high pH, 2-methyl-2-propane-sulfinate (250) and -sulfonate (251) anions. 4-Nitrophenyl p-toluenesulfonate (252) has been reacted with hydroxylamine anion. S N 2 reaction of methylnaphthalene-2-sulfonate (174) with Br- under micellar conditions was mentioned earlier. 3 1 The reaction of p-nitrophenyl benzenesulfonate (253) with substituted phenoxide ions in aqueous DMSO mixtures at 25 "C, with release of p-nitrophenoxide and formation of the sulfonates (254), has been

2 Reactions of Acids and their Derivatives

79

examined.201 The authors have used the data to construct traditional type Brernsted plots, in which the phenoxides were varied while the solvent was held constant and secondly, novel 'Buncel-type' plots in which variation in phenoxide pK, was imparted by varying the solvent rather than the phenoxide. The first method yielded a family of Brernsted plots with Bnuc decreasing from 0.75 to 0.60 on varying the solvent from 40 to 90 mol% DMSO; this novel method yielded a single straight line with Bnuc = 0.60. The results were interpreted using the Marcus equation. Aminolysis reactions (N-methylaniline, n-butylmethylamine) of the alkyl sulfonates (255; R' = Cl2HZ5,R2 =Me; R' =Me, R2= CI2Hz5;R' = C7H15,R2 = C9H19)have been studied and some interesting variations in reactivity noted.202 Using Hammett, Brernsted and cross-interaction-constant data, novel mechanistic criteria have been derived for reactions of (mostly) sulfonate esters. Different signs and magnitudes of these parameters are associated with SNl, dissociative and associative S Nreactions, ~ SAN,and concerted SAN mechanisms. When it is possible to look at three or four of these constants together, this approach should be very helpful in assessing the finer nuances of substitution rne c hanism~ .The ~ ~ hydrolysis of aryl N-(substituted phenylsulfony1)carbamates (74) was discussed earlier." Peroxymonosulfate ion (HSO;) in aqueous acetonitrile readily converts aryl thiobenzoates (256) into carboxylic and sulfonic acids (Scheme 16). Reactions are second order and substituent effects are small ( p x - 0.6).'03 Reaction of 2-methyl-2-propanesulfenicacid (257) with methyl arylsulfenates (258) gives the condensation products S-aryl 2-methyl-2-propanethiosulfinates (259) quantitatively. Reaction is first order in each reactant and negative entropies of ca - 130 J mol-' K-' are observed. A Hammett p value of - 1.39 was obtained under

R'SO~R~

(255)

0 I/ ArC -S Ar'

Bu'SOH

ArSOMe

Bu'S(0)SAr

(256)

(257)

(258)

(259)

SCHEME 16

Organic Reaction Mechanisms 1995

80

acidic conditions. Initial protonation of the sulfenate ester followed by slow attack of the acid on the ester is considered to be the most likely mechanism.204 A study of the decomposition mechanism of alkylsulfenyl alkylsulfinyl thioanhydrides (260) has been made using (260; R = Bu'). The decomposition is complex and a detailed mechanism is proposed.205 Features include the involvement of a tbutylsulfinyl cation (261) and a t-butyl disulfide anion (262).

bH

t

0

In recent work, Okuyama206has obtained evidence that the ring-opening reactions of (263) and (264) involve hypervalent sulfurane-type intermediates (265), whereas ring opening of (266) does not involve such an intermediate. This important distinction is made on the basis of the fact that the hydrolyses of (263) and (264) are buffer-catalysed, whereas that of (266) shows no buffer catalysis. This work on attempts to detect hypervalent sulfur intermediates is the subject of a timely review (1 8 references) by O k ~ y a m a . ~Support '~ for such species was found for alkyl sulfenates (pH-rate profile and nucleophilic reactivity) and for sulfinamides (pH-rate profile and "0 exchange) (see next section). Additionally, the acid-catalysed reactions of methoxymethyl sul fenates and sulfoxide may involve such intermediates.

(b) Sulfur-nitrogen compounds A combination of hetero-nuclear NMR relaxation studies and ab initio theoretical calculations allowed relative basicities and sites of protonation to be determined for a number of sulfenamides RSNR2 and sulfinamides RS(O)NR2 (R = alkyl, ary1).208A break in the pH-rate profile at "0 exchange in the acid hydrolysis of the Narylbenzenesulfinamides (267; X = H, p-Me, p-MeO) has been interpreted in favour of a trigonal bipyramidal reaction intermediate (sulhrane) in the hydrolytic pathway.'09 A similar report involving the sulfinamides (268; R = H, Me; Ar = Ph and substituted phenyl) has appeared from Korean

2 Reactions of Acids and their Derivatives

81

Work on various types of sulfonamides has been reported in a number of papers; pKa values have been determined for a series of N-benzylbenzenesulfonamides (269; R=Ph, substituted phenyl) in DMSO and, in some cases, in water; they lie in the ranges 14.0-16.4 and 10.1-1 1.5, respectively.2" Rates in 50% viv aqueous MeOH for the hydrolysis of N-(benzenesulfony1)-C-(N-methylani1ino)imidoylchloride derivatives (270) have been studied. An S N l mechanism via an azacarbenium ion intermediate (PH < 9) and a nucleophilic addition-elimination mechanism (pH > 10) are favoured.212 The alkaline hydrolysis of a series of methyl 4-sulfamoyl-N-arylanthranilates(271) in dioxane-water at 45-85 "C has been rep~rted."~The kinetics of hydrazinolysis of the glutarimides (272; X = Meo, Me, H, Br, N02) giving (273) involves intramolecular hydrogen b ~ n d i n gl4. ~ The pKa values for a series of cyclic sulfamates (X-3H-1,2,3-benzoxathiazole-2,2dioxides) (274) in EtOH-H20 (60 : 40, v.v) have been determined potentiometrically and give a Hammett p value of 2.74.Ab initio calculations on sulfamic acid as a model were used to examine the effect of geometry changes on pKa. The calculations showed that sulfamates with ring-like geometry should be about 3.6 pKa units more acidic than acyclic sulfamates. The sulfamate (275) was reacted with the nucleophiles, imidazole, benzylamine, t-butylamine, azide, fluoride, pyridine, and hydroxide. No reaction was observed with pyridine; HO- attacked the endocyclic S atom and all the other nucleophiles attacked the exocyclic (tosyl) S Aminolysis (R'NH2) and hydrolysis in 50% vlv aqueous acetonitrile of a series of sulfamate esters (276) leading to sulfamide RNHS02NHR' and sulfamate RNHSO;.R'NH$ products, have been A pacylvalue of - 1.8 was obtained for a series of aromatic esters. The reaction was independent of amine type and concentration, and the reacting species was the anion of (276), which exists in the presence of excess amine. The mechanism is seen as being ElcB involving a sulfonylamine (RNH = S02) on the reaction path. The dimethyl sulfamate ester (277) did not react. (c) Other suEfur compounds The hydrolysis of methylthiazolium ions and slow breakdown of the resulting tetrahedral intermediate (9) leading to the enethiolate products (10) was discussed earlier.' In related work,217the hydrolysis of a series of thiazolium cations (278) has been shown to follow the reaction sequence (Scheme 17) where (279), (280), and (281) could be detected as intermediates. The most important representative of the thiazoles is thiamine pyrophosphate (vitamin B) and, in a follow-up study, the hydrolysis of thiamine at 25 "C over the pH range 0.5-10.5has been studied.*I8A series of equilibria involving the thiazolium cation (282), the pseudobase (283),and the ring-opened thiolc (284) have been examined using stopped-flow techniques. The oxidation with sodium perborate of 26 S-arylmercaptoacetic acids (285) to give the corresponding thiophenols has been studied in acidic media. A mechanism involving a protonated arylsulfinylacetic acid intermediate (286), which slowly rearranges to (287) and then loses a proton to give products, has been s u p p ~ r t e d . ~ ' ~ MO calculations on the structure and electronic properties of aryl thiocyanates (ArSCN) using both the semiempirical AM1 and MNDO methods and the ab initio

Organic Reaction Mechanisms 1995

82

c1

I PhS02N=C-N(Me)Ph (270)

C02Me H2NS02

1,

p-XChH4S02NHN H 0

NHAr

(272)

(271)

X

I H (274)

yyJJo* \ O2N

I

Ts

(275)

H HO H

tl

tl

2 Reactions of Acids and their Derivatives

83

3-21G and 6-31G** methods have been reported. Nucleophilic attack may occur at the cyan0 carbon in preference to the sulfur atom. The fungicidal activity of these thiocyanates did not correlate with simple molecular properties.220 Reaction of various S-methyldithiocarbonates (xanthates) (288) with rl-methyl(difluoroiodo)benzene (289) gives the corresponding alkyl fluorides (RF). This is thus an easy way to convert an alcohol (after making the xanthate) into a fluoride.22' The kinetics of NO group transfer between the nitrosothiol (290) and nine thiolate anions R'S-, mostly based on the cysteine structure, are second order. The reaction is depicted in Scheme 18. The pH-rate constant profile indicates that reaction occurs via the thiolate anion. Electron-withdrawing substituents in (290) promoted reaction.222

+

OH2

+

ArSCH2C02H

ArS(OH)CH2C02H

(285)

(286)

RSNO

+

R'S

I

ArSCHC02H

1287)

RS-

+ R'SNO

SCHEME 18

The rates of hydrolysis of the three benzoate esters (37) containing C-S bonds were discussed earlier!034' The nature of the transition state in the pyrolysis of N-thioacetylpropanamide (291), leading to (292) and (293), has been i n ~ e s t i g a t e d . ~ ~

84

Organic Reaction Mechanisms 1995

A route from acylthioamides to p-lactams was highlighted earlier,82 aminolysis of phenyl dithiobenzoates (131) was also discussed,’056and the esterolytic activity of the mercaptomethylbenzimidazoles (170) has been considered already.129 S II

MeC-NH-CEt (291)

0 II

S II

MeC-NHz (292)

MeCH=C=O (293)

Other Acids

Acid hydrolysis of 1-phenylethyl nitrite (177) in water and aqueous micellar solutions has been studied. 134 A new book entitled ‘Nitroalkenes-Conjugated Nitro Compounds’ (275 pp.) has appeared.223 The topics covered include biological applications of nitroalkenes and their relevance in the pharmaceutical and other industries, synthesis, reactions, and functionalized derivatives. The diastereoselectivity of nucleophilic addition to P-chiral acylsilanes, RC(Me)CH2C(0)SiMe3, has been utilized to prepare (inter aka) calcitriol lactone, a major metabolite of vitamin D3.224 References

’ Park, Y. S., Kim, C . K., Lee, B.-S., Lee, I., Lim, W. M., and Kim, W. K., .IPhys. 0%.Chem., 8, 325

(1995). Kellogg, B. A,, Tse, J. E., and Brown, R. S., . I Am. Chem. Soc., 117, 1731 (1995). Hengge, A. C . and Hess, R. A,, 1 Am. Chem. Soc., 116, 11256 (1994). Lee, I., Bull. Korean Chem. Soc., 15, 985 (1994). Lajis, N. H., Noor, H. M., and Khan, M. N., .IPharm. Sci., 84, 126 (1995). Castro, E. A., Cabrera, M., and Santos, J. G., In[. 1 Chem. Kinet., 27, 49 (1995). Castro, E. A., Muiioz, G., Salas, M., and Santos, J. G., Int. . IChem. Kinet., 27, 987 (1995). * Washabaugh, M. W., Gold, M. A,, and Yang, C. C., 1 Am. Chem. Soc. 117,7657 (1995). See Org. React. Mech., 1993, 19. in Jenkins, H. D. B., Kelly, E. J., and Samuel, C. J., Tetrahedron Lett. 35, 6543 (1994). I ’ Lee, I., Chem. Soc. Rev., 1995, 223. l 2 Williams, A,, Chem. Soc. Rev., 1994, 93. l 3 Antipin, 1. S., and Konovalov, A. I., Zh. Org. Khim., 29, 1505 (1993). l4 Krcsge, A. J., Chemtract.s: Org. Chem., 7, 318 (1994). Bordwell, F. G., Zhang, S., Zhang, X.-M., and Liu, W.-Z., J Am. Chem. Soc., 117, 7092 (1995). 16 Xu, D., Prasad, K., Repic, O., and Blacklock, T. J., Tetrahedron Lett., 36, 7357 (1995). 17 Skrzypek, J., Sadlowski, J. Z., Lachowska, M., and Turzanski, M., Chem. Eng. Process;, 33,413 (1994): Chem. Abs., 122, 55422 (1995). 1R Vapirov, V. V. and Tunina, S. G., Zh. Obshch. Khim., 64, 1256 (1994). 19 Liu, X., and Wu, T., Gaoxiao Huaxue Gongcheng Xuebao, 8, 195 (1994); Chem. Abs., 122, 264703 (1995). 20 Ishihara, K., Kubota, M., Kurihara, H., and Yamamoto, H., 1 Am. Chem. Soc., 117, 4413 (1995). ” Watanabe, Y., Ishimaru, M., and Ozaki, S., Chem. Lett., 1994, 2163. ” Yu, S., Huaxue Shiji, 16, 257 (1994); Chem. Abs., 122, 213188 (1995). 23 Nakamura, K., Kawasaki, M., and Ohno, A,, Bull. Chem. Soc. Jpn, 67, 3053 (1994). 24 Cockayne, G. A. and Taylor, P. J., 1 Chem. Res. (S), 1995, 21 I .

’

’’

2 Reactions of Acids and their Derivatives 25

85

Jubian, V , Veronese, A,, Dixon, R. P., and Hamilton, A. D., Angew. Chem., Int. Ed. Engl., 34, 1237

(1995). 26

27

” 29

30 31

32 33

34

”

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36

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5x 59

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CHAPTER 3

Radical Reactions: Part 1 A . J. CLARKand S . M . Room

Department of ChemisqJ. University of Wanvick Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Group Migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Scission (Ring Opening) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ring Expansion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intramolecular Addition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tandem Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radical Annulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fragmentation, Recombination, and Homolysis . . . . . . . . . . . . . . . . . . . . . Atom Abstraction Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydrogen Abstraction by Carbon-centred Radicals . . . . . . . . . . . . . . . . . . . Hydrogen Abstraction by Heteroatom-centred Radicals . . . . . . . . . . . . . . . . . Halogen Abstraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Addition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Addition to Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Addition to Oxygen-containing Multiple Bonds . . . . . . . . . . . . . . . . . . . . . Addition to Nitrogen-containing Multiple Bonds . . . . . . . . . . . . . . . . . . . . . Addition to Thiocarbonyl Bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Homolytic Substitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aromatic Substitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SH2 and Related Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactivity Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Polarity and Philicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stability of Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stereoselectivity in Radical Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . Stereoselectivity in Cyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stereoselectivity of Addition to Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . Stereoselectivity of Atom Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Redox Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radical Ions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anion Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cation Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Peroxides, Peroxyl, and Hydroxyl Radicals . . . . . . . . . . . . . . . . . . . . . . . . Peroxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Peroxyl Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydroxyl Radical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diazoalkanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Organic Reaction Mechanisms I995 . Edited by A . C . Knipe and W. E . Watts 0 1997 John Wiley & Sons Ltd

91

92 92 92

93

95 95

95

98 99 101

102 102 104

105 105 105

105

107 108 108 108

108

109 110 110 110 111 111 111 113 114 116 116 117 117 117 117 118 118 118

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Organic Reaction Mechanisms 1995

Introduction The stereochemical aspects of radical reactions, in particular radical additions and abstractions, continue to be an exciting area of research. In this area the effect of allylic strain on the ground-state conformations of radicals, their transition-state conformations, and the stereochemistry of addition to alkenes has been reviewed.' The mechanistic interest in radical cyclization and rearrangement reactions has also continued to be a rich area of research and has proved valuable in synthesis. 1,5-Bu3Sn group-transfer reactions from carbon and oxygen have been reviewed2 as have the kinetics of 5-endo-trig radical cyclization~.~ A review entitled 'open shell analogues of closed shell reaction paths: the SRN2'case and the Sm2 pathway-a mechanistic alternative for radicals in polar media?' has been written by Curran: a leading international radical chemist. A particularly useful and thorough review on redox-induced radical and radical-ion reactions in C-C bond formation has a ~ p e a r e d .Other ~ reviews include the kinetics of low-temperature combustion of alkanes,6 the factors which determine the activation energy of radical abstraction reactions,' the effect of spin stereochemistry on the formation of C-C bonds between reactive radicals in supercages,' and the kinetics of 'NO3 reactions with organic compounds in solution.'

Rearrangements Group Migration An in-depth mechanistic study of the rearrangement of (P-phosphatoxyl)alkyl radicals has been reported." Evidence was presented to show that migration does not occur via fragmentation to a cage pair and recombination. In addition, it was shown that phosphoranyl radicals were not involvcd. Instead, evidence from "0 and deuteriumlabelling studies indicated an intramolecular process proceeding via 1,2- and 2,3-shift pathways. Similar results were reported for (B-acyloxy)allyl radical migrations. These migrations when facilitated by Bu3SnH were suppressed by the addition of catalytic quantities of diphenyl diselenide." This is due to initial reduction to PhSeH, which rapidly reduces the intermediate radicals prior to migration. Neophyl rearrangements can also be suppressed using this method. 1,2-Migration of a pivaloyl group from the anomeric centre of (1) followed by stereoselective trapping of the anomeric radical with allyltributylstannane under photo-initiated conditions gives the ally1 nucleoside (2) (Scheme 1).l2 Other 1,2-migrations recently studied include 1,2-silyl migrations of CIsilyl-p-stannylalkoxy radicals (e.g. Scheme 2).13 These radicals, which were generated from 5-exo cyclization of a-stannylated radicals on to acyl silanes, undergo radical Brook rearrangement followed by ,&scission to give silyl en01 ethers. The 1,2-migration of F' in fluorinated cyclohexadienyl radicals has been studied by ESR.14 The neophyllike rearrangement of alkoxy radicals has been re-examined using laser flash and laser drop photolysis techniques.I5 The conversion of (3) into (4) was found to occur with an activation energy of 5.9 f0.4 kcal mol- I with the lifetime of (3) ca 400 ns (Scheme 3). Further studies found that the intermediate (5) was not detectable on the nanosecond time-scale, indicating that the previous characterization of (5) should be revised. The

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first example of a 1,2-aryl radical migration from carbon to nitrogen via an intermediate spirocyclohexadienyl radical has been rcported.l6

OCOBu'

AcO

i i ACO Br

'0

OTMS

TMS

6 S n B u 3

A

O S n B u 3

-

6

OTMS

SCHEME 2

1,5-Migrations have also attracted interest from mechanistic chemists. 1,SMigration of the Bu3Sn' from carbon and oxygen has been reviewed.* 1,5-Hydrogen transfer has been observed in 2-alkylbenzoyloxy radicals and the rate constant for translocation of the 2-methylbenzoyloxy radical has been determined (1.7 x lo7 s-' at 23 'C).I7 N-Propyl-N-arylmethansulfonamide radicals generated from the corresponding halides and Bu3SnH and AIBN undergo radical isomerization via intramolecular ipso attack to give the corresponding N-(3-arylpropyl)methylsulfonamides in good yield (Scheme 4). * Pyrrolidine nitroxyl radicals have been prepared by Favorskii rearrangement of the 3-bromo-4-oxo-2,2,6,6-tetramethylpiperidin-l -oxyl radical with various bases."

[j-Scission (Ring Opening)

The kinetics of ring opening of alkoxycarbonyl-substituted cyclopropylcarbinyl radicals (6) have been studied. The rate was determined by competitive trapping with PhSeH at 25 "C and found to be 7 x 10'' and 12 x 10" s p l for the (trans-2-ethoxycarbon-

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94

72%

I

S02Me 5%

ScnmE 4

ylcyclopropy1)methyl radical (6; R = Et) and the (trans-2-t-butoxycyclopropyl)methyl radical (6; R = But), respectively.20 Competition methods have also been used to determine the rate of ring opening of the (2-methylenecyclopropyl)methyl radical (7). Ring opening is regioselective to give the 2-vinylallyl radical with a rate of ( 3 4 ) x lo9 s-’ at 5 oC.21The rate of ring opening of the cinnamyl derivative (8) of the oxiranylcarbinyl radical has been measured and is in good agreement with high-level calculations performed on the parent oxiranylcarbinyl radical which indicated a kinetic preference for C-0 cleavage (AHt =4.8 kcal mol-’) over C-C cleavage (AHs = 1 1.5 kcal mol- 1).22 The aza analogue of the cyclopropylmethyl radical (9) has been studied. Radical ring opening of a number of aziridines furnished allylamines as e~pected.’~

Ring opening of a number of cyclobutylcarbinyl radicals has been reported. In particular, bicyclo[3 .%.O]heptanonesundergo ring opening [across C( 1)-C(7) bond] to give cis-disubstituted cyclopentenes (Scheme 5).24 No fragmentation across the C(I)-C(5) bond to give the ring-expanded seven-membered ring ketone occurred. The regioselectivity of cleavage can be rationalized because the rigidity of the bicyclo system allows efficient overlap of the C(2) radical SOMO with the C(1)-C(7) bond.

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p-Scission reactions of basketyl, cubylcarbinyl, homocubyl, and other polycyclic radicals have been investigated using ab initio calculation^.^^ The effect of benzylic stabilization on the regioselectivity of ring opening in the bicyclo[3.1 .O] system has been measured, and rate constants estimated. The regioselectivity is similar to the parent system (no benzylic substituent), which indicates that the benzylic stabilization does not alter the position of the transition state for ring opening.26 0 x 0 radicals generated from the cyclization of aminyl radicals on to aldehydes undergo fragmentation to give N-formyl amides. Fragmentation in a six-membered ring was found to occur 60 times faster than in the corresponding five-membered ring.27

SCHEME 5

Ring Expansion Cis-fused methylenecycloheptanes (10) have been synthesized in a radical ringexpansion reaction in which fused methylenecyclobutanes react with Bu3SnH in the presence of AIBN (Scheme 6). The ring expansion occurs via the now classical cyclization-fragmentation strategy and complements ring-expansion reactions of cyclobutanones.''

Intramolecular Addition Cyclization The kinetics of 5-endo radical cyclization have been re~ iew ed. ~ A number of approaches for the production of alkyl radicals have been reported. Heating of cyclohex-l,4-diene-3-carboxylates(11) at 140 "C, using di-t-butyl peroxide as initiator, furnishes initially the cyclohexadienyl radical, which undergoes aromatization and decarboxylation to give toluene, COz, and the hex-5-enyl radical.29

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Cyclization followed by atom transfer from another molecule of the starting ester furnishes cyclized products. (Tributy1tin)cobaloxime has been utilized as a nonreductive reagent for the facilitation of radical c y c l i z a t i ~ n s .Photolysis ~~ of the cobaloxime with alkyl halides generates alkyl radicals by abstraction by Bu3Sn'. Cyclization followed by p-elimination of Col"H furnishes functionalized alkenes. Dioxolanyl radicals which undergo stereoselective 5-exo and 6-ex0 cyclizations have been generated from nitrate esters." The rate constants of a number of 5-ex0 and &ex0 radical cyclizations continue to be reported. In particular, 5-ex0 cyclization of 1-methoxy-6,6-diphenyIhex-5-enyl radicals (3.8 x lo7 s-') and the much slower 6-ex0 cyclization of the 1-methoxy-7,7diphenylhept-6-enyl radical (1.5 x lo5 s- I ) have been studied,32 as have the rate constants for 5- and 6-ex0 cyclization of primary alkyl radicals on to N-aziridinylimines (2.5 x 10* and 4.7 x lo6 s-' at 80 "C, re~pectively).~~ Absolute rate constants for the cyclization and reduction by Bu3SnH of a number of a-carboethoxy- and a-cyanosubstituted radicals (12) have been measured by laser flash kinetic studies. For secondary cr-carboethoxy radicals (12; X = CO,Et, R = H) the rate of cyclization was similar to that of normal secondary alkyl radicals whereas tertiary a-carboethoxy radicals (12; X = CO,Et, R = Me) cyclized at a reduced rate to that of their analogues.34 Competition studies have indicated that cyclization of alkyl radicals (13) occurs predominantly on to the aminocyano-substituted alkenyl group regardless of the nature of the substituent (R) on the other alkene (6-p0sition).~~ The electronic effects on the regioselectivity of cyclization of nucleophilic alkyl radicals on to imines and hydrazones indicate that 5-ex0 cyclization predominates regardless of the electronic nature at the 5- or 6 - p o ~ i t i o n 4-Exo . ~ ~ cyclization of alkyl radicals on to enamides bearing terminal sulfur substituents has been rep~rted.~' Aryl radical cyclization on to a number of imines indicated that the regiochemical outcome of the reaction is dependent upon the position of the nitrogen atom in the sidechain. For compounds of type (15), preferential 5-ex0 cyclization to give indanamines is observed (4 x lo's-' at 80 "C), whereas the alternative precursor (16) cyclizes preferentially in a 6-endo manner to give the corresponding tetrahydroisoquinolines (1 x lo's-' at 80 "C) (Scheme 9)'' In this latter case the major product was postulated to arise as a result of the shoi-ter bond lengths and angles in the tethered radical making the endo carbon more accessible than in the corresponding parent alkene system. In addition, z*orbital coefficients for the C=N bond indicate a greater coefficient at carbon in the LUMO. 6-Endo cyclization has also been observed in the cyclization of vinyl radicals produced by the addition of Bu3Sn' to terminal alkynes. This approach was used to synthesize the A-B ring of ( f) - f o r ~ k o l i nCyclization .~~ of vinyl radicals produced from vinyl bromides and Sm12 have been ~tudied.~" Further examples of the cyclization of acyl radicals have been reported. The rate constant for 5-exo-trig cyclization of the hex-5-enoyl radical (2.2 x 10' s-') was found to be similar to that of the hex-5-enyl radical.41 Cyclization of acyl radicals on to enol ethers is possible. Treatment of acyl selenides with Ph3SnH and Et3B generates the desired acyl radicals, which cyclize in a 5-ex0 manner to form cis-2,5-disubstituted tetrahydrofuran-3-ones in good yields.42

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Ph

X = CO2Et or CN R = H or Me n = I or2

(14) a; R = NMePh, R' = H b; R = H, R' = NMePh (14a) : (14b) = 34 : 36 SCHEME X

Two new methods for the formation of aminyl, amidyl, carbamyl, and uredeidyl radicals using Bu3Sn* mediated homolysis of 0-benzoyloximes and hydroxamic acid derivative^^^ or thiocarbazone derivatives have been reported.44 Cyclization of these radicals furnishes pyrrolenines, pyrrolidinones, and cyclic carbamates and ureas, respectively. Addition and cyclization reactions of aminyl radicals and ammoniumyl radical cations have been predicted to be irreversible using high-level ab initio molecular orbital c a l c u l a t i ~ n s .Silicon-centred ~~ radicals generated from alkoxydialkylsilanes by radical translocation react with suitably placed alkenes in a 5-endo manner.46Cyclization was most efficient when the alkyl groups on silicon were t-butyl (R = Bu') (Scheme 10). Alkoxy radicals generated from N-(alky1oxy)pyridine-2(1 4 thiones or benzenesulfenic acid 0-esters undergo fast cyclization (2 i~1 x lo8 s-') to give tetrahydrofuryl radicals, which can be trapped by either hydrogen or chlorine atoms.47 A systematic study of the stereochemical outcome of the cyclization of substituted pent-4-enols reveals that the stereoselectivity is similar to that of the hex-5enyl radical.

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Organic Reaction Mechanisms 1995

Ab initio methods have been used to reinvestigate the auto-aromatization thermodynamics of the Bergman reaction, where (Z)-hex-3-ene-1,5-diyne undergoes the auto-aromatization reaction to give the singlet p-benzyne biradi~al.~'

SCHEME 10

Tandem Reactions Dienes and enynes undergo radical addition-cyclization-abstraction sequences. Alkyl radicals derived from addition of tris(trimethylsily1)silylradicals to alkenes undergo 5 ex0 cyclization on to p-alkenyloxy enones (Scheme 1 l).49 The synthesis of a range of five- to eight-membered ring lactams was accomplished by sulfonyl radical additioncyclization of a number of dienylamides. The effect of substituents on the stereoselectivity and regioselectivity in 5-ex0 cyclizations was probed.5o Stannyl formylation of 1,6-dienes under pressurized conditions of CO has been r e p ~ r t e d . ~ ' Aldehyde (17) arises via stannylation of (18) followed by cyclization, trapping with CO, and reduction (Scheme 12). A trace amount of the bicyclic structure (20) is thought to arise via intramolecular SH2attack of the cyclized radical at tin. In a similar sequence, 1,5- and 1,6-dialdehydes and diketones undergo Bu3SnH-mediated intramolecular pinacol coupling to give cis-l,2-diols in very high ~electivity.~'A possible mechanism involves initial addition of the Bu3Sn' to one carbonyl group, cyclization on to the second carbonyl group, and SH2displacement of a Bu group from tin by the resulting alkoxy radical. A novel cascade cyclization, CO trapping, and boron-mediated coupling process has been reported (Scheme 13).53This process was facilitated by irradiation of

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alkyl iodides in the presence of Pd(PPh3),, CO, and alkylboranes. Initial reaction of (21) with Pd(0) furnishes the hex-5-enyl radical and Pd’l. Cyclization followed by trapping by palladium and insertion of CO followed by coupling of alkyl-9-BBN derivatives furnishes the observed ketones (22). MM2 calculations have been applied to predict accurately the stereochemical outcome of tandem cyclizations which lead to the formation of the C/D-ring system of steroids. Possible structures for the radicals involved were determined by initial Monte Carlo random search in MacroModel followed by minimization using the extended MM2* force field with the radical cyclization parameters. Based on a Boltzmann distribution of the optimized transition structures, it was possible to predict the observed major prod~cts.’~ The synthesis of novel allenylidene tetrahydrofurans via a tandem 5-exo-trig radical cyclization-oxiranyl vinyl radical ring opening has been reported. s5

Radical Annulation Irnidoyl radicals generated from the addition of vinyl radicals to isonitriles undergo cyclization on to suitably placed nitriles. The resulting iminyl radicals can undergo further reaction in a 6-endo manner to suitably positioned aromatics.56This novel 4 + 1 radical annulation was initiated by the addition of AIBN to phenylacetylene. Indoles can be produced by a radical annulation process. Addition of aryl radicals generated from the homolysis of the C-I bond of imine (23) undergo addition to phenylacetylene followed by 5-ex0 cyclization of the resulting vinyl radical onto the imine (Scheme 15).57 The synthesis of 12-membered crown thiolactones has been achieved by the addition of 1,2-bis(mercaptoacetoxyl)cyclohexanes to alkynes in the presence of Pr3B and O2 as an initiat~r.~’ A novel one-pot annulation procedure to furnish 1,3-dithiol-2ones (24), important precursors to tetrathiafulvalenes, has been reported (Scheme 16).59 This was achieved by the addition of thiyl radicals (25) (prepared from diisopropyl xanthogen disulfide and AIBN) to alkynes followed by a 5-endo-trig cyclization of the resulting vinyl radical (26) on to the C=S bond with loss of the isopropyl radical.

I

83%

‘Si(TMS)3

SCHEME 11

Organic Reaction Mechanisms I995

100

Bu

eo-

Bu?SnH, CO AIBN, 80°C

Bu

3 Radical Reactions: Purl I

101

(26) SCHEME 16

Fragmentation, Recombination, and Homolysis Reviews have appeared on alkyl radical decomposition and recombination reactions with oxygen,6 and C-C bond formation in a super-cage.' An extension to the Gorin model for radical-radical recombination has been proposed by Pitt et aL6' It has been shown that the recombination of transient radical pairs can be controlled using 'spin manipulation.' In this process, irradiation with strong microwaves in an appropriate magnetic field lead to 'spin locking' leading to cage escape of radicals and escape product formation. If lower microwave irradiation was used, spin inversion occurred and the radicals could combine to give the cage recombination product.61 The second-order rate constant for a range of alkyl radical-radical recombination reactions in neat hydrocarbon solvents has been measured by pulse radiolysis.62 Rates were not proportional to the inverse of the viscosity of the solvent used, indicating that the rate is not completely diffusion controlled. The combination and disproportionation of the vinyl radical has been studied and the deuterium isotope effect mea~ured.'~ Unsurprisingly, no effect was detected for the dimerization of the vinyl radical, but a KHIKD value of 1.20 was determined for the disproportionation reaction. The rate constants for the dimerization of a number of resonance-stabilized carbon radicals were all found to be near the diffusion-controlled limit.64On the other hand, their trapping by TEMPO gave a much larger variation in rate constant, indicating that the N-0 bond made an important contribution in the reaction. Evidence for the mechanism of fire suppression by perfluoroalkylamines has been obtained by ab initio calculations on the reactions between the trifluoromethyl radical and hydroxyl or hydrogen radical^.'^ The recombination of the triplet 4-benzoylphenylthiyl radicals has been studied using picosecond transient absorption spectroscopy.66The majority of the radicals underwent recombination in competition with cage escape, indicating a fast intersystem crossing ( > 100 ps) of the thiyl radicals. Acctyl and t-butyl radicals formed from the photolysis of pinacolone react with phenolic compounds to form aryl acetates and acylphenols by initial phenolic hydrogen atom abstraction and rec~mbination.~'Hindered phenoxy radicals (27a) and (27b) have been shown to undergo reversible C-C coupling to give bis(cyc1ohexadienes) (28) and (29) (Scheme 17).68The spectra and kinetics of the recombination of alkyl and alkylperoxy radicals originating from di-t-butyl ether have been studied using a pulse radiolysis UV absorption technique.69 A number of thermal reactions have been investigated behind reflected shock waves. The thermal decompositions of buta-1 ,2-diene7' and but-1-yne7*have been investigated at 1 100-1600 K, while the reactions of the methyl radical have been reported at 12242520 K.72 The thermolyses of a number of alkyl and propargyl amines at 380-510 "C

Organic Reaction Mechanisms I995

102

+

(28) SCHEME 17

indicate that decomposition occurs via a six-centred cyclic transition state; however, a free-radical mechanism was suggested for the decomposition of diethylcyanomethylamine.73 Thermolyses of a range of di- 1-adamantyl-t-alkylmethanes have been studied and the activation energies correlated with the difference in strain energy between the starting material and the corresponding radicals.74 In addition, an interesting rearrangement of di-1-adamantyl-3-noradamylmethane to 1,2-diadamantyl was reported. Thermolysis of acetophenone and benzophenone oxime arenesulfonates has been postulated to occur via a free-radical mechanism.75 Chloroalkanes, important species in atmospheric chemistry, undergo oxidation mediated by chlorine atoms to give chloromethoxyl radicals which undergo intramolecular elimination of HCl.76 An important reaction in the high-temperature oxidation of benzene is the fragmentation of the phenoxyl radical to CO and 'C5H5. Ab initio calculations indicate that decomposition is likely to take place via an electrocyclic mechanism involving the 6-oxobicyclo[3.1.O]hex-3-en-2-y1 radical.77 The rate constants for decarboxylation of a range of substituted benzoyloxyl radicals have been measured using laser flash photoly~is.~'Ortho-substituted radicals were found to decarboxylate much faster than other isomers. In addition, the rate was found to be heavily dependent upon the solvent used. The significant non-planar geometry of thc ortho-substituted radicals was thought to be responsible for the rate-accelerating effect.

Atom Abstraction Reactions Hydrogen Abstraction by Carbon-centred Radicals The factors which determine the activation energy of radical abstraction reactions have been r e ~ i e w e d In . ~ addition, the activation energies for H-abstractions by a number of radicals have been calculated using bonding and antibonding Morse c u ~ e sValues . ~ ~ were found to be in good agreement with published experimental data. The model used highlights the importance of repulsive forces and requires only bond length, dissociation energy, and TR stretching frequency data for calculation. The abstraction of a hydrogen atom from acetonitrile by the methyl radical has been studied by both the

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ab initio MO and reaction dynamics methods to determine the mechanism at low temperature." It was concluded that quantum mechanical tunnelling strongly affects the reaction rate. Hydrogen atom abstraction by acyl radicals has received some attention. The rate constants for reduction of primary, secondary, and tertiary acyl radicals by (TMS)&H and Bu3SnH have been measured and the KSnHIKsIH values were found to be very similar (12.32-14.45).*' In addition, the rate constants for hydrogen abstraction from Bu3SnD were measured (propanoyl radical, 3 x lo5 1 mol-' s-I) and thiophenol (benzoyl radical, 4.8 x lo7 I mo1-I s - ' ) . ~ ' Radical translocation (intramolecular H-abstraction) has continued to be used to generate radicals which then undergo further reactions such as cyclization. Siliconcentred radicals have been produced by 1,5-H abstraction by vinyl radicals46 or alkyl radicals8* The latter were studied with the aim of developing unimolecular chaintransfer reactions (UMCT). The application of this technique for the mediation of particularly slow bimolecular reactions has proved successful. Reaction of (3 1) with (30) using the conventional syringe pump-high dilution method furnished only starting material (31) and reduced phenyl acetate, whereas the addition to (32) produced the addition product (33) in 71% yield (Scheme 18). Radical translocation has also been used in a translocation-trapping strategy.*3 Barton decarboxylation of the 2mercaptopyridine-N-oxide ester of the acid (34) with Bu'SH followed by fast 1,5hydrogen transfer and trapping with oxygen gave the hydroxylated product (35) (Scheme 19). The rate constant for translocation was found to be 6 x lo6 s-' at 25 "C. The synthesis of oxindoles via a translocation-cyclization strategy, initiated by 1$hydrogen transfer to aryl radicals, has been rep~rted.'~

Bur/ Bur /

OSiBur2H

Bu!

Br

Organic Reaction Mechanisms 1995

104

SCIIEME I9

The reaction of phenyl radicals with a range of cycloalkanes has been probed by utilization of the cavity-ring-down te~hnique.'~Results were in good agreement with data obtained by the relative rate method. Hydrogen Abstraction by Heteroatom-centred Radicals An analysis of published data relating to polar substituent effects on hydrogen atom abstractions and other radical reactions in terms of perpendicular effects in More O'Ferrall-Jencks diagrams has been discussed. It was concluded that entropic dominance leads to behaviours inconsistent with the reactivity-selectivity principle.86 The rate of H-abstraction from a number of hydrocarbons, fluorohydrocarbons and alcohols by the CF@' has been determined using the relative rate technique and conclusions regarding the fate of the C F Q in the atmosphere have been made.87Habstraction from phenol and t-butyl hydroperoxide by cumyloxyl radicals has been found to be dependent on the solvent." It was postulated that more polar solvents complex more strongly with the reactant hydroxyl group, thus decreasing the rate of hydrogen abstraction. Pulsed radiolysis has been used to determine the absolute rate constants for the reversible H-abstraction reaction from thiols to radicals (derived from alcohols or cyclic ethers).89 Typical values for the forward reaction of radicals with thiols are of the order of 107-10s 1 mol-' s-', whilst the reverse reaction of the hydrogen donors with thiyl radicals were of the order of lo4 times less. R' + R'SH

C RH

+

R'S'

(1)

Kinetic solvent effects for the H-abstractions from a-tocopherol and phenol by tbutoxyl, 2,Z-diphenyl-1-picrylhydrazyl and cumyloxyl radicals have been measured.90 The kinetic solvent effect was found to be almost identical for the same substrate and independent of the radical. This provides a method for predicting the rate constant for the reaction of a radical with a substrate in any solvent providing the kinetic data are available for the reaction of another radical in the same range of solvents. The absolute reaction rate between chlorine atoms and a large number of alkanes has been studied at various temperatures (273-333 K) using the VLPR technique9' and the relative rate m e t h ~ d .In~ addition, ~ , ~ ~ ah initio calculations on H-abstraction by halogen radicals from ethane and propane using UHF, UHF/MP2, and UHFIMP4 (6-31G* basis

3 Radical Reactions: Part I

105

set) methods have shown that the transition state occurs with the abstracting halogen atom, hydrogen atom and carbon atom c01inear.~~ The kinetics of the reaction between CF3C02H (a potential oxidation product of HFC and HCFCs), H2S, D2S, CH3SH, and CD3SH with atomic chlorine have been The reaction of photo-dissociated CC14 and C12 with H2 at 193 and 35 1 nm, respectively, fbmishes varying amounts of H atoms, with the former producing a much larger con~entration.~~ H-abstraction from a-amino acids by thiyl radicals has been studied at pH 10.5. Radicals were generated from cysteine, homocysteine and glutathione by the azide radical.98 Chiral silanethiyl radicals have been used in an attempt to perform kinetic resolutions. Only low resolutions were obtained in H-abstraction from racemic C(2) symmetric s i ~ a n e s . ~ ~ The kinetics of H-abstraction from secondary amines by 1,Cbenzoquinone monoimine have been reported. loo

Hulogen Abstraction The dissociation energies of the C-X bond in 73 different compounds have been calculated using the corresponding rate constants for halogen abstraction. A diverse range of alkyl, aryl, heteroaryl, and vinyl halides as well as a number of carboxylic acid derivatives were evaluated."' The kinetics of halogen abstraction fi-om a number of halogenated hydrocarbons by various radicals have been studied.'02 In particular, the rates of abstraction by aminoboryl and triethylsilyl radicals have been measured by EPR spectroscopy.I o 3 The rate of abstraction increases with the addition of P-alkoxyl substituents to the organo-halogen radical precursor due to charge-transfer effects operating in the transition state. EPR spectroscopy has also been used to establish that cross-cage interactions exist in 3-substituted bicyclo[ 1.1. Ilpent-1-yl radicals. Io4 During the course of this study the rates of abstraction of bromine atoms from I-bromo-3substituted derivatives were examined. Abstraction from the 1-brorno-3-fluoro derivative was much faster than for the corresponding 3-unsubstituted derivative, indicating a strong polar effect.

Halogenation The addition of HBr across styrene in an anti-Markovnikov manner to give 2bromoethylbenzene has been re-examined both in the presence and absence of 2bromo-2-methylpropan01.'05 A far greater selectivity for the formation of the antiMarkovnikov product was obtained with the additive. The kinetics of chlorination of hexane by various N-chlorosulfonamides have been reported. O6 Competing H-abstraction by C1' or by the sulfonamidyl radical was observed. Addition Reactions

Addition to Alkenes The absolute rate constants for the addition of benzyl, cumyl, cyanomethyl, t-butoxycarbonylmethyl, 07,'Ox and hydro~yrnethyl'~~ radicals to a variety of mono-, 1 , l - and 1,2-disubstituted and trisubstituted alkenes have been measured using

'

Organic Reaction Mech.anisms 199.5

106

time-resolved electron spin resonance. Rate constants were found to vary from 3.3 x lo3 1 mol-' s-' (ethene) to 2.4 x 106 1 mol-' s - ' (1,l-diphenylethene) for the cyanomethyl radical, and from 1.1 x lo4 1 mol-' s-' (ethene) to 1 x lo7 1 mol- s- (1,l -diphenylethene) for the t-butoxycarbonylmethyl radical. Cumyl and benzyl radicals were found to undergo addition to acrylate and styrenes at similar rates. The relative rates and regioselectivity for the addition of a number of electrophilic radicals to pyrrole, furan, and thiophene have been measured.Ito A study of the addition of alkyl radicals to vinylborane derivatives, which investigated the effect of the different boron substituents on the rate and regioselectivity of the reactions, has been reported.' The reactivity of the t-butyl radical with diethyl tartrate-derived vinylboronic ester was found to be similar to that of acrylamide. Theoretical treatments for analysing alkyl radical additions to alkenes have been evaluated.'I2 Ab initio calculations at a range of levels of theory identified UQCISD or UQCISD(T) energies with the 6-3 1 1G**basis set and UHF/6-3 1G* geometries to be best suited. Principal component analysis has been applied to separate polar and enthalpic effects for alkyl radical addition reaction^."^ The rate constant for the addition of the methyl radical to 2-methyl-2-butene has been studied in the temperature range 405444 K.' l 4 The additions of radicals generated from cyclic ethers, alcohols, and alkyl iodides to perfluorenol esters have indicated that these esters are particularly good acceptors of nucleophilic radicals owing to their low-lying LUMOs which allow them to react with radicals which possess relatively high SOMO energies.'I5 2-Substituted vinyl radicals, prepared from the corresponding iodides using either Bu3SnH or TTMSS, add to a variety of alkenes to give (Q-1,2-disubstituted products exclusively. However, the stereoselectivity of the addition of 1,2-disubstituted vinyl radicals was shown to be dependent upon the substituents (Scheme 20). The photoaddition of [60]fullerene to silylketene acetals gives rise to a-fullerene-substituted carboxylic esters instead of the expected 2 2 cycloaddition products.'I7 A mechanism involving a fullerene-ketene acetal radical ion pair was postulated to explain the outcome of the reaction. The relative reactivities of a number of monomers (acrylonitrile, methyl acrylate, methyl methacrylate, and styrene) and dienes (butadiene, isoprene, 2,3-dimethylbutadiene, and 2,3-diphenylbutadiene) with the 1-methyl- 1-(methoxycarbonyl)ethyl radical have been determined. l 9 The data were compared with those obtained from the addition of poly(methy1 methacrylate) radicals to the same acceptors. Results utilizing the monomers showed that the poly(methy1 methacrylate) radical can be modelled adequately by the 1-methyl- 1-(methoxycarbonyl)ethyl radical. Radical allylation has been studied by a number of workers. a-Silyl-a-phenylselenoacetic esters undergo radical allylation with a number of allyltributyltin compounds to hrnish the corresponding a-allyl-a-silylacetic esters, important precursors to di- and tri-substituted THF compounds (Scheme 2 1).I2O A new monoallylstannane radical allylation procedure has been developed which furnishes the desired allylated products in good yield (Scheme 22).12' The stannane (36) is readily available and the organotin by-product undergoes facile hydrolysis and is easily removed from the reaction mixture. The rates of addition of various radicals to a number of allylstannanes have been measured.122 When nucleophilic radicals were used, the best allylating reagent was

' '

'

+

' ' *,'

3 Radical Reactions: Part 1

107

found to be tributyl[2-(trimethylsilyl)prop-2-enyl]stannane, whereas with electrophilic radicals the tributyl(2-methylprop-2-enyl)stannane was superior. BuiSnH

I

R

R‘

SCHEME 20

SCHEME 21

(36)

SCHEME 22

The additions of phenylthiyl radicals to styrene, vinyl acetate, methyl methacrylate, and methacrylonitrile in the presence of the 1,1,3,3,-tetramethy1-2,3,-dihydro1Hisoindol-2-yloxyl radical have been reported. 123 Diphenylphosphinoyl radicals were found to be more nucleophilic than the corresponding dimethoxyphosphinoyl radicals, with the former reacting 10 times faster with acrylonitrile than with vinyl acetate.’24 The additions of a number of phosphorus- and silicon-centred radicals to both diethyl maleate and diethyl fumarate have been studied by ESR.Iz5 Azide radicals can be generated by the addition of TMSN3 to PhIO and The mechanism for the addition of nitrogen dioxide to alkenes has been probed.I2’ The rate constants and Arrhenius expression for the reactions of 1,1-dichloroethene and (E)-l,2-dichloroethene with the nitrate radical, an important oxidant in the troposphere, have been obtained.I2* It was deduced from these data and previous results that elimination of a chlorine atom from the substrates was not an important step. The kinetics of a number of reactions of mono- and di-substituted phenacyl radicals, important intermediates in photo-induced paper yellowing, have been r e ~ 0 r t e d . IThe ~ ~ addition of perfluoropolyether hypofluorites [X(CF20),(CF2CF20),CF2OR; X = OCF3, or OCF20F] to perfluoroalkenes has been studied by EPR and ENDOR technique^.'^^ Products arising from either addition of a fluorine atom or the partner radicals were detected.

Addition to Oxygen-containing Multiple Bonds A tandem process involving cyclization of a primary radical on to an alkene followed by addition to a C=O group and fragmentation has been reported (Scheme 23).131 The product arises from cleavage of bond a, because this cleavage leads to the maximal relief of ring strain. The kinetics of cyclization of aminyl radicals onto aldehydes have been st~~died.~’ For Sex0 cyclization, the rate constant was found to be 5.1 x lo5 s-’, whereas for 6-ex0 cyclization the rate constant was 3.1 x lo4 s-‘. a-Stannyl radicals

Organic Reaction Mechanisms I995

108

undergo 5-exo-trig cyclization onto acyl silanes to give cyclic enol e t h e r ~ . 'The ~ rate constant for the addition of primary alkyl radicals to carbon monoxide has been measured (2.7 x lo5 1 mol-' s-' at 50 "Cj and found to be similar to that for secondary r a d i ~ a 1 s . I ~ ~

SCHEME 23

Addition to Nitrogen-containing Multiple Bonds Cyclization of aryl radicals on to the N or C atoms of imines occurs in a 5-exa-trig manner. Minor amounts of phenathridine products were detected and were shown not to have arisen from rearrangement via a cyclohexadienyl radical intem~ediate.~'The kinetics of the association reactions of a series of chlorofluoromethyl radicals with NO have been measured using pulsed laser photolysisitime-resolved mass spectrometry at various pressures and temperatures. 133 The results were analysed by the variational RRKM method. Addition to Thiocarbonyl Bonds Primary and secondary alkyl radicals derived from irradiation of O-acylthiohydroxamates undergo reactions with thionitrile esters to furnish nitroso compounds which dimerize to form trans nitroso d i m e r ~ . ' ~ ~

Homolytic Substitution Aromatic Substitution The cyclization of carbon-centred radicals on to 2-indolylaryl sulfides and sulfoxides occurs via an intramolecular ipso aromatic substitution reaction (Scheme 24j.135 Intramolecular ips0 substitution has also been observed in N-aryl-N-propyl radicals. @so attack was found to be most efficient when the intermediate cyclohexadienyl radical was captodatively stabilized. Intramolecular aromatic substitution of a-amide radicals gives o ~ i n d o l e sThe . ~ ~reactions were carried out at 160 "C in t-butylbenzene

3 Radical Reactions: Part 1

109

using di-t-butyl peroxide as initiator. Possible mechanisms for the re-aromatization are discussed. The reaction of the hydroxyl radical with a number of aromatic compounds has been studied by ab initio molecular orbital calculations. 13' The observed experimental isomeric distribution was adequately explained by comparison with the calculated HOMO orbital coefficients. Coupling of a number of P-dicarbonyl anions with gemchloro-nitro derivatives via S R N 1 reactions produces alkenes, butenolides, or spiro-1nitro-y-butyrolactones, depending on the reactants. 137

SH2 and Related Reactions Ah initio calculations have been used extensively to investigate theoretically a number of SH2reactions. Calculations (MP2, QCISD) into SH2reactions of hydrogen, methyl,

silyl, germyl, and stannyl radicals at sulfur or selenium in methanethiol and methaneselenol indicate that no hypervalent (9-E-3) intermediates are likely.' 38 On the other hand, this type of intermediate was indicated for substitution at tellurium in methanetellurol. Calculations on the SH2reactions of the above radicals at halogens in alkyl and hydrogen halides have also been conducted. 39 Results indicate that no hypervalent (9-X-3) intermediates are formed even for the iodides. Calculations indicate that homolytic substitution at phosphorus in phosphine or methylphosphine by H' or Me' is particularly facile (14-33 kJ mol-' energy In addition, it was concluded that hypervalent phosphoranyl radical intermediates are involved and that they should not undergo pseudorotation before dissociation (10-3 1 kJ mol- '). Intramolecular homolytic substitution of peroxides to give glycidic esters has been accomplished by adding radicals generated fiom alkyl iodides to ethyl 2-(t-butylperoxymethyl)propenoate (37) (Scheme 25).14'

'

Organic Reaction Mechanisms 1995

110 Reactivity Effects Polarity and Philicity

The relative reactivities for the addition of the electrophilic radicals 'CH2CN, 'CH,CO,Et, and 'CH(CO,Et)2 to pyrrole, N-methylpyrrole, fixan, and thiophene have been measured and found to be in the order N-methylpyrrole > pyrrole x hran > thiophene.' l o In addition, the selectivity for addition at the orand P-positions was shown to be high (al8 ratios > 50). These results were explained by invoking an interaction between the radical SOMO and both the HOMO and LUMO of the substrates. Stability of Radicals The structures of acyl radicals in solution have been studied using time-resolved infrared spectro~copy.~' The carbonyl stretching frequencies for a number of acyl radicals were measured and they were found to be higher than those for the respective aldehydes due to their higher C=O bond order. The preferred conformations of N-alkylN-trialkylsilylmethylaminyl radicals have been probed by EPR spectro~copy.'~~ The preferred conformation is that in which the P-C-Si bond eclipses the singly occupied N-2pn orbital. Hindered rotation about the C-N bond was also observed. In addition, the facile rearrangement of this radical to give 'CH2N(Bu?SiMe3 has been confirmed and is postulated to proceed by an intramolecular 1,2-shifi of the SiMe3 group. The stability and structure of a range of 8-substituted radicals (.'CH2CHXOMe) have been studied using ab initio calculations.143 Rotamer analysis showed an anomeric effect for X = F and NH2. A significant amount of extra stabilization via the anomeric effect was found for 'CH2CF20Me. The activation parameters and radical stabilization enthalpy were determined for the formation of the 1,3-di-t-butylallyl radical by thermolysis of meso- and ( f)-5,6-di-tbutyl-2,2,5,5-tetrmethylde~a-3,7-diene.'~~ Reactions of hydroxamic acid (38) with

4

0

OH

3 Radical Reactions: Part 1

111

potassium hexacyanoferrate(II1) led to the nitroxyl radical (39), which disproportionated to give the nitroso compound (40) (Scheme 26).145The facile disproportionation is thought to occur due to the fixed Z configuration of the nitroxyl radical. The first demonstration of the formation of a-keto-carbon radicals in an enzymatic system based upon pyruvate formate lyase has been r e ~ 0 r t e d . IThe ~ ~ kinetics of the unimolecular decomposition of the 1-chloroethyl radical have been studied as a function of temperature (849-980 K) in He, Ar, and N2.147

Stereoselectivity in Radical Reactions Stereoselectivity in Cyclization High stereo-control has been observed in the 5-exo-trig cyclization of imidoyl radicals (Scheme 27).14* Moderate diastereoselectivities (58-65%) are obtained in 6-endo cyclizations on to imines. The major diastereomers were postulated to arise via a Felkin-Ahn transition state.38Both 1,2- and 1,5-stereo-induction in the cyclization of substituted hex-5-enyl radicals, produced from tosyl radical addition to 1,6-dienes, have been reported (Scheme 28).i49The results indicated that while 1,2-induction was total (trans), 1,5-control was not (predominance of 1,5-cis). The reported results were in good agreement with MM2 calculations.

Y S=C=N

D

M

S

2. I . Ru$nH, SiOz, H 2 AIBN 0

C02Et

H SCHEME 27

79

21

SCHEME 28

Stereoselectivity of Addition to Alkenes Factors which effect the stereoselectivity in radical reactions have been reviewed. A number of studies have indicated that the method chosen for conducting radical addition reactions can have a significant outcome on the stereoselectivity of the process.

112

Organic Reaction Mechanisms 1995

The addition of radicals (prepared either by the reduction of alkylmercury halides or by Bu$SnH/UV-mediated reduction of alkyl halides) to a series of silyl protected alkyl 2(1 -hydroxyalkyl)propenoates (41) has been probed (Scheme 29). Is' The diastereoselectivity in the addition of 'C6Hll was found to bc dependent on the method of radical formation [41; R', R2 = Me, R3 = Bu'Me2Si; unti :syn = 5 : 1 (Hg), 1 : 1 (Sn)]. Selectivity also increased with the size of the silyl protecting group R3. The addition of alkyl radicals to methylenoxazolidinones (42) has also been shown to be dependent upon the method for radical gencration; however, this time the tin method was superior (Bu3SnH>RHgH).''' In the majority of cases the major product was the trans diastereomer. The diastereoselectivity was also found to be dependent on the size of the radical and the nature of the nitrogen substituent, with carbamate derivatives giving reversed selectivity. Temperature can also have a significant effect on the outcome of a radical process. The diastereoselectivity of addition of chiral acetoxyallyl radicals to methyl acrylate was found to be temperature-de~endent.'~' A temperature dependence was also found for the stereoselective allylation of (1R,1R,4S)-8-phenylmenthyl-N-Boc2-bromoglycinate with allyltributylstannane. Is3 A study on the 1,2-stereochemical induction in the addition of alkyl radicals to y-oxya,/l-unsaturated ester derivatives (43) has indicated that the role of the alkoxy group (R) is important (R=TBDMS, syn:anti=10.2: 1; R=MOM, syn:anti= 15.8: 1). The dioxolane (44) only showed selectivity in the Z series. An explanation based on allylic strain in the transition state was pr~posed.''~ Selective attack from the re-face gave i-ise to syn products preferentially. Efficient 1,2-induction in the addition of radicals to 3hydroxy-1-(methy1thio)-1-(p-toly1sulfonyl)alk-1-eneshas been observed.'" X-ray and NOE studies in solution have identified the preferred ground-state conformation of the substrate, and selectivity is explained by reduction from the least-hindered face in the captodative intermediate. The importance of taking into account both electronic and steric effects when facilitating stereoselective radical additions has been highlighted. 156 Stereoselectivity in the radical allylation of a number of uridine-5'-monoselenoacetals was found to be heavily dependent on the protecting groups at the 2'-0, 3'-0, and 5'-0 positions. Radical reduction or allylation of the alkoxyindene (45) was highly stereoselective ( > 100 : 1) when the free hydroxyl (R = H) was complexed with methylaluniiniumbis(2,6-di-t-butyl)(-4-methylphenoxi~e (MAD) (Scheme 30).'57 Selectivities were very low when bulky R groups were used, whether they were complcxed or not.

3 Radical Reactions: Part I

113

U L 0qN

R'

\

(re-facc)

.4'

Ph

R'

(si-face)

SC'HEM~J 30

Stereoselectivity of Atom Transfer Lewis acids have been shown to play an important rolc in the stereo-control of many reduction processes. The stereochemistry of deuteriation of stabilized benzylic radicals containing a-alkoxy substituents (46) has been investigated. 58 Bulky substituents gave only modest selectivities (R = ButPh2Si, u : 1= 4.1 : 1); however, these could be enhanced if the reaction was carried out on the free hydroxyl (R=H) after complexation with (MAD) (u : I = 13 : 1) (Scheme 3 1). The sense of stereochemical induction in the deuteriation of 1,2-dioxy-substituted radicals can be reversed when carried out in the presence of bidentate Lewis acid c he la tors.''^ This reversal in selectivity on complexation has also been reported for the butylation of y-substituted-crmethylenebutyrolactones. 160 The use of TTMSS and BuI gave high cis selectivities while the use of Bu3SnH in the presence of bulky diphenoxyaluminium chloride furnished the trans compounds as the major products. Stereoelectronic factors have also been shown to effect the outcome of many reduction reactions. The stereoelectronic effect of a /I-fluorine substituent on the diastereoselectivity of reduction of the 2-fluorocyclopentyl radical by Bu3SnD has been reported.I6l The role of a-donation in the outcome of reduction of a number of oxazolidinones (47a; X = NH, Y = CO), dioxolan-2-ones (47b; X = 0, Y = CO), ylactone (47c; X=CH2, Y=CO), and tetrahydrohrans (47d; X, Y=CH2) has been determined.'62 Examination of the reduction reactions of enolate radicals that contain adjacent polar stereo-centres has indicated that when R = t-Bu (48) there is no effect on the diastereoselectivity on changing the X group [(49) : (50); X = Me, 96 :4; MeO, 95 : 5; F, 98 : 2) (Scheme 32).'63 This is in contrast to recently published results, which indicate a major stereoelectronic effect in related radicals [(49) : (50); R = Ph; X = Me, 46 : 34; MeO, 97 :3; F, 95 : 5).

Organic Reaction Mechanisms 1995

114

SePh (46)

D A!

D 1

SCHEME 31

Redox Reactions Redox-induced radical C-C bond-forming reactions have been re~iewed.'~The Saveant theory of adiabatic dissociative electron transfer has been tested using the reduction of di-t-butyl peroxide by aromatic radical anions. From the data it was shown that reduction is not adequately described by the SavCant theory and a non-adiabatic dissociative electron-transfer mechanism was proposed.'64 The use of iron compounds to mediate redox reactions continues to be of interest. Oxidation of isopropylbenzene with iron tetraphenylporphyrin in the presence of iodosobenzene has been ~tudied.'~'A significant amount of acetophenone was detected which was shown to arise from reaction of cage-escaped cumyl radical with iodosobenzene. The rearrangement of 1,2,4-trioxane into diol monoesters using Fe"S04 has been reported.'66 A mechanism involving initial reduction to an oxyl radical followed by 1,s-hydrogen transfer and oxidation was proposed to explain the observed outcome (Scheme 33). A number of catalysts for the hydrodiazotization of diazonium salts have been evaluated and the best, Fe"S04, was found to serve as an electron donor. 16' Intermediate radicals were detected by trapping experiments. 9Benzylpurine can be alkylated at the 9-position via radicals generated by the Minisci procedure. The use of Sm12to mediate cyclizations of alkyl and vinyl radicals has been explored. The mechanism of intramolecular cyclization of a number of 1-substituted-6-halo- 1ynes with Sm12 has been probed (Scheme 34).16' The results for the cyclizations of

3 Radical Reactions: Part 1

115

alkyl halides indicate that the major pathway is radical. Cyclization of vinyl radicals generated from vinyl halides and Sm12 have also been studied in great detail4' Cyclization of 3-bromopropenyl 3-(trimethylsily1)propynyl ether (51) furnished a mixture of products including alcohol (52), which may arise from radical (53) by either reduction followed by [2,3]-sigmatropic Wittig rearrangement or by a 5-end0 cyclization and samarium Boord reaction (Scheme 35). R

R

R

R

SCHEME 33

12%

47 %

1%

SCHEME 34

SCHEME 35

Photo-cyclization of vinylmethoxynaphthylenes are catalysed by CU(OAC)~. *" The yield and rate of cyclization were increased when oxygen was present in the reaction, suggesting a singlet-state involvement. Copper catalysis has also been investigated for the BdOzH (TBH)-mediated oxidative addition of alkyl, aryl, and acyl radicals to

Organic Reaction Mechanisms I995

116

acrylonitrile (Scheme 36).17' Transfer of the peroxy group was shown to be more selective than the transfer of halides or other pseudohalide groups. The kinetics and mechanism of the oxidation of methyl-a-D-glucopyranosideto sodium methyl-cr-D-glucopyranosiduronateby TEMPO, NaBr, and HOCl have indicated that two mechanisms may operate depending on the reaction condition^.'^^ Radical cyclizations of iodoalkenes facilitated by irradiation in the presence of Pd(PPh3)4 have been shown to proceed via a redox mechanism.53

RH

-

Bu'OzH. CUOAC @CN

Bu'02H + Cu' Bu'O + Bu'02H

R

y

N

O~BU'

-

Bu'O + CU" + -OH

BdOH + Bu'02'

SCHEME 36

(54)

SCHEME 37

Radical Ions Anion Radicals The competition between polar and radical mechanisms in the trimethylstannylation of 1-iodonorbornane has been re-examined and found to be heavily dependent on the choice of counterion (Me3SnLi, radical :polar, 79 : 21; Me3SnNa, radical : polar, 32:68).'73 The study concludes that the use of 1-iodonorbornane as a model to investigate radical nucleophilic substitution reactions is inappropriate and 1haloadamantanes are suggested instead. The photochemically initiated reaction betwecn 1-iodoadamantane and arenethiolate anions has been in~estigated.'~~ Evidence was presented for a non-chain SRNlsubstitution mechanism, with the initial expulsion of an electron from the thiolate. A new SRNl reaction utilizing l-chloromethyl-5nitroisoquinoline and the anion of 2-nitropropane has been reported.'75 Mechanistic evidence includes inhibition by O2 and TEMPO. The reactions of SOT with various azoline nitrogen heterocycles has been explored under a variety of reaction condition^.'^^ In acidic or neutral media the reactions proceed by initial hydrogen abstraction from the NH group to give neutral radicals, whereas in basic solution radical

3 RadicaE Reactions: Part I

anions are formed. No products arising from SO: detected.

117 addition to the C=C bond were

Cation Radicals 2,6-Diarylocta-1,6-dienes undergo a moderately stereoselective ET-induced intramolecular 2 2-cycloaddition via cation radical intermediates.177 The electron-transfer photochemistry of 7-methylnorbornadiene and 7-methylquadricyclane in MeOH has been studied and the products identified.17’ Nucleophilic capture of the initially generated radical cations by MeOH hrnishes radicals which then undergo rearrangement to more stable ally1 radicals. The photo-sensitized valence isomerization of quadricyciane to norbornadiene by dibenzoyltnethanatoboron difluoride shows a CIDNP effect which is reversed when the reaction is carried out in the presence of durene. ‘79 This evidence suggests formation of a triplex which promotes intersystem crossing between the intermediate ion-radical pairs.

+

Peroxides, Peroxyl, and Hydroxyl Radicals Peroxides The thermal decompositions of a range of fluoroalkanoyl peroxides,’” diacyl peroxides,’8 1 and di-t-butyl trioxide’” have been studied and mechanistic conclusions discussed. In addition, the effect of the medium on the rate constants for thermal decomposition of di-t-butyl trioxide has been determined using chemiluminescence.IR3 Studies into the steric and electronic effects of substituents on the rate of decomposition of t-alkyl peroxidesIK4 and p-substituted a-cumyl t-butyl peroxides’s5 have been undertaken. The thermolysis kinetics of t-butyl hydroperoxide have been reported.Ix6 The homolytic cleavage of 9-(t-butylperoxy)fluorene with t-butyl hydroperoxide has been shown to be catalysed by various chromium corn pound^.'^^ Peroxyl Radicals The kinetics for the formation of a number of peroxyl radicals by the addition of O2 to substituted methyl radicals’88 and vinyl radicals’89 have been studied by laser photolysis photo-ionization mass spectrometry. For the addition of substituted alkyl radicals, the reactivity was found to increase with electron-donating substituents (e.g. OMe and NH2) and decrease with electron-withdrawing substituents (e.g. CN). The relative rates of oxidation of a number of cycloalkanes by peroxyl radicals have been determined by competitive oxidation with c ~ m e n e . ” The ~ reactivities of the C-H bonds in five-, seven- and eight-membered rings were found to be much higher than those of six-membered rings. The rate constants for the reactions between peroxyl radicals and a number of flavanoids and catechols, known inhibitors of lipid peroxidation, have been measured using the kinetic chemiluminescence method.”’ The recombination reaction of t-butylperoxyl radicals to give di-t-butyl tetroxide has been studied and the equilibrium constant determined.45The parabolic model has been used to study the kinetic data of the reaction between peroxyl radicals and aromatic

118

Organic Reaction Mechanisms 1995

amines, thiols, phenols, and alkylhydroxylamines. 192 The one-electron reduction potentials of alkylperoxy radicals have been estimated using thermodynamic data. 193 Hydroxyl Radical

Reactions between the hydroxyl radical and various halogenated alkanes have attracted a lot of attention.194Ab initio studies of the reaction between the hydroxyl radical and trifluoromethane (MP2 level) have been reported.'95 The calculated rate constant was in good agreement with experimental data and a half-life of 65.5 years for CHF3 in the troposphere was proposed. Ab initio studies have also been undertaken on the reactions between the hydroxyl radical and various fluorinated e t h a n e ~ . 'Transition-state ~~ geometries were optimized at the HF/6-31G(d) and MP2/6.31G(dp) levels of theory. It was concluded that 'hydroxyl radicals are the most likely initiators of tropospheric degradation of HCFC, HFC, and CFCs.' The reaction with CF3CH2Fhas been studied in more detail between 255 and 424 K using the discharge-flow resonance fluorescence te~hnique.'~' The kinetics for the reactions between the hydroxyl radical and a number of chlorine- and fluorine-substituted acetates have been reported. '91 In aqueous media the reactivity was found to increase with decreasing halogen substitution, but no reactivity differences were observed for related chloro and fluoro compounds. The mechanism and kinetics for the reaction of the hydroxyl radical with dimethyl ether, diethyl ether, di-n-propyl ether, di-iso-propyl ether, di-n-butyl ether, 199 and t-amyl methyl ethe?" have been determined. Rate constants for the reactions between the hydroxyl radical and methyl glyoxal,201cis-hex-3-en-1-01, cis-hex-3-enyl acetate, transhex-2-enal, linaloo1,2024-methylpentan-2-one and 2,6-dimethylheptan-4-0ne~'~have been determined.

Diazoalkanes The thermal decompositions of a number of para- and meta-substituted 1,4-diamyl-2,3diaza[2.2.l]bicyclohept-2-ene derivatives (54) have been studied in order to probe the electronic effects of this reaction (Scheme 37).204The results indicated the importance of polar effects on the rate of reaction with both radical- and anion-stabilizing substituents enhancing the rate. Analysis of the data by two-parameter Hammett treatment was reported.

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Guindon, Y., Slassi, A,, Rancourt, J.? Bantle, G . , Bencheqrous, M., Murtagh, L., Ghiro, E., and Jung, G., 1 Org. Chem., 60, 288 (1995). l h 3 Hassler, C., Batra, R., and Giese, B., Tetrahedron Lett., 36, 7639 (1995). 164 Wcrkntin, M. S., Maran, F., and Wayner, D. D. M., 1 Am. Chem. Soc., 117, 2120 (1995). l h 5 Baciocchi, E., d'Acunzo, E, Galli, C., and Ioele, M., 1 Chem. Soc., Chem. Commun., 1995, 429. 166 Bloodworth, A. J. and Shah, A,, Tetrahedron Lett., 36, 7551 (1995). 167 Wassmunett, F. W. and Kiesman, W. F., 1 Org. Chem., 60, 1713 (1995). lb8 DCsaubry, L. and Bourguignon, J.-J., Tetrahedron Lett., 36, 7875 (1995). 16') Zhou, Z., Larouche, D., and Bennett, S . M., Tetrahedron, 51, 11623 (1995). 170 Kar, S. and Lahiri, S . , 1 Chem. Soc.. Chem. Commun., 1995, 957. Araneo, S., Fontana, F., Minisci, F., Recupero, F., and Sem, A., . I Chem. Soc., Chem. Commun., 1995, 1399. 172 dc Nooy, A. E. J. and Besemer, A. C., Tetruhedron, 51, 8023 (1995). 173 Adcock, W. and Clark, C. I., 1 0%.Chem., 60, 723 (1995). 174 Ahbala, M., Hapiot, P., Houmam, A,, Jouini, M., Pinson, J., and Savkant, J.-M., 1 Am. Chem. Sac., 117, 11488 (1995). Venelle, P., Ralhelot, I?, Maldonado, .I. and , Crozet, M. P., Heterocycl. Commun., 1, 41 (1995); Chem. Abs., 122, 105046 (1995). 176 Shohoji, M. C. B. L., Novais, H. M., and Vicira, A. J. S. C., 1 Chem. Soc., Perlcin Truns. 2, 1995, 2101. 177 Takahashi, Y., Ando, M., and Miyashi, T., 1 Chem. Soc., Chem. Commun., 1995, 521. 17* Weng, H., Du,X., and Roth, H. D., 1 Am. Chem. Soc., 117, 135 (1995). 17' Yang, L., Zhang, M.-X., Liu, Y.-C., Liu, Z.-C., and Chow, Y. L., 1 Chem. Soc., Chem. Commun., 1995, 1055. 18" Sawada, H., Mitani, M., and Molya, Y., Zaiyo Gijutso, 12,290 (1994); Chem. Abs., 122, 105121 (1995). Guo, Q., Liu, P., Li, Y., and Liu, Y., Lanzhou Duxue Xuebao, Ziran Kexueban, 29, 148 (1993); Chem. Abs., 122, 30850 (1995). Khursan, K. L., Shereshovets, V. V., Shishlov, N. M., Khalizov, A. F., and Komissarov, V. D., React. Kinet. Catul. Lett., 52, 249 (1994); Chem. Abs., 122, 55487 (1995). Khalizov, A. E, Makarova, 0. N., Khursan, S. L., and Shereshovets, V V., React. Kinet. Catul. Lett., 54, 427 (1995); Chem. Abs., 123, 32535 (1995). Matsuyama, K., Sugiura, T., and Minoshima, Y., 1 Org. Chem., 60, 5520 (1995). Hendrickson, W H., Nguyen, C. C., Nguyen, J. J., and Simons, K. T., Tetrahedron Let?.,36, 7217 (1995). Batt, L., Kham, M. A., and Mitchell, T. J., Symp. (Int.) Combust. [Proc.], 1994, 793; Chem. Abs., 123, 82678 (1995). lE7 Muzart, J. and Abdelaziz, N. A., 1 Mol. Catal., 92, 141 (1994); Chem. Abs., 122, 9296 (1995). Masaki, A,, Tsunashima, S., and Washida, N., 1 Phys. Chem., 99, 13126 (1995). Knayazev, V. D. and Slagle, 1. R., 1 Phys. Chem., 99, 2247 (1995). Iqu Hamish, R., Lauterbach, G., and Prtizkow, W., J: Prakt. ChemKhem. Ztg., 337, 60 (1995); Chem. Abs., 122,213385 (1995). 19' Belyakov, V. A,, Roginsky, V. A., and Bors, W., 1 Chem. Soc., Perkin Truns. 2, 1995, 2319. Denisov, E. T., Kinet. KataL, 36, 345 (1995); Chem. Abs., 123, 143235 (1995). I q 3 Merenyi, G., Lind, J., and Engman, L., 1 Chem. Soc., Perkin Trans. 2, 1994, 2551. 194 Hsu, K.-J. and DeMore, W B., 1 Phys. Chem., 99, 1235 (1995). Fu, Y., Lewis-Brown, W., and Tyrrell, J., 1 Phys. Chem., 99, 630 (1995). '91 Martell, J. M. and Boyd, R. J., 1 fhys. Chenz., 99, 13402 ( 1 995). '91 Gen-Hou, L. and Yuan-Pem, L., 1 Chin. Chem. Soc. (Taiyei), 41, 645 (1994); Chem. Abs., 122, 55548 (1 995). Iy8 Maruthamuthu, P., Padmaja, S., and Huie, R. E., In?. 1 Chem. Kinet., 27, 605 (1995). 199 Mellouki, A,, Teton, S., and IeBras, G., Int. 1 Chem. Kinet., 27, 791 (1995). Smith, D. F., McIver, C. D., and Kleindienst, T. E., Int. 1 Chem. Kinet., 27, 453 (1995). 201 Tyndall, G. S., Staffelbdch, T. A., Orlando, J. J., and Calvert, J. G., Int. 1 Chem. Kine?., 27, 1009 (1995). Atkinson, R., Arey, J., Aschmann, S. M., Corchnoy, S. B., and Shu, Y., Int. 1 Chem. Kinet., 27, 941 (1995). 2u3 Atkinson, R. and Aschmann, S. M., Int. 1 Chem. Kinet., 27, 261 (1995). '04 Nau, W. M., Harrer, H. M., and Adam, W., 1 Am. Chem. Soc., 116, 10972 (1994).

"' '*

'"'

CHAPTER 4

Radical Reactions: Part 2 I. I. BILKIS

Institute of Biochemistry, Food Science and Nutrition, Faculty ofdgriculture, The Hebrew University of Jerusalem Structure, Stereochemistry, and Stability . . . . . . . . . . . . . . . . . . . . . . . . . Carbon-centred Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Nitrogen-centred Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxygen-centred Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nitroxides and Spin Trapping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Homolytic Oxidation and Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electron-transfer Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photo-induced Electron Transfers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Electron Transfers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radical Ions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radical Cations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radical Anions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biradicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thermolysis and Pyrolysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photolysis and Radiolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

123 123

123

129 132 133 137 138 138 I45

151

151

157 162 169 171 174

Structure, Stereochemistry, and Stability Carbon-centred Radicals

ESR spectra of alkyl- and fluoroalkyl-C60free radicals'32of general formula CXYZ-C60 (1) have been described, and the structure of the most stable conformer has been established for each particular case. The relative stability of different conformations is determined by the electronegativity of atoms or groups X, Y, or Z, and also by the charge distribution on the surface of C6*. The conformation wherein an electronegative group X resides above the pentagon is the most stable. According to semiempirical quantum-chemical calculations, this is due to a favourable electrostatic interaction between the group and positively charged sites in the pentagon. For systems with two equivalent electronegative groups X = Y, there are two enantiomeric conformations equal in energy. Their mutual transformations occur above 200 K at a rate detectable by EPR. Organic Reaction Mechanisms l Y Y 5 . Edited by A. C. Knipe and W. E. Watts IQ 1997 John Wiley & Sons Ltd

123

Organic Reaction Mechanisms I995

124

a;

x = Y = Z = H; b; X = F , Y = Z = H ;

(1) C;

X = OH, Y = Z = H; d; X = CO,H, Y = Z = H;

e; X = Y = F, Z = H; f X = Y = Z = F g; X = Y = H, Z = CH,; h; X = Y = F, Z = CH3; i; X = CF3, Y = Z = H; j; X = CF?, Y = F, Z = H; k; X = CF3, Y = Z = F; I; X = H, Y = Z = CH3; m;X = CFx, Y = H, Z = CHI; n; X = Y = C F ? , Z = H 0; X

= Y = CF3,Z= F

Muonium, which models the chemical behaviour of the hydrogen atom, adds to imidazoline derivatives via positions 2 and 5.3 Interaction of muonium atoms with C7" fullerenes leads to the formation of five isomeric radicals of p-C,,j! Based on calculations and experimental data, an attempt was made to ascribe the muon-electron isotropic hyperfine interaction (hfi) constants to particular isomers. The structure of the tricyclohexylmethyl radical was studied by EPR. A complex hyperfine structure of the EPR spectrum was interpreted using semiempirical quantumchemical calculations within the MNDOAJHF approach. The radical is characterized by the C 3 h symmetry, with the cc-carbon and three fl-carbons lying in the same plane. The temperature dependence of the hfi constants with cc- and fi-protons is attributed to torsional movement of cyclohexyl fragments around the C,-Cp bond.' Internal rotation of methyl groups in the t-butyl radical was studied by EPR. The activation energy of the process was found to be 6 kcal mol-' .6 EPR and ENDOR spectra of radicals trapped during the photo-induced polymerization of trimethacrylate and vinylmethacrylate monomers were reported. Radical decay during post-irradiation heat treatment and dynamic phenomena involving radicals have been interpreted in the light of a dispersive kinetic model.' The 2-@-dimethylaminopheny1)indane-1,3-dion-2-yl radical (an intermediate in the inhibited liquid-phase oxidation of alkylarenes) was prepared at 350 K and ENDOR and EPR spectra of its toluene and diethyl phthalate solutions were described.8 Free radicals resulting from interactions of the t-butoxyl radical with seven terpenes, i.e. a-pinene, b-pinene, a-terpinene, y-terpinene, car-2-ene, car-3-ene, and limonene, were characterized by EPR. Despite the presence of several potentially labile hydrogen atoms, for most systems one prevailing radical species, either substituted cyclohexenyl or substituted cyclohexadienyl radical, was detected.' High-level quantum-chemical calculations have indicated that the free radical HCCCO can be attributed to two minima on the potential-energy surface of its ground electron state, with the minima corresponding to two non-equivalent canonical structures, namely propynonyl(2 j and propadienonyl(3j. In other words, structures (2) and (3) are the real isomers rather than resonance structures.'" The quantum-chemical

4 Radical Reactions: Part 2

125

calculations suggest that multiple minima may be the common feature of several 2A' ground-state free radicals.' In order to find possible stable conformations of the glycine radical in protein structures, a systematic study of the radicals resulting from the corresponding dipeptide was carried out by quantum-chemical methods.I2 The free radicals exhibit slow conformational mobility in comparison with the starting dipeptide. The flat and nearly flat conformations that contribute largely to delocalization of n-electrons are energetically most favourable.

(4)

a; X = H , Y = N 0 2 ; b; X = Y = NOz; c; X = Y = CO2H; d; X = y = co2Me; e; X = Y = COCl; f X = Y = H

A series of inert mono-and di-rnetu-substituted perchlorotriphenylmethyl radicals (4) were synthesized, and their EPR spectra, magnetic susceptibility, and electrochemical behaviour were characterized.l 3 The relative stability of hetero-substituted allyl radicals CH2=CHX (X = Be, BH, NH, 0, Mg, AIH, SiHz, PH, S) was estimated using ab initio and DFT methods. These radicals are stabilized if all atoms forming the allyl skeleton possess comparable electronegativity. In this situation, an unpaired electron is shared between terminal atoms. Tf the electronegativity of the heteroatom is markedly different from that of carbon, stabilization of the radical system is weak and the unpaired electron is predominantly localized on a less electronegative atom.l4 An equation has been suggested for estimating the relative stability of polyenyl radicals of general formula C-(C=C)N: Es(N)

=

-13.2

+ 3.95 -15.8(2)-2"

This equation was used for predicting the stabilities of the weakest C-H, C-C and C-OH bonds in vitamin A and similar compounds.l 5 'Strain-free' stabilization energies were determined for alkyl radical with a-(4-pyridyl) (7.9 kcal mol-'), a(1 -naphthyI) (12.0 kcal mol-'), and a-(2-naphthyl) (8.7 kcal mol-') fragments,I6 different a-carbomoyl substituents (CONR'R2),I7 and two or three a-methoxycarbonyl

Organic Reaction Mechanisms I995

126

groups.'* The effect of o-methyl groups on stability of cumyl radicals was discussed." Factors determining the facile formation of diphenyl(2-, or 3- or 4-pyridy1)methyl radicals from the respective dimers were the subject of the study.** The various approaches to the assessment of the relative stability of free radicals (R') produced from amphihydric compounds, such as substituted 9-phenylfluorenes, triphenylmethanols, 9-phenylxanthenes, 2-aryl- 1,3-dithianes, and 2-aryl-1,3-dioxolanes, were discussed.21 Dissociation energies of the C-H bond in acetophenone derivatives with one or two functions of divalent sulfur, i.e. -SCH2COPh and (-S),CHCOPh, were determined. The introduction of one S-substituent decreases the dissociation energy of the C-H bond. The second S-substituent leads to additional weakening of the C-H bond provided that both sulhr atoms are incorporated in a five-, six-, or seven-membered ring.22 The G2, G2(MP2), CBS-4, and CBS-Q models were used to calculate dissociation energies for H-X, CH3-X, CH,=CH-X, CH=C-X, and C H 3 C ( O F X bonds, where X is a first- or second-row substituent. A comparison with available experimental data has shown that the CBS-Q and G2 models yield the best results (the average error is 1 kcal mol-'). There are good correlations between dissociation energies for R-X and H-X bonds. For coordinatively unsaturated substituents X (Li, BeH, NH2, Na, MgH, and AIHZ), the line slopes are similar [cf. 1.20 for CH2-X, 1.20 for CH2=CH-X, 0.91 for CH=C-X, and 0.93 for CH3C(0)-XI. The other group consists of substituents X having unshared electron pairs (NH2, OH, F, PH2, SH, and Cl). In this case, linear dependences between dissociation energies for H-X and R-X bonds have different slopes [cf. 0.75 for CH3-X, 0.85 for CH,=CH-X, 0.46 for CH=C-X, and 1.16 for CH,C(O)-X]. The established correlations have been analyzed in terms of Pauling's electronegativity interpretation of covalent and ionic contributions to bonding.23

Nitrogen-centred Radicals EPR was employed to investigate the structure of aminyl radicals produced via the addition of photochemically generated trialkylsilyl radicals R3Si' (R = Me, Et, Pr') to N-methylene-t-butylamine(H2C=NBut) or via interaction of alkoxyl radicals (R'O') with aminophosphanes (EtO)2PN(R)CH2SiMe3.24 R3Si'+ CH2=NBuf R'O'+ (EtO),PN(R)CHzSiMe3 R

=

-----f

R3SiCH2-fi- But

+

(5) Me3SiCHz-N-R

+ (EtO),POR'

Me, Bu'

The resulting aminyl radicals (5) give preference to conformations (5a) and (5b) in which the B-C-Si bond eclipses the N 2pn orbital formally populated by one electron. Lineshape effects, observed in EPR spectra, indicate a hindered rotation around the R3SiCH2-N bond.

4 Radical Reactions: Part 2

127

There is some evidence that the aminyl radicals (5) rearrange to a-aminomethyl radicals ( 6 ) due to an intramolecular 1,2-shifi of the trialkylsilyl group from the carbon to nitrogen atom:

(5)

-+

'CH2N(But)SiR3 (6)

A number of aminyl radicals (7), stabilized by capto-dative interaction of alkoxyl substituent (donor) with a 4-X-2,6-dinitrophenyl substituent (acceptor), were obtained by oxidation of the corresponding mines with lead tetr aa~ etate.The ~ ~ values and signs of the hfi constants of unpaired electron with nitrogen, fluorine, and hydrogen nuclei were determined by ENDOR and TRIPLE resonance spectroscopy. The EPR spectrum

RO-I? NO2

(7) a; R = Me, X = H; b; R = Me, X = NO5 c; R = Et, X = H; d; R = Et, X = NOz; e; R = Pr', X = NOz; f R = Me, X = CF3; g; R = Et, X = CF3; h; R = Me, X = Me; i; R = Et, X = Me

of the 2,6-dinitrophenylaminylradical (7a), observed during oxidation of the respective amine, tends to transform quickly to the spectrum of the 2,4,6-trinitrophenyl derivative (7b). A possible mechanism of the substitution of a nitro group for a hydrogen atom in position 4 of the aromatic fragment is discussed. Aminyl radicals (7) are stable in an inert atmosphere, but in the presence of oxygen tend to transform to the corresponding nitroxides. A number of persistent, isolable, and oxygen-insensitive aminyl radicals (8)--(10) were obtained via reaction of PbOz with the corresponding anilines.26p28The stability of aminyl radicals was found to depend on the nature of substituents in aromatic fragments of both aniline and thiol parts. Specifically, radicals (8) are most stable when X and Y are electron-acceptor groups.26 EPR spectra of radicals (8H10)have been described. The synthesis of partly deuteriated aminyl radicals (9) and (10) made it

Organic Reaction Mechanisms 1995

128

(8) X = 4-Me, 4-C1,4-Br, 2,4-C12, 3,5-c12, 3-N02, 4-N02; Y = 4-Me, H, 3-C1,4-C1

possible to determine hfi constants and thus get a picture of the spin-density distribution in those There is still no loss of interest in short-lived aminyl radicals and their protonated forms. Researchers' attention was mainly focused on a search for high-level quantumchemical methods for the accurate estimation of spin-density distribution in these species,29 determination of the acidity of protonated forms,30 and characterization of their relative reactivity in (a) addition to the double and (b) abstraction of hydrogen atom.30Thus, multi-reference CI and DFT methods were used to study the geometry and spin-density distribution in the radical cation of azetidine and its deprotonated form, i.e. azetidin-1-yl radicaL2' According to the calculations, the radical cation has a planar geometry, whereas a neutral aminyl radical is puckered with an optimized puckering angle of 22-23". The spin-density distribution in the radicals, calculated by the above methods, was found to be in satisfactory agreement with experimental values. Ab initio investigation" of the addition of aminyl radicals and their protonated forms to the double bond has indicated that the radical-cation form is much more reactive than the neutral form, which is in good agreement with e~periment.~' The experimental data have shown that the radical-cation form is about four times as active as is the free-radical form in addition to the double bond, whereas in the process of hydrogen-atom abstraction their reactivities are ~omparable.~'Several

4 Radical Reactions: Part 2

129

I

Ph SCHEME 1

types of radical clocks based on cyclization or fragmentation reactions of dialkylamine radical cations (Scheme 1) were propo~ed.~' The radical clocks can be used fbrther for the quantitative characterization of different kind of reactivities of the species. However, as indicated3' application of the radical clocks is complicated by the fact that both cyclization and fkagmentation reactions are very pH sensitive (the pK, of dialkylamine radical cations is about 7), and also can be sensitive to the polarity of media.

Oxygen-centred Radicals The absorption spectra and chemical behaviour of 2-alkylbenzoyloxyl radicals have been described. Intramolecular transfer of the hydrogen atom takes place in these radicals, leading to the formation of the corresponding 2-carboxybenzyl radicals32 (Scheme 2).

* O Y O

R%

\

-

H-oYo R

y

\ J

R = H, Me, Ph SCHEME2

A previously proposed simple method for the assessment of energy of homolytic cleavage of A-H bonds in weak AH acids with the use of the pKAHand oxidation potentials of conjugated anions A- was applied to evaluate such energy of 0-H bonds in 18 phenols.32 The theoretical values are in agreement with the experimental values within ca 2 kcal mol-' . The results suggest that introduction of two t-butyl groups in positions 2 and 6 of phenol derivatives decreases the energy of homolytic cleavage of

Organic Reaction Mechanisms 1995

130

the 0-H bond by 3.6-10.3 kcal mol-'. Such a decrease is caused by destabilization of the initial state due to increasing steric strain in the vicinity of the OH group rather than by additional stabilization of the radical. The same approach was used to evaluate structural effects on the enthalpies for homolytic cleavage of the 0-H bonds in different k e t o ~ i m e s . ~ ~ Geometry, spin-density distribution, and vibrational frequencies and their isotope shifts have been calculated for the phenoxyl radical by taking advantage of different high-level quantum-chemical methods. The results of DFT calculations are in satisfactory agreement with experiment, and also with more expensive UNOCASIICASSCF calculation^.^^ The DFT approach was also used to calculate geometry, spin-density distribution, and vibrational frequencies and their isotope shiRs for biologically important tyrosinylphenoxyl radical (1 1). The results obtained permit a more reliable identification of this radical in biological systems.36 Using t-butoxyl radical and 1,3,5-trimethoxybenzeneas an example, the first spectral evidence for the existence of 7c-complexes between alkoxyl radicals and electron-rich aromatic compounds was obtained.37 Absorption spectra of a series of (arylcarbiny1)oxyl radicals (12H14) have been described.37Different from simple alkoxyl radicals, the radicals (12)-(14) are characterized by strong absorption in the visible region, with Amax ranging from 460 to 590 nm depending on the structure of the (ary1carbinyl)oxyl radical. The substitution of a methyl or phenyl group for benzyl hydrogen atoms, as well as substitution of an electron-donor group for aromatic hydrogen atoms, causes shifts of Amax to the long-wavelength region. Similar dependences are characteristic of the absorption spectra of peroxyl radicals. For example, as distinct from alkylperoxyl radicals with absorption at 250 nm, arylperoxyl radicals Ar02' (Ar = phenyl, 4biphenylyl, 1- and 2-naphthyl, 9-~henanthryl,~' and 2-pyridyI3') absorb in the visible region. Their wavelength depends strongly on the nature of the aromatic fragment and ranges from 490 to 700 nm. The substituents in the aromatic fragment also exert a significant effect?' Specifically, insertion of electron-donor substituents into the pposition of phenylperoxyl radical leads to a strong shift of A,, towards the IR region. Like arylperoxyl radicals, vinylper~xyls~' are characterized by absorption in the visible

'0

WNH2 7' (y -

H

(11)

',,,

%02H

'0

R2

-

(12)

a; R' = R2 = H; X = H, 4-Me, 4-OMe b; R' = R2 = Me; X = H, 4-Me, 4-OMe C; R' = Ph; R2 = H; X = H

d; R ' = Ph; R2 =Me; X = H

4 Radical Reactions: Part 2

131

A, is at 440 nm and is strongly region: for vinylperoxyl radical CH2=CH-02', dependent on the nature of the substituents at the carbon atoms of the double bond. The aforementioned arylperoxyl and vinylperoxyl radicals were obtained by interaction of the corresponding aryl radicals with molecular oxygen. These reactions occur with rates exceeding 2 x lo9 s-' .38241 Unlike alkylperoxyls, both aryl- and vinyl-peroxyl radicals are strong oxidants which are reduced with organic electron donors, such as 2,2'azobis(3-ethylbenzothiazolined-sulfonate ion), chlorpromazine, and 6-hydroxy2,5,7,8-tetramethylchroman-2-carboxylicacid, at very high rates.38339341 Ab initio calculations were applied for modelling the potential-energy surface of interaction of vinyl radical with molecular oxygen.42The results obtained indicate that the process, the final products of which are 'CHO and CH20, follows a complex mechanism that involves cyclization of the first-formed vinylperoxyl radical to the dioxiranylmethyl radical (15) (Scheme 3) rather than the dioxetanyl radical (16) (Scheme 4) proposed earlier.

SCHEME 3

(16) SCHEME 4

The ab initio and DFT calculations for reactions of intramolecular rearrangement of methylperoxyl and ethylperoxyl radicals were published.43 For CH302 ', the main reactions are re-dissociation to CH3 ' 0 2 , dissociation to CH30' + 0, and isomerization producing 'CH200H radical that decomposes hrther into CH20 and 'OH. Ethylperoxyl radical is isomerized due to 8-self-abstraction producing 'CH2CH200H that further undergoes transformation by one of two routes, one of

+

132

Organic Reaction Mechanisms I995

which leads to the formation of ethene and H02' and the other to the formation of oxirane and 'OH radical. Experimental and theoretical methods were used to study the thermochemistry and kinetics of the first step of interaction of ol-chloroethyl radical with molecular oxygen.44 EPR and UV-visible spectra of thiylperoxyl radicals in various organic and aqueous matrices have been described. Unlike alkylperoxyls, thiylperoxyl radicals are characterized by absorption within the visible spectral region (A,,, = 560 nm), and also by comparable hfi constants for terminal and inner oxygen. Unusual features of thiylperoxyl radicals have been interpreted assuming the specific nucleophilic solvation of the sulfur atom in polar solvents, which stabilizes the charge-transfer state RS'OO;. To support this assumption, ub initio calculations were applied to a series of systems for which nucleophilic assistance provided by solvent was modelled by interaction of the sulfur atom with anions X- (HO-, F-, SiH3 -). An attempt has been made to relate structural features of thiylperoxyl radicals to their r e a ~ t i v i t yFor . ~ ~aerobic oxidation of malonic acid by Ce(IV), the peroxymalonyl radical was detected by EPR, and the kinetics of its formation from malonyl radical were studied.46

Miscellaneous Radicals UMPYDZP/TZP ab initio calculations were used to examine the geometric structure and spin-density distribution in Si-centred free radicals of general formula Y,SiMe3-, (Y = C1 or SiMe3, n = O-3).47 The calculated values are in satisfactory agreement with the hfi constants for unpaired electron with 29Si [ ~ ( ~ ~ s Noticeable i)]. changes of u ( ~ ~ caused S ~ ) by gradual substitution of the electron-acceptor chlorine atom for a methyl group are due to the electronic effect of the substituent rather than to the change of geometry of the radical centre. In contrast, substitution of the electron-donor trimethylsilyl group for a methyl group makes the radical centre less pyramidal. It has been noted that application of the correlation between a(*'%) and J(29Si-H), as a source of information about geometry of both silyl radicals Y,SiMe3-, and their precursors Y,SiHMe3-,, is correct, in the strict sense, only for a radical family (where the structure of substituent Y is fixed). According to Guerra?' there is no direct unambiguous relationship between hybridization of the rr(Si-H) bonding MO and the SOMO of the silyl radical and the spatial orientation of bonds of the central silicon atom. Of great importance is the electronic nature of substituents, which has a profound effect on hybridization of the above orbitals for a definite geometry of the central fragment. The same is also true for alkyl and phosphonyl radicals.48From the results reported by G ~ e r r a , ~it' follows that geometric interpretation of the influence of the nature of the P-substituent on hfi constants with 8-hydrogen atoms should be used with care. The methods of generation, spectral characteristics, structural features, and reactivities of silyl radicals have been discussed at length in a re vie^.^'

4 Radical Reactions: Part 2

133

Nitroxides and Spin Trapping The synthesis, structure, properties, and applications o f a number of perfluoroalkyl nitroxides have been re~iewed.~’ 2-Amino-substituted quinazolidine-4(3H)-ones (17) are oxidized by p-nitroperbenzoic acid @-NPBA) to produce mainly endo- (18) or exocyclic (19) nitroxide depending on the nature of substituent R in the 2-amino group (Scheme 5). When the Bu‘02H-PbO;! system is used as an oxidant, the main oxidation product is exocyclic nitroxide (19). The nitroxides formed were identified by EPR.”

0’

p-NPBA

(,

X

SCHEME 5

Nitroxides are among the major products resulting from bas :-catalyzed oxidation of secondary aromatic amines with molecular oxygen.52 Mona .yclic biradicals o f the imidazoline series were obtained by treating 1-hydroxy-3-imic fzolidine-3-oxide with alkyl- or phenyl-lithium with subsequent oxidation. Anisotropi, EPR spectra of the biradicals so obtained were ~haracterized.~~ A new series of pH-se. citive nitroxide diand tri-radicals (20) and (21) with a protonated amino group were sy ~ t h e s i ~ eEPR d.~~ spectra of the polyradicals depend on the nature of solvent, temperatui and pH. The spin-spin exchange increases considerably with decreasing pH. Proto,,ation of the central nitrogen atom seems to promote stabilization of those conformations where nitroxyl centres are located most closely to each other. Crystal structures and magnetic properties have been characterized for a number of compounds with one or two nitronylnitroxide (N) or iminonitroxide (I) groups bound to thiophene (22j(26),552,2’-bithienyl (27)-(30),55thieno[3,2-h]- (31), (32) or thieno[2,3-h]-thiophene (33), (34) rings.56

134

Organic Reaction Mechanisms 1995

I

0' (21)

R = C02Me, p-C6H&02Me, CH20H COzH, P - C ~ H ~ C O ~ H

2-[p-(N-t-Butyl-N-oxyamino)phenyl]-4,4,5,5-tetramethyl-4,5-dihydroimidazo1-3-ox-

ide- 1-oxyl (a stable biradical with a triplet ground state) was ~ y n t h e s i z e dTheoretical .~~ results suggest that not only monomers of nitroso compounds but also their dimers and radical anions can play the role of spin traps, although the last two are less effective. These results should be taken into account for the analysis of kinetic spin-trapping e~perirnents.~~ An alternative route for spin-adduct formation from nitrones in oxidative systems was discussed. Radical cations of nitrones, whose structure was confirmed by EPR and UVvisible spectra, were shown to react readily with nucleophilic reagents yielding nitroxyl radicals (path a; Scheme 6) ('inverted spin trapping'), which formally corresponds to the addition of free radicals from nucleophile to nitrone. Another alternative to the traditional route (path b; Scheme 6) of formation of spin adducts from nitrones and nucleophiles in oxidative conditions is that of addition of nucleophile to nitrone followed by oxidation of the adduct to nitroxide (path c; Scheme 6).59 Photo-induced reactions were used to obtain spin adducts from N-haloimides and four spin traps (2-methyl-2-nitrosopropane, phenyl t-butyl nitrone, N-t-butyl nitrone, and 1,l-di-t-butylethylene).In the case of the first three spin traps, the formation of spin adducts is preceded by intermediate formation of radical cations of the spin traps due to electron transfer from the trap in excited state to N-haloimide.60 As in the previously mentioned work,59 'inverted spin trapping' is discussed. The first examples of solutionstable radical cations of dimeric forms of nitroso compounds were reported.6' Spin adducts of short-lived free radicals from C-H acids were detected in alkaline solutions containing a trap (2-methyl-2-nitrosopropane or phenyl t-butyl nitrone) and C-H acid. Nitroxides were formed upon heating or UV irradiation of the system in the

4 Radical Reactions: Part 2

PhtH-N-Bu' I 0'

I

PhCH=N-Bur

I

0'

4 b-

PhCH-N-Bur

135

U

Y-

b

Y'

C

-e SCHEME 6

*

PhCH-N-Bu' I I Y

136

Organic Reaction Mechanisms I995

absence of a special source of free radicals. The mechanism of spin-adduct formation has been proposed.62 Spin trapping made it possible to establish the structure of short-lived radicals formed: (a) by radiolysis of CF2CICF2CI, CFC13, CFC12CH3, CHF2CF2CF2CI, CF9CHFCF3, CC4, and CF2C1CFC12;63 (6) during reduction of CF2C1CFICl and CF21CFC12 by zinc;63 and (c) by sonolysis of aqueous solutions of N,Ndimethylf~rmamide.~~ Interaction of hydroxyl radicals with deoxyribonucleic acid (DNA) (one of the possible reasons for radiation damage of DNA) with its components was studied in the presence of 2-methyl-2-nitrosopropane as a trap. Pynmidine bases, nucleotides, and nucleosides were found to add the hydroxyl radical to the C ( 5 t C ( 6 ) double bond. In some cases for nucleotides and nucleosides, large amounts of other radicals were formed due to abstraction of the hydrogen atom from a sugar fragment. Formation of the two types of radicals (from the base andor sugar fragment) was also observed for purine nucleotides and nucleosides. The results obtained are regarded as evidence for a fast transfer of the radical centre from base moiety to the sugar fragment. According to EPR spectra of spin adducts of DNA and primarily of its low-molecular-weight fragments (obtained by interaction of partly immobilized DNA with enzyme DNase or an acid), pyrmidine bases are the sites of the primary attack in DNA.6s Aryl radicals showed similar behaviour with respect to DNA and RNA.662-Methyl-2-nitrosopropane was also employed to examine another possible route of radiation damage of DNA, whose key step was interaction of radical cations of pyrimidine bases with nu~leophiles.~'The EPR spectra of spin adducts indicate that radical cations of 1substituted uracil attach nucleophiles (H20 or HP0d2-) to position 5 , and radical cations of thymine to position 6, while radical cations of cytosine derivatives undergo opening of the cycle in the course of interaction with nucleophiles. The regioselectivities of hydroxyl radical addition to pyrimidine bases and of water addition to their radical cations are different, although in both cases the same products are formed. The spin adduct formed by addition of hydroperoxyl radical to 5-diethoxyphosphoryl-5-methyl-I-pyrroline-N-oxide (DEPMPO) is more stable than its analogue formed from 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). Hence DEPMPO may be regarded as a promising trap for peroxyl radicals.68 EPR spectra have been characterized for ten nitroxide radicals in ten different solvents. The nitroxides can be attributed to addition of hydrogen atom and C-centred radicals (Me', 'But, 'Ph, 'Phd5, 4-FC6H4', 4-CIC6H4', 4-MeC6H4', 2-MeC6H4') to DMPO. The results obtained will allow a more reliable identification of short-lived radicals from EPR spectra of the corresponding spin ad duct^.^^ Also described were the EPR and ENDOR spectra of spin adducts of a series of C- and 0-centred radicals with new spin traps, i.e. 2substituted-DMPO-type nitrones, namely 2-phenyl-5,5-dimethyIpyrroline-N-oxide, 2,5,5-trimethyl- 1-pyrroline-N-oxide, and 2-phenyl-3,3,5,5-tetramethylpyrroline-Noxide. In many cases, data on the aN hfi constant, together with long-range ay-H hfi constants of spin adducts, allow the determination of the structure of short-lived radical precursor.70

4 Radical Reactions: Part 2

137

Homolytic Oxidation and Reduction Dopamine (35) is spontaneously oxidized by molecular oxygen in neutral and slightly alkaline solutions. A detailed kinetic study has shown that abstraction of a hydrogen atom is the rate-determining step. Subsequent reactions yielding dopaminochrome (36) are relatively fast and cannot be examined. Further, dopaminochrome undergoes polymerization producing melanine. The polymerization process is insensitive to pH and oxygen concentration. The second main reaction product is hydrogen peroxide. Metal ions, except for Mn2+, do not affect the rate of aut~xidation.~'

A dramatic effect of molecular oxygen, benzoquinone, and TEMPO on the yield and composition of reaction products of alkane oxidation by dimethyldioxirane suggests that the process follows a free-radical mechanism.72 Additional support for this suggestion comes from radical-trapping experiments: alkyl, a-alkoxyalkyl, and acyl radicals were trapped by protonated 2-methyIq~inolines~~ or CBrC13 and C U C I in ~~~ reactions of alkanes, ethers, and aldehydes with dimethyloxirane, respectively. A free-radical mechanism was suggested for the oxidative deamination of primary amines by benzyl A radical non-branched chain mechanism has been proposed for oxidative decarboxylation of cyclohexanecarboxylic acid induced by hydrogen peroxide.77 The kinetics of thermal autoxidation of all-trans-p-carotene in chlorobenzene were measured at 50°C. For the initiation step, the reaction is first-order with respect to oxygen and p-carotene. The rate constants and activation parameters of this step have been determined. The effect of promoters (azobisisobutyronirile) and inhibitors (atocopherol) on the {&carotene oxidation rate has been characterized.'* The kinetic behaviour and regioselectivity of autoxidation of n-alkanes have been d e ~ c r i b e d . ~ ~ Chlorodifluoromethylbenzene undergoes reductive dechlorination by samarium diiodide in the presence of various alcohols. The reaction mechanism involves intermediate formation of a,a-difluorobenzyl radical and the corresponding anion. The suggestion is supported by data on the influence of radical traps (various alkenes and alkynes) and of carbanion traps (trimethylsilyl chloride, ketones, and aldehydes) on the composition of reaction products." Pentafluorobenzoic acid undergoes reductive defluorindtion in liquid ammonia in presence of sodium and zinc. While reduction with sodium affects a small part of the starting compound, causing extensive defluorination and loss of three (p-and two 0-)or more fluorine atoms, reduction with zinc is complete and is accompanied by removal of one fluorine atom from only the p-position. The reasons why the reductants exert

Orgunic Reaction Mechanisms 1995

138

different effects have been analyzed. The factors responsible for regioselectivity of reductive defluorination have been discussed.” p-Substituted 3-phenylprop-I -yl hydroperoxides are reduced with iron(I1) in the presence of copper(I1) producing p-substituted 3-phenylpropan-l-ols, 3-phenylpropanals, and a mixture of small amounts of 6- and 7-substituted chromans (Scheme 7). The nature of the substituents in the aromatic fragment and the reaction conditions affect the structure and composition of reaction products. Assuming the key role of 3arylpropoxyl radicals, the structure of intermediates leading to cyclic products and the effect of substituents on their relative stabilities have been proposed.82

SCHEME 7

Electron-transfer Reactions Photo-induced Electron Trunsfers Photo-induced electron transfer (PET) between fkllerene c60 and N,N,N’,N’tetramethylbenzidine was studied by laser flash photolysis in polar and non-polar solvents and their mixtures. Electron transfer was found to follow two different mechanisms for polar and non-polar solvents. For solvent mixtures, the two mechanisms occurred sim~ltaneously.~~ Photo-reduction of fdlerene c60 with triethylamine results in the production of cyclic adduct N-ethyl-trans-2’,5’dimethylpyrrolidino[3’,4’:1,2]c60 hllerene. The reaction mechanism involves electron transfer, proton transfer, and recombination of C60H’ and a-aminoalkyl radicals. The resulting adduct with both electron-donor and electron-acceptor fragments transforms to a cyclic adduct by the above sequence of elementary stages.84 Irradiation of bicyclo[m. 1.O]alkanones (rn = 3-6) in the presence of triethylamine and lithium perchlorate causes opening of the cyclopropane ring and the formation of either 3-methylcycloalkanones or ring-expanded alkanones depending on the substituent in position 3 and the size of the cycle.*’ The reaction mechanism involves electron transfer from triethylamine to ketone and opening of the cyclopropane ring in the radical anion of the starting ketone. Regioselectivity of the ring opening is controlled by the relative stabilities of distonic radical anions (Scheme 8). The structure of the primary products formed during irradiation of the dye 5,7diiodo-3-butoxy-6-fluorone (polymerization photo-initiator) in the presence of electron donors, tertiary amines, or borate salts has been established. When tetrabutylammonium triphenylbutylborate was used as an electron-donor, the only intermediate was the

4 Radical Reactions: Part 2

139

R' = H, Bu, COzMe

R=H;n=1,2

R' = H, C02Me. n = 2 R" = H, C02Me. n = 3,4 I R"

radical anion of the starting dye resulting from one-electron reduction of the dye triplet state. However, for N,N-dimethyl-2,6-diisopropylanilinethe neutral radical, which resulted from protonation of the first-formed radical anion, was detected for the first time. Proton transfer from the radical cation of amine to the radical anion of the dye was so fast that could not be detected on the nanosecond time-scale.86 Photo-reduction of m-trifluoromethylbenzoate ester (37) by N-methylcarbazole was used for generation of 5,6-dihydro-5-hydroxythymid-6-yl radical (38) (Scheme 9). Rate constants for the radical-centre transfer to the sugar moiety, as well as those of dehydration for the radical (38), fall within the range of the lowest rate constants of strand scission. Consequently, neither of the processes can be responsible for the strand scission.87 To model the behaviour of the radical pair resulting from thermal electron transfer in aliphatic nucleophilic substitution, photo-reaction of 9-phenylfluorenyl anion with 6iodo-5,5-dimethylhex-l-enehas been studied. Owing to electron transfer, this yields two types of products with acyclic and cyclic alkyl fragments via isomerization of the alkyl radical intermediate (Scheme 0

HO

hv

F

N-methylcarbazole MeCN - H20 ( I :3)

OH

(37)

OH (38)

Organic Reaction Mechanisms 1995

140

0,. -a,-,P \

+

-

SCHEME 10

The effect of a magnetic field on the recombination of radical ion pairs arising from irradiation of chemically bound donor and acceptor fragments (polymethylene-bound pyrene and N,N-dimethylaniline) was examined in solvents of different polarity. A new model has been proposed to explain the influence of solvent polarity on the effect of magnetic field on the yield of recombination products: exiplexes and pyrenyl triplets.89 Radical cations of diarylalkenes or diarylalkanes are formed via electron transfer from the parent compounds to electron-acceptor photo-sensitizer. The influence of substituents (m-andp-cyano groups, m- andp-methoxy groups) on the reactivity of the radical cations toward nucleophilic addition and cleavage of the C-C and C-H benzylic bonds was chara~terized.~' In the radical cations of aliphatic esters produced by photo-induced electron transfer, either the C-H or the C-C bond is broken. The direction of fragmentation can be predicted from simple thermochemical estimates." Using adamantane, cyclohexane, and 2,3-dimethylbutane as model compounds, it has been shown that alkanes can be functionalized via the primary, secondary, and tertiary C-H bonds as a result of their one-electron photo-oxidation to radical cation followed by depr~tonation.~~ The various donor systems (t-BuX) suitable for generation o f t butyl radical under mild conditions have been characterized. The process consists of photo-induced oxidation of the donor t-BuX by 1,2,4,5tetracyanobenzenethat leads to

4 Radical Reactions: Part 2

141

formation of the radical cation t-BuX+'. The radical cation decomposes easily producing t-butyl radical and an electrophilic leaving group Xf . Further, t-butyl radical can be involved in the interaction with either radical anion of polycyanoarene or electron-acceptor-substitutedalkenesY3Such an approach was employed for generating a-aminoalkyl radicals from a-silylcarbamates by irradiation of these latter compounds in the presence of catalytic amounts of 9,lO-dicyanoanthracene and biphenyl.94 Photochemically excited dicyanoanthracene oxidizes biphenyl to the radical cation that in turn oxidizes a-silylcarbamate, whose radical cation undergoes C-Si bond cleavage into an a-aminoalkyl radical and trimethylsilyl cation. The a-aminoalkyl radical interacted with an electron-acceptor-substituted alkene to yield finally a yacceptor-substituted amino derivative (Scheme 1 1).

A

A = electron-acceptor group

A

SCHEME 11

To examine the effect of homoconjugation on the reactivity of radical cations of substrates having strained rings as well as olefinic moieties in suitable positions, the products formed by irradiation of 7-methy lenenorbomadiene (39) and 7-methylenequadricyclane (40) in the presence of 1,4-dicyanobenzene and phenanthrene were analyzed in detail.95The data obtained indicate that the main reaction of cation radicals (39'') and (40+') is exo-addition of the nucleophile to olefinic carbons in (39+') and cyclopropane carbons in (40+') with subsequent rearrangement of the resulting free radicals (41) and (42) to the intermediate (43) (Scheme 12). Different from radical cation (40+'), the radical cation (39+') is subjected to some extent to endo-attack by the nucleophile. Although exo-methylene groups participate in delocalization of spin density,y6they are not attacked by the nucleophile in either of the radical cations. However, exo-methylene groups affect the reactivity of primary free radicals by stimulating their isomerization to radicals of ally1 type (43) (Scheme 12).y5

142

Organic Reuction Mechanisms 1995

(39+')

(41)

(42)

(40+')

SCHEME12

The electron-transfer-inducedisomerization of two chiral vinylcyclopropane systems, (1R,5R)-( )-sabinene (44) and (1S,5s)-( +)-a-thujene (46), has been described; (44) and (46) transform to less-strained conjugated dienes (s)-( )-B-phellandrene (45) and (s>-( )-a-phellandrene (47), respectively, due to stereoselective sigmatropic rearrangement of the radical cation intermediates (Schemes 13, 14).97 Photo-oxidation of 3,6-diethyl-3,6-dimethyl-1,2-diazocyclohexene(48) by 9,lOdicyanoanthracene yields the distonic radical cation (49), for which a 1,5-shift of the hydrogen atom takes place (Scheme 15). By taking advantage of labelled and optically pure starting compounds, it was possible to determine that this shift occurred stereospecifically and regio~electively.~~

+

+

+

(47)

SCHEME 14

I

4 Radical Reactions: Part 2

143

SCHEME 15

Irradiation of a complex of the diazene (50) with tetracyanoethylene (TCNE) leads to the formation of radical ion pair (51) of distonic radical cation and radical anion of TCNE (Scheme 16). In polar solvents the radical ion pair recombines forming the final bicyclic product (52). In non-polar solvents, an alternative route is prefered. This route involves the back electron transfer from the radical anion of TCNE to distonic radical cation and subsequent addition of the resulting biradical to the double bond of TCNE.99 The mechanism of photo-cycloaddition of tetraarylthiirane with TCNE was investigated.loo The primary radical cation formed upon irradiation of the complex of tetraarylthiirane with TCNE is characterized by localization of SOMO on electrondonor aromatic fragment @-anisyl moiety, for instance). The further opening of the thiirane ring in the radical cation is caused by stereospecific cleavage of the C-C bond. Interaction of the resulting distonic radical cation with radical anion of TCNE yields the cycloaddition product.

x

& NcxCN NC

CN

CN

(52)

;CHEME

16

144

Organic Reaction Mechanisms 1995

+

The only products of 2 2-photo-cycloaddition of quinones to cis- and transanetholes @-propenylanisole) are oxetanes. Stationary and time-resolved CIDNP experiments, and combined CIDNP detection with photo-induced electron-transfer sensitization, have helped to elucidate the role of radical ion pairs, produced by photoelectron transfer, in the mechanism of formation of final reaction products."' Electrocyclization of 1,2-bis(l -phenylvinyl)benzene (53) to o-xylylene (54) was induced by photo-electron transfer to TCNE or 9,lO-dicyanoanthracene (Scheme 17). Evidence for the formation of o-xylylene was obtained spectroscopically (Ama = 446 nm) and from analysis of the product of its interaction with TCNE (55).'02 Ph

6h

(53)

Ph

Ph

NcxcNl

. NC

CN

Ph

(54)

+

NC

NC

NC Ph

Ph

SCHEME 17

(55)

Irradiation of diphenylphosphinous acid (56) and 10-methylacridinium iodide (57) in an inert atmosphere was shown to result in the formation of diphenylphosphinic acid (58) and 10-methylacridan (59) (Scheme 18). From the data on the effects of medium, atmosphere, and iodide ion and molecular iodine additives on the composition of the reaction products, it was concluded that the excited state gave rise to the radical cation of (56) and 10-methylacridinyl radical.lo3 The role of radical cations of hexamethylbenzene in the formation of products of irradiation of hexamethylbenzene-molecular oxygen complexes is discussed.lo4 The effect of solvent, substituent, and isotopic substitution on the rates of back electron transfer in contact radical ion pairs resulting from irradiation of complexes of CIO with substituted benzenes in aprotic polar solvents has been characterized. Basic difficulties associated with extracting accurate information on the exothermicity of reactions,

4 Radical Reactions: Part 2

145

SCHEME 18

reorganization energies, and electron coupling from measured rate constants have been re~ealed.'~' Other Electron Transfers

In a review'06 of the results of long-standing investigations, it was concluded that, in addition to the classical SN1 and sN2 mechanisms of aliphatic nucleophilic substitution, the mechanism involving electron transfer from nucleophile to substrate should be taken into consideration. The parameters of reacting systems which contribute to the accomplishment of each mechanism have been determined. Interactions of geminal dihaloalkanes (6,6-dichloro-5,5-dimethylhex-l-ene and 6,6diiodo-5,5-dimethylhex-l -ene) with lithium diisopropylamide,lo' sodium diphenylphosphide,Io8 and lithium na~hthalenide"~have been studied. Data on the structure and ratio of products formed in the first two cases were compared with the results obtained for lithium naphthalenide, which usually acts as a one-electron reductant in reactions with alkyl halides. The comparison suggests that 6,6-diido-5,5-dimethylhex-l -ene interacts with lithium diisopropylamide and sodium diphenylphosphide by the electrontransfer mechanism, while the 6,6-dichloro analogue reacts by the mechanism involving electron transfer from only sodium diphenylphosphide. Lithium diisopropylainide behaves as a base with respect to 6,6-dichloro-5,5-dimethylhex1-ene. Investigations of nucleophilic substitution reactions of the SRNl type have continued. The range of substrates and nucleophiles participating in these reactions has become wider, and the synthesis potential offered by this mechanism is being used. It has been shown that, in DMSO, 1-iodoadamantane takes part in S R N l reactions with enolates of acetone, of acetophenone, of propiophenone, and of anthrone."' The anion of nitromethane is inert in this reaction; however, adamantylnitromethane can be obtained if the reaction is carried out in the presence of acetonate ion. Relative reactivities of the above anions towards the adamantyl radical have been obtained. The results have been interpreted on the basis ofpK, data for conjugated acids and on the change of system 71-energy during the coupling reaction. l o The SRNl reaction can be considerably accelerated by introducing a carbonyl group into a- and p-positions of l-chlorobicyclo[2.2. llheptane and 1 -chlorobicyclo[2.2.2]octane, which has been demonstrated for the reaction of 1-chloro-3,3-dimethyl-2oxobicyclo[2.2.1Iheptane, 4-chloro- 1,7,7-trimethyl-2-oxobicyclo[2.2.1Iheptane, and 1chloro-3,3-dimethyl-2-oxobicyclo[2.2.2]octanewith diphenylphosphide anion in liquid

Organic Reaction Mechanisms 1995

146

ammonia. The carbonyl group considerably decreases the effective activation energy of the reaction due to its mediator role in electron-transfer processes."' It has been demonstrated that sulfonamides are suitable substrates for the accomplishment of the SRN1reaction via the nitrogen atom. Thus, as a result of the SR,l pathway, the interaction of N,N-dibutyl-p-toluenesulfonamidewith diphenylphosphide anion with subsequent oxidation produces the corresponding phosphinic amides (Scheme 19).

"'

Vicinal dinitro derivatives of dioxane can be synthesized by the SRN1reaction either by interaction of geminal chloronitroalkanes with the anion fi-om 5-nitro-l , 1dimethyldioxane or by interaction of the anion from nitroalkane with geminal chloronitrodimethyldioxane. The first provides better possibilities for the optimization of the yield of the target product. ' I 3 2-Chloromethyl-3-nitroimidazo[ 1,2-a]pyrimidine (60) participates in the SRNlreaction with the anion of 2-nitropropane in conditions of phase-transfer catalysis. The C-alkylated products (61) and (62) are obtained in good yields'14 (Scheme 20). The sodium salt of 1,3,6-trimethyI-5-nitrouracilreacts with alkylating agents such as p-nitrobenzyl chloride and 2,2-dinitropropane by the S R N l mechanism to form new

SCHEME 20

4 Radical Reactions: Part 2

147

potentially bioactive 5-nitrouracil derivatives. 1,3-Dimethyl-5-nitro-6-chloromethyluracil can also be involved in the SRNl reaction with the anion of 2-nitropropane."' Conditions have been found in which dichloroarenes yield products of monosubstitution as a result of an electrochemically induced SRNl reaction. Suitable are those nucleophiles which provide the role of electron-donor substituents upon insertion into the aromatic fragment, e.g. phenoxides and enolates. It was specified that electrolysis should be performed with a low current and in the presence of a redox mediator."' To increase the number of vinyl systems capable of participating in SRN 1 reactions, some stilbene derivatives having an electron-acceptor group at the double bond (63), (64) have been synthesized. However, none of the synthesized compounds reacts with pinocolone enolate by the SRN 1 mechanism. The other transformation pathways turned out to be energetically more favourable. Compounds (63) and (64) interact with pinacolone enolate producing diphenylacetylene, most probably due to two successive steps of electron transfer. Compounds (65) and (66) take part in the process of ionic deformylation caused by addition of pinacolone enolate to aldehydic carbonyl. Methylphenylacetylene is formed as end-product of the reaction. Fluorenylidene derivative (67) follows the classical ionic addition-elimination mechanism.'

X

Ph

I

"XY,,# (63)

(64)

a; X = I, Y = NOz b;X=Y=I c;X=Y=Br

NO2 Ph

Br Ph

CHO

-Me

(65)

Ph

Me

P

O

M

e

Br%O (66) -

(67)

An electron-transfer mechanism has been proposed as one of the main pathways of debromination of erythro- 1,2-dibromo-1pnitrophenyl-2-phenylethanein the presence of the anion of 2-nitropropane, leading to the formation of trans-p-nitrostilbene.' l 8 Reductive dehalogenation of 9,lO-dibromo- and 9,1O-diiodo-2-nitro-9,1O-ethano-9,10dihydroanthracene, assisted by a series of tertiary carbanions, has been studied.' l 9 A chain mechanism involving both inter- and intra-molecular electron-transfer steps has been proposed. Quantitative studies have shown that reductive dehalogenation is regioselective. The reduction occurs preferentially at the benzylic bridgehead position para to the nitro group. However, the ratio of para to metu reduction products is only 1.6 : 1, which is much lower (by about two orders of magnitude) than the difference between the dehalogenation rate constants for other p - and m-nitrobenzyl systems. Possible reasons for the differences observed have been discussed.' l 9 A review'20 reports on a possible reductive activation of nucleophilic substitution in aromatic systems containing electron-acceptor groups. The concept of topologically controlled coulombic interactions has been used to choose appropriate model objects.

Organic Reaction Mechanisms I995

148

Tetrathiafulvalene (TTF) catalyses the formation of cyclic products from suitable arenediazonium salts (AD) (Scheme 2 1). The reaction mechanism implies electron transfer from TTF to arenediazonium salt, loss of dinitrogen, radical cyclization, trapping of the obtained radicals by radical cation TTFf' via either sulfur or carbon atom, and nucleophilic substitution of TTF. The reactions are catalytic in TTF.'2'.'22

AD

TTF

R+OH R' SCHEM 2 I~

An effective procedure for dealkylative coupling of benzyl alkyl ethers to give the corresponding diarylmethanes has been de~cribed."~The reaction was induced by oxidation of starting compounds to radical cations, either electrochemically or by small amounts of one-electron oxidants. It follows the chain mechanism whose key steps are coupling of the benzyl alkyl ether with its radical cation, rearrangement and fragmentation of thhe resulting distonic radical cation leading to diarylmethane radical cation, and one-electron oxidation of parent ether by diarylmethane radical cation (Schemc 22). It has been found that Diels-Alder addition of trans-stilbene to 2,3-dimethylbuta- 1,3diene,Iz4 and also cyclopropanation of the former by dia~oacetate,"~are catalysed by salts of triarylamine radical cations. These radical cations cause oxidation of transstilbene to its radical cation, which then adds to 2,3-dimethylbuta-l,3-dieneor diazoacetate. The products resulting from interaction of tricyclo[3 .2.0.02,4]hept-6-enes(68) and quadricyclanes (69) with one-electron oxidants (salts of triarylamine radical cations)

x -x-

4 Radical Reactions: Part 2

ArCHzOMe

MeOCHzOMe

149

[ArCH20Me)"

ArCHzAr

[ArCHzAr]"

ArCH20Me

Scmm 22

have been characterized. The key role in the reactions is played by bicyclo[3.2.0]hept-6ene-2,4-diyl radical cations (68+') and quadricyclane radical cations (69+') which yield reaction products via valence and/or skeletal isomerization and final one-electron reduction. Factors that control the influence of substituents R on the direction of structural changes are discussed.Iz6

(68) a;R=Me

(69) a;R=Me b; R = Ph

b;R=Ph

Rearrangement of vinylcyclopropanes to form cyclopentenes is accelerated by salts of triarylamine radical cations of F e ( ~ h e n ) ~The + . rearrangement is a stepwise process that involves one-electron oxidation of the starting compound.127The role of electron transfer in cycloadditions of 1,4-bis(dimethylamino)buta-1,3-diene,12' 2,3-bis(dimethylaminomethylene)bicyclo[2.2.l]heptane, and 2,3-bis(dimethylaminomethylene)bicyclo[2.2.2]0ctane'~~with the various electron-acceptor alkenes has been discussed. In situations where the oxidation potential of the donor component closely matches the reduction potential of the acceptor component, the reaction rate increases markedly, the reactions lose stereospecificity, and EPR spectra of radical species resulting from electron transfer can be observed. The products of electron-transfer-induced4 2-cycloaddition of 2-vinylindoles (70) to p-aminomethacrylates, such as (71), and nitriles (72), or to 1,4,5,6-tetrahydropyridines (73) have been chara~terized.'~~ The results are of synthetic interest because such reactions can be used to build an alkaloid skeleton in high yield. A mechanism involving electron transfer is regarded as a possible path of formation of vinyl fluorides in reaction of vinyltrimethylstannanes with XeF2 induced by silver(1) triflate. 1 3 ' One-electron oxidation of monosubstituted benzenes by nitrogen trioxide is

+

150

a;R=Me b; R = CH2CH20Et

Organic Reaction Mechanisms 1995

a; R' = CN, R" = H b; R' = C02Me, R" = H c; R' = C02Me, R" = Me

used to interpret the results of nitration of toluene and chlorobenzene by the ternary system NO-N02-02,'3z and anilides and phenyl esters by the binary system NOz03.133

One-electron oxidation of enols by radical cation salts of triarylamines in the presence of nucleophiles leads to carbonyl compounds containing a nucleophilic group in the a-position. The reaction mechanism involves the formation of the radical cation of the enol, its deprotonation, and oxidation of the resulting a-carbonyl radical to carbocation, which, by attaching a nucleophile at the positively charged a-carbon atom, produces the end-product of the r e a ~ t i 0 n . In I ~place ~ of enols, their trimethylsilyl ethers can be used.'35 Proton donors and acceptors speed up electron-transfer reactions that occur with participation of 1-cyanoalkyl and 1,2-dicyanoalkyl radicals-the key intermediates of tbutylation of a$-unsaturated nitriles by t-butylmercury iodides assisted by iodide ion.136 In the presence of proton donors (e.g. NH4'), I-cyanoalkyl radicals are protonated at the nitrogen atom of the cyan0 group, which enhances its one-electron reduction by t-BuHgl2 - and formation of products of reductive alkylation (cyanoalkanes). 1,2-Dicyanoalkyl radicals can be deprotonated by bases such as DABCO, which enhances oxidation by t-BuHgI and the formation of products of oxidative alkylation (dicyanoalkenes). The electron-transfer mechanism has been proposed to explain tetracyanoethylenecatalysed C-C bond formation and reduction in reactions of aldehydes, ketones, and acetals with silylated nucleophiles (trimethylsilyl cyanide, aryltrimethylsilane, aryl methyl ketone, trimethylsilyl enol ethers and triethylsilane). 13' Nitric oxide promotes the aerial oxidation of chlorpromazine and related phenothiazines (74) to the corresponding sulfoxides. The reaction mechanism involves one-electron oxidation of the starting phenothiazine derivative followed by the reaction of the radical cation obtained with nitrate ion. The radical species, attributed to the structure (75a), were detected when triphenylphosphine was mixed with azodicarboxylate.139 The mechanism of radical cation formation consists of electron transfer from triphenylphosphine to azodicarboxylate and subsequent addition of the radical cation of triphenylphosphine to the starting diazo compound. These elementary steps are the key reactions in the new chain-radical mechanism proposed to describe the formation of betaine (75b).'39

4 Radical Reactions: Part 2

151

RCO~-N-~~-O~CR I

Ph3P+

RCO~-N--N-O~CR I

Ph,P+

R (74) a; R = CH2(CH2)2NMe2,X = C1 b; R = CH2(Me)NMe2, X = H

c; R = CH2(CH2)2N(CH2CH2)2NMe2,X = CF3 d; R =Me, X = H e; R = Ph, X = H

Radical Ions Radical Cations The Raman spectrum of trans-stilbene radical cation has been published.140 Unrestricted HF, MP2 and DFT methods were applied to study the potential-energy surface of norbornane radical cation. 14' According to MP2 and DFT calculations, this radical cation is characterized by the C2, symmetry (see below) in the gas phase. MP2 calculations have made it possible to detect two additional minima on the potentialenergy surface, one of which corresponds to C, symmetry and the other to C1 symmetry. A comparison of calculated and experimental hfi constants indicates that the C, structure occurs in CFC13, CF3CC13,and CF2C1CFCl2matrices, and the C,, structure in perfluoromethylcyclohexane and perfluorooctane matrices.

The electronic and geometric structures of radical cations of general formula CsHg +*, namely radical cations of cyclooctatetraene (COTf'), semibullvalene (SBVf'), and bicyclo[3.3.0]octa-2,6-diene-4,8-diyl (BODf') were reported. Quantum-chemical methods were employed to characterize the potential-energy surface that binds these species (Scheme 23). Photochemical induction was used to carry out rearrangements of COT+' to BOD+', the driving force for which is a strong Jahr-Teller distortion characteristic of the second excited state of COT+'. 142 Photo-induced mutual transformations of BODf' and its four isomers, corresponding to different dihydropentalene isomers (DHP+'), have been studied. A set of rules based on frontier

Organic Reaction Mechanisms I995

152

BOD+'

COT"

SBV+'

BOD+'

(-Jy+' - (+Jy+* hv

I,5-DHP+'

1,4-DHP+' SCHEME 23

molecular orbitals was developed to describe the photo-rearrangement of DHP+' isomers.143 The formation energy and geometric and electronic structures of radical cations of polycyclic rigid [I. 1.1. llpagodanes (76) and isopagodanes (77), and of corresponding bis(seco)- (78) and seco-dodecahedradienes (79) have been studied by different methods (cyclic voltammetry, EPR, and quantum-chemical calculations).144-146 According to ab initio calculations (PMP2/3-21G//3-21G), a minimum on the potential-energy surface corresponds to the radical cations of each isomer (76)-(79). A comparison of calculated and experimental hfi constants indicates that oxidation reactions of (76) and (78) lead to the same radical species, namely radical cation (78+'). It looks likely that the radical cation of cyclobutane type (76+') can easily rearrange to form the diene isomer (78+'). In the case of oxidation of isopagodane (77) and secododecahedradiene (79), the radical cation of cyclobutane type (77+') is formed. Transition to the homologues [2.2.1. Ilpagodanes (80) and isopagodanes (81) and their corresponding dienes (82) and (83) reverses the The effects of substituents on (a) oxidation potentials of [1.1.1.llpagodanes (76), bis(seco)- (77), seco- (84), and -dodecahedradienes (85) and (b) the extent of conjugative stabilization of the resulting radical cations were described.146 One-electron oxidation of initially planar bicyclopropylidene (86) (D2h symmetry) was found to yield radical cation (86+'), with cyclopropane fragments being turned

4 Radical Reactions: Part 2

153

relative to each other (D2symmetry).'47 Further, this radical cation undergoes a number of transformations whose directions depends on the nature of matrices in which it has been generated. It undergoes opening of the cyclopropane fragments with the formation of distonic radical cation (87+'). In a CF2C1CFCl2 matrix, detachment of H+, producing the ally1 radical (88), is preferential. Azulene radical cation and its alkyl derivatives were generated by UV irradiation of the starting hydrocarbon with mercury(I1) trifluoroacetate in dichloromethane. The hfi constants were determined by EPR, ENDOR, and TRIPLE spectroscopies. Introduction of alkyl groups into the 1- and 3-positions of azulene enhanced considerably the stability of resulting radical cations. In the absence of substituents at least in one of those positions, radical cations of azulene derivatives dimerized, producing finally radical cation 1,I '-biazulenyls. The high reactivity of radical cations of azulene derivatives at positions 1 and 3 is in agreement with high spin density at these

position^.'^^

154

Organic Reaction Mechanisms 1995

EPR spectra of the products of interaction between hexamethyl(Dewar benzene) and Tl(II1) trifluoroacetate in trifluoroacetic acid under irradiation have been presented. These EPR spectra were compared with those for radical cations of hexamethylbenzene, pentamethylbenzene, pentamethylbenzyl ethers, and pentamethylbenzyl esters. The EPR spectrum registered during oxidation of hexamethyl(Dewar benzene) can be attributed to the radical cation of pentamethylbenzyl trifluoroacetate. These results call for a critical revision of the earlier spectral data for the radical cation of hexamethyl(Dewar benzene). The kinetics of oxidation of hexamethyl derivatives of benzene and of Dewar benzene by TI(II1) trifluoroacetate have been studied, and a reaction mechanism has been proposed. A strong kinetic isotope effect on the rate of oxidation was detected when D was substituted for H in hexamethylbenzene and solvent.'49'' 50 EPR spectra of radical species resulting from oxidation of different dimethyl derivatives of naphthalene, as well as of the corresponding derivatives of binaphthyl and perylene, have been obtained. Except for situations where peri methyl groups can interfere with the dimerization processes, the EPR spectra taken during oxidation of dimethylnaphthalenes are ascribed to radical cations of binaphthyls rather than of perylenes. The proposed reaction mechanism involves the formation of a n-complex between dimethylnaphthalene radical cation and starting arene as the first reaction step.I5' It is r e p ~ r t e d ' ~ ~ -that ' ' ~ 1,1,1,3,3,3-hexafluoropropan-2-ol (HFP) is an excellent solvent to promote generation of radical cations of aromatic compounds in oxidation systems. HFP solutions of radical cations are fairly stable, even at room temperature, which permits recording of highly resolved EPR spectra for these species. HFP slows down the interaction of radical cations with nucleophiles, such as trinitromethanide ion, but exerts no effect on reactivity in radical r e a ~ t i 0 n s . EPR l~~ spectra of radical cations of benzo-crown ethers, generated by irradiation of the starting compounds in CH2C12in the presence of dichlorodicyanoquinone and trifluoroacetic acid, have been described. Trifluoroacetic acid protonates semiquinone anion, thus preventing back electron transfer.'55 The radical cation salts of bis-annulated hydroquinone ethers (89E(91), which are stable in air, were synthesized. Despite their very similar structures, the radical cations have dramatically different reduction potentials. According to X-ray crystallographic analysis, this difference is due to different capabilities of their methoxy groups of participating in delocalization of positive charge spin density.t56 EPR and ENDOR methods were employed to investigate the structures of radical cations of a number of substituted bis-, ter-, and quater-thiophenes. Being free from

4 Radical Reactions: Part 2

155

steric hindrances, oligothiophene radical cations have a planar structure and exist as mixtures of cis and trans conformers; however, a single type of species is formed for sterically hindered non-planar radical cations. 157 The possibility of synthesis of stable radical cation salts based on polyalkoxy derivatives of dibenzothiophene has been examined. It was found that 2,3,7,8-tetramethoxydibenzothiopheneand 2,3:7,8bis(methylenedioxy)dibenzothiophene produce stable salts, which can be isolated as crystals.'58 New radical cation salts were obtained in one-electron oxidation of 4,7disubstituted benzotrithioles (92) by NOfPF6 -. These salts are stable, and their structures in solutions have been confirmed by 31PNMR and EPR methods.'59

R

R (92)

(93)

(94)

a; R = Prl

b; R = OMe

Electrochemical oxidation potentials of 14 p-substituted arylmethyl chalcogenides (sulfur, selenium, and tellurium derivatives)I6' and of ten 0-,m- and p-substituted anilines'6' have been evaluated. Electrochemical oxidation of a homologous series of tris(ary1)phosphines (2,6-disubstituted, 2-substituted or monosubstituted) showed a good correlation between the oxidation potentials and the sum of Hammett of parameters of the substituents carried by the phenyl ring of the phosphines.16' The influence of a- and P-phenyl groups on the electrochemical oxidation potentials of bisN,N-bicyclohydrazines (93) and (94) and on the rate constants of electron exchange between the parent compounds and their radical cations has been examined. 163 EPR and ENDOR spectroscopy were used to study the spin-density distribution in radical cations generated during the oxidation of 3,8-dihydro-l,3,6,8-tetramethylpyrimido[4,5,6-gh]pyrimidine-2,7-( 1H,6H)-dione (95), 1,2:3,6,7,8-hexahydro-1,3,6,8-tetramethylpyrimido[4,5,6-gh]pyrimidine (96), and 3,6,7,7-tetrahydro-l,3,6&tetramethylpyrimido[4,5,6-glz]pyrimidin-2(lH)(97) by radical cations of tris(4-bromophen~1)amine'~~ and of 1,3,5-tris(diarylarnino)benzenes by radical cations of thianthrene. 165 A review of organosilicon radical cations covers such problems as energetics of the formation of these species in the gas phase and in solution, and their spectral characteristics and reactivity. EPR and electron absorption spectra for radical cations of oligosilanes (SinR,+1R~+,;n = 2-6) are similar to those for radical cations of monomeric silanes and indicate absence of delocalization of unpaired electron in radical cations of polymers.'67 By taking advantage of EPR and ENDOR spectroscopy,

Organic Reaction Mechanisms 1995

156

MeN

1

NMe

(&I$$@ \

MeNn

NMe

MeN

1

NMe

\

MeN-NMe

MeNKNMe

MeN-NMe

0

(95)

(96)

(97)

it was possible to elucidate the structure of radical cations formed from aryltrimethyland tetraaryl-silanes and corresponding organogermanes. 168 As shown by the EPR method, radical cations of furan and M r a n in Freon medium produce sandwich dimeric corn pound^.'^^ Electronic absorption spectra have been characterized for monomeric radical cations of trans- and cis-stilbenes, and also for products of their interaction with starting neutral molecules (71- and a-dimeric radical cations). Formation rate constants for these species have been estimated. Moreover, these species were found to play a key role in cis-trans isomerization of radical cations. The rate constants for interaction of stilbene radical cations with C1- were also dete~mined.'~'The monomolecular channel for cis-trans isomerization of stilbene radical cations becomes important when aromatic fragments of stilbene have methoxy groups in the p-position. This observation and the finding of higher rate constants of interaction of radical cations of methoxy derivatives with molecular oxygen are explained by a stronger separation of charge and unpaired electron localization sites in these radical cation^.'^' Interaction of radical cations with parent neutral molecules, leading to the formation of head-to-head o-dimeric radical cations, is also typical of a wide spectrum of styrene derivatives in non-nucleophilic solvents. This process occurs with almost diffusion-controlled rate constants. At high concentrations of the starting styrenes, trimeric radical cations are formed. In the case of the generation of radical cations of styrene in aqueous solutions, the main channel of their decay is reaction with water, producing p-hydroxybenzyl radicals. 172 Laser flash photolysis was employed to determine rate constants of interaction (addition and/or deprotonation) of the various radical cations of styrene with different nucleophiles (N-, C1-, Br-, MeC02-, CO;!-, CN-, N03-, aliphatic and aromatic amines, and alcohols) in different solutions. Rate constants for cycloaddition of radical cations of styrene derivatives to different alkenes have also been e ~ t i m a t e d . ' ~ ~ High-level quantum-chemical calculations were used to model the interactions of radical cations of alkenes with H20174and NH3.17'Addition of the nucleophile to the radical cation of the alkene yields distonic radical cations (provided the radical cation does not have stabilizing electron-donor groups), and proceeds almost without an energy barrier. 1747175 The possibility of electron transfer fi-om the nucleophile to the radical cation is also discussed. This pathway becomes a competitive if a radical cation

4 Radical Reactions: Part 2

157

fragment and nucleophilic group belong to the same molecule and are separated by a short spacer.'75 Ab initio calculations and valence-bond-mixing modelling were used to develop paradigms permitting prognosis of pathways of nucleophilic s ~ b s t i t u t i o n ' and ~~ electron transfer177in the interaction of nucleophiles (Nu) with a-type radical cations (GI-GZ +'). Depending on charge and spin-density distribution in the transition states, nucleophilic substitution reactions of radical cations fall into two groups.'76 The first group includes 'homopolar' reactions whose transition states are characterized by approximately equal positive charge distribution over nucleophile (Nu), central atom (GI), and leaving group ((32). The second group includes 'heteropolar' reactions where, in the transition states, the positive charge is located predominantly on the central group (GI) bound to Nu and Gz' by dative bonds. For electron-transfer reactions from nucleophile to radical cation, two additional mechanisms, along with the outer-sphere mechanism, have been found.'77 The first is a one-step mechanism according to which the reaction route andor transition state are characterized by a strong binding of a nucleophile to the radical cation ('concerted electron transfer'). The second is a stepwise mechanism according to which the process that formally corresponds to electron transfer occurs through a succession of formation-rupture of chemical bonds, specifically due to a shuttle transfer of atoms or groups of atoms from nucleophile to radical cation. Rate constants for fragmentation of radical cations of trimethylsilyl ethers 17* and acetates179of sterically hindered 2,2-dimesityl-l-R-ethenols were determined by cyclic voltammetry. The reactions result in the formation of an a-carbonyl radical and trimethylsilyl or acetyl cations, respectively. The rate of fragmentation depends on the polarity of the medium and the presence of nucleophiles which, in particular, promote cleavage of the 0-Si bond by stabilizing the resulting trimethylsilyl cation. The methods of quantum chemistry were applied to study the energy of fragmentation of naphthalene radical cation into acetylene and the radical cation of benzocyclobutadiene. Experimental data on the formation of complexes between radical cation of fbllerene and methane, caused by their high-energy collision, are reported. Chemical properties of organosulfur distonic radical cation 'CH2SH2 have been studied.IX2 In the course of interaction with neutral bases (aniline, cyclopentanone, dimethyl disulfide, thiophene, 1,Cdioxane, furan, toluene, benzene, and methyl iodide), 'CH2SH2+ rearranges to give CH3SH+', which further oxidizes neutral base to radical cation.'** Distonic radical cations, which are phenyl radicals with a positively charged substituent at the p-position, have been generated. These radicals are nearly as reactive as neutral phenyl r a d i ~ a 1 . IOxidation ~~ of ketenes with air oxygen, producing succinic anhydrides, is initiated by salts of radical cations of triarylamines which are capable of binding molecular oxygen and activating it with respect to ketenes.Ig4

*'

*'

+

Radical Anions

EPR and ab initio quantum-chemical calculations were used to characterize the electronic and geometric structures of radical anions of azulene and its alkyl derivatives.

158

Organic Reaction Mechanisms 1995

Spin density is concentrated in positions 6, 4, 8, and 2, which indicates an unpaired electron orbital which is symmetric relative to the symmetry plane that is perpendicular to the molecule plane.'" The principle of similarity of EPR spectra of radical anions and cations of planar alternant hydrocarbons is not valid for the corresponding derivatives of dibenzo[b,h]biphenylene. This phenomenon is interpreted in terms of the Finnegar-Streiwieser model of the Mills-Nixon effect.Is6 Radical anions of the dialkyl ketone series RzCO (R = Me, Et, P i , But) and cyclobutanone were generated in an argon matrix at 4 K. Based on hfi constants with fihydrogen and a-carbon (I3C) atoms, and also on ab initio calculations, a pyramidal structure of the radical centre and preferential conformations of aliphatic fragments were c~nducted."~ The inversion barriers were determined for cyclic fragments in the radical anions of five-,'** six-,'** and seven-memberedIx9 cyclic ketones and thioketones. Interaction of diethyl oxalate with four equivalents of aryl- or hetaryl-lithium compounds yield radical anions of ketones due to addition of organolithium compounds at the carbonyl groups, followed by C-C bond rupture in the dianions formed.''' Similar results were obtained for the reactions of diary1 diketones with two equivalents of aryl- or hetaryl-lithium compounds. 19' Fourier transform ion-cyclotronresonance measurements and ab initio quantum-chemical calculations were employed to characterize carbonyl I3C and deuterium isotopic effects on the electron affinity (EA) of benzophenone in the gas phase. Experimental and theoretical values of isotopic effects are in good agreement [EA(12C)/EA('3C) = 1.03(exp.) and 1.026(calc.); EA(C6Ds)/EA(C6H5) = 1.35(exp.) and 1.32(calc.)] and differ markedly from earlier published data for liquid ammonium solutions of benzophenone.'" EPR, pulse radiolysis, and potentiometric methods were used to evaluate the one- and two-electron reduction potentials of 2-t-butyl-l,4-benzoquinone (one of the metabolites of antioxidants 2- or 3-t-butyl-4-hydroxyanisole)in aqueous solutions. Electron-transfer reactions of this quinone and products of its one-electron (semiquinone) and twoelectron reduction (hydroquinone) with molecular oxygen and superoxide ion were also studied. 192 Oxidation of 4-methylcatechol by molecular oxygen in the presence of hydroxide and methoxide ions was studied by EPR, and the mechanism of formation of primary and secondary semiquinone radical anions was proposed.'93 Hfi constants for radical anions of ubiquinone (98) and the derivative (99), labelled with I3C in different positions, were found using EPR and ENDOR spectroscopy. The spectral parameters of these radical anions in protic and aprotic media were found to be

4 Radical Reactions: Part 2

159

dramatically different. According to AM1, PM3, and TNDO quantum-chemical calculations of hfi constants, the effect of the medium on spin-density distribution is caused by the formation of hydrogen bonds between the solvent molecule and radical anion of the ubiquinones. 94 Radical trianions, resulting from one-electron oxidation of alkaline (NaOH) water-alcohol solutions of 3,3’,4,4’-tetrahydroxybiphenyl by dioxygen, exist as ion pairs with sodium cations. In solutions with high cation concentrations ma+] > 0.02 M, the ion pairs undergo cation exchange. The influence of temperature on EPR spectral parameters and the rate of cation exchange has been ~haracterized.’~~ The interaction of 3-substituted 9,lO-phenanthraquinones with Grignard reagents leads to the formation of radical anions of the starting quinones. The effect of substituents in position 3 on spin-density distribution in these radical anions has been examined.‘96 EPR spectra of radical anions and trianions of benzo[g][ 1,2,5]thiadiazolo[3,4b]quinoxaline-5,lO-dione (100a) and its selenium analogue (100b) have been described. In the radical anions, unpaired electron density is localized mainly on a heterocyclic fragment, whereas in the radical trianion it is localized on the naphthoquinone part.’97

(102) a;X=O b;X=S

An EPR spectrum of a radical trianion of another quinone fused with two sulfur heterocycles, i.e. 2,3,6,7-tetracyanobenzo[1,2-6:4,5-b’]bis-dithiol-4,8-dione (IOl), is presented. 19’ Radical anions of 2,5-bis(tricyanovinyl)-furan (102a) and -thiophene (102b) were generated in solvent mixtures of different polarity and in the presence of different counterions (Lif, Na+, K+, and Cs+). In most cases, radical anions (102a;) and (102b;) are in the form of free ions for which, of the three possible conformations of the radical anion, namely antilanti, antilsyn and synlsyn, the second is energetically the most favourable. The radical anion (102b;) can also exist in the synlsyn conformation when an ion pair with a metal cation is formed. It has been demonstrated that the radical anion (102b;) is highly selective with respect to metal cations provided that ion pairs are formed. The selectivity for the formation of ion pairs depends on the size of the cation and on the distance between two proximate cyan0 groups.’99 Similar behaviour has been revealed by the radical anion 2,5-bis( 1-phenyliminoethyl)pyrazine (103). In the absence of coordinating cations, it exists as an equilibrium mixture of three conformers .s-cisls-cis, s-cisls-trans, and s-transls-trans in acetonitrile or tetrahydrofuran solutions; however, in the presence of cations, the last becomes more prefered. The same paper reported EPR spectra for the radical anion of N-t-butylpyridine-2-

160

Organic Reaction Mechanisms 1995

carbaldimine (104).200As shown by EPRENDOR measurements, the unpaired electron occupies different orbitals in radical anions of phenanthroline (105a), its 4,7-dimethyl derivative (105b), and its 3,4,7,X-tetramethyl derivative (10%). The first two radical anions have SOMOs of ' h l symmetry. The SOMO of the last is of 'a2 symmetry. The same MOs are occupied by unpaired electron in complexes of these radical anions with dimesitylplatinum.20'

(104)

(105) a; R = R'= H b; R = H, R' = M e c ; R = R' = Me

Radical anions of nitroarenes were detected after mixing arylamines with sodium nitrite and ascorbic acid followed by alkalinization of those solutions. The proposed mechanism involves formation of aryldiazonium salts and their subsequent reduction to aryl radicals. These interact with nitrite ion to produce radical anions of the nitroarenes.2"2 The only EPR spectrum registered during the generation of the radical anion of thiophene in water-alcohol solutions belongs to its protonated form (2-hydrothienyl radical), owing to the high basicity of this radical anion. One-electron reduction of 2bromo- and 2,5-dichloro-thiophene leads to radical anions of the a*-type, characterized by localization of unpaired electron in the C-Br a*-orbital or in one of the two equivalent C-CI a*-orbitals. Experimental data have been compared with the results of PM3 quantum-chemical calculationszo0 Raman resonance spectra of vanadyl and zinc complexes of "N- and D-labelled and non-labelled octaalkylporphyrins have been interpreted in terms of a Jab-Teller static effect.204 The combination of ab initio quantum-chemical calculations and timeresolved Raman resonance spectroscopy has made it possible to describe in detail the electronic structures of products of one-electron reduction of isonicotinic acid and its protonated and deprotonated forms. An extra electron in the isonicotinate radical dianion is localized on the nitrogen atom rather than on the carboxylate group. Owing to this fact, basicity of the nitrogen atom increases by ten orders of magnitude. The radical dianion can be fully protonated at the nitrogen atom even at pH 14.'OS The stoichiometry and mechanism of protonation of alkali metal-benzophenone radical anion salt by weak acids, and their relevance to the base-catalyzed decomposition of benzopinacol, was studied.206 The effect of a substituent on the electron affinity of acetophenone and methyl benzoate has been characterized. The results were treated using Tsuno's correlation

4 Radical Reactions: Part 2

161

approach and compared with the data obtained previously for nitrobenzene, benzaldehyde, and benzonitrile derivative^.^^' The radical anion 'CH2C02 - was generated in the gas phase. Its proton affinity, the energy of its dissociation into CH2; and C02 fragments, and the products of its interaction with NO, NO2, S02, and MeSSMe were determined.208 Kinetic parameters for the reductive splitting of the C-Hal bonds in and t-buty12" halides in polar media have been calculated. The AM1 method was applied to interpret experimental data on the influence of substituent and halogen atom, and their mutual location, on the rate of fragmentation of radical anions of substituted aryl and hetaryl halides. Quantum-chemical calulations were performed assuming that the transformation of the first-formed x-radical anion to the o-radical anion is the ratedetermining step. The intramolecular electron transfer from the n*-SOMO of the aromatic fragment to the o*-orbital of the C-Hal bond occurs through a non-polar transition state. The measured rates of fragmentation of radical anions of halogensubstituted acetophenones and benzonitriles are in good agreement with the calculated values of E (the energy gap between n*-and o*-states of the radical anions); however, this parameter does not always describe differences in rates of halide-ion elimination from m- and p-positions.212A detailed analysis of the effects of medium and of ionic association on the rates of fragmentation of radical anions of aromatic compounds was presented.213A significant difference has been found between the behaviour of radical anions characterized by strong delocalization of a negative charge (haloanthracenes, for example) and that of radical anions bearing electron-acceptor substituents (carbonyl or nitro) on which a negative charge is mostly concentrated. Fragmentation rates of the former systems are almost independent of the counterion and tend to increase slightly upon addition of water, which seems to be due to specific solvation of a leaving group. In contrast, ion-pair formation and specific interactions with proton-donor solvents stabilize the latter systems toward halide-ion elimination. Moreover, addition of protondonor solvents may change the direction of the reaction: reduction of an electronacceptor group rather than fragmentation may take place. These results have been rationalized in terms of rate-determining transformation of first-formed x-radical anion to a-radical anion.213An alternative approach has been described.214The effect of medium on the rate of cleavage of radical anions of aryl halides was rationalized in terms of the key role of the o-radical anion fragmentation step.214Rate constants of C-Cl bond cleavage in radical anions of chlorinated benzaldehydes in aqueous solution were measured by a pulse radiolysis technique.215A theoretical study of the stability of radical anions of polychlorobenzodioxins towards halide-ion elimination has been undertaken.216 Radical anions of silyl-substituted pyrenes and silyl-bridged dipyrenes are unstable and undergo fragmentation of the Si-Si and S i x bonds.217 Transformation of ion pairs of radical anions of furan-2,5-dicarbaldehyde2" and of benzene- 1,4-dicarbaldehyde2I9to radical anions of the corresponding semidiones was observed. Several papers deal with theoretical and experimental investigations of factors controlling the competition between the polar and electron-transfer mechanisms in reactions of radical anions with alkyl halides. Ab initio calculations of the interaction of radical anions of formaldehyde with methyl chloride have shown that the process follows two different mechanisms: x-plane backside attack of the radical anion on

162

Organic Reaction Mechanisms 1995

methyl chloride leads to the electron-transfer transition state (ET-TS), while oxygen lone-pair backside attack on methyl chloride leads to the transition state for nucleophilic substitution (SUB-TS). An important point is that the ET-TS is characterized by a definite stereochemistry and a high degree of binding of reactants.220 Two similar types of transition states were observed for an intramolecular process involving interaction of ketyi anion and CHzCl fragments that are separated by two or three methylene groups. Since ET-TS and SUB-TS have different steric requirements, the length of the carbon bridge affects significantly the direction of the reaction: whereas for two methylene groups ET is the main route, for three methylene groups nucleophilic substitution becomes energetically preferentiaLz2’ The isotope effects220,221 ~ ~ . I ~ C I / ~ Cor, D ~ respectively, CI ~ C H ~ C ~ / ~ Ccan D ~ Cbe I ,used to discriminate between ET and SUB transition states. The effect of the nature of a leaving group on the ET to SN2 rate ratio has been characterized using the interaction of the radical anion of anthracene with methylating agents MeX (X = -%Me2, I, Br, Cl) as examples. From the data on yields of methylation products and regioselectivity of methyl-group incorporation (at positions 2 and 9 of anthracene), it was concluded that the proportion of the SN2 route increased from 0 to 97% in the above order of alkylating agents.222 The possibility of switching from an &2 to an ET mechanism in the arene radical anion alkylation by introduction of an electron-acceptor substituent into aromatic moiety was demonstrated for the first time.223 Whereas the radical anion of benzonitrile reacts with alkyl halides via an sN2 mechanism, the radical anion of 1,4-dicyanobenzene prefers the ET pathway. Cyclopropylmethyl bromide was used as a test reagent: cyclopropylmethyl radical, formed by the ET mechanism, isomerizes easily to the but-3-enyl radical, leading to the corresponding alkylation products (Scheme 24). Intramolecular electron transfer in radical anions of 9,9’-bianthryl and 10,lO’-dirnethoxy-9,9’-bianthryl has been studied. At 298 K, the rate constants of electron exchange in dimethylformamide were found to be 4.2 x lo7 and 2.2 x lo7 s-’, respectively. The results have been rationalized in terms of the Marcus theory.224The same theory was used to explain a 20% increase in rate constant of electron exchange between naphthalene and its radical anion upon substitution of deuterium atoms for all the hydrogen atoms in arene.225 Radical anion SO4; reacts with imidazolin-2-one, pyrazolin-3-one, and related compounds by hydrogen-atom abstraction fiom the NH group, possibly via oneelectron oxidation followed by deprotonation. The pK, values of the resulting radicals were determined.226 Biradicals A brief analysis of the development of theoretical and experimental methods of investigation of monomolecular reactions involving the formation of biradicals as intermediates was presented.227The femtosecond laser technique, in combination with mass spectrometry in laser beams, was applied to identify biradical species resulting from photolysis of cyclobutane, cyclopentanone, and its 2,2,5,5-tetramethyl derivative. The effect of the structures of biradical species (tetramethylene and trimethylene), their

4 Radical Reactions: Part 2

163

SCHEME 24

energies, and the incorporation of methyl groups into radical sites on the rate of transition-states passage has been characterized.228 CASSCF and CASPT2N quantum-chemical calculations have shown that singlet biradical cyclopentan-2-one-l,3-diyl(107) is more stable than the corresponding bicyclic form bicyclo[2.1.O]pentan-5-one (108). According to calculation, the structures (107) and (108) are characterized by different vibration frequencies of the C=O bond, which allows their experimental d i ~ c r i m i n a t i o n A . ~ ~comprehensive ~ theoretical study of auto-aromatization of (a-hex-3-ene- 1,5-diyne (109) to p-benzyne singlet biradical (1 10) (the Bergman reaction) was performed. The reaction and activation enthalpies and entropy effects were estimated by the CCSD(T) and CASPT2(gl) methods with the use of a wide range of basic sets. The results were shown to depend strongly on both the calculation method and the basis set. Specifically, the difference in reaction enthalpies obtained by CCSD(T) and CASPT2(gl) is 7 kcal mol-'. The difference is somewhat less (4 kcal mol-') for activation enthalpies. Both methods were also used to estimate relative energies for p - , 0-,and rn-ben~ynes.'~' The energy of singlet-triplet splitting has been determined for biradicals of the trimethylenemethane type ( l l l t ( 1 1 3 ) . It is higher than 14 kcal mol-' for planar structures and is only 6 kcal mol-' for structures with mutually orthogonal radical fragments. In all cases, the basic state is triplet.231 Differently, Ullman's nitroxide biradicals, bis[2,2'-(1-oxy-3-oxido-4,4,5,5-tetramethyl-dihydro-1H-imidazoyl](114) and bis[2,2'-( 1 -oxy-4,4,5,5-tetramethyldihydro-1H-imidazolyl](1 15), have a singlet basic state regardless of mutual orientation of radical fiagments, as shown by ab initio

164

Organic Reaction Mechanisms 1995

calculations of model systems [methyl groups in structures (114) and (115) replacing hydrogen atoms]. The singlet-triplet energy gaps calculated for model biradicals, with reference to the experimental angles between radical fragments, are in good agreement with experimental values for biradicals (114) and (115).232

Data on the isomerization of a cyclopropane fi-agment during photolysis and pyrolysis of 2,4-benzylidenebicycIo[3.1.O]hexan-3-one (116a,b) indicate the formation of a pentamethylenepropane-type biradical intermediate (1 17) or transition state (Scheme 25). Although, in accordance with the quantum-chemical calculations, the energy of the triplet state of pentamethylenepropane-type biradicals is 2 kcal mol-I less than the energy of the singlet state, the attempts made to identify this species were unsuccessful, even at low temperatures.233 The structure and relative formation rates of isomeric triplet biradical intermediates formed by photo-cycloaddition of cyclopent-2-enone and its 2- and 3-methyl derivatives to substituted alkenes CH2=CXY (X = Y = X = Y = F,234 X = H, Y = C02Me23S)have been determined. The composition of products of direct and triplet-sensitized photolysis of syn- and anti-isomers of azoalkanes (118) is in accord with intermediate formation of singlet or triplet biradical, respectively. The triplet biradical has a planar structure; syn- and antiisomers of azoalkanes (1 18) yield the same thermodynamically controlled mixture (96:4) of anti- and syn-housanes (119). Unlike the triplet biradical, the singlet

4 Radical Reactions: Part 2

165

(116a)

(116b)

biradical has a puckered conformation, because direct photolysis of syn- and antiisomers of the parent compound produces housanes that preserve to a large extent the conformation of the precursor. Both triplet and singlet 1,3-biradicals can be effectively trapped by nitroxyl radicals. The generation of triplet biradicals by triplet-sensitized photolysis of azoalkanes (118) has been confirmed by EPR under matrix isolation conditions.236

hv or

Me-N

_t

Me-N

0

0

(118)

0

(119)

a; R = Me, R = R” = H b; R = Me, R’ = Ph, R“ = H (syn-lllb, anti-119b) R = Me, R‘ = H, R” =Ph (anti-ll(lb, syn-119b) c; R = Me, R‘ = R” = Ph d; R = Ph,R’= R” = H SCHEME 26 The ratio of products resulting from photolysis of 2,3-diazabicyclo[2.2.2]oct-2-ene (120) depends on the electron spin state of the biradical intermediate cyclohexane-l,4diyl(l21). The singlet cyclohexane-l,4-diyl biradical in the ‘boat’ conformation (121a) undergoes cyclization forming bicyclo[2.2.0]hexane (122). In the triplet state (121b), this biradical changes its geometry from the high-energy ‘boat’ conformation to the lower-energy ‘twist’ conformation (123b). Its subsequent transformations involve intersystem crossing to the ‘twist’ singlet state (123a), in which the biradical undergoes either ring opening producing hexa- 1,4-diene (124) or ring closure producing bicyclo[2.2.0]hexane (122). The rate ratio of the latter two processes is 7:3. The electronic state of the cyclohexane-l,4-diyl biradical depends on the conditions of photolysis (direct irradiation, singlet or triplet sensitization) and on the probability of intersystem crossing in the primary biradical (125), formed by rupture of the C-N bond in the excited state of the starting diaza compound237(Scheme 27).

Organic Reaction Mechanisms f 995

166

Donor-acceptor substitution exerts very little effect on intersystem crossing rates in 1,3-diarylcycIopenta-1,3-dienyl triplet biradicals (126). The lifetimes for substituted and unsubstituted systems are comparable.238 The effect of an external magnetic field on CIDNP in biradicals produced by photolysis of large-ring cyclic ketones (cycloundecanone and cyclododecanone) was studied at different concentrations of CBrC13 used as a radical scavenger. This approach has allowed the elucidation of different channels of intersystem crossing in biradicals in low magnetic fields, the evaluation of the kinetics of recombination in biradical systems, and the determination of rate constants for interaction of biradicals with CBrC13.239The effect of external magnetic field and of magnetic isotopes on the

\ / [ * = . I m - [ou-] I

3

Li

Li

(126) a; X = Y = OMe b; X = Y = NO2 c; XIY = OMe/NO2 d:X=Y=H

(127)

4 Radical Reactions: Part 2

167

lifetimes of biradicals obtained during the photolysis of benzophenone derivatives, resulting from intermolecular transfer of a hydrogen atom, has been examined.240The biradical intermediate (127) formed in reaction of 2-alkylbenzotriazoles with lithium diisobutylamide was identified by EPR.241 The generation of biradical intermediates during 1,2- and 1,Ccycloaddition of buta1,3-diene to the exo-double bond in 3-substituted 5-methylene-2(5H)-fones is suggested.242 1,4-Dehydronaphthalene biradicals, generated by thermolysis of enediynes (128), are trapped by nitroxyl radicals producing finally 1,4-naphthaquinones243(Scheme 28).

G

Q

?

0 ' I

R 0

(128) a; R,R' = H b; K,R'= Me c; R,R' = OMe d; R-R' = OCH20 e; R-R' = (CH& f R = Me, R' = Et

SCHEME 28

Biradicals play a key role in processes of formation of naphthalene derivatives by irradiation of silicon-tethered phenylalkynes (129)244 and of anthracene and phenanthrene derivatives during exposure of 6,7-benzobicyclo[8.3.O]trideca-6,10diene-3,8-diyne-l,Sdiols (130) to mesityl chloride in the presence of triethylamine, followed by treatment with water.245 Irradiation of 5s-5-0-t-butyldimethylsiloxymethylfUran-2(5H)-one (131) in acetonitrile leads to dimerization of the starting compound with the formation of C2-symmetric bis(1actone) (132), along with intramolecular photo-cycloaddition with the formation of bicyclic product (133).246 The mechanism of formation of the bicyclic product involves intermolecular transfer of the hydrogen atom from the t-butyl group to the biradical formed primarily as a result of irradiation of the starting compound (Scheme 29).

168

Organic Reaction Mechanisms I995

ASiPJPh Y

'

O

X Ph

SCHEME 29

4 Radical Reactions: Part 2

169

An enthalpy profile for the equilibrium between dispiro[2.2.2.2]deca-2,4-diene(134) and two biradical intermediates (135) and (136) has been characterized. The possibility of a non-concerted path for the equilibrium (134) (136) is being discussed.247 Interaction of polyfluorinated cyclopropanes with halogens leads to the opening of the ring accompanied by the formation of 1,3-dihalofluoropropane derivatives. It is postulated that the reaction involves the formation of a biradical intermediate due to C-C bond cleavage in polyfluorocyclopropane.248

Thermolysis and Pyrolysis Possible pathways of monomolecular decomposition of CH30F have been studied by ab initio methods. Of four pathways leading to the formation of CH20 and HF, the most preferential are the following two. The first occurs via a synchronous one-step elimination of HF, and the second via formation of methoxyl radical and atomic fluorine in the first step and subsequent interaction between them to yield the final reaction product. The two pathways are characterized by nearly the same free energies of activation (ca 38 kcal m ~ l - l ) . ~ ~ ~ Thermal decomposition of CF2C12 was investigated over a wide temperature range (1446-2667 K) at different concentrations of the starting compound in Kr diluent. The rate constants for following reactions have been determined: CFzC12 'CF2Cl

+M +M

4

-+

'CF2Cl + 'C1 (+M) CF2 'C1 (+M)

+

A one-step elimination of molecular chlorine with the formation of difluorocarbene is not accomplished. Enthalpies of formation of CFzCl and fragmentation of this radical via C-CI bond rupture have been estimated.250 A kinetic study of the formation of ethane through homogeneous pyrolysis of propane at 500°C has been reported, and the rate constant of initiation of this reaction has been measured.25' The mechanism for the thermal decomposition of trunsazoisopropane has been studied using ab initio quantum-chemical approaches.252Rate constants and activation parameters of elementary reactions that occur during thermal decomposition of azoisopropane in the presence of trans-but-2-ene were measured over a wide temperature range from 489 to 540°C.253 The ab initio method was applied to evaluate two possible mechanisms of thermal decomposition of pyridine, pyrimidine, pyrazine, and ~ y r i d a z i n e .One ~ ~ ~ of the mechanisms involves intermolecular rearrangement of hetarenes to the bicyclic Dewar isomer followed by its decomposition into acetylene and HCN. This mechanism is hardly probable since the associated critical energy parameters for most hetarenes exceed markedly experimental values of activation barriers. The only exception is pyridine. The second mechanism is the chain-radical pathway that involves rupture of the C-H bond (at the position ortho to the nitrogen atom) in the initiation stage. Subsequently, the hetaryl radical decomposes yielding the CN radical as one of the products. This radical, along with the hydrogen atom, is responsible for the continuation of the chain. The calculated energies of the most important steps of the

170

Organic Reaction Mechanisms 1995

radical pathway coincide with experimental values within the limits of 10 kcal mol-’ , which led the authors to give preference to this mechanism. A chain-radical mechanism has been proposed for cracking of phenethyl phenyl ether (137) at 330425°C that models thermal behaviour of lignite and low-rank The process occurs via two competitive pathways (Scheme 30), the rate ratio of which depends on the regioselectivity of interaction of phenoxyl and benzyl radicals with the starting compound. The first pathway leads to styrene and phenol, whereas the second affords toluene and benzaldehyde. Styrene and phenol result from p-scission of a free radical of benzyl type (138) into styrene and phenoxyl radical, which transforms to phenol via abstraction of the hydrogen atom from the starting compound. Toluene and benzaldehyde are produced via transformation of the a-phenoxyalkyl radical (139), which undergoes a 1,2-shift of a phenyl group from oxygen to carbon and P-scission producing benzaldehyde and benzyl radical. The latter abstracts a hydrogen atom from the starting compound with the formation of toluene. The reaction is initiated by the scission of the CH,-OPh bond in the starting compound and can be accelerated by adding free-radical sources.*” The products and mechanism of pyrolysis of ethynylben~ ene~ ~ ~and ~ ’~ 1,4’ diphenylbut-l-en-3-yne2” have been studied in detail. In both cases, the composition of products depends on the nature of the carrier gas and the temperature at which the process is performed. Pyrolysis of ethynylbenzene2’6 at 700°C in a nitrogen atmosphere brings about the formation of 1- and 2-phenylnaphthalenes, 1-methylene-2-phenyl-lHindene, 1-methylene-3-phenyl-IH-indene, and 5,1O-dihydroindeno[2,1-a]indenc. However, at higher temperatures ethynylarenes, as well as benzene, naphthalene, acenaphthylene, biphenyl, pyrene, fluoranthene, and the other CI6HIOisomers, are formed. As hydrogen is used as a carrier gas, the main products are styrene and benzene. It is assumed that the process follows a radical mechanism.256Major radical intermediates were scavenged with dimethyl d i ~ u l f i d eThese . ~ ~ ~were phenyl, 0-,m-, and p-ethynylphenyl, 2- and 1-phenylvinyl, 1- and 2-naphthyl, methyl, hydrogen atom,

I

(139)

Ph

PhCH2’ SCHEME 30

+

PhCHO

4 Radical Reactions: Part 2

171

and radicals resulting from the addition of ethynylphenyl and phenyl radicals to the triple bond of the parent compound. Small amounts of carbenes, e.g. phenylvinylidene, were also detected. Based on the analysis of the concentration profiles of radicals and the main products of pyrolysis, a well justified scheme of pyrolysis of ethynylbenzene has been proposed. In the presence of suitable donors of hydrogen atoms, pyrolysis of 1,4-diphenylbut-l-en-3-yne, or its fluoro derivative, is controlled by radical processes; however, if the system is deficient in hydrogen atoms, the key role is played by vinylidenecarbene species.25x Thermal and photochemical cyclization reactions of perfluorohepta-1,6-dienehave been studied. In both cases, cyclization occurs by a stepwise mechanism with the formation of a biradical intermediate (Scheme 3 1). However, in a thermal process, the biradical intermediate is characterized by a six-membered ring (140) and in a photochemical process by a five-membered ring (141). Thermal treatment of perfluorohepta-l,3,6-triene leads to the formation of two types of products: (a) the kinetically more favourable allylcyclobutene (142) via reversible four-electron pericyclic process; and (b) the thermodynamically more favourable bicycloheptene (143) via a stepwise mechanism involving a biradical intermediate (144) (Scheme 32). The ratio of the products changes in favour of bicycloheptene (143) with increasing temperature of the process.259

major product

Fq:

major product

(141)

SCHEME 31

Photolysis and Radiolysis Photolysis of perfluoroazooctane (145) in the presence of cycloalkanes C,H2, (n = 5 , 6, 7) leads to the formation of the corresponding perfluorooctylcycloalkanes CsF17CmH2m-I(m = 5, 6 , 7) (Scheme 33). The reaction mechanism involves intermediate formation of perfluoroalkylazocycloalkane CXHI7N=NCmH2,,-, (146) whose photolysis produces the end-product with a quantum yield close to unity. It is postulated that azo compound (145) is transformed to azo compounds (146) due to

Organic Reaction Mechanisms 1995

172

SCHEME 32

photo-induced cleavage of one C-N bond resulting in perfluorooctyldiazenyl (147) and perfluorooctyl radicals. The latter remove the hydrogen atom kom the solvent (cycloalkane) with subsequent formation of cycloalkyl radical that recombines with perfluorooctyldiazenyl radical (147).260 Irradiation of a-brominated xylenes in benzene, isooctane, and benzene-cyclohexene mixture results in the formation of xylenes containing either fewer or more bromine atoms than in the parent compound. Possible mechanisms of reaction product formation are discussed.26' The mechanism of the photolysis of 2-hydroxypyridine-2-thione derivatives (148), which have been widely used as a source of free radicals in recent years, was studied. The starting compound in its excited state undergoes N-0 bond cleavage producing 2-pyridylthiyl radical and acyloxyl (RCO;) or carbon-centred radicals (R') depending

f

n = 0 , 1,2

(146)

4 Radical Reactions: Part 2

173

on the structure of R. The reactivity of R' towards molecular oxygen, methyl methacrylate, cyclohexa-l,3-diene, and benzhydrol has been characterized. An additional chain route of RC02' and R' formation, involving interaction of the starting compound with the radical R' (Scheme 34), has been found.262 A new method of transformation of alkyl halides to oximes has been suggested. Irradiation of alkyl iodides in the presence of m y 1 nitrite and hexabutylditin leads to the production of high yields of the corresponding alkyloximes. This reaction may be also valid for benzyl bromides. Interesting results were obtained with the use of alkyl iodides, which produce cyclizable free radicals upon irradiation. The oximes formed contain a cyclic fragment, provided that the system is capable of forming a fivemembered ring. In other situations the main reaction products are acyclic ~ x i m e s . ' ~ ~ The 193 nm photolysis of vinyl methyl ketone leads to the formation of methyl and vinyl radicals. The combination of two vinyl, vinyl and methyl, or two methyl radicals yields butadiene, propylene, and ethane, respectively. Disproportionation of two vinyl radicals results in the formation of ethylene and acetylene. A comparison of data on the ratio of the products of photolysis of vinyl methyl ketone and its perdeuteriated analogue has shown that the isotopic effect occurs in only disproportionation of two vinyl radicals.264 Using pulse radiolysis, it was possible to generate alkyl radicals from cycloalkanes (C, to Clo) and normal alkanes (c6to CI7).Rate constants of interactions between alkyl radicals and their reaction with molecular iodide have been determined.265

O ,0 dR

R' 0

OKR 0

SCHEME 34

+ CO2

174

Organic Reaction Mechanisms I995

As shown by pulse radiolysis, bromine-centred radical cations of starting haloalkanes are formed via interaction of hydroxyl radical with 1-bromo-n-chloroalkanes in strongly acidic aqueous solutions. These radical cations are stabilized due to interaction of the positively charged bromine atom either with uncharged bromine atom of the other molecule (via formation of the intermolecular 3e-2c bond) or with the uncharged chlorine atom of the same molecule (via formation of the intramolecular 3e-2c bond). For n = 2, 5, and 6, stabilization occurs via an intermolecular path, whereas for n = I , 3, and 4 it is via both inter- and intra-molecular paths. Experimental data are in good agreement with AM1 estimates of the strength of 3e-2c bonds.266Radical cations of brombenzene were detected during interaction of hydroxyl radical with the starting arene in strongly acidic aqueous solutions.267Hydroxycyclohexadienyl radical, formed in the first step, undergoes acid-catalysed dehydration. The redox potential of radical cation C6H5Br+' was determined. This radical cation was shown to oxidize Br- and SCN- anions, and also organic sulfides, at high rates. Pulse radiolysis was employed to estimate rate constants of interaction of hydrox yl radical with hydroxymalonic acid in solutions at various pH values. In oxygencontaining solutions, the addition of the a-hydroxyalkyl radical to dioxygen is followed by removal of H 0 2 or 02.Ketomalonic acid is the main product of radiolysis (along with H202) in aqueous acidic solutions (pH 3); however, in alkaline solutions (pH lo), it undergoes oxidation producing finally oxalic peracid and C02.*@ To establish the mechanism of nitroarene action as a radiosensitizer, radiolysis of N20-saturated aqueous solutions of I ,4-dioxane, 1,3-dioxane, tetrahydrofuran, and dimethyl ether, which model the sugar moiety in the DNA molecule, was carried out in the presence of 4-nitrobenzonitrile. a-Monoalkoxyalkyl radicals, formed via abstraction of a hydrogen atom from the above compounds by hydroxyl radical, add to the oxygen atom of nitro group to give N-alkoxy nitroxides, ArN(0')OR. In contrast to amonoalkoxyalkyl radicals, a,a-dialkoxyalkyl radicals (1,3-dioxan-2-y1), with stronger electron-donor properties, cause reduction of 4-nitrobenzonitrile to its radical anion. Subsequent transformations of N-alkoxy nitroxides have been characterized. These radicals undergo either homolytic cleavage via the N-OR bond, producing nitroso compounds and alkoxyl radical RO', or heterolytic cleavage via the NO-R bond producing the radical anion of nitroarene (ArN02;) and carbocation R+. Finally, in the presence of appropriate reductants (e.g. ascorbic acid), the N-alkoxy nitroxides can be reduced to the corresponding hydroxylamines. Radiolysis of 1,4-dioxane in an oxygencontaining medium leads to the same products (although in different ratio) as in its radiolysis in the presence of 4-nitrobenzonitrile. This is accounted for by the key role of alkoxyl radicals RO' formed in the both cases in the formation of final products.269

References

' Morton, J. R., Negri, F., and Preston, K. F., Chem. Phys. Lett., 232, 16 (1995).

Morton, J. R., Negri, E, Preston, K. F., and Rucl, J., 1 Chem. Snc., Perkin Trans. 2, 1995, 2141. Rhodes, C. J., Morris, H., and Reid, I. D., 1 Chem. Soc., Perkin Trans. 2, 1995, 2107. Lappas, A., Vavekis, K., and Prassides, K., J Chem. Sac., Perkin Trans. 2, 1995, 2743. Luff, S., Morton, J. R., Negri, F., Sharifi. M., and Sutdiffe, L. H., Mugn. Resnn. Chem., 33, 312 (1995). Kubota, S., Matsushita, M., Shida, T., Abu-Raqabah, A,, Symons, M. C. R., and Wyatt, J. L., Bull. Chem. Suc. Jpn, 68, 140 (1995).

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German, E. D., Kuznetsov, A. M., and Tikhomirov, V A,, 1 Phys. Chem., 99, 9095 (1995). Gcrman, 6.D. and Kuznetsov, A. M., Elektrokhimiyu, 30, 1189 (1994); Chem. Ahs., 122, 9320 (1995). Tikhomirov, V A., German, E. D., and Kuznetsov, A. M., Chem. Phys., 191, 25 (1995). 'I2 Pierini, A. B. and Duca, J. S., 1 Chem. Soc., Perkin Trans. 2, 1995, 1821. * 1 3 Andrieux, C. P., Robert, M., and Saveant, J.-M., 1 Am. Chem. Soc., 117, 9340 (1995). Kimura, N. and Takamaku, S., 1 Am. Chem. Soc., 117, 8023 (1995). 2's Solar, S., Getoff, N., Holcman, J., and Schcsted, K., 1 Phys. Chem., 99, 9425 (1995). 216 Borisov, Y. and Vorob'eva, N. P., Im Akad. Nauk, Ser. Khim., 1994, 1902; Chem. Ahs., 122, 290065 (1995). 'I7 Gherghel, L., Baumgarten, M., Declerq, D., and De Schryver, F. C., Chem. Phys. Lett., 232, 567 (1995). 218 Scholz, M., Gesheidt, G., and Daub, J., 1 Chem. Soc., Chem. Commun., 1995, 803. 2'9 Shohoji, M. C. B. L., Tetrahedron Lett., 36, 6167 (1995). 220 Sastry, G. N. and Shaik, S., 1 Am. Chem. Soc., 117, 3290 (1995). 22 I Sastry, G. N., Reddy, A. C., and Shaik, S., Angav. Chem., Int. Ed. EngL, 34, 1495 (1995). bjerg, K. and Christensen, T. B., Acta Chem. Scand., 49, 128 (1995). 223 Panteleeva, E., Vaganova, T. A,, Shteingarts, V D., and Bilkis, I. I., Tetrahedron Lett., 36, 8465 (1995). 224 Grampp, G., Kapturkicwicz, and Salbeck, J., Chem. Phys., 187, 391 (1995). 225 Stevenson, C. D. and Rice, C. V, 1 Am. Chem. Soc., 117, 10551 (1995). 22h Shohji, M. C. B. L., Novais, H. M., and Vieira, A. J. S. C., 1 Chem. Soc., Perkin Trans. 2, 1995, 2101. 227 Bcrson, J., Science, 266, 1338 (1994). 228 Pedersen, S., Herek, J. L., and Zewail, A. H., Science, 266, 1359 (1994). 229 Powell, H. K. and Borden, W. T., 1 Org. Chem., 60, 2654 (1995). 230 Lindh, R., Lee, T. J., Benhardsson, A,, Persson, B. J., and Karlstrom, G., 1 Am. Chem. Soc., 117, 7186 (1995). 23' Roth, W., Winzer, M., Korell, M., and Wildt, H., Liebigs Ann., 1995, 897. 232 Castell, O., Caballol, R., Subra, R., and Grand, A,, 1 fhys. Chem., 99, 154 (1995). 233 Kearley, M. L., Ishimura, A. S., and Lahti, I? M., 1 Am. Chem. Soc., 117, 5235 (1995). 234 Andrew, D. and Weedon, A. C., 1 Am. Chem. Soc., 117, 5647 (1995). *" Andrew, D., Hastings, D. J., and Weedon, A. C., .I; Am. Chem. Soc., 116, 10870 (1994). *" Adam, W., Goller, K., Kammel, T., and Peters, K., 1 Org. Chem., 60, 308 (1995). 237 Anderson, M. A. and Grissom, C. B., 1 Am. Chem. Soc., 117, 5041 (1995). 238 Kita, F., Nau, W., and Adam, W., 1 Am. Chem. Soc., 117, 8670 (1995). 239 Yurkovskaya, A. V, Morozova, 0. B., Sagdeev, R. Z., Dvinskikh, S. V, Buntkowsky, G., and Vieth, H.M., Chem. Phys., 197, 157 (1995). 240 Nakagaki, R., Takahira, O., and Hiruta, K., Chem. Phys. Lett., 233, 41 (1995). 24 1 Dalal, N., Xu, R., Katritzky, A. R., Wu, J., and Jesorka, A,, Magn. Reson. Chem., 32, 721 (1994). 242 Ochoa de Echaguen, C. and Ortuno, R. M., Tetrahedron Lett., 36, 749 (1995). 243 Grissom, J. W. and Gunawardena, G . U., Tetrahedron Lett., 36, 4951 (1995). 244 Bradford, C. A,, Fleming, S. A,, and Ward, S. C., Tetrahedron Lett., 36, 4189 (1995). 245 Matsumoto, Y., Hasegawa, T., Kuwatani, Y., and Ueda, I., Tetrahedron Lett., 36, 5757 (1995). 246 Brown, D., Cardin, C. J., and Mann, J., 1 Chem. Suc., Chem. Commun., 1995, 825. 247 Roth, W. and Unger, C., Lie& Ann., 1995, 1361. 248 Yang, Z.-Y., Krusic, P. J., and Smart, B. E., 1 Am. Chem. Soc., 117, 5397 (1995). 249 Apeloig, Y. and Albrecht, K., 1 Am. Chem. Soc., 117, 9564 (1995). 2su Kumaran, S. S., Lim, K. P., Michael, J. V, and Wagner, A. F., 1 fhys. Chem., 99, 8673 (1995). *" Belmeliani, A,, Perrin, D., and Martin, R., 1 Chim. Phys. Phys.-Chim. Bid., 91, 313 (1994). 2 s 2 Hu, C.-H., Ma, B., and Schaefer, H. F., Mol. Phys., 85, 769 (1995). 253 Seres, L., Fisher, R., Schemer, K., and Gorgenyi, M., 1 Chem. Sac., Faraday Trans., 91, 1303 (1995). 254 Jones, J., Bacscay, G. B., Mackie, J. C., and Doughty, A,, 1 Chem. Soc., Faraday Trans., 91, 1587 (1995). 255 Britt, I? F., Buchanan, A. C., and Malcolm, E. A,, 1 Org Chem., 60, 6523 (1995). 256 Hofmann, J., Zimmermann, G., Guthier, K., Hebgen, P., and Homann, K.-H., Liebigs Ann., 1995, 631. 2s7 Guthier, K., Hebgen, P., Homann, K.-H., Hofmann, J., and Zimmermann, G., Liebigs Ann., 1995, 637. 258 Hofmann, J., Zimmermann, G., and Homann, K.-H., Liebigs Ann., 1995, 841. *" Jing, N. and Lemal, D. M., 1 Org. Chem., 60, 89 (1995). 260 Nakamura, T. and Yabe, A,, 1 Chem. SOC.,Chem. Commun., 1995, 2027. Rezende, D. B., de Armda Campos, 1. P., Toscano, V G., and Catalani, L. H., 1 Chem. Soc., Perkin Trans. 2, 1995, 1857. 2 62 Aveline, B. M., Kochevar, I. E., and Redmond, R. W., 1 Am. Chem. Sac., 117, 9699 (1995). 263 Fletcher, R. J., Kizil, M., and Murphey, J. A,, Tetruhedmn Lett., 36, 323 (1995). 264 Fdhr, A. and Laufer, A. H., 1 Phys. Chem., 99, 262 (1995).

2"y

"" "'

180 265

267 268

269

Organic Reaction Mechanisms 1995

Laverne, J. A. and Wojnarovits, L., 1 Phys. Chem., 99, 12635 (1995). Maity, D. K., Mohan, H., Chattopadhyay, S., and Mittal, J. P., 1 Phys. Chem., 99, 12195 (1995). Mohan, H. and Mittal, J. P., 1 Phys. Chem., 99, 6519 (1995). Schuchmann, M. N., Schuchmann, H.-P., and von Sonntag, C., 1 Phys. Chem., 99, 9122 (1995). Nese, C., Schuchmann, M. N., Steenken, S., and von Sonntag, C., J Chem. Soc., Perkin Trans. 2, 1995, 1037.

CHAPTER 5

Oxidation and Reduction G. W. J. FLEET

Dyson Perrins Laboratory, Oxford UniversiQ, South Parks Road, Oxford OX1 3QY Oxidation by Metal Ions and Related Species . . . . . . . . . . . . . . . . . . . . . . Chromium and Manganese. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Silver, Copper, Mercury, Thallium, and Lead. . . . . . . . . . . . . . . . . . . . . . . Cerium, Titanium, Vanadium, Molybdenum, and Tungsten. . . . . . . . . . . . . . . Group VIII Metals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxidation by Compounds of Non-metallic Elements . . . . . . . . . . . . . . . . . . Nitrogen, Selenium, Sulfur, and Tellurium . . . . . . . . . . . . . . . . . . . . . . . . Halogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ozonolysis and Ozonation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Peracids and Peroxides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photo-oxygenation, Singlet Oxygen, and Superoxide . . . . . . . . . . . . . . . . . . Atomic Oxygen, Triplet Oxygen, and Autoxidation . . . . . . . . . . . . . . . . . . . Other Oxidations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reduction by Complex Metal Hydrides . . . . . . . . . . . . . . . . . . . . . . . . . . Other Reductions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

181 I81 184

185 188

191 191 193 194 195 199 20 1 202 203 205 207

Oxidation by Metal Ions and Related Species Chromium and Manganese A mechanism involving chromate esters and mono- and bi-equivalent redox processes has been proposed to accommodate fourth-order kinetics found in the chromic acid oxidations of cyclohexanol and benzyl alcohols;’ oxidations of a number of alcohols by chromic acid involve rate-determining proton loss from intermediate chromate esters.2 Substantial primary kinetic isotopes effects are found in the oxidation of primary alcohols with 2,2‘-bipyridinium chloro~hromate.~ Electron-donating substituents in the pyridine rings enhance the rates of 2,2’-bipyridyl-~atalysedoxidations of primary4 and secondary’ alcohols by chromic acid. The oxidation of diols by pyridinium fluorochromate involves rate-determining intramolecular cyclic hydride transfer in a chromate ester intermediate (Scheme 1).6 The lack of effect of added acrylonitrile on the rate of oxidation of ally1 alcohol by pyridinium fluorochromate demonstrates the absence of a radical pathway for the reaction.’ A Hammett relationship has been observed in the oxidation of benzaldehydes by quinolinium fluorochromate in which electron-donating groups accelerate the Orgunic Reaction Mechanisms 19YS. Edited by A. C . Knipe and W. E. Watts 0 1997 John Wiley & Sons Ltd

181

Organic Reaction Mechanisms 1995

182

products

f -

L

J

SCHEME 1

reaction.8 Chromium-containing medium-pore molecular sieve efficiently catalyses the epoxidation of alkenes with t-butyl hydroperoxide as an oxidant.' A chromate ester of hydrated cinnamaldehyde is an intermediate in the oxidation of cinnamaldehyde by chromium(VI)." Kinetic studies on the oxidation of cinnamic acid by chromium(V1) have been reported." The oxidation of formic and oxalic acids by pyridinium bromochromate involves initial formation of an intermediate anhydride which fragments via a symmetrical cyclic transition state. The oxidation of phenoxyacetic acid to benzoquinone by pyridinium fluorochromate in the presence of oxalic acid is catalysed by manganese(I1) sulfate and proceeds via a three-electron transfer.I3 Two competing pathways have been identified in the chromium(V1) oxidation of succinic acid.I4 Reviews on the oxidations of ketones15 and ethers16by chromium(V1) and other oxidants have appeared.

The products obtained from the oxidation of (1) have been used to compare the oxygen-transfer mechanisms for high-valent transition metals; permanganate gives exclusively (2) whereas ruthenium tetraoxide forms (2) as the major product together with small amounts of (3). In contrast, (3) is the predominant product from the reaction of (1) with chromyl chloride. Oxygen transfers from permanganate and ruthenium tetraoxide are initiated by complexation between the central metal atom and the oxygen end of the sulfoxide dipole whereas oxidation by chromyl chloride probably involves a single-electron-transfer pathwayI7 (see also under Molybdenum later).

5 Oxidation and Reduction

183

A two-electron-transfer process is involved in the oxidation of chloro- and nitrosubstituted benzyl alcohols by permanganate, whereas a one-electron pathway predominates in the oxidation of methoxy-substituted aryl alcohols. A hydndetransfer mechanism involving significant tunnelling has been proposed to account for the unusually large kinetic deuterium isotope effect (kHf kD = 14.7) in the hydroxide-ion catalysed permanganate oxidation of PhCD(CF3)OH.l 9 Proton transfer from the pmethylene group to the permanganate ion is involved in the self-oxidation of cetyltrimethylammonium permanganate (CTAP) during the manganese(VI1) oxidation of benzyl alcohol.20The oxidation of styrylpyridinium dyes in aqueous permanganate is faster than that by CTAP in chloroform but proceeds by the same mechanism in the two different solvents; the relative rates may be rationalized by the hydrophobic effect.21 Autocatalysis by a soluble form of rnanganese(1V) is involved in the permanganate oxidation of phenylalanine.22 Kinetic studies on the permanganate oxidation of b e n ~ a n i l i d eand ~ ~ gallic acid24 have been reported. The relative rates of permanganate oxidation of substituted alkenes are excellently correlated with their ionization potentials (IP) with lower TP corresponding to a lower relative rate: the reaction is a nucleophilic addition dependent predominantly on electronic effects.25 Catalytic effects involving the phase-transfer agents in the presence of acetic acid and also of acetic acid alone have been identified in the permanganate oxidation of cyclohexene in biphasic systems.26

'

But

B u1

a: a (4)

',,, -

+ NaOCl

(4)

'0

a. (6) major

(8) minor

SCHEME 2

184

Organic Reaction Mechanisms 1995

Five-membered cyclic manganese esters derived from 1,2-enediols are formed as key intermediates in the oxidation of a number of hexoses by alkaline mangane~e(VI).'~ Although enantioselective epoxidation of alkenes by mimics of monooxygenases has been well developed,28 enantioselective oxidation of saturated C-H bonds is rare; chiral (sa1en)manganese complexes such as (4) have been shown to catalyse the asymmetric hydroxylation of chiral epoxides with benzylic C-H bonds. Thus, enantioselective oxidation of dihydronaphthalene ( 5 ) gives the epoxide (6) as the major epoxide in 86% enantiomeric excess (Scheme 2); however, the minor enantiomer (8) undergoes much more rapid hydroxylation to (9) at 4.8 times the rate of oxidation of ( 6 ) to (7).29 Some selective oxidation catalysts mimicking cytochrome P450-dependent monooxygenases based on iron(II1) and manganese(II1) in the presence of oxidants such as hydrogen peroxide have been de~cribed.~'Single-electron transfer from the sulfide to the 0x0 complex is the rate-determining step in the oxidation of organic sulfides by oxo(salen)manganese() complexes; the redox potentials of the manganese(V)-manganese(1V) couple have been estimated by applying Marcus theory to the experimentally observed rate constant^.^^ A complex between formate and a manganese(1V) species is involved in the manganese(1V)-catalysed oxidation of formic acid by ozone.32A number of competing pathways occur in the oxidation of substituted hydrazines by manganese(III), all of which involve free-radical intermediate^.^' Added anions alter the reaction rate and mechanism of the manganese(II1) oxidation of aspartic and glutamic acids by changing the formal redox potential of the manganese(I1t rnanganese(II1)

Silver, Copper, Mercury, Thallium, and Lead EPR has been used to study the mechanism of the reactions of copper(I1) and the formation of organic radicals. The reaction of copper(I1) with thiols in the presence of oxygen or peroxides affords copper(1) and the corresponding disulfide in a 1 : 1 stoichiometric process; subsequent electron transfer to the peroxide regenerates ~ o p p e r ( I I ) Irradiation .~~ in air of solutions of alkanes in acetonitrile in the presence of catalytic amounts of quinone and copper(I1) acetate gives mainly the corresponding alkyl hydroperoxide; organic radicals, formed by hydrogen abstraction from the alkane by photo-excited quinone, react with oxygen to form peroxide radicals which are reoxidized by ~ o p p e r ( I I ) .Free ~ ~ radicals are also involved in the oxidations of ethanolamine by diperiodato~uprate(II1)~~ and of copper-catalysed oxygenations of Oxidation of a-tocopherol (10) with silver oxide causes quantitative conversion to the quinone methide (11) which can be trapped by electron-rich alkenes (Scheme 3).39 Kinetic studies on the silver(1)-catalysed oxidation of benzaldehyde by peroxodisulfate have a~peared.~' The regioselective oxidation of the cyclic hydroxylamine (12) affords (14) as the major product; the oxygen substituent causes relatively easy deprotonation of the nitrosonium ion (13) at the adjacent methylene group to give (14) rather than (15).41A key feature in the thallium(II1)-induced cyclization of 2'-hydroxychalcones to aurones is the incorporation of a solvent derived alkoxy group at C(4) of the aurone (Scheme

5 Oxidation and Reduction

185

4).42 Mechanistic studies on the oxidations of a$-unsaturated carboxylic acids by thallium(IIT)43 and of aliphatic acetals by lead(IV)44have been reported.

9

(14)

Cerium, Titanium, Vanadium, Molybdenum, and Tungsten Mechanisms consistent with MNDO simulations have been proposed for the oxidation of dihydrofurans with c e r i ~ m ( I V ) . Radical ~~ intermediates are involved in the ~~ phenols,"8 a n i ~ o l e ~ ~ cerium(1V) oxidations of cy c l o ~ ct an e s ,diphenylmethane~,~' and other arene~.~' The rate-determining step in the oxidation of malonic acid by cerium(1V) is the electron-transfer reaction between the enolate-like malonate ion and cerium(1V); the rate depression at high concentrations of malonic acid can be explained by the

SCHEME 4

186

Organic Reaction Mechanisms f 995

formation of 1 :2 chelate between cerium(1V) and malonate.” Among other studies on the Belousov-Zhabotinskii (BZ) reaction and other oscillating reactions?2 a decrease in pressure results in a dramatic change in the oscillation parameters in the oscillating BZ reaction with oxalic acid.53 In the ruthenium(II~bromoma1onic acid-bromate BZ system, two different negative feed-back loops are involved: the reaction of bromide with bromous acid, and the reactions of organic radicals with BrO, radicals.54 The manganese(l1)-catalysed reaction of bromate ion with a series of alkylmalonic acids shows oscillating behaviour similar to the cerium(II1)-catalysed BZ reaction with malonic acid.55Plausible mechanisms have been suggested to account for the micellar effects in the manganese(I1) BZ oscillating reactions with citric acid.56Tron(1l) (ferroin) behaves very differently from cerium(II1) or manganese(l1) in catalysing the BZ reaction with phenylmalonic acid.57 A number of transition metals catalyse the nonlinear kinetics of thiourea with a number of oxidants; the oscillatory reduction of chlorite by thiourea shows very little variation in periodic character even with the addition of large amounts of copper(I1) or iron(I1) to the system.’* The non-local density functional method has been used to model the titaniumcatalysed epoxidation of alkenes and allowed a number of conclusions to be drawn:59 (i) the conformational preference for a spiro over a planar transition structure is due to a more favourable interaction between the HOMO of the alkene and the LUMO of TiOOR; (ii) the spiro transition state is nearly symmetrical with the two C-0 bonds forming to a similar extent; (iii) the electrophilic nature of the addition reaction is indicated by a small gap between the HOMO of the alkene and the LUMO of the TiOOR, and by a negative charge transfer of about 0.2 units from to C=C unit to the TiOOR in the transition structure; and (iv) the transition structure for a possible monomeric mechanism favours square-pyramidal geometry with the open site in the opposite direction of the C=C bond orientation-this is different from the geometry in the Corey ion-pair modeL6’ In agreement with earlier proposals by Sharpless, the ester groups on the reactive titanium centre are not involved in coordination with the titanium in the transition structure; the model accounts for the importance of the bulky peroxide and ligand structure in the enantioselectivity of the reaction.61A highly efficient kinetic resolution of unsymmetrical divinylmethanols by a modified Sharpless asymmetric epoxidation has been described.62Asymmetric epoxidation of trans-cinnamyl alcohol is a key step in a synthesis of the side-chain of taxol and t a ~ o t e r e Silica . ~ ~ treated with titanium tetraisopropoxide is an efficient catalyst for the t-butyl hydroperoxide epoxidation of non-functionalized alkenes and allylic alcohols.64 A system derived from titanium silicate molecular sieve with hydrogen peroxide causes stereoselective epoxidation of allylic alcohols.65 Some bifunctional aluminosilicate catalysts containing titanium are highly selective for carrying out multi-step reactions with selectivities close to those obtained with epoxidases; this has been demonstrated in the oxidation of linalool to cyclic hydroxy ethers.66 The oxidation of titanium enolates with t-butyl hydroperoxide gives the corresponding cc-hydroxy ketones; high diastereoselectivities were obtained when titanium enolates of camphor were used.67 A highly unusual oxidative cleavage of methyl diphenyltartrate is promoted by a titanium tetrachloridepyridine system (Scheme 5); a titanium(1V) enolate (16) undergoes a key fragmentation to give titanium(II1) in the oxidative step.68

187

5 Oxidation and Reduction

P h V P h Me02C

Ti(IV)

C02Me

0

,Titv

0

PhCOC02Mc

Ph)=;(nMe

+ PhCH(OH)CO?Me + Ti(II1) 1

3

(16) SCHEME 5

The hydrogen peroxide-urea complex in the presence of a vanadium(V) complex oxidizes cyclohexane to cyclohexyl hydroperoxide in good yield under mild conditions. The key stage is the abstraction of hydrogen by a hydroxyl radical formed from the interaction of hydrogen peroxide with the vanadium complex; benzene is oxidised by the same reagent to phenol.69 Kinetic studies on the oxidation of malic acid by ~anadium(V)~'and of L-ascorbic acid with bromate and iodide in the presence of vanadiumv) and molybden~m(V1)~' have been reported. Thianthrene 5-oxide (1) is oxidized by MoOS(HMPT)to the sulfide sulfone (2) and bis-sulfoxides (3) by competing pathways both of which are simple bimolecular transfers from the oxidant to substrate with no complexation between the two reactants; this analysis may indicate limitations in the use of (1) as a mechanistic probe in oxygentransfer reactions.72 Mechanistic studies on the oxidations of organic substrates by

TPPM(II1)

+

TPPM(V)=O

PhI=O

+

H+Me

Me Ph

2

t

Me TPPM(1V)OH

HO+Me

Ph

+

Me .+Me Ph (17)

SCHEME 6

Phi=O

+

Me *+Me Ph (17)

Me -

4

Ph-;-O+Me Ph

(18)

-

PhI

+

Me 6+Me

(19)

O<Me SCHEME 7

I

Ph

Ph

+Me'

Organic Reaction Mechanisms 1995

188

hydrogen peroxide catalysed by molybden~m(V1)~~ and t u n g ~ t e n ( V I ) have ~ ~ , ~been ~ discussed.

Group VIII Metals

In the hydroxylation of C-H bonds catalysed by tetraphenyl metalloporphyrins [TPPM(III), where M is iron or manganese], the reaction usually occurs by abstraction of hydrogen by a metal-oxo complex to form (17), followed by in-cage hydroxyl radical recombination as exemplified for cumene in Scheme 6; a previously unobserved trapping of the organic radical (17) by the oxygen donor (Scheme 7) has been observed to form (19), probably by way of the iodine-centred radical (18).76An alkylperoxoiron(II1) intermediate has been prepared and its role in the oxidation of aliphatic C-H bonds has been i n ~e st iga te d.~~ In the epoxidation of alkenes by iodosylbenzene catalysed by an iron(II1) porphyrin, the dominant determinant of the rate is the influence of alkene substituents on the formation of the complex with the active oxidant and the rate of subsequent breakdown of the inte~mediate.~~ chloroperoxidase _ ___t

Ph

Me

Ph

Ph

'4,.

CH2O

The use of the enzyme chloroperoxidase in asymmetric epoxidations has been evaluated. Chloroperoxidase also performs benzylic hydroxylations in high enantiomeric excess; its reaction with the radical probe substrate (20), to give as the major products (21), (22), and (23), suggests that radicals cannot be involved in such reactions. The reaction probably proceeds by transfer of the oxygen atom from the highvalent iron-oxo intermediate directly to the substrate.79In enzymatic and biomimetic oxidations of sulfides and sulfoxides by iron-oxo complexes, the most likely pathway is by direct oxygen transfer, rather than pathways involving single-electron transfer.*' In the hydroxylation of maleic acid by hydrogen peroxide, the hydrolysis leading to tartaric acid proceeds much faster in the presence of an iron(II1) catalyst.*' The oxidation of substituted anilines by hexacyanoferrate(II1) proceeds by a two-stage process, the first of which follows a 2 : 1 oxidant: amine stoichiometry with azobenzenes as the main products.82A mechanism involving 14 elementary reactions has been proposed to account for the autoxidation of aldehydes in the presence of ~obalt(II).*~ The cobalt(I1)-catalysed oxidation of imines with molecular oxygen in the presence of an aldehyde as co-reductant gives oxaziridines (Scheme 8); a characteristic green colour that develops during the reaction indicates the presence of a cobalt(II1) inte~mediate.~~ In the oxygenation of alkenes in the presence of nickel(l1) compounds, the nickel(I1) complex can activate the dioxygen molecule without changing its oxidation state.85

5 Oxidation and Reduction

189 0

R

t

-8,P\

CO(III)C1~

R

SCHEME 8

Diketones are formed in the ruthenium(II1)-catalysed oxidation of ketones by bromate.86 A ruthenium(\/) species is implicated as the active oxidant in the ruthenium(II1)-catalysed oxidation of phenoxyacetic acids by lead tetraacetate." Kinetic studies on ruthenium(II1)-catalysed oxidations of and of amidesg9 have been reported. A Hammett p value of 1.7 in the oxidation of benzyl methyl ethers by ruthenium tetraoxide indicates only a moderate charge separation in the transition state of the oxidation. This and other evidence suggests the mechanism of the reaction does not involve hydride transfer or radical abstraction; the data are consistent with a concerted reaction or with a reversible oxidative addition of the ether to Ru04 followed by a slow concerted step to afford the pr~duc t.~' Oxygen transfer to sulfides from perruthenate involves an initial expansion of the ruthenium coordination shell through incorporation of a hydroxide ion; reaction of a sulfur lone pair with either a vacant ruthenium d-orbital or with the Ru=O n*-orbital then initiates oxygen transfer (Scheme 9). This mechanism is consistent with the observed base catalysis, the negative Hammett p value, and the unfavourable entropy of activation." An authoritative review on mechanistic and other aspects of catalytic asymmetric dihydroxylation (AD) has appeared.'2 The Sharpless AD has been expanded to include the use of allylic 4-methoxybenzoates as precursors of a wide variety of substituted chiral glycerol derivatives; some divergent views of the mechanistic rationale of AD have been discussed.93Poor asymmetric induction on an initial hydroxylation can be turned to synthetic advantage by exploiting the efficient kinetic resolution of alkenes through recycling; this strategy has been exemplified by an amplified AD of a racemic cyclopentene." The rate of oxidation of phenyl styryl ketones by periodate catalysed by osmium(VII1) is enhanced by electron-releasing substituents and retarded by electron-

Organic Reaction Mechanisms I995

190

withdrawing substituents on either aromatic ring.95 In contrast, a V-shaped Hammett curve is found for the osmium(VII1)-catalysed oxidation of substituted trans-cinnamic acids by chloramine-B with both electron-donating and -withdrawing substituents increasing the rate of the reaction.y6 Kinetic studies have been reported on the osmium(VII1)-catalysed oxidation of dimethyl sulfoxide by vanadi~tn(V):~palladium(I1)-catalysed oxidations of primary amines by he~acyanoferrate,~~ and iridium(II1)catalysed oxidations of glycols by N-bromos~ccinimide.~~ The regioselectivity of the Wacker oxidation of acetonides of allylic diols is completely reversed when the diol is protected as a carbonate; differential complexation of palladium to the protected diols may be used to rationalize the different course of reactions.'00

i

-H20

I

Ar

SCHEME 10

Methylrhenium trioxide (24) catalyses the epoxidation of styrenes by hydrogen peroxide with the monoperoxide (25) and diperoxide (26) as the active species; both (25) and (26) epoxidize a given styrene at similar rates. It is unlikely that there is any binding of rhenium to the substrate prior to the oxygen-transfer step; the diperoxide (26) is likely to have a similar mechanism to that (Scheme 10) for the monoperoxide (25)."' The monoperoxide (25) is principal reactive oxidant in the oxidation of anilines to nitroso compounds by hydrogen peroxide catalysed by methylrhenium trioxide (Scheme 11); the diperoxide (26) only oxidizes aromatic amines slowly.'o2 The monoperoxide (25) is the active oxidant in the conversion of phenols into

5 Oxidation and Reduction

191

p-benzoquinones; '03 radicals are not intermediates in the oxidation of anisole by hydrogen peroxide with (24) as a cataly~t."~

ArNH2

+

p-

if

MeRe03 (241

MeReO2(Oz)

ArNH2+

(25)

ArN=O

-HzO

ArNHOH

0-

I

A~N~IOH

SCHEME 11

Oxidation by Compounds of Non-metallic Elements Nitrogen, Selenium, Sulfur, and Tellurium The aerial oxidation of phenothiazines to the corresponding sulfoxides is catalysed by nitric oxide and related nitrogen oxides; the reactive intermediate in the catalysed autoxidation is the phenothiazine cation radical which is subsequently converted into the sulfoxide by nitrate present in the reaction medium.lo5 Stable nitroxyl radicals such as TEMPO (27) can act as mediators for the oxidation of primary and secondary alcohols; oxidation of (27) with halogen gives the nitrosonium ion (28), which is the actual oxidant. Reaction of (28) with an alcohol gives an intermediate which, in base, fragments via an intramolecular cyclic transition state, whereas under acid conditions the oxidation proceeds via an acyclic transition state (Scheme 12).'06 There are conditions in the oxidation of vitamin C (ascorbic acid) by nitrous acid where the autoxidation of nitric oxide is the rate-determining step.lo7 The complex (29) is the critical intermediate in the oxidation of sulfides to sulfoxides in air with catalytic amounts of nitrogen dioxide present; photo-activation of (29) gives the thioether radical cation (30).lo8 Nitrogen dioxide transforms acetals to ketones in the presence of silica gel under neutral anhydrous and mild conditions (Scheme 13).lo9 Oxone (peroxymonosulfate) in aqueous acetonitrile converts thiobenzoates into carboxylic and sulfonic acids (Scheme 14); the initial step of the oxidation is very similar to oxone oxidation of sulfides, which has similar solvent and substituent effects."' The initial step in the oxidation of 2,3-dialkylindoles by both oxone and peroxodisulfate is electrophilic attack by a peroxidic oxygen at C ( 3 ) of the indole ring. l 1 Kinetic studies on the oxone oxidation of amines have been reported.' l2 The

Organic Reaction Mechanisms 1995

192

Q

intramolecular

+

R2CHOH

0 II

f

-3 acid

R

\

Q

I

OH

+

'0

HO'

R

JrH R

SCHEME 12

[R&NO]

(29)

N03-

R*S+*

products

(30)

SCHEME13

high negative entropy of activation in the oxidation of some semicarbazones by peroxodisulfate suggests that the activated complexes in the reaction are addition complexes of the substrate and oxidant.'I3 The reactions of some telluroxides, R,TeO, or their hydrates with glutathione to give tellurium dyes and glutathione disulfide have at least two discrete steps, a fast reaction

193

5 Oxidation and Reduction

Ar'

0 II C 'SAr'

HSOSH20

ArC02H

+

Ar'S03H

SCHEME 14

followed by a slow reaction, both of which are first-order in both glutathione and telluroxide. Diphenyl selenoxide displays similar, but slower, oxidative behaviour.' l 4

Halogens The oxidation of organic compounds by aqueous bromine, in which the bromine acts as an external electrophile in intermolecular hydnde transfers, has been reviewed.Il 5 Mechanisms involving hydride transfers to bromine have been proposed for the oxidations of arylthioacetic acids' l 6 and substituted benzyl alcohols' l 7 by pyridinium hydrobromide perbromide. Among other studies,' kinetic investigations of oxidations by N-chloro compounds of N-amino-3-azabicyclo[3.3.0]octane,'l 9 indigocarmine,12" heterocyclic secondary alcohols,'21 and p-hydroxybenzoic acid'22 have been reported. A 16-step mechanism has been proposed for the oxidation of acridine orange with bromate ion;'23 nine species have been detected as intermediates in the reaction of bromate with phenol. '24 A number of features of the periodate glycol reaction have been clarified in the reaction of pinacol with periodic acid as a hnction of pH and temperature. For the most part, pinacol and periodic acid undergo a direct bimolecular reaction, although there is a minor reaction with periodate ion; the methyl groups of pinacol, as compared with

OH H

H

OH

= H

0-

H OH

0

SCHEME 15

slow

HO

+ ,s+\I

+

H

J

I

Organic Reaction Mechanisms 1995

194

ethylene glycol, retard the reaction by steric effects.'25 The selectivity in the oxidation of 1,4-diols to y-lactols by o-iodoxybenzoic acid may be explained by a rate-limiting carbonyl-forming elimination pathway in which the carbinol proton is abstracted internally in a six-atom cyclic transition state (Scheme 15).'26 The stereoselectivity in the oxidation of the phosphorus(II1) amino acids (31) by carbon tetrachloride in alcohol to afford (32) is determined by stereomutation of intermediate pentacoordinate phosphorus corn pound^.'^^

Ozonolysis and Ozonation The reaction of ozone with an alkene in which both the double bond and adjacent single bond are cleaved is known as anomalous ozonolysis.'28 A distinct mechanistic pathway

0 3

HO

4 3

Ph

Me

CHzC12

d e P h HO

-

o~ HO

Me

Me

(33)

Ph

I

Ph

Ph

(34)

(35)

SCHEME 16

Ph

5 Oxidution and Reduction

195

(Scheme 16) has been elucidated for the anomalous ozonation of the cyclohexenol (33) by X-ray crystallographic analysis of the acetate (34); reaction of (34) with sodium hydroxide gave the cyclohexenone (35). Neighbouring-group participation by a carbomethoxy functionality in the ozonolysis of a santonin derivative (36) resulted in the unexpected formation of (37), a h-lactone (Scheme 17).130 Alkoxy substituents exert an anti-directive effect on the geometry of formation of carbonyl oxides in the ozonolysis of vinyl ethers, so that the carbonyl oxide formed has the opposite geometry to that of the precursor vinyl ether.131A linear-free-energy study on the ozonolysis of ring-substituted a-methylstyrenes indicates that the overall process is one of electrophilic attack on the alkene.'32 The presence of oxygen and carbon dioxide inhibits the ozonolysis of hexafluoropropylene.1 3 3 Steric effects significantly slow ozonolysis for all 1,l-disubstituted alkenes and also for 1-alkenes that bear s- or t-butyl g r 0 ~ p s . Mechanistic l~~ studies on the reaction of ozone with aliphatic ethers in carbon tetrachloride have been reported. 135

'0

Peracids and Peroxides Dioxiranes, such as (38) and (39), constitute a new, powerful set of oxidants characterized by the propensity for easy electrophilic oxygen transfer to nucleophilic substrates as well as oxygen-insertion reactions into unactivated C-H bond^.'^','^^ The reaction of a series of p-substituted cumenes with (38) to give the corresponding alcohols (Scheme 18) afforded a Hammett p value of 2.76, indicating that the insertion

196

Organic Reaction Mechanisms 1995

Mexz F3cxz Me

Me

reaction is an electrophilic process. The best correlations for the conversion of a series of adamantanes into the corresponding adamantanols were obtained with Tafi ts* and c1 constants which gave a p* of 1.08 and a p i of 2.39, again indicating that the insertion reaction in this aliphatic system is electrophilic (Scheme 19).13*The hydroxylation of alkanes by cytochrome P450 and by dimethyldioxirane (38) show a number of common features, most notably that radicals which can diffuse freely through the solution are not involved; it has been generally accepted that such insertion reactions of (38) are ~ 0 n c e r t e d . lHowever, ~~ radicals have been observed in the oxidation of adamantane by (38) in BrCC13;140radicals in the oxidation by (38) of alkanes, ethers and aldehydes have also been trapped by protonated q~inolines.'~'Oxidation by (38) of phenylacetaldehyde to either phenylacetic acid or benzyl acetate depends on the presence or absence of oxygen; these results and the epoxidation or allylic oxidation of alkenes under the same conditions can be explained by a general free-radical mechanism for oxidation by (38). In contrast, it has been shown that the oxidation of 2cyclopropylpropane (Scheme 20) is not a free-radical chain reaction.I4* Some heteroarene N-oxides are partially deoxygenated by (38) to produce the corresponding amines (Scheme 21); the formation of singlet oxygen suggests a polar, rather than a radical, mechanism for the r e a ~ t i 0 n . I ~ ~ Less polar solvents give a notably higher diastereoselectivity in the epoxidation of chiral allylic alcohols by (38); this can be interpreted in terms of a dipolar transition

SCHEME18

x

SCHEME 19

SCHEME 20

5 Oxidation and Reduction

xMe

0-0

R$-0-

+

197 R3fi4-0

Me

0'02

Me

+

R3N

+ Me*C=O

SCHEME 21

state with OH association through hydrogen bonding to the dioxirane for which a preferential dihedral angle of 130" is e ~ t i m a t e d .The ' ~ ~ oxidation of the amides (40) by (38) to give (41) provides the first spectroscopic evidence for enamide oxides; above 50°C, (41) dimerizes, whereas in the presence of methanol the epoxide is trapped to form a hemiaminal (Scheme 22).'45 Reaction of (42), possessing both an alkene and a tertiary amine, with (38) gives (43), in which the amine has undergone highly selective

0

OMe

SCHEME 22

(43)

then (38)

(44)

\

Organic Reaction Mechanisms 1995

198

oxidation; initial treatment of the amine with boron trifluoride protects the amine so that treatment of the adduct (44) with (38) allows epoxidation of the C=C to give (45).'46 Alkenes are converted into epoxides in aqueous medium by formamide-hydrogen peroxide as the oxidant; the epoxidation is independent of pH and performic acid is probably the active 0 ~ i d a n t . IThe ~ ~ oxidation of S-mercaptoacetic acids by sodium perborate involves formation of a protonated arylsulfinic acid intermediate which subsequently undergoes an intramolecular Pummerer-type of rearrangement. 148314y Some lipophilic cyclic ketones underwent the Baeyer-Villiger reaction to form the corresponding lactones using mynstic acid and hydrogen peroxide catalysed by Candida antarctica lipase. " A monooxygenase from Pseudomonas has been used in the kinetic resolution of cyclic ketones and has provided a synthesis of enantiomerically enriched ( )-lipoic acid.I5' Kinetic studies of the oxidations of 9-alkenyl~arbazoles"~ and unsaturated aldehydes' s3 by peracids have been reported. The application of t-butyl hydroperoxide as an oxidant has been reviewed.154 Steric control of nucleophilic epoxidation of oxygenated a$-unsaturated sulfones containing allylic oxygen substituents, such as (46) and (47) by t-butyl hydroperoxide can be controlled by the choice of oxygen protecting group^.'^^,'^^

'

+

Tn the electrophilic oxidation by peroxides, the reactivity of sulfoxides is considerably less sensitive to substituent effects than that of sulfides. A theoretical study has shown that the reactivity of the sulfides is mainly dependent on the charge on the sulfur atom; such charge is usually small in sulfoxides, so that for these substrates the rates are dominated by the interaction between the HOMO of the sulfoxide and the LUMO of the 0 ~ i d a n t . lAb ~ ~initio calculations on the first step in the oxidation of disulfides to thiosulfinates by hydrogen peroxide indicate a two-stage process in which the initial step is a high-barrier 1,2-hydrogen shift involving hydrogen peroxide to form water oxide.'58 Other studies have shown that solvation effects and exo- versus endothermicity of oxygen transfer from a peroxy acid has a much more significant effect on the relative nucleophilicity than polari~ability.~~' Guanine (49) is the only one of the four DNA bases that is prone to electrophilic oxidation by 1,2-dioxetanes such as (48); the other DNA bases merely catalyse the decomposition of these labile peroxides. Model studies on the acylated guanosine (50) (Scheme 23) show initial formation of an intermediate (51) which can undergo alternative nucleophilic attack by methanol resulting in deglycosylation to give (52) or modification of the purine ring to give (53). The pathways uncovered in these studies may provide a general rationale for the oxidative DNA cleavage by peroxides.

'"

5 Oxidation and Reduction

199

CH20Me

(51) nucleophilic attack at C ( 8 )

0

Acd

OAc (53)

+

PhCOCH20Me

+ (49) SCHEME 23

Photo-oxygenation, Singlet Oxygen, and Superoxide A number of heterocyclic substrates undergo reactions with ozone at low concentrations to form products typically associated with oxygenation by singlet oxygen.'6' In the reaction of sulfenamides with singlet oxygen, there are two intermediates on the photooxidation reaction surface; one of the intermediates acts as a nucleophile and the other as an electrophile in their reactions with diaryl sulfoxides and diaryl sulfides. The

Organic Reaction Mechanisms I995

200

mechanism of the reaction has a number of similarities to the photo-oxidation of diethyl sulfides.'62 The major process in the oxygenation of diazoalkanes is the cycloaddition of singlet oxygen to form a dioxadiazole (54), which can undergo cyclo-elimination to form either a carbonyl oxide and nitrogen, or a ketone and nitrous oxide with the relative proportions being determined by the relative stability of the carbonyl oxide (Scheme

FN2

1,3-dipolar cycloaddi tion

x:Y O,

/

1,3-dipolar


I

0-

or

)=o<

(54)

'02

bo+

NP"

+ N3N 0-

SCHEME. 24

J

\

\

radical path way

A

0'"' SCHEME 25

'02

"ArO H B "But '

Ar

The unique geometrical features of trans-cyclooctene (55) allow a perepoxide intermediate (56) formed in the reaction with singlet oxygen to be trapped by triphenyl phosphite to give the epoxide (57) (Scheme 25); these results support a mechanism for ene singlet oxygenations that involves a perepoxide or a structurally closely related

5 Oxidation and Reduction

20 1

inte~mediate.'~~ The anti selectivity for hydrogen abstraction in the ene reaction of trisubstituted alkenes with singlet oxygen is related to the steric congestion on the more-substituted side of the alkene, non-bonded interactions in the new double bond formation, and the lack of interaction of oxygen with two allylic h ~ d r 0 g e n s . IThe ~~ singlet oxygenation of alkenes (58) gives dioxetanes (59), whose thermal stability and chemiluminescent half-life induced by fluoride are significantly affected by the 3alkoxy group.'66 The kinetics of the singlet oxygenation of cyclic 1,3-dienes have been studied in 28 solvents and the reaction has been found to be highly solvent dependent. In the past, the supposed lack of solvent effect had caused many workers to propose that the reaction was a concerted cycloaddition; however, it is considered likely the reaction involves a two-stage mechanism with the first stage being an equilibrium producing an exciplex with charge-transfer character.'67n-Facial diastereoselectivity in the addition of singlet oxygen to a number of chiral naphthalene derivatives may be rationalized in terms of attraction or repulsion induced by substituents on a 4 2 cyclic transition state.I6* The reaction of superoxide ion with cinnamyl bromide (60) in toluene gave dicinnamyl ether (61) and the epoxy acetal (62); substantial evidence supports the proposed mechanism (Scheme 26).'69

+

I

0

7 +CHZCH=CHAr r

$ H ArCH=CHL0

/

'OCH2CH

=CHAr

SCHEME 26

Atomic Oxygen, Triplet Oxygen, and Autoxidation Reaction of oxygen atoms in the O(3P) ground state are of importance in atmospheric and combustion chemistry. The reaction of atomic oxygen with some small alkenes has been studied at low pressure. The radical branching ratios for propene and for butene decrease with pressure; the reaction pathways at room temperature have been ~tudied.'~' The temperature dependence of the rate constants of oxygen atoms with a number of small alkenes have also been determined.I7' The first step in the reaction of O(3P)with acetylene is the formation of a complex HCCHO which has two channels of dissociation, giving either H and ketene or carbon monoxide and m e t h ~ 1 e n e . lThe ~~ kinetics of the reaction of O(3P)with tifluoronitrosomethane have been studied.'74

''

(a-

202

Organic Reaction Mechanisms 1995

Amide ions generated from secondary aromatic amines are readily oxidized by oxygen in the presence of potassium hydroxide and 18-crown-6 in dimethyl sulfoxide; the rate-limiting stage of the reaction is the interaction of oxygen with amide ions and is determined by the extent of ionization of the amine and the reactivity of the amide ions towards d i 0 ~ y g e n . The I ~ ~ products of the reaction are nitroxyls, quinone nitrones, and quinone imines; nitroxyl radicals are the primary paramagnetic products and do not form by the interaction of the aminyl radicals with d i 0 ~ y g e n . Ab l ~ ~initio calculations have been used to probe the attachment of dioxygen to amide ions.'77 t-Amy1 methyl ether (TAME) is proposed for use as an additive to increase the oxygen content of gasoline; kinetic studies on the reaction of OH with TAME have been reported and mechanisms involving OH abstraction of each of the four different H atoms of TAME have been suggested.17*The inhibitory effect of hydroquinoline dithiolethiones on the oxidation of hydrocarbons is greater than that of the parent hydroq~inolines.'~~ The oxidation chemistry of the tetrahedrane (63) and the cyclobutadiene (65) is governed by the formation of the radical cation (64); reaction of (65) with oxygen generates a stable oxete.'" Quantum-mechanical calculations have been used to investigate the transition state for the oxidation of methane in water.'" Kinetic studies on the oxidation by molecular oxygen of 8-monohydroperfluorooct-1-ene,182trifl~oroethane,''~propene, 184 and acetic acid'85 have been reported.

Other Oxidations The reversible organic redox couple of anthraquinone-anthrahydroquinone may be useful in metal-free re-chargeable batteries, mainly in acid electrolytes. However, the anthraquinone undergoes an acid-catalysed disproportionation reaction to yield anthraquinone and anthrone; the dependence of this irreversible second-order sidereaction on the type of acid, solvent, and acid concentration has been investigated.IR6 Kinetic studies on the oxidation of amides by trichloroisocyanuric acid have been reported.IR7 An unusually large kinetic isotope effect was found for the reduction of the tryptophan tryptophylquinone (TTQ) prosthetic group of aromatic amine dehydrogenase (AADH). These data support the proposed mechanism for the reductive halfreaction of AADH in which TTQ reduction is linked to proton abstraction from a covalent enzyme-substrate complex and in which the release of aldehyde product is partially rate limiting. The large deuterium isotope effect ( k ~ / =k 8.6-1 ~ 1.7) is nearly identical with values for similar reactions catalysed by methylamine dehydrogenase, which also possesses TTQ, and plasma amine oxidase, which uses the topaquinone

5 Oxidation and Reduction

203

cofactor. It is suggested that these three quinoproteins share a very similar mechanism for catalysing the oxidative deamination of primary arnines.lg8 In model studies on topaquinone-dependent amine oxidases, it was found that 2-hydroxy-1,4-benzoquinones with bulky substituents can act as efficient catalysts for the oxidation of benzylamine in acetonitrile; the bulky substituent at C(5) is necessary to prevent dimerization of the substrate Schiff base intermediate.Ig9 The functional form of topaquinone in the active site of copper amine oxidases may best be represented as a 2hydroxy-l,4-benzoquinone.I9O Enzymes, synthetic catalysts, and catalytic antibodies can all be used to perform asymmetric reactions; criteria with which to compare such different catalysts have been proposed and illustrated for asymmetric epoxidation.’” The oxidation ofp-anisidine by peroxidase in organic solvents has been studied.192

Reduction by Complex Metal Hydrides The mechanism of the Meenvein-Ponndorf-Verley-Oppenauer reactions (MPVO) usually involves a cyclic six-membered transition state in which both the oxidant and reductant are coordinated to the metal centre of an alkoxide catalyst. In aluminiumcatalysed MPVO reactions, ligand exchange dominates the rate of the reaction so that traditional aluminium catalysts usually have too slow ligand exchange to permit the use of catalytic amounts. In contrast, in MPVO reactions catalysed by lanthanides, hafnium, or zirconium, ligand exchange is much faster so that reaction rates are determined by hydnde transfer as well as ligand exchange. Optimized conditions involve 1-(4dimethylaminopheny1)ethanol as the reducing alcohol with zirconium tetra-t-butoxide in catalytic amounts in toluene as solvent; aldehydes and ketones are reduced to the corresponding alcohols at room temperature in a few hours in quantitative yields.193 High enantioselectivity in the MPV reduction is obtained using a chiral lanthanum(II1) alkoxide as a ~ a t a 1 y s t . l ~ ~

One rationale for the diastereoselectivity in the hydride reduction of carbonyl groups is that hyperconjugation can lower the energy of the transition state sufficiently to make a sufficient contribution to the observed product ratios. Ab initio and semiempirical calculations for the reduction of 5-substituted adamantanones (66) with AlH, show bond lengthening in a four-centre transition state and molecular orbitals consistent with hyperconjugative stabilization; the C-C bond which is antiperiplanar to the incoming

204

Organic Reaction Mechanisms 1995

nucleophile is lengthened, and ring distortions consistent with minimization of torsional strain and improvement of orbital alignment are present. These effects are also found in the syn and anti transition states for the reduction of the azaadamantanone N-oxide (67); the favoured syn approach has an alignment of the nucleophile with the more electron-rich C-C bonds which is closer to the ideal antiperiplanar orientation and with less torsional strain than is found in the transition state for anti attack.'95 The preferential syn delivery of hydride in the reduction of 5-fluoroadamantanone (66; X = F) is inverted if the identities of all the hydrogen and fluorine atoms are reversed; in this case, the periplanar bonds are no longer capable of stabilizing the transition state by electron donation and instead do so by accepting electron density from the incipient bond into the CT*0rbita1s.I~~ In hydride reductions of the diketone (68) by sodium borohydride, lithium aluminium hydride, and sodium cyanoborohydnde, the first reduction step showed little regioselectivity between attack at the different carbonyl groups but highly diastereoselectivesyn attack at C(2) and ex0 attack at C(9); transition structures for all possible additions of lithium hydride to (68) were analysed by MNDO and ab initio methods.'97 High diastereoselectivitieswere found in the reduction of ciscyclopropyl ketones (69) by hydride reagents to give (70), while there is virtually no facial selectivity in the reduction of the trans-analogues (71).19* Diastereoselectivity in the hydride reductions of some azabicyclic ketones'99 and a-selenoalkyl aryl ketones2" has been investigated. A transition structure involving a complex between a chiral amine, boron trifluoride, borane, and the ketone has been used to rationalize the asymmetric reduction of prochiral ketones by borane-amine complexes in the presence of chiral amine-boron trifluoride catalysts.*"

Conformational preferences of the iminium ion (72) and the effective size of the reducing agent can be used to rationalise the formation of (73) as the major product with sodium triacetoxyborohydride but of (74) as the major product with sodium cyanoborohydride.202Reduction of glycofuranolactols (75) with triethylsilane-boron

5 Oxidation and Reduction

205

trifluoride gives a stereo-controlled approach to tetrahydrofurans (76)in which hydnde delivery occurs cis to an adjacent oxygen function.203The nature of the protecting group of the amine function determines the diastereoselectivity in the sodium borohydride reduction of 6H-1,3-thiazines substituted by a chiral amino acid group.2o4

CHzC02Bn (73) major

(74) major

Other Reductions The single-electron-transfer ability of samarium diiodide can be enhanced by electronrich ligands; many acid derivatives are reduced with samarium(I1) in the presence of water, acid, or base as ligands. Samarium(I1) iodide with phosphoric acid reduces aromatic primary amides to aldehydes in good yield.205 An electron-transfer mechanism has been postulated to account for the reduction of terephthalodinitrile by potassium and the subsequent quenching of the reaction with primary alkyl bromides.206The enzymic reduction of aromatic nitro compounds by nitro reductases proceed by oxygen-atom transfer to the molybdenum(IV)=O centre of the enzyme; it has been shown that thiols are viable electron donors in the catalytic reduction of nitrobenzene to aniline mediated by a molybdenum(V1) catalyst which is converted into molybdenum(1V) as the active entity.207The outcome of the catalytic asymmetric hydrogenation of oximes is significantly affected by the original E- or Z-geometry of the starting rnateriaL2O8The asymmetric titanocene-catalysed hydrogenation of imines proceeds by reaction of the imine with a titanium hydride in a fast 1,2-insertion step to form a titanium amide intermediate, followed by slow reaction of the amide complex with hydrogen to produce the amine and regenerate the titanium hydride; a stereochemical model has been proposed on the basis of steric and electronic considerations to account for the observed enantio~electivity.~~~ Ab initio calculations, taking account of the experimentally determined absolute rate constants for the reaction of the h a r a t e with diimide, support the notion of a synchronous, concerted, doublehydrogen transfer pathway for the reduction."' Micellar effects of the reduction of p nitroso-N,N-dimethylanilinehave been investigated.21 Charge-transfer complexes are

Organic Reaction Mechanisms 1995

206

discrete intermediates in the hydride transfer from Michler’s ketone to 2,3-dichloro-5,6dicyano-p-benzoquinone.212 There is a striking similarity between the transition-state geometries calculated for general acid-catalysed hydride reduction of carbonyl groups by a number of different theoretical methods for a range of hydride and proton donors; all the transition states indicate that proton transfer is further advanced than hydride transfer. Although the use of simple models for hydride (such as methylamine), substrate, and proton (ammonium ion) donation-rather than complex species such as NADH-affects the energetics, the nature of the transition state is not materially affected.213The Marcus theory of hydridetransfer reactions has been reviewed.214

I

Me

(77)

(79)

Ab initio calculations indicate that hydride-transfer reactions of protonated pyridinium ion with 1,4-dihydropyridine, and protonated nicotinamide with 1,4dihydronicotinamide, show a strong preference for a syn or stacking approach of the two rings in the transition structure, with the pyridine rings being slightly puckered into a boat confirmation. In a cis conformation, the 3-amide group of nicotinamide slightly increases the activation energy for the hydride transfer, whereas in a trans conformation it significantly reduces the activation energy for the transfer. The relevance of these findings to enzymic processes involving NADH has been discussed.215The nature of hydride transfer in reactions involving NADH has been reviewed.216The transitionstate structure for hydride transfer to pyruvate to form lactate by lactate dehydrogenase has been the subject of semiempirical calculation^.^'^ The observed enantioselectivities in the reductions by the chiral NADH models (77) and (78) in the presence of

5 Oxidation and Reduction

207

magnesium ions can be rationalized in terms of ternary complexes between the metal ion, the model, and the substrate.21s A series of NADH models in which the nicotinamide is attached to a glucohranose ring, such as (79) and (80) have been prepared; their stereoselective biomimetic reduction of benzoyl formate has been interpreted in terms of molecular-orbital calculations.219A chiral NADH model in the pyrrol0[3,Cb]pyridine series has been studied in the asymmetric reduction of methyl benzoylformate.220The rate constant for the aerial oxidation of NADH by Methylene Blue has been determined.221The effects of alcohol structure and reaction conditions on the horse liver alcohol dehydrogenasecatalysed reduction of cyclohexanone has been investigated with in situ regeneration of NADH by alcohols.222 References

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(1995). Raghavi, D. E., Sundar, S. B., and Murti, P. S . R., 1 Inst. Chem. (India), 66, 65 (1994); Chem. Ahs., 122, 213390 (1995). Rathore, S., Sharma, P. K., and Banerji, K. K., Indian 1 Chem., 348, 702 (1995); Chem. Abs., 123, 169093 (1995). Lin, T.-Y., Zeng, H.-W, and Chuo, C.-M., 1 Chin. Chem. Soc. (Taipei), 42,43 (1995); Chem. Abs., 122, 239030 (1995). Zeng, H.-W., Lin, Z.-Y., and Mao, Y.-L., Youji Huaxue, 14,526 (1994); Chem. Abs., 122, 105091 (1995). ti Khanchandani, R., Sharma, P. K., and Bane@, K. K., J. Chem. Res. (S), 1995,432. Palaniappan, A,, Sekar, K. G., and Ravishankar, M., Oxid. Commun., 18, 52 (1995); Chem. Abs., 122, 264769 (1995). Pandurangan, A. and Murugesan, V, React. Kinet. Catal. Lett., 54, 173 (1 995); Chem. Abs., 123, 198139 (1995). Joseph, R., Sasidharan, M., Kumar, R., Sudalai, A,, and Ravindranathan, T., J. Chern. Soc., Chem. Commun., 1995, 1341. 10 Chellamani, A., Alhaji, N. M. I., and Selvanjan, S . , Asiun 1 Chem., 7, 365 (1995); Chem. Abs., 122, 290171 (1995). Sabapathymohan, R. T., Gopalakrishnan, M., and Sekar, M., Oxid. Commun., 18, 173 (1995); Chem. Abs., 123, 198126 (1995). Rathore, S., Sharma, P. K., and Baneji, K. K., 1 Chem. Res. (S), 1994, 504. l 3 Nagarajan, S. and Gopalakrishnan, M., Oxid. Commun., 18,162 (1995); Chem. Abs., 123,198124 (1995). l4 Varea-Amo, M. C., Mata-Perez, F., and Alvarez-Macho, M. P., An. Quim., 90, 166 (1994); Chem. Abs., 122, 239025 (1 995). l 5 Sharma, K., Sharma, V: K., and Pandey, A,, Asian 1 Chem. Rev., 5, 1 (1994); Chem. Abs., 122, 186622 (1995). " Chen, M., Ding, L., and Cai, K., Youji Huaxue, 15, 348 (1995); Chem. Ahs., 123, 197920 (1995). 17 May, B. L., Yee, H., and Lee, D. G., Can. 1 Chem., 72, 2249 (1994). Sen, F! K., Sanyal, A,, and Sen Gupta, K. K., Int. 1 Chern. Kinet., 27, 379 (1995). Thibblin, A,, 1 Phys. Org, Chem., 8, 186 (1995). 2o Dash, S. and Mishra, B. K., Int. 1 Chem. Kinet., 27, 627 (1995). Dash, S. and Mishra, B. K., Bull. Chem. Soc. Jpn, 67, 3289 (1994). 22 Insausti, M. J., Mata-Perez, F., and Alvarez-Macho, M. P., Int. 1 Chem. Kinef.,27, 507 (1995). 23 Uma, M., Kabilan, S., and Kirubasankar, P., Oxid. Commun., 18, 166 (1995); Chem. Abs., 123, 198125 (1995). 24 Chaudhary, R. B. and Singh, S. N., Asian J Chem., 7, 99 (1995); Chem. Abs., 122, 186777 (1995). 25 Nelson, D. J. and Henley, R. L., Tetrahedron Lett., 36, 6375 (1995). 2h Luca, C., Parvulescu, V:, and Vass, M., Ptog. Catal., 3, 67 (1994); Chem. Abs., 123, 255960 (1995). 27 Rao, K. V, Rao, M. T., and Adinarayana, M., fnt. 1 Chem. Kinef., 27, 555 (1995). zn Collman, J. P., Zhang, X . , Lee, V J., Uffelmad E. S., and Brauman, J. I., Science, 261, 1404 (1993). 2y Larrow, J. F. and Jacobsen, E. N., J. Am. Chem. Soc., 116, 12129 (1994).

' '

208

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30

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209

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I2O

5 Oxidation and Reduction

21 1

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"'

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'15 216 217 218 219 220 22' 222

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CHAPTER 6

Carbenes and Nitrenes J. G. KNIGHT

Department of Chemistry, University of Newcastle-upon-Tyne ~~

Structure and Reactivity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Generation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Addition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Insertion and Abstraction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rearrangement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nitrenium Ions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nucleophiles and Electrophiles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Silylenes and Germylenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

~~

213 216 219 223 224 226 226 221 228

Structure and Reactivity

A review concerning metalloporphyrin-catalysed nitrene and carbene transfers has appeared.' Photolytic loss of COz from matrix-isolated fluoromaleic anhydride gives fluoro(keteny1)carbene (1) and fluorocyclopropenone (2).2 Carbene (1) is rapidly converted into fluoroacetylene and CO. Ab initio calculations suggest that the barrier to interconversion of the syn-conformer (1) to the anti-(3) is 25 kcal mol-'; ring closure of (1) to (2) has a barrier of 2.7 kcal mol-', and the conversion of anti-conformer (3) to fluoroacetylene has a barrier of 1 I kcal mol-'.

"Y" 0

Photolysis of matrix-isolated 2,2,2-trifluorodiazoeu,ane (NZCHCF3) gives a mixture of H(CF3)C:, the diazirine, and trifl~oroethene.~ The carbene is converted into trifluoroethene by fixther irradiation. Ab initio calculations predict a triplet ground state for 2,2,2-trifluoroethylidenewith a singlet-triplet splitting of 8.5 kcal mol- '. The barrier to 1,2-F shift is calculated to be 21.5 kcal mol-' for the singlet and 50.8 kcal mol- for the triplet state, showing previously reported computational results to be in error. Organic Reaction Mechanisms 1995. Edited by A. C. Knipe and W. E. Watts 0 1997 John Wiley & Sons Ltd

213

Organic Reaction Mechanisms 1995

214

Irradiation of matrix-isolated l-diazopropynes (4; X = I3C, Y = C) and (4; X = C, Y = I3C) gave products with identical IR and ESR ~ p e c t r a .The ~ experimental IR spectrum agrees with that calculated for the C, structure (5) and not with an equilibrating mixture of propargylic carbenes. Analysis of the ESR spectrum suggests a bond angle of 155 O at the carbene carbon. The conventional wisdom that triplet acetylenic carbenes are linear is thus incorrect in the parent case. Ab initio calculations on Bu'(H)C: reveal a bridged geometry in which the carbene p-orbital is stabilized by interaction with the C-C and C-H bonds of an adjacent methyl group (6).5 Calculations indicate that CH insertion to form a cyclopropane is more favourable that 1,2-C shift to form 2-methylbut-2-ene. In agreement with this, deoxygenation of 2,2-dimethylpropanal by carbon at low temperatures produces only the CH insertion product.

Two ab initio studies predict, in accord with recent experimental results, a singlettriplet splitting of 1.64 and 1.4 kcal mol- (with a singlet ground state) for Ab initio calculations on the decomposition of diazoethane and methyldiazirine found no evidence for concerted H-migration and C-N bond breaking.* The stepwise formation of ethene via Me(H)C: was found to have a barrier of 26.9 kcal mol-' for diazoethane and 30.1 kcal rnol-' for the diazirine. Ab initio calculations on 4oxocyclohexa-2,5-dienylidene(7) predict a ground-state triplet of B1 symmetry.' The lowest singlet state is predicted to be an open-shell structure with B1 symmetry 10 kcal mol-' higher in energy. The thermal rearrangement of (7) to 1Hbicyclo[3.1 .O]hexa-3,5-dien-2-one (8) was predicted to involve the formation of the lowest 'B1 state followed by intersystem crossing to the ground-state triplet. Picosecond optical grating calorimetry was used to study the photochemical decomposition of diazomethane in benzene." The results suggest the formation of a weak .n-complexbetween benzene and singlet methylene. Laser absorption was used to follow the removal of singlet methylene by various oxygen-containing organic species." The ratio of singlet- to triplet-derived products decreases as the size of the 1alkyl substituent (R) increases in fluorenylidenes (9).12When R is Bu', CH insertion of the singlet carbene gave the corresponding cyclopentafluorene and the alkene (10) was formed from the triplet carbene by 1,5-H abstraction to give a biradical intermediate followed by neophyl-type rearrangement. Detailed analysis of collision-induced dissociation mass spectra (CIDMS) established the aminohydroxycarbenes H2N(OH)C: and MeNH(0H)C: as stable species in the gas phase.13 Laser flash photolysis (LFP) of diazo ketones in the presence of pyridine gives rise to ylides.l4 Plotting the formation of ylide against the pyridine concentration gave estimates for the half-lives of the intermediate carbenes (or oxirenes) of (0.22.3) x l o p 9 s. The yield of ylide correlated well with the percentage of the anti conformer of the diazo precursor (11) in support of the Kaplan-Meloy-Mitchell

'

6 Carbenes and Nitrenes

215

in which the anti conformer gives rise to a carbene and the syn conformer leads directly to the ketene (RCH=C=O). The activation barrier from the reactive intermediate to the ketene was estimated at ca 2 kcal mol-'. The lifetime of dicarbomethoxycarbene (Me02C)2C:, produced by LFP of the diazo compound, was measured by the pyridine ylide method as between 1 x 10V9 and 4 x l o p 9 s in cy~lohexane.'~ The lack of solvent isotope effect suggests that the carbene lifetime is controlled by Wolff rearrangement rather than by CH insertion. Metal-catalysed decomposition of dicyclohexyl diazomalonates in styrene led to products of cyclopropanation using CuOTf and to intramolecular CH insertion products (12) and (13) using Rh2(OAc)4.'* The formation of p- and y-lactones was controlled by steric factors.

The imidazolin-2-ylidene (14), prepared by deprotonation of the corresponding imidazolinium chloride, was found to be a stable crystalline solid." The X-ray crystal structure differed only slightly fkom that of the corresponding unsaturated imidazol-2ylidene. Unsaturation in the imidazole ring is thus not required to produce a stable carbene. Photolysis of the matrix-isolated diazo compounds led to p-carboranylcarbene (15) and the rn-analogue.20EPR spectrometry showed triplet ground states. Analysis of zero-field splitting parameters indicated that 0-,m-,and p-carboranylcarbenes show a similar amount of delocalization as a typical dialkylcarbene and that there is little overlap between the orbitals of the carbene and those of the cage. The stereoselectivity of additions to and (q-but-2-ene gave an estimate of 10-15% reaction via the triplet. Ab initio calculations have been performed on 0-carboranyl species (16) with a carbene (HC:) or nitrene (N:) substituent in the 1-, 3-, or 9 - p o ~ i t i o n .All ~ ~ of the carbenes and nitrenes were found to have a triplet GS except for the 1-carbene. FVP and matrix photolysis of a variety of precursors to the C7H7N hypersurface have been studied.22 Under FVP conditions, the benzoazetine (17) was not observed. However, matrix-isolated precursors gave both (17) and the quinone methide (18). While photolytic loss of N2 from 2-tolylazide gave the nitrene, the corresponding

(a-

Organic Reaction Mechanisms 199.5

216

I

@

[): IAr

(14) Ar = 2,4,6-Me3C6H2

$

\

\ Ar

H

(15)

9

(16)

formation of a carbene could not be observed from 2-(diazomethy1)aminobenzene. This could be due to a large singlet-triplet splitting for the nitrene relative to the carbene, or to the importance of tunnelling in the rearrangement of the carbene to the quinone methide (18). Good agreement has been found between the heats of formation of several nitrenes calculated from experimental data and by a group contribution method.23 Triplet diphenoxyphosphorylnitrene (PhO)2P(0)N:, generated by LFP of the corresponding azide, has been studied by UV and EPR spe~trometry.~~ The half-life in ethanol was 3.8 f0.6 ps and stronger transient absorptions in hydroxylic solvents support the idea that H-bonding catalyses intersystem crossing in nitrenes. The delocalization of the nitrenic electrons is limited and this nitrene is similar to alkyl- and acyl-nitrenes in this respect.

Generation A review of the trifluoromethylation of organic halides using difluorocarbeneprecursors has appeared.25 1,2-H shift in dimethylsilylcarbene, Me2SiH(H)C:, has been used to prepare 1,1-dimethylsilene, Me2Si=CH2.26Reaction of this silene with formaldehyde was studied under matrix-isolation conditions and by ab initio calculations. At 30 K, the thermally stable carbene (19) was identified by IR spectrometry. The observed rearrangement to the silapropanal (20) was predicted to have a barrier of 4.7 kcal mol-’.

The reaction of difluoromethylphenyl selenoxide, F2CHSe(0)Ph, with acetic anhydnde in the presence of cyclic ethers or thioethers (21; n = 1-4) gave rise to difluoro(phenylse1eno)methylation products (22).27 The formation of F2C: from the Pummerer intermediate (23) followed by electrophilic attack on the ether to form an ylide (24), which was then ring opened by AcOSePh was proposed. The unexpected formation of benzonitrile and the aminotriphenylphosphonium salt of phenylmalononitrile in the Staudinger reaction between Ph3P and PhCH(N3)CNwas postulated to involve loss of CN- from the anion PhC(N3)CN to generate

6 Carbenes and Nitrenes

217

phenyl(azido)carbene, Ph(N3)C:.28 Thermolysis of 2-nitroarylethanoate derivatives (25) leads to 3,4-fused isoxazoles (26).29Loss of ethanol to give a ketene which was trapped by the nitro group to give (27) was suggested. Loss of COZ from (27) leads to the o-nitrosocarbene (28) which then ring closes to the isoxazole.

(26)

(27)

X.Y = CH, N; R’- Me, Et; 2 = C02R2, CN, COR2 The carbene (29) was proposed to explain the products of diazo transfer from tosyl azide to the lithiated silyl dithiane (30).30A theoretical study of the decomposition of the oxadiazoline (31) indicated that initial loss of nitrogen to form the carbene (32) does not involve a carbonyl oxide intermediate, that cyclization of the carbene on to the alkyne to give carbene (33) is concerted (rather than occurring via a cyclopropene), and that reaction of (33) with acetone to form an epoxide does not proceed via a carbonyl oxide.31 Calculations indicated that the reaction of carbenes with ketones to form epoxides may be either cheletropic or occur via carbonyl ylides depending on the carbene structure.

Treatment of the dihalides (34) with PhzPNa gives rise to a range of products including carbene-derived cycl~propanes.~~ Evidence for the formation of the carbene from a radical precursor is presented. Dibromocyclopropene (35;X = Br, R =H) ring opens to form carbene (36).33Cyclopropanationof electron-rich alkenes by this carbene was consistent with a singlet state and the reaction with electron-deficient alkenes gave

218

Organic Reaction Mechanisms 1995

cyclopropanes with the vinyl group cis to the electron-withdrawing substituent. Unlike the stereoselective ring opening of the dichlorides (35; X = C1, R = C1, OMe, Ph), the homologous dibromides (35; X = Br; R = CH2Br, CH20Me) showed little stereoselectivity in the trapping of the derived vinylcarbenes by alkenes. Careful analysis of the products of pyrolysis of ethynylbenzene in the presence of MeSSMe showed that the major pathways involve radical intermediate^.^^ The bis(thiomethy1) compound (37), which is produced from the carbene PhCH=C:, was isolated in very small amounts.

Cyclopropanation of alkenes by the alkylidenecarbene derived from the iodonium species (38) by base-induced a-elimination was found to be stereospecific, implying the singlet state.35 Hammett analysis gave a p value of - 0.55, suggesting that the free carbene is slightly electrophilic. Treatment of the enol triflates (39) with KOBu' gives the corresponding cyclopentenoates by I ,5-CH insertion of the intermediate alkylidenecarbene~.~~ A review covering the singlet nitrene mechanism of nitrogen loss in the thermal decomposition of organic azides has appeared.37 The effects of solvents and additives on the pyrene-sensitized photolysis of p-butylphenyl azide in the presence of diethylamine led to the proposal that the azepine (40) arises mainly from the singlet nitrene while one-electron reduction of the azide produces p-b~tylaniline.~'

Substantial electrostatic stabilization in a charge-separated transition state (41) was invoked to explain the high rates of thermolysis of a-azido five-membered-ring heterocycle^.^^ This idea removes the need to postulate appreciable ring opening in the transition state. Thermal decomposition of the unsymmetrical hydrazine (42) leads to the esters (43) and (44).40 The lack of crossover products supports a 1,l-elimination mechanism via a nitrene intermediate even though attempts to trap this intermediate were unsuccessful. The aziridine (45) serves as a source of phthalimidonitrene under mild thermal condition^.^' With 1,3-dirnethoxybenzenes,(45) provides unusually stable 2H-azepines (46) which undergo 1,5-H shift to form the corresponding 3H-azepines.

219

6 Carbenes and Nitrenes

(41)

x = NR', 0 , s

0

(43)

(44)

Addition Analysis of the effects of pressure on the reaction of ethene with singlet [13C]methylene,generated by photolysis of diazomethane, revealed the rearrangement of excited [3-'3C]propeneto give [1-13C]-and [2-13C]-propene!2 LFP has been used to determine the absolute rate constants for additions of the ambiphilic carbenes MeO(C1)C: and (CF3CH20)ClC: to alkenes. The addition of MeO(C1)C: to (E)-but-2ene to give the cyclopropane (47) occurs with a bimolecular rate constant of 330 dm3 mol-' s-', which is the lowest reported rate constant for carbene addition to an alkene in solution.43The rate constants for addition of trifluoroethoxycarbenes to alkenes were determined by LFP studies in the presence of ~ y r i d i n e . ~ ~

0

(45)

PhthN (46)

M e 0 Ci (47)

The reactions of di- and tri-t-butylcyclopentadienes with dihalocarbenes (X2C:; X = C1, Br, F) have been studied.451,3,5-Tri-t-butylcyclopentadienereacts exclusively on the 2,3-double bond to give the spectroscopically detected cyclopropane (48). In the absence of base, (48) remanges by ring opening to the ally1 cation (49) followed by loss of 2-methylpropene and H+ to give 2,4-di-t-butylchlorobenzene(50; R = H) only. In the presence of base, the cation (49) can competitively lose H+ to form the tri-t-butyl species (50; R = Bu?.

Organic Reaction Mechanisms I995

220

The modified Reimer-Tiemann reaction of methylindoles has been investigated using electrochemically generated CI2C: to avoid the presence of base. For 2,3dimethylindole, the ratio of ring-expanded to five-membered-ring products vaned with the proton-donating ability of the solvent, in support of a single intermediate which equilibrates between the two forms (51) and (52)!6 Reaction of the phosphinocarbene (53) with a large excess of benzonitrile gave a good yield of the 2H-azirine (54), which was characterized by X-ray structure de t e rmina ti ~n. ~ ~

The bimolecular rate constant for addition of Ph2C:, generated by LFP of the diazo compound to C60 was determined to be 4.0 x lo8 dm3mol-' s-l by UV absorption spectro~copy.~~ The products of reactions of CG0with carbenes were found to be predominant when CC14 was injected into a chemical ionization source.49 Since carbenes are not the principle fragments in the source atmosphere, c6o must react with carbenes very efficiently. Vinyl carbenes (55), generated by thermal ring opening of the corresponding cyclopropenes, were found to react with C60 to give the products of I 2- and 3 4-cycloaddition in a temperature-dependent ratio.5o The 5,6-double insertion product (56) was obtained on thermolysis of diethyl diazidomalonate in the presence of C60.5' Excellent diastereocontrol was observed in the hydroxyl-groupdirected, Rh-mediated cycloaddition of cyclic diazocarbonyl compounds with hydroxyvinyl ethers.s2 Vinyl ether (57) gave the tricyclic species (58) as a single diastereoisomer. Several reports of the metal-catalysed reaction of carbenes and imines to form aziridines have appeared. No significant enantioselectivity was observed in the addition of methyl diazoacetate to imines using chiral Rh catalysts.53 The copper-catalysed addition of ethyl diazoacetate to imines (59) was found to be very dependent on the N substituent (R2 = Ph was most e f f e ~ t i v e ) The . ~ ~ cis-aziridine (60) was found to be the major product in most cases. Reaction of an intermediate copper carbenoid with the

+

+

6 Carbenes and Nitrenes

22 1

K O

X

R.

imine lone pair was postulated to give an azomethineylide which could ring close to the aziridine or decomplex from the metal and undergo cycloaddition to diethyl hmarate to generate a racemic pyrrolidine (6l)? The use of the chiral ligand (62) allowed the enantioselective preparation of aziridines in up to 67% ee.

Photolysis of a bridged calix[6]arene containing an aryl azide gave rise to the fused azepine (63).56The poor flexibility of the intermediate nitrene, confined in the rigid system, evidently makes addition to the benzene ring followed by isomerization more favourable than the usual ring expansion of the aryl nitrene. A report concerning cycloaddition reactions of arylnitrenes has appeared.” Thermal decomposition of ally1 azidoformates (64) in 1,1,2,2-tetrachloroethannegave rise to chloromethyloxazolidinones (65) with moderate to good dia~tereoselectivity.~~ Addition of the nitrene (which could be intercepted by toluene) to form an aziridine was proposed to be followed by ring opening by HCl, produced by solvent decomposition. 3-Acetoxyquinazolin-4(3H)-ones react with tertiary amines to give unstable imides (66), detected by ‘H NMR.59The reaction of imides (66) with alkenes to give aziridines is independent of the amine, suggesting that the addition occurs via the N-nitrene (67). An attractive interaction between the carbonyl of the nitrene and the phenyl ring of

Organic Reaction Mechanisms I995

222

B u'

B u'

BUf

Bu7

R

A H

LCI

styrene is postulated to explain the kinetic preference for formation of the Z-nitrogen invertomer of styrene aziridine. Ethoxycarbonylnitrene, generated by base induced aelimination of the N-nosylate, was found to add to cyclic allylsilanes (68) predominantly anti to the methyl group regardless of the stereochemistry of the silyl substituent.60 The enantioselectivity of the aziridination of various alkenes by ArINTs, catalysed by a chiral copper species, was found to be independent of the nature of the aryl group (Ar).61This, together with the observation that identical ee values were obtained using PhINTs or photolysis of TsN3, suggests that a discrete copper nitrenoid is involved. A good linear correlation between the ee of cyclopropanation and that of aziridination of 1,2-dihydronaphthalene using a range of chiral ligands (69) lends weight to the suggestion that the transition-state arrangements for these two processes are similar.

The regioselectivity of copper-catalysed aziridination of 1,3-dienes by PhINTs has been studied.62The major product normally results from addition to the most electronrich double bond, e.g. (70). In some cases, rearrangement to the corresponding 3pyrroline was observed and this process occurred exclusively to form (71) from cycloocta-1,3-diene.

6 Curbenes und Nitrenes

223

Insertion and Abstraction Reviews covering synthetic applications of OH insertion reactions63 and certain CH insertion reactiod4 have appeared. The insertion of nucleophilic dialkoxycarbenes [R'O(R20)C:] into the C-0 bond of cyclic anhydrides has been studied.6s In unsymmetrical anhydrides, the most electrophilic carbonyl is attacked. A mechanism involving nucleophilic attack by the carbene to give a zwitterion (72) followed by 1,2-0 shift was suggested.

OR' Ts N 1:6

0

Intramolecular CH insertion of lithium carbenoids (73; X = Li), generated by deprotonation of the corresponding bromide (73; X = H), gives rise to cyclic bromides (74).66 Base-induced elimination of HBr then produces cyclic enediynes. The Rh2(0Ac)4 catalysed decomposition of a-alkoxydiazo ketones (75) produces tertiary alcohol derivatives (76) by 1,s-CH insertion.67The regioselectivity depended on steric and electronic factors and a silyloxy substituent (75; R'=Me, R2 = CH2CH20SiBu'Me2) promoted CH insertion to give the six-membered-ring product.

In an attempt to use the CH insertion of alkylidenecarbenes (77; X = C:, Y =0)for the synthesis of tertiary alcohols, pyruvate (77; X = Y =0) was treated with (Me0)2P(O)CHN2 in the presence of base.68 The failure of the alkylidenecarbene to undergo CH insertion was ascribed to the unfavourable conformation of the ester and to possible deactivation of the C-H bond by the electron-withdrawingacyloxy group. The corresponding reaction of the 2-oxopropyl ether (77; X = 0, Y = H2) gave a good yield of the 1,s-CH insertion product (78). In an approach to the synthesis of taxol, the tartaric acid-derived alkylidenecarbene (79), generated by base-induced or-elimination from the vinyl chloride, underwent efficient 1,S-CH insertion.69 Deuterium-labelling

224

Organic Reaction Mechanisms 1995

studies have shown that 1,4-CH insertion of vinylvinylidene (80) to give cyclobutadiene does not occur during FVP of b~t-l-en-3-yne.~'

Thermolysis of a$-epoxy-N-aziridinylimine (81) gives the corresponding alkylidenecarbene (82) which undergoes 1,5-insertion into the Si-0 bond to give a d ih y dr ~ f u r a n The .~ ~ failure of the corresponding ally1 or benzyl ethers to give products of 2,3-sigmatropic rearrangements suggests that oxonium ylides are not involved in this reaction. The addition of external alkynes was found to increase greatly the yield of quinones generated by intramolecular benzannulation reactions of chromium siloxycarbenes (83).72 Coordination of the external alkyne to a vinylcarbene intermediate, produced by intramolecular alkyne insertion, was proposed.

Photolysis of aryl azides (84; n = 0 - 3 ) showed that insertion of the nitrene into benzylic C-H bonds was only significant for n = 1 or 2.73Intramolecular CH insertion was unable to compete with azepine formation in the presence of diethylamine and photolysis in alcohols gave results which suggested that CH insertion occurs via an H-abstraction-recombination sequence involving the triplet nitrene.

Rearrangement Reviews covering intramolecular carbenic rearrangement^^^ and ring-opening rearrangements of isoxazolone, isoxazole, and Meldrum's acid derivative^^^ have appeared. Analysis of the products of 1,2-H (or D) shift in the conformationally locked cyclohexylidene (85; A = H, D), generated by thermolysis of the tosylhydrazone salt,

6 Carbenes and Nitrenes

225

showed that an equatorial Me group assists the migration of a geminal H more efficiently than does an axial Me group by a factor of 4.6.76 Owing to a favourable kinetic isotope effect, d2-benzylchlorocarbenecould be produced and characterized on photolysis of the corresponding matrix-isolated diazirir~e.~~ 1,2-D rearrangement was observed to give (Z)-/?-chlorostyrene-dz as the predominant product. The experimental IR spectrum of the carbene was found to be consistent with that calculated for the gauche isomer. This was thought to reflect the higher barrier to 1,2-H(D) shift in the gauche isomer relative to the s-Q-isomer which rearranges under the conditions of precursor photolysis. Picosecond time-resolved absorption spectroscopy enabled the lifetime of carbene (86; R = H ) to be measured as 20 ps in methanol.78 The rate constants for reactions of carbenes (86) with aliphatic alcohols and water were deduced to be > 3 . 5 x 108s-'. 0

Photolysis of matrix-isolated cyclopropanecarbonyl chloride gives rise to cyclopropylidene ketone (87).79Irradiation of the ketene (87) gives chlorocyclopropane and propa- 1,2-diene, suggesting the intermediacy of cyclopropylidene (88). Kinetic data showed that the rate of rearrangement to allene was roughly twice that of reaction with HC1. Ah initio calculations on the reaction of HNC with H2C=SiH2 show that the primary cycloadduct (89; X =NH, Y = CH2) rearranges to the more stable silaziridine (89; X = CH2, Y =NH) via the cyclic carbene (90)."

A kinetic study of the 1,2-Si shift of the disilacyclobutane (91) to give (92) revealed that log A = 12.48 and the activation barrier is 54.09 kcal mol-1.81 Ah initio calculations predicted that the transition state was late and corresponded to the carbene (93). Borylmethyleneboranes [94; All = (Me3Si)&=C=CR] were found to isomerize by 1,2-carbon-to-boron followed by 1,2-boron-to-carbon migration, via diborylcarbenes (95)." An ab initio investigation of the concerted ring expansion of singlet cyclopropyinitrene gave a barrier height of 38.89 kJ r n ~ I - ' . * ~The pyrolysis of 3azido-3-phenylazetidinesgave rise to products of heterocyclic ring expansion of the intermediate nitrene~.'~ Irradiation of (aminoalky1)phenyl azides (96; R = H or Et) gave rise to bicyclic azepines (97) in good yield even in the presence of diethylamir~e.~~

226

Organic Reaction Mechanisms 1995

Nitrenium Ions Flash photolysis and product analysis of 4-azidobiphenyl (and 2-azidofluorene) indicated that the initially formed singlet nitrene is protonated in water to form the nitrenium ion (98).'6 The results suggest that the acid dissociation constants for these nitrenium ions are less than Nucleophiles and Electrophiles Time-resolved LFP techniques have been used to study the mechanism of photodecomposition of 2-methoxy-1,2-diphenyldiazoethane in methan01.~' The results are consistent with thermal equilibration between the singlet and triplet states, followed by reaction of the singlet with methanol to form an ether. The reaction of diarylcarbenes, Ar2C:, generated by photolysis of the corresponding diazo compounds, with alcohols was studied by picosecond absorption spectroscopy." Protonation to form the contact ion pair (99) was observed to occur with rate constants between 0.4 x lo9 and 4.7 x lo9 dm3mol-' s-I. No evidence for nucleophilic attack by the alcohol was seen. The carbomethoxyarylcarbene (100) formed from the diazo compound, was protonated by HC104 to give a benzyl cation with a rate constant of 3.5 x lo9 drn3 mol-' s - ' . ' ~ The stable carbene (101), generated by reaction of the corresponding 2(3H)-thione with potassium, has a pK, value of 24 in (CD3)$30.90Reaction of the carbene with 2bromopropane gave an elimination : substitution ratio of 20 : 80, comparable to that obtained with the commonly used base DBN. The reaction of Ph(Cl)C:, generated by photolysis of the diazirine, with alkyl azides was studied by LFP9' The bimolecular rate constants were found to be (1.5-3.8) x lo7 M-' s-', comparable to the rate of reaction with alkenes. The reaction with benzyl azide has a barrier of 0.04 kcal mol-' and entropy of activation of - 25.7 & 1 eu. The results are consistent with initial attack on N(l) of the a i d e to form a zwitterion. Photolysis of diazo compounds (102; n = 1,2) in chloroform led to products resulting from trapping of the intermediate carbenes by the dimethylamino group to form ammonium ylides (103).92The electrophilicity of lithium carbenoids, caused by metal-

227

6 Carbenes and Nitrenes

assisted ionization, enables intramolecular nucleophilic substitution to occur (104) to produce benzofurans, thianaphthenes, and indoles (105; X = 0, S, NH).93 Me

Bromodifluoromethylimides (106; X = Br) were formed diastereoselectively by reaction of the imide enolates with Br2CF2.94The reaction was proposed to occur via attack of the enolate on in situ-generated F2C: to produce an anion (106; X = Li) which abstracted bromine from Br2CF2 to form the product and regenerate F2C:. The enantioselective formation of ylides (107; X = S, Se) was achieved by chiral copperand rhodium-catalysed reaction of the allylic sulfides (or selenides) with ethyl d i a z ~ a c e t a t e .The ~ ~ ylides (107) underwent 2,3-sigmatropic rearrangement to give products in up to 41% ee. DBN was found to react with the phosphinophosphoniocarbene (108; R=NP?!) to give the tricyclic adduct (109).96 Initial attack by N(5) of DBN on the phosphino phosphorus was proposed.

Silylenes and Germylenes A high-level ab initio study of 1-silavinylidene H2C=Si: corrects the previously large discrepancy between experimental and calculated harmonic vibrational freq~encies.~' The regioselective addition of hindered silylene (1 lo), generated by photolysis of a trisilane, to C70 (which has eight distinct types of C-C bond) was reported.98 The adduct Ar2SiC70was formed as a 2 : 1 ratio of isomers with selectivity controlled by HOMO(silylene)-LUMO(C70) interactions. The pentacoordinate ethoxydisilane (11 1;

228

Organic Reaction Mechanisms 1995

X=NMe2) was found to be thermally unstable, losing EtOSi(Me)zPh to generate a silylene at 110 0C.99The corresponding tetracoordinate disilane (111; X = H) was stable up to 200 "C. The extremely hindered disilenes (112) underwent dissociation at 70 "C to produce the divalent silylene which was trapped by a range of species.'" Reaction of the silylene with benzene and naphthalene gave 1 2-adducts which were characterized by X-ray structure determination.

+

High-level ab initio calculations on the dimerization of silylenes Y(H)Si: (Y =OH or NH2) predict that bridged structures (113) are more stable than the disilenes Y(H)Si=Si(H)Y.''' Reaction of a lithium phosphide with a germanium dihalide gave rise to the diphosphanyl-substituted germylenes (1 14).'02 The corresponding diarsanylsubstituted germylenes, and diphosphanyl- and diarsanyl-substituted stannylenes and plurnbylenes were synthesized in a similar manner. H I &.Y.,,, SiG ,Si

Y I H (113)

PR~R~

/ :Ge \

PR~R* (114) R' = SiArzF, R2=P@i

References

' Mansuy, D. and Mahy, J. P., Catal. Met. Complexes, 17, 175 (1994);

*

lo

"

12

l3 l4

l5 l6

Chem. Abs., 122, 104945 (1995). Dailey, W. P., 1 0%.Chem., 60, 6737 (1995). O'Gara, J. E. and Dailey, W P,1 Am. Chem. Soc., 116, 12016 (1994). Seburg, R. A,, DePinto, J. T., Patterson, E. V, and McMahon, R. J., 1Am. Chem. Soc., 117, 835 (1995). Annstrong, B. M., McKee, M. L., and Shevlin, P. B., 1 Am. Chem. Soc., 117, 3685 (1995). Matzinger, S. and Fulscher, M. I?, 1 Phys. Chem., 99, 10747 (1995). Richards, C. A,, Kim, S.-J., Yamaguchi, Y., and Schaefer, H. F.,1 Am. Chem. Soc., 117, 10104 (1995). Miller, D. M., Schreiner, P. R., and Schaefer, H. F., 1 Am. Chem. Soc., 117, 4137 (1995). Sol&,A,, Olivella, S . , Bofill, J. M., and Anglada, J. M., 1 Phys. Chem., 99, 5934 (1995). Khan, M. I. and Goodman, J. L., 1Am. Chem. Soc., 117, 6635 (1995). Gutsche, G. J., Lawrance, W. D., Staker, W. S . , and King, K. D., 1Phys. Chem., 99, 11867 (1995). Tomioka, H., Kawasaki, H., Kobayashi, N., and Hirai, K., 1 Am. Chem. Soc., 117, 4483 (1995). McGibbon, G. A,, Burgers, F! C., and Terlouw, J. K., Int. 1 Mass Spectmm. Ion Processes, 136, 191 (1994); Chem. Abs., 122, 105118 (1995). Toscano, J. I?, Platz, M. S., and Nikolaev, V, J Am. Chem. Soc., 117, 4712 (1995). Kaplan, F. and Meloy, G. K., 1Am. Chem. Soc., 88, 950 (1966). Kaplan, F. and Mitchell, M. L., Tetrahedron Left., 1979, 759.

6 Carbenes and Nitrenes

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Wang, J.-L., Toscano, J. P., Platz, M. S., Nikolaev, V, and Popik, V, 1 Am. Chem. Soc., 117, 5477 (1995). Chelucci, G. and Saba, A,, Tetrahedmn Lett., 36, 4673 (1995). 19 Arduengo, A. J., Goerlich, J. R., and Marshall, W. J., 1 Am. Chem. SOC.,117, 11027 (1995). 20 Arthur, L. G., Colella, S. M. A., Blanch, R. J., Bian, N., Jones, M., Lahti, P. M., and Kalgutkar, R., Tetrahedron Lett., 36, 5299 (1995). 21 McKee, M. L., 1 Phys. Chem., 98, 13243 (1994). 22 Morawietz, J., Sander, W., and Traubel, M., 1 Org. Chem., 60, 6368 (1995). 23 Orlov, Yu. D., Lebedev, Yu. A,, and Krestov, G. A,, Dokl. Akad. Nauk, 338,776 (1994); Chem. A h . , 123, 143237 (1995). 24 Houser, M., Kelley, S., Maloney, V., Marlow, M., Steininger, K., and Zhou, H., 1 Phys. Chem., 99,7946 (1995). 25 Chen, Q.-Y., 1 Fluorine Chem., 72, 241 (1995); Chem. Abs., 123, 168925 (1995). 26 Trommer, M., Sander, W., Ottosson, C.-H., and Cremer, D., Angav. Chem., Int. Ed. Engl., 34, 929 (1995). 27 Uneyama, K., Maeda, K., Tokunaga, Y., and Itano, N., 1 Org. Chem., 60, 370 (1995). 28 Molina, P., Lbpez-Leonardo, C., Llamas-Botia, J., Foces-Foces, C., and Femandez-Castaiio, C., 1 Chem. SOC., Chem. Commun., 1995, 1387. 29 DutTy, K. J. and Tcnnant, G . , 1 Chem. SOC., Chem. Commitn., 1995, 2457. 30 Benati, L., Calestani, G., Montevecchi, P. C., and Spagnolo, P., 1 Chem. SOC., Chem. Commun., 1995, 1999. 31 Smith, W. B., 1 Org. Chem., 60, 7456 (1995). 32 Ashby, E. C. and Deshpande, A. K., 1 Org. Chem., 60, 7117 (1995). 33 A1 Dulayymi, A. R., A1 Dulayymi, J. R., Baird, M. S., and Rajaram, L., Tetmhedmn, 51, 8371 (1995). 34 Guthier, K., Hebgen, I?, Homann, K.-H., Hohann, J., and Zimmermann, G., Liebigs Ann. Chem., 1995, 637. 35 Ochiai, M., Sueda, T., Uemura, K., and Masaki, Y., 1 Urg. Chem., 60, 2624 (1995). 36 Ohira, S., Yamasaki, K., Nozaki, H., Yamato, M., and Nakayama, M., Tetrahedron Lett., 36, 8843 (1995). 37 Prokudin, V G., Pmc. Int. Pyrotech. Semin., 19, 19 (1994); Chem. A h . , 122, 9176 (1995). 38 Murata, S., Nakatsuji, R., and Tomioka, H., 1 Chem. Sac., Perkin Trans. 2, 1995, 793. 39 L'Abb6, G., Dyall, L., Meersman, K., and Dehaen, W., 1 Chem. Soc., Perkin Trans. 2, 1994, 2401. 4a De Almeida, M. V, Barton, D. H. R., Bytheway, I., Ferreira, J. A,, Hall, M. B., Liu, W., Taylor, D. K., and Thomson, L., 1 Am. Chem. Soc., 117, 4870 (1995). 41 Jones, D. W. and Thomton-Pett, M., 1 Chem. SOC., Perkin Trans. 1 , 1995, 809. 42 Doering, W. von E. and Zhao, D.-C., 1 Am. Chem. Soc., 117, 3432 (1995). 43 Moss, R. A,, Ge, C.-S., Wlostowska, J., Jang, E. G., Jefferson, E. A,, and Fan, H., Tetrahedron Lett., 36, 3083 (1995). 44 Moss, R. A,, Jang, E. G., and Ge, C.-S., Pol. 1 Chem., 68,2501 (1994); Chem. Abs., 122, 105056 (1995). 45 Dehmlow, E. and Bollmann, C., Tetrahedron, 51, 3755 (1995). 46 De Angelis, F., Inesi, A,, Feroci, M., and Nicoletti, R., J. Urg. Chem., 60, 445 (1995). 47 Alcaraz, G., Wecker, U., Baceiredo, A., Dahan, F., and Bertrand, G., Angav. Chem., Int. Ed. Engl., 34, 1246 (1995). 48 Chateauneuf, J. E., 1 Am. Chem. SOC., 117, 2677 (1995). 49 Guo, X., Liu, Z., Song, F., and Liu, S., Chin. Sci. Bull., 38, 1494 (1993); Chem. Abs., 122, 105145 (1995). 50 Tokuyarna, H., Isobe, H., and Nakamura, E., Bull. Chem. SOC.Jpn, 68, 935 (1995). " Dong, G.-X., Li, J.-S., and Chan, T.-H., 1 Chem. SOC., Chem. Commun., 1995, 1725. 52 Pimng, M. C. and Lee, Y. R., 1 Chem. Soc., Chem. Commun., 1995, 673. 53 M o m , M., Bernardinelli, G., and Muller, P., Helv. Chim. Acta, 78, 2048 (1995). 54 Rasmussen, K. G. and Jmgensen, K. A,, 1 Chem. SOC.,Chem. Commun., 1995, 1401. 55 Hansen, K. B.,Finney, N. S., and Jacobsen, E. N., Angm. Chem., Int. Ed. Engl., 34, 676 (1995). 56 Tokitoh, N., Saiki, T., and Okazaki, R., 1 Chem. SOC., Chem. Commun., 1995, 1899. 57 Leistner, A. and Abraham, W., 1 InJ Rec. Muter., 21, 583 (1994); Chem. Abs., 122, 213339 (1995). 58 Bergmeier, S. C. and Stanchina, D. M., Tetmhedron Lett., 36, 4533 (1995). 59 Atkinson, R. S. and Barker, E., 1 Chem. SOC.,Chem. Commim., 1995, 819. 6o Loreto, M. A,, Tardella, P. A,, and Tofani, D., Tetrahedron Lett., 36, 8295 (1995). 6' Li, Z., Quan, R. W., and Jacobsen, E. N., 1 Am. Chem. SOC.,117, 5889 (1995). 62 Knight, J. G. and Muldowney, M. €?, Synlett, 1995, 949. Miller, D. J. and Moody, C. J., Tetrahedron, 51, 10811 (1995). 64 Oku, A,, Yuki Gosei Kagaku Kyokaishi, 53, 2 (1995); Chem. Abs., 122, 159772 (1995). 65 Pole, D. L. and Warkentin, J., Liebigs Ann. Chem., 1995, 1907. 66 Jones, G. B., Huber, R. S., and Mathews, J. E., 1 Chem. SOC.,Chem. Commun., 1995, 1791. 67 Lee, E., Choi, I., and Song, S. Y., 1 Chem. SOC.,Chem. Commun., 1995, 321. l7

''

''

Organic Reaction Mechanisms 1995

230 68 h9

70 7'

72

73 74

75

76 77 78

79

Ohira, S., Noda, I., Mizobata, T., and Yamato, M., Tetrahedron Lett., 36, 3375 (1995). Tabcr, D. F., Sahli, A,, Yu, H., and Meagley, R. P.,1 Org. Chem., 60, 6571 (1995). Hofmann, J., Zimmennann, G., and Findeisen, M., Tetrahedron Lett., 36, 3831 (1995). Kim, S. and Cho, C. M., Tetrahedron Lett., 36, 4845 (1995). Gross, M. F. and Finn, M. G., 1 Am. Chem. SOC.,116, 10921 (1994). Murata, S., Yoshidome, R., Satoh, Y., Kato, N., and Tomioka, H., 1 Org. Chem., 60, 1428 (1995). Moss, R. A,, Pure Appl. Chem., 67, 741 (1995). Wentrup, C., Kappe, C. O., and Wong, M. W., Pure Appl. Chem., 67, 749 (1995). Kenar, J. A. and Nickon, A., Tetrahedron Lett., 35, 9657 (1994). Wierlacher, S. and Sander, W., 1 InJ Rec. Matez, 21, 579 (1994); Chem. Abs., 122, 159907 (1995). Vleggaar, J. J. M., Huizer, A. H., Kraakman, P. A,, Nijssen, W. P. M., Visser, R. J., and Varma, C. A. G. O., 1 Am. Chem. Soc., 116, 11754 (1994). Monnier, M., Allouche, A., Verlaque, I?, and Aycard, J.-P., 1 Phys. Chem., 99, 5977 (1995). Nguyen, M. T., Vansweevelt, H., De Neef, A,, and Vanquickenborne, L. G., 1 OE. Chem., 59, 8015 (1994).

** 83

Barton, T. J., Lin, J., Ijadi-Maghsoodi, S., Power, M. D., Zhang, X., Ma, Z., Shimizu, H., and Gordon, M. S., 1 Am. Chem. Soc., 117, 11695 (1995). Menzel, M., Winkler, H. J., Ablelom, T., Steiner, D., Fau, S . , Frenking, G., Massa, W., and Bemdt, A,, A n g m . Chem., Int. Ed. Engl., 34, 1340 (1995). Sun, H., Liu, C., Zhao, L., and Deng, L., Chem. Phys. Lett., 228, 268 (1994); Chem. Abs., 121, 300303 (1994).

84

Bartnik, R., Lesniak, S., Mloston, G., and Romanski, J., Pol. 1 Chem., 68, 1347 (1994); Chem. A h . , 122, 105116 (1995).

Murata, S., Miwa, M., and Tomioka, H., 1 Chem. SOC.,Chem. Commun., 1995, 1255. 86 McClelland, R. A., Davidse, l? A., and Hadzialic, G., 1 Am. Chem. Soc., 117, 4173 (1995). 87 Sung, D. D., Lim, G. T., Kim, M. S., and Park, D. K., Bull. Korean Chem. Soc., 16, 47 (1995); Chem. Abs., 122, 186795 (1995). 88 Dix, E. J. and Goodman, J. L., 1 Phys. Chem., 98, 12609 (1994). 89 Schepp, N. P. and Win, J., 1 Am. Chem. SOC.,116, 11749 (1994). 90 Alder, R. W., Allen, P. R., and Williams, S . J., 1 Chem. Soc., Chem. Commun., 1995, 1267. 9' Moss, R. A,, Jang, E. G., and Krogh-Jespersen, K., Tetrahedron Lett., 36, 1409 (1995). " Tomioka, H., Yamada, S., and Hirai, K., . I Org. Chem., 60, 1298 (1995). y3 Topolski, M., 1 O x . Chem., 60, 5588 (1995). 94 Iseki, K., Asada, D., Takahashi, M., Nagai, T., and Kobayashi, Y., Tetrahedron Lett., 36, 371 1 (1995). 95 Nishibayashi, Y., Ohe, K., and Uemura, S . , 1 Chem. Soc., Chem. Commun., 1995, 1245. 96 Dyer, I?, Guerret, O., Dahan, F., Baceiredo, A., and Bertrand, G., 1 Chem. Soc., Chem. Commun., 1995, R5

2339.

98

Shemll, C. D. and Schaefer, H. F., 1 Phys. Chem., 99, 1949 (1995). Akasaka, T., Mitsuhida, E., Ando, W., Kobayashi, K., and Nagase, S., 1 Chem. SOC., Chem. Comrnun.,

y9

Tamao, K., Nagata, K., Asahara, M., Kawachi, A,, Ito, Y., and Shiro, M., 1 Am. Chem. Soc., 117, 11592

97

1995, 1529.

(1995).

loo

I"' lo'

Suzuki, H., Tokitoh, N., and Okazaki, R., Bull. Chem. SOC.Jpn, 68, 2471 (1995). Apeloig, Y. and Miiller, T., 1 Am. Chem. SOC., 117, 5363 (1995). Driess, M., Janoschek, R., Pritzkow, H., Rell, S., and Winkler, U., Angew Chem., Int. Ed. Engl., 34, 1614 (1995).

CHAPTER 7

Nucleophilic Aromatic Substitution MICHELR. CRAMPTON Department of Chemistq University of Durham General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The SNAr Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Heterocyclic Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Meisenheimer and Related Adducts . . . . . . . . . . . . . . . . . . . . . . . . . . . . Benzyne and Related Intermediates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23 1 233 239 24 1 243 244

General There has been a review of the preparation and reactivity of arenediazonium ions.' Theoretical studies of the nature of C-N bonding in diazonium ions indicate that the electron-density distribution is consistent with a dative bonding model; the benzenediazonium ion can best be thought of as a carbenium ion closely associated with an internally polarized N2 group.* The structures and reactivities towards both gaseous and liquid nucleophiles of free arylium cations, formed by dediazoniation,have been in~estigated.~ Electrospray mass spectrometric study of 4-substituted-2-nitrobenzenediazonium ions shows a surprising stability of the intact ions to collisionally activated loss of nitrogen. This contrasts with the behaviour of monosubstituted benzenediazonium ions. The 2-nitro-substituted compounds may experience loss of the 4-substituent or substitution of the nitro group by water.4 Iron(I1) ions have been shown to be efficient catalysts in hydrodediazoniation reactions (replacement of the diazo group by hydrogen) in dimethylf~rmamide.~ The catalyst acts as an electron donor to initiate the sequence shown in Scheme 1. Replacement of a diazonium group by fluorine (the Balz Schiemann reaction) has been investigated in [2.2]metacyclophane derivatives. The 8,16-dimethoxy compound carrying a single diazonium group is unusual in that a difluoro derivative is formed, probably by a mechanism involving radical^.^ The Sandmeyer reaction involves homolysis of a diazonium ion followed by copper-catalysed substitution. Absolute rate constants have been estimated for the Fe2++ ArN2+ ArN2'

-

Ar'+ solvent ---+

Fe3++ ArN2' Ar'+Nz ArH

SCHEME 1 Organic Reaction Mechanisms 1995. Edited by A. C . Knipe and W. E Wans 0 1997 John Wiley & Sons Ltd

23 1

Organic Reaction Mechanisms 1995

232

transfer of chloride ligands from Cu(I1) to the 2-benzoylphenyl radical, and relative rate constants for the transfer of chloride and water ligands to other substituted phenyl radicals have been obtained.' A key step in the SR,l chain reaction is the unimolecular fragmentation of a radical anion. A theoretical study by the AM1 method has been reported of haloaromatic radical anions. Intramolecular electron transfer between the 7c* and the CT* antibonding C-Hal orbital is thought to be the rate-determining step in the cleavage of these species and a good correlation was found between the energy difference between these orbitals and experimental fragmentation rates.' The dual photo- and electro-chemical activation of m-halonitrobenzenes in acetonitrile has been reported. The process involves light absorption by the radical anions, (Ha1C6H4NO2)', followed by fragmentation by halide loss. The resulting nitroaryl radicals form nitrobenzene. The dual activation is successful only with halide loss, and the groups CN, NO2, SOR, and S02R cannot be similarly lost.' An mechanism has been proposed for the photochemically activated alkoxycarbonylation of aryl halides using carbon monoxide in the presence of a cobalt catalyst." The feasibility of monosubstitution of 1,4-dichlorobenzene and of dichloropyridines in electrochemically initiated S,, 1 reactions has been investigated. It was found that monosubstitution can be observed only when the nucleophiles act as electron-donating substituents, which, interestingly, is the reverse of the behaviour found using photochemical initiation." Paired electrosynthesis has been used to effect the nucleophilic substitution of hydrogen by lH-tetrazoles in 1,bdimethoxy- and 1,3,5trimethoxy-benzenes;l 2 reaction between anions of the nitrogen heterocycles, generated at the cathode, and radical cations of the electron-rich aromatics, generated at the anode, yield products such as (1). H

N

I

OMe

I

F

(1)

of electrochemical studies of the reactions with There has been a further nucleophiles of p-dinitrobenzene, p-nitrobenzonitrile and polyfluoronitrobenzenes. The results are not compatible with the s,&!mechanism, which involves nucleophilic attack on a radical anion. The reductive activation which is observed may be due to an enhanced rate of cleavage of zwitterionic intermediates such as (2). Possible competition between SNand ET pathways has been observed in the reactions with cyclopropylmethyl bromide of the radical anions of benzonitrile and 1,4dicyanobenzene. The former radical yields benzylcyclopropane so that direct S N attack on the cyclopropylmethylbromide is indicated. The latter yields products derived from the ring-opened alkyl halide, indicating that the initial step is electron transfer to give the cyclopropylmethyl radical.l5

7 Nucleophiiic Aromatic Substitution

233

The SNAr Mechanism Theoretical studies, by the MNDO-PM3 method, have been reported of nitro-group substitutions in 1,3,5-trinitrobenzene and 2,4,6-trinitrotoluene by methoxide16 and phenoxide” nucleophiles. The calculations support an addition-elimination mechanism for the reactions in polar solvents. There has been a theoretical study, using SCF and MP2 methods, comparing the substituent effects of nitro and nitroso groups in aromatic systems.18 There is continued interest in the mechanism of base catalysis in substitutions by amine nucleophiles. IOnetic studies have been reported of the reactions of phenyl aryl ethers with aliphatic amines in DMSO. It was arguedI9 that here general base catalysis is the result of rate-limiting proton transfer from initially formed zwitterionic adducts (3), followed by rapid uncatalysed loss of phenoxide from the anionic intermediates (4). This contrasts with the behaviour of alkyl aryl ethers where the rate-limiting proton transfer is to the leaving group (the SB-GA mechanism). In non-polar media, association phenomena between reagents is likely and may contribute to catalytic effects. A study by 19FNMR spectroscopy in [2H8]tolueneas solvent has identified the association of nitrofluorobenzenes and of 2-fluoropyridine with primary amines2’ The relative probabilities of amine catalysis in non-polar solvents by stepwise, dimeric, and cyclic mechanisms has been considered.21 PhO ,

+NHR‘R2

.__I

O z N O N o 2 \

I

-

+R~R~NH

+ + R1R2NH2

slow

/

J 02N@N02

+ R1R2NH + PhOH

NO2

It has been reported that the reactions in DMSO of 1-fluoro-2,4- and -2,6dinitrobenzene with N,N-dialkylamines in the presence of potassium carbonate, which yield dinitrophenyl N,N-dialkylcarbamates such as (5), probably involve the prior formation of carbamate ions.22The reaction of the dichlorodiphenylethylenederivative (6)with N,N-dimethylformamidein the presence of sodium hydroxide gives a product in which both the ring chlorine atoms have been replaced by NMe2 groups.23

Organic Reaction Mechanisms 1995

234

There have been hrther reports of the reaction under high pressure of mono-, di-, and tri-chloronitrobenzenes with N-substituted cyclic amines. Substitution of chloride yields quaternary ammonium salts such as (7), which may undergo dealkylation or ring ~pening.’~’’~ Reaction, also under high pressure, of 2,3,5,6-tetrachloronitrobenzene with ethylenediamine gave a 1 : 1 substitution product and a bridged 2 : 1 product by substitution of a nitro group and/or a chlorine atom. However reaction with N,N‘dimethylethylenediamine gave cyclized products through successive substitutions of an ortho-chlorine atom and the nitro group.26 There have been kinetic studies of the reactions of picryl chloride with 2,6-diamin0pyridine*~and with 3-amino-l,2,4triazole.28

It has been reported that substitution of 1,2-dihal0-4,5-dinitrobenzenewith primary or secondary amines proceeds by nitro-group replacement, to give products in which the halogen substituents are available for further reaction cherni~try.’~ Displacement of a nitro group is also observed in the reactions of 1,2- or 1,4-dinitrobenzene with electrogenerated aryl sulfide ions or aryl disulfide ions in N,N-dimethyla~etamide.~’ A convenient synthesis of 4-fluoro-1-naphthaldehyde (8) has been r e p ~ r t e d ; fluoride ~ is readily displaced from (8) by a variety of nucleophiles in DMSO. Am I

Am I

H Am

7 Nucleophilic Aromatic Substitution

235

A kinetic study of the hydrolysis of 1-pyrrolidino-, 1-piperidino-, and 1-morpholino2,4-dinitrobenzenes to yield 2,4-dinitrophenol has shown catalysis by both hydroxide and by amine. The catalysis is due to the formation of a-adducts (9) and (lo), respectively, by nucleophilic attack at an unsubstituted ring position. The addition of the nucleophile favours displacement by causing rotation of the 1-substituent from the ring plane hence decreasing conjugation with the n-system of the aromatic ring3* Kinetic study of the reaction of 2,4-dinitrobenzaldehydewith hydroxide ions in water has led to the mechanism proposed in Scheme 2. Initial attack of hydroxide at the carbonyl function yields the hydrate anion (11). Attack of hydroxide at the 1-position leads to displacement of formate, and the final step is loss of hydroxide to give the nitroso function. The final product is in equilibrium with its hydroxy o - a d d ~ c t . ~ ~

?” No,

HO’

N ‘0-

SCHEME 2

There is evidence from kinetic and equilibrium studies of 4-nitrosoanisole and 4nitrosophenyl phenyl ether in aqueous acid that hydrolysis involves nucleophilic attack by water at the ring carbon bearing the alkoxy or aryloxy substituent of the protonated substrate.34Kinetic and spectroscopic studies of the hydrolysis in water or in DMSO of bis(2,4-dinitrophenyl ether)s of poly(ethy1ene glycol) show that hydroxide attack may occur at the C(1) position.35 There has been a report of pronounced solvent and cation effects in the nucleophilic coupling of alkali metal 2-naphthoxides with 1-bromo-2-naphthols; halogen exchange between reacting partners may occur c onc ~rre nt ly.3-Bromoazulenequinone ~~ (12) has been shown to undergo substitution with a range of nucleophiles to give the 3substituted product; however, reaction with butanethiolate yields the 2,3-bisbutylthio deri~ative.~~

236

a

Organic Reaction Mechanisms 1995

0

0

Br

No2

There is current interest in mechanisms of the substitution of ring hydrogen atoms by nucleophiles. Replacement of a ring hydrogen by a methylamino group in 1,3dinitrobenzene and some of its monosubstituted derivatives may be achieved38 by reaction with liquid methylamine containing potassium permanganate; there is NMR evidence for the intermediacy of methylamino a-adducts such as (13). There has been a report of the vicarious nucleophilic substitution of hydrogen in nitro- 1,6-methano[lO]annulenes (14) by a variety of carbanions including those derived from halomethyl aryl s ~ l f o n e s .Treatment ~~ of nitroarenes with the carbanion derived from 1(phenylsulfonylmethy1)benzotriazole (15) yields products of vicarious substitution. However, unexpectedly, it is the phenylsulfonyl group rather than the benzotriazole which is cleaved. Small quantities of products resulting from the oxidation of initially formed a-adducts are also pr~duced.~’ It has been demonstrated that the initial attack of carbanions derived from phenylacetonitriles on nitroarenes occurs at unsubstituted ring positions and may lead to the products of vicarious substitution of hydrogen. Contrary to a previous report, it was shown4’ that the phase-transfer-catalysed reaction of phenylacetonitrile with 4-chloro-3-(trifluoromethyl)nitrobenzeneproduces the benzisoxazole derivative (16) rather than the straightforward substitution product (17). Reaction of (pentachloropheny1)lithium with a-lithio-a-arylacetonitrilesresults in displacement of the halogen at the 4-position to give a-aryl-cc-(2,3,5,6-tetrachloropheny1)acetonitriles; a four-centred transition state (18) was proposed.42

Ph

Q” PhyHCN

NO*

(17)

Li I

7 Nucleophilic Aromatic Substitution

237

A theoretical study using SAM1, AM1, and PM3 methods has been reported of the halogen exchange and fluorodenitration reactions of 2,4-dichloronitrobenzenewith free fluoride ion and with tetramethylammonium fluoride (TMAF). A key role in the reaction with TMAF is the association of the tetramethylammonium ion with the nitroaromatic structure.43An inexpensive form of potassium fluoride with high surface area, which shows enhanced activity in nucleophilic aromatic displacements, has been prepared44 by recrystallization from methanol by slow evaporation of the solvent followed by drying at 100 "C. Acetophenones labelled at the 4-position with '*F have been produced4' by reaction of 4-haloacetophenones with an ['*F]fluoride-cryptandoxalate system; the relative efficiency of halogen replacement was F > C1> Br > I. A quantitative treatment has been reported of micellar effects on nucleophilic substitution of 2-chloro-3,5-dinitropyridineby hydroxide and azide ions in the presence of cetyltrimethylammonium halides. The anionic concentrations at the micellar surface depend upon both specific and non-specific coulombic interactions, which were calculated by solving the Poisson-Boltzmann equation.46The substitution of 1-chloro2,4-dinitrobenzene by glutathione in reverse micelles has been used as a model system to assess the transition-state stabilization in glutathione transferase-catalysed conjugat i ~ n . ~ ~ Intramolecular nucleophilic substitutions of fluoride or chloride, activated by orthoor para-nitro groups, to yield biaryl ether bridges have been used in syntheses of model ring systems for the antibiotic tei~oplanin.~*-~' Two intramolecular aryl-aryl coupling reactions of 2'-bromoreticulines have been described. The regioselectivity depends on the cyclization method; palladium catalysis gives a salutaridine derivative whereas a photochemically induced SRN 1 reaction gives the aporphine ~keleton.~' The intramolecular Smiles photo-rearrangement shown in Scheme 3 is subject to general base catalysis.52A Brsnsted plot shows classic Eigen behaviour with a break at pH 6 consistent with the pK, value expected for the intermediate (19). Study of the photo-reactions of 2,6-difluoro-4-nitroanisolein the presence of nucleophiles shows that one fluorine is replaced by hard nucleophiles and the methoxy group by softer nucleophiles. Little reduction occurs and one fluorine atom is not replaced so that the reagent my be useful as a biochemical p h ~ t o - p r o b e . Irradiation ~~ of 1,2,4,5tetracyanobenzene in the presence of aliphatic ethers results in electron transfer and may yield products in which a cyan0 group is substituted to give alkyltricyanoben~enes.'~

(19)

SCHEME 3

238

Organic Reaction Mechanisms 1995

Coordination of arenes with tricarbonylchromium results in activation towards nucleophilic attack. It has been shown that reaction of Cr(C0)3-complexed oalkylanisoles with carbon nucleophiles may result in tele-substitution of the methoxy group.55 The deprotonatiodsilylation of methoxy- and (1,2-dimethoxybenzene)Cr(CO), derivatives may yield silylated products with high enantioselectivity when a chiral lithium amide is used as base.56 (Haloary1)copper nucleophiles have been prepared from active copper and the corresponding haloiodobenzene; cross-coupling of the reagents with alkyl and acyl halides yields the respective alkyl-substituted haloarenes and haloaryl ketones.57 Copper(1) has been shown to catalyse the reactions of iodoarenes with sodium arenesulfinates yielding unsymmetrical diary1 ~ u l f o n e s .The ~ ~ nickel-catalysed substitution of the sulfonyl group in aryl t-butyl sulfones has been reported in reactions with aryl Grignard reagents which lead to the formation of biaryls. This reaction may be used in conjunction with the powerful ortho-lithiating effect of the 1-butylsulfonyl group to prepare unsymmetrical ortho-substituted b i a r y l ~ . ~ ~ There has been a report of the catalysis by a combination of copper cyanide and palladium of the coupling of aryl iodides and a-lithioamines to yield 2-aryl-substituted amines.60Palladium catalysis is also effective in the synthesis of arylamines by reaction of aryl halides with secondary amines in the presence of silylamide base.61The Heck reaction, in aqueous media, has been used to produce styrylamino acids from arenediazonium salts derived from phenylalanine and tyrosine.62 There has been a report of the selective hydrodehalogenation of halogenated aromatic ketones by hydrogen in the presence of palladium on carbon.63This catalyst may also be effective in the Stille reaction, the palladium-catalysed cross-coupling of aryl halides or triflates with organostannanes; it was found that the yield and reaction rate are enhanced by the addition of copper iodide as co-catalyst and triphenylarsine as l i g a ~ ~ d . ~ ~ It has been reported that the initially formed intermediate in the Stille reaction resulting from oxidative addition of Pd(0) into the aryl halide may undergo aryl-phenyl exchange with triphenylphosphine ligand leading to mixtures of biaryl products.65 Pd(0) in combination with lithium chloride has been used to promote the cross-coupling of trimethyl(4-pyridy1)stannane with polybromoarenes to yield poly(4-pyridyl)-substituted aromatic compounds.66There have been reports of the palladium-catalysed reaction of organostannates with aryl halides in aqueous media,67and of the solid-phase synthesis of biphenyls by heterogeneous cross-coupling of trialkylphenylstannanes with aryl ele~trophiles.~~ The Pd-catalysed cross-coupling of pyridyl triflate with aryl bromides in the presence of hexamethylditin is thought to involve the intermediacy of a labile pyridyl~tannane.~~ The Suzuki reaction, the Pd-catalysed reaction of aryl halides with boronic acid derivatives, has been used to produce arylboronic esters from the pinacol ester of diboronic acid.70 The Pd-catalysed intermolecular cross-carbonylation of aryl iodides with dihydrofbrans may be achieved by reaction with carbon monoxide in the presence of a tertiary a m i ~ ~ eThe . ~ ' Pd-catalysed coupling of allylic cyclic carbonates with iodobenzene was found to give phenyl-substituted allylic alcohols; however, arylation without reductive ring opening was achieved using diphenyliodonium tetraflu~roborate.~~ There have been reports of Pd catalysis in the intramolecular cyclization of an iodoaryl

7 Nucleophilic Aromatic Substitution

239

n i t r ~ a l k e n eand ~ ~ in the reactions of substituted aryl iodides with allenes, which may yield bicyclic products enantio~electively.~~

Heterocyclic Systems There have been fill reports of interesting studies of the nature of the transition states in substitutions in 1,3,5-triazinederivatives. Substitution of 4-nitrophenolate ions from 2(4-nitrophenoxy)-4,6-dimethoxy-1,3,5-triazine by substituted phenolate ions in aqueous solution obeys a linear Brmsted-type equation over a range of pKa values both greater and less than the pKa value of the leaving The absence of curvature is consistent with a mechanism involving the single transition state (20). By contrast, the pyridinolysis of 1-(4,6-diphenoxy-1,3,5-triazin-2-yl)pyridinium chloride with substituted pyridines shows a non-linear Brernsted plot with a break-point when the pK, of the pyridine nucleophile equals that of the leaving group; this result is consistent with a traditional two-step mechanism involving the intermediate (21). The results indicate that there is negligible coupling between the bonding changes in the two steps, and substituent effects show that bond formation is about half complete in the addition step.76

Kinetic studies have been reported of the substitution reactions of the thiophene derivatives (22: L = Br, OPh, OC6H4N02;Y = CONH2,C02Me) with aliphatic amines in benzene. Base catalysis was observed with the compounds containing phenoxy or nitrophenoxy leaving groups, and the effects of the ortho-like Y substituents were discussed.77Reactions of 3-bromo-2-nitrobenzo[b]thiophene(23) with amines in N,Ndimethylformamide yield the expected substitution products, the 3-amino derivatives, together with the isomeric 2-amin0-3-nitrobenzo[b]thiophenes.~~

Organic Reaction Mechanisms 1995

240

There have been reports of base catalysis in the reactions of 2-alkoxy-N-alkylpyridine salts with piperidine in a ~e toni tril eand ~~ of the effects of acid and base catalysts on the reaction of 4-chloroquinoline with 1,2,4-t1iazole.~~Kinetic studies of the piperidinodechlorination of 2,4-diamino-6-chloropyrimidine(24; R = H) in DMSO show the absence of base catalysis, indicating that piperidine attack at the 6-position is rate limiting. The corresponding N-(3)-oxide (25; R = H) is slightly more reactive towards nucleophilic substitution. A much more marked increase in reactivity was found in the N-acetyl derivative (24; R = COMe). However, the reactivity of (25; R = COMe) was reduced since it was converted into an anionic form by piperidine.81There has been a kinetic study of the relative rates for successive displacement of the three chlorine atoms in 2,4,6-trichloro- 1,3,5-triazine (cyanuric chloride) by butylamine in Nmethylpyrrolidine and by morpholine in propan-2-01.~~ Oligomeric porphyrins have been prepared by the stepwise nucleophilic substitution of aminoporphyrine monomers on to cyanuric chloride.83 The reactions of cyanuric chloride with dialkylamines have been used to prepare both symmetrical and non-symmetrical trisubstituted triazines; NMR experiments indicate that rotation about Ar-N bonds may be r e ~ t r i c t e d .An ~~ attempt has been made to correlate reactivity to substitution in heterocyclic compounds with chemical shifts in their I3C NMR spectra.85

NHR

(24)

The reaction of 2-chloro-3,5-dinitropyridinewith hydroxide yields the pyridine derivative by the ANRORC mechanism as shown in Scheme 4; there has been a study86 of solvent effects on the rates of formation and disappearance of the ring-opened intermediate (26). It has been reported that in alkaline solution 3,Sdiacetyl- and 3,5dicyano- 1,2,6-trimethylpyridinium salts are converted by recyclization into N,5dimethylanilines and 2-methylaminopyridines, re~pectively.~~ Reaction of 1,2,3triarylbenzo[h]thiophenium ions with alkoxide results in ring-opening with retention of configuration.88

SCHEME 4

7 Nucleophilic Aromatic Substitution

24 1

There have been several reports of the vicarious nucleophilic substitute (VNS) of hydrogen by carbanions containing leaving groups, and the method has been applied to nitro derivatives of thiophene, furan, and pyrr~le.~’ It was reported that 5- and 6nitrobenzoxazoles (27) undergo nucleophilic attack at the 2-position resulting in ringopened products. However, when the 2-position is blocked VNS may occur in the carbocyclic ring.” The VNS reaction of 2-substituted-5-nitrobenzoxazoleswith 4chlorophenoxyacetonitrile resulted in the formation of 4-cyanomethyl derivatives and was used in an attempted synthesis of tetrahydropyrroloquinoline alkaloids.” It has been shown” that a phenylmethylsulfonyl group may be introduced regiospecifically at the 4-position of 3-substituted pyridazines by VNS reaction of the pyridazinium dicyanomethylides (28). In all these reactions the initial step is nucleophilic attack at a ring-carbon carrying hydrogen. Similarly, in the unusual substitution reactions of 3trichloromethylpyridine (29) and its derivatives, the first step is attack at the unsubstituted a-position and this is followed by loss of chloride and hydrogen migration to the ~ide-chain.’~

Meisenheimer and Related Adducts There has been a major review rationalizing the regioselectivity of anionic addition to nitro-activated arenes and noting the importance of stereoelectronic stabilization in C( 1) a d d ~ c t sThe . ~ ~use of anionic o-adducts in organic synthesis has been reviewed,95 and a spectrophotometric method has been reported for the determination of some phenolic drugs. This involves nitration followed by the formation of strongly coloured Janovsky adducts by reaction with acetone in alkaline ~olution.’~ Alkylation of adducts formed by carbanion addition to 9-nitroanthracene may ultimately yield 1O-substituted-9anthroxime~.’~The reaction of 1,3,5-trinitrobenzene with tetrahydroborate gives the trihydro adduct (30), which yields 1,3,5-trinitrocycIohexaneon acidif icati~ n.Kinetic ~~ studies of the hydrogen isotope effect, kHlkD, have provided evidence for proton tunnelling in the reactions with tertiary amines of 2,4,6-trinitrotoluene, 2,4,6trinitrobenzyl chloride, and hexanitrobibenzyl.” Kinetic and equilibrium data have been reported for the reaction of carbanions derived from 12 ring-substituted benzyl cyanides with 1,3,5-trinitrobenzene, to give (31), and with 4-nitrobenzofuroxan. With increasing carbanion reactivity, rate constants approach a limit of ca lo9 dm3 mol-’ s-’, and the results were used to measure the intrinsic reactivities of the carbanions in these a-adduct-forming reactions.loo Reactions of carbanions derived from nitroalkanes with 4,6-dinitrobenzofuroxan (DNBF) yield

242

Organic Reaction Mechanisms 1995

the adducts (32). Rate and equilibrium measurements in water indicate that these adducts have stabilities 105-108 times greater than those of the corresponding cradducts from 1,3,5-trinitrobenzene, emphasizing the extremely high electrophilic character of DNBF. Reaction of adducts (32) with base results in the b-elimination of nitrous acid to give alkenes (33) which were characterized by NMR.'" b-Elimination reactions have also been observed on treatment with potassium fluoride in acetonitrile of the adducts (34) formed from DNBF with sulfonium ylides.''* The reactions of methoxide ions with 7-methyl-4-nitrobenzofuroxan result in rapid attack at the unsubstituted 5-position followed by isomerization to give the thermodynamically preferred 7-methoxy-7-methyl adduct (35). The unusual preference for the latter process over proton loss from the methyl side-chain was ascribed to the absence of steric strain at the 7-position (allowing methoxide addition) and to the high intinsic barrier expected for deprotonation.Io3

base

(32)

(33)

It is reported that reactions of dinitrophenyl crown ethers with alkali metal hydroxides in aqueous DMSO may lead to the concerted formation of anionic 0adducts and complexes with the metal cation^.''^ The hydroxide adduct (36) of a triazolotriazine has been prepared and its crystal structure dete~ mined. '~ Spiro ~ adducts containing 1,3-dithiolane and 1,3-0xathiolane rings at the 8-position of 5,7dinitroquinoline have been prepared and characterized.Io6 Crystallographic studies of the spiro adducts (37; R = H, NO2) have been reported and their thermal decomposition pathways determined.lo7 There have been spectroscopic studies of the salts formed

243

7 Nucleophilic Aromatic Substitution

R

I

(341

(35)

from (37; R=NOz) with a variety of metal cations,"* and solvent effects on the electronic spectra of a series of a-adducts have been examined."'

Benzyne and Related Intermediates Theoretical studies have been reported of C6H4X- anions (X = F, C1, Br) which may, in the gas phase, show characteristics of benzyne-halide complexes. Ab initio calculations predict a dramatic decrease in binding energy from C6H4F- to C6H4Cl- and to C6H4Br- (226, 96, and 60 kJ mol-'). In agreement with experiment, the C,&Brion is calculated to undergo a bromide transfer rather than hydrogen abstraction when reacting with methanol."0 Calculations at the MP2, MP3, and MP4 levels established two structures, with a low energy barrier, for C6H&-: (a) a bromophenide ion and (b) a bromide-benzyne complex where the bromide ion straddles the ortho- and metahydrogens of the ring."' An experimental study of the ion-molecule reactions of hydroxide and methoxide ions with bromobenzene indicates benzyne formation initiated by proton abstraction followed by loss of halide. Experiments with monodeuteriated bromobenzenes suggest that reactions with hydroxide are the result of long-lived complexes in which extensive scrambling of hydrogen-deuterium occurs. Reactions of amide ions with bromobenzene result in the formation of all the isomeric bromophenoxide ions without isotopic scrambling indicating weak binding in the collision complexes.' "

Organic Reaction Mechanisms 1995

244

It has been shown that phenyl[o-(trimethylsilyl)phenyl]iodonium triflate (38), which may be readily prepared from o-bis(trimethylsily1)benzene and the hypervalent iodine reagent iodobenzene diacetate, is a useful precursor of benzyne.'I3 A study of the decomposition of 1-(2'-carboxyphenyl)-3,3-dimethyltriazene (39) and its tetrahaloanalogues has identified the arenediazonium-2-carboxylates as intermediates in aryne formation.' l4 A re-investigation of the decomposition of benzenediazonium-2carboxylate in mixed nucleophilic solvents indicated the operation of a number of mechanistic pathways. In addition to benzyne, products derived from 2-carboxyphenyl cations and 2-carboxyphenyl radicals were observed; benzyne formation is favoured in halogenated solvents and occurs by concerted loss of nitrogen and carbon dioxide."' Reaction with borates and borinates of zirconocene complexes (40) of substituted benzynes leads to the regioselective formation of heterodimetallic compounds, which may be converted into halophenols.' l 6 The relative reactivities of 4-substituted benzynes towards methanol, ethanol, and propan-2-01 have been examined. l7

'

OTf

R

The regioselective cycloaddition of an a-alkoxybenzyne with an angularly hsed CIsiloxyfuran has permitted the synthesis of benz[a]anthraquinone derivatives. There have been reports of the intramolecular Diels-Alder reactions of an aryne and an azadiene to give lycorine alkaloids' l 9 and of benzyne with an acyclic diene.'*'

''

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'

Broxton, T.J., Colton, R., and Traeger, J. C., 1 Phys. Org. Chem., 8, 351 (1995). Wassmundt, F. W. and Kiesman, N. F., 1 Org. Chem., 60, 1713 (1995). Tsuge, A,, Moriguchi, T., Mataka, S., and Tashiro, M., 2 Chem. Res. (S), 1995, 460. Hanson, P., Hammond R. C., Gilbert, B. C., and Timms, A. W., 1 Chem. Soc., Perkin Trans. 2, 1995, 2195.

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l2 l3 14

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l5

Panteleeva, E. V, Vaganova, T. A,, Shteingarts, V D., and Bilkis, I. I., Tetrahedron Lett., 36, 8465 (1995).

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’*

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67

'" "'

7 Nucleophilic Aromatic Substitution

241

I08

Glaz, A. I., Shakhkel'dyan, I. V., Gitis, S. S., and Atroshchenko, Yu. M., Zh. Ohshch. Khchim., 64, 1017 (1994); Chem. Ahs., 122, 203707 (1995). Io9 Alifanov, E. N., Gitis, S. S., Kaminskii, A. Ya., Shatskaya, V. N., and Sychev, V S., Zh. Obshch. Khim., 64, 1811 (1994); Chem. Abs., 122, 264804 (1995). ' I 0 Wong, M. W, 1 Chem. Sac., Chem. Commun., 1995, 2227. Ill Morgan, N. H., Custodio, R., and Riveros, J. M., Chem. Phys. Lett., 235, 436 (1995); Chem. Ahs., 122, 290122 (1995).

'I2

Linnert, H. V and Riveros, J. M., Int. 1 Mass Spectmm. Ion Processes, 140, 163 (1994); Chem. A h . , 122, 105051 (1995).

Kitamura, T. and Yamane, M., 1 Chem. Sac., Chem. Commun., 1995, 983. 'I4 Buxton, P. C. and Heaney, H., Tetrahedmn, 51, 3929 (1995). ' I 5 Buxton, P. C., Fensome, M., Heaney, H., and Mason, K. G., Tetrahedron, 51, 2959 (1995). 116 de Rege, F. M. G . and Buchwald, S. L., Tetrahedron, 51, 4291 (1995). 'I7 Pyun, C., Yoon, S., and Kim, J. H., 1 Korean Chem. Sac., 38,701 (1994); Chem. Ahs., 122,9251 (1995). ' I 8 Matsumoto, T., Sohma, T., Yamaguchi, H., Kurata, S., and Suzuki, K., Tetruhedron, 51, 7347 (1995). ' I 9 Gonzalez, C., Perez, D., Guitian, E., and Castedo, L., 1 Org. Chem., 60, 6318 (1995). I20 Buszek, K. R., Tetrahedmn Lett., 36, 9125 (1995). 'I3

CHAPTER 8

Electrophilic Aromatic Substitution R. G. COOMBES Department of Chemistq Brunel University, Uxbridge General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nitration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alkylation, Acylation, and Related Reactions. . . . . . . . . . . . . . . . . . . . . . . Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

249 249 250 252 256 256

General A valence-bond study' of benzene, phenol, and benzonitrile, and the arenium ions formed by them on protonation, has shown that, although the spin-coupled wavefunctions for the aromatics can be interpreted in terms of valence-bond structures, the charge delocalization in the ions is achieved through a single spatial configuration of semi-delocalized orbitals. The form of a spin-coupled wavefunction for the ions demonstrates clearly the effect of the substituents. Rates of nitration of monosubstituted benzenes2 from MNDO calculations have been related to substrate ionization potential. The interaction of solvent with the transition-state structures for some reactions including Friedel-Crafts substitution has been discu~sed.~ A correlation between the regioselectivity of substitution in some heterocyclic compounds with 13C NMR chemical shifts has been e ~ p l o r e dRecent .~ criticism, reported last year, of the use of the reactivity ratio of mesitylene to durene as a probe of transition-state structure in many substitutions and its use to distinguish between conventional ionic and electron-transfer pathways has been firmly rebutted as a general propo~ition.~ The importance of the involvement of dicationic species as the effective electrophiles in Gatterman, HoubenHoesch, and Friedel-Crafts reactions of unactivated benzenes has been demonstrated.6 + For example, N,N-diprotonated hydrogen cyanide (HE=NH,) is effective in the Gatterman reaction of benzene with cyanide and protonated acyl cations are effective in, for example, the acetylation of benzene by MeCOSbF6 at high acidities (see also references 34-36).

Halogenation Formic and sulfuric acids have been shown to promote electrophilic fluorination by elemental f l ~ o r i n esuggesting ,~ that it may indeed be possible to use fluorine as a viable Organic Reaction Mechanisms 1995 Edited by A. C. Knipe and W E Watts 0 1997 John Wiley & Sons Ltd

249

250

Organic Reaction Mechanisms I995

reagent in organic synthesis. 4-Fluorobenzoic acid is, for example, converted smoothly and cleanly into 3,4-difluorobenzoic acid in 66% yield at room temperature in formic acid and pentafluorobenzoic acid can be formed from 2,4-difluorobenzoic acid in concentrated sulfuric acid, again at room temperature. There is the possibility of hypofluorite intermediacy. Chlorination of phenol with sulfuryl chloride (S02C12) is catalysed by primary and secondary amines in non-polar solvents and under these conditions reaction to give monochlorinated products is rapid and highly regiospecific for ortho substitution (olp > 4).' The high regioselectivity is attributed to in situ N-chloroamine formation, the N-chloroamine attacking the ortho position of phenol, facilitated by intramolecular hydrogen bonding. Regioselective para bromination of anilines occurs on reaction with bromine and nitrosonium bisulfate in concentrated sulfuric acid, the nitrosonium salt being essential for reaction.' A route involving the appropriate aniline radical cation is suggested (cf. reference 26). The orienting effect of the 1-0-(2,3,4,6-tetra-O-acetyl-j3D-glucopyranosyl) group in aromatic bromination by bromine in dichloromethane has been described" and also, when used in conjunction with hydroxy andor methoxy groups, a number of high-yield regioselective brominations of potential synthetic utility have been achieved. The iodination of phenols in free ortho and para positions is readily achieved in dichloromethane solution using bis(sym-collidine)iodine(I) hexafluorophosphate (1).l 1 With aniline and N,N-diethylaniline, however, regioselective para iodination in excellent yield was observed. A convenient new procedure for the direct iodination of unreactive aromatic compounds has been reported.I2 The procedure involves passing fluorine diluted with nitrogen at room temperature through a mixture of iodine, concentrated s u l h c acid, and the substrate. Nitrobenzene is converted into 3-iodo- 1nitrobenzene in 70% yield under these conditions. The mechanism may involve the intermediacy of iodine fluoride, a hypervalent iodine species, or a hypofluorite derived from sulfuric acid.

Nitration Studies of reactions which do not have the conventional mechanism of electrophilic aromatic substitution continue. Two further substrates have been studied in the photochemical nitration reaction with tetranitromethane, which has importance in mechanistic arguments. In the case of 1,2,3,4-tetramethylben~ene,'~ the structure of a

8 Electrophilic Aromatic Substitution

25 1

nitro-cycloadduct has been determined by X-ray crystallography. In the case of 1meth~xynaphthalene,'~ evidence is presented that the products, including 1-methoxy-4and 1-methoxy-2-nitronaphthalene result from highly labile nitro- or nitritotrinitromethyl adducts, including (2). N-Nitrosuccinimide (3) has been used" as the reactant in a related reaction to produce a range of products from very electron-rich aromatics (e.g. N,N-dimethyl-p-toluidine). The photolysis with tetranitromethane has been used in related studies as a method of preparation of methyl-substituted naphthalene radical cations.l 6 A report has a p ~ e a r e d of ' ~ measurements by Raman spectroscopy of the variation with temperature of the concentration of nitronium ions in nitric acid-sulfuric acidwater mixtures. Conclusions drawn, however, concerning kinetic behaviour at low nitronium ion concentrations merit further discussion. The nitration of some alkylbenzenes, catalysed by mercury(I1) acetate, has been studied in a number of solvents." With toluene a mercuriation-nitrosodemercuriation sequence, giving a change in product isomer ratio from the normal, was identified in nitric acid-acetic acid and dilute nitric acid. Isomer proportions of 0- 30%, m- 6% and p- 64% could be achieved. Further evidence has been adduced for the operation of nitrogen trioxide (NO;) as the electrophile involved in electron transfer in ozone-mediated nitrations with nitrogen dioxide (kyodai nitration).l 9 The ratios of dinitrobenzenes and of nitrophenols formed as side-products in the nitration of benzene are significantly different from those formed under conventional conditions. Cyclic acetals of aromatic carbonyl compounds (4) can be nitrated smoothly under kyodai conditions in the presence of magnesium oxide as an acid scavenger.20o- and p-Nitro-compounds, in addition to significant proportions of m-nitro derivatives, are formed, the acetal ring remaining almost intact. The ternary mixture NO-N02-02 has been found to be more effective than NOT02 as a nitrating agent for non-activated aromatic compounds and again nitrogen trioxide is implicated as the reactive species.21This observation is related to one made previously.22Kyodai nitration of anilides and aryl esters gives a mixture of ortho- and para-nitro derivatives in which the former isomers p r e d ~ m i n a t e .Intermediacy ~~ of (5) or (6) formed by reaction of NO2 with the appropriate radical cation is suggested to explain the ortho predominance. The use of dinitrogen pentaoxide in liquid sulfur dioxide as a nitrating agent has been explored. Reaction with benzene and monosubstituted derivatives at - 11 "C gave

(4)

Organic Reaction Mechanisms 1995

252

results similar to those obtained from mixed acid nitration.24Results from competition experiments and the nitration of bibenzyl indicated reaction at a rate faster than mixing. A number of heterocyclic compounds including pyrimidine did not react, but reaction with pyridine and a number of its derivatives was successhl. Further investigation of the nitration of pyridine has led to the suggestion25of the intermediacy of two species. First, a pyridinium-S02-N205 complex (7) was formed and then, on addition of water, a 1,Cdihydropyridine complex was formed which decomposed by a first-order process to give mainly 3-nitropyridine.

(7)

(8) a; X = H

b; X = N 0 2

Reaction of aniline with nitrosonium bisulfate followed by nitric acid in concentrated sulfuric acid to give nitrophenyldiazonium ions involves nitrosonium ion-catalysed nitration in the para-position with normal meta- and para-nitration followed by diazotization on dilution with water.26Mixed-acid nitration of 6,6-dimethylbenzosuberone (8a) at 25 "C gives the unexpected rearrangement product (9).27 The unrearranged nitro-compound (8b) is only formed at 0 "C and rearranges to (9) in acid solution at 25 "C, a process for which the presence of the nitro group is necessary.

Alkylation, Acylation, and Related Reactions Treatment of porous support materials (e.g. silica having a 70 average pore diameter) with aluminium chloride in solution produces an entirely heterogeneous form of aluminium chloride, which is highly active in the liquid-phase alkylation of aromatics using alkenes and chloroalkanes.28 Selectivity towards monoalkylation is improved over homogeneous reactions and the supported reagent catalysts are re-usable and easily recovered by filtration. A review29 in Chinese includes comment on the application of iron(II1) chloride in Friedel-Crafts reactions. A semiempirical study3' of the mechanisms of alkylation of arylamines has been carried out. Calculations on the acid-catalysed ortho-alkylation by an alkene support a mechanism similar to that of the ene reaction, i.e. involving (10). An alternative route for alkylation of aromatics with alkenes in the gas phase has been demonstrated from a radiolytic study of the reaction of benzene and propene in methyl fluoride containing oxygen and dimethyl ether.3' Alkylation occurs within an ion-molecule complex formed upon addition of an arenium ion to the alkene.

8 Electrophilic Aromatic Substitution

253

The Y-type zeolite HZZ-360 has been shown to be an effective catalyst for the electrophilic monoalkenylation of a range of aromatic compounds by phenylethyne in 1,2-dichlorobenzene at 110 O C 3 ’ Reaction is believed to occur on the external surface of the catalyst particles. Vinylation is also achieved33 by reaction of alk-1-ynes, phenols, tin(1V) chloride, and tributylamine in refluxing acetonitrile, when orthoalkenylphenols are formed. 1,2-Dicarbonyl compounds react with benzene in the presence of trifluoromethanesulfonic acid to give high yields of gem-diphenylated ketones.34Involvement of 0,Odiprotonated 1,2-dicarbonyl species [e.g. 1,2-dihydroxyethene dication (1l)] as the initial electrophiles is suggested. Under superacid conditions benzaldehyde reacts readily with benzene to give a high yield of triphenylmethane and there is evidence for the involvement of diprotonated be n~a l de hydeAb .~~initio calculations suggest that the latter species is the O,C(aromatic)-diprotonated dication (12). In contrast, other workers36suggest that 0,O-diprotonated benzaldehyde (13) is the reactive intermediate in the reaction of benzene with benzaldehyde in the presence of, for example, trifluoromethanesulfonicacid to give initially triphenylmethane. Here NMR deuteriumexchange experiments seem to rule out (12).

Two sequential and regioselective Friedel-Crafts reactions of gem-dihalocyclopropanecarbonyl chlorides with substituted benzenes have been rep~rted.~’ (E)-3-Aryl-2,2dihalocyclopropanecarbonyl chlorides [e.g. (14)] afforded 4-aryl-3-halo-1-naphthols [e.g. (15)], while 2,2-dichlorocyclopropanecarbonyl chlorides 1e.g. (16)] gave 4-aryl-lnaphthols [e.g. (17)] with benzene or p-xylene. A cyclialkylation strategy has been used to make hydr~phenanthrenes.~~ The annulations occur in synthetically useful yields if the aromatic ring is electron rich and if conformational effects favour cyclization. Compound (18a), for example, does not cyclize in the presence of BF3.Et20, whereas (18b) forms (19). Trifluoromethane-

Organic Reaction Mechanisms 1995

254 OH

OH

sulfonation of the allylic alcohol of a piperonylated conduritol (20) induces intramolecular electrophilic alkylation of the aromatic ring.39 The prevalence of substitution ovtho or @so to the CH20 bridge is controlled by the nature of the ring substituent Z. @so attack is followed by 1,2-alkoxymethylmigration. 1,l'-Biphenyl-2yl isocyanide dihalides (21) undergo novel Lewis acid-catalysed c y c l i ~ a t i o n sto~ give ~ the hitherto difficulty accessible 6-chloro- and 6-bromo-phenanthridines. The thermolyses of N-mono- and N,N-di-substituted benzyl derivatives of 2-aminopyridines have been studied41 to investigate their possible roles in the ring benzylation reaction. The formation of 2-benzylamino-5-benzylpyridiniumchloride occurs by rearrangement of N,N-disubstituted benzyl derivatives only. A complementary MNDO study of electrophilic substitution in 2-aminopyridines was performed. The Gatterman-Koch formylation reaction has been compared with other electrophilic substitutions in super acid^.^^ Formylation has priority over the other reactions under conditions where most of the substrate is protonated, because the formyl cation is formed close to the substrate, in particular by protonation of carbon monoxide by the protonated substrate. An efficient mild procedure for the acylation and perfluoroacylation of activated aromatic substrates (e.g. 1-methoxynaphthalene) has been reported.43 The reagent system is (RC0)20-Me2S-BF3 in dichloromethane and it is believed that dimethylacylsulfonium salts (RCO'SMe2 RC02BF3) are the active acylating species. Hafnium trifluoromethanesulfonate has been found44 to be an extremely efficient catalyst for the acid anhydride acylation of a range of reactive aromatics. Anisole has been regioselectively acylated in the para position by reaction with carboxylic acids at > 150 "C over H-ZSM-5 zeolite.45 Substitution at the ortho and meta positions was not observed but ester formation was significant and dominant at lower temperatures. The full results4' of the investigation of the mechanism of the bisacylation of aromatics with 0-phthaloyl dichlorides in the presence of aluminium chloride to give anthraquinones has indicated the importance of the asym-dichlorides (22), which react initially with the aromatic compound to give o-benzoylbenzoic acid pseudochlorides (23), which then undergo cyclization. In unexpected contrast to benzenoid aromatics, which are alkylated, N-methylpyrrole undergoes acylation on reaction with lactones in the presence of aluminium chloride in chloroform solution at 60 "C, the reaction being most efficient with y- and a - l a c t o n e ~ . ~ ~ Annulation reactions are possible, for example the formation of mainly (24) from the lactone of 4-hydroxypentanoic acid.

8 Electrophilic Aromatic Substitution

255

@ @ /

x x

(18) a; X = H b; X = M e

Me

Me (19)

(21) X,Y = C1, Br combinations

Organic Reaction Mechanisms 1995

256 Other Reactions

The arenium ions from simple aromatics (e.g. benzene) have been studied by UVvisible and 'H NMR spectroscopy at room temperature in AIC13/Br3-Me3SBr-HBr melts.48 This allows, for example, the positive charge distributions on the five sp2 carbons of the pentamethylbenzenium ion to be confirmed by 'H NMR studies. AM1 calculations have been carried out on polyfluorobenzenes and their related protonated forms.49Proton affinities of the former have been estimated as have activation energies for 1,2-hydrogen shifts in the latter. The sulfonations of biphenyl and various activated derivatives by sulfur trioxide in dichloromethane have been studied and indication of the positions of successive reactivity obtained." The sulfonation of dimethoxynaphthylenes has been investigated.51 A linear-free-energy relationship has been demonstrated for substituent effects in the Reimer-Tiemann reaction of a number of phenols.52Vilsmeier reaction of, for example, N,N-dimethyl-4-methylaniline with N-formyl-N-ethylaniline in phosphoryl chloride results in initial ortho substitution to give (25).s3 This is followed by a 1,5-sigrnatropic hydrogen shift to give an iminium ion (26) in which electrophilic attack on the adjacent aromatic ring occurs to give a dibenzo[b, f ][ 1,5]diazocine.

I

Me, +, NO S

I

The reaction of anisole with NO+ AlCI, in SO2-CD2CI2 at - 70 "C has been demonstrated by 'H, 13C, and "N NMR spectroscopy to give the n-complex (27).54In contrast, the reaction of thioanisole, which was studied by similar methods, gives the complex (28). Results of MIND0/3 calculations are in agreement with these observations. References

'

'

Raos, G., Gerratt, J., Karadakov, E? B., Cooper, D. L., and Raimondi, M., 1 Chem. Soc., Faraday Trans., 22,401 1 (1995). Games, A. M. E. A. N. F., Bo1.-Soc. Porf Quim., 49, 16 (1993); Chem. A h . , 122, 238968 (1995). Bertran, J., Lluch, J. M., Gonzalez-Lafont, A., Dillet, V, and Perez, V, ACSS'mp. Ser, 568, 168 (1994); Chem. A h . , 122, 9264 (1995). Ding, J., Daxue Huaxue, 9, 51 (1994); Chem. A h . , 122, 30782 (1995). Baciocchi, E. and Galli, C., 1 Phys. Org. Chem., 8, 563 (1995). Sato, Y., Yato, M., Ohwada, T., Saito, S., and Shudo, K., 1 Am. Chem. SOC.,117, 3037 (1995). Chambers, R. D., Skinner, C. J., Thomson, J., and Hutchinson, J., 1 Chem. SOC.,Chem. Commun., 1995, 17. Gnaim, J. M. and Sheldon, R. A., Tetrahedron Lett., 36, 3893 (1995). Gorelik, M. V, Lomzakova, V I., Khamidova, E. A., Shteinian, V Y., Kuznetsova, M. G., and Andrievsky, A. M., Mendeleev Commun., 1995, 65.

8 Electuophilic Aromatic Substitution 10

257

Mabic, S. and Lepoittevin, J.-P., Tetrahedron Lett., 36, 1705 (1995). Brunel, Y.and Rousseau, G., Tetrahedron Lett., 36, 8217 (1995). 12 Chambers, R. D., Skinner, C. J., Atherton, M., and Moilliet, J. S., 1 Chem. SOC.,Chem. Commun., 1995, 19. 13 Butts, C. P., Eberson, L., Foulds, G. J., Fulton, K. L., Hartshom, M. P., and Robinson, W. T., Acta Chem. Scand., 49, 76 (1995). 14 Butts, C. P., Eberson, L., Hartshom, M. P., Persson, O., and Robinson, W. T., Acta Chem. Scand., 49, 253 (1995). 15 Calvert, J., Eberson, L., Hartshom, M. P., and Svensson, J. O., 1 Chem. Soc., Perkin Trans. 2, 1995, 645. 16 Eberson, L., Hartshom, M. P., and Persson, O., 1 Chem. SOC.,Perkin Trans. 2, 1995, 409. 17 Zaman, M. B. and Hanson, C., Bangladesh 1 Sci. Ind. Res., 29, 143 (1994); Chem. Abs., 123, 111324 (1995). I8 Greenop, M. W. and Thomas, C. B., 1 Chem. Soc., Perkin Trans. 2, 1995, 1595. 19 Suzuki, H. and Mori, T., J: Chem. Soc., Perkin Trans. 2, 1995, 41. 20 Suzuki, H., Yonezawa, S., and Mori, T., Bull. Chem. Sue. Jpn, 68, 1535 (1995). 21 Suzuki, H. and Mori, T., 1 Chem. Soc., Perkin Trans. 1, 1995, 291. 22 Ross, D. S. and Blucher, W. G., Report 1980, ARO-13831.3-CX, Order No. AD-A085324, Avail. NTIS; from Gov. Rep. Announce. Index (US.), 1980, 80(20), 4255; Chem. Abs., 94, 120451 (1981). 23 Suzuki, H., Tatsumi, A., Ishibashi, T., and Mori, T., 1 Chem. Soc., Perkin Trans. 1, 1995, 339. 24 Bakke, J. M., Hegbom, I., Ovreeide, E., and Aaby, K., Acta Chem. Scand., 48, 1001 (1994). 25 Bakke, J. M. and Hegbom, I . , J Chem. Soc., Perkin Trans. 2, 1995, 1211. 26 Gorelik, M. V., Lomzakova, V. I., Khamidova, E. A., Shteiman, V. Y., and Kuznetsova, M. G., Mendelem Commun., 1995, 64. 27 Garcia, J. G., Enas, J. D., Fronczek, F. R., and VanBrocklin, H. F., 1 Org. Chem., 59, 8299 (1994). 28 Clark, J. H., Martin, K., Teasdale, A. J., and Barlow, S. J., 1 Chem. Soc., Chem. Commun., 1995, 2037. 29 Yu,S., Huaxue Shiji, 16, 257 (1994); Chem. Abs., 122, 213188 (1995). 30 Chaka, A. M., Int. 1 Quantum Chem., 53, 617 (1995); Chem. Abs., 122, 159855 (1995). 31 Aschi, M., Attina, M., and Cacace, F., Angew. Chem., Int. Ed. Engl., 34, 1589 (1995). 32 Sartori, G., Bigi, F., Pastorio, A,, Porta, C., Arienti, A,, Maggi, R., Moretti, N., and Gnappi, G., Tetrahedron Lett., 36, 9177 (1995). 33 Yamaguchi, M., Hayashi, A,, and Hirama, M., 1 Am. Chem. Soc., 117, 1151 (1995). 34 Yamazaki, T., Saito, S., Ohwada, T., and Shudo, K., Tetrahedron Lett., 36, 5749 (1995). 35 Olah, G. A,, Rasul, G., York, C., and Prakash, G. K. S., 1 Am. Chem. Soc., 117, 11211 (1995). 36 Saito, S., Ohwada, T., and Shudo, K., . I Am. Chem. Soc., 117, 11081 (1995). 37 Nishii, Y. and Tanabe, Y., Tetrahedron Lett., 36, 8803 (1995). 38 Majetich, G., Liu, S., and Siesel, D., Tetrahedron Lett., 36, 4749 (1995). 39 Doyle, T. J., VanDerveer, D., and Haseltine, J., Tetrahedron Lett., 36, 6197 (1995). 40 Currie, K. S. and Tennant, G., 1 Chem. Soc., Chem. Commun., 1995, 2295. 41 Kowalski, P., Bull. Soc. Chim. Belg., 104, 97 (1995). 42 Tanaka, M., Fujiwara, M., and Ando, H., 1 Org. Chem., 60, 3846 (1995). 43 Kiselyov, A. S. and Harvey, R. G., Tetrahedron Lett, 36, 4005 (1995). 44 Hachiya, I., Moriwaki, M.. and Kobayashi, S., Tetrahedron Lett., 36, 409 (1995). 45 ' Wang, Q. L., Ma, Y., Ji, X., Yan, H., and Qiu, Q., J: Chem. Soc., Chem. Commun., 1995, 2307. 46 Sartori, G., Bigi, F., Tao, X., Porta, C., Maggi, R., Prdieri, G . , Lanfranchi, M., and Pellinghelli, M. A,, J: Org. Chem., 60, 6588 (1995). 47 Harrowven, D. C. and Dainty, R. F., Tetrahedron Lett., 36, 6739 (1995). 48 Ma, M. and Johnson, K. E., 1 Am. Chem. SOC.,117, 1508 (1995). 49 Borisov, Yu. A. and Kurbanbaev, R. M., lm Akad. Nauk, Ser Khim., 1993, 1878; Chem. A h . , 123,255954 (1995). 50 Cerfontain, H., Yousi, Z., and Bakker, B. H., Phosphorus Sulfur Silicon Relat. Elem., 92, 231 (1994); Chem. Abs., 122, 160028 (1995). 5 1 Lin, J. and Zou, Y., YingyongHuuxue, 12, 51 (1995); Chem. Abs., 122, 238972 (1995). 52 Min, H. and Lubing, Y., Liaoning Shfan Duxue Xuebao, Ziran Kexueban, 17, 131 (1994); Chem. Abs., 121,280090 (1994). 53 Meth-Cohn, 0. and Taylor, D. L., 1 Chem. Soc., Chem. Commun., 1995, 1463. 54 Borodkin, G. I., Podryvanov, V. A,, Shakirov, M. M., and Shubin, V G., 1 Chem. Soc.. Perkin Trans. 2, 1995, 1029. 11

CHAPTER 9

Carbocations ROBINA. Cox

Department of Chemistg University (f Toronto, Cunudu Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OpenSystems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Benzyl Cations and Related Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . Benzhydryl, Trityl, and Related Systems . . . . . . . . . . . . . . . . . . . . . . . . . Oxocarbenium and Related Ions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nitrenium Ions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Destabilized Carbocations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aromatic Cations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Arenium Ions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vinyl, Aryl, and Related Cations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CyclicSystems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bicyclic Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bridged Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

259 260 26 1 262 263 263 265 266 266 267 269 269 27 1 273 275

Introduction

A number of reviews of different aspects of carbocation chemistry have been published. George Olah in his Nobel lecture address has reviewed much of his career work on carbocations, particularly those stabilized by superacid media.’ A review on the reactivities of short-lived carbocations prepared by flash photolytic methods has appeared,’ and the stabilizing effects of silicon on carbocations are included in a general review of silicon in organic chemi~try.~ Tertiary carbenium ion stabilities and rates of formation are discussed in the light of an empirical MM2 force-field method for calculating steric or strain ener gie~Other .~ calculations reproduce experimental data such as heats of formation, bond dissociation energies, gas-phase acidities and proton affinities for a considerable number of molecular, radical, anionic, and cationic specie^.^ The thermodynamics of C-H bond breaking by proton transfer and hydride-ion transfer provide a useful criterion for carbocation and carbanion stabilities.6 The matrix isolation of unstable carbocations and their examination by IR spectroscopy has been summarized.’ Carbocation rearrangement mechanisms can be elucidated by making use of the ICAR computer program.8 A new method for making Organic Reaction Mechanisms 1995. Edited by A. C . Knipe and W. E. Watts 0 1997 John Wiley & Sons Ltd

259

260

Organic Reaction Mechanisms I995

carbocations in ambient-temperature molten salt media has been described.' The DielsAlder reactions of carbocations have been reviewed."

Open Systems Two calculational studies of CHf are reported.' ' , I 2 The hydrogen-bridged structure for the ethyl cation is calculated to be 6-8 kcal mol-' more stable than CH3CH;, and an unusually small JCHof 13 Hz is predicted for this ~pecies.'~ Protonated acetylene is also bridged, with three hydrogens permuting cyclically among the possible positions. l2 High-level calculations on R3Sif indicate that these cations interact more strongly with solvent than do the corresponding carbocations, in which the charge is hyperconjugatively and inductively delocalized.l4 At high levels of theory CH,SiH; is reported to be the only minimum on the SiCHf potential energy surface, although SiH3CHl is also a minimum at lower levels." Semiempirical and ab initio calculations on protonated allylic and diallylic alcohols indicate that the ally1 cation structure is considerably stabilized with respect to the protonated alcohol, and that reactivity differences in these alcohols may be related to protonation-dehydration energy differences in addition to structural differences. l 6 Rate constants observed for the reaction of n nucleophiles with carbocations are at least eight orders of magnitude greater than those calculated for a single-electron-transfer mechanism, meaning that the polar reaction in which charge transfer is associated with C-C a-bond formation is favoured. Trimethylsilylazide is an efficient carbenium ion scavenger in the gas phase, trapping the ions within s of formation by displacing Me3Sif; intermediate carbocation structures can be inferred from the resulting stable RN3.18 The gas-phase reaction of Me3C+ with 2,2-dimethylbutane is pressure dependent, and the pressure dependence of reaction efficiency is proposed as a criterion for the recognition of anchimeric assistance in hydride transfers. l 9 Me3C+ attacks the unlabelled ring of C6H5(CH2)2C6Ds 1.5 times faster than the labelled ring, but (C6H5CH2)2 and (C6D&H2)2 are both attacked at the same rate.2o However, Me3%+ reacts 1.5 times faster in both cases, and a collision complex is inferred to play a role in this process.20 In solution, the Me$+ cation is a proposed intermediate in the solvolysis of 2-methyl2-propanesulfonyl chloride, which cleaves to Me&+ and ClSO; in aqueous solution over a wide range of P H . ~ '

Some acyclic 1-hydroxy-, 1-amino-, and 3-hydroxy-pentadienyl cations have been characterized by low temperature NMR spectroscopy, and computationally; the 3hydroxy cations cyclize to 1-hydroxycyclopentenyl cations.22 Activated aziridines (1)

26 1

9 Curbocations

N3

++-a (4)

ring open in acidic alcohol media.23The resulting cations, (2) and the rearranged (3), may lose a proton to give allylamides, homoallylamides, or enamides, may be externally trapped to ethers, or, if of suitable structure, ring close to oxazolines and dihydr~xazines.~~ Amines (5) can be synthesized by an intermolecular Schmidt reaction, using aliphatic azides and carbocations (4) derived from benzylic or tertiary alcohols.24The cationic polymerization of several vinyl ethers has been the subject of a mechanistic in~estigation.~~

Benzyl Cations and Related Systems The barrier to carbocation-nucleophile combination reactions, primarily those involving benzyl cations, has been the subject of a comprehensive review.26It appears that resonance interactions are expressed to a smaller extent than polar interactions in the transition state for formation of the combination product, and that the opposite applies to its reaction.26

c 6 H

X

+

N3

X

I

fast

H&3

A

6 X

X

The ci-azido group stabilizes an adjacent carbocation centre by resonance,

Organic Reaction Mechanisms I995

262

(8) Z = o-Me, rn-Me, m-Bur, H

for instance in (6)." Benzaldehydes (7) are the only products; the p values show that the magnitude of electron donation by a-N3 and a-OMe to a benzyl carbocation centre is similar, much larger than for a-meth~l.~' Micelle-induced changes in reaction rate and solvation for two benzyl cations have been investigated; substitution with retention of configuration is enhanced and substitution with inversion is decreased in anionic miceiles.28 The most hindered benzyl cation yet observed as a stable species is (8), prepared by treating the parent alcohol with FS03H-S02C1F at -78 0C.29 Two crown ethers incorporating stable carbocations, (9) and (lo), have been ~repared.~'Benzyl group transfer in (E)-arylmethanediazoates and aryldiazomethanes in aqueous solution can take a benzyl cation or a benzyldiazonium ion route, qepending on the substituent in the aryl ring.3' The kinetics of the reactions between PhCHX (X = F3BO-, Cl,BO-, p MeOC6H4, MeO) and allylsilanes and alkenes have been studied.32 The reactivity varies strongly with the substituent X, but it is almost independent of the allylsilane or alkene. Benzhydryl, Trityl, and Related Systems

-

(11)

NCCPh2

NCCPh2

(12)

(13)

The 2-cyano-l , 1,2,2-tetraphenylethyI cation (1l), prepared from the corresponding chloride with AgSbF6 or SbFS in CH2CI2, is stable and long-lived below -55 0C.33 However, when prepared using AlC13 in benzene, it ring closes at above -78 "C to (12), leading to (13). The equ'valent cation with OMe instead of CN simply undergoes a 1,2-phenyl shift to Ph3C- APhOMe.33 Substituent effects in the reactions between benzhydryl cations and nucleophiles are mainly enthalpic in origin, AS: remaining constant as long as an enthalpic barrier remains.34 When the barrier is gone, hrther

9 Carbocations

263

decreases in the electron-donating ability of ring substituents cause an increase in reactivity due to an increase in A difision clock for determining carbocation reactivities has been used to obtain electrophilicity parameters for benzhydryl cations.35 Several highly stable azulenyl trityl cation species have been prepared as PF; salts, viz. (14),36 (15)," and (16) and its di- and mono-azulenyl mono- and di-phenyl

R = H, Me, C02Me

R', R2 = H, Me, C02Me, CMe3

analogues.37pKR+values in the 11-12 range are reported,37and the ring flips occumng in these species have been studied.36337 Some triarylcarbenium salts have been prepared from the corresponding alcohols by treating them with acid in bulky alcohol solvents.38

Oxocarbenium and Related Ions

0

The pinacol-type rearrangement of protonated ethers (17) provides a novel route to substituted cyclopentanones (18).39 The hydrolysis of three (2-deoxy-P-D-glucopyranosy1)pyridinium salts permitted the estimation of > 2.5 x lo-" s for the lifetime of the glucopyranosyloxocarbenium ion in aqueous s~lution.~' Appropriate sulfoxides can be transformed into sulfides, dithioacetals, and vinyl sulfides, by way of sulfurstabilized carbocations, by treating them with magnesium a m i d e ~ . ~ '

Nitrenium Ions Arylnitrenium ions (20) in the singlet state are generated when the precursors (19) are flash photolysed; these are trapped by the alcohol or water reaction solvent with rate constants in the 106-109 M p l sC1 range.42 The reaction rates of substituted + arylnitrenium ions (ArNY, Y = H, Me, Ac) do not correlate with the o+ values of the aryl substituents, unlike the corresponding dimethyl carbocations, which is taken to mean that in the nitrenium ions the positive charge is largely in the aryl ring rather than on the nitrogen.43

Organic Reaction Mechanisms 199.5

264

Nu-

NHAc

NHAc

I-H+

(Ar =

H

C6F5,

3-NO2Ph

OCOAr

t NHAc

VHAc

9 Carbocations

265

O-Aroyl-N-acetyl-N-(2,6-dimethylphenyl)hy~oxylamines give products of the Nacetylarylnitramine, but the mechanism is not clear; at least three cationic intermediates seem to be involved, some of them with exceedingly short lifetimes.44N-Acetyl-N-(4biphenyly1)- and N-acetyl-N-(2-fluorenyl)-nitreniumions can be selectively trapped at a diffusion-controlled rate by 2'-deoxyguanosine in aqueous solution.45 O-Aroyl-Nacetylhydroxylamine (21) gives a variety of meta- and para-substituted 2,6dimethylacetanilide products in aqueous acid as shown; however, none of them involve nitrenium ion precursor^.^^ Destabilized Carbocations

y' oNCMe3 Ph-C-C

Me

N-OMe

1

4

dl

\H

Ph-C-C

-c1-

H

Ph

Me

\+

f-F Ph

/--OMe

H

-

Me \

I

&CMq

Ph

1

t

Me

\

IN-oMe

Ph

(25)

t

The a-imino- and a-oximino carbocations (23) and (26) have been ~tudied.~' Chloride (22) solvolyses in methanol faster than does 1-chloro-1-phenylethane, and the resonance contributor (24) apparently makes a substantial contribution to the stability of the intermediate carbocation (23). Both (27) and (28) are important contributors to the stability of (26), derived fiom (25); this compound solvolyses in methanol faster than does 2-chlor0-2-phenylpropane.~~ Calculations show the stabilizing effects of agroups in carbocations of this type to be in the order CH=NOCH3 E CH=CH2 > CH=NHCH~> CH=S > CH=O = H > CN > ~ 0 ~ . 4 7 The effect of the cr-carbomethoxy group in (29) has been ~tudied.~' With a 4-methoxy group in the aryl ring the cation can be detected in water, but the p-tolyl and phenyl cations can only be detected in HFIP. Overall the solvolysis reactions are much slower

Organic Reaction Mechanisms 1995

266

than those of the a-unsubstituted benzyl cations.48A number of 7-(perfluoroalkyl)-7bicyclo[2.2. llheptyl derivatives have been prepared.49 The extent of delocalization in the cations resulting from their solvolysis was obtained by comparing the solvolysis rates of the a-H and a-(perfluoroalkyl) derivatives, the former being faster by factors ranging from 8 to ca lo4; the a-CF3 group slowed the reactions relative to the a-C2FS group by factors between 1.1 and 8.0.49 The products revealed a general trend of destabilization of both localized and delocalized carbocations by perfluoroalkyl groups.49 High-level calculations have been carried out on several a-thioformamidyl carbocations, and the circumstances under which the bridged and open forms are preferred have been delineated.50Highly reactive a-carbonyl cations are suggested as intermediates in the skeletal rearrangements observed during the N02BF4 nitrations of some a$-unsaturated ester^.^' Aromatic Cations CpIf-N-C-Ph I

1

3 mol MeOH

v

toluene

(Ar = C hF5)

The stable cyclopropenylium betaine (30) has been the subject of an X-ray crystal structure d e t er m i n ati ~n.~~ Detropylation of N-tropylacetamide in acid apparently involves an N-protonated amide or other high-energy intermediate; the process is general-acid-catalysed and the products are tropylium cation and a ~ e t a m i d eRate . ~ ~ and equilibrium constants for the detropylation of N,N-dimethyltropylamine have been determined in aqueous HC1 and various buffer media.53Some electrophilic reactions of the dibenzo[a,&ropylium ion have been studied, and an electrophilicity parameter for it e~tab l i s h ed The .~~ crown ether (10) with a pKR+of ca 3.8 is rep~rted.~'

Arenium Ions Two possibilities have been suggested for protonated benzene, the edge-protonated ccomplex Wheland intermediate structure (3 1) and the face-protonated x-complex structure (32). Calculations suggest that (31) is the more stable of the and it

9 Curbocations

267

appears to have that structure in solution,56but experimental evidence that (32) is the more stable structure in the gas phase has been ~btained.'~ A theoretical study of the C 12H17+ energy surface in the 2,3-dimethyl-3-phenyl-2-butyl cation region suggests that this cation is not likely to be a reaction intermediate; the most favoured isomer is (33), but the phenonium ion (34) is only 0.29 kcal mol-' above it in energy.57The Cram phenonium ion (37) is observed when (35) is protonated, the presumed intermediate (36) not being ~ b s e r v a b l e .Carehl ~~ study showed that (37) has the structure shown and that it is not non-classical; neither is (38), which was also observed.58 Treatment of trialkylsilanes with Ph&+(C6F5)4B- in the presence of benzene derivatives only gives silylated Wheland intermediates and not long-lived trisubstituted silicenium cations, according to a comparison of experimental and ub initiolIGL0 29Si NMR re~ults.'~ The persistent arenium ions formed when various benzopyrenes are protonated in superacid have been studied.60 Vinyl, Aryl, and Related Cations Calculations on the allene dication H&C=&I give singlet electronic-state energief in agreement with measured values.61The C2H21+potential-energy surface has H2C=C-I as a global minimum, although the symmetrical iodine-bridged species is very close to it in energy, according to an ab initio study.62 Photolysis of benzenediazonium salts at low temperature can give either triplet or singlet aryl cations, depending on the ring substituent, although most of the observed reaction products are singlet-deri~ed.~~ The arylium ions XC6H4+ (X =NO2, CN, C1,

Organic Reaction Mechanisms 199.5

268

Br, OH, OMe), formed from multi-tritiated XC6H5 by tritium decay, react with methanol in the liquid phase and with methanol and methyl halides in the gas phase to give the unrearranged 40% ortho, 40% meta and 20% para ratio of products.64 The observed reactivity is compared with calculated values.64

(40)

R=Me,H

(44)

(43)

(42)

(45)

(X = Br, I, OTf)

The phenyl iodide group in (39) is a 106-fold better leaving group than is triflate ion.65 The solvolysis reactions of the resulting vinyl cation have been studied and evidence for internal return from an intimate ion-molecule pair was obtained.65The /?silyl group effect in vinyl cations such as (40) and (41) has been evaluated in terms of hyperconjugative stabilization and geometrical distortion by an experimental and computational comparison with suitable vinyl cations without silicon.66 lt has been found that the selectivities of the less stable carbocations (42) and (43), and the two vinyl cations (44) and (45), towards the nucleophiles Mg12 and MgBrz in aprotic solvents are all nearly the same, although the reaction rates differ by more than three orders of magnitude; a theoretical explanation in terms of the constant selectivity principle is offered.67 OEt

I

=C -C -0Et I H (Z = S, Se)

PhZ-C

BF3-Et20

PhZ-C

+/ OEt

-C -C,

(46)

R -C 3 C -N2+X-

H (47)

The prop-2-ynyl cations (46) do not rearrange to allenyl cations when treated with mild nucleophiles, simply giving direct substitution products.68Bis-silylated ynamines do not give the ethynyl cation precursors (47) when treated with nitrosating agents; the

9 Carbocations

269

only products are those of attack at the P - ~ a r b o n .The ~ ~ hydrolysis of N(benzenesulfony1)-C-(N-methylani1ino)imidoyl chlorides in 50% aqueous methanol has been the subject of+ an extensive kinetic study; the reaction involves the azocarbocation PhSOzN=CNMePh below pH 9.70 Cyclic Systems

The cycloaddition reactions of the cyclopropylcarbinyl cation (48), for instance to give (49) with ethylene and to give a cyclooctenyl cation with buta-1,3-diene, have been characterized the~retically.~~ A high-level MO study of the cyclization of (50) to (51) is reported.72 The AJ equation has been applied to the 13C-lH coupling constants observed for the dicyclopropylcarbinyl cations (52)-(55) in superacids; the positive charge was found to be delocalized into both cyclopropyl rings.73 Theoretical calculations relevant to the molecular rearrangements of (-)-a-cedrene observed in superacids are reported.74 Bicyclic Systems The bridgehead bicyclo[ 1.l.l]pent-1-yl cation (57) is an intermediate, or perhaps a transition state, in the reactions of (56); the products are (58) and (59).75The rearranged cation (60) is implicated as a reaction intermediate but (61) is not. The cations (62) and (63) were also studied; changing the aryl group substituents in (63) led to a Hammett p

270

Organic Reaction Mechanisms 1995

value of - 1.7.75 A series of 5-substituted bicyclo[3.1. llheptyl bromides has been solvolysed in alcohol solvents.76 Direct replacement of the bromine by an alkoxy group, presumably via the bridgehead carbocation, accounts for about one third of the product for the H and CHzCl substituents, and nearly two thirds when the substituent is CO;Na+; however, little or none was found for 11 other sub~tituents.~~

9 Carbocations

27 1

Bromination of (64) and its endo isomer involves cations such as (65) and (66), both of which are classical.77Semiempirical calculations on proton addition to these systems show a thermodynamic preference for the formation of (67) from both isomers, and enable detailed stereochemical predictions to be made.78 Unsymmetrical phenyl bridging favours (68) over (69) for the cation derived from 2-t-cumyl-2-adamantanol and 2-isopropenyl-2-phenyladamantanein magic acid solution, according to experimental and theoretical results.79 The stereoselectivity of secondary adamantyl carbocations attributed to a-participation is effectively suppressed by charge-stabilizing methyl or phenyl groups at C(2) in the tertiary cations (70), which are classical.80

Bridged Systems The recently obtained X-ray crystal structures of several carbocation species stabilized by bridging or by hyperconjugation have been the subject of a review." The accuracy of ab initio geometries at several theoretical levels has been obtained by comparison with these crystal structures, and by comparing theoretical and experimental NMR chemical shifts and vibrational frequencies; agreement is fairly good now, and improving.82

KCH20H SbFs

SiMe3

S02CIF-SO2F2 -130 "C

*

The 1-(trimethylsilyl)bicyclobutonium ion (71) has been the subject of an experimental and theoretical study.83The results are consistent with a set of degenerate, interconverting bicyclobutonium cation structures, with no ring inversion occurring and no evidence of any contribution from cyclopropylmethyl structures.83The homocubyl triflate (72) is pressure-sensitive; at 10 000 atm pressure the deuterium label becomes totally scrambled, presumably via structures like (73).84 Cation (74) with a

272

Organic Reaction Mechanisms 1995

pentacoordinated carbon atom is ‘remarkably stabilized compared to its parent compound,’ according to calculations, representing a ‘missing link’ between the bicyclo[3.2.O]hept-3-yl and 7-norbornyl cations.85

Several studies relevant to norbomyl cation chemistry are reported. A combined ab initio-Monte Carlo study showed that the classical norbomyl cation structure is not significantly more stabilized than is the non-classical structure in water, the nonclassical structure being the only stable form both in the gas phase and in solution.86 Cyclopropyl participation is apparent in the bridged norpinyl cation (76), formed from (75); some direct solvolysis product (77) is found, but rearrangement to (79), presumably via (78), predominate^.'^ Cation (79) can also be formed from (80) directly; the solvolysis product is (81) in endo and ex0 isomers, primarily ~ x o . ’However, ~ the unsubstituted norpinyl cation (82) is 16 kcal mol-’ less stable than is the norbornyl cation (83), which is responsible for most of the observed products, and it is formed much more slowly than is (84) under the same conditions.88This norpinyl-norbomyl rearrangement has also been studied by product analysis,” and the effect of the presence of the destabilizing substituents CN and CF2CF3 in the substrate on the

9 Curbocutions

273

reaction and its products has been examined.89Nitroxylation of (85) gives a product mixture from which the presence of (86) is inferred."

Dicatioas An X-ray crystal structure of the ditriiodide salt of (87) is reported; the central bond has a 53" twist, in agreement with PM3 calculation^.^^ The crystal structure of [5.5]bis(cyclopropenylium)ophane (88) is also reported.92 Dications such as (90), formed from (89) and similar compounds in superacid, may consist of two antiaromatic

Organic Reaction Mechanisms 1995

274

cations linked by a single bond, cross-hyperconjugation being a factor in their ~tability.’~

-

Ph& hP: Ph

S02CIF FS03H

OH

~Ph,=.~~

-78 OC

OH

Ph

2’

Ph

0

II

+C

I

R

(92)

(93)

No evidence was found for ‘Y-aromatic’ stabilization in the (hexaphenyltrimethylene)methane dication (91), which is stable to -20 0C.94The entire n-system is twisted, and all six phenyls must be present or intramolecular allylation to indenyl cations occurs. The analogue (91; Ph =p-CF3C6H4) was also observed, but this is only stable at -90 0C.94Dications (92) are stable in superacid at -80 “C when R = Ph or Me, but not when R = cy ~l o p r opyl .~~ The diacylium species (93) has also been obser~ed.’~

-

MeS + FC-N-OH MeS (95)

MeSFN02 MeS

(94)

MeS

N-OH

5 MeS+< MeZ

X

(96)

ZMe Z = S, 0;X = MeS, F, Ar

MeZ

M ~ S N

‘0

,KO-

(97)

HF-SbFS

Me=Me

Me

9 Carbocations

275

Dication (95) is formed when (94) is treated with CF3S03H or HF-SbF5 at 0 "C or below, as determined by NMR spectroscopy; treatment with nucleophiles can give either (96) or (97).96Diprotonation of a$-enones such as (98) in superacid leads to dications such as (99); the methyl derivative shown is reported to undergo rearrangement and intramolecular cyclization to

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276 4L 42 43 44

45 46

47 48

49 50

52 53

54

55 56

57

58 59

6o

61

62

63 b4 65

66 67

68 69

70 7’

72

73 74 75

76

77 78 79

8o

8’ 82

83 84 85

86 87 88

Organic Reaction Mechanisms 1995

Kobayashi, K., Kawakita, M., Kouichi, Y., Mannami, T., Yamamoto, K., Morikawa, O., and Konishi, H., Bull. Chem. SOC.Jpn, 68, 1401 (1995). Robbins, R. J., Yang, L. L.-N., Anderson, G. B., and Falvey, D. E., 1 Am. Chem. SOC.,117, 6544 (1995). Novak, M., Kahley, M. J., Lin, J., Kennedy, S. A,, and Swanegan, L. A., 1 Am. Chem. SOC.,116, 1 1626 (1 994). Fishbein, J. C. and McClelland, R. A,, 1 Chem. SOC.,Perkin Trans. 2, 1995, 663. Novak, M. and Kennedy, S. A,, 1 Am. Chem. SOC.,117, 564 (1995). Fishbein, J. C. and McClelland, R. A,, 1 Chem. SOC.,Perkin Trans. 2, 1995, 653. Creary, X., Wang, Y.-X., and Jiang, Z., 1 Am. Chem. Soc., 117, 3044 (1995). Schepp, N. P. and Wirz, J., 1 Am. Chem. Soc., 116, 11749 (1994). Nelson, D. W., O’Reilly, N. J., Speier, J., and Gassman, P. G., 1 Org. Chem., 59, 8157 (1994). Bertone, M., VuckoviC, D. L. J., Cunje, A,, Rodriquez, C. F., Lee-Ruff, E., and Hopkinson, A. C., Can. 1 Chem., 73, 1468 (1995). Hewlins, S. A,, Murphy, J. A,, and Lin, J., Tetrahedron Lett., 36, 3039 (1995). Erker, G., Ahlers, W., and Frohlich, R., 1 Am. Chem. SOC., 117, 5853 (1995). Palou, J., Robinson, P. M., and Wan, C. I. F., 1 Chem. SOC., Perkin Trans. 2, 1995, 1999. Henninger, J., Mayr, H., Patz, M., and Stanescu, M. D., Liebigs Ann. Chem., 1995, 2005. Glukhovtsev, M. N., Pross, A,, Nicolaides, A,, and Radom, L., 1 Chem. SOC.,Chem. Commun., 1995, 2347. Mason, R. S., Williams, C. M., and Anderson, P. D. J., 1 Chem. SOC.,Chem. Commun., 1995, 1027. Stoelting, D. T. and Fry, J. L., 1 Ox.Chem., 60, 2835 (1995). Olah, G. A,, Head, N. J., Rasul, G., and Surya Prakash, G. K., 1 Am. Chem. Soc., 117, 875 (1 995). Olah, G. A., Rasul, G., Buchholz, H. A., Li, X.-Y., and Surya Prakash, G. K., Bull. SOC.Chim. Fr., 132, 569 (1995). Laali, K. K., Hansen, P. E., Houser, J. J., and Zander, M., 1 Chem. Soc., Perkin Trans. 2, 1995, 1781. Andrews, S. R., Parry, D. E., and Harris, F. M., J. Chem. Soc., Faraday Trans., 21, 1 181 (1 995). Campos, I? J. and Rodriguez, M. A., 1 Chem. Soc., Chem. Commun., 1995, 143. Gasper, S. M., Devadoss, C., and Schuster, G. B., 1 Am. Chem. Soc., 117, 5206 (1995). Filippi, A,, Lilla, G., Occhiucci, G., Sparapani, C., Ursini, O., and Speranza, M., 1 Org. Chem., 60, 1250 (1995). Okuyama, T., Takino, T., Sueda, T., and Ochiai, M., 1 Am. Chem. SOC.,117, 3360 (1995). Siehl, H.-U., Pure Appl. Chem., 67, 769 (1995). Garcia Martinez, A,, Alvarez Martinez, R., Teso War, E., Garcia Fraile, A,, Osio Barcina, J., and Subramanian, L. R., Tetrahedron, 51, 7077 (1995). Yoshimatsu, M., Shimizu, H., and Kataoka, T., 1 Chem. Soc.. Chem. Commun., 1995, 149. Martinez Alvarez, R., Hanack, M., Schmid, T., and Subramanian, L. R., 1 Phys. Org. Chem., 8, 191 (1995). Kwon, K.-S. and Song, Y.-Y., 1 Korean Chem. Soc., 39, 650 (1995); Chem. Abs., 123, 255923 (1995). Cramer, C. J. and Barrows, S. E., 1 Org. Chem., 59, 7591 (1994). Mann, M. and Fabian, J., 1 Phys. Org. Chem., 8, 536 (1995). Kelly, D. P., Banwell, M. G., Ryan, J. H., Phyland, J. R., and Quick, J. R., 1 0%.Chem., 60, 165 1, 5364 (1995). Polovinka, M. P., Korchagina, D. V, Shcherbukhin, V V, Gatilov, Y. V, Rybalova, T. V, Zefirov, N. S., and Barkhash, V A,, Tetrahedron Lett., 36, 8093 (1995). Wiberg, K. B. and McMurdie, N., 1 Am. Chem. SOC., 116, 11990 (1994). Della, E. W. and Elsey, G. M., Aust. 1 Chem., 48, 967 (1995). Bumtt, A,, Coxon, J. M., Steel, P. J., and Whittington, B. I., 1 Org. Chem., 60, 2812 (1995). Bumtt, A,, Coxon, J. M., and Maclagan, R. G. A. R., Tetrahedron, 51, 11557 (1995). Stoelting, D. T., Forsyth, D. A,, and Fry, J. L., J Org. Chem., 60, 2841 (1995). Henmann, R. and Kirmse, W., Liebigs Ann. Chem., 1995, 699. Laube, T., Acc. Chem. Rex, 28, 399 (1995). Schleyer, P. v. R. and Maerker, C., Pure Appl. Chem., 67, 755 (1995). Siehl, H.-U., Fuss, M., and Gauss, J., 1 Am. Chem. SOC.,117, 5983 (1995). Spitz, U. P. and Eaton, I? E., Angew Chem., Int. Ed. Engl., 34, 2030 (1995). Szabo, K. J. and Cremer, D., 1 Org. Chem., 60, 2257 (1995). Schreiner, P. R., Severance, D. L., Jorgensen, W. L., Schleyer, P. v. R., and Schaefer, H. F., 1 Am. Chem. SOC., 117, 2663 (1995). Henmann, R. and Kirmse, W., Liebigs Ann. Chem., 1995, 703. Bentley, T. W., Norman, S. J., Kemmer, R., and Christl, M., Liebigs Ann. Chem., 1995, 599.

9 Cavbocations 89

90 91

92

93 94

95 y6

97

277

Fendel, W., Kautz, C. B., Kirmse, W., Klar, M., Siegfried, R., and Wonner, A., Liebigs Ann. Chem., 1995, 1735. Krasutsky, F’. A,, Likhotvorik, I. R., Dubinina, T. V, Nesterenko, V V, and Jones, M., Tetrahedron Lett., 36,3079 (1995). Bock, H., Nather, C., and Havlas, Z., 1 Chem. Soc., Chem. Commun., 1995, 1111. Gleiter, R., Merger, M., Oeser, T., and Imgartinger, H., Tetrahedron Lett., 36,6425 (1995). Malandra, J. L., Mills, N. S., Kadlecek, D. E., and Lowery, J. A., J: Am. Chem. SOC., 116,11622 (1994). Head, N. J., Olah, G. A,, and Surya Prakash, G . K., 1 Am. Chem. Soc., 117, 11205 (1995). Heagy, M. D., Wang, Q., Olah, G. A,, and Swya Prakash, G. K., 1 Org. Chem., 60,7351 (1995). Coustard, J.-M., Tetrahedron, 51, 10929 (1995). Koltunov, K. Y. and Repinskaya, I. B., Zh. 0%.Khim., 30, 90 (1994); Chem. Abs., 122, 30783 (1995).

CHAPTER 10

Nucleophilic Aliphatic Substitution J. SHORTER School of Chemistry, University of Hull, Hull HU6 7RX Vinylic Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Allylic Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Polycyclic Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epoxide Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Small Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Substitution at Elements Other than Carbon. . . . . . . . . . . . . . . . . . . . . . . Intramolecular Substitution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anchimeric Assistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ambident Nucleophiles and Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . Isotope Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gas-phase Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radical Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medium Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phase-transfer Catalysis and Other Intermolecular Effects . . . . . . . . . . . . . . Structural Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hammett Equation and Other LFERs . . . . . . . . . . . . . . . . . . . . . . . . . . . Nucleophilicity and Leaving-group Effects . . . . . . . . . . . . . . . . . . . . . . . . Kinetic Studies (Miscellaneous) . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

280 280 281 282 286 287 289 290 290 29 1 291 293 294 296 297 297 297 298 298 298

Vinylic systems Rappoport’s work has continued.I4 Rate constants of elementary steps in the additionelimination mechanism of nucleophilic vinylic substitutions (SNV) have been determined for the reactions of a-nitro-p-X-stilbenes (1) and (2) (X = OCH2CF3, OMe, or NO2) with various nucleophiles in 50% v/v DMSO-H20.’ When X = OCH2CF3 and the nucleophile is HOCH2CH2S-, the reaction intermediate accumulates to detectable levels, and when X =OMe and the nucleophile is CF3CH20-, the intermediate actually constitutes the ‘product,’ since the loss of MeO- is too slow to be observed. Interesting structure-reactivity relationships were observed with the various leaving groups and nucleophiles. The reactions of P-methoxy-a-nitrostilbene with methoxyamine and with Nmethylmethoxyamine are the first examples of SNVsubstitutions by amine nucleophiles in which the anionic intermediate (formed by deprotonation of the zwitterionic intermediate) accumulates to detectable levels.2 The above nucleophiles show the Organic Reaction Mechanisms 1995. Edited by A. C. Knipe and W. E. Watts 0 1997 John Wiley & Sons Ltd

279

Organic Reaction Mechanisms 1995

280

enhanced reactivity expected for a-effect nucleophiles. A series of stilbene halides bearing one electron-withdrawing substituent on the double bond has been studied in an attempt to encourage vinylic substrates to undertake an SRNl-likeroute of nucleophilic substitution, a process that requires acquisition of one ele~ tron.The ~ attempt was not particularly successful and it was concluded that competition by other routes hampers the occurrence of the SRNlprocess. Ph

NO2

c, =c\

\

/

X

Ph

Ph

/C =c \ X NO2 \

Ph

I

(2)

(1)

Z

E

(3)

Label incorporation and Z -+ E isomerization in the reaction of 3-azidomethylenedihydro-(3H)-furan-2-one (3) with NaI5NNz in 1 : 1 acetone-H20 have been measured as a probe for internal clockwise versus anticlockwise rotation in the intermediate ~arban i o n .~ The energies of the lowest vacant orbitals of a series of model vinylic systems with substituents differing in electron-withdrawing power have been computed at the 321G*//3-21G*, 6-31G*N3-21Gt, or 6-31 IG*l/3-21G* level^.^ When the first vacant orbitals with cr and n symmetry at the carbon centres are separated by > 0.01 hartree, an almost complete correspondence is found between the symmetry of the lowest orbital and the stereochemical outcome of nucleophilic substitution on the corresponding real substrates. Allylic Systems

Chiral p-phosphinocarboxylic acids, e.g. (4), available by conjugate addition of lithium diarylphosphides to chiral cr,fl-unsaturated carboxylic esters, form chelate complexes with Pd.6 These will catalyse allylic substitutions of cyclic substrates, giving up to 99% enantiomeric excess, the S configuration being preferred, e.g. (5). Substitution reactions of ally1 alcohol derivatives with diethylamine, phenol or dimethyl malonate are efficiently catalysed by Ni(dppb)2 (dppb = 1,2-diphenylphosphinobutane), ammonium salts, or bases being added as promoters or ~o-reagents.~ Nucleophilic substitution, in the gas phase, on 0-protonated but-1-en-3-01 and transbut-2-en-] -01 by methanol, proceeds via a concerted sN2' mechanism in competition with the SN2mechanism' (&2' = allylic substitution with rearrangement).

I0 Nucleophilic Aliphatic Substitution

28 I C02R

* f y c o * R n-4

S

n = 5 , 6 or 7 X = OAc or C1

(4)

R = Me or Bur (5)

Ab initio MO calculations have been carried out for the non-identity ally1 transfer processes X-

+ C H ~ = C H C H ~ Y ~ C H ~ = C H C H+ ZY-X

where X = H, F, or C1 and Y = H, NH2, OH, F, PH2, SH, or Cl.9 The Marcus equation applies well. 'The transition state (TS) position along the reaction coordinate and the TS structure are strongly influenced by the thermodynamic driving force, whereas the TS looseness is originated from the intrinsic barrier.'

Miscellaneous Polycyclic Systems Sulfonate esters (triflates, mesylates, or tosylates) of a series of compounds related to 7perfluoroalkyibicyclo[2.2.l]heptan-7-ol(6t(12) have been solvolysed in various solvents to examine the competition between destabilization of the carbocationic intermediates by perfluoroalkyl groups and stabilization by neighbouring-group participation." The former effect was measured by comparing the rates of solvolysis of the 7-H and 7-RF compounds: the k7-Hlk7-RF ratios range from 8 to about lo4, depending on the extent to which anchimeric assistance can compensate for the inductive destabilization by RF.The CzF5group exerts a slightly smaller retarding effect than CF3; k7 - c,F, lk7 - CF, varied between 1.1 and 8.0. For the Ag(1)-catalysed methanolysis of the N-chloro derivatives of 7-azabenzonorbornadienes, the relative ability of substituted aryl rings to participate in selective reaction of the anti-invertomers (13) has been estimated qualitatively.' Rates of solvolysis in 80% EtOH-H20 have been measured for a series of 5substituted bicyclo[3.1.l]heptyl bromides (14).12 The substituent X acts mainly in accordance with its g I value, but the parent and the 5-OMe derivative deviate from the appropriate plot. The enhanced rate for the former is attributed to nucleophilic solvent assistance, while the deviation of 5-OMe is attributed to anchimeric assistance. Rates of solvolysis in various solvents have been determined for l-chlorospiro[adamantane-2,2'-adamantane] (otherwise 1-chloro[ lldiadamantane) (1S).l3 This substrate is about lo8 times more reactive than 1-chloroadamantane, and the solvolysis rate, even at 0 "C, can only be measured in solvents less ionizing than 80% EtOH-H20. The high reactivity is attributed mainly to F-strain arising from steric interactions between the Cl- leaving group and the closest CH2 hydrogen atoms. MM2 calculations support this idea. Nucleophilic attack on the aminoaziridinium cation (17) [derived from the sesquidiazabicyclooctane dication (16)] by PhS-, NC-, MeCO;, or F- results in

'

282

x x

Organic Reaction Mechanisms 1995

C-N+ bond cleavage with inversion at carbon.l4 For attack by MeCO; or F only the axially substituted derivatives (18) are produced, but with PhS- and NC-, 40% and 15%, respectively, of the em-substituted derivatives (19) are initially formed. ~

Epoxide Reactions

A long series of papers on the regiochemical control of the ring opening of 1,2epoxides by means of chelation involving metal ions has been extended to oxirane systems derived from cyclopentene, bearing a polar substituent, CHzOBn or C02Me, in a homoaliylic relationship to the oxirane ring.I5 As found previously for other systems, chelate bidentate species participate in the ring-opening process under appropriate conditions. In a further paper the work is extended to mono- and di-functionahzed

283

10 Nucleophilic Aliphatic Substitution

aliphatic systems, bearing the heterohnctionality OR in a homoallylic and/or allylic relationship to the oxirane ring. l6 A chemoselective reaction of amidines or guanidines (21) with a-cyan0 epoxides (20) leads to 4-amino-5-carbethoxy-, 4-hydroxy-5-cyano-, or 4-carbethoxy-5-awl-imidazoles." Depending on the steric hindrance of the epoxides, the nucleophile reacts on either the nitrile or the ester group. The reaction medium is also important in governing the chemoselectivity. In contrast to the solvolyses of cyclic allylic epoxides, the acid-catalysed solvolysis of optically pure 1,2-epoxybut-3-enein water or an alcohol as solvent shows a high degree of inversion of configuration.l 8 Titanium and zirconium complexes of bis(pico1inic) amides catalyse the ring opening of cyclohexene oxide by trimethylsilyl azide.'' The product, 1-azido-2-trimethylsilyloxycyclohexane,was obtained with up to 7 1YO enantioselectivity when a catalyst prepared from (S,S)-N,N'-bis(2-pyridinecarboxamide)- 1,2-diphenylethane and zirconium tetra-t-butoxide was used. NH2

R3-N=C

/

\

R4

(21)

a; R3 = R4= Ph b; R' = Ph, R4 = NHPh

284

Organic Reaction Mechanisms 1995

The reactions of oxiranes with carbon disulfide can lead to various products.’’ When alkali metal halides are used as catalysts, high yields of 1,3-0xathiolane-2-thiones(22) are obtained at room temperature. Lithium bromide is the best catalyst and THF is the best solvent for high selectivity. Ab initio MO calculations (MP2/6-3 1 G**//MP2/63 1 G*)have been carried out for the gas-phase reactions of methyloxirane with HOand of methylthiirane with HO- and HS-.21 With HO- as nucleophile, elimination is slightly favoured over addition, but with HS- addition is easily preferred.

+

+

S

An experimental and theoretical (molecular mechanics and semiempirical MO) study of the methanolysis of dicyclopentadiene diepoxide (23) has been presented.22 With NaOMe, chemo-, regio-, and stereo-selective opening of the epoxycyclopentane fragment occurs, but in the acid-catalysed reaction both epoxy groups are attacked. The selectivities of the reactions of 0,O’-dialkyldithiophosphoricacids with epichlorohydrin (24) have been studied.23 Under the alkaline conditions used, epichlorohydrin is converted into the corresponding thiirane and the ultimate reactions are nucleophilic displacements of C1- by thiophosphate anions. Detailed kinetic studies have been made of the catalysis of the reaction of 0-cresol with epichlorohydrin by quaternary ammonium and phosphonium salts containing various alkyl groups and anions.24 The kinetics and mechanism of esterifications of acetic acid by oxirane or epichlorohydrin have been in~e st iga te d.~~ The reactions are base-catalysed by acetates of alkali metal, quaternary ammonium, or Cr(II1). Regio- and stereo-selectivity have been studied for the ring opening of hryl- and thienyl-glycidates (25) with benzylamine or trimethylsilyl For (25a), attack on C(2) is overwhelmingly predominant, with the former reagent favouring anti and the latter syn ring opening. These and other results are rationalized through AM1 calculations. The presence of a trans-acetonide group in 1,2 : 5,6-dianhydro-3,4-0-isopropylideneD/L-hexitol has been found to exert a dramatic influence on the selectivity of the reaction of the substrate with b e n ~ y l a m i n e The . ~ ~ opening of the two epoxide rings leads exclusively to a 7-endo-tet-type cyclization process, achieving the synthesis of 3,4,5,6-tetrahydroxyazepanein good yield.

10 Nucleophilic Aliphatic Substitution

285

(25)

-

2-fury1 b R = 2-glycidyl

a; R

The stereospecific acetolysis of threo- and elythro-2-aryl-2-[1-(methylthio)ethyl]oxiranes has been studied.’* It is suggested that the various products are generated from thiiranium ionic intermediates, because they all completely retain the configuration of the initial oxiranes. Several series of fluorinated epoxy ethers (26) have been found to react with Lewis acids to give different ring-opening products, depending upon the structure and the experimental condition^.'^ Both nucleophile-assisted and stepwise processes can occur. In all cases, except when a phenyl group stabilizes the Cp secondary carbenium ion [i.e. R = P h in (26)], the C,-0 bond is broken, leading to addition, transposition, or cyclization products. A kinetic study has been carried out of the ring opening of phenyl glycidyl ether by 4-dodecylbenzenesulfonicacid.30The reaction is inhibited by water. Ring-opening reactions of optically pure 2-aryl-3,3-dimethyloxetaneshave been studied in strongly protic or Lewis acidic condition^.^^ For hydrolysis or alcoholysis catalysed by sulfuric acid, ring opening occurred at the benzylic position and partial inversion of configuration was observed. In other reactions studied, attack occurred at the least-hindered carbon and the configuration of the asymmetric centre was unaffected. The SN2reactivity and product distribution were determined for the reactions of six dioxetanes (27) with m ~ r p h o l i n eThe . ~ ~ overall reactivity and product distribution are strongly dependent on the nature of X and Y. Thus, reactivity is enhanced by electronattracting substituents X (e.g. Cl) and the product is almost entirely the adduct (28). Reactivity is also increased by electron-attracting substituents Y (i.e. NOz), but diminished by electron-releasing substituents Y (i.e. OMe). The effects of such substituents on product distribution are to increase and to decrease, respectively, the proportion of fragmentation product (29).

Organic Reaction Mechanisms 1995

286 Other Small Rings

A long series of papers on regiochemical control of the ring opening of epoxides by means of chelation involving metal ions has been extended to cis- and trans-aziridines (30) and (31) derived from 4-(benzyloxy)~yclohexene.~~ The regioselectivity for the trans substrates was largely in favour of C(l) product, but that for the cis substrates varied with reaction conditions. Certain cis substrates changed from almost complete C(1) selectivity under some conditions to almost complete C(2) selectivity in the presence of metal ions. The role of chelate bidentate intermediate structures involving metal (or sometimes proton) was postulated. The regio- and stereo-selectivity of the ring-opening reactions of the 3-arylsubstituted aziridines (32) and (33) have been studied.34 The regiochemical outcome appears to be determined by a balance of electronic activation at C(3) by Ph and the chelating effects of the C( 1) oxygen functionality, which can direct nucleophiles intramolecularly to C(2) or C(3).

6

6

x

2,

2X

'

\" '

(31) trans

X = NH, NCOZEt, or NTs

Ts

Ts

I

I

Ph

I

(32)

(32)

R =H or Bn

2 R'

I

R'

I

Phu PhN=C=S N

NaI

+

(34)

,c=s

Ph

I

Ph

R' = SO*Ph, S02C6H4Me-4, or S02C6H4CI-4

Substituted N-(arylsulfony1)aziridines have been found to give a cycloaddition reaction with aryl or alkyl isothiocyanates in the presence of sodium iodide as catalyst,

10 Nucleophilic Aliphatic Substitution

287

e.g. reaction (34).35In the case of reaction (34), it is suggested that the catalysis involves ring opening by attack of I- at the C to which Ph is attached. The reactions involving alkyl isothiocyanates seem to have a different mechanism. The same research group has studied the reactions of N-arylsulfonylaziridines with dimethylsulfoniumethoxycarbonyl methylide, -CH(CO,Et)SMe,f, to give 1-arylsulfonyl-2-ethoxycarbon y l ~ e t i d i n e sThe . ~ ~ reactions are both regio- and stereo-selective. Aziridines containing an allylsilane moiety at the end of a polymethylene chain, (CH,), or (CH2)4, may undergo Lewis acid-catalysed cyclization to form cyclopentane and cyclohexane derivatives, respectively, e.g. (35H37).37In the cyclopentane case the cis isomer (36) predominates, but in the corresponding reaction leading to cyclohexane derivatives, the trans isomer is formed primarily. Possible transition states were discussed, but no explanation of the above difference in stereoselectivity was achieved. SiMe3

/

(35)

(36) cis

(37) trans

The reactivity of 2,3-aziridino-2,3-dideoxy-~-lyxono-y-lactone derivatives (rigid analogues of aziridine-2-carboxylic esters) towards soft nucleophiles and hard nucleophiles has been studied.38 The main matters of interest are the control of lactone versus aziridine ring opening and C(2) versus C(3) regioselectivity. Soft nucleophiles gave products of aziridine ring opening, whereas hard nucleophiles gave products arising from initial attack of the lactone ring. The stereochemical outcome and diastereoselectivity of the reactions of racemic lithiated methyl phenyl sulfoxide with two equivalents of racemic oxaziridines have been determined.39A possible transition state was suggested. The intervention of an aziridinium ion intermediate has been suggested in connection with the following reactions: the hydrolysis of chlorambucil (a nitrogen mustard) and chlorambucil-spermidine conjugate in aqueous buffer solutions:' and the decomposition of N-phosphorylated nitrogen mustards4' (see also related work by the same group4'). The reactions of 1,2,3-triarylbenzo[b]thiopheniumsalts (38) with alkoxide anions leads to the exclusive formation of (a-alkoxy-substituted alkenes (39).43This indicates that the nucleophilic ring opening proceeds with complete retention of configuration.

Substitution at Elements Other than Carbon This section is entirely concerned this year with substitution at silicon. The work of Eaborn and his colleagues has continued.44345In the reactions of (Me3Si)3C[Si(CD&I] with silver salts AgY in non-hydroxylic solvents, unrearranged

288

Organic Reaction Mechanisms 1995

NaOR(2eq.) ROH

,c=c

(38)

'ArI

Ar2

Ar', Ar2 = Ph or anisyl X = Br or C1O4 R = Me, Et, Pr' or Me3CCH2

OR

(39)

products (Me3Si)3C[Si(CD3)2Y]usually predominate over the rearranged products (Me3Si)2C[Si(CD3)2Me](SiMe2Y), revealing the inadequacy of the simplest mechanistic picture in which a methyl-bridged cationic intermediate (40) has two bridged silicon centres that are equally available for attachment of a n ~ c l e o p h i l e .Various ~~ alternative possibilities were considered. The relative reactivities of a series of compounds related to the crowded (Me3Si)2(Ph2MeSi)CSiMe21 towards silver salts or IC1 have been studied.45The results support the proposal that for the above substrate, and also for (Me3Si)2(PhMe2Si)CSiMe21, the rate-determining step involves generation of a Ph-bridged cation (41), and so anchimeric assistance by a Ph group to the departure of I-.

(41) R = Phor Me

(42) R = M e or H

The consecutive reactions of diethoxydimethylsilane and triethoxymethylsilane with MeO- in MeOH have been followed by FT-IR monitoring.46 The consecutive rate constants for the former are 1.93 irO.12 and l.OOiz0.12 1 mol-' s-' at 295 K, while those forthe latter substrate are 1.12f0.09, 0.82f0.10, and 0.51 50.06 1 mol-' s C 1 at 295 K. The results for the diethoxy compound are considered to show a statistical 2 : 1 relationship, within the limits of experimental error, but those for the tiethoxy compound do not show a 3 : 2 : 1 relationship, owing to the intervention of steric and inductive effects. The reactions of the pentacoordinate silicon compounds (42) with nucleophilic reagents such as lithium amides, alkyllithiums, and Group I metal alkoxides have been studied.47 The results are complex, depending on the nature of R and of the nucleophile, the reaction conditions and stereoelectronic factors. When R =H, hydride transfer is important.

10 Nucleophilic Aliphatic Substitution

289

Intramolecular Substitution The relative rates of cyclization of the phosphinate anions BrCH2CH2(CH2),CH2(Ph)P(0)O- in dichloromethane are 4.3 : 1 for n = 0 and 1, giving five- and six-membered ring products, re~pectively.~~ The corresponding values for ClCH2CH2(CH2),CH2(Ph)P(S)Oin cyclization via sulfur are 30 : 1. These values are surprisingly small for ease of formation of five-membered rings compared with sixmembered rings. Ab initio MO calculations at MP2/6-3 1 G**//MP2/6-3 1 G* level have been used to examine the potential-energy surfaces for the ring closures of HSCH2CH2S-, HSCH2CH2CH2S-, and HSCH2CH2CH2CH2S- to give thiirane, thietan and tetrahydrothiophene, re~pectively.~~ The activation barriers are 19.2, 29.4, and 23.1 kcal mol- respectively, i.e. the formation of the three-membered ring has the lowest barrier, even lower than that for an analogous sN2 reaction, e.g. 25.0 kcal mol-’ for MeS- EtSH. An explanation is offered. The cyclization of allenic amines leading to seven-membered and larger azacycles may be effected by using iodine as the electrophilic trigger.” These reactions have been studied in detail for the allenic sulfonamides (43), giving first the diiodides (44), which may then form either the smaller ring (45) or the larger ring (46).5’ While the sulfonamide (43) with n = 1 gave predominantly the corresponding pyrrolidine (45), in all other cases (n = 2-5) the larger ring (46) was either the major or the exclusive product. Thus path (b) involving attack of a primary site by N in an sN2 process is usually preferred to path (a), which involves an sN2’ process.

+

+

’,

+

‘m

/I

NaH.DMPU

/

(45)

The products and stereochemistry have been studied for various reaction systems essentially involving internal nucleophilic attack by 0 - in an SN’displacement of Brfrom an enolate, e.g. (47) giving (48).52The cyclization of the substrate (49) to give the pyrrolidine (50) is said to be the first reported case of intramolecular nucleophilic substitution on nitr~gen.’~ Yields of product diminished as the bulk of the substituent R’ was increased.

Organic Reaction Mechanisms 1995

290

-

:

+

Br-

(49)

Anchimeric Assistance The acid-catalysed hydrolysis of the methyl ether linkage in (51) proceeds at least 1700 times faster than the corresponding reaction of the reference compound (52).54This was attributed to participation involving the neighbouring amide group in (51). The compound PhSCD2CH2Cl reacts with 1- in dry acetone to give PhSCD2CH21 through an SN2process.55 The iodo compound then undergoes anchimerically assisted ionization (53) to give product with the deuterium label scrambled. In further work, rates of displacement of halide ions by halide ions showed the expected nucleophilicity order C1- > Br- > I- and normal leaving-group order I- > Br- > CI-.

,

0

YNL (51)

Ambident Nucleophiles and Electrophiles There appear to be no studies of ambident nucleophiles to report this year. Second-order rate constants have been measured for the reactions of N-methyl-Nnitrosotoluene-p-sulfonamide(MNTS) and of 2-ethoxyethyl nitrite (EEN) with oxygen

10 Nucleophilic Aliphatic Substitution

29 1

nucleophiles, sulfur nucleophiles and I-.56 For MNTS, soft nucleophiles react at the nitroso group, whereas hard nucleophiles react at least in part at the sulfonyl group. A complicated situation was found for EEN. The application of the nucleophilicity scales N+ and n was discussed. N-Nitrosoiminium cations are ambident ele~trophiles.~~ Azide ions may either trap such cations by attack at C or lead to denitrosation through attack at NO. Isotope Effects Secondary kinetic isotope effects (KIEs) involving deuteriated nucleophiles have been reviewed by Lee58with respect to the theory of secondary a-deuterium KIEs, the crossinteraction constants of the forms of Hammett equation much applied by this author and his co-workers, and transition-state variations for associative and dissociative SN2 reactions. The 11C/14CKIE has been used to investigate steric hindrance in Menshutkin reactions of various substituted amines with labelled methyl iodide.59This KIE is about 1.2, and increases slightly as the nucleophile becomes more sterically hindered. Thus it is 1.220 f0.009 for 2,6-lutidine, compared with 1.189 f0.012 for 2,4-lutidines, in acetonitrile at 30 "C. A water-promoted, concerted E2 reaction of 9-(l-X-ethyl)fluorene (54) in 25 vol.% acetonitrile in water yielding 9-( 1-ethylidine)fluorene (55) has been found to compete with stepwise substitution and elimination reactions via the ion pair which lead to 9(1 -hydroxyethyl)fluorene (56), 9-(1-acetamidoethyl)fluorene (57), and 9-vinylfluorene (5tQ60 The evidence includes a detailed study of the various KIEs for the rate coefficients characterizing the various processes. Extended basis set calculations with electron correlation have been carried out for reactant and transition state properties of the gas-phase SN2 reactions: X-

+ MeY + MeX + Y-

(X = C1, Y = Br; X = C1, Y = I; and X = Br, Y = I).61Rate constants for these reactions and their perdeuteriated analogues have been calculated. KIEs and their temperature dependences were calculated and analysed. The KIEs for the first two reactions were in fair agreement with experimental values, but the third reaction showed a marked discrepancy. Gas-phase Reactions In the gas-phase ion-molecule reactions of C1- or I- with MeBr or Me1 at elevated collision energies [studied by guided ion beam and selected ion flow drift tube (SIFDT) techniques], dihalide products have been observed, i.e. the products of processes of the type62

X-

+ RY + XY- + R:

The details of the study led to the conclusion that such products arise from collinear attack of X- at the halogen in RY and this is supported by ab initio calculations at the MP2LANLlOZ level.

292

q

Organic Reaction Mechanisms I995

Y CY3

(54)

X = Br or I L = 'H or 2H Y = ' H or 2H

Y CY3

Transition-state structures have been found in ab initio calculations of identity reactions of LiF, LiC1, or NaCl with MeF or MeC1, as a p p r ~ p r i a t e .The ~ ~ retention transition state can be considered as an SNitype in which Me+ interacts with a metal halide triple ion, MX;. The inversion transition state, which can also be considered as an ionic assembly, is highly bent from the rectilinear X 1. . C . . .X of the ionic analogues. Definitive ab initio predictions have been made for the SN2 identity exchange reaction64 F-

+ MeF + FMe + F-

Calculations have employed a range of basis sets and include accounting for electron correlation. The final predictions for the complexation energy and for the intrinsic activation barrier are - 13.6 k 0.5 and 12.8 d= 1.5 kcal mol-', respectively, placing the net SN2barrier 0.8 kcal mol-' below the separated reactants. High-level ab initio calculations have also been carried out for the above reaction and for the corresponding reactions of the other halide ions and methyl halides.65The ionmolecule complexation energies in the order F, Cl, Br, and I are - 57.1, - 43.7, - 40.5, and - 35.3 kJ mol-' at 298 K, respectively, the central bamers are 46.1,

293

10 Nucleophilic Aliphatic Substitution

53.5,45.0, and 40.8 kJ mol-' at 298 K, respectively, and the overall barriers relative to the reactants are therefore - 11.0, 9.8, 4.5, and 5.5 kJ mol-' at 298 K, respectively. The same research group has also carried out a high-level computational study for the gas-phase identity reactions of halide ions at neutral nitrogen?

X-

+ NH2X

--+

XNH2

+ X-

The results are compared with those for the analogous reactions at saturated carbon (see earlier). The central barriers are surprisingly similar: in the order F, C1, Br, and I 58.2, 58.5, 46.9, and 39.1 kJ mol-', respectively. Computer simulations and animations of the motions of atoms as a chemical reaction proceeds give a detailed picture of how the reaction occurs at a microscopic level. Applications to SN2 reactions have been reviewed.67 The same research group has carried out statistical rate theory calculations for the reaction6' C1-

+ MeBr -+ ClMe + Br-

Three different statistical theoretical models and three different potential-energy surfaces were used to calculate the rate constant as a function of temperature, translational energy, and H(D) isotopic substitution. Overall, there is poor agreement between calculated and experimental results. Ab initio studies at the HF and MP2 levels using 6-3 1 + G** basis sets have been made on the SN2identity (mainly allyl) exchange reactions69

+

RCHzX

+ X-

+ X-

+ RCH2X

For R = CH2=CH, X = H , NH2, OH, F, PH2, SH, and C1, and for R = M e or CH=C, X = C1. The activation barriers are closely related to the electronegativities of R and X. The same group has also carried out ab initio MO studies on the identity gas-phase nucleophilic substitution reactions of CH2=CHCH2X by X- with X = H, F or C1, using 6-3 1 G** basis sets, including electron correlation at the MP2 level.70When X = H (the weakest nucleofuge), reaction occurs by a stepwise sN2' mechanism, whereas when X = C1 (the strongest nucleofuge), the concerted SN2 reaction is favoured. For X = F there is competition between various pathways. Transition-state structures for gas-phase SN2 reactions of substituted pyridines with MeCl, MeBr, or Me1 have been localized by the AMPAC program using the AM1 H a m i l t ~ n i a n .The ~ ~ activation barriers are ca 70 kcal mol-'. The order of leavinggroup abilities is I- < Br- < C1- and the C-N bond length in the transition state increases in the same order. Substitution by electron-withdrawing groups in the para position has very little effect on the structure of the transition state, but bulky groups in the ortho position lead to looser and earlier transition states. The concept of a transition-state structure is well defined in the gas phase, but it needs clarification for reactions in solution.72The problem has been discussed for various types of reaction, including SNland Menshutkin reactions.

++

Radical Processes The possible contribution of non-chain electron transfer (ET) to nucleophilic aliphatic substitution has been surveyed and explored in This may be the rate-

294

Organic Reaction Mechanisms I995

determining step when the nucleophile is a good electron donor and steric hindrance in the transition state excludes the classical sN2 mechanism. When a reaction appears to have some characteristics of ET and some of S N ~the , authors favour interpretation in terms of an intermediate transition state, rather than a competition between two reaction paths. The 9-phenylfluorenyl anion does not react with neopentyl iodide, but on irradiation it undergoes efficient reaction to form the products of nucleophilic aliphatic s~b s t i t u t i o n With .~~ the sterically analogous cyclizable molecule 6-iodo-5,5-dimethylhex-1 -ene, no ground-state reaction is observed, but both cyclized and uncyclized products of substitution are produced upon irradiation. 'Thus photoproducts clearly involving electron-transfer-induced radical intermediates can result without accompanying free-radical cyclization. These results suggest that, although the observation of cyclized products in the reaction of a cyclizable radical probe with a nucleophile is evidence of a radical intermediate, the absence of such cyclized products does not require the absence of radical intermediates.' p-Bromophenacyl bromide reacts with tetrabutylammonium bromide in cumene at 100 "C for 66 h to give a 47% yield ofp-bromoa~etophenone.~~ It is claimed that this supports a SET mechanism for the identity reaction of the substrate with Br-, i.e. the cumene scavenges the radical anion intermediate and reduces the radicals to pbromoacetophenone. Other evidence is also given. The photo-stimulated reactions of 1-iodoadamantane with various carbanions (anions from acetone, acetophenone, propiophenone, anthrone, nitromethane, or fluorene) in DMSO have been ~tudied.'~ Product analyses were interpreted in terms of an SRNl mechanism.

Medium Effects Grunwald-Winstein treatments of the rate constants of solvolysis of a series of secondary and tertiary benzylic toluene-p-sulfonates, p-nitrobenzenesulfonates, chlorides, and bromides are nearly all improved by including an h1 term, where h is the sensitivity towards changes in the (recently developed) aromatic ring parameter I.77 The value of h is increased by a second aromatic ring at the a-carbon, on introduction of an electron-withdrawing a-CF3 group or by introducing an electron-releasing aromatic ring substituent. The solvolysis of 4-bromobut- 1-ene proceeds by an sN2 mechanism in a wide range of solvents, as indicated by sensitivity of the rate to solvent nucleophilicity, and other evidence." There is a minor SN1 component in 97% TFE, and this becomes dominant in 90% HFIP. Solvolysis rates of p-nitrobenzyl and 3,5-bis(trifluoromethyI)benzyl p-toluenesulfonates have been determined in a wide variety of solvents.79 The 2-adamantyl YoTs parameter by itself gave poor results in correlation analysis of these data. The introduction of a solvent nucleophilicity term effected a considerable improvement in the correlations. The same research group has also studied solvent effects on the anchimerically assisted solvolyses of threo-2-aryl-1-methylpropylp-toluenesulfonates.80 As above, yo^, by itself gave poor results in correlation analysis. The

I0 Nucleophilic Aliphatic Substitution

295

introduction of a parameter Y A , based on solvolysis of 2-@-methoxyphenyl)-2methylpropyl p-toluenesulfonate, led to considerable improvement. The same parameter has also found considerable application to the solvolyses of benzyl ptoluenesulfonates containing electron-donating substituents.'l Solvolyses of monosubstituted benzhydryl bromides have been found to give excellent linear correlations of log k with CT+ constants, but solvent effects do not correlate well with YBnBror YB,.82Correlation analyses involving the use of log k values for a-t-butyl-2-(2-naphthyl)methylbromide in the appropriate solvents provided evidence for the importance of different extents of solvation in the delocalized transition states and for nucleophilic solvent intervention in solvolysis of benzhydryl systems. Rates at several temperatures in acetonitrilemethanol mixtures have been measured for the reactions of ethyl and 2-phenylethyl benzenesulfonates with aniline or benzylamine, and activation parameters have been ~alculated.'~Transfer enthalpies were measured for the nucleophilic reagents in the same solvents and used in the interpretation of the activation enthalpies. 180-scrambling studies were carried out for the solvolyses of a-(t-buty1)benzyl tosylates in several solvents.84 Extensive ion-pair return, comparable to product formation, was found. Similar studies were also carried out for benzyl tosylates, substituent and solvent dependence of ion-pair return being examined for this 'borderline' s o l v o l y ~ i s Ion-pair .~~ return is decreased significantly by more electronwithdrawing substituents and in more nucleophilic solvents. A picosecond kinetic study has been carried out for the formation of contact ion pairs by the heterolysis of the C-C1 bond in benzhydryl chloride, the solvents being MeCN and EtCN.86 The activation energies for collapse of the ion pair are 3.2 and 2.8 kcal mol- ', respectively. It was concluded that ion-pair recombination occurs in the 'polarization caging regime.' In a long series of papers on the kinetics and mechanism of unimolecular heterolysis of industrial organic halides, rate constants have been determined for diphenyldichloromethane heterolysis in 11 protic and 17 aprotic solvent^.^' The rate was governed mainly by the polarity and electrophilicity of solvents, with a negative effect of nucleophilic solvation being observed for protic solvents. Activation parameters were determined for the reaction of methyl iodide with triethylamine in eleven acetone-ethanol mixtures.88Rate constants were correlated with the Dimroth-Reichardt ET(30) parameter. Rate constants of the Menshutkin reaction between triethylamine and iodoethane have been measured at 3 13 K in seven primary and secondary alkanols at various pressures.89Calculations of volumes of activation by several model-based equations are compared and procedures for dissecting intra- and inter-molecular contributions to the volume of activation are discussed. A semiempirical study has been made of the solvent effect on the reactions of MeX (X=CI, Br, or I) and NH3.90 A 'multicavity self-consistent reaction field' was employed and two dielectric media corresponding to hexane and water were modelled. The potential-energy surfaces for the three reactions are similar in different media, indicating broad similarity of reaction mechanism. However, the details thereof depend substantially on the solvent employed e.g. in hexane the

296

Organic Reaction Mechanisms I995

ion pair MeNH:Xis formed, whereas in water the reaction results in free ions. Rate constants and activation parameters were measured for the reactions of carboxylate ions with ethyl iodide in acetonitrilemethanol mixtures.” Enthalpies of solution were measured for the tetraalkylammonium salts of the relevant nucleophiles. ‘An empirical correlation incorporating nucleophiles and transition-state anions has been found between the derived quantities, namely the specific interaction enthalpies for anions and the number of methanol molecules participating in hydrogen bonding with the anions.’ The kinetics of the reaction of iodide ion with methyl p-toluenesulfonate have been studied at five temperatures in several hydroxylic or non-hydroxylic solvents, and in acetone-water mixtures.92The expected ct-proton abstraction step in the reaction of 4trifluoromethylbenzyl chloride in alkaline dioxane-water media does not take place.93 Instead, an SN2 reaction followed by an etherification step, forming bis(4trifluoromethylbenzyl) ether, occurs. These consecutive reactions were studied kinetically in several dioxane-water media at various temperatures. Molecular dynamics computer simulation has been used to relate the thermodynamic properties along the reaction coordinate to microscopic solvation for the SN2 reaction of C1- with MeCl in supercritical water as a function of temperature and density.94 In a long series of papers on the kinetics and mechanism of unimolecular heterolysis of organic halides, the nature of the lithium perchlorate salt effect during ionization of benzhydryl bromide in 6-butyrolactone has been in~estigated.~~ The effect of verdazyl indicators on the salt effect was examined. The effects of added trifluoroacetate, triflate, and tosylate salts on the trifluoroacetolysis of 1-(4’-tolyl)-2,2,2-trifluoroethyltosylate have been studied, including reactions of 180-labelledand optically active substrate^.'^ The salt effects on the solvolytic rate constant hv,the polarimetric rate constant k,, and “0 scrambling were examined in detail and the results interpreted in terms of ion-pair formation and disappearance by competitive return and reaction with solvent or salt.

Phase-transfer Catalysis and Other Intermolecular Effects The nucleophilic substitutionreactions of n-octyl sulfonates are catalysed by complexes of alkali metal salts MY with polyethers (PEGs, crown ethers, or cryptands; M = Li, Na, or K, Y = I or Br) in low-polarity solvents (chlorobenzene, o-dichlorobenzene, or toluene) at 60 0C.97With complexes of PEGs and crown ethers, rate constants for a given substrate increase in the order Kf < Na+ < Li+, but such effects diminish with increasing nucleofugality of leaving group. For cryptate complexes the rate constants are virtually independent of the cation. The addition of the non-ionic surfactant dodecyl(dimethy1)phosphineoxide (CI2PO) to aqueous cetyltrimethylammonium bromide (CTABr) inhibits the micellar-mediated reaction of Br- with fully bound methyl naphthalene-2-sulfonate (MeONs).” Reaction in the micellar pseudophase depends on the concentration of Br- in the interfacial surface region. On addition of CI2P0, [Br-] is decreased by increases in both the fractional micellar ionization and the volume of the micellar pseudophase.

10 Nucleophilic Aliphatic Substitution

297

The first examples of surface-catalysed SN2 reactions have been reported.99 These involve the dehydrative coupling of alcohols to form ethers over the zeolite HZSM-5 or the fluorocarbon sulfonic acid resin Nafion-H, either at 100 "C under about 10 atm total pressure, or in concentrated sulfuric acid solution at 100 "C and ambient pressure.

Structural Effects The role of ion pairs and ion-molecule pairs in solvolytic substitution, elimination, and rearrangement reactions has been reviewed. O0 Relative reactivities have been studied for the aminolysis reactions of alkyl alkanesulfonates and sundry interesting observations have been made,'" e.g. the greater reactivity of N-methylbutylamine than N-methylaniline is due to differences in entropy of activation rather than differences in activation energy. C12H25S03Meis considerably more reactive than MeSO3CI2H25. Nucleophilic substitution reactions of 3-trichloromethylpyridine, its N-oxide, and 3,5-bis(trichloromethyl)pyridine occur in most cases by way of attack at ring C, followed by hydrogen migration to the side-chain, although attack at the trichloromethyl C has also been observed.'02 Hammett Equation and Other LFERF Lee' O3 has reviewed recent advances in the application of cross-interaction constants. He has also reviewed the subject in Korean.lo4 and p - and The relationship between the signs of the Hammett p values pi(,,), the validity of the reactivity-selectivity principle (RSP) has been discussed"' (the symbols are for Lee's extended Hammett equation, involving the combined effect of two substituents in different benzene rings). The RSP is said to be valid when W = pi(o)p,(~)lpiiis negative. About 100 reaction series were analysed and various mechanistic significances of the RSP were derived. The kinetic data for six reactions of Y-phenylalkyl or Y-phenacyl Z-arenesulfonates with X-anilines or X-benzylamines have been re-analysed.lo6 It was concluded that in five of the six cases the errors associated with the cross-interaction term pxyz are large and the contribution this makes to the overall analysis is probably statistically insignificant. The rates of Menshutkin-type reactions of R2C6H40S02C6H4R1with substituted pyridines in acetonitrile at 35 "C have been measured by the conductometric method, and the second-order rate constants were analysed by means of the Hammett equation.lo7 Rate constants and activation parameters have been determined for substitution reactions of P-substituted bromoethanes and bromopropanes with thiourea in various solvents. O8 Isokinetic and Taft relationships were applied. Nucleophilicity and Leaving-group Effects The anilino thioethers 3- or 4-02NC6H4N(Me)CH2SC6H4-2-CO~undergo concerted bimolecular nucleophilic substitution with various nucleophiles in aqueous solution at 25 OC.lo9Attack is on CH2 and the leaving group is -SC6H4-2-CO;. In Swain-Scott

Organic Reaction Mechanisms 1995

298

correlations the two substrates show low and approximately equal sensitivities to the nature of the nucleophile, i.e. s z 0.4. The rate constants for 41 compounds bearing a C=S function reacting with MeX (X = I or Tos) span seven orders of magnitude"' (the solvent was acetone, acetonitrile or methanol). The photoelectron spectra of the nucleophiles show two low-energy peaks, corresponding to the n,-s bonding orbital of C=S and the lone-pair orbital ns. Various correlations between rate data and PES data were attempted. The best one involves In k versus the inverse of the energy EB of the sulfur lone pair (r = 0.96 for about 40 points). Solvolysis of 9-(1-X-ethyl)fluorene (X=I, Br, C1, OTs, or OBs) in 25 vol.% acetonitrile in water gives the elimination products 9-( 1-ethylidene)fluorene and 9vinylfluorene and the substitution products 9-( 1-hydroxyethyl)fluorene and 9(1-acetamidoethyl)fluorene.' Added strong nucleophiles open up a competing SN2 pathway. The importance of this route is leaving-group-dependent. This 'synergism' between nucleophile and leaving group favours SN2 reaction with 1- > Br- > C1- > TsO-, BsO- leaving groups. Additional experimental work on rates of solvolysis of highly reactive methanesulfonates, together with literature data, are the basis for updating the scale of leavinggroup effects for SNl reactions of 1-phenylethyl substrates in 80% ethanol-water at 75 oC.112The scale covers a range of 10l6 in relative rates, from 5 x l o p 8 for MeCO; to 1.1 x lo9 for CF3SOT (C1- is the standard at 1.0).

Kinetic Studies (Miscellaneous) Kinetic studies have been made for the following reactions: the methanolysis of certain amines of trivalent phosphorus (phosphonites), with a view to finding cases of intramolecular catalysis;''3 the hydrolysis of 2-bromomethyl-3,5,6-trimethylpyrazine over the pH range 1-1 1;l14the acid-catalysed hydrolysis of t-butyl phenyl ether;'" and the first-order ethanolysis of benzhydryl chloride as a model reaction for exploring links between the theoretical rate law and the experimental response surface.16

Acknowledgement The hospitality of the University of York, UK, during the writing of this chapter is gratefully acknowledged.

References Bemasconi, C. F., Schuck, D. E, Ketner, R. J., Weiss, M., and Rappoport, Z., 1 Am. Chem. Soc., 116, 11764 (1994).

* Bemasconi,

' '

C. F., Leyes, A. E., Eventova, I., and Rappoport, Z., 1 Am. Chem. Soc., 117, 1703 (1995). Amatore, C., Galli, C., Gentili, P., Guamieri, A., Schottland E., and Rappoport, Z., 1 Chem. Soc., Perkin Trans. 2, 1995, 2341.

Jonas, J., Mazal, C., and Rappoport, Z., 1 Phys. Org. Chem., 7, 652 (1994). Lucchini, V, Modena, G., and Pasquato, L., 1 Am. Chem. Soc., 117, 2297 (1995). Knuhl, G., Sennhenn, P., and Helmchen, G., 1 Chem. Soc., Chem. Commun., 1995, 1845. Bricout, H., Carpentier, J.-F., and Mortreux, A,, 1 Chem. Soc., Chem. Commun., 1995, 1863. Dezi, E., Lombardozzi, A., Pizzabiocca, A,, Renzi, G., and Speranza, M., 1 Chem. Soc., Chem. Commun., 1995, 547.

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11

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Hu, W.-P. and Tmhlar, D. G., 1 Am. Chem. Soc., 117, 10726 (1995). Cyr, D. M., Scarton, M. G., Wiberg, K. B., Johnson, M. A,, Nonose, S., Hirokawa, J. H., Tanaka, H., Kondow, T., Moms, R. A,, and Viggiano, A. A., 1 Am. Chem. SOC.,117, 1828 (1995). 63 Harder, S., Streitwieser, A,, Petty, J. T., and Schleyer, I? v. R., 1 Am. Chem. Soc., 117, 3253 (1995). 64 Wladkowski, B. D., Allen, W. D., and Brauman, J. I., 1 Phys. Chem., 98, 13532 (1994). 65 Glukhovtsev, M. N., Pross, A,, and Radom, L., 1 Am. Chem. SOC., 117,2024 (1995). 66 Glukhovtsev, M. N., Pross, A,, and Radom, L., 1 Am. Chem. Soc., 117, 9012 (1995). 67 Hase, W. L., Science, 266, 998 (1995); Chem. Abs., 122, 30793 (1995). 68 Wang, H. and Hase, W. L., 1 Am. Chem. Soc., 117, 9347 (1995). 69 Lee, I., Kim, C. K., and Lee, B.-S., 1 Phys. Org. Chem., 8, 473 (1 995). 70 Park, Y. S., Kim, C. K., Lee, B.-S., and Lee, I., 1 Phys. Chem., 99, 13103 (1995). 71 Berg, U., Chanon, M., Gallo, G., and Rajzmann, M., 1 Org. Chem., 60, 1975 (1995). 72 Bertran, J., Lluch, J. M., Gonzalez-Lafont, A,, Dillet, V., and Perez, V,ACS Symp. Ser, 1994, 568; Chem. Abs., 122, 9264 (1995). 73 Lund, H., Daasbjerg, K., Lund, T., and Pedersen, S. U., Acc. Chem. Res., 28, 3 13 (1995). 74 Tolbert, L. M., Sun, X.-J., and Ashby, E. C., 1 Am. Chem. Soc., 117, 2681 (1995). 75 Haberfield, I?, 1 Am. Chem. Sac., 117, 3314 (1995). 76 Rossi, R. A,, Pierinin, A. B., and Borosky, G. L., 1 Chem. Soc., Perkin Trans. 2, 1994, 2571. 77 Kevill, D. N. and D'Souza, M. J., 1 Chem. Soc., Perkin Trans. 2, 1995, 973. 78 Kevill, D. N. and Abduljaber, M. H., 1 Chem. Soc., Perkin Trans. 2, 1995, 1985. 79 Fujio, M.,Susuki, T., Goto, M., Tsuji, Y., Kim, S. H., Ahmed, G. A.-W., and Tsuno, Y., Bull. Chem. SOC. Jpn, 68, 673 (1995). 80 Fujio, M., Saeki, Y., Nakarnoto, K., Yatsugi, K., Goto, N., Kim, S. H., Tsuji, Y., Rappoport, Z., and Tsuno, Y., Bull. Chem. SOC.Jpn, 68, 2603 (1995). 81 Fujio, M., Susuki, T., Yatsugi, K., Saeki, Y., Goto, M., Kim, S . H., Tsuji, Y., Rappoport, Z., and Tsuno, Y., Bull. Chem. SOC.Jpn, 68, 2619 (1995). 82 Liu, K.-T., Chin, C. I?, Lin, Y.-S., and Tsao, M.-L., Tetrahedron Left., 36, 6919 (1995). 83 Huh, C., Lee, H. W., and Lee, I., Bull. Korean Chem. Soc., 16, 52 (1995); Chem. Abs., 122, 132349 (1995). 84 Tsuji, Y, Yatsugi, K., Fujio, M., and Tsuno, Y., Tetrahedron Lett., 36, 1461 (1995). 85 Tsuji, Y., Kim, S. H., Saeki, Y, Yatsugi, K., Fujio, M., and Tsuno, Y., Tetrahedron Left.,36, 1465 (1995). 86 Deniz, A. A., Li, B., and Peters, K. S., 1Phys. Chem., 99, 12209 (1995). 8i Dvorko, G. F., Cherevach, T. V., Kulik, N. I., and Ponomareva, N. E., Zh. Obshch. Khim., 64,979 (1994); Chem. Abs., 122, 186811 (1995). 88 Nevecna, T. and Bekarek, V., Acta Univ. Palacki. Olomuc., Fac. Rerum Nat., 112, 77 (1993); Chem. Abs., 121, 300427 (1994). 119 Viana, C. A. N., Calado, A. R. T., and Pinheiro, L. M. V., 1 Phys. Org. Chem., 8, 63 (1995). 90 Maran, U., Pakkanen, T. A., and Karelson, M., 1 Chem. SOC.,Perkin Trans. 2, 1994, 2445. " Kondo, Y., Sugitani, W., Tokui, M., and Takagi, T., 1 Chem. SOC.,Perkin Trans. 2, 1995, 1049. 92 Bao, B. andHu, K., Hangzhou DuxueXuebao, Ziran Kexueban, 21,422 (1994); Chem. Abs., 122, 186712 (1995). 93 Riad, Y., Gundermann, K. D., and Bardan, A. A. El, Egupt. 1. Chem., 37, 123 (1994); Chem. A h . , 122, 238955 (1995). 94 Flanagin, L. W., Balbuena, €? B., Johnston, K. P., and Rossky, I? J., 1 Phys. Chem., 99, 5196 (1995). 95 Dvorko, F., Golovko, N. N., Pervishko, T. L., and Ponomareva, E. A., Zh. Obshch. Khim., 64, 1281 (1994); Chem. Abs., 122, 132417 (1995). 96 Allen, A. D., Fujio, M., Tee, 0. S., Tidwell, T. T., Tsuji, Y., Tsuno, Y., and Yatsugi, K., 1 Am. Chem. Soc., 117, 8974 (1995). 97 Gobbi, A,, Landini, D., Maia, A,, and Secci, D., 1 0%.Chem., 60, 5954 (1995). 98 Blask6, A., Bunton, C. A,, Toledo, E. A., Holland, P. M., and Nome, F., 1 Chem. Soc., Perkin Trans. 2, 1995, 2367. 99 Sun, Q., Herman, R. G., and Klier, K., 1 Chem. Soc., Chem. Commun., 1995, 1849. 100 Thibblin, A,, Spec. Publ. R. SOC.Chem., 148, 415 (1995); Chem. Abs., 123, 111257 (1995). 101 Roberts, D. W., Ward, R. S., and Hughes, P. J., 1 Chem. Res. (S), 1995, 70. lo' Cartwright. D., Ferguson, J. R., Giannopoulos, T.,Varvounis, G., and Wakefield, B. J., Tetrahedron, 51, 12791 (1995). lo3 Lee, I. Spec. Publ. R. SOC. Chem., 148, 361 (1995); Chem. Abs., 123, 111254 (1995). Io4 Lee, I. C., Hwahak Sekye, 34, 204 (1994); Chem. Abs., 122, 9166 (1995). Lee, I., Lee, B.-S., Koh, H. J., and Chang, B. D., Bull. Korean Chem. Soc., 16, 277 (1995); Chem. A h . , 122, 264860 (1995). 61

62

10 Nucleophilic Aliphatic Substitution Io6 lo' lo'

'09 111

I12

Kevill, D. N. and D'Souza, M. J., J. Chem. Soc.. Perkin Truns. 2, 1994, 2427. Cheong, D.-Y., Park, J.-H., Kweon, J.-M., Yoh, S.-D., and Shim, K.-T., 1 Koreun Chem. Soc., 38, 915 (1994); Chem. Abs., 122, 105054 (1995). Ryazantsev, G. B., Sukhov, L. L., Lys, Ya. I., and Fedoseev, V M., Vestn.Mask. Univ., Serr 2: Khim., 35, 502 (1994); Chem. Abs., 122, 132336 (1995). Eldin, S. and Jencks, W. P., 1 Am. Chem. SOC.,117, 9415 (1995). Arbelot, M., Allouche, A., hrcell, K. F., and Chanon, M., 1 Org. Chem., 60, 2330 (1995). Meng, Q. and Thibblin, A,, 1 Am. Chem. Sac., 117, 9399 (1995). Bentley, T. W., Christi, M., Kemmer, R., Llewellyn, G . , and Oakley, J. E., 1 Chem. Sac.. Perkin Truns. 2, 1994, 2531.

'I4 'I5

'I6

301

Nifantyev, E. E. and Gratchev, M. K., Tetrahedron Lett., 36, 1727 (1995). Ye, D., Wang, S., Yang, C., and Jin, J., HuudongLigong DuxueXuebuo, 21, 244 (1995); Chem. Abs., 123, 169038 (1995).

Lajunen, M. and Tanskanen-Lehti, K., Actu Chem. Scand., 48, 861 (1994). Axelsson, A.-K. and Carlson, R., Actu Chem. Scund., 49, 663 (1995).

CHAPTER 11

Carbanions and Electrophilic Aliphatic Substitution A. C . KNIPE

School of Applied Biological and Chemical Sciences, University of Ulster, Coleraine Carbanion Structure and Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MO Calculations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Organolithiums . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aromatic and Other Delocalized Anions . . . . . . . . . . . . . . . . . . . . . . . . . Carbanion Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enolates and Related Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Heteroatom-stabilized Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Organometallic Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Proton-transfer Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrophilic Aliphatic Substitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

303 303 305 306 308 308 321 323 328 330 332 332

Carbanion Structure and Stability

MO Calculations For 166 molecules, radicals, anions, and cations, the CBS-4, CBS-Q, G2(MP2) and G2 energies have been calculated and found to reproduce experimentally determined heats of formation, bond dissociation energies, gas-phase acidities, and proton affinities with an average error of only 1 kcal mol-'.' A Gaussian-2 ab initio study of the rearrangements of ethyl, ethenyl, and ethynyl anions and of the stabilities of these anions towards spontaneous electron loss has been reported;2 the ethyl anion is predicted to lose an electron spontaneously whereas the ethenyl and ethynyl anions will not. Barriers for 1,2-hydrogen shift for ethynyl, ethenyl, and ethyl anions are calculated to be 85, 228 (syn) or 234 (anti), and 200 kJ mol-', respectively. The gas-phase acidities associated with deprotonation at the two different sites of buta- 1,3-diene have been determined, under relatively low-pressure conditions in a Fourier transform ion cyclotron resonance mass spectrometer, by proton abstraction using strong anionic bases; the corresponding conjugate anions have been identified by means of a probe reaction with nitrous oxide.3 The 1-butadienyl anions are found to be ca I0 kJ mol- less stable than the 2-butadienyl anions and this is confirmed by highlevel ab initio calculations which predict a planar charge-localized structure for the former (in which the butadiene n-system is still intact) but the attainment of additional

'

Organic Reaction Mechanisms 1995. Edited by A. C . Knipe and W. E. Watts 0 1997 John Wiley & Sons Ltd

303

304

Organic Reaction Mechanisms I995

stabilization of the latter by 100 O rotation of the central C-C bond, thereby achieving allylic charge delocalization and a structure with two nearly orthogonal n-systems. Ab initio calculations, using Gaussian 92, have also been used to establish that the ion CSH- has a ground-state triplet structure with a nearly linear carbon skeleton but with the terminal H at a marked angle to the carbon backbone! Anions C,H- are of interest since the neutral hydrocarbons C,H ( n = 2-6) have been detected in circumstellar gas. The AM1 method has been used to calculate the geometric structure, charge distribution, and heats of formation of 9-R', 10-R2-9,10-dihydroanthracenes (R' = R2 = H, Me, Ph; R' = Me, Ph or CN R2 = H) and of their mono- and di-anions formed on deprotonation at positions 9 and There is a correlation between the nelectron densities and the change in I3C chemical shift upon anion formation from the neutral species and the resulting pattern of negative charge distribution is similar to that for substituted diphenylmethanes. The hybridization of the deprotonated carbon is nearly sp2, the dianions being somewhat more planar than the monoanions, and the thermodynamic stabilities estimated for the gas phase follow the pattern of first and second acidity constants reported for substituted 9,lO-dihydroanthracenes in the liquid phase. Ab initio calculations of the structure and bowl-to-bowl inversion barriers of corannulene and its dianion and tetraanion have established that the barriers decrease from 14.2 kcalmol-' for neutral corannulene to 7.9-9.2 kcalmol-' for the dianions and to 3.2kcalmol-' for the tetranion; the curvature flattens with introduction of negative charge but a bowl-shaped geometry still prevails for the tetraanion, for which the charge distribution is not consistent with an anion-within-a-trianion model;6 however, see also reference 22. The AM1 method has been found to have practical advantage for predicting the CH acidity of fluoroorganic compounds in gas phase and in solution; calculated proton affinities of the carbanions have been compared with the corresponding pK, values and kinetic acidities, and the influences of ionic association and solvation have been addres~ed.~ Ab initio calculations of the structure and stabilities of gas phase C6H4X- (X = F, C1 and Br) anions have lent support to an earlier suggestion that C6H4Br- and C6H41p display the characteristics of halide-benzyne complexes.8 The calculations predict that the binding energy of the donor-acceptor complex decreases dramatically on going from C6H4F- to C6H4C1- and to C6H4Br- (226, 96 and 60 kJmol-', respectively) as a consequence of the decrease in orbital overlap with increase in size of the halogen; the prediction that C6H&r- will therefore undergo bromide ion transfer, rather than hydrogen abstraction, on reaction with methanol is consistent with experimental reports. AM 1 calculations of the gas-phase stabilities of enolates formed on deprotonation of bicyclo[2.2.2]octane-2,5-dione,bicyclo[2.2.2]octane-2,6-dione~1-hydroxy-4-0x02,2,6,6-tetramethylpiperidine, 4-0~0-2,2,6,6-tetramethyIpiperidine-l-oxyl, 9-hydroxynorpseudopelletierine, and norpseudopelletierine-9-oxy110 have been correlated with measurements of the corresponding rates of enolization in 60 : 40 (v/v) dioxaneD20. Ab initio geometry optimizations at the MP2/6-3 1 + G* theoretical level have been applied in a study of the effects of the cyano, aldehyde, and nitro groups on the acidity

305

11 Carbanions and Electrophilic Aliphatic Substitution

'

of methane, propane, and cyclopropane. The experimental gas-phase acidities are well reproduced and the trends observed have been explained with reference to the degree of charge transfer from the carbanion (Me M Pf > cyclopropyl) to the substituent (NOz= CHO > CN > NC). Thus, whereas cyclopropanecarboxaldehyde and nitrocyclopropane are ca 10kcalmol-' less acidic than their isopropyl counterparts, only small differences apply in the case of the corresponding nitriles and isonitriles. AM1 calculations of excess charge density in nitromethyl anions reveal the predominant contribution of resonance form HzC=Nf(O-)2; the influence of heteroatomic a-substituents and of solvation on the proton affinities of anions of aliphatic and alicyclic nitro compounds has also been probed. l 2 A theoretical study of the structure of acetonitrile and its anion CH3CN- has been reported.13

Organolithiums Results of a study of Lewis base (LB) complexation, aggregation and reactivity of three a-organolithiums suggest that for RmLim.nLBsystems: smaller coordinatively saturated aggregates lose LB more easily, because they contain more LB to provide assistance; fractional reaction orders of RLi are indicative of aggregate-substrate complexes; and predissociation of tetramer to dimer could be a prerequisite of complex formation for substrates that are weak donors, but may not be needed for strong donor ~ubstrates.'~ 13CNMR lineshape analysis of the monomeric aryllithiums (la) and (lb) in THF has revealed the mechanism of 7Li relaxation, the dynamics of intermolecular bond exchange, and the mechanism of rotation around carbon-lithium bonds; the asymmetric nature of the tridentate complex formed between (lb) and pentamethyldiethylenetriamine has also been established. Li Li+

R

(1) a; R = But

b;R=Me

(4)

The (2-THF& structure of the THF-solvated dimer of dilithiated 1-di-t-butylhydroxymethyl-3,3-dimethylcyclopropene(2) has been shown by X-ray analysis to feature tetracoordinate carbons (R'R2CLiz fi-agments)approaching planarity and unusual C-C bond lengths in the cyclopropene ring.I6 A combination of 'H and 13C NMR techniques has been applied to determine the structure of sulfur-stabilized lithiated allylic carbanions (3) and (4).17The structure of lithiated 0 - 1-(t-butylthio)but-2-ene (3) is described as a transoid carbanion in which

306

Organic Reaction Mechanisms 1995

allylic carbon atoms C( l), C(2), and C(3) have intermediate sp2-sp3 hybridization; the Bu'S group plays no significant role in carbanion stabilization. In contrast, lithiated (Ql-(phenylthio)but-2-ene (4) exhibits cis geometry about the C( 1)-C(2) bond and the phenylthio group participates in stabilization of the allylic charge. By monitoring the coalescence of signals of diastereotopic groups in the 'H NMR spectra of secondary benzyllithium compounds in THF it has been possible to determine the effects of benzylthio, benzylseleno, and isopropyl(methy1)amino asubstituents on the barrier to racemization; in each case breaking of the carbon-lithium bond with formation of a solvent-separated ion pair or larger dipole is likely to be the rate-limiting step of the racemization, as evidenced by the negative activation entropies which have been determined for reaction in THE" Interest in the synthetic application of the ambident dianionic nucleophiles obtained on deprotonation of unsaturated carboxylic acids by two equivalents of lithium dialkylamide has prompted a theoretical modelling of solvated lithium dienediolate of but-2-enoic acid." The chemical reactivity and I3C NMR spectral data are consistent with the s-trans dienediolate structure proposed and semiempirical ab initio calculations have revealed that in taking account of dianion solvation by a discrete number of solvent molecules it is important to use ether rather than water molecules when a conformational equilibrium is possible. Semiempirical PM3 calculations have been performed on the complexes formed between the chiral ligand (R,R)-2,3-dimethoxy-1,4-bis(dimethylamino)butane and several organolithium compounds.20 The nature of the ligand binding, by oxygen atoms, nitrogen atoms, or both, has been found to depend on the aggregation state of the organolithium. While the complex with t-BuLi exists as a monomer, those formed with other organolithiums studied are primarily dimeric in character. For aldehyde alkylation by BuLi, reaction via a monomeric precomplex has been shown to have a smaller activation barrier than for that via the dimeric complex. Spectroscopic studies of a series of silicon- and sulfur-substituted chiral organolithium reagents have probed the interplay of chelation and solvation by THF and HMPA in determining their ion pair structure, solvation and configurational stabilities2' Aromatic and Other Delocalized Anions Superaromaticity is considered to arise when the benzene units of a benzenoid molecule are annealed in such a way that all benzene units form a macrocyclic system, whereas aromaticity arises from cyclic conjugation alone. The difficulties in quantifying superaromaticity have been addressed and three alternative hardness indices, which differ in the way in which their reference hardnesses are defined, have been applied in order to determine the degree of superconjugation in kekulene, coronene, and corannulene tetraanion.22Each of the hardness indices, which are more sensitive than resonance energy indices, predict that the structures are superaromatic, and lend support to the suggestion that the corannulene tetraanion structure may be viewed as an annulene-within-an-annulene(as suggested by NMR data); however, see also reference 6.

1I Carbanions and Electrophilic Aliphatic Substitution

307

A full report on the formation, chemistry, and structure of the tribenzacepentalene dianion (6) has included comment on the structure and reactions of 4,7tribenzodihydroacepentalene derivatives (7) which are readily formed by its reaction with electrophiles (R'X) and feature an extremely out of plane C( l)=C( 10) double bond which is correspondingly of increased reactivity.23 The formation of (6)-K2 on treatment of (5a-d) with Lochmann-Schlosser base (BuLi-KO'Pen) is believed to proceed via the mono- (8) and di- (9) anions (which can be observed in most cases) followed by eliminative loss of RH,presumably via a short-lived trianion (10). The relative abundances of (6)-K2 versus the combined relative abundances of (8) plus (9) correlate with the relative stabilities of the expelled anions, i.e. H- >> Bn- > Me- > Et- and can be adjusted by limiting the amount of base used. The structure of (6)-Li2 crystallized from DME was found to feature layers of dianions (6) alternating with layers of DME-complexed lithium counteranions; each lithium cation is chelated by three DME molecules; the central acepentalene fragment adopts C3 symmetry and is bowl-shaped, although each indan subunit is planar.

Hexane

___)

LSB

1

"\

-H+

(7)

R= a H;b Me; c Et; d Bn

-R-

I

H

K'

(9)

(10)

Further investigation of the effects of nitro groups on acidic and homolytic bond dissociation enthalpies of the acidic C-H bonds in carbon acids and their radical anions has been reported.24 The increase in C-H heterolytic bond dissociation energies (acidities in DMSO) effected by nitro substitution of methane on the a orpara positions of toluene (ca 50, 40, and 30 kcal mol-', respectively) is in contrast with the corresponding small decrease in homolytic bond dissociation energies (BDEs) (ca 7.6, 2.8, and 1.5 kcal mol-', respectively). While nitro groups stabilize radicals by delocalizing the odd electron, they also exert a destabilizing influence by inductive electron withdrawal; both effects are stabilizing in the case of carbanions.

308

Organic Reaction Mechanisms I995

BDEs have also been determined25 for a number of malononitriles, 2-substituted dialkyl malonates, alkyl 2-cyanoacetals, and related compounds by combination of measurements of equilibrium acidities (pKHA)and oxidation potentials [Eox(A-)] of the corresponding conjugate anions in DMSO, according to the relationship BDE = 1.37pKHA 23.1EOx(A-) c. The pKHAvalues of dialkyl malonates increase from 15.9 to 16.4 to 18.4 as the dialkyl groups are changed from dimethyl to diethyl to di-t-butyl, yet the BDEs (95.3 z t 0.3 kcal mol- ’) remain unaffected. Introduction of methyl, ethyl, isopropyl and t-butyl groups to position-2 of diethyl malonate causes the BDE value to decrease by 4.4, 3.7, 2.5, and 0.8 kcal mol-’ and the PKHA value to increase by 2.0, 2.4, 3.8, and 8.0 units, respectively, whereas a phenyl group weakens the acidic C-H bond by 10 kcal mol-’ but has no effect on acidity. The marked acid weakening effect of the 2-t-butyl group (to which BDE is insensitive) can be ascribed to steric hindrance to anion solvation; the marked reduction of BDE by a 2-phenyl group is a consequence of radical stabilization by conjugation, yet for the anion this is apparently precluded by a chelating effect of K+, which confines the phenyl group to an orthogonal position relative to the chelate ion plane. NMR-based charge mapping and metal ligand properties of carbanions derived from bispyridyl- and bisquinolyl-methanes have been explored.26

+

+

Carbanion Reactions Enolates and Related Species The synthetic scope, asymmetric induction, and diastereoselectivity of aldol, Michael, and related reactions of tin(I1) enolates have been reviewed.27 BF3.0Et2-promoted addition of allyl- and p-methallyl-stannanes to aldehydes (lla) and (14a) have been found to follow opposite stereochemical paths; this is in keeping with the stereochemical dichotomy found for aldol addition of enol silane to anti-substituted aldehydes (lla) and ( l l b ) versus syn-substituted aldehydes such as (14a) and (14b).28 For (lla) and (1 lb) preferential formation of the Felkin/l,3-anti-diastereoisomer (12a and 12b, respectively) is favoured since those factors that control u- and pstereoinduction are mutually reinforcing; for (14a) and (14b) the carbonyl face selectivity changes from Felkin to anti-Felkin as the size of the enolsilane substituent R is decreased (from Bu‘ to Me), since the diastereofacial bias imposed on the carbonyl moiety by u and fl substituents are now non-reinforcing. Thus, it is clear that carbonyl addition reactions of unhindered trigonal nucleophiles that proceed through polar transition states may be influenced by p-heteroatom substituents. This is believed to be the first report of anti-Felkin selectivity for Mukaiyama aldol reactions performed under conditions which preclude chelate organization. A firther study of Lewis acid-mediated aldol reactions of enol silanes has revealed that silylketene acetals (17) derived from 2-pyridylthioester react with benzaldehyde in the presence of Tic& to give exclusively the syn-aldol product (19) whereas the BF3mediated reactions afford the corresponding anti-adduct (18) as the major pr~duct.’~ This is the first report of syn-selectivity for reaction of the silyl ketene acetal of achiral thioesters with achiral simple aldehyde; this has been explained with reference to a transition state in which the coordination of titanium ion with both benzaldehyde

I I Carbanions and Electrophilic Aliphatic Substitution OP O H c p p r l

Me

OH

309 OH

OP

R

Nu

BF3.0Et2 CHZC12

OP Pri

Me

Me

(12) Felkin

(12) anti-Felkin

(15) Felkin

(16) anti-Felkin

a; P = PMB b; P = TBS

carbonyl and pyridine nitrogen of the silyl ketene acetal completes the formation of a cis-octahedral complex, thereby reducing conformational freedom of the system. The degree of threo-selectivity (22 > 24) observed on aldol reaction between the lithium enolate of 2,6-dimethylcyclohex-2-enone(20) and aromatic aldehydes or 2- and 3-furaldehyde has been found to exceed that for analogous reactions of 2,6dimethylcyclohexanone and 2,2,6-trimethylcyclohexanone.This has been ascribed to a repulsion or non-bonding interaction between the cyclohexenic double bond and the .n-aromatic system of the aldehyde (cf. 21 and 23); aromatic ring substituents on the aldehyde exert only a modest influence.”

anti

d

OTBS PhCHO

(17) R = Me, Et, Bu, Hex, Pr‘

YF3.OEtz

syn

phI(LsJQ R

The diastereoselectivity displayed in an aldol-type reaction used for asymmetric synthesis of cr-substituted serines from achiral aldehydes has been shown to depend on

Organic Reaction Mechanisms 1995

310

Ar

2.ArCHO

\

the Lewis acid-base or the cationic lithium-base combination chosen to promote the double chiral recognition process.31 Results of a kinetic study of the intramolecular addition of enolate ion (26) to its neighbouring carbonyl group have shown that the electrophilic reactivity of the benzaldehyde-type carbonyl group is comparable to that of weakly acidic tertiary ammonium ions.32 In water, the conversion of (25) to (28) occurs by rate-limiting formation of (27), which undergoes subsequent fast reaction; the rate of deuteroxide ion-catalysed exchange of deuterium into (25) to give (25-D) is slower than the formation of (28), since kHoH < k,, but in 3-quinuclidinone buffer (0.1 M) the exchange occurs faster than aldol addition (kBD[BD+] > k,. With increasing concentration of 3quinuclidinolbuffer (50% fi-ee base, pH = 10.1) the apparent second-order rate constant for the conversion of (25) to (28) approaches a limiting value with a change from ratedetermining buffer-catalysed deprotonation of (25) (k, > kHoH ~ B H [ B H + to ] ) ratedetermining uncatalysed cyclization of (26) when k B ~ [ B H > f ]k,. The estimate of k, = 1.6 x lo6 s-' is remarkably close to the rate constant previously reported for conversion of a bimolecular encounter complex, between the enolate of acetone and benzaldehyde, to the aldol adduct and consistent with an effective molarity of approximately unity for the intramolecular enolate addition reaction. Values of kB and kBH/kcfor a series of 3-substituted quinuclidine buffers have also been determined and correlated with pKBH to give Brnnsted slopes of /?=(IS3 and -a=-0.48, respectively; the hypothetical quinuclidine corresponding to log(kBHlkc)= 0 has P K B H = 13.2. The interplay between complementarity and basicity and the use of hydrogen bonding to lower the pK,s of guest molecules has been explored for molecular recognition of enolates in a~etonitrile.~~ By use of polyazaclefts (29) and (30) (illustrated in idealized binding models with hexa- 1,3-dienone enolate) as the receptors

+

11 Carbanions and Electrophilic Aliphatic Substitution

31 1

for a range of methylene compounds, in an attempt to model the enolase and racemase enzymes, it has been established that complementarity of the guest to host is the dominant factor in enolate binding although binding will increase with basicity for enolates of the same shape and hctionality. Only a small fraction of the large pK, shifts found for enolase and racemase enzymes can be ascribed to effects of hydrogen bonding analogous to those reported in this study.

Carbonates (32a-c) derived from l,l'-binaphthalene-8,8'-dio1(31) have been used as chiral proton sources in order to achieve enantioselective protonation of enolates (32ac); the ee values are insensitive to R but much higher for protonation of magnesium enolates than for lithium e n ~ l a t e s . ~ ~

Organic Reaction Mechanisms I995

312

(31) R = H (32) R = CONR'2

(33)

(34)

a; R' = Me b; R' = Et c; R' = Pr'

The enantioselectivity observed on deprotonation of 2-r-butyl-2-methyl-1,3-dioxan5-one and tropinone with chiral lithium amide bases is enhanced if one or more equivalents of LiCl are present; in some cases the opposite enantiomer, formed on reaction with an electrophile, may be caused to p r e d ~ m i n a t e Chiral . ~ ~ chelated amide bases have also been used for enantioselective deprotonation of prochiral cyclic ketones, regioselective deprotonation of optically active 3-keto steroids, kinetic resolution of 2-substituted cyclohexanones, enantioselective aldol reaction, and enantioselective alkylation of achiral ketones.36 The desymmetrization of 2,4-dimethylbicyclo[3.2.l]octan-3-oneby enantioselective deprotonation with a variety of chiral amine bases has also been studied37and catalytic asymmetric C-C bond formation reactions of lithium enolates have been reviewed.38 Novel sulfonyl electrophiles have been used to trap ketone enolates in an attempt to develop CD ring synthons of relevance to vitamin D3.39 An unusual enantioselective aldol-type reaction between aldehyde and the 9-BBN enolate of camphor-derived N-acetyloxazolidinethione (a chiral thioimide) has been explained with reference to a boat-like transition structure.40 The stereoselectivity of aldol addition of chiral boron enolates, R1R2C=C(OBL:)2 of mono- and di-substituted acetic acids to benzaldehyde has been found to depend strongly on the type of chiral ligand used, to the extent that the enolate may be directed to add predominantly to either the re or si face of the aldehyde, where L* = 2-%r or 4-dIcr, respectively (Icr = di-4-isocaranylchloroborane).4' Chiral boron enolates which have previously been found to induce enantioselective synthesis of aldols have now been used for stereoselective aldol reactions involving chiral N,N-diprotected a-aminoaldehyde~.~~ Acyclic diastereofacial selectivity in the Baylis Hillman reaction, whereby ambident vinyl a-anions derived from acrylic esters and methyl vinyl ketone add to protected chiral a-hydroxy- and a-amino-aldehydes under the catalytic influence of tertiary amines, has been investigated; the preference for anti-selectivity for these nonchelation-controlled aldol-type additions has been interpreted in terms of the Felkin model and the Anh-Eisenstein proposals for 1,2-asymetric induction.43 High n-facial differentiation has been reported for titanium-mediated chelationcontrolled aldol-type reactions of acetate thioimide enolates with representative aldehydes.44 For non-chelation-controlled aldol bond formation reactions of acetate

I I Carbanions and Electrophilic Aliphatic Substitution

313

imide enolates a switch in n-facial selectivity can be achieved by alternation of either the imide enolate ligand or the geometry of the boryl catalyst. It has been shown by NMR assignments that the effect of ( 3 4 - and (3S)-3-benzyl substituents, respectively, on the stereochemistry of aldol condensations of the lithium enolates of 1,4-bis[(S)-1-phenylethyl]piperazine-2,5-dionederivatives with benzaldehyde, acetaldehyde, and acrylaldehyde is to induce prevalent cis-induction; this is not the case for reaction with rnetha~rylaldehyde.~~ Stereochemical control in formation of p-lactams by zinc-mediated ester enolateimine condensation reaction has been explored.46247 The cisltrans ratio of lactams (37) formed on reaction of the chlorozinc enolate (35) with imines (36) in THF is increased in the presence of strongly coordinating co-solvents (HMPA, DMPU, TMU, or NMP), which apparently favour a transition state for reaction via (E)-enolate; furthermore, the high asymmetric induction ( > 98% ee) observed on formation of cis-/I-lactams from (35) with chiral imine [36; R' =Et, R2 = (R)-PhCHMe], suggests that the transition state is highly ordered and features (a-enolate aligned with (4-imine. All of the results have been interpreted with reference to relative stabilities of transition states (38a) and (38b), together with the presence of a fast (E)-(2)-enolate equilibrium. Metal counterion, temperature, and substituents have been shown to influence the distribution of products obtained on reaction of dienolates of but-3-enoic, 3-methylbut2-enoic, pent-3-enoic, and 4-phenylbut-3-enoic methyl esters with imines (36);47 reaction at the 2-position of the dienolate occurs reversibly at low temperature (-78 "C)

OZnCl

OEt

(35)

a; X = H, Y = Me,Si,

r - 73 M e - r N

(a-enolate

I

n b; Y = H, X = Me*Si, .SiMez N

I

(E)-enolate

3 14

Organic Reaction Mechanisms I995

to give the a-coupling product, a 8-amino ester, whereas y-coupling at the 4-position occurs at ca -20 "C to give the corresponding a,P-unsaturated ester. The C-C coupled products may subsequently undergo irreversible ring closure to form p-lactams or 5,6dihydropyridin-2-ones, respectively, which may exhibit high asymmetric induction when a chiral amine such as [36, R' = 2-pyridy1, R2 = (R)-PhCHMe] is used. P-Lactam formation is favoured by the use of zinc dienolates, 4-substitution of the dienolates, non-aromatic imine N-substituents, and low reaction temperature. a-Coupling and preferential formation of trans-8-lactams are believed to occur by reaction of the zinc dienolate in its Z-conformation. The diastereoselective y-coupling reactions have been interpreted with reference to a six-membered cyclic transition state in alternative boat and chair (cf. 38) forms. A study of enolate protonation by chiral amines has established, for example, that the naproxen amide (42) can be obtained with an enantiomer excess of77% on treatment of a 1 : 1 : 1 mixture of enolate (39), amine (40), and lithium amide (41 with BF3.0Et2;the enantioselective protonation reaction proceeds by internal proton return (ipr) within a mixed aggregate containing the enolate and the chiral amine.48Direct proton transfer to an enolate may occur when the pKaDMSO of the amine is lower than that of the enol, otherwise BF3.OEt2 is necessary to activate the N-H bond and facilitate ipr to amide, ester, lactam, or lactone enolates. It seems that direct proton transfer requires the minimum number of bond-breaking and bond-forming events while BF3.OEtz-induced ipr in an enolate-amine complex involves prior cleavage of at least one of the bonds between lithium and a nitrogen electron pair.

(40) M = H, R = CH2CH2NMe2 (41) M = Li, R = CH2CH2NMe2

(42)

A revised model for five-membered ring enolate alkylation, based on steric and stereoelectroniceffects, as well as ring conformations, has been proposed to account for unexpected contrasteric formation of (43) rather than (45) on reaction of (44) with methyl iodide (EI) when R2 = R3 = OR.49

11 Carbanions and Electrophilic Aliphatic Substitution

315

Factors which may influence the asymmetric alkylation of amide enolates having pseudoephedrine or ephedrine as chiral auxiliaries have been highlighted5' and a marked effect of HMPA on the diastereoselectivity of the condensation reaction between the enolate dianion of diethyl (5')-malate and imines, to give 2-pyrrolidinone derivatives, has been rep~rted.~' The formation of ethyl 2-cyanoacrylate, on reaction of ethylcyanoacetate with formaldehyde catalysed by 6-aminocaproic acid, has been shown to involve dehydration of the intermediate HOCH2NH(CH2)5C02Hin the rate-determining step; the reaction is of first order in HCHO and 0.5 order in ethyl ~yanoacetate.~~ Rate and equilibrium measurements have been reported for formation of o-adducts (49) on reaction of benzyl cyanide anions (48) with 1,3,5-trinitrobenzene(46) (and with 4-nitrobenzofuroxan) in methanol.53Values of K1 for deprotonation of benzyl cyanides (47) by methoxide ion, and of hMe for addition of MeO- to (46), have been used to obtain k2K1,kL2,and hence K2, from the rate of equilibration of (46) and (49) for which kobs= (k2Kl[RC6H4CH2CN][MeO-])/(1 hMe[MeO-]) k-2). Values of K1K2, which were also obtained by direct observation of the extent of conversion of (46) to (49), are insensitive to ring substituents R, since increases in the value of K1 with increasing electron withdrawal by R are exactly balanced by corresponding decreases in the values of K 2 this ; implies that the negative charge is completely transferred to the trinitrosubstituted ring of (49). With increasing reactivity of the benzyl cyanide anions (48) the very high values of k2 (consistent with a poorly delocalized anion) approach the limit of just under lo9 dm3 rnol-' s-l and values of kW2 decrease steadily. By

+

+

o*NTNo2 +

MeO-

+

MeO-

KOMe

TNEL-MeO-

NO2

(46)

CHzCN

I

RQ (47)

NO2

/

Organic Reaction Mechanisms 1995

316

extrapolation to log K2 = 0 the value of the intrinsic rate constant for the C-C bond forming reaction, log b = 2 . 5 f 0 . 5 , is obtained; thls is 1.5 units lower than that for proton transfer to a nitrogen acid, with consequent location of negative charge on N, and may again be influenced by delocalization on to the trinitrobenzene ring. Alkylations of nitrile anions by a range of tertiary a-halo ketones and nitriles have been inve~tigated~~ in an attempt to detect fiuther occurrence of the SRNlmechanism which has already been established for reaction of resonance stabilized carbanions with tertiary benzyl halides; the alkylations of [NCC(Me)C02Et]- and [NCC(Me)CN]with p-02NC6&COCX(Me)2 were found to take place by the SRNlprocess, as evidenced by the inhibiting effect of (But)2NO'. It has been shown previously that ammonium benzylide salts (50, R f H ) , when treated with a weak base, afford isomeric products (52) and (55) derived from ylides (51) and (54), respectively, by [2,3]- and [ 1,4]-sigmatropic rearrangement. It has now been confirmed through isotopic labelling that both rearrangement manifolds apply in the case of (50a)for which it would otherwise be impossible to determine the origin of the product (52)= (55).55The [2,3]-rearrangement accounted for 44, 85, and 100% of the rearrangement product obtained from (50a) on reaction in DMSO, DMF, and CH2C12, respectively, while for (50b) the corresponding percentages were 33, 54, and 100%. A [1,2] (Stevens) rearrangement of both (50a) and (Sob), to give diastereoisomers of 4-RC6H4(CHCN)2NMe2,is favoured when solid NaHC03, rather than K2C03, is used in DMF.

*CN

R'

barelsolv~

R

ayN MeSOd-

\

baselsolvenl

a;R=H b; R = C1

*FN

*FN

R

The kinetics of reaction of malononitrile with alkyl nitrites in aqueous basic medium have been explored in order to determine the probable mechanism of this C-nitrosation reaction, which is believed to proceed via the carbanionic form of the nitrile.56 The kinetics of formation of the corresponding oxime, HON=C(CN)*, were consistent with

11 Carbanions and Electrophilic Aliphatic Substitution

317

pre-equilibrium formation of the nitrile anion, followed by its reaction with nitrite in a rate-limiting step:

CH2(CN)2 -CH(CN)2

+ RON0

&

ka

-CH(CN)2

+

H+

HON=C(CN)2

+ ROH

Consequently, the reaction is inhibited by acid at high acidity and unaffected by general acid-base catalysts. Correlation of the values of log k2, obtained for various alkyl nitrites, with the corresponding Taft o* values gives a high positive value of p* = 3.49, which reflects stabilization of the incipient alkoxide leaving group and a decreased selectivity for nitrosation of this highly reactive nucleophile. Quantitative antihydrophobic effects, as a probe for transition-state structure, have been discussed with particular reference to the benzoin condensation reaction between benzaldehyde cyanohydrin anion and benzaldehyde.” For reaction in water (ko)the free energy of the starting materials is lowered by the effect of added ethanol on the exposed phenyl groups and the same effect on the transition state is to be expected unless some fraction (h) of the hydrophobic surface is hidden. For reaction in presence of various co-solvents the dependence of rate constant k on benzaldehyde solubility S is given by log (k&) = hC log (S/So), with h = 0. I 9 (attributed to ca 40% shielding of a hydrophobic face of each phenyl group). It has been argued that the carbanion orbital overlaps n* of the carbonyl by back-side approach, such that the phenyl rings are only partly occluded (Scheme 1). These results have been compared with those for displacement reactions involving a phenyl group on each reactant.

’H,CN

0- OH

SCHEME 1

A semiempirical MO study (MNDO and PM3) of the transition states for Michael addition reactions of the lithium (2)-enolates of N-alkylideneglycinates to a$unsaturated esters has attributed the exclusively high anti-selectivity to the attractive MO interaction between the imine moiety of the donor and the a-carbon of the acceptor.58 The potential for asymmetric synthesis has prompted the first stereochemical investigation of 1,Cconjugate addition reactions of readily available chiral and racemic P-keto sulfoxides and P-keto sulfones with highly stabilized Michael acceptor^.^^

Organic Reaction Mechanisms 1995

318

Reactions with arylidenemalononitriles and benzylidenecyanoacetates were investigated since the 1P-addition is followed by O-ring closure to give an amino-4H-pyran ring amenable to analysis of the extent of asymmetric induction at the electrophilic carbon during the nucleophilic addition process; the results reveal that the type of functional residue attached to the sulfur moiety does not affect the stereochemical course of the Michael addition. Cyclopentyl-substituted dienone and trienones have been synthesized by Michael addition of y-methoxy allylsulfonyl anions to mono- and bi-cyclic cyclopentenyl phenylsulfones followed by hydrolysis of the intermediate adducts to give 6-sulfonylsubstituted enones which undergo eliminative formation of dienyl ketones.60 The chemistry depicted in Scheme 2 is illustrative of the transformations involved.

PhS02 HMPA, THF

Me0

Me0

n = 5-7 ca -65 "C

I

-Li02SPh

SCHEME 2

The lithium enolate of p-(phenylsulfony1)isobutyrophenone has been shown to exist mainly as a dimeric aggregate in THF at 3 x l o p 3 M.61 Spectroscopically distinct monomer and dimer can be detected on dilution to 5 x l o p 5 M, thereby allowing the determination of the dimerization constant Kd= (5 f0.1) x lo4 M-' and monomer pK = 14.69. The kinetics of reaction with p-t-butylbenzyl bromide reveal that alkylation occurs via the monomeric ion pair even in the presence of a large excess of dimer, The mechanisms of reaction of sodium hydroxide with 2-, 3-, and 4-nitrobenzyl sulfones, to give azoxybenzene derivatives, have been explored.62 The carbon-bonded a-adducts (59a-d) obtained on reaction of nitroalkane anions (58a-d) with 4,6-dinitrobenzofuroxan (57) can be isolated as crystalline alkali metal

11 Carbanions and Electrophilic Aliphatic Substitution

319

salts63and have been shown by rate and equilibrium measurements to be 105-10s times more stable than the analogous a-adducts of 1,3,5-trinitrobenzene. For (59a-d) in DMSO the addition of base (MeO-, CF3CH20-, NEt,) promotes formation of (60ad) by base-catalysed 8-elimination of nitrous acid, there being no evidence of deprotonation at C(a) to form the corresponding dianion in the case of (59a-c), where R' = H. The anioas (60a-d), which are the conjugate bases of the corresponding 7-R4,6-dinitrobenzofuroxans,have been characterized by N M R spectroscopy. Thus, the overall reaction constitutes a nucleophilic aromatic substitution of hydrogen, assisted by the departure of a vicarious nitro group from the nucleophile. Structural features of the diastereomeric a-adducts (59b,c) formed on reaction of (57) with (58b,c) have been discussed.

It has been shown that 4-substituted-5,5-dimethyloxazolidin-2-ones are effective chiral auxiliaries for stereoselective enolate alkylations and conjugate additions of attached N-acyl moieties, as illustrated by the high degree of asymmetric induction achieved for reactions depicted in Schemes 3 and 4.64 The auxiliaries are readily available from cc-amino acids and can be recycled following efficient removal by hydrolysis (LiOH, THF-HzO, 0-20 "C). Intramolecular Michael addition reaction between 8-keto ester and enol moieties has featured in studies of formation of 14-membered macro cycle^.^^ Diastereoselective bromination of lithium and boron enolates derived from 2-acyI-2ethyl-l,3-dithiane-l-oxideshas been achieved with limited success using NBS as the source of electrophilic halogen.66 Results of normal anionic polymerization of methylmethacrylate promoted by 9methylfluorenide as a nucleophilic catalyst have been compared with those for an analogous group transfer polymerization which occurs if a silyl ketene acetal initiator, 1-methoxy-1-(trimethylsiloxy)-2-methylprop-1-ene, is also present;67 it is concluded that the ester enolate anions are propagating intermediates in each case. Tetrabutylammonium salts of carbon acids (malonic acid diesters and diamides, nitropropane, phenylacetic and phenylpropionic acid esters and 9-ethylfluorene) have been found to initiate polymerization of acrylates and methacrylates at room temperature.68 Narrow molecular weight distributions can be achieved but the side reactions observed suggest that the growing polymer chain does not feature the naked

Organic Reaction Mechanisms 1995

320

81-97% de from (61)

75-95% de from (62)

(i) LDA, 0 "C (ii) PhCH2Br (iii) Me1 R = Me, Ph, Bu, Pr' SCHEME 3

95% de from (63)

92% de from (64)

(iv) CuBr, (Me)2S/PhMgBr, THFhle2S (2:l) (v) CuBr, (Me)zS/MeMgBr

SCHEME 4

anion expected of a true living polymerization process, possibly as a consequence of hydrogen bonding between the anion and metal-free action. Photostimulation has been shown to induce reaction of 1-iodoadamantane with a range of carbanions in DMSO. The SRNlmechanism has been proposed and the following reactivity order of carbanions towards 1-adamantyl radicals in the first propagation step has been determined by competition experiments: acetone enolate ion (1 .O) < acetophenone enolate ion (1 1) < nitromethane anion (32) < anthrone anion (80); the carbanion reactivity in the photostimulated electron transfer increases with the pK, of the corresponding conjugate acids.69 A 'H, I3C, and 29Si NMR spectroscopic analysis has established that 2-bromo-l(trimethylsi1oxy)ethylene (65) is converted exclusively into the carbanionic species (66) on addition to t-BuLi in Et20.70In contrast, when THF is used, the initially formed (66) undergoes complete transformation to the enolic structure (67) over a period of 8 h by an intramolecular 1,3-rnigration of the trimethylsilyl group. The results are consistent

11 Carbanions and Electrophilic Aliphatic Substitution

32 1

with product distributions previously reported for reaction of electrophiles with (65) in various solvents following bromine-lithium exchange. Novel intramolecular attack at the a-carbons of cyclopropanone-Favorskii intermediates by enolate ions has been shown to provide a route to functionalized tri- and tetra-cyclic systems.71A linear steric energy correlation has been established for a cyclic condensation of alkyl acetoacetates with 1,3,5trinitrobenzene in presence of base.72

Heteroatom-stabilized Species Reviews of regioselectivity and stereoselectivity of heterosubstituted carbanions have highlighted the role of silylallyl anions in organic synthesis73aand the influences of counterion, solvent, and heteroatom on coupling reactions of charge-delocalized car bani on^.^^' The chemistry and thermochemistry of silicon-containinganions in the gas phase have also been reviewed.74 a-Silyl effects on the acidities of carbon acids and on the corresponding homolytic bond dissociation enthalpies have been reported. Introduction of a Me3Si group into the 9-position of fluorene or the methyl group of PhS02CH3 increases the acidity by 2 and 4.2 kcal molrespectively; likewise, incorporation of the Ph3Si group causes increases of 5.9 and 10.5 kcal molre~pectively.~~ In contrast, corresponding increases in the BDEs are small and indicative of destabilizing effects on radicals adjacent to silicon. The acidity increases have been attributed to a combination of (a) anion stabilization through polarizability effects of the silyl groups and (b) relief of steric strain on deprotonation of the substrate. a-Silyl carbanions have been implicated in the synthesis of thiophenes from allenyl s u l f o n e ~and ~ ~from ~ a-silylallenepho~phonates;~~' in each case the anions, generated by heteroconjugate addition, reacted with SO2 to form intermediate ap-unsaturated sulfines which underwent subsequent rearrangement. Kinetic and mechanistic studies of enantiomerization of a-thio-, a-seleno- and atelluro-substituted alkyllithium compounds have been rep~rted.'~ Dimesitylphenylboranes (68) have been found to form corresponding dianions in THF on reduction with Na-K or K mirror; the spectral data suggest that the dominant canonical structure is (69) rather than (70).78

',

',

Scheme 5 is believed to account for the formation of imine (78) from dimethylvinylsulfonium iodide and (71) since reaction of intermediate anion (74) by an alternative 1,2-hydride shift with displacement of dimethyl sulfide would proceed without loss of deuterium from the product.79

Organic Reaction Mechanisms 1995

322

It SCHEME 5

A full report of the high diastereoselectivity found for reaction of the anion of trans1,3-dithiacyclohexane 1,3-dioxide with aromatic aldehydes has been published.80 The stereochemistry of addition is highly selective only when the reactions are under equilibrium control; this can be achieved using the sodium salt whereas for other metals (Li, Mg, Al, Ce, Ti) poorer selectivity results. It has been argued that preferential complexation of the metal alkoxide with the axial sulfoxide results in a conformation in which the equatorial sulfoxide electronically repels the aromatic ring and thereby disfavours one of the two possible diastereoisomeric products. Lochmann-Schlosser base has also been applied in a study of the relative rate and stereochemistry of formation of carbanions derived from 1,3-dioxanes bearing methyl and/or phenyl substituents at C(2) or C(4).81. It has been concluded that while two adjacent oxygen atoms mildly stabilize equatorial carbanions, the stereoelectronic effect of the lone pairs is to prevent the resulting carbanion from becoming planar, and there is a very large ratio of relative kinetic acidities for equatorial and axial hydrogens at C(2). Thus, 2-phenyl- 1,3-dioxanes can be deprotonated to give a pyramidal anion (similar to that for 2-phenyl- 1,3-dithianes and reprotonated stereoselectively from the equatorial side) provided that the phenyl group occupies an axial position, whereas either equatorial or axial hydrogen can be removed from 4-phenyl-l,3-dioxanes to give the benzylic carbanion which is planar and therefore similar to the phenylcyclohexyl carbanion.

I 1 Carbanions and Electrophilic Aliphatic Substitution

323

Asymmetric induction has been reported for reaction of prochiral electrophiles with the configurationally stable sulfoxide carbanions derived from dithioacetal sulfoxides which incorporate the thiacyclopentane ring.82 Tricarbonyl(styrene)chromium(O) has been shown to react with sulfur and phosphorus ylides (and a-chloro organometallics) to give tricarbonylchromium(0) complexes of mono-, di- and tri-substituted cyclopropane~.~~ Reaction mechanism and synthetic applications of the Wittig-Horner reactions have been reviewed84and the origin of the stereoselectivity exhibited in Wittig reaction of aromatic ketones has been addressed.85The high E-stereoselectivity found for reaction of arylsulfonamido-substituted phenyl 3-pyndyl aromatic ketones with non-stabilized carboxyphosphonium ylides [Br-Ph3P+(CH2)n+lC02H,n = 2-71 has been ascribed to stabilization of a trans-oxaphosphetane intermediate through interaction of the sulfonamido and carboxylate groups by either hydrogen bonding or salt bridge formation; removal of either of these groups results in preferential (4-alkene formation. The conclusions are supported by semiempirical conformational analysis of the four uncharged diastereomeric oxaphosphetane intermediates in each case. The nitrile imine HCNNH (80), an isomer of diazomethane (79), has been formed in the gas phase by a cation beam experiment and shown to exist as a stable molecule; theoretical calculations on the interconversion of (79), (80), and (81) have been reported.86

Organometallic Species Means of lithiation of fluorinated benzenes and fluorinated bromobenzenes have been explored.87Lithium diisopropylamide (LDA) in THF-hexane causes clean removal of the most acidic proton, whereas butyllithium in diethyl ether-hexane can be used to achieve clean bromine-lithium exchange. The lithiated intermediates so formed were identified either by trapping with acetone or by thermal conversion to the corresponding benzyne, which was then trapped by Diels-Alder addition. Results of a study of the directed lithiation of unprotected benzoic acids, using standard conditions (Bu'Li-TMEDA-THF, -90 "C) followed by reaction of the lithiated product with electrophiles, have aided development of routes to benzoic acids contiguously tri- and tetra-substituted with a variety of functionalities.88Although the carboxylate group directs ortho-lithiation of the parent acid, it is only of intermediate directing ability, as evidenced in intramolecular competition with methoxy, chloro, fluoro, or diethylamido groups in ortho- and para-substituted benzoic acids. Further investigation of the orientation of lithiation of 1- and 2-alkylbenzotriazoles has revealed that the 2-isopropyl derivative reacts only at the a-CH of the isopropyl group whereas the 1-isopropyl derivative is lithiated mainly at three positions of the

324

Organic Reaction Mechanisms 1995

benzene ring; the l-methyl and 1-ethyl derivatives undergo predominant a-CH lithiati~n.'~ A report of a PM3 and MNDO study of the mechanism and the regioselectivity of the lithiation of lithium methyl-l- and methyl-2-naphthylcarbamate, lithium 1,2,3,4tetrahydroisoquinolinecarbamate, toluene, and phenol has cautioned that regioselectivity predicted by semiempirical methods may be erroneous when two differently hybridized carbon centers of the substrate are in c~mpetition.'~ In contrast with the exclusive formation of 3-lithio-2-methoxypyridine(83) and the high yield of 1,4-adduct (84) already reported for reaction of 2-methoxypyridine (82) with LDA and n-BuLi, respectively, it has been found that a 1 : 1 aggregate of BuLi with Me2N(CH2)20Li induces predominant formation of (85) by metalation at C(6).91

The reactivity of methyllithium with bridgehead nitrogen imidazoheterocycles has been e~plored.'~ The well established regioselective ortho-deprotonation of arene chromium tricarbonyl complexes bearing a-electron-withdrawing or chelating substituents has been extended to include regioselective ortho-substitution of diphenylsulfoxide chromium tri~arbonyl.'~The sulfoxide substituent can induce regio- and stereoselective ortho-deprotonation and can subsequently be removed to give its @so anion. The mono- and di-anions derived from diphenylsulfoxide chromium tricarbonyl and lithium diisopropylamide show complementary stereoselectivities in their reactions with electrophiles (D+, MeI, Me3SiC1). Ortho-deprotonation of (1s)-1 -phenethyl (phenyl chromium tricarbonyl) ether with marked stereoselectivity has been exploited in asymmetric synthesis of homochiral diarylcarbinols from the resulting ~ a r b a n i o n . ~ ~ Intramolecular coordination of lithium ion with the penultimate 2-pyridyl group of 1lithio-1,3-bis(2-pyridyl)butane is believed to account for the stereoselective formation of meso-like products of its alkylation, silylation, and other electrophilic reactions conducted in THF at -78 0C.95 Unprecedented 1,6-nucleophilicaddition of organolithiums (in pentane at -78 "C) to aromatic aldehydes and ketones (Scheme 6) has been promoted, in high yield, by initial complexation of the carbonyl compound with aluminium tris(2,6-diphenylphenoxide) (ATPH).96 Primary, secondary, and tertiary alkyllithiums can be introduced and the distribution of aromatization to dearomatization products can be influenced by choice of solvent and quenching method. Highly diastereoselective non-chelate-controlled 1,2-addition of 1-bromo- 1-1ithioalk1-ene carbenoids to O-protected a- and P-hydroxyaldehydes has been used to introduce

1I Carbanions and Electrophilic Aliphatic Substitution

325

SCHEME 6

the synthons -CH20H and THO?' A method for the diastereoselective preparation of substituted epichlorohydrins by reaction of a-bromo- or a-chloro-carbonyl compounds with chloro- or iodo-methyllithium, respectively, has been reported;98the epichlorohydrins have been used for regioselective preparation of ally1 alcohols. Electron-withdrawing groups (R = COZEt, COMe) have been found to induce unusual 1,4-addition of MeMgI to benzoco~marins.~~ On exposure of a mixture of and (Z)-2-(2-methylpropylidene)cyclohexanone to MeMgI the Z-isomer remains unreactive and the E-isomer forms two stereoisomers of 1-methyl-2-(2-methylpropylidene)cyclohexanol, preferentially with the hydroxyl group in the equatorial position.loo Highly diastereoselective ring-opening reactions of chiral acetals, derived fiom I ,4-di-t-alkoxy-(2S,3S)-butane-2,3-diols and ArCHO, by secondary or sterically hindered Grignard reagents are believed to proceed with bidentate complexation of magnesium with acetal and t-alkoxy oxygens."' The enantioselective addition of diethylzinc to arylaldehydes, to give optically active 1-arylpropanols, can be achieved in good yield and with enantiomeric excess of up to 88% by use of the optically active N-1-phenylethyl derivatives of (lR)-2-amino-lphenylethanol as chiral auxiliaries.' 0 2 The auxiliary features stereogenic centres in 1,4positions, whereas the most common promoters of the asymmetric addition of EtzZn to aldehydes are chiral at adjacent positions. Twenty new ligands, all analogues of TADDOL (86a), have been evaluated as titanium ligands for catalysis of asymmetric addition of methyltitanium and diethylzinc reagents to ben~aldehyde."~The ligands featured replacement of the dioxolane ring of the TADDOL by cyclobutane, cyclopentane, cyclohexane, cyclohexene, bicyclo[2.2.1]heptane, bicyclo[2.2.1Iheptene, bicyclo[2.2.2]octane and bicyclo[2.2.1Ioctene; replacement of the aryl groups by H or alkyl was also explored. It was found that both axial and equatorial aryl groups are necessary for ligand-accelerated catalysis of these reactions and that TADDOL (86b) is superior to all other ligands. Enantioselective addition of dialkylzincs to benzaldehyde to give enantiomerically pure secondary alcohols can be achieved under the catalytic influence of certain chiral P-dialkylamino alcohols. It has now been established that non-linear effects on the rate and stereoselectivity of such reactions arise when stereochemically, or chemically,

(a-

Organic Reaction Mechanisms 1995

326

OH

R

OH

O

(86) a;R=H b; R = Me, Ar = Ph

impure catalyst is used; the influence of (2S)-3-exo-(dimethylamino)isoborneoland its stereoisomers and also achiral 2-(dimethylamino)-l , 1-dimethyl ethanol has been explored systematically.lo4 The expectation that enantioselectivity of a reaction may vary linearly from 100% S to 100% R as a h c t i o n of the ratio of the S and R catalyst is no longer valid when the catalyst enantiomers interact in the reaction system. Thus, for reaction of diethylzinc with benzaldehyde in toluene in presence of racemic amino alcohol (87) the reaction proceeds 13 times slower than in presence of the enantiomerically pure S or R catalyst; furthermore, although racemic (87) promoted the formation of racemic product, the ee values were not otherwise directly related to the ratio of the catalyst enantiomers used. It has been concluded that the reaction is catalysed by the tricoordinate ethylzinc aminoalkoxide (88, R = Et), formed fiom diethylzinc and [(S)-XI- or [(R)-X]-(87),which is in equilibrium with its dimer (89). When both enantiomers of the catalyst are present, the alternative homochiral or

heterochiral diastereomeric dimers (89) may be formed from the monomers (88) by self-recognition or non-self-recognition, respectively. The heterochiral dimer has been found, by cryoscopy, to be overwhelmingly more stable than the homochiral dimers, thereby ensuring that most of the minor enantiomer is incorporated in heterochiral dimer whereas the excess of the dominant enantiomer exists as homochiral dimer in equilibrium with the corresponding monomer which promotes enantioselective alkylation. This accounts for the marked chiral amplification observed when partially resolved (87) is used as catalyst and for attainment of a rate minimum when racemic (87) is used as catalyst.

1 I Carbanions and Electrophilic Aliphatic Substitution

327

The fl-dialkylamino alcohol-promoted reaction of dialkylzincs with aldehydes has also been modelled by an ah initio MO study, using 2-aminoethanol, dimethylzinc, and formaldehyde.lo5 The methylzinc alkoxide (90), formed from dimethylzinc and 2aminoethanol by elimination of methane, has been confirmed as the actual catalyst and shown to exist in equilibrium with stereoisomer dimers (anti>syn) (cf. 89). The catalyst is bifunctional and sequentially coordinates dimethylzinc and formaldehyde (in either order) to give a complex (91) which undergoes intramolecular alkyl migration to give (92); tetramer (93) is obtained from (92) by reaction with either formaldehyde or dimethylzinc. Although addition of dimethylzinc to formaldehyde is highly exothermic, the alkylation reaction does not occur in absence of an amino alcohol, or when 100 mol% of the amino alcohol is added.

H2

[

"ZnMe O/

H2

H2

(MeZnOEt)4

I

I

MeyZn -. Me

Me

The effect of a Lewis acid catalyst on nucleophilic ring opening of vinyloxiranes by organocopper reagents has been fiuther explored.'06. The reaction of methyl (E)-4,5epoxypent-2-enoate (94) with arylcopper reagents (such as PhCu and Ph2CuLi) has been shown to proceed primarily with formation of (95); the effect of BF3 is to increase the yield and reverse the regioselectivity, in favour of the apparent SN2'product (96). It has been concluded that (94) reacts with all phenylcopper reagents via an S N ~ mechanism but that the effect of BF3 is to promote initial SN2 reaction with LiBr (if present from generation of the phenylcopper reagent) to give bromo alcohol (97) and its regioisomer which is converted into (96) by a subsequent sN2' reaction. It is not clear why the sN2 product (95) predominates, without formation of (97), on reaction with Ar2CuLi.BF3when o,o'-disubstituted (Me, Me or Me, OMe).

Ar

Ar

(94)

(95)

(96)

+ QH

Organic Reaction Mechanisms 1995

328

A synclinal transition state in which the CH2SnBu3group is gauche to oxygen has been proposed to account for the effects of alkene geometry on the stereoselectivity of BF3.EtzO-mediated addition of crotylstannanes to achiral aliphatic, aromatic or ct,Punsaturated aldehydes; reactions with ct-alkoxy- and P-alkoxy-aldehydes have also been investigated.'07.

Proton-transfer Reactions Efficient catalysis of proton transfer by antibodies generated in response to rationally designed model compounds has been discussed"* and the role of His 95 in promoting intramolecular proton transfer reactions of triose phosphate isomerase has been recon~idered.'~~ Amphihydric compounds (RH) are those for which all three of the species Rf, R' and R- are sufficiently stable to be generated in solution. The thermodynamics of the corresponding C-H bond breaking by transfer of H-, H' or H+ and for interconversion of the species by electron transfer have been reported (e.g. for 9-arylxanthene and 2aryl- 1,3-dithiane series) and relationships between these properties have been discussed.' l o AM1 calculations of the gas-phase stabilities of enolates formed on deprotonation of bicyclo[2.2.2]octane-2,5-dione, bicycl0[2.2.2]octane-2,6-dione,~, 1-hydroxy-4-0~02,2,6,6-tetramethylpiperidine,4-0~0-2,2,6,6-tetramethylpiperidine-l-oxyl, 9-hydroxynorpseudopelletierine and norpseudopelletierine-9-oxyl'ohave been correlated with measurements of the corresponding rates of enolization in 60 :40 (v/v) dioxane-D20. For the acid series GCH2COMe, GCHzCO,Et, GCHZCONMe2 it has been shown that for seven sets of data [G = H, Ph, PhS, C-(CHZ)~S~CH, Me3Nf, Ph3P+, or MeCO] the homolytic BDEs of the acidic C-H bond increase progressively with the change from ketone to ester to amide, in line with the + R effects of the groups Me < OEt < NMe2. This is further illustration of the general conclusion that for weak acids decreases in ground-state energies tend to increase the BDEs of the acidic A-H bonds, and vice versa. The equilibrium acidities of these carbon acids in DMSO and the oxidation potentials of their conjugate bases have also been measured for the seven sets. For each set a progressive increase in PKHA and a smaller progressive cathodic shift of E,,(A-) accompanies the progressive small increase in BDE of the acidic C-H bond. BDEs and equilibrium acidities in DMSO have also been determined for the N-H bonds of 15 carboxamides; the average PKHA is 25.5 and the average BDE is 108 f 2 kcal mol-I. Gas-phase acidity measurements, using proton transfer kinetics in a flowing afierglow/selected-ion flow tube, have yielded values of AGacid/kcalmol- (in parentheses, f2-5 kcal mol- ') for CHz=C=CH-H (372.8), H-CH,C=CH (374.7), CH3C-C-H (373.4), and CH,=C=C'H (364), Erom which the respective values of AHa&kcal mol-l (381.1, 382.7, 381.1, and 372) were calculated using ASacicid. ' I 2 Measurements of electron affinities have been combined with values of AHacidin order to obtain the corresponding bond dissociation energies (88.7, 90.3, 130.2, and 100 kcal mol- respectively). Problems associated with determination of

'"

',

1 I Carbanions and Elech-ophilic Aliphatic Substitution

329

gas-phase acidity values by proton transfer reactions for systems which may isomerize are discussed. Isotope, solvent, steric, and temperature effects which govern the rates of proton/ deuteron transfer reactions of 2,4,6-trinitrotoluene, 2,2',4,4',6,6'-hexanitrobibenzyl (HNBB) and 2,4,6-trinitrobenzyl chlorides (TNB)with tertiary amines in DMSO and CHzC12 have been e~plored.''~The upward curvature of Arrhenius plots at low temperature for TNT and TNB is indicative of tunnelling and the observed rate constants agree well with those predicted by application of Bell's theory. A study of the ionization and enolization of 2-phenylacetylfuran has revealed (by comparison with deoxybenzoin) that the effect of the oxygen of the furan ring is to (a) enhance the acidity of the enol and (b) stabilize the keto relative to the enol tautomer."4 Rate constants for enolization (measured by iodination) and of ketonization (measured by quenching the enolate and monitoring enol) of 2-phenylacetylfuran were combined to give KE=[enol]/[ketone]= 1.32 x (pKE=5.88); pK,= 14.38 was also determined and used with pKE, to give PK,"~= 8.5 for the enol tautomer. For deoxybenzoin the values pKE= 5.15, and pK?" = 9.6 have already been reported. The kinetics of deprotonation of 2-nitroethanol (98) and 2-nitropropane-1,3-diol(99) by hydroxide ion, water, amines, and carboxylate ions have been studied in order to examine the potentiaI effect of H-bonding in the nitronate ion on the thermodynamic and kinetic acidities of (98) and (99).'15 The pK2" values for (98), (99) and CH3N02 are 8.60, 7.68, and 10.22, respectively, and the acidifying effect of the CH20H groups is believed to be a consequence of inductive electron withdrawal and hyperconjugative stabilization of the nitronate ion which may also be stabilized by intramolecular Hbonding. The increase in rate of proton transfer on substituting nitromethane with one CH20H group indicates that the Brmsted tl value is positive and in contrast with the abnormal behaviour found previously for deprotonation of nitromethane, nitroethane, and 2-nitropropane by HO-; it is argued that the deprotonation transition state is nonetheless imbalanced in each case. The acid dissociation constants (pK,OH = 13.33 and 12.60, respectively) determined for the alcoholic hydroxyl groups of (98) and (99) are consistent with an earlier correlation of RCH20H acidities with o*. 02NCH2CH20H

HOCH2CHCH20H

I

N02

(98)

(99)

Bromine or chlorine substitution has been found to increase the gas-phase acidities of benzene and naphthalene by 13-14 kcal mol-', primarily by an inductive effect which decreases by 2.5-3.5 kcal mol-' per bond separating the acidic site from the halogenbearing carbon; larger effects are caused by fluorine substitution.'I6 The acidities were determined by a flowing afterglow technique using the silane cleavage method; linear correlations between meta and para position acidities of halobenzenes with those for corresponding rn- and p-haiophenols, -haloanilines, and -halotoluenes were found. Ab initio calculations have been used to define five stationary points on the potential energy surface for proton transfer between methane and amide anion in the gas

Organic Reaction Mechanisms 1995

330

phase.’ l 7 Theoretical studies have also addressed: tunnelling contributions to the dynamics of tautomerization in gas-phase formamidine and its monohydrated complex (a hydrogen-bonded system);’ bifurcation of tunnelling trajectories of two-proton transfer reaction^;''^ and proton and heavy atom motions during tautomerization of oxalamidines.120 Errors inherent in studies of the tunnelling mechanism of liquid phase proton transfer based on kinetic isotope effects have been highlighted. A study of the deprotonation of intramolecularly hydrogen-bonded monoanions of phenylazoresorcinols (100) has been extended to include determination of the effects of substituents R’-R’ on the rate coefficient kf and equilibrium constant K.‘” The values of K increase with increasing electron-withdrawing ability of R3, such that log K = 0 . 5 5 ~ ~2.29, in 90% (v/v) DMSO-H20. Electron-withdrawing substituents R’ and R’ cause a remarkable reduction in the rate of removal of the hydrogen-bonded proton by hydroxide ion (via an open intermediate) and permit the reactions to be followed over a period of minutes.

’”

+

OR2 RI j

I

+

HO-

1:91-.2 N

NO

+

H20

A nearly temperature-independent kinetic isotope effect for the reverse proton transfer of 7-hydroxyquinoline has been confirmed, and rationalized in terms of associated solvent reorganization.”’ The kinetics of proton transfer from the N-H acid 1,8-bis(4-toluenesulfonamido)-2,4,5,7-tetrani~onaphthalene to various N-bases in acetonitrile have been interpreted with reference to the structure of the transition state.lZ4

Miscellaneous A bimolecular E2cB /?-elimination mechanism has been suggested for the transfer of hydride ion from carbanion salts RM (M = Li, MgBr) and R2N-Li+ to tetrasubstituted activated alkenes of type ArzC=C(CN)C02R (R = Me, Et);’25 the reaction occurs in competition with Michael addition and is favoured by a benzyl substituent at C(/?) of RM or a small size of RM.

1I Carbanions and Electrophilic Aliphatic Substitution

331

The mechanism of benzoin condensation of benzaldehyde in dry DMSO, using tBuOK as base and catalysed by 2-I3C-labelled 3-benzyl and 3-methylthiazolium salts, has been probed using a-I3C- and w2H-labe1ledbenzaldehyde.126 A stable intermediate 2-(a-hydroxybenzyl)thiazolium ion is formed, by nucleophilic addition of the C(2) carbaniodylide to the carbonyl carbon, without rearrangement of the benzaldehyde C(ajH and subject to the expected inverse isotope effect kH/kD = 0.83. The intermediate is rapidly converted to benzoin once even a trace of water or methanol is added to the solution. These results are in contrast with the conclusion that for benzoin condensations promoted by thiazolium cations in mild basic conditions the actual catalytic species are bis(thiazo1in-2-ylidene)~;a second-order kinetic dependence on both aldehyde and thiazolium cation has been found.12' The activity of 3,3'polymethylene-bridged thiazolium and benzothiazolium salts as base catalysts of the benzoin condensation depends strongly on the methylene bridge length and suggests that, in aprotic medium, bis(thiazo1in-2-y1idene)s rather than thiazolin-2-ylidenes are implicated.12* For other discussion of benzoin condensation, see reference 57. Sequential base-induced addition, elimination, and cyclization steps have been proposed to account for the cycloaddition products (pyrroles) formed on reaction between tosylmethyl isocyanide or (t-butoxycarbony1)methyl isocyanide, (XCH2CN), to 1,Cdisubstituted 2,3-dinotrobuta-1,3-dienes.129 Reactions of arylazosulfones (ArN=NS02Tol-p) with active-methylene compounds (CH2XY; X,Y = CN, C02Et) have been found to proceed by successive condensation processes to form tetrasubstituted ethylenes, such as ArNHCX=CXY.I3O Diastereoselective addition of the dianion of 4-(phenylsulfonyljbutanoic acid to a chiral a-benzyloxymethyl imine has been studied.I3' Catalytic antibodies capable of promoting Dieckman cyclization and related carbanion reactions have been generated in response to bifunctional five-membered ring haptens which feature a sulfone group, to represent the transition state(s) associated with the tetrahedral intermediate, and an amino group, to encourage formation of a general base.'32 Internal clockwise versus anticlockwise rotation of the carbanion formed on addition of I5NN; to an electrophilic vinyl azide, 3-azidomethylenedihydroro-(3H)-furan-2-one, has been probed by monitoring label incorporation and Z to E is~merization.'~~ Despite the relatively low nucleofbgality of azide, N; expulsion occurs more rapidly than complete equilibration of the carbanion conformers. Nonetheless, the percentage of label incorporation on starting from the E, relative to Z, isomer indicates that incorporation and isomerization are connected; competition between 60 a and 120 rotations has been discussed. The products of reaction of 1-hydroxyprenyl monoanion with Br(CH2),Br (n = 2-4) form by alkylation at position 3a or 5, followed by deprotonation and intramolecular alkylation.134 It has been reported that 2- and 3-nitro-l,6-methano[l0]annulenesand their 11,lldifluoro derivatives undergo vicarious nucleophilic substitution of hydrogen (ortho or para to the nitro group) on reaction with a carbanion bearing a leaving group X at the carbanionic centre; this involves nucleophilic addition, base-induced p-elimination of HX, and p r ~ t o n a t i o n . ' ~ ~ O

332

Organic Reaction Mechanisms 1995

cl-Lithio conjugated enyne sulfones have been found to form 2,4-diynols in high yield on reaction with carbonyl compounds; the reaction proceeds by a carbonyl addition, syn-dehydrosulfonylation sequence. 36 Stereoselective additions of a-sulfinyl ester enolate to benzaldimine~l~'and of organolithium reagents to chiral imines derived from erythro-2-amino- 1,2-diphenylethan01'~' have been reported.

Electrophilic Aliphatic Substitution Results of a study of the kinetics of reaction of N-bromosuccinimide to amines and amino acids suggest that the electrophilic transfer of Br+ from nitrogen to nitrogen occurs via a concerted reaction in which the unprotonated amino group of the substrate attacks the NBS bromine. 139 The corresponding second-order rate constants increase with increasing basicity of the amino substrate; the activation enthalpies for these fast processes are small and the large negative entropies of activation are indicative of a highly solvated transition state. The kinetics of chlorination of a m i n e ~ ' ~ ~and ' ' ~ N' rnethyla~etamide'~~ in aqueous hypochlorite have also been interpreted. An SN2-type mechanism is believed to apply for fluorination of a range of nucleophilic substrates (metal enolates, silyl en01 ethers, 1,3-dicarbonyl compounds, o-metallated aromatics, RLi and RMgX) by N-fluoro-o-benzenedisulfonimide or o-benzendisulfonic acid. 143 Results of a study of the solvent dependence of the kinetics of nitrosation of ureas by nitrous acid in THF-water and DMSO-water mixtures suggest that only at high THF concentrations ( > 80%, wlw), when catalysis by chloride ion can be observed, does the mechanism differ from that in pure water.'44 Ab initio calculations have revealed that the two viable pathways for reaction of ethane with NO+ are in contrast with the generally discussed mechanisms for electrophilic substitution of alkanes and lead to (a) the nitrosomethylene cation and methane through C-C bond cleavage and (b) protonated nitrosoethane via abstraction of a hydride followed by addition of HNO to the ethyl cation; the respectively activation energies (33.5 and 31.1 kcal mol-') and small primary H/D isotope effects (2.6 and 2.9) for attainment of the non-linear transition structures are ~ o m p a r a b l e . ' ~ ~ The complex situations which arise when an ambident nucleophile reacts with a nitrosating agent, perhaps bearing two electrophilic centres, have been discussed'46 and the kinetics of nitrosation of dibenzylamine by NaN02 in aqueous buffers have been reported. 147 Remote conformational bias effects on diastereofacial selectivity in SE2' additions of 8-oxygenated allylic stannanes to chiral enals have been interpreted.14'

References

' Ochterski, J. W., Petersson, G. A,, and Wiberg, K. B., 1 Am. Chem. Soc., 117, 11299 (1995).

'

Sou, and Li, W.-K., 1 Chem. Res. (S), 1995, 464. de Visser, S. P., de Koning, L. J., van der Hart, W J., and Nibbering, N. M . M . , Reel. Trav. Chim. PaysBus, 114, 267 (1995). Dua, S., Sheldon, J. C., and Bowie, J. H., 1 Chem. Soc., Chem. Commun., 1995, 1067. Nir, M., Hoffman, R. E., Shapiro, I. O., and Rabinovitz, M., 1 Chem. Sac., Perkin Trans. 2, 1995, 1433. Sygula, A. and Rabideau, I? W., THEOCHEM, 333, 215 (1995); Chem. Abs., 123, 32424 (1995).

I 1 Carbanions and Electrophilic Aliphatic Substitution

333

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' Wong, M. W, 1 Chem. SOC.,Chem. Commun., 1995, 2227.

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''

*'

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1 1 Carbanions and Electrophilic Aliphatic Substitution Io3

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Io9 I10

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”’

CHAPTER 12

Elimination Reactions J. R. GANDLER Department of Chemistry, California State University, Fresno, CA 93 740-0070, USA Mechanisms of Elimination Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . ElcB and Related Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E2 Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eliminations via Carbocations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pyrolytic Eliminations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions of Carboxylic Acids and Related Reactions . . . . . . . . . . . . . . . . .

Nitrogen Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alkyl Halides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cyclo-eliminations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Theoretical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E2 and Related Eliminations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cyclo-eliminations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pyrolytic Eliminations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eliminations via Carbocations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Elimination Reactions in Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Eliminations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

337 337 34 1 344 344 344 346 347 348 349 349 351 352 353 353 357 360

Mechanisms of Elimination Reactions ElcB and Related Mechanisms The base-promoted hydrolyses of a series of aryl N-(arylsu1fonyl)carbamates (1) in aqueous solution have been reported.' The products in these reactions are the corresponding benzenesulfonamides, phenols and COz. The Hammett p value (using Hammett r Y substituent constants) for changes in substituents in the leaving aryloxide ion is large and positive ( p = 2 . 9 3 ) , consistent with rate-limiting expulsion of the aryloxide ion in an ElcB mechanism, rather than direct rate-limiting nucleophilic addition to the carbonyl group. Further support for this mechanism includes a Hammett p value of - 0.66 for substituent changes in the benzene ring of the arylsulfonyl group. This is consistent with increasing rates of expulsion of the aryloxide ion from the conjugate base of the substrate that is favoured by electron-donating substituents (the substrates are largely or completely ionized at the pH values used to determine the Hammett p value). The logarithm of the rate constants for expulsion of phenoxide ions from the conjugate bases of substrates of the type m C 0 2 P h , where R =Me, H, Ph, p02NC6H4, MeCO, PhCO, Cl,CCO, and PhS02, against the pK, of these substrates, is Organic Reaction Mechanisms 1995. Edited by A. C. Knipe and W. E. Watts 0 1997 John Wiley & Sons Ltd

337

Organic Reaction Mechanisms 1995

338

impressively linear and extends over ca 15 pKa units of substrate acidity (slope = 0.74). Rates vary over lO”-fold. This result extends the relationship first reported by Williams and co-workers.

0

ArSO2NH-4

O

K,

\

ArSO2N KOAl

OAr

(1) ArS02NH2+ C 0 2 + ArOH

H20,

HO-

C--

ArS02N=C=O

+ ArO-

Rate constants for expulsion of CF3CH20- and MeO- from (2) and (3) have been reported as part of a continuing study of nucleophilic vinylic substitution reactions in which the overall reaction is analysed, and rate constants for all the elementary steps determined.2Relative leaving-group abilities of the two alkoxide ions from these stable and strongly delocalized carbanions show a strong dependence on their pK, values. For example, values of PI, (the slope of a plot of log k against the pK, of the leaving group) are near - 1, suggesting extensive cleavage of the C-0 bond in the transition state for leaving group expulsion. Steric acceleration of the loss of CF3CH20- contributes somewhat to these large (3, values.

Nucleophilic vinylic substitution reactions of P-methoxy-a-nitrostilbene (4) with methoxyamine and N-methylmethoxyamine have been r e p ~ r t e d .The ~ intermediate nitronate ion is detectable in these reactions, but not in reactions with more basic amines, because expulsion of methoxide ion from the intermediate carbanion is more strongly dependent on the pKa of the amine (owing to the ‘push’ of the amine’s nonbonded electrons) than is nucleophilic addition to the substrate. As a result, loss of methoxide is slowed to an extent that the intermediate nitronate ion is detectable. Significant amounts of the intermediate can be generated, even with the less basic amines, at pH values where deprotonation of the zwitterion intermediate helps drive the equilibrium towards the carbanion.

12 Elimination Reactions

339 RR~NH+

Ph'

Ph

Ph'

(4)

RR'N

Ph

The hydroxide-promoted hydrolyses of aryl o-hydroxycinnamate esters (5) have been studied in dioxane-water (20 : 80, v / v ) . ~Nine phenoxide leaving groups ranging in leaving-group ability from 2,6-dinitrophenoxide ion (pK1, E 3.7 1) to 4-cyanophenoxide ion (pKl, = 7.95) were studied. A change in mechanism is suggested to occur from an ElcB mechanism, via the o-oxoketene intermediate (6), for leaving groups whose pK, is less than 6, to an addition-elimination mechanism for substrates with more basic leaving groups. The change in mechanism is supported by a break in a Brsnsted plot of the logarithm of the apparent second-order rate constant for reaction against PICl,, the pK, of the leaving group. For weakly basic leaving groups Plg= - 1.11, consistent with rate-limiting expulsion of a phenoxide ion via the ElcB mechanism. For more basic phenoxide ion leaving groups, Blg = -0.25, consistent with rate-limiting addition of hydroxide ion to the carbonyl group. An ElcB mechanism is also supported for the reaction of 2,4-dinitrophenyl-2'-hydroxycinnamate,based on a rate constant calculated from the Hammett equation that is 330 times greater than expected for the associative mechanism, and on entropies of activation that are 40 cal mol-' K-' larger than for the BAc2 reaction of 2,4-dinitrophenylcinnamate.

?H

Q-

340

Organic Reaction Mechanisms 1995

For the amine- and substituted pyridine-promoted decomposition of a variety of ozonides, a 1,2-eliminationvia an ElcB mechanism has been suggested, although an E2 mechanism seems more likely, rather than direct nucleophilic attack on oxygen.’ For example, when 1-phenylcyclopentene reacts with ozone, it forms (7). With tertiary amines and substituted pyridines, (7)reacts to give 5-0x0-5-phenylpentanoic acid (S), the product of 1,2-elimination. On the other hand, if breakdown of (7) proceeded via nucleophilic attack on oxygen, 5-0x0-Sphenylpentanal would have been produced instead. The authors show that, for the reaction of a wide variety of alkenes, ozonolysis followed by work-up with triethylamine is faster and results in better yields than a traditional work-up with dimethyl sulfide.

The aminolysis and hydrolysis reactions of several sulfamate esters (RNHS020Np, where R=PhCH2, Ph, 4-MeC&, 3-MeC6H4, 4-FC6H4, 4-C1C6H4, and H, and ONp =p-nitrophenoxide) have been studied in an acetonitrile-water solvent mixture (50 : 50).6 The products of the reactions are RNHS02NHR and RNHSO; RNH,f. The results are consistent with an ElcB elimination, via a sulfonylamine intermediate (RN=S02), with rate-limiting formation of the intermediate from the conjugate base of the substrate. The base-promoted elimination reactions of the sulfoxides and sulfones of sulfur mustard (2-chloroethyl ethyl sulfide) have been studied in aqueous s ~ l u t i o n Unlike .~ sulfur mustard, where the major reaction is substitution (via a cyclic episulfonium ion), for the sulfoxides and sulfones the only observed reaction is elimination of HCl to form alkenes. The mechanism is likely to be either ElcB, or E2 via a carbanion-like transition state. The base-promoted reactions of several ally1 ethers (9) (1-ethoxybut-2-enes, 1methoxybut-2-enes, 1-ethoxyprop-2-ene) have been studied experimentally in the gas phase by Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry* and theoretically by density-functional theory. A variety of bases were employed, including H2N-, Ph-, Me2N-, HO-, MeO-, EtO-, and F- ions. The major reaction pathway is 1,Celirnination to give, presumably, buta-l,3-diene, and the detectable ionic products, viz. the alkoxide ion either free (RO-) or solvated by the conjugated acid of the base (RO- HB). Proton-transfer reactions (from the 6 carbon), 1,2-eliminations, aliphatic SN2, and SN2’ reactions also contribute, although to a small extent, to the overall reaction of these substrates. The 1,Celimination reaction is suggested to follow an ElcB mechanism that may proceed through either single-, double- or triple-well pathways.

12 Elimination Reactions

341

R = Et, Me

E2 Mechanisms Elimination reactions in acetonitrile-water mixtures of (E)-O-p-nitrophenyl-2,4dinitrobenzaldoxime (10; R = H) promoted by triethylamine in triethylaminetriethylammonium (1 : 1) buffer solution have been r e p ~ r t e d .The ~ mechanism is suggested to be E2, with syn elimination, despite the presence of a strongly activating 2,4-dinitrophenyl group and a moderate aryloxide leaving group. The evidence for the E2 mechanism includes the observation of general base catalysis by triethylamine and a significant leaving-group effect: the 2,4-dinitrophenoxide/4-nitrophenoxideleavinggroup rate ratio is 33 in water-acetonitrile (95 :5 ) , a ratio that appears too large for a mechanism involving rate-limiting proton transfer.

&R

0"

+

O2N

NO,

(10) R = H, NO2

A water-promoted concerted E2 mechanism in acetonitrile-water (25 : 75, v/v) has been suggested for the reactions of 9-(1-X-ethyl)fluorene (ll),where X = Br or I. An E2 elimination reaction yielding 9-( 1-ethylidene)fluorene (12) competes with stepwise elimination (yielding 9-vinylfluorene) and substitution reactions that proceed via an ion pair." For the iodide and bromide, 95% and 69%, respectively, of the product is (12). The reaction promoted by solvent takes place with a significant primary kinetic isotope effect, kH/kD= 2.0 and 3 .O, for the bromide and iodide substrates, respectively, consistent with a concerted E2 mechanism, rather than a stepwise mechanism via a free or ion-paired carbocation. This elimination reaction is promoted by substituted acetate

Organic Reaction Mechanisms 1995

342

ions, giving rise to a Brsnsted value for general base catalysis of 0.42 and 0.41 for the bromide and iodide substrates, respectively. Water shows a ca sevenfold negative deviation from the Brsnsted correlation line. If the previously studied reaction of 9(chloromethy1)fluorene follows an E2 mechanism, as has been proposed based on structure-reactivity studies, it is likely that the compounds studied in this work do also. In a closely related paper,' the reactions of (11) were investigated with X = chloride, tosylate, and brosylate leaving groups. Evidence is presented that the tosylate derivative undergoes elimination via an ion-pair mechanism rather than by the E2 mechanism. The authors suggest that, unlike SN2/SN1 substitution reactions, in these systems the concerted E2 mechanism is not enforced by the short lifetime of the ion-paired carbocation intermediate. Rather, it is concluded that both the stepwise and concerted mechanisms may proceed simultaneously by two parallel competing pathways. The hydroxide-promoted reaction of 2-(4-nitrophenyl)ethyl bromide was studied12 in the presence of cationic chemo-degradable surfactants, [2-alkyl(1,3-dioxalan-4-y1) methyl]trimethylammonium bromides (13). Rate enhancements of up to 50-fold were observed relative to the hydroxide ion-promoted reaction in the absence of surfactants. The authors conclude that the major source of the rate enhancement is increased reactant concentration in the micellar reaction volume.

'

RXH Me3N+

Br-

The carbanions of nitromethane, nitroethane, 1-nitropropane, and 2-nitropropane add to the very strongly electrophilic 4,6-dinitrobenzofuroxan (14) to form stable carbonbonded a-adducts, similar to Meisenheimer or anionic a-cornplexe~.~Addition of base (in Me2S0 solution) does not result in deprotonation of the adducts (this would give rise to dinitronate ions), but instead results in elimination of HN02 to give an alkene (15) via an E2 or ElcB mechanism.

12 Elimination Reactions

343

Reactions of 1-(2-chloroethyl)-3-alkyl-3-acyltriazenes(16) with isopropylamine, npropylamine, diethylamine, and pyrrolidine (in the amine as solvent), and with hydroxide ion in aqueous solution, result in dehydrohalogenation to give 1-vinyl-3alkyl-3-acylt~iazenes(17). The authors favour an E2 mechanism for the reaction with a transition state that has significant carbanion character.l4 For several of the substrates the initial product undergoes subsequent deacylation. There is no hydrogen-deuterium exchange into the substrate during the course of the reaction as determined by ‘H NMR. Direct SN2substitution andor deacylation rather than elimination were observed under reactions conditions that favour these mechanisms.

(16)

(17)

R = Me, benzyl Acyl = N-methylcarbamoyl, acetyl, carboethoxy

Treatment of threo- and erythro-1-methyl-2-phenylpropyl tosylate with butyllithium at room temperature results in stereospecific syn elimination; the threo isomer yields (@-2-phenylbut-2-ene, whereas the erythro isomer yields (Z)-2-phenylbut-2-ene, in 98% and 94% isomeric purity, respectively.” Evidence is presented that suggests the elimination involves o-lithiation of the tosyl group followed by syn elimination via the o-lithiated intermediate.

Organic Reaction Mechanisms I995

344

The kinetics of the debromination reactions of erythro-dl-1-aryl-1,2-dibromo-2nitropropanes by secondary amines in acetonitrile have been reported. The reactions are stereospecific (anti elimination) resulting in the formation of (E)-1-aryl-2nitropropenes. The rate law consists of terms that are both first and second order in amine. Correlation with Hammett CJ values (rather than 0- values) suggests that the reaction is initiated by attack on the Br that is M to the nitro group. Based on Hammett p values, Brernsted p values, and the bromide/chloride leaving-group rate ratio (the element effect), an E2 mechanism with a carbanion-like transition state is proposed for the reactions of these substrates. The dehydrohalogenation reactions of N-(2,3-dibromo-3-chlorobutyl)trimethylammonium bromide by alcoholic potassium hydroxide have been reported. Dehydrobrominations of a series of 1,2-dibromo-l-diaryl-ethanesand -propanes have been reported in CCl4 solution promoted by the following solid catalysts; powdered NaBr, LiC1, Fe', FeBr;?,FeBr3, and silica gel.''

'

Eliminations via Carbocations A review with 20 references has been published on ion pairs and ion-molecule pairs in solvolytic substitution, elimination, and rearrangement reactions.l 9 The reaction of 2-methyl-2-propanesulfonylchloride has been investigated in aqueous solution over the pH range 3.5-13.0.*' Reaction apparently proceeds via ionization to the t-butyl carbocation, which gives rise to products of both substitution (tbutyl chloride, t-butyl alcohol, and, at high pH, 2-methyl-2-propanesulfonate ion) and elimination (isobutene). The reactions of alkyl vinyl ethers and alkyl vinyl sulfides with trifluoroacetic anhydride in CC14 solution (in the absence of added base) has been reported.;?' 'H NMR and IR spectra show that addition of trifluoroacetic anhydride to the double bond results in the formation of stable adducts (18), which undergo slow elimination of trifluoroacetic acid to give trifluoroacetylated alkenes. Depending on substrate structure, the elimination step is suggested to proceed by the Ei, E2, or El mechanism.

CH,=CHXR

(CFK0)20

OCOCF3

I

CF3COCH2CHXR

slow

(18)

CF3COCH=CHXR

X = 0 (trans product) X = S (cis and trans product)

Pyrolytic Eliminations Reactions of Carboxylic Acids and Related Reactions Rate constants for the gas-phase pyrolysis of a series of N-benzoyl- (19) and N-acetylpropanamides (20), and N-benzoyl- and N-acetyl-2-methypropanamideshave been

12 Elimination Reactions

345

measured.22Reactions proceed via a six-membered transition state that is favoured (up to a factor of 12) by methyl substitution at the j3-position (the site at which the proton is removed). Two modes of elimination are possible for the N-acetyl compounds, via transition states (21) and (22). Since acetamide is not formed in the reaction, but RIRzCHCONH2 is, (where R1 and Rz are either H or methyl), the reaction is suggested to proceed via loss of one of the N-acetyl methyl protons, via (22).

R'

R2

0&YH PhCONHCOCHR'R2

'

---+

NY0

(19)

b; R1 = H, R2 = Me c; R' = R2 = Me

(20)

NH2COPh

+ R1R2C=C0

Ph

a; R I = R* = H

MeCONHCOCHR'R*

-

(21)

-

0

-

1.

R'R~CH

0'

i .H

CHzCO

+ NH2COCHR'R2

(22)

The kinetics of gas-phase pyrolysis of chloroacetic acid, 3-chloropropionic acid, 2chlorobutyric acid, 3-chlorobutyric acid, 5-chlorovaleric acid,23 and 2-bromo-3methylbutyric acid24have been studied in a static reaction vessel, seasoned with ally1 bromide, in the presence of the free-radical inhibitors cyclohexene or toluene. The reactions were studied at temperatures ranging from ca 300 to 400 "C. Products are formed via several reaction channels. However, for the dehydrohalogenation reactions of a-halo acids, a reaction via a polar five-membered transition state giving rise to an alactone (23) intermediate appears to be the most probable mechanism. For example, chloroacetic acid gives rise to HCl, CO, HzCO?~2-chlorobutyric acidz3 gives rise to propanal (80%) and but-2-enoic acid (1 5%) (but-2-enoic acid is apparently formed by dehydrohalogenation via a four-membered transition state), and for the reaction of 2bromo-3-methylbutyric acidz4 the major products are isobutyraldehyde, CO, and HBr. The gas-phase elimination reactions of 2-hydroxy-2-methylbutyricacid and 2-ethyl-2hydroxybutyric acid also presumably proceed by the same mechanism, via an a-lactone, in which the carboxyl hydrogen assists loss of OH.25On the other hand, for the reaction of 3-chloropropionic acid, acrylic acid, ethylene, C02, and HCl are prod~ced.'~ Acrylic acid is formed by dehydrohalogenation via the four-membered transition state, whereas ethylene is suggested to form via breakdown of an intermediate 8-lactone (24). In the reaction of 3-chlorobutyric acid23 the major products are propene (63%) (via a B-

Organic Reaction Mechanisms 1995

346

lactone) and but-2-enoic acid (28%). Smaller amounts of but-3-enoic acid are also formed (9%). Finally, 5-chlorovaleric acid reacts to give d-valerolactone.

ClCH2CH2C02H

CH2=CH;?

+

CO;?

CH2=CHCO;?H

Unimolecular rate constants and Arrhenius activation parameters have been reported for the gas-phase elimination reactions of pentane-2,4-dione, methyl and ethyl acetoacetate, 3-phenylhydroazopentane-2,4-dione, and ethyl 3-0x0-2-phenylhydrazonobutyrate at temperatures ranging from 500 to 783 0C.26 Rate constants and activation parameters for the gas-phase elimination of methanesulfonic acid from but-3-ene-1-methanesulfonate and 3-methylbut-3-ene-1 methanesulfonate at temperatures ranging from 290 to 300 "C have been rep~rted.'~

Nitrogen Compounds The thermal dealkylation at 250 "C of a series of 2-(N-t-alkylamino)-4,6-dichloro-striazines has been reportedF8 The pyrolyses reactions of allylcyanomethyl-, diallylcyanomethyl-, diethylcyanomethyl-, and diethylpropargyl-amines have been studied in a stirred-flow reactor at 380-510 "C at pressures of 8-15 Torr using toluene as a carrier gas.29 The pyrolyses reactions of N-(t-buty1thio)allylamine (25) and N-(t-buty1thio)diethylamine (26) have been studied in a stirred-flow reactor at temperatures ranging from 3 10 to 410 "C and pressures between 8 and 15 Torr, using toluene as the carrier gas.30For the reaction of N-(t-butylthio)diethylamine, the major products are isobutene and N,N-diethylthiohydroxylamine, Et2NSH, consistent with a unimolecular fourmembered cyclic transition state for the elimination reaction; N-(t-buty1thio)allylamine gives rise to N-allylthiohydroxylamine,and isobutene and propene, in a 3 : 1 ratio. Propene is suggested to result from decomposition of N-allylthiohydroxylamine, CH2=CHCH2NHSH (a product formed in the elimination reaction of the substrate) via a cyclic six-membered transition state (a retro-ene reaction with 1 3 hydrogen-atom

12 Elimination Reactions

347

transfer). Arrhenius parameters are reported and are consistent with the mechanistic assignments.

The thermal decompositions of 2-pyrrolidinone and 2-pyrrolidinethione have been studied in a flow system by following changes in UV photoelectron spectra.” The reactions of 2-pyrrolidinone and 2-pyrrolidinethione yield largely CO, ethylene, H2, and HCN, and pyrrole and HzS, respectively. MO calculations at the PM3 and 6-3 1G levels of theory of the transition-state structures in the two reactions show significant differences that are a result of the change from a carbonyl to a thiocarbonyl group. A continuous-wave (cw) COz laser has been used as a heat source to promote the vacuum pyrolysis of 1,2,3-benzotriazine (27; R = H) and 4-methyl-l,2,3-benzotria ~ i n e . The ~ * UV photoelectron spectrum (PES) of 1,2,3-benzotriazine at a laser power of 40 W results in changes that are consistent with the formation of l-azabenzocyclobutene (benzazete) (28). Peak assignments in the PES were made with HAM/3, using optimized geometries calculated with Gaussian 92 at the HF/6-31G** level of theory. At a laser power of 54 W further changes in the PES are noted, including the formation of HCN. The changes in the PES are consistent with formation of benzyne via elimination of HCN from the diradical intermediate (29).

R

R

I

-

(27) R=H,Me

Alkyl Halides

The vacuum pyrolyses of 6,6-dibromobicyclo[3.1.O]hexane, 6,6-dichlorobicyclo[3.1.O]hexane, and exo-6-bromo-endo-6-chlorobicyclo[3.1 .O]hexane have been studied by using a 50 W cw COz laser as a directed heat source.33The reactions were monitored by photoelectron spectroscopy. Compounds (30a) and (30b) eliminate HX (rather than Xz as observed in solution) to yield 2-halocyclohexa-1,3-dienes, whereas (30c) selectively loses HC1. The results are consistent with a concerted 1,3-elimination of HX.

Organic Reaction Mechanisms 1995

348

(30) a; X = Y = Br

b; X = Y = CI c; X = CI, Y = Br

Cyclo-eliminations The thermal decomposition of 3,4-dihydro-2H-pyran (31) has been studied by two methods: by a shock wave laser-Schlieren technique at 900-1500 K (at 110-560 Torr), and in a flow tube at 663-773 K at a pressure 0.5 Torr above atmospheric pressure. In the latter method, the decomposition of ally1 ethyl ether was used as an internal standard.34 The reaction, a retro-Diels-Alder reaction, gives rise to ethylene and acrolein under all reaction conditions. RRKM theory is used to fit the laser-Schleiren data. The Arrhenius parameters derived from both methods are in good agreement and are consistent with most, but not all, of the data reported previously for this reaction.

In the conrotatory electrocyclic ring-opening reactions of cyclobutenes (32) to give butadienes, substituents on the 3-position of the cyclobutene ring may twist either inwards or outwards during ring opening (referred to as the torquo-selectivity of the reaction). Theoretical studies of the thermal ring-opening reactions of cyclobutenes fused to cyclohexenes have been reported, and compared with previously reported experimental data, in order to understand better the electronic and steric factors that influence the course of these reaction^.^' Relative activation energies for ring opening with outward and inward rotation of the ethoxyearbonyl group (see below, for example) were determined by carrying out a single-point MM3* force-field calculation of the ab initio transition-state geometry (obtained at the HF/3-2 1G level of theory; higher level calculations gave results that were in agreement with results obtained with RHF/3-21G calculations). The electronic component of the reactions, corresponding to the interaction of the r~ and r ~ * orbitals of the breaking C-C bond and the p or 71 orbitals of the substituent at the 3-position of the cyclobutene ring, was determined by comparing relative activation energies for inward and outward rotation determined by ab initio and MME* force-field calculations (the latter takes only steric factors into account). The difference between the two represents the inherent electronic component of the torquo-selectivity. In this way good agreement between the calculated and experimental data was obtained.

12 Elimination Reactions

8” O

K

349

)I--I

In a related paper, reactions of seven 3,3-disubstituted cyclobutenes (33) show that only substituents that are strongly electron-withdrawing can cause inward rotation.36 For example, the formyl group (CHO) strongly favours inward rotation. The results are in good agreement with the preferences derived from relative activation energies determined by HF/3-2 1G calculations. A table of these rotational preferences is included in the paper for seven substituents (relative to hydrogen).

When heated, 1,4-0xathiine-S-oxides, such as (34), undergo a retro-Diels-Alder elimination reaction to form a,a’-dioxosulfine (35).37 The dioxosulfine is a reactive intermediate which can be trapped; it can act as both a diene and dienophile in Diels-Alder reactions.

Theoretical Studies E2 and Related Eliminations

+

Ab initio calculations, at the MP2/6-3 1 + GI* and MP2/6-3 1 G* levels of theory, of the potential-energy surfaces for gas-phase reactions of HO- and HS- with methyloxirane and methylthiirane have been rep~rted.~’ When HO- is the nucleophile, E2 elimination (attack at the methyl group) is slightly favoured over SN2substitution, consistent with experimental findings. The importance of ring strain in the substitution reactions was assessed by comparing the reactions of the cycliccompoundswith their acyclic analogues, i.e. the reactions of HO- with ethyl methyl ether and ethyl methyl sulfide,and the reaction of HS- with ethyl methyl sulfide. Surprisingly, a large amount of the ring strain (75% in the reaction of methyloxirane) is released at the transition state despite the fact that the transition state occurs early along the reaction coordinate. For the anti elimination reaction

Organic Reaction Mechanisms 1995

350

of methyloxirane, reaction proceeds through a transition state in which the 0-C1 -CB-H dihedral angle is 160 '. This twisted conformation for anti elimination is apparently favoured in order to avoid eclipsing interactionsbetween the methyl group and the C1-C2 bond of the oxirane ring that are present in the antiperiplanar conformation. For the same reason, a dihedral angle of 28 rather than 0 O is observed for the syn elimination reaction. As expected from previous work, the transition state for syn elimination has more carbanion character (a shorter C1-0 bond length) than for anti elimination, but is 4.4 kcal mol- less stable. This result contrasts with the result for this same reaction in solution, where the syn elimination pathway is favoured. This is consistent with ion pairing in solution that stabilizes the transition state for syn elimination. For the syn elimination reaction of methylthiirane with hydroxide ion, an H-Cp-C1 -S dihedral angle of 38 O is observed. Syn elimination is 6.2 kcal mol-' less favourable than anti elimination for this reaction and proceeds through a more carbanion-like transition state. Compared with the hydroxide ion-promoted eliminations, transition states for the HS- promoted elimination reactions of methylthiirane are more central (synchronous), have more double-bond character, have greater C- S bond cleavage, and react through conformations that are nearly periplanar. The reaction barriers, however, for HS - promoted eliminations are high so that S Nsubstitution ~ is the favoured pathway. High-level ab initio and DFT calculations have been reported on the fluoride-induced elimination of HF from ethyl fluoride.39The G2 method (which uses large basis sets and extensive electron correlation corrections) and DFT calculations using a basis set with diffuse fhctions (aug-cc-pVDZ) gave consistent results. Significant discrepancies with previously reported DFT calculations are noted and discussed. The results show that anti elimination is favoured over substitution, because of a smaller reaction barrier and a reaction that is entropically favoured. Two theoretical papers, published simultaneously, report on the decarboxylation of 3carboxybenzisoxazole (36). In the first paper, the reaction in aqueous solution was investigated via a combined Monte Carlo quantum mechanical and molecular mechanical simulation method.40 The method is presented as an automated procedure for simulating reactions in solution. The calculated and experimental free energies of activation are in excellent agreement (26.1 and 26.3 kcal mol-', respectively). An analysis of solute-solvent interactions is discussed. In the second paper, the reaction is investigated in detail by ab initio method^.^' The effect of water on transition-state geometries (the effect is dramatic) was investigated by including one or two water molecules in the calculations. 13C isotope effects are calculated and are in good agreement with experimental values for the reaction carried out in water. Solvent effects are also estimated in several solvents (chloroform, acetonitrile, tetrahydrofuran, methanol, and ethanol) using Monte Carlo free-energy perturbation calculations. O

'

+

35 1

12 Elimination Reactions

Calculations at the MP2/6-3 lG* level of theory of transition-state geometries, and primary and secondary kinetic hydrogen and heavy-atom isotope effects for several intramolecular syn elimination reactions have been reported.42The unimolecular Cope and ylide elimination reactions (37), (38), and (39) shown below were studied.

+

CH3CH2NH20-

120 "C

CH2=CH2

+ HONH2

Agreement between experimental and calculated isotope effects are reasonable, although differences are expected, because the experimental values are based on reactions (in some cases carried out under different reaction conditions) of substrates whose structures are in many cases significantly different (e.g. j-phenylethyl systems, for which a large amount of reliable isotope effect data is available) than those for which the calculations were done. Nevertheless, the results do support the value of calculations of transition-state geometries at this level of theory. The reaction dynamics of thermal, gas-phase decomposition reactions of vinyl bromide have been reported. The calculations use classical trajectory methods on a global potential-energy surface generated via ah initio calculations and experimental thermochemical, spectroscopic, and structural data.43Ah initio calculations, including electron correlation corrections, were carried out using 6-3 lG(d,p) basis sets for carbon and hydrogen, and Huzinaga's (4333143314) basis set augmented with split outer s andp orbitals and an f orbital for Br. Cyclo-eliminations The conversion of bicyclo[ 1.1.O]butane into buta- 1,3-diene has been studied using multi-configurational based wavef~nctions.~~ The isomerization reaction is predicted to occur via the concerted conrotatory mechanism, consistent with experimental observations. The calculated barrier for the concerted conrotatory mechanism is 42 kcal mol--', within 1 kcal mol-' of the experimental value. The less-favoured concerted disrotatory and stepwise mechanisms have calculated barriers of 56 and 116 kcal mol- respectively. Semiempirical calculations of activation energies underscore the importance of orbital overlap in thermal reverse homo-Diels-Alder and intramolecular reverse ene reactions.45 Calculations were carried out for the reactions of cis-3,6-dimethyl-3,6dihydropyridazine (40), diazabicycloalkenes (41), and stereoisomers of cyclopropanes

',

(42).

Organic Reaction Mechanisms 1995

352

+

The [2s 2a] thermolysis of azetidine to produce ethylene and methylenimine has been studied by semiempirical and ab initio SCF MO (3-21G and 6-31G*) methods.46

(42) R = H,C1, Me

Pyrolytic Eliminations The potential-energy surfaces for the unimolecular thermolysis of 1,2-dioxetane (and the dimethyl and trimethyl derivatives) have been studied via semiempirical calculations using the PM3 and AM1 Hamiltonions with multielectron configuration intera~tion.~' The calculated activation barrier (18 kcal mol- ') for 1,2-dioxetane decomposition occurs on the ground-state surface (it is thermally activated), consistent with experimental results. On the ground-state surface, the 0-0 bond stretches and abruptly breaks at a bond length of 2.55 P\, corresponding to extensive stretching of the 0-0 bond and consistent with a diradical mechanism. The triplet state is degenerate in energy with the ground-state surface for bond distances between 2.0 and 2.55 A, allowing intersystem crossing and the formation of some formaldehyde in the triplet state. Multiconfigurational self-consistent-field calculations, using a polarized basis set, of activation energies and transition-state structures for the gas-phase unimolecular decomposition of acetic acid have been reported.48 The results suggest that decarboxylation via a four-centred transition state is the favoured pathway (resulting in formation of CH4 and COz) and proceeds with an activation barrier of 71.8 kcal mol-'. The dehydration reaction, which produces H20 and CH2=C=0, is suggested to proceed via a two-step mechanism: 1,3-hydrogen migration to give the enediol, followed by elimination of water, with an overall activation barrier of 73.1 kcal mol- The results are consistent with previously reported experimental activation energies which range from 67.5 to 72.5 kcal mol-' and from 64.9 to 72.7 kcal mol- for the dehydration and decarboxylation reactions, respectively. In a related paper, the potential-energy surface for the thermal decomposition of acetic acid was re-examined using ab initio MO calculation^.^^ The results are consistent with the results noted previously. Ab initio calculations have been carried out on the unimolecular elimination reactions of cis- and trans-dichloroethane, 1,l-dichloroethane, and trichloroethane. Reactions involving three- and four-centred HCl eliminations, H2 and Clz eliminations, and H and C1 migration reactions are disc~ssed.~'

'. '

12 Elimination Reactions

353

Ah initio (HF/3-21G) and AM1 calculations have been reported for the pyrolysis of 2-haloacetic acids. The calculated reactivity decreases in the order F > C1> Br.” Semiempirical calculations using the AM1 method have been reported for the thermolysis of alkyl acyloxyformatess2and for the thermolysis of t-butyl ethers.53For the latter reaction, activation energies were calculated. The results indicate that elimination occurs via a four-centred cyclic transition state that results in the formation of butylene. Semiempirical calculations, using the AM 1 method, of the thermal elimination reactions of carbonic acid and carbonic acid esters have been rep~rted.’~ Classical trajectories for the four-centred elimination reaction of vinyl fluoride have been calculated at the HF/3-21G level of theory. At this modest level of theory, qualitative agreement is noted between calculated and experimental results.5s The RHF/6-3 1G**method with MP2 quantum chemical energy correction was used to calculate activation barriers for 1,l- and 1,2-eliminationsof HF from ethyl fluoride.s6 Calculations on the thermal elimination of RC(0)OON02, using the AM1 method, have been reported, where R = Me, CH2=CMe and Ph.57

Eliminations via Carbocations Theoretical studies, using the AM1 method, have been carried out for the acid-catalysed dehydration reactions of 15 arene dihydrodiols (43).’* The substituted o-phenol products are favoured both kinetically and thermodynamically, because the intermediate carbocation leading to these products can be stabilized by electron-donating, ringactivating substituents X. The electron-withdrawing substituents, PhSO and CF3, deactivate the ring, thus favouring formation of the corresponding m-phenols.

Elimination Reactions in Synthesis A study of stereoselectivity in the Wittig reaction of aromatic ketones (aryl 3-pyridyl ketones) (44) with carboxyphosphonium ylides has been rep~rted.’~ For the reactions of a variety of 3-substituted phenyl 3-pyridyl ketones, the (Z)-aryl-3-pyridylalkenoic acid (45) is favoured over the E-isomer by factors ranging from 1.5- to ca 4-fold. However, when the substituent at the 3- or 4-position on the phenyl ring is a (benzenesulfony1)amino group (NHS02Ph), the product is the (E)-alkenoic acid, formed (with one exception) in greater than 90% yield. Semiempirical calculations at the AM1 level of

3 54

Organic Reaction Mechanisms 1995 0 Bu'OK

(44)

b

'X

x (45) E and Z

theory suggest that the increase in stereoselectivity is a result of a hydrogen bond or salt bridge between the (benzenesulfony1)amino group and the carboxylate group that stabilizes a trans-oxaphosphetane intermediate. This intermediate then breaks down to give the (E)-alkenoic acid. This conclusion is also supported by experimental results which show 'normal' EIZ ratios (slight preference for the Z-isomer) when either the carboxyl group of the phosphonium ylide group, or the acidic hydrogen of the (benzenesulfony1)amino group of the aryl ketone, is removed and replaced with a methyl group. N,N-Disubstituted hydroxylamines (46) connected to vinyl groups by three or four carbon atoms yield pyrrolidine and piperidine-N-oxides by a concerted reverse-Cope elimination reaction." The reaction of (46), as shown, is an example of pyrrolidine ring formation. The reactions are reversible and proceed via stereospecific syn addition, consistent with a concerted mechanism (a reverse-Cope reaction). The results are not consistent with a free-radical mechanism. The scope and synthetic utility of this reaction is discussed. Phenyl[o-(trimethylsilyl)phenyl]iodonium triflate (47) and several derivatives have been prepared as precursors for benzyne. The compound (47) is a crystalline solid, and can be stored for extended periods.61Renzyne is generated by reacting the compound, dissolved in CH2C12, with Bu4NF dissolved in THE Reactions with a variety of dienes yield Diels-Alder adducts in high or quantitative yields.

OTf I

(46) a; R = CH2CH=CHPh

b; R = CH2CH=CHMe

c; R = CH2CH=CMe2 d; R = CH2C(Me)=CH2

I

1Me a; R ' = CH2Ph; R2 = H

b; R' = Et; R2 = H

c; R ' = i-Pr; R2 = H d; R' = R2 = Me

(47)

12 Elimination Reactions

355

(R)-l-t-Butyl-4-ethylidenecyclohexane (48) ( z 98% of the desired isomer) has been synthesized from 4-t-butylcyclohexanecarboxylic acid via the optically active plactone.62 Decarboxylation of the Ij-lactone proceeds, as expected with retention of configuration.

Buf

0

Bur

(48)

A novel ring-opening reaction of tropone oxime tosylate (49), promoted by a variety of nucleophiles, results in the formation of substituted (352)-hexa- 1,3,5-trienecarbonitriles (50).63 This contrasts with previously studied nucleophilic and electrophilic reactions of troponoid compounds in which the ring skeleton is normally retained. Nucleophiles that promote this reaction include secondary amines, alkoxide ions, and Grignard reagents (methyl- and phenyl-magnesium bromides). PM3 calculations suggest that ring opening proceeds via formation of a tetrahedral intermediate (similar to a Meisenheimer complex) that results from nucleophilic attack at C(2). The intermediate is then suggested to break down via concerted C(l)-C(2) and N-0 bond cleavage. "OTs N nucleophile

H

(49)

H H

(501

H

Elimination reactions of methiodide derivatives (51) of isoxazolidines have been studied.64 The reactions are promoted by a 10% sodium hydroxide solution at reflux. The cis-isoxazolidines eliminate to yield tetrahydro- 1,3-oxazines (52) and a$-enones (53), whereas, the trans-derivatives (54) yield only a,P-enones. The mechanism of 1,3oxazine formation is suggested to involve abstraction of an N-methyl hydrogen yielding a 0-hydroxyiminium intermediate, which then undergoes cyclization with ring expansion. This reaction shows a product isotope effect of 2.5 when the hydrogens of one of the N-methyl groups are replaced with deuteriums. Formation of a$-enones is suggested to proceed via initial abstraction of a hydrogen a to the isoxazolidine oxygen. For the trans-isomer, enones are presumably formed because the antiperiplanar arrangement of the C-H and 0 - N bonds is stable. On the other hand, for the cisisomer, because of steric interactions between substituents on C(3) and C(5), the antiperiplanar arrangement becomes energetically unfavourable so that this mode of elimination is no longer favoured.

Organic Reaction Mechanisms I995

356

Quinoline-4(lH)-thiones (55) have been synthesized via pyrolysis of enamino-thioesters (56). The reaction presumably occurs via the formation of an imino-thioketene intermediate (57), formed via 1,4-elimination, which then undergoes c y ~ l i z a t i o n . ~ ~ Compound (58) reacts with SOC12 at -18 "C to give (59) via a Beckmann fragmentation reaction.66A possible mechanism involving a cyclic six-membered N - 0 sulfite intermediate is proposed. Ph

R'

6xR2 S

I

Q

41O-47O0C,

~

R'

XEt

R2

(56)

x=s,o R' = alkyl

(57)

S

&R2

I H (55)

R'

12 Elimination Reactions

357

Other Eliminations The elimination of I2 from (60) yields (61), 3,7-dimethyltricyclo[3.3.0.03~7]oct-1 (5)ene, a highly strained, ‘pyramidalized’ alkene, that is identified by trapping, via DielsAlder cycloaddition with 1,3-diphenylisobenzofuran and 11,12-dimethylene-9,10dihydro-9,lo-ethan~anthracene.~~ r

-l

-

Diels-Alder adducts

fi-Lactones undergo two types of reactions when treated with anhydrous MgBr, in diethyl ether solution: ring enlargement and fi-elimination.68These competing pathways were investigated for the reactions of (62) and (63), and the related compound (64) in which a five-membered ring replaces the six-membered ring. For (62) and (64), R1 and Rz are H and methyl, H and isopropyl, or H and t-butyl. Both epimers were investigated. Compounds (62) and (64) undergo ring expansion: e.g. compound (62) forms (65). On the other hand, (63) undergoes p-elimination to give (66). A rule is proposed that pelimination will occur only if C(4) is tertiary and both C(5) positions are secondary. The C(4) position corresponds to the spiro-carbon in these systems. Interestingly, the regioselectivity of the elimination reaction is high: > 95% of the product is accounted for by (66). The high regioselectivity is rationalized in terms of a steric effect in which the carboxylate oxygen is complexed by MgBrz (after ring opening) and that this moiety is rotated away from the phenyl or alkyl substituent and toward the smaller hydrogen. This favours removal of the syn 5-hydrogen leading to (66).

5 ’ 1

(63)

4

R = Ph, t-Bu, Me, SPh

Organic Reaction Mechanisms 1995

358

When 1-(2'-carboxytetrahalogenophenyl)-3,3-dimethytriazenes (67) are heated, tetrahalogenobenzynes are formed.69 The benzynes are apparently formed via a twostep process in which dimethyamine is first eliminated producing benzenediazonium-2carboxylates, which then break down to the benzynes via apparent synchronous loss of N2 and C02. The benzynes were trapped via Diels-Alder cycloaddition using 2,5dimethylfuran, p-xylene, m-dimethoxybenzene, and N-methylpyrrole. The reaction in the presence of N-methylpyrrole produces (68).

xGGN-N\ /

CHClZCHC12, heat

\ /

X

N-methylpyrrole

I

~

X X

C02H

(68)

(67)

X = C1, Br, H

The kinetics of the reaction of triphenylphosphoniocyclopentadienides (69) with tetrafluoro-p-benzoquinone (fluoranil) in methylene chloride solution have been rep~rted.~' Reaction proceeds with substitution by an addition-elimination mechanism, and yields both mono- and 2,6-di-substituted products (only the disubstituted product is isolated). For the reaction leading to both products, the rate is independent of added base (quinuclidine), and there is no isotope effect when the tetradeuteriated ylide is employed. The results are consistent with rate-limiting addition of the ylide. It is suggested that loss of HF from an intermediate a-adduct occurs via a concerted fourmembered transition state and is not base-catalysed. Carbon-13 kinetic isotope effects have been reported for the decarboxylation of oxalic acid in sulfuric and phosphoric acids7'

0

+ F

F 0

2,6-disubstituted product

I 2 Elimination Reactions

359

Ethane- 1,2-disulfonic anhydride and 2,2-dimethylisothiazolidinium-l, 1-dioxide fluorosulfate react with triethylamine via direct displacement at sulfur rather than by an elimination-addition mechanism via the ~ulfene.~' Compound (70) undergoes reaction by three parallel routes in basic solution: the main reactions are hydrolysis of each lactone group, and a p-elimination reaction to give (71); the latter reactions accounts for only 6% of the product, however. Rate and equilibrium constants and activation parameters are reported.73 Bu

0

Me

*

Me O

Y C02H B U

The reactions of triflamides (72) with alkyllithium reagents have been studied. Reaction can proceed via either p-elimination to give an imine and the triflinate ion (the imine is then subsequently alkylated via addition of the alkyllithium reagent), or by direct substitution of the CF3 group by the alkyllithium reagent.74Steric hindrance and substrate acidity are factors that determine the reaction mechanism.

Several alkyl- and aryl-substituted buta-l,2,3-trienes (74) have been ~ y n t h e s i z e dvia ~~ a tetrabutylammonium fluoride induced 1,4-elimination reaction of the corresponding acetate esters of silyl propynylic alcohols (73). Simple alkyl derivatives of (74) polymerize readily, whereas phenyl- or 1-butyl-substitutedderivatives may be stored in hexane solution at -30 "C for days.

(73)

(74)

E- and Z-isomers

Reaction of tris(trimethylsilyl)germyllithium-3THF with 2-adamantanone (75) in hexane at - 78 "C yields after work-up the I ,2-digermacyclobutane (76);76 (76) is

360

Organic Reaction Mechunisms 1995

presumably formed via the germene (759, which is suggested to be formed via a Peterson-type elimination reaction. This is the first reported example of a germene with silicon substituents on germanium; (76) is apparently also the first reported example of a 1,2-digermacyclobutane (1,3-digermacyclobutanes are known). Further evidence for the formation of (77) was provided by carrying out the reaction in the presence of buta1,3-diene, in which case the expected Diels-Alder reaction takes place.

References Vigroux, A., Bergon, M., Bergonzi, C., and Tisnes, P., I Am. Chem. Soc., 116, 11787 (1994). Bemasconi, C. F., Schuck, D. F., Ketner, R. J., Weiss, M., and Rappoport, Z., J Am. Chem. Soc., 116, 11764 (1994).

lo

” l3

l4

l6

17

‘*

Bernasconi, C. F., Leyes, A. E., Eventova, I., and Rappoport, Z., J: Am. Chem. Soc., 117, 1703 (1995). Cevasco, G. and Thea, S., 1 0%.Chem., 60, 70 (1995). Hon, Y. S., Lin, S. W., Lu, L., and Chen, Y. J., Tetrahedron, 51, 5019 (1995). Spillane, W. J., Hogan, G., and McGrath, ,!F J: Phys. Org. Chem., 8, 610 (1995). Tilley, R. I. and Leslie, D. R., Ausf. 1 Chem. 48, 1781 (1995). Bickelhaupt, F. M., Buisman, G. J. H., de Koning, L. J., Nibbering, N. M. M., and Baerends, E. J., 1 Am. Chem. Soc., 117, 9889 (1995). Cho, B. R., Yoon, C. M., and Song, K. S . , Tetrahedron Lett., 36, 3193 (1995). Meng, Q. and Thibblin, A,, I Am. Chem. Soc., 117, 1839 (1995). Meng, Q. and Thibblin, A., J: Am. Chem. SOC., 117, 9399 (1995). Wilk, K. A., Bieniecki, A., and Matuszewska, B., I Phys. Org. Chem., 7, 646 (1994). Temer, F., Goumont, R., Pouet, M., and Halle, J., 1 Chem. Soc., Perkin Trans. 2, 1995, 1629. Famsworth, D. W., Pruski, B., and Smith, R. H., 1 Org. Chem., 60, 4641 (1995). Sakai, M., Shimim, N., Tsuno, Y., and Inam, T., Mem. Fac. Sci., Kyushu Univ., Ser: C, 19, 139 (1994); Chem. Abs., 122, 9247 (1995). Cho, B. R., Lee, S. J., and Kim, Y. K., 1 Org. Chem., 60, 2072 (1995). Gyul’nazaryan, A. Kh., Saakyan, T. A., Markatyan, N. D., Kocharyan, S. T., and Babayan, A. T., Zh. Obshch. Khim., 65, 525 (1995); Chem. Abs., 123, 255913 (1995). SuLez, A. R., Suhez, A. G., Martin, S. E., and Mazzieri, M. R., Can. 1 Chem., 73, 56 (1995). Thibblin, A,, Spec. Publ., R. SOC. Chem., 148, 415 (1995); Chem. Abs., 123, 111257 (1995). King, J. F., Lam, J. Y. L., and Dave, V, 1 Org. Chem., 60, 2831 (1995).

’’ 2o

12 Elimination Reactions

361

Moriguchi, T., Endo, T., and Takata, T., 1 Org. Cliem., 60, 3523 (1995). Al-Awadi, N. A,, Al-Omran, F. A,, and Mathew, T., Int. 1 Chem. Kinet., 27, 1 (1995). 23 Chuchani, G., Martin, I., Rotinov, A,, Dominguez, R. M., and Perez, M., 1 Phys. OE. Chem., 8, 133 (1995). 24 Chuchani, G. and Dominguez, R. M., Int. 1 Chem. Kinet., 27, 85 (1995). ” Chuchani, G., Martin, I., and Rotinov, A., Int. 1 Chem. Kinet., 27, 849 (1995). 26 Al-Awadi, N. A,, El-Nagdi, M. H., and Mathew, T., Int. 1 Chem. Kinet., 27, 517 (1995). 27 Chuchani, G., Martin, I., and Dominguez, R., Int. L . Chem. Kinet., 27, 657 (1995). 28 Boncic-Caricic, G. A,, Tadic, Z. D., and Muskatirovic, M. D., 1 Serb. Chem. SOC.,59, 929 (1994); Chem. Abs., 122, 80594 (1995). 2y Martin, G., Ascanio, J., and Rodriguez, J., Int. 1 Chem. Kinet., 27, 99 (1995). 30 Martin, G., Ascanio, J., and Rodriguez, J., 1 Phys. Org. Chem., 7, 585 (1994). 3 ’ Chin, W. S., Mok, C. Y., Huang, H. H., and Rzepa, H. S., 1 Chem. SOC.,ferkin Trans. 2, 1995, 421. ” Werstiuk, N. H., Roy, C. D., and Ma, J., Can. 1 Chem., 73, 146 (1995). 33 Werstiuk, N. H., Roy, C. D., and Ma, J., Can. 1 Chem., 72, 2537 (1994). 34 Besseris, G . J., Kiefer, J. H., Zhang, Q., Walker, J. A., and Tsang, W., Int. 1 Chem. Kinet., 27,691 (1995). 3s Nakamura, K. and Houk, K. N., 1 Org. Chem., 60, 686 (1995). 36 Niwayama, S., Wang, Y., and Houk, K. N., Tetrahedron Lett., 36, 6201 (1995). 37 Capozzi, G., Fratini, P., Menichetti, S., and Nativi, C., Tetrahedron Lett., 36, 5089 (1995). 38 Gronert, S. and Lee, J. M., 1 Org. Chem., 60, 4488 (1995). 39 Gronert, S., Memll, G. N., and Kass, S. R., 1 Org. Chem., 60, 488 (1995). 4” Gao, J., 1 Am. Chem. SOC., 117, 8600 (1995). 41 Zipse, H., Apaydin, G., and Houk, K. N., 1 Am. Chem. SOC.,117, 8608 (1995). 42 Bach, R. D., Gonzalez, C., Andres, J. L., and Schlegel, H. B., 1 Org. Chem., 60, 4653 (1995). 43 Abrash, S. A., Zehner, R. W., Mains, G. J., and Raff, L. M., 1 fhys. Chem., 99, 2959 (1995). 44 Nguyen, K. A. and Gordon, M. S., 1 Am. Chem. Soc., 117, 3935 (1995). 45 h a i , T.-G. and Yu, C.-H., 1 Chin. Chem. SOC. (Ihipei), 41, 631 (1994); Chem. Abs., 122, 80556 (1995). 46 Chen, G. and Fu, X., Beijing Shtfan Dame Xuebao, Ziran Kexueban, 30, 495 (1994); Chem. Abs., 123, 2’

22

47 48 49 50

51

52

53 54 55 56

57

58 59 60

61

62 63 64

65

66 67 68 69

143170 (1995).

Wilson, T. and Halpern, A. M., 1 fhys. Org. Chem., 8, 359 (1995). Duan, X. and Page, M., J. Am. Chem. Soc., 117, 5114 (1995). Nguyen, M. T., Sengupta, D., Raspoet, G., and Vanquickenborne, L. G., J Phys. Chem., 99, 11883 ( I 995). Riehl, J.-F., Musaev, D. G., and Morokuma, K., 1 Chem. Phys., 101, 5942 (1994); Chem. Abs., 122, 80527 (1995).

Chen, L.-T., Chen, G.-J., and Fu, X.-Y., Chin. 1 Chem., 13, 10 (1995); Chem. Abs., 122, 159859 (1995). Hong, S.-G. and Wang, S., Huaxue Xuebao, 52, 1047 (1994); Chem. Abs., 122, 105124 (1995). Hong, S . 4 . andFu,X.-Y., GaodengXuexiao HuaxueXuebao, 15, 1381 (1994); Chem. Abs., 122, 159848

(1995).

Li, Y , Hong, S., and Wang, S., WafiHuaxue Xuebao, 11, 414 (1995); Chem. Abs., 123, 1 1 1291 (1995). Takayanagi, T. and Yokoyama, A., Bull. Chem. SOC. Jpn, 68, 2245 (1995). Li, Q.-M., Fang, D.-C., and Fu, X.-Y, Chin. Sci. Bull., 39, 86 (1995); Chem. A h . , 121, 280091 (1995). Feng, W., Hong, S. H., and Wang, S., Beijing Shyan Darue Xuebao, Ziran Kexueban, 30, 253 (1994); Chem. A h . , 122, 238889 (1995). Kim, C. K., Chung, D. S., Chung, K. H., Lee, B. S., and Lee, I., 1 fhys. Org. Chem., 8, 127 (1995). Takeuchi, K., Paschal, J. W., and Loncharich, R. J.. 1 Org. Chem., 60, 156 (1995). Ciganek, E. and Read, J. M., 1 0%.Chem., 60, 5795 (1995). Kitarnura, T. and Yamane, M., J Chem. SOC., Chem. Commun., 1995, 983. Mulzer, J., Speck, T.,Buschmann, J., and Luger, I?, Tetrahedron Lett., 36, 7643 (1995). Machiguchi, T., Wada, Y.,Hasegawa, T., Yamabe, S., Minato, T., and Nozoe, T., 1 Am. Chem. SOC.,117, 1258 (1995).

Casuscelli, F., Chiacchio, U., Rescifina, A., Romeo, R., Romeo, G., Tommasini, S., and Uccella, N., Tetrahedron, 51, 2919 (1995). Moussonga, J. E., Bouquant, J., and Chuche, J., Bull. SOC. Chim. Fr., 132, 249 (1995). PejanoviC, Y M., PetroviC, J. A,, Csanadi, J. J., StankoviC, S. M., and Miljkovic, D. A,, Tetrahedron, 51, 13379 (1995).

Camps, P., Bardia, M. F., Perez, F., Solans, X., and Vizquez, S., Angm. Chem., Int. Ed. Engl., 34, 912 (1 995). Mulzer, J., Pointner, A,, Strasser, R., and Hoyer, K., Tetrahedron Lett., 36, 3679 (1995). Buxton, P. C. and Heaney, H., Tetrahedron, 51, 3929 (1995).

362 70

” 72 73 74

75

76

Organic Reaction Mechanisms 1995

Pla, F. P., Hall, C. D., Speers, P., and Palou, J., 1 Chem. Soc., Perkin Trans. 2, 1995, 2499. Zietinski, M., Zielinska, A,, Papiemik-Zielinska, H., Stadter, W., Kasprzyk, G., Czarnota, G., Gehre, M., Hofling, R., and Strauch, C., Nukleonika, 39, 51 (1994); Chem. A h . , 122, 159959 (1995). King, J. F., Cuo, Z. R., and Lock, J. D., Phosphorus Su&r Silicon Relat. Elem., 97, 191 (1 994); Chem. Abs., 122, 264727 (1995). Aldridge, D. C., Nicholson, S., and Taylor, P. J., J. Chem. Soc., Perkin Trans. 2, 1995, 1929. Bozec-Ogor, S., Salou-Guiziou, V, Yaounanc, J. J., and Handfel, H., Tetrahedron Lett., 36, 6063 (1995). Chow, H. F., Cao, X. P., and Leung, M. K., 1 Chem. Soc., Perkin Trans. I , 1995, 193. Bravo-Zhivotovskii, D., Zharov, I., Kapon, M., and Apeloig, Y., 1 Chem. Sac.. Chem. Commun., 1995, 1625.

CHAPTER 13

Addition Reactions: Polar Addition PAVELKOCOVSKY Department of Chemisty, University of Leicestel; Leicester LEI 7RH, UK Reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrophilic Additions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Halogenation and Related Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . Additions of ArSX, ArSeX, and Related Reactions . . . . . . . . . . . . . . . . . . . Additions of Hydrogen Halides and Other Acids . . . . . . . . . . . . . . . . . . . . Addition of Electrophilic Carbon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Addition of Electrophilic Nitrogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Additions Initiated by Metals and Metal Ions as Electrophiles . . . . . . . . . . . . Hydroboration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Electrophilic Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . Nucleophilic Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Additions to Multiple Bonds Conjugated with C=O . . . . . . . . . . . . . . . . . . Additions to Multiple Bonds Activated by Other Electron-withdrawing Groups . . Additions of Organometallics to Activated Double Bonds . . . . . . . . . . . . . . . Miscellaneous Nucleophilic Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

363 363 364 368 368 368 370 371 378 379 382 382 387 392 393 396

Reviews The main protagonists of the mechanism of alkene bromination have summarized their work in reviews focused on new mechanistic insight into the electrophilic bromination of alkenes,’ fates of bromonium ions in solution with regard to the short lifetime and competing reaction pathways; and stereo-, regio-, and chemo-selectivity of bromination of ethylenic compound^.^ Other reviews published during the coverage period of this chapter, include the stepwise electrophilic additions with novel synthetic ramifications of an old ~ o n c e p t electrophilic ,~ cleavage of bicyclo[ 1.1 .O]butanes,’ the utilization of tin(I1) enolates in Michael and related reactions,6 control of asymmetry through conjugate addition^,^ and the regiochemistry of nucleophilic additions to C60.8

Electrophilic Additions The remote substituent effect on the electrophilic additions to 1,3-dienes has been studied with the aid of model compounds such as (1)9 Organic Reaction Mechanisms 1995 Edited by A C Knipe and W E Watts fu 1997 John Wiley & Sons Ltd

363

Organic Reaction Mechanisms 1995

3 64

n

X

Halogenation and Related Reactions The stereochemistry of electrophilic additions (Br2, NCS, or NBS) to methylenecyclohexanes (2) to give products (4) has been shown to be consistent with the Cieplak model, involving axial attack by the electrophile, (2) -+ (3). The corresponding epoxidation is less stereoselective, presumably owing to the more crowded transition state, which renders the axial approach more difficult.l o

A full account on the large inverse deuterium kinetic isotope effect (IDKIE), observed for the electrophilic bromination of 7-norbornylidene-6'-norbornane (5), has now appeared.' The reaction kinetics and product distribution in the bromination of (5a) and its perdeuteriated analogue (5b) were studied in AcOH and MeOH as a function of added Br-. In all cases a significant IDKIE on the rate constant of bromination has been observed. Thus, in AcOH, the IDKIE effect (kD/kH) is 1.56 and 1.83 at [Br-] = 0 and 0.040 M, respectively. Apparently, added Br- causes a significant retardation, indicating the intervention of a reversibly formed bromoniumion intermediate. Four kinds of products have been isolated, namely the normal dibromide (7) and the P-bromo solvate (8), and two others, namely (11) and (13), that originate from capture of the a-bromo cation (10) arising via a Wagner-Meenvein rearrangement of the originally formed bromonium ion (6). In AcOH, adding Brresults in increasing the amount of the normal dibromide (7) at the expense of the solvent-intercepted and rearranged products. By contrast, in MeOH the dibromide (7) is never an important product at any [Br-] investigated, the two major isolated products being the normal methoxy bromide (8) and the rearranged ketone (13). Little isotope effect has been observed on the product distribution. Further evidence for the Brf transfer from the bromonium ion of adamantylideneadamantane to reactive alkenes (e.g. cyclohexene, w-alken- 1-ols, and pent-4-enoic acid) has been accumulated.l 3 Bromination of alkenes (e.g. ally1 alcohols, but-2-enone, etc.) and akynes (e.g. PhCECH) with bis(dimethy1acetamide) hydrogen bromide, i.e., [AcNMe2. . . H+ . . .

',"

13 Addition Reactions: Polar Addition

365

(5) a;L=H b;L=D

H20

work-up

0

Organic Reaction Mechanisms I995

366

AcNMez]Br3, afforded the corresponding dibromides [e.g. BrCH2CH(Br)CHz0H, BrCH2CH(Br)COMe, and cis- and trans-PhC(Br)=CHBr, respectively] in good yields. Cyclohexene gave stereoselectively the trans-dibromide (77%).l4 The reactions of PhCH=CHCHzOH with NBS in 50% aqueous Bu'OH at 35 "C, giving PhCH(OH)CH(Br)CH,OH, exhibits a large positive dielectric effect and follows the rate equation dmBS]ldt= (2.2 x 10V2[alkene] 2.7 x 10-6/[H'])~BS].'5 Bromination of exo-ethylenic acetals, such as (14), has been reported to yield either the cis- or the trans-dibrominated derivatives. When R = alkyl, the cis-isomer is obtained and can be isomerized to the trans-product. By contrast, aryl-substituted acetals (R = aryl) afford the trans-isomer, except when there is an electron-withdrawing group on the aryI.l6

+

Kinetic and spectral studies of iodofluorination of CFz=CFz, CF3CF=CFz, and CF30CF=CF2 by the Iz-IF5SbF3 system revealed that the reaction is initiated by the 1: attacking the double bond. l 7 A study of the iodofluorination of the lactams (15) and (16) revealed an interesting dependence on the N-protective group. Thus, the BOC-protected lactam (15) is iodofluorinated to give mainly (17), whereas its henzyl-protected counterpart (16) favours the formation of the rearranged product (18). This behaviour has been attributed to the different nucleophilicities of the nitrogen atoms in (15) and (16).18

0

R=BOC

F

0

0

(15) R = BOC (16) R = PhCH2

Tetrahydrodianthracene (19) has been reported to react with halogens to give transannular (20) and ring-opened (21) products, the ratio being remarkably dependent on the solvent. Thus, transannular addition is favoured in solvent of medium polarity, whereas preferential ring opening has been observed both with increasing and decreasing polarity. For instance, Clz in toluene gives ca 100% of (21), in CH2CI256%

13 Addition Reactions: Polar Addition

367

of (20), and in CF3CH20H again ca 100% (21). The authors suggested three different mechanisms to rationalize these findings. l 9

The mechanism of iodolactonization of CH2=CHCH2CH(C02Et)2 and CH2=CHCH2C(Me)(C02Et)PO(OEt)2 has been formulated. Large amounts of iodine and higher reaction temperatures led to increased yields.20 The hydroxy bromination of HCsCCH20H with NBS in aqueous acidic medium has been found to be first order with respect to NBS, propargyl alcohol, and Ht, and inverse first order with respect to succinimide. The kinetic results point to solvated bromonium ion as the reactive species.21 The iodination of a-allenic alcohols (22) has been found to proceed via a radical-type isomerization of the initially formed mixture (ca 1 : 1) of E and Z-isomers, affording predominantly the Z-product (23).22

Bromination of ArCH=CHCsCCH=CHAr' in Et20 or AcOH in the LiBr gave a mixture of four types of products corresponding to (dibromocumulenes), addition to the triple bond (dibromostilbenes), (dibromoallene), and tetrabrominated derivatives. The electronic effects position have some control over the reaction outcome.23

presence of 1,6-addition 1,Caddition in the para

368

Organic Reaction Mechanisms I995

Additions of ArSX, ArSeX, and Related Reactions N-Phenylthiophthalimide and N-phenylselenophthalimide, combined with pyridine.9HF or Et3N.3HF complexes, allow the formal addition of PhSF or PhSeF, respectively, across C=C or C=C bonds. A strongly acidic reagent, such as pyridine.9HF, is required to polarize the C-N bond sufficiently to allow the reaction to occur. On the other hand, selenium adducts can also be obtained in good yields using the less acidic Et3N.3HF (avoiding, e.g., acetal cleavage or isomerization). The addition to propargylic alcohols is entirely regioselective. Steroidal alkenes, such as (24), proved to afford mainly diequatorial products (27) and (28) owing to the thermodynamically driven equatorial cleavage of the intermediate sulfonium ions (25) and (26) (note that the usual axial cleavage is rever~ible!).’~

\I

PhS+

(26)

J

Additions of Hydrogen Halides and Other Acids The FeC13-catalysed hydrochlorination of vinylidene chloride is characterized by the induction period, which appears to be due to the formation of the inactive anionic complex of the catalyst with HCl in the presence of small amounts of water. A decrease in water content results in an increase in the concentration of the catalytically active forms of FeC13 and, finally, in the auto-acceleration of the hydrochlorinati~n.~~ The kinetics of the addition of arenesulfinic acids to 4-substituted 2-nitroethenylarenes have been studied by means of UV spectrophotometry. The effects of para substituents in benzenesulfinic acids and the change in the reactivity of the nitroethylene system (due to electron-withdrawing groups) have been assessed. The substituent effect fits Hammett’s equation, the p-value being - 1.12 (at 298 K).26

Addition of Electrophilic Carbon The reaction of electron-rich alkenes, such as vinyl ether (29a) and vinyl sulfide (29b), with (CF&0)20 in cc14, CHC13, or CHZC12 has been elucl ‘ated by NMR

13 Addition Reactions: Polar Addition

369

spectroscopy. The initial formation of the addition products (30) has been found to occur via a stepwise mechanism. The latter intermediates then undergo a self-catalysed Ei, E2, or E l reaction, depending on the stability of the intermediates to give the products (32a) and (32b), respectively.

i29)

a;Z=0 b;Z=S

(32) a;Z=0 b;Z=S

o-Phenylenediamine (33) has been reported to afford via intermediate (34) two types of products on reaction with aqueous formaldehyde and cyclopentadiene in THFMeCN, namely (35) and a mixture of (36) and (37); the latter two predominate if an excess of CH20 is employed.**

A Homophthalic anhydride (38) has been reported to afford cyclo-condensation products (40) on reaction with I-aza-l,3-dienes (39).29

370

Organic Reaction Mechanism I995

The kinetic studies of the polymerization of Pr'OCH=CH2 and ClCH2CH20CH=CH2, initiated by HI in CH2C12 in the presence and absence of Bu4N+I- as common anion salt, revealed that the reaction proceeds directly through the carbon-iodide termini without any necessary electrophilic activator. In accord with the previous observations, it has now been found that the addition of small amounts of the salt (0.5-10% with respect to the initial [HI], depending on the monomer) dramatically reduces the polymerization rate and leads to living-type polymerizations. Higher amounts of the salt have no W h e r influence. This general behaviour, observed for all the vinyl ethers studied, suggests a common-ion salt effect and, therefore, an ionic polymerization mechanism involving ion pairs and free ions. In the absence of the salt, both ion pairs and free ions of higher reactivity participate in the propagation, whereas only the ion pairs contribute to the propagation in the presence of a commonion salt. According to this scheme, the living character of the polymerization can be assumed to result from a propagation reaction governed by non-dissociated ionic species.30 Addition of Electrophilic Nitrogen (PTAD) (41) and MeOH to cis- and The addition of 4-phenyl-l,2,4-triazoline-3,5-dione trans-but-2-ene, 1-methylcyclopentene, and (@-2-methylbut-2-ene-1,1,1-d3 gives pure anti-addition adducts, e.g., (42). On the other hand, partial loss of stereochemical integrity was observed with substituted inde ne ~.~Aziridinium ' intermediate (43) has been directly observed by NMR spectroscopy on reaction of (41) and transcyclooctene. *

Ph

N=N

MeOH

0

4 NH N/

OMe

Aziridination of allylic alcohols with 3-acetoxyaminoquinazolinones,such as (44), is known to occur with similar (if not better) stereoselectivity than the corresponding

I3 Addition Reactions: Polar Addition

371

A transition state (46) for the aziridination of epoxidation with peroxy electron-rich allylic alcohols, e.g. (45), has now been proposed.35

I

products

Pyridinium imides (47), as well as 3-acetoxyaminoquinazolinones (44) from which they can be prepared, have been reported to aziridinate alkenes as diverse as styrene and diethyl f i ~ m a r a t eSimilarly, .~~ the corresponding triethylamine imide gives aziridines on reaction at - 30 "C. The reactivity of the aziridinating intermediate is consistent with its formulation as an azaimide ( N - ~ ~ i t r e n e ) . ~ ~ The cyclic 8-dicarbonyl compounds (48) and silyl enol ethers (50) undergo aziridination with (44) to produce the corresponding cc-(oxoquinazoliny1)amino ketone derivatives (49) and

Additions Initiated by Metals and Metal Ions as Electrophiles The mechanism of the ruthenium-catalysed rearrangement of acyclic alkenes, e.g. (52) -+ (53), has been studied with the aid of a model system consisting of 3phenylpropene-3,3-d2 (52) and [Ru(H~O)~]+ in different solvents. The latter reaction turned out to yield stereospecifically trans-phenylpropene with deuterium content on all carbon atoms of the propyl chain (53)-(57). A kinetic isotope effect kHlku=2.3 has been observed (compared with the reaction of the non-deuteriated 3-phenylpropene). A competition experiment revealed an intermolecular deuterium transfer. The results are

372

Organic Reaction Mechanisms 1995 0

0

OSiMeq

0

consistent with a stereospecific syn-l,2-addition~elimination of an intermediate metal hydride, arising predominantly from attack of the metal on position 2 (58).39

phDq -MD

Ph

-MH

(52)

& ’,

Ph

I . +MD 2.-MDw

Ph

M

(53)

Ph (54)

(52)

1. +MD 2. -MD

D (56) 1. +MH 2. -MD

(55)

13 Addition Reactions: Polar Addition

373

The deuterioformylation (2H, CO) of hex-1-ene, catalysed by rhodium coordinated to chelating diphosphines, has been elucidated in order to shed more light on the mechanism. The reaction gives rise, nearly exclusively, to a mixture of regioisomeric aldehydes Me(CH2)$HDCH2CD=0 and Me(CH2)3CH(CD=O)CH2D,with deuterium label at the B-carbon and at the carbonyl carbon. Very little deuterium was incorporated into the recovered hexene. These results established that the regiochemistry of aldehyde formation is dictated by an essentially irreversible addition of a rhodium hydride to coordinated hex-1-ene to produce an alkylrhodium intermediate that is committed to aldehyde f~rmation.~' Increased a-selectivity of the Rh(1)-catalysed hydroformylation of methyl acrylate in favour of (59) rather than (60) has been attained by adding bis(dipheny1phosphino)butane (dppb) as the ligand.41

Formation of an inclusion complex of dec-1-ene with cyclodextrin has been proposed to account for the remarkably regioselective hydroformylation (61) -+ (62).42 In addition to the well established MOP (63), a new monodentate ligand (64) has been introduced into hydrosilylation chemistry and shown to effect high asymmetric induction in the Pd-catalysed hydrosilylation of substituted styrenes (65) -+ (66) with 89-96% ee.43

Cyclohexene

(63) X = OMe (MOP) (S) (64) X = H (H-MOP) ( R )

The Pd-catalysed cyclization of aryl iodides on to a proximal allene moiety (67)has been reported to occur at the central atom of the allene system, generating the 71-ally1

Organic Reaction Mechanisms I995

374

intermediate (68). The latter species can then be attacked by secondary mines such as (69); the regioselectivity of this process is sensitive to added inorganic base, steric effects, and the nature of the adjacent h e t e r ~ a t o m . ~ ~

+AMe

0

0

(68)

QNMe 0

0

Studies on alkene epoxidation, catalysed by ruthenium(T1I) Schiff bases, have demonstrated the superiority of bidentate ligands. When camed out in the presence of surfactants (e.g. Triton X- loo), the reaction is believed to occur via carbocationic

intermediate^.^^

A comparison of the course of catalytic osmylation of steroidal alkenes in the presence and absence of a complexing amine showed that, in the absence of the amine (Et,N), the reaction is significantly slower and gives substantial amounts of allylic byproducts (Scheme 1). The results were interpreted in terms of a stepwise, non-concerted Sharpless mechanism. The co-oxidant may determine the formation of some products; thus, interaction of the osmate ester with But-OOH in the absence of the complexing amine leads to the formation of an a-hydroxy ketone (Scheme Z).46 A highly enantioselective catalytic dihydroxylation of p-methoxyphenyl ethers of homoallylic alcohols, such as tvans-RCH=CHCH*CH*OC6H4oMe, has been reported.47 Farnesyl acetate (70) has been dihydroxylated with 120 : 1 positional selectivity, using the mechanistically designed bis-cinchona alkaloid ligand (71),

375

I3 Addition Reactions: Polar Addition 0,

-c-c=c HI O T

+o

0€4

/

;

1 1 '

3

c-c-

I

/ ib

products

,o [ \'o

bo=os'

I

J

SCHEME 1

/O 0sO>'O H-C-C- I O,\

r'

I 1

pOBut

-

OH

SCHEME 2

instead of the common PHAL; the usual M e 0 group in the alkaloid moiety (Q) was replaced with the bulkier Pr2CH0 group.48 Catalytic, regio- and stereo-selective nickel(0)-catalysed addition of Grignard reagents to allylic ethers can now be achieved (Scheme 3), provided that a Lewisbasic, coordinating group is present in the substrate molecule (72). In the absence of such a group, no reaction occurs. The reaction proceeds catalytically in the presence of (Ph3P)NiC12, presumably via the corresponding q3-comp1ex (73). The bidentate complexes, such as (dppe)NiC12, are ineffective, apparently owing to their lower dissociation ability, which precludes the crucial coordination to the pendant phosphine in (72).49

Organic Reaction Mechanisms 1995

376

J Pent,.,

MeMgCl

Me

H

\

-Ni(O)

Me

I

Me

i

PentPPhz (74) SCHEME 3

A study of the regio- and enantio-selectivities of the organolanthanide-catalysed alkene hydrosilylation revealed that, e.g. for a-alkenes, the turnover and the 2,lregioselectivity can be enhanced by openness of the metal ligation sphere and increasing the Ln3+ radius. For substituted styrenes, complete 2,l -regioselectivity (i.e. Si delivery to the benzylic position), rate enhancement by a para-electron-donating substituent, and turnover fiequencies as high as 400 h-' (at 60 "C) have been observed. For hex-1-ene, 2,l -addition regioselectivities are as high as 76% and turnover frequencies > 1000 hFor 2-phenylbut-l-ene, (R)-Me2SiCp[(- )-menthyl-

'.

377

13 Addition Reactions: Polar Addition

c~lSrnCH(SiMe~)~ and (S)-Me,SiCp[( - )-menthylCp]SmCH(SiMe3)2 have been shown to effect hydrosilylation with 68% and 65% ee, respectively (at 25 “C). The The mechanism has former reaction obeys the rate law v = k[Sm]1[alkene]o[PhSiH3]1. been discussed in terms of a hydride-alkyl cycle involving rapid, exothermic alkene insertion into an Ln-H bond followed by turnover-limiting Si-HLn-alkyl transposition (delivery of the alkyl group to Si).” The trans-hydrostannylation of alkynes (Scheme 4) can now be effected in the presence of Lewis acids (ZrC14 or H~Q).~‘ RC3CH Bu3SnH

+

-&

ZrC14

,C1, BU~S~’,: , ~ r ~ 1 3 H’

Bu3SnH

H

H

SCHEME 4

Elucidation of the mechanism of titanocene dichloride-catalysed hydromagnesation of alkynes with alkyl Grignard reagents confirmed the individual steps as illustrated in Scheme 5.52

I

2Pr’MgCI

R

H

Cp2TiH PriMgCl

RCrCR H

TiCp2

SCHEME 5

The kinetics and mechanism of the oxidative chlorination of acetylene in solution of CuCl and CuC12 have been reported; optimum conditions for the formation of CH2=CC12 have been identified.53

Organic Reaction Mechanisms 1995

318

Several ruthenium complexes, such as (PhOMe)(Ph3P)RuC12, (p-cymene)(Ph3P)RuC12, @-cymene)(Bu3P)RuC12,and CpRu(COD)Cl, have been shown to catalyse the ene addition of unactivated alkenes to unactivated alkynes, the latter complex exhibiting the highest conversions and regioselectivities. Monosubstituted alkenes are required while both terminal and internal alkynes react. A mechanism involving the formation of a ruthenacyclopentene has been proposed.54 Rhodium-catalysed, intramolecular silylformylation of an acetylenic bond has been found to be dominated by the exo-dig ring closure: (75) -+(76)”

(75) n=1,2

Hydroboration Facial selectivity in the hydroboration of allylic alcohols has been studied with the aid of steroidal model compounds (77) and (78). The hydroxyl group apparently tends to direct the reaction to occur from the anti-face. Thus, the 3b-hydroxyalkene (77) gives the 4a-alcohol (79), whereas the 3a-epimer (78) favours the formation of the 4P-isomer

13 Addition Reactions: Polar Addition

379

The reaction of B3H7 with acetylene has been studied theoretically, with geometries computed at the MP2/6-31G(d) level and relative energies estimated at the [MP4/63 11 G(d,p)] level. The initial reaction of B3H7 C2H2 has been found to give an addition product with little or no barrier. Loss of H2 leads first to cyclic C2B3H7 carboranes and then, through two methyleneborane intermediates, to the known nidoC2B3H7.Two pathways have been identified for the loss of H2 from the latter species, one synchronous and the other asynchronous, to the final product 1,2-C2B3H5.57

+

+

Miscellaneous Electrophilic Additions Benzothiazole (81) adds to aliphatic, open-chain and cyclic alkenes at 80 "C under p TsOH catalysis. Terminal alkenes give Markovnikov products. If a large excess of acid is used alkenes have been found to isomerize partly prior to the reaction so that mixtures of products are ~btained.~'

RL?3 ,0SiMe3 027

380

Organic Reaction Mechanisms I995

The product analysis in the reaction of a,P-unsaturated esters with NO$F; at - 16 "C suggests the intermediacy of highly reactive ci-carbonyl cation^.'^ Sulfonation of allylsilanes such as (82) with SO3 at -60 to 25 "C in CH2C12(with a 1.5 molar excess of dg-dioxane over SO3) has given various adducts, which can rearrange to more stable compounds (83) or (S4).60 The Richter reaction (85) -+ (87) has been revisited and the mechanism refined. The elucidation of the reaction course has led to the interception of the intermediate halide (86) that can now be obtained in a preparative procedure.6'

Acid-catalysed cyclopropane ring opening in (88) with methanol has been found to occur via both 'corner' and 'edge' protonation.62By contrast, bromination of the exoand endo-isomers (88) and (89) turned out to be initiated at the double bond; both isomers are preferentially attacked from the exo-face of the C=C bond. The stationary points on the potential-energy surface that result from the bromine addition have been identified by semiempirical methods. The non-classical bromonium ions appear to be less stable than the classical structure^.^^ Mercury(I1)-mediated cleavage of cyclopropane ring in (90) has been revisited and shown to be highly regioselective in the case of n = 1 or 2 and less regioselective for n = 0. In all three cases, the main product arises via the cleavage between the least- and the most-substituted carbon of the three-membered ring; the nucleophile enters preferentially at the carbon more distant from the electron-withdrawing OH group (in consonance with the cleavage of analogous epoxy alcohols). The reaction reflects the variation in nucleophilicity. Thus, if carried out in methanol with (CF3C02)*Hg,the product obtained is the methoxy derivative (91; R=Me), reflecting the poor nucleophilicity of the CF3CO; ion. With other mercury salts, such as Hg(NO3)2 or ( A C O ) ~ Hthe ~ , corresponding nitrate (91; R =NO2) or acetate (91; R = Ac) are obtained, re~pectively.~~

13 Addition Reactions: Polar Addition

381

It X = Br (1 1 %) X = OMe (29%)

+

X = Br (1 1%) X = OMe (49%)

X X = Br (4%) X = OMe (37%)

X = Br (17%) X = OMe (31%)

Organic Reaction Mechanisms 1995

382 Nucleophilic Additions

Additions to Multiple Bonds Conjugated with C=O The cation (Kf or Naf) in 2,6-di-t-pentylphenolates(ArOK or ArONa) has been found to affect the kinetics of their Michael addition to CH2=CHC02Me. It has been suggested that this effect is associated with the ability of ArONa to replace the cation with H+ originating from the product.65 The intramolecular Michael addition of sulfur anion generated from (92) has been reported66to give preferentially the cis-substituted heterocycle (93) in accordance with the Cieplak (9 : 1 to 1 : 1);66the Felkin-Ahn-t~pe~~ product (94) is formed in minute amounts.66By contrast, the analogous 0-nucleophile, published p r e v i o ~ s l y , ~ ~ ~ ~ ' prefers the Felkin-Ahn model. The difference has been rationalized in terms of differences in orbital stabilization.66Unfortunately, there are several serious errors in the original paper66 so that it is difficult to read.

c-'

H C02Me

He C O i M e I

Cieplak model

(93)

SAC

(92)

R = Bu'MeZSi or Me

H Felkin-Anh model

(94)

As expected, the reaction of trans-chalcone PhCH=CHCOMe with primary amines RNH2 (R = Pr, Bu, C6H13) in heptane or benzene has been found to exhibit a decrease in the reaction rate constant with increased solvent basicity (due to the solvation of ammonium ions).72A similar effect has been observed for the addition of piperidine to benzylidenemalonic ester (i.e. the final step in the Knoevenagel c~ ndensation). ~ ~ The kinetics of the reaction of I , I , I -trichloro-4-methoxypent-3-en-2-one (95) with various aliphatic and aromatic amines at 25 "C in H20, Me2S0, EtOH, CHC13, toluene, or hexane have resulted in the formulation of an addition mechanism. The preferential 2-geometry of the product (96) is dictated by an intramolecular hydrogen bonding.74

13 Addition Reactions: Polar Addition

383

A study of diastereocontrol in the Lewis acid-catalysed Michael reactions of 4siloxycyclopentenone (97) with ketene silyl acetals (98) has demonstrated a competition between the stereoelectronic and steric effects. Thus, the sterically disfavoured syn preference (to the d o x y group) has been observed for the acetals with small steric demands (99), whereas sterically bulky acetals give rise to the reversal of diastereoselection

b

TBSO

(97)

Rx0siR3 \ 2’

TBSO‘

+

R

G,

‘’

--CO*R’

(99)

OR’

A

R=Me

(98)

Michael-type additions of 2-methyl(benzylimino)cyclohexane, reacting as its secondary enamine tautomer (101), to methyl methacrylate, methyl crotonate, and maleic anhydride has been found to proceed with excellent diastereoselectivity, which apparently originates from the chair-like transition state.76

w

Me H

P m / C02R

-MeOH

0

I

-Ph

Dilithiated P,y-unsaturated secondary amides (102) undergo diastereoselective

( 5 95 : 5) conjugate addition to cyclopentenone; the stereoselectivity has been

rationalized via the transition state (103).77 MNDO and PM3 calculations indicate that the lithium (2)-enolates, derived from Nalkylideneglycinates (104), react with a,,&unsaturated esters through a stepwise mechanism, including the initial anti-selective formation of Michael adducts. The second step consists of the stereoselective ring formation or a 1,3-dipolar addition. The energy difference between individual transition states reflects the steric hindrance

Organic Reaction Mechanisms 1995

384

caused by the alkylidene moiety: bulky alkylidene substituents prefer the formation of Michael adducts, whereas the small substituents favour 1,3-dipolar adducts. The high anti-selectivity observed in the first step has been attributed to the attractive MO interaction between the imine moiety of the donor molecule and the C, of the acceptor.78

R4NnC02Me

(104)

+

Me

-CIO,Me

base

MeOZC,

CfMe "'T02Me

H

The Michael-type addition of heteroaromatics, such as furans (105), indoles, and thiophenes to a,S-unsaturated ketones (including methyl vinyl ketone) can now be carried out in the presence of BF3.Etz0.79

R = H (79%) R = Me (80%)

Mono- and 2,6-di-substituted quinones (108) and (109) have been obtained from the reaction of the tetrahalo-p-benzoquinones (106) and triphenylphosphoniocyclopentadienide (107) as a result of two parallel, irreversible second-order reactions, which are well separated in time. The rate of formation of the monosubstituted product was determined using the stopped-flow technique and its half-life was found to be in the millisecond range. Kinetic data for the mono- and di-substitution products indicate that both reactions proceed in two steps involving rate-limiting addition to form a polar betaine intermediate followed by El elimination of hydrogen halide.80 Mere eight-fold acceleration has been demonstrated for the conjugate addition of pyrrolidine to a,B-unsaturated lactones in the presence of the catalytic amounts (0.1 equiv.) of the guanidinium salt. The effect has been attributed to selective hydrogen bonding (110).81 The first antibody-catalysed Michael addition of CN- to a,S-unsaturated ketones has been reported.*'

13 Addition Reactions: Polar Addition

385

Whereas the reaction of the vinyl chloride (111) with ethyl a-thioacetate gives the expected product of vinylic substitution (112) that can be isolated, further treatment with a strong base (e.g. NaH) triggers an intramolecular Michael addition to give, eventually, (113).83 An interesting Michael-type macrocyclization of (1 14) has been successfully executed with the cis-isomer; the corresponding trans-isomer, as well as the analogous acetylene derivative, proved to prefer an intermolecular reaction.84 Michael addition of DBU to dimethyl acetylenedicarboxylate, followed by intramolecular condensation of the adduct, afforded the tricyclic derivative (1 15)? Polyfluoroalk-2-ynoic acids (116; R = CHF2, CF3, or CHF2CF&F2) readily undergo an intermolecular Michael addition, followed by a Michael-type cyclization, with a variety of bifunctional nucleophiles, such as (117; X = NH, NMe; Y = NH, S, 0, NMe) or o-phenylenediamine, to give the corresponding imidazolidine, thiazolidine, and oxazolidine derivatives (118) in moderate to good yields.86

Organic Reaction Mechanisms 1995

386

7yF35F3 -

It

f-

Ph

C02Et

I

MeOzC-COzMe

Ph

Ph

C02Et

S-

C02Et

5

387

13 Addition Reactions: Polar Addition

Rf-CGC-CO2H

(116)

+

-

HX WYH (117)

RfXCH2c02H xuy (118)

Rf = CHF2, CF3, CHF2CF2CF2

x, Y = s, 0

Additions to Multiple Bonds Activated by Other Electron-withdrawing Groups

The AdN-E and sN2-V mechanisms in bimolecular nucleophilic substitution at vinyl carbon (Scheme 6 ) have been assessed, in particular with regard to the relevance of the LUMO symmetry of the electrophile (Figure 1). To this end, the lowest vacant orbitals of a series of vinylic compounds with substituents of different electron-withdrawing power (X = RSH+, Ph+, C1, TfO, F, MeI+, MeCl+, etc.) have been computed at the 321G*//3-21G*, 6-31G1;//3-21G*, or 6 3 1 1Gt//3-21G* levels (Figure 2). In substitutions where the first vacant orbitals with (T- and n-symmetry at the carbon atoms are separated by >0.01 hartree, an almost complete correspondence has been found between the symmetry of the lowest orbital (LUMO) and the stereochemical outcome of nucleophilic substitution on the corresponding substrates. This finding is in accord with the assumption that the interaction of the approaching nucleophile with the orbital of TCsymmetry directs the attack orthogonally to the molecular plane (AdN--!?mechanism, leading either to retention or inversion of configuration (Scheme 7; route a), while interaction with the a-symmetrical orbital dictates the attack in the molecular plane (SN2-Vmechanism, leading to inversion of configuration; route b). The situations where this correlation fails are related to substrates where either the energy gap is smaller or for which other mechanisms (non-concerted or steered by pre-coordination) have been proposed; route c.~? The silyl enol ethers derived from cyclohexanone and cyclopentanone (119) undergo a 1,4-addition to p-nitro- and P,P-dicyano-styrenes (120) (but not to a,fl-unsaturated carbonyl compounds) in 5 M LiC104-Et20 at room temperature to afford the corresponding Michael adducts (121) in good yields and with moderate stereo-

SCHEME 6

Organic Reaction Mechanisms 1995

388

Nu

SCHEME 7

FIGURE 1

selectivity (1.3 : 1 to 3.5 : 1). The experimental evidence has suggested the involvement of transfer of the silyl group to the Michael acceptor.88Similar Michael additions of pketo sulfoxides and P-keto sulfones (122) have also been reported.89

b

OSiMe3

+

Y

EtzO, r.t.

13 Addition Reactions: Polar Addition Nucleophile

Transition state

3 89 Electrophile

FIGURE 2. Orbital correlation diagram in nucleophilic substitutions. Reprinted with permission from Lucchini, V., Modena, G., and Pasquato, L., J. Am. Chem. Soc., 117,2297 (1995). Copyright (1995) American Chemical Society.

Rate constants for the elementary steps in the addition-elimination of nucleophilic vinylic substitutions (SNV)have been determined by studying the reactions of stilbenes (124) and (125) with HO-, CF3CH20-, piperidine, and HOCH2CH2S- in Me2SOH20 (1 : 1) at 20 "C. In the reaction of (124) with HO- and piperidine, and also in the reaction of (125) with HO-, piperidine, and HOCH2CH2S-, the SNV intermediate, whose formation is the rate-limiting step, does not accumulate to detectable levels. By contrast, in the reaction of (124) with HOCH2CH2S-, the intermediate (126) was directly observable, which allowed a kinetic determination of all steps involved in the reaction. The structure dependence of the various rate constants has been rationalized in terms of an interplay of electronic, steric, resonance, and anomeric effects. The observed dependence of the rates of the departure of the alkoxide ion (MeO- vs CF3CH20-) from the intermediates on the pK, of the respective alkoxide ion suggests a large amount of C-0 bond cleavage in the transition state."

"'HX Y

Ph

(124) X = NO*, Y = CF3CHzO (125) X = Y = NO2

Ph

I

I

,Ph

CF~CU~O-C-C+

N02SCHzCH20H

(126)

Organic Reaction Mechanisms I995

390

Another kinetic and spectroscopic study, namely that of the reactions of NHzOMe and MeNHOMe with /3-methoxy-a-nitrostilbene(127) in MeS02-H20 (1 : l), has also led to the direct observation of the intermediate in nucleophilic vinylic substitution. Thus, with MeNHOMe, the reaction of the latter stilbene gave rise to the expected enamine substitution product (128). With NH20Me, the product at high pH is the anion (129), while at low pH it is the imine form (130) rather than the enamine. On the other hand, at high pH and high amine concentrations, the concentrations of the S N V intermediates (131; R = H or Me) rise to detectable levels, which allowed their spectroscopic and kinetic characterizations. These reactions represent the first examples of a nucleophilic vinylic substitution by amine nucleophile in which the intermediate is directly observable. The structure-reactivity comparisons between the MeNHOMe reaction and the reaction of (127) with piperidine and morpholine, reported previously, are consistent with a relatively weak dependence of the nucleophilic addition step ( k l ) on the amine basicity (Pnuc= 0.25) but a strong dependence of the leaving-group expulsion step (k2) on the amine pK, (ppush = 0.71). This explains why the intermediate is observable in the reaction with the relatively weakly basic NH20Me and MeNHOMe but not with more strongly basic amines. Steric effects appear to play a major role in the MeNHOMe reaction. One type of steric effect has been attributed to crowding in the intermediate, which reduces the rate and equilibrium constants for intermediate formation and enhances leaving-group departure. The other type is steric hindrance to n-overlap in the product and the preceding transition state, which reduces the push by the nitrogen lone pair of the intermediate and hence decreases k2 for leaving-group expulsion; the latter effect seems to be stronger than the former.”

MeNHOMe

Me0

Ph

Ph MeNOMe (128)

NH20Me

Ph

NO2

phHNo2hcH:

MeON

Ph

MeON

Ph

Ph I MeO-C-C,

p 0 2 -

I

dOMe

ph

(131)

The reaction of aqueous acids with the product of addition of CF3CH20- to (124), i.e. (132), has been found to lead almost exclusively to the corresponding acetal (134) by carbon protonation. By contrast, the CH30- adduct (133), arising from (127), leads almost exclusively to the recovery of (1 27) by acid-catalysed expulsion of MeO-.92 The addition of arenesulfinic acid to 4-(2-nitroethenyl)toluene, giving aryl 2-nitro-1(p-tolylethyl)sulfones, has been shown to be an overall second-order process. The rate-

I3 Addition Reactions: Polar Addition

(124)

CF3CH20-

Ph

39 1

I

+NO1

H30+

I

Ph

(R=CF&Hz)

RO-C-C, RO

Ph

I

CF~CHZO-C-CH,

I

CF3CH20

,Ph NO2

MeO-

(132) R = CF3CH2 (133) R = M e

(127)

determining step is the addition of the sulfinate anion to the olefinic double bond of 4(2-nitroethenyl)tol~ene.~~ The addition of PhCH2NHMe (MBA) to styrene (St), catalysed by PhCHzN(Li)Me (LMBA), has been found to follow kinetics expressed by the equation v = l@t][LMBA]o.5[MBA]; the calculated activation entropy is - 1.7 x lo2 J K mol-'. The mechanism has been shown to be different from that for the Et2NH addition (catalysed by Et2NLi). Dimer formation of LMBA and strong solvation of the activated complex have also been d e m ~ n s t r a t e d . ~ ~ Addition of the lithium enolate of dioxanone (135) to (a-P-bromovinyl sulfone has been reported to give the corresponding product of vinylic substitution (136) with high stereoselectivity. On the other hand, addition to the Z-isomer proved to be poorly stereoselective, producing a 1.6 : 1 mixture of (137) and (138), respectively. Nevertheless, in both cases the geometry of the double bond was hlly preserved. Reactions of the corresponding (tJ-P-bromoacrylate follow the same pattern.95

1. LHMDS THF, -78 "C 2' BrdfiS02Ph

0

I.

e

S02Ph

Organic Reaction Mechanisms I995

392

Conjugate addition of nucleophiles to the nitroalkene (139) followed by in situ ozonolysis, results in the formation of a-substituted thioesters (141), having in most cases the 'unexpected' syn relative configuration, which is in sharp contrast to the addition to cQ-unsaturated esters.96

Stereoselective, intramolecular carbolithiation of vinyl sulfides, such as (142), has been reported.97

P Meh

G

R Sph

~

I . BuLi, THF

phM

2. MeOH

Me Me

SPh

Additions of Organometallics to Activated Double Bonds Competition between 1,2- and 1,4-addition, an evergreen in organometallic chemistry, has been investigated with the aid of model compounds for which the latter reaction is disfavoured by severe steric hindrance, e.g. with wootkatone (143) and other enones. The best 1,2- to 1,4-ratio in favour of the latter (up to 1 :4.5) has been found for Me3Al in the presence of a catalytic amount of (acac)2Ni. Other reagents, such as cuprates, favour 1,2-additi0n.~~

2-(2-Methylpropylidene)cyclohexanone has been reported to give a 1,4-addition product with MeMgI in the presence of C U C ~ . ~ ~ Facial selectivity in lithium dialkylcuprate addition has been elucidated with the aid of substituted endo-tricyclo[5.2.1.02'6]decadienones(144). The results (Scheme 8) have been interpreted in terms of steric and stereoelectronic effects.loo

I 3 Addition Reactions: Polar Addition

(144)

393

endo

exo

X

exo; endo

H C02Et OMe SPh SePh S(0)Ph

-100: 0 86: 14 2 3 ; 77 0 : 100 0 : 100 0 : 100

SCHEME 8

The novel sulfonylalkyne (145) has been reported to favour 'normal' Michael addition (146) when treated with cuprates. By contrast, other nucleophiles give rise to 'anti-Michael' products (147). Attempts have been made by the authors to rationalize this behaviour in terms of MO theory.'"

TsqSePh - =I RZCuCNLiz

R

Ts

SePh

Nu

(N, 0, S, Se)

Nu

SPh

Miscellaneous Nucleophilic Additions Trimethylsilyl cyanide has been reported to add to the nitrone (148) with essentially complete stereoselectivity. This outcome has been rationalized by the favoured transition state (149).'02 y-Methoxy sulfonyl anions (150) undergo conjugate addition to mono- and bi-cyclic cyclopentenyl sulfones. The primary adducts (151) tend to cyclize to spirocyclic cyclopropane derivatives (152), which can be hydrolysed to afford 6-sulfonylsubstituted enones (153).'03 Several pathways in the reaction of cyclohexanone enamines with a,p-unsaturated acid chlorides and 2- and 3-chloropropionyl chlorides have been reported. The actual choice of the preferred reaction channel is dependent on the reaction condition^."^ In accord with the expectation, the addition of nucleophiles to RC6H4N=C=0 (R = H, Me, Br, C1, NH2, NO*) has been shown to correlate with the positive charge located at the carbon atom of the NCO group. The charge was calculated using the EHMO method. '05

394

Organic Reaction Mechanisms I995

on S02Ph

S02Ph

I

____)

Me0

-78 "C THF, HMPA

(151) PhSOzLi -65 "C

S02Ph

SOzPh

H20

silica

f--

THF reflux

Me0

Primary aliphatic amines add across the triple bond of ClCrCCl to give various products, depending on the reaction conditions. O6 Investigation of the alleged 6(O)"-endo-digcyclization of (154) revealed an unusual acid-catalyzed rearrangement of the benzofuran (155), initially formed by the 5(0)"exo-trig ring closure (!), to afford (156) as the final prod~ct."~

'

13 Addition Reactions: Polar Addition

395

The competition between the Michael addition and Diels-Alder reaction of avinylpyrrole and dimethyl acetylenedicarboxylate has been studied at the PM3 semiempirical level. It has been found that substituents dramatically influence the orbital level and, consequently, the reaction preference.log The reactivity of the bridgehead-substituted bicyclobutanes (157) towards nucleophiles has been compared with that ofthe analogous vinylic compounds (158). Ab initio calculations suggest that electron-withdrawing substituents (EWG) exert nearly the same energetic effects on the ground state of the two systems. The observed difference in reactivities must, therefore, stem from the different nature of the corresponding transition states."'

The stereochemistry of the anionic polymerization of 2-vinylpyridine and related vinyl monomers has been reported to depend on subtle steric interactions between the prochiral anion and the alkyl group of the reagent (ROLi2)+ 'counterion.' This effect shifts the equilibrium between the diastereoisomeric pro-meso and pro-rac ion pairs in favour of the latter species, which reacts with the monomer in syn fashion to produce meso sequences. It has been argued that a helical conformation of the growing chain can be expected to favour such a pro-meso species, leading to rapid, isotactic chain growth."' The tetrabutylammonium salts of CH-acidic compounds [malonic diesters and diamides, MeN02, PhCH2C02R, PhCH(Me)C02R, and 9-ethylfluorene] have been reported to serve as inexpensive initiators for the anionic polymerization of acrylates and methacrylates at room temperature. Molecular weights of 1500-25 000 can be reached, with the distribution being fairly narrow (D= 1.1-1.4 in optimized cases). The X-ray analysis of the tetrabutylammonium salts of PhCH2C02R, PhCH(Me)C02R, and MeCH2CH(Ph)C02R showed that anions and cations interact with one another via hydrogen bonding. Therefore, the initiators cannot be considered to be naked anions."' The role of the enolate anions in the silicon-mediated polymerization (group-transfer polymerization, GTP) of CH2=C(Me)C02Me (MMA) has now been investigated using Cs+, Bu4Nf, and Li+ salts of 9-methylfluorenide as the nucleophilic catalysts. The results of normal anionic polymerization of MMA using these carbanion salts were compared directly with the analogous GTP processes carried out in the presence of the silyl ketene acetal initiator 1-methoxy-1-(trimethylsiloxy)-2-methylprop-1-ene (MTS). In the absence of MTS, these reactions are characterized by low conversion (14-25%), no control of Mn, and broad molecular-weight distribution. By contrast, in the presence of MTS, controlled MMA polymerization is observed. The authors concluded that the results are consistent with an associative GTP mechanism only if it is postulated that the chemistry and stereochemistry of a pentacovalent siliconate anion are the same as those of an ester enolate anion intermediate.lI2

396

Organic Reaction Mechanisms I995

References Bellucci, G., Chiappe, C., and Bianchini, R., Ind. Chem. Libr, 7, 128 (1995); Chem. Abs., 123, 82546 (1995). Brown, R. S., Ind. Chem. Libs, 7, 113 (1995); Chem. Abs., 123, 255845 (1995). Ruasse, M.-F., Ind. Chem. Libr, 7, 100 (1995); Chem. Abs., 123, 111244 (1995). Smit, W. A,, Caple, R., and Smoliakova, I. P., Chem. Rev., 94, 2359 (1994). Christl, M., Adv. Stmin Org. Chem., 4, 163 (1995); Chem. Abs., 123, 55102 (1995). Mukaiyama, T. and Kobayashi, S., Org. React. @.Y), 46, 1 (1994); Chem. Abs., 122, 186541 (1995). Leonard, J., Contemp. Org. Synth., 1, 387 (1994); Chem. Abs., 122, 55316 (1995). Hirsch, A,, Lamparth, I., and Karfunkel, H. R., Proc. Electrochem. SOC.,1995,94; Chem. Abs., 122,9175. Mosimann, H., Dienes, Z., and Vogel, P., Tetrahedron, 51, 6495 (1995). Bellucci, G., Chiappe, C., Lo Moro, G., and Ingrosso, C . , 1 Org. Chem., 60, 6214 (1995). I ’ Slebocka-Tilk, H., Motallebi, S., Nagorski, R. W., Turner, P., Brown, R. S., and McDonald, R., 1 Am. Chem. Soc., 117, 8769 (1995). l 2 In this chapter last year (Org. React. Mech., 1994, 335), it was erroneously stated that deuterium ‘increased’ the steric hindrance rather than ‘decreased’. 13 Neverov, A. A. and Brown, R. S., Can. 1 Chem., 72, 2540 (1994). l4 Rodygin, M. Yu., Mikhailov, V. A,, Zurbritskii, M. Yu., and Savelova, V. A., Zh. Org. Khim., 30, 339 (1994); Chem. Abs., 122, 132239 (1995). l 5 Karunakara, C. and Manimekala, A,, 1 Pol. Chem., 68, 2065 (1994); Chem. Abs., 122, 55424 (1995). l 6 Amadji, M., Vadecar, J., Schimmel, U.,PI& G., and Plaquevent, J.-C., 1 Chem. Res. (9,1995, 326. l 7 Marazov, A. Y and Maksimov, B. N., Zh. Org. Khim., 30, 1167 (1994); Chem. Abs., 123, 32440 (1995). l 8 Toyota, A,, Ono, Y., and Kaneko, C . , Tetrahedron Lett., 36, 6123 (1995). l 9 Herges, R. and Neuman, H., Liebigs Ann. Chem., 1995, 1283. 2o Wang, Z., Yin, C., Zhang, B., and Zhang, Q., Zhonguo Kexue Jishu Daxue Xuebao, 25,82 (1 995); Chem. Abs., 123, 227450 (1995). ” Karunakaran, C., Ismail, J., and Manan, S. M., React, Kinet. Catal. Lett., 53, 191 (1994); Chem. Abs., 122, 159893 (1995). 22 Fnesen, R. W., Bayly, C. I., and Fogg, J. A., 1 Org. Chem., 60, 448 (1995). 23 Olejnik, M., Jasiobedzi, W., Janowski, M., and Migdal, W, Bull. Pol. Acad. Sci., Chem., 41, 77 (1993); Chem. Abs., 123, 143082 (1995). 24 Saluizo, C.; La Spina, A.-M., Picq, D., Alvernhe, G., Anker, D., Wolf, D., and Hauffe, G., Bull. SOC. Chim. F j , 131, 831 (1994). 2s Bogomolov, A. Yu., Smimov, V. V, Rostovshchikova, T. N., and Gerasimov, P. Y, Kinet. Catal. (Engl. Transl. Kinet. Katal.), 36, 232 (1995); Chem. Abs., 123, 255930 (1995). 26 Aleksiev, D. I. and Ivanova, S . , Phosphorus Sulfur Silicon Relat. Elem., 90,41 (1994); Chem. Abs., 122, 105040 (1995). 21 Moriguchi, T., Endo, T., and Takata, T., 1 Org. Chem., 60, 3523 (1995). 28 Mellor, J. M., Meniman, G . D., and Mitchell, P. L., Tetrahedron Lett., 51, 12383 (1995). 29 Georgieva, A., Stanoeva, E., Spassov, S., Haimova, M., De Kjmpe, N., Boelens, M., Keppens, M., Kemme, A,, and Mishnev, A., Tetrahedron, 51, 6099 (1995). 30 Cramail, H. and Deffieux, A,, 1 Phys. Org. Chem., 8, 293 (1995). 31 Smonou, I., Khan, S., Foote, C. S., Flemes, Y., Mavridis, I. M., Pantidou, A., and Orfanopoulos, M., 1 Am. Chem. Soc., 117, 7081 (1995). 32 Poon, T. H. W., Park, S. H., Elemes, Y., and Foote, C. S., 1 Am. Chem. SOC., 117, 10468 (1995). 33 Atkinson, R. S. and Kelly, B. J., 1 Chem. SOC.,Perkin Trans. I , 1989, 1515. 34 Atkinson, R. S., Fawcett, J., Russell, D. R., and Williams, P. J., 1 Chem. SOC.,Chem. Commun., 1994, 203 1 . 35 Atkinson, R. S., Fawcett, J., Russell, D. R., and Williams, P. J., Tetrahedron Lett., 36, 3241 (1995). 36 Atkinson, R. S., Barker, E., Edwards, P. J., and Thomson, G. A., 1 Chem. Soc., Chem. Cornmun., 1995, 727. 37 Atkinson, R. S. and Barker, E., 1 Chem. SOC.,Chem. Commun., 1995, 819. 38 Atkinson, R. S., Barker, E., Edwards, P. J., and Thomson, G. A,, 1 Chem. SOC.,Perkin Trans. 1, 1995, 1533. 39 Karlen, T. and Lund, A,, 1 Am. Chem. Soc., 116, 11375 (1994). 40 Casey, C. P. and Petrovich, L. M., 1 Am. Chem. Soc., 117, 6007 (1995). 41 Lee, C. W. and Alper, H., 1 Org. Chem., 60, 499 (1995). 42 Monflier, E., Fremy, G., Castanet, Y., and Mortreux, A., Angew. Chem., In?. Ed. Engl., 34, 2269 (1995).

13 Addition Reactions: Polar Addition 43

44 45 46

47

48

49 51 52

53

397

Kitayama, K., U o m i , Y., and Hayashi, T., 1 Chem. Soc., Chem. Commun., 1995, 1533. Grigg, R., Sridharan, V., and Xu, L.-H., 1 Chem. SOC.,Chem. Commun., 1995, 1903. Agarwal, D. D. and Rastogi, R., Indian 1 Chem., 33B, 787 (1994); Chem. Abs., 121, 280110 (1994). Hanson, J. R., Hitchcock, P. B., Liman, M. D., and Manickavasagar, R., 1 Chem. Rex (S), 1994,466. Corey, E. J., Guzman-Perez, A,, and Noe, M. C . , Tetrahedron Lett., 36, 3481 (1995). Corey, E. J., Noe, M. C., and Lin, S., Tetrahedron Lett., 36, 8741 (1995). Didiuk, M. T., Morken, J. F!, and Hoveyda, A. H., 1 Am. Chem. Soc., 117, 7273 (1995). Fu, I?-F., Brard, L., Li, Y., and Marks, T. J., 1 Am. Chem. Soc., 117, 7157 (1995). Gao, Y. and Sato, F., 1 Chem. SOC.,Chem. Commun., 1995, 659. Brailovskii, S. M., Man'khoan, K., and Temkin, 0. h?,Kinet. Katal., 35, 734 (1994); Chem. Abs., 122, 159897 (1995).

Asa, N., Liu, J.-X., Sudoh, T., and Yamamoto, Y., J. Chem. Soc., Chem. Commun., 1995, 2405. 54 Trost, B. M., Indolese, A. F., Miiller, T. J. J., and Treptow, B., 1 Am. Chem. Soc., 117, 615 (1995). 55 Monteil, F., Matsuda, I., and Alper, H., 1 Am. Chem. Soc., 117, 4419 (1995). 56 Hanson, J. R., Hitchcock, F ! B., Liman, M. D., andNagaratnan, S., 1 Chem. SOC.,Perkin Trans. I , 1995, 2183. 57 McKee, M. L., 1 Am. Chem. SOC.,117, 8001 (1995). 58 Katritzky, A. R., Puschmann, I. B., Stevens, C. V, and Wells, A. P., 1 Chem. SOC.,Perkin Trans. 2, 1995, 1645. 59 Hewlings, S. A., Murphy, J. A,, and Lm, J., 1 Chem. SOC.,Chem. Commun., 1995, 559. 6o Cerfontain, H., Kramer, J. B., Schonk, R. M., and Bakker, B. H., Recl. Trav. Chim. Pays-Bas, 114, 410 (1995). 61 Vasilevsky, S. F. and Tretyakov, E. V, Liebigs Ann. Chem., 1995, 775. Bumtt, A,, Coxon, J. M., and Steel, P J., 1 Org. Chem., 60, 7670 (1995). 6 3 Coxon, J. M., Steel, P. J., Burritt, A,, and Wittington, B. I., Tetrahedron, 51, 8057 (1995). 64 KoEovskL, F!, Grech, J. M., and Mitchell, W. L., 1 Org. Chem., 60, 1482 (1995). Volod'kin, A. A,, ID. Akad. Nauk, Ser Khim., 1994, 827; Chem. Abs., 122, 132334 (1995). 66 Gung, B. W. and Francis, M. B., Tetrahedron Lett., 36, 2579 (1995). 67 Cieplak, A. S., 1 Am. Chem. SOC., 103, 4540 (1981). For leading support and critique of the Cieplak model, see: ( a ) Hahn, J. M. and le Noble, W., 1 Am. Chem. SOC.,114, 1916 (1992); (6) Wu, Y. D., Tucker, J. A,, and Houk, K. N., 1 Am. Chem. SOC.,118, 5018 (199 I). 69 Anh, N. T., Top. Curr Chem., 88, 145 (1980). 70 Gung, B. W. and Wolf, M. A,, 1 Org. Chem., 58, 7038 (1993). 7' Gung, B. W. and Francis, M. B., 1 Org. Chem., 58, 6177 (1993). 72 Kostecki, M., Szczesna, J., andKinastovski, S., Rocz. Akad. Roln. Poznaniu, 256,25 (1993); Chem. Abs., 123, 169044 (1995). 73 Mroczyk, W., Szczesna, J., and Kinastowski, S., Rocz. Akda. Roln. Poznaniu, 256,65 (1993); Chem. Abs., 123, 169045 (1995). 74 Gesser, J. C., Zucco, C., and Nome, F., 1 Phys. Org. Chem., 8, 97 (1995). 75 Otera, J., Fujita, Y.,Fukuzumi, S., Hirai, K., Gu, J.-M., and Nakai, T., Tetrahedmn Lett., 36, 95 (1996). 76 Pfau, M., Tomas, A,, Lim, S., and Revival, G., 1 Org. Chem., 60, 1143 (1995). 77 Haynes, R. K., Starling, S. M., and Vonwiller, S. C . , 1 Org. Chem., 60,4690 (1995). 78 Tatsukawa, A,, Kawatake, K., Kanemasa, S., and Rudzinski, J. M., 1 Chem. Soc., Perkin Trans. I , 1994, 2525. Dujardin, G. and Poiner, J.-M., Bull. SOC. Chim. Fr, 131, 900 (1994). 80 Pla, €? F., Hall, C. D., Speers, F!, and Palou, J., 1 Chem. SOC., Perkin Trans. 2, 1994, 2499. Alckar, V., Morin, J. R., and de Mendoza, J., Tetrahedron Lett., 36, 3941 (1995). 82 Cook, C. E., Allen, D. A,, Miller, D. B., and Whisnant, C. C., 1 Am. Chem. Soc., 117, 7269 (1995). 83 Amaud, R., Bensadat, A,, Ghobsi, A., Laurent, A,, Le Drean, I., Lesniak, S., and Selmi, A,, Bull. SOC. Chim. Fr, 131, 845 (1994). 84 Crkvisy, C., Couturier, M., Dugave, C., Dory, Y. L., and Deslongchamps, P., Bull. SOC.Chim. FK,132,360 ( I 995). 85 Ma, L. and Dolphin, D., 1 Chem. Soc., Chem. Commun., 1995, 2251. 86 Funabiki, K., Tamura, K., Ishihara, T., and Yamanaka, H., Bull. Chem. SOC.Jpn, 67, 3021 (1994). 87 Lucchini, V., Modena, G., and Pasquato, L., 1 Am. Chem. SOC.,117, 2297 (1995). Saraswathy, V. G. and Sankararaman, S., 1 Org. Chem., 60, 5024 (1995). 89 Marco, J.-L., Fernandez, I., Khiar, N., Fernandez, P., and Romero, A., 1 Org. Chem., 60, 6678 (1995). Bernasconi, C. F., Schuck, D. F., Ketner, R. J., Weiss, M., and Rappoport, Z . , 1 Am. Chem. SOC.,116, 11764 (1994).

''

'"

398 91

92 93 94

95 96 97

98

99 100 101

I02 103 104 105

I Oh 107

I08 109

I10 Ill 112

Organic Reaction Mechanisms 1995

Bemasconi, C. F., Leyes, A. E., Eventova, I., and Rappoport, Z., 1 Am. Chem. SOC.,117, 1703 (1995). Bemasconi, C. F., Schuck, D. F., Ketner, R. J., Eventova, I., and Rappoport, Z., 1 Am. Chem. Soc., 117, 2719 (1 995). Alexiev, D. I. and Ivanova, S . M., Zh. Org. Khim., 30, 720 (1994). Hamana, H., Hagiwara, T., and Narita, T., Saitama Kogyo Daihgu Kiyo, 3, 22 (1 994); Chem. A h . , 122, 159887 (1995). Bmncko, M. and Crich, D., 1 Org. Chem., 59, 7921 (1994). Barren, A. G . M. and Rys, D. J., 1 Chem. Soc., Perkin Trans. I , 1995, 1009. Krief, A,, Kenda, B., and Remade, B., Tetrahedron Left., 36, 7917 (1995). Kabbara, J., Fleming, S., Nickisch, K., Neh, H., and Westermann, J., Liebigs Ann. Chem., 1995, 401. Cuza, O., Caravaniez, D., and Zavoianu, D., Rev. Chem. (Bucharest), 45, 368 (1994); Chem. Abs., 122, 80508 (1 995). Zhu, J., van der Hoeven, J., Slief, J.-W., Klunder, A. J. H., and Zwanenburg, B., Tetrahedron, 51, 10953 (1995). Back, T. G. and Wehrli, D., Tetrahedron Lett., 36, 4737 (1995). Merchan, F. L., Merino, P., and Tejero, T., Tetrahedron Lett., 36, 6949 (1995). Jin, 2. and Fuchs, P. L., 1 Am. Chem. Soc., 117, 3022 (1995). Butkus, E. and Bielinyte-Williams, B., Collect. Czech. Chem. Commun., 60, 1343 (1 995). Zhang, S. and Jing, Ch., Huaxue Shijie, 34, 275 (1993); Chem. Abs., 122, 30781 (1995). Pielichowski, J. and Czub, P., Bull. SOC. Chim. Belg., 104, 407 (1995). Weingarten, M. D. and Padwa, A., Tetrahedron Lett., 36, 4717 (1995). Domingo, L. S., Jones, R. A,, Picher, M. T., and Sepulveda-Arques, J., Tetrahedron, 51, 8739 (1995). Azran, C. and Hoz, S., Tetrahedron, 51, 11421 (1995). Hogen-Esch, T. E., Jin, Q., and Dimov, D., 1 Phys. Org. Chem., 8, 222 (1995). Reetz, M. T., Hiitte, S., and Goddard, R., 1 Phys. Org. Chem., 8, 231 (1995). Quirk, R. P. and Kim, J.-S., 1 Phys. Org. Chem., 8, 242 (1995).

CHAPTER 14

Addition Reactions: Cycloaddition N. DENNIS

Australian Commercial Research and Development Ltd, GPO Box 2481, Brisbane, Queensland 4001, Australia

+ + +

2 2-Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3-Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 4-Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Cycloadditions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

399 403 413 427 433

A practical guide to photochemical cycloadditions has been published.'

2

+ 2-Cycloaddition

+

+ +

Factors determining the outcome of competing 2 2- and 2 4-cycloaddition reactions are discussed.2 The stereo- and regio-selectivity of 2 2-photo-cycloadditions of alkenes have been investigated by PMO and FMO method^.^ Semiempirical MO theory has shown that fluorine andor amine substituents reduce the potential-energy barrier of the 2 2-cycloaddition reactions of ethylene with formaldehyde? Global potentialenergy contour plots have been developed for reactions involving stepwise concerted addition of two alkenes to form cy~lobutane.~ Kinetic studies of the zwitterionic 2 + 2cycloaddition of TCNE and bis(4-methoxycinnamyl) ether decisively exclude an ET mechanism in favour of a polar mechanism.6 The thermal reaction of hnctionalized cyclobutenes (1) with 1,l-dimethoxyethene yields the expected 2 2-adducts, bicyclo[2.2.0]hexanes (3) and new 4 2-adducts, bicyclo[4.2.0]octenes (4) via the intermediate (2) (Scheme l).' The photo-sensitized intramolecular 2 2-cycloaddition reactions of 2,6-diarylocta1,6-dienes are potentially stereoselective via a 1,4-cation radical intermediate.8 The photo-induced intramolecular ortho cycloadditions of 2-substituted 4-(3-methylbut-3en- 1-oxy)acetophenones (5) itre 100% regioselective syn, yielding initially adduct (6) which is converted into the stable cyclobutene (8) via the cyclooctatriene (7) (Scheme 2).9 Also, the photochemical cycloaddition of silicon-tethered enynes (9) produces substituted cyclobutenes (10) with high regiospecificity in high yields (Scheme 3)." Ab initio calculations on the photo-cycloadditions of triplet cyclohexenones with alkenes show that the origin of the regioselectivity is in the bond-forming step." Triplet 1,4-biradical intermediates in the photochemical 2 2-cycloaddition reaction between cyclopenten-2-one with methyl acrylate and ethyl vinyl ether have been trapped with

+

+

+

+

+

Organic Reaction Mechanisms 1995. Edited by A. C. Knipe and W. E. Watts Q 1997 John Wiley & Sans Ltd

3 99

Organic Reaction Mechanisms 1995

400 OMe &OMe

($:

OMe

+

SOTCHCI3

Rl

R'

COR2 (1) R1 = H, C02Me, COPh; R2 = OMe, Ph

-

R1

C02Me OMe OMe (3)

(F.\

Me0

+

O OMe (2)

R' = H, COzMe

I

P h O C g ; Me0

OMe (4)

SCHEME 1

hv

*

-

MeO

hv

c--

A

\ / o

O

Mk

(7)

R = Me,CF3, OMe SCHEME 2

O

14 Addition Reactions: Cycloaddition

Bu'zSi

,O--WPh

40 1

1. hv, MeCN

____)

2. NH4F

HO

R

(9)

R = H,Ph, C02Me, SiMe3

SCHEME 3

hydrogen selenide.l 2 N-Alkenoyldihydropyridinones (11) and 3-acetyl-N-alkenoyltetrahydropyridines undergo diastereoselective intramolecular photochemical cycloaddition to yield cyclobutaquinolizidones (12) and cyclobutaindolizidinones,respectively (Scheme 4).13

The Paterno-Buchi reactions of methacrylonitrile with 5-substituted adamant-2-ones exhibit n-face ~electivity,'~ which can be reversed by inclusion in P-cyclodextrin.l5 An extensive review on the 2 2-cycloadditions of ketenes has been presented.l6 A kinetic study of the cycloaddition of t-butylcyanoketene with styrenes indicates a concerted asynchronous mechanism involving a transition state with some degree of charge ~eparati0n.l~ The first example of stereospecificity in the aryne-alkene cycloaddition between benzyne and ketene silyl acetals has been reported.'* Both MgBr2.Et20I9 and methylaluminium bis(4-bromo-2,6-di-t-butylphenoxide)zohave been successfully used in the stereoselective 2 2-cycloaddition reaction of trimethylsilylketene with aldehydes. Ab initio calculations predict that electrostatic solute-solvent interactions are critical in the control of the stereoselectivity of keteneimine cycloaddition reactions.21 5H, 7H-Thiazolo[3,4-c]oxazolium-1-oxides react as ketenes with imines to produce spirocyclic b-lactams and lH,3H-imidazo[1,5c]thiaz~les?~ Dichloroketene reacts with 1,3,5-tri-t-butylcyclopentadiene(13) to yield the expected 2+2-cycloadduct (14), but in the presence of zinc a complex rearrangement yields the 'abnormal' adduct (15) (Scheme 5).23 The aminium saltinitiated reaction of ketenes produces succinic anhydrides via a formal 2 + 2 dimerization of the ketenes with the incorporation of an additional oxygen atom.24 PM3 calculations of the addition of allenes to imines indicate that the reaction proceeds via a non-concerted two-step mechanism where the allene attacks towards the

+

+

Organic Reaction Mechanisms I995

402

C1~CCOCl

Zn

____)

I

t

IB"' *M e

+

lone pair of the imine nitrogen atom.25The intramolecular 2 2-cyclization reaction of phenylsulfonyl-substituted allenes with unactivated alkenes proceeds across the C(l)-C(2) double bond of the allene with complete stereoselectivity.26 1-Seleno-2-silylethenes react with methylenemalonate esters in the presence of a Lewis acid to form 2 2- and 2 + 1-cycloadd~cts.~~ Bis(trimethylsily1)admantylidenegermene (16) spontaneously dimerizes in a head-to-head fashion to produce the single dimer (17) (Scheme 6).28

+

SCHEME 6

403

I 4 Addition Reactions: Cycloaddition

+

qr

A 2 2-cycloaddition is involved in the conversion of 4-methyldithieno[3,4-b : : 3’,2’-d]pyridinium iodide (18) into the cycloadduct (19) on treatment with 2 equiv. of DMAD (Scheme 7).29

DMAD

DMAD

H

R

H

R

I

R

Me

A

I

R R

-S

f--

Me R

H

Me

(19)

R = C02Me SCHEME 7

2

+ 3-Cycloaddition

For the photochemical 1,3-dipolar cycloaddition of ethylene to benzene, the semiempirical MO method, SINDO1, favours the reaction mechanism involving a prefulvene intermediate rather than one involving an exciplex intermediate.30 AM1 calculations of the BF3-catalysed 1,3-dipolar cycloaddition of azide anion to nitriles confirm a stepwise mechanism.31v32Second-order rate constants were determined for the cycloaddition of phenyl azide to norbornene in aqueous solutions and these show large reaction rate increases in aqueous media.33 2-Azido-5trimethylsilylthiophene cycloadds with trimethylsilylacetylene to yield a single triazole cycloadduct, whereas 2-azido-5-methylthiopheneyields a mixture of regioisomeric triazole c y c l o a d d ~ c t s .The ~ ~ asymmetric 1,3-dipolar cycloaddition reactions of acylnitrenes have been inve~tigated.~~

Organic Reaction Mechanisms 1995

404

A review of stereo- and regio-control of 1,3-dipolarcycloaddition reactions of imines with nitrile oxides by metal ions has been published.36The 1,3-dipolar cycloaddition of nitrile oxides to sugar nitroalkenes and @,/?-unsaturatedcarbonyl sugar derivatives yields sugar isoxazolines as single diastereoi~omers.~~ y-Alkoxyvinyl sulfones react with benzonitrile and acetonitrile oxides to produce isoxazolines with complete regioselectivity and moderate anti stereo~electivity.~~ The stereochemical outcome of 3 + 2-cycloadditions of nitrile oxides to Baylis-Hillman adducts can be explained by the ‘inside alkoxy effect.’39A new dispiroacetal-protected but-3-en- 1,2-diol undergoes regiospecific and diastereoselective addition to nitrile oxides.4o Perturbational analysis shows a strong H O M O ~ i o ~ o ~ ~ d e ~ y d e interaction -LUMOn~~o as the principal reason for the high thione reactivity in 1,3-dipolar cy~loadditions.~”~~ The 3 + 2-cycloaddition of nitrones with cinnamates proceeds with high endo selectivity ( > 99% ee) in smectic liquid crystalline solvent (BPCD).43 The regioand stereo-selectivity of the reaction of aldonitrones of 3-imidazoline-3-oxides with monosubstituted alkenes depend mainly on the substituent on the dip~larophile!~ Intramolecular cycloaddition of nitrones (20) with lithium enolate furnished 4-hydroxy4-methyl-3-oxa-2,7-diazabicyclo[3.3.0]octanes (21) with high diastereoselectivity (Scheme 8).45 A single stereogenic centre a to the oxime moiety can control the diastereoselectivity of 1,3-dipolar cycloadditions. Thus the aldoxime (22) derived from L-threose reacts cleanly with divinyl sulfone to yield an intermediate nitrone (23), which cycloadds to yield a single isomeric cycloadduct (24) (Scheme 9).46The intramolecular 1,3-dipolar cycloaddition of propylidene nitrones produces cycloadducts which rearrange to 5-azahydr1ndan-8-ones.~~ The 1,3-dipolar cycloadditions of cyclic nitrones with (4-y-hydroxy- and ( 8 - y alkoxy-a,/?-unsaturatedesters yield adducts derived from endo-transition states with antifacial approach.48 a,/?-Unsaturated y-lactams derived from (4-pyroglutaminol readily undergo 1,3-dipolar cycloaddition with N-methylnitr~ne!~Regiospecific 1,3-

R

\ I

0-

q

8” /

N

Me (20) R =Bu‘,Bz,Me

T

0

?z

LDA, THF,

-78 “C

SCHEME 8

R,&pyk,q/ I

0-

Me

O-Li+

I 4 Addition Reactions: Cycloaddition OH

/

R

+x

405

R

I

Ph2SiO

0-

A + PhMe, 24 h

(22)

R = Bu' R

SCHEME 9

dipolar cycloaddition of C-aryl-N-alkylnitrones to chiral dipolarophiles produces 5substituted isoxazolidines which can be converted into polyhydroxylated piperidine~.~' CJV-Diphenylnitrones also react with vinyl sulfoximines to produce 4-sulfonimidoyli~oxazolidines.~'A mechanism has been proposed for the dramatic change in regioselectivity observed in the Mg and Zn ion-mediated nitrone cycloadditions with ally1 alcohols.52 Ab initio and semiempirical PM3 calculations of the 1,3-dipolar cycloadditions of pyridine-N-oxides and isocyanates provide theoretical evidence of concerted and nonsynchronous mechanisms with zwitterionic ~ h a r a c t e r2,2-Dimethyl-3,4-dihydro-2H.~~ pyrrole-N-oxide undergoes intramolecular 1,3-dipolar cycloaddition with optically active cQ-unsaturated esters to yield isoxazolidines whose stereochemistry support an exo-transition state.54 The asymmetric 3 2-cycloaddition between 2,3,4,5-tetrahydropyridine-1-oxide and (2)-@)-vinyl sulfoxides to yield the isoxazolidines (25) and (26) has been utilized in the efficient synthesis of enantiomerically pure piperidine alkaloid, (+)-sedndine (27; R = Me) (Scheme lo)? The 1,3-dipolar cycloaddition of benzonitrilium N-phenylimide with 4-arylmethylidene-3-phenylisoxazol-5(4H)-ones (28) produces 5-aryl-1,3-diphenylpyrazole-4-carboxylic acids (29) by the elimination of benzonitrile from the initially formed cycloadduct (Scheme 1l).56 The 3 2-annelation of allylidene(tripheny1)phosphoranes with 1,2-diacylethylenes produces substituted cyclopentadienes but no cycl~hexadienes.~'A novel phosphinecatalysed 3 2-cycloaddition of buta-2,3-dienoates(30) or but-2-ynoates with electronefficient alkenes yields cyclopentene derivatives (31) via the mechanism outlined in Scheme 12." Intramolecular palladium-catalysed 3 2-cycloadditions of methylene-

+

+

+

+

406

Organic Reaction Mechanisms 1995 0

I

SCHEME 10

phtc N,O

0

+

+

Ph-CZN-G-Ph

(28) Ar = Ph, 4-MeC6H4, 4-MeOC6H4, 4-BrC6H4, 3-BrC6H4, 3-thienyl

1

-PhCN

SCHEME 11

cyclopropanes with acetylenic esters provides an entry into bicyclo[3.3.0]octane and bicyclo[4.3.O]nonane systems.59 The 1-pyrazoline (33) derived from 5-diazo-10,ll -dihydro-SH-dibenzo[a,dIcycloheptene (32) and 2,5-dimethyl-l,4-benzoquinoneundergoes thermal 1,3-dipolar cycloreversion to produce the cyclopropane (34) in competition with nitrogen extrusion (Scheme 13).6096' Lewis acid-catalysed 1,3-dipolar cycloaddition of 2H-chromenes with 1,4-benzoquinone mono- and bis-imides (35) provides a new synthesis of azapterocarpans (36)(Scheme 14).62

14 Addition Reactions: Cycloaddition

407

PPh3

-

* PhH, Nz, r.t. i C02Et (30)

1

diethyl fumarate

C02Et

c

+PPh3

C02Et

SCHEME 12

-

+ Me

r.t. a 50 "C

0

Me Me 0

SCHEME 13

(34)

408

a

Me0

Organic Reaction Mechanisms 1995 ___) BF2.0Et2

+

S02Ph

CH2C12, -78 "C

(35)

/

(36)

OMe

SCHEME 14

The 1,3-dipolar cycloaddition of 1-(phthalazin-1-yl)pyridinium-3-olate with 27~electron addends produces the expected substituted 8-axabicyclo[3.2.l]oct-3-en-2ones.63 However, the reaction of 3-dimethylamino-1-methyl-1,2,4-triazinium-5-olates (37) with DMAD did not produce the expected 3 +2-adduct (38) but the tetrahydropyrrol0[3,4-~]pyrazole derivative (39) via the rearrangement shown in Scheme 1 5.64 3-Aroylaziridines react with diphenylcyclopentenone to produce anhydro-3-hydroxy-2,4-diphenyl-6-aroylpyrylium hydroxides (40), which undergo stereospecific 1,3-dipolar cycloaddition with dimethyl cyclobut-1-ene- 1,2-dicarboxylate to produce exo- and endo-cycloadducts (41) and (42) (Scheme 16).65 Base treatment of 5-aminothiazolium chlorides (43) yields mesoionic thiazoles (44), which undergo 1,3-dipolar cycloaddition with DMAD and methyl propiolate followed by extrusion of isothiocyanate to provide substituted pyrroles (45) in good yield (Scheme 17).66 The intramolecular 1,3-dipolar cycloadditions of N-(phenylmethy1ene)benzenesulfonamide with the munchnones (46) are highly regiospecific, producing 2,5disubstituted imidazoles (47) as outlined in Scheme 18.67 The effect of high pressure on the transition metal-catalysed cycloaddition of trimethylenemethane-PdLz to coumarin is to decrease the reaction rate and to invert the regioselectivity.68 Under solvent-free conditions, azomethine ylides from imidates of a-amino-esters react with imino alcohols to produce new imidaz~lones.~~ Non-stabilized azomethine ylides have been shown to undergo 1,3-dipolar cycloaddition with P-nitrostyrenes to yield trans-3-aryl-4-nitr0pyrrolidines.~~ Menthyl acrylate undergoes asymmetric 1,3dipolar cycloaddition with metallo-azomethine ylides (49) derived from imines (48) in the presence of LiBr or AgOAc to give homochiral cycloadducts (50) (Scheme 19).71,72 Substituted 5-phenyl-3,4-dihydro-2H1,4-oxazin-2-ones are precursors of azomethine ylides which react with N-phenyl- and N-methyl-maleimidesyielding exclusively exoN'

Me

(37)

Me

0

(38)

R = H, Me, Ph

SCHEME 15

409

14 Addition Reactions: Cycloaddition

- rn

(43)

R’ Ph Ph Me Me

(44)

T2

’6

Ph

R2 Me CH2Ph CHzPh CH2C02Et

R3

But But Bur Bu‘

R4 Ph NMe2 NMe2 NMe2

R2 SR‘ ;R3NCS

R * 4

E

(45)

E

NR3 17 SCHEME

c y c l o a d d ~ c t s[60]Fullerene .~~ readily undergoes 1,3-dipolar cycloaddition with imines of cr-amino acid esters to produce two isomers of fidlerene-fused proline derivative^.^^ 5R-(1‘R,2’S,S’R-Menthyloxyl)-2(SH)-kanone and N-acetyl-5R-isopropoxy-2(5H)pyrrolone undergo asymmetric 1,3-dipolar cycloaddition with metallo-1,3-dipoles derived from both aryl and aliphatic imines from a-amino esters in the presence of A~OAC-DBU-THF.~~ Metallo-azomethine ylides also undergo facile stereospecific and regiospecific cycloaddition with ethyl (E,)-4,4,4-trifl~orobut-2-enoate~~ and chiral

Organic Reaction Mechanisms I995

410

I

Me (46)

R' = R2 = Ph R1 = Ph; R2 = Me R' = Me; R2 = Ph

J-co2 Ph

Ph

R'

I

I

Me

Me SCHEME18

AgOAc, NEtl

\

0

/

P

DMSO, 1 h

3

AcO-Ag -0

(50)

R' = 2-naphthyl, R2 = menthyl SCHEME 19

en one^.^^ In the exo-diastereoselective 1,3-dipolar cycloaddition of azomethine ylides also derived from a-amino acid esters to (2R)-3-benzoyl-4-methylene-2-phenyloxazolidin-5-one, LiBr-DBU-THF was found to be especially effective.78 The intramolecular 3 2-cycloaddition of the nitrone (51) derived from 2-( 1,2propyny1oxy)benzaldehyde and N-methylhydroxylamine yielded the expected 4isoxazoline (52) as a transient intermediate which rearranges to the only characterizable product, 4-methyl-2,5-endo-oxo-2,3,4,5-tetrahydro[ 1,4]benzoxazepin (53), via the mechanism outlined in Scheme 20.79

+

I 4 Addition Reactions: Cycloaddition

41 1

PhH

95 "C. 4.5 h

(53) R = Me,Bu'

SCHEME 20

1-Acetoxy-2-hydroxycyclohexa-3,5-diene reacts with diazomethane to b i s h 3 + 2cycloadducts showing complete syn-facial selectivity.80The cycloaddition of chiral a$unsaturated y-alkoxy or y-amino ketones with diphenyldiazomethane affords conjugated A*-pyrazolines with high diastereofacial selectivity.81 Again, 2 equiv. of diphenyldiazomethane react with acyl isothiocyanates to give 4,5-dihydro-l,3-oxazole4-spiro-2'-thiiranes (54), which isomerize to the thietan-3-imines (55) (Scheme 2 In the presence of an Ag(1) catalyst, acetylenic a-diazo ketones (56) bearing gem-

R = CCl,, C02Me, Ph, OEt, Bu'

(54) SCHEME 21

Organic Reaction Mechanisms I995

412

dimethyl substituents undergo intramolecular 1,3-dipolar cycloaddition to produce bicyclic pyrazole derivatives (57) in 47-55% yield rather than the normal Wolff rearrangement (Scheme 22).83 0

0

/acc1 +: "&/ II

-E

10 mol% Ag20 EtOH, 78 "C, 1 h

J

L SCHEME 22

+

Carbonyl oxides readily undergo 3 2-cycloaddition with imines to afford the The corresponding 1,2,4-dioxazolidines with high degrees of ~tereoselectivity.~~ photolysis of benzofuro-annulated oxanorbomadiene (58)in the presence of CC and CN dipolarophiles yields propellanes (60) via the intermediate carbonyl ylide (59) (Scheme 23).85The thermal decomposition of 2,5,5-trimethyl-2-trimethylsilyloxy-A3-

E = C02Me, R = (NC)CH=C(Bu')

I

SCHEME 23

14 Addition Reactions: Cycloaddition

413

1,3,4-oxadiazoline produces a reactive carbonyl ylide which can be trapped with DMAD.~~ Intramolecular 3 2-cycloaddition of an azoxy group and an adjacent parallel olefinic bond in a cage compound (61) produces the so far unknown 1,2,3oxadiazolidine (62) (Scheme 24).87,88

+

& & 0

150T

___)

O

h

PhH, 2 h

(61) SCHEME 24

2

+ 4-Cycloaddition

(62)

+

A theoretical study of the aromatic character of the transition states of allowed 271 471and forbidden 2n + 2ncycloaddition has been reported.89 Ab initio MO calculations provide evidence for the dominant role of secondary orbital interactions in determining the endolexo product ratio of Diels-Alder reactions of cyclopropene with dienes.” At levels of theory up to MP2lcc-pVDZ, the gas-phase cycloadditions of ethylene and buta- 1,3-diene with cyclopropylcarbinyl cation are asynchronous but c~ncerted.~’ DFT methods have been used to study the Diels-Alder reactions of ethylene with buta-l,3diene and cycl~pentadiene.~~ The cycloaddition of 1,4-dioxabuta-1,3-diene with ethylene and vinyl alcohol has been investigated using ab initio MO calculation^.^^ The photo-sensitized electron-transfer intramolecular cycloaddition of 1,1,8,8-tetraphenylocta-l,7-diene (63) yields a single 4e 2e-adduct (64) (Scheme 25).94 Electron transfer has been demonstrated spectroscopically in the Diels-Alder reactions of 2,3bis(dimethylaminomethy1ene)-bicyclo[2.2.llheptane and -bicyclo[2.2.2]octane with electron-deficient alkenes such as TCNE.95,96The formal transfer of a substituent from a dienophile to a diene via a Diels-Alderlretro-Diels-Alder tandem reaction has been investigated by AM1 semiempirical MO methods.97

+

Ph Ph

Ph Ph

hv MeCN-PhH (3: 1)’ CbH4(CN)2- 1.4

Organic Reaction Mechanisms 1995

414

The dimerization of (E)-l,3-diphenylbuta-1,3-diene follows a concerted pathway and not a diradical mechanism as previously assumed.98 Diels-Alder dimerizations of various spiro[2.4]hepta-4,6-dieneshave been studied theoretically and e~perimentally.~~ The effect of substituents on the 4+2-dimerizations of acylketenes has been investigated using semiempirical Ah41 calculations.Io0 N-Arylamino-l,3-diazabutadienes undergo 4 2-cycloaddition with ketenes to yield pyrimidinones."' The reactions of pent-3-ene-2-thione with ethyleneIo2and of thiochalcone with alkeneslo3 have been investigated by AM 1 calculations of the transition-state structures. Chiral titanium reagents catalyse the enantio- and endo-selective Diels-Alder reactions of (E)- 1-phenylsulfonylalk-3-en-2-ones with ~yclopentadiene."~The reactivity of a$-unsaturated dimethylhydrazones in 4 +- 2-cycloaddition reactions has been studied using AM 1 semiempirical calculations.lo5 N-Acylthioformamides react as dienophiles in Diels-Alder reactions.lo6The 4 2-cycloaddition reactions of diarylselenoketones with trans,trans- and cis,trans-hexa-2,4-dieneproceed stereospecifically.lo7 Competition kinetics of the tris(4-bromopheny1)ammonium salt-catalysed DielsAlder additions of stilbenes to 2,3-dimethylbuta-1,3-diene provide evidence for a cation radical mechanism.Io8Rate enhancement of Diels-Alder and ene reactions have been investigated in several inorganic perchlorateeorganic solvent solutions. Small rate accelerations are the result of increases in the medium internal pressure while large rate enhancements are consistent with a catalysis of the metal ion behaving as a Lewis acid.lo9 The effect of solvents on the Diels-Alder reactions of cyclopentadiene and isoprene with electron-deficient dienophiles has been analysed by AM1 and PM3 calculations.' l o Small quantities of Lewis acids (Cu2', Ni2+, Ca2+, Zn2+) can efficiently catalyse Diels-Alder reactions in water.' A pseudo-dynamic analysis of the rate acceleration of Diels-Alder reactions in water provides evidence that the rate enhancement is due to hydrogen-bonding stabilization of the polarized activated complex and to the decrease of the hydrophobic surface area of the reactants during the activation p r ~ c e s s . " ~ ~ " ~ Electronic and nuclear polarization effects in aqueous solution are crucial factors in the diastereofacial selectivity of Diels-Alder reactions.' l 4 Quantitative antihydrophobic effects have been used as probes for transition-state structures in Diels-Alder reactions.' l 5 A catalytic enzyme, Diels-Alderase, isolated from cell-free extract of Alternariu solani, has been shown to catalyse the intramolecular 4 2-cycloaddition of prosolanapyrone 111 (65) to the exo-adduct solanopyrone A (66) (Scheme 26).'16 For the first time, an antibody-catalysed hetero-Diels-Alder cycloaddition between trans-piperylene and a nitroso dienophile has been re~0rted.l'~ Methodology has been presented for the preparation of antibody catalysts for the Diels-Alder reaction by using flexible haptens.' I8 fi-Cyclodextrin exhibits a catalytic effect on the Diels-Alder reaction of cyclopentadiene and electron-deficient dienophiles. This effect has been explained by a molecular model involving 8-cyclodextrin transition structures.' l9 Aqueous solutions of fi-cyclodextin can control the regioselectivity in Diels-Alder reactions between 1,4benzoquinones and the dienes, isoprene and penta-1 ,3-diene.I2' High pressure has been shown to accelerate the Diels-Alder reaction between cyanoacetylene and cyclohexa-1,3-diene.I2' The high-pressure intramolecular Diels-

+

+

+

415

14 Addition Reactions: Cycloaddition

OMe

OHC

Diels-Alderase

30 "C, 10 min

Alder reaction of 1-oxobuta-1,3-diene exhibits a pressure-induced increase in diastereoselectivity.y.'22The effect of pressure, temperature, and catalyst on the diastereofacial selectivity in Diels-Alder reaction of (5S)-(E)-5,6-O-isopropylidenehex-3-en-2-one with cyclopentadiene has been investigated.lZ3 The first example of a highly enantioselective catalytic Diels-Alder reaction of an achiral dienophile, N-arylmaleimide, with an achiral diene, 2-methoxybutadiene, has been reported. 124 Also, chiral 2-alkoxy- 1,3-butadienes undergo 4 2-cycloaddition with PTAD, NPM and TCNE with moderate to high face ~e1ectivity.l~~ Chiral openchain dienols possessing 1,3-allylic strain due to the presence of a cis-substituent produce highly like-selective 4 2-adducts with maleic anhydride, N-phenylmaleimide, and 4-phenyl- and 4-methy1-1,2,4-tria~oline-3,4-dione.'~~ (Phenyl)[o-(trimethylsilyl)phenyl]iodoniu triflate is a new and efficient precursor of benzyne under mild and neutral condition^.'^^ The first example of an intramolecular Diels-Alder reaction of a benzyne with an acyclic diene (67) to produce a cycloadduct (68) has been reported (Scheme 27). The course of the reaction is dependent on the diene geometry.128

+

+

OMe

OMe

SCHEME 27

Ab initio and PM3-CI calculations were used to study the transition structures for Diels-Alder additions of hetero-dienophiles to butadiene'29 and cyclopentadiene.'30 The Diels-Alder reaction of unsubstituted 2-aza- 1,3-dienes with trans-diimide was studied using semiempirical AM1 calculation^.'^ The intermolecular hetero-Diels-

'

416

Organic Reaction Mechanisms 1995

Alder reaction of enamino ketones with ethyl vinyl ether exhibits a high pressuredependent increase in diastereoselectivity in favour of the trans adducts.I3' The formal hetero-Diels-Alder reactions of N-arylamines (69) produce tetracyclic decahydro7,7,11-trimethylindolizino[3,4-b]quinolines(70) and (71) in a ratio which is dependent on the coordination number of the acidic catalyst (Scheme 28).'33

-

n

Lewis acid

CH~C12,42h

+ Me

Me

H

Me

,Me

SCHEME 28

Semiempirical calculations (AM1 and PM3) were used to explain the stereodivergent facial differentiation of the intermolecular hetero-Diels-Alder reaction of chiral l-oxabuta-l,3-dienes in the presence of TMS-OTf or Me2A1C1.'34 4Acetoxyazetidin-2-one reacts with 2-(t-butyldimethylsilyloxy)buta-1,3-diene to form Diels-Alder adducts, carbacephem~.'~~ The first example of the 4 2+-cycloaddition of a thienium cation with a 1,3-diene has been rep01-ted.l~~ Multiple-stage mass spectrometry has been applied to the study of polar 4 2+ Diels-Alder cycloadditions of nitrilium and immonium ions in the gas phase.' 37 N-Methyl-4H-pyrazolium cation (72) behaves as an electron-deficient diene in the 4+ + 2-cycloadditions with cyclic alkenes to form the cationic cycloadduct (73), which rearranges to the phthalazinecarboxylate (74) (Scheme 29).13' The intramolecular polar 4+ 2-cycloadditions of cationic 2-azabutadienes with various dienophiles provides a facile synthesis of 1,2,3,4-tetrahydroquinolinespossessing high regio- and diastereo-selectivity. 39 Ab initio calculations indicate the reactivity of thiophene with acrylonitrile is similar to that of butadiene with eth~1ene.l~' The AM1 semiempirical method has been used to predict the reactivity of benzo[b]- and benzo[c]-thiophenes as dienes in Diels-Alder reactions'41 and to predict that thiophenes are best activated towards Diels-Alder reactions by conversion into the corresponding S-methylthiophenium anions.142 The photochemical Diels-Alder reaction between thiophene derivatives bearing electronwithdrawing substituents and phenylacetylenes provides o-substituted biphenyls.143 Ab initio calculations of the cheletropic and Diels-Alder reactions of sulfur dioxide with 1,3-dienes have been completed'44 and results suggest that 1-methoxycyclohexa1,3-diene should react with SOz to produce a sultine in preference to a ~ u lf o le n e . The '~~ retro-Diels-Alder reaction of 1,4-oxathiine-S-oxide (75) generates up'-dioxosulfine (76),which cycloadds with dienophiles and dienes (Scheme 30).146

+

+

+

'

417

I4 Addition Reactions: Cycloaddition

A, MeCN

Me0

Me0

N

Ph (74)

E = C02Me

SCHEME 29

(75)

(76)

SCHEME 30

A

0

418

Organic Reaction Mechanisms I995

MO calculations for the reaction of ethylene with nitrosoethylene in the presence of BH3 showed that the reaction is an inverse-electron-demand Diels-Alder cycloaddition in which boron is an effective catalyst. 147 Electron-poor 2-azadienes undergo inverseelectron-demand Diels-Alder reactions with trans-cyclooctene and cispuns-cyclooctadiene to produce trans-cycloalkanotetrahydropyridines.148 AM1 calculations have been used to study the Diels-Alder reaction between buckminsterfullerene (C60) and 2,3-dimethylidenebicycl0[2.2.2]octane.'~~ The photochemical reaction between N-ethoxycarbonylazepine and [60]fillerene produced two photo-cycloadducts by formal 4 + 2- and 6 2-cycloaddition reactions.'50 The reaction of [60]fullerene with the nickel phthalocyanine (77) yields a green Diels-Alder adduct (78) which exhibits multiple reductions (Scheme 3 l).15'

+

mcN . @ :J$R

+

3 @

CN

WAch

CN

N-Ni-N

DBU, pentanol, reflux

R

R = heptyl

RN \ E/

R

(77) Cm. PhMe,

reflux

SCHEME 31

Ab initio MO calculations were used to investigate the transition structures for heterodienophile addition to 1,3,4-0xadiazole'~~ and 4 H - p y r a ~ o l e ~the ' ~ ~tautomer most suitable as a diene in Diels-Alder reactions.lS4 MP3 semiempirical calculations have

419

I 4 Addition Reactions: Cycloaddition

been used to investigate the Diels-Alder reactions of pyrr~le,’~’ oxazole, and isoxazole with a l k e n e ~ . ”4-Nitro-3-phenylisoxazole ~ reacts as a dienophile with open-chain and cyclic carbodienes.”’ Indole-2,3-dienoate (79) undergoes facile 4 2-cycloaddition with a variety of dienophiles to produce substituted carbazoles (80) (Scheme 32).’58 Bicyclic anhydro-4-hydroxy-2-0x01,3-thiazinium hydroxides undergo 4 2-cycloaddition with dienophiles to yield 1,4-cycloadducts which can extrude COS to form bicyclic pyridin-2-0nes.”~

+

+

OLi I

Me (79)

!

E-CLC-E E = C02Me

N

I

I

Me

Me

(80)

SCHEME 32

The thermolysis of olefinic benzocyclobutenes (81) yields o-quinodimethanes (82) which undergo intramolecular Diels-Alder addition, The stereochemical course of the addition is influenced by the nature of the protective group and the substituent of the ally1 alcohol (Scheme 33).160 Kinetic studies of the photochemical 4 2-cycloaddition of 2,4-dimethylhexa-2,4diene to 9,lO-dichloroanthracene support a singlet mechanism for adduct formation.16’ The cyclohexa-1,3-diene hexacyclo[ 10.2.1.02’”.04’9.09”3]pentadeca-5,7-diene-3, 10dione (83) undergoes Diels-Alder reaction with polyhalocyclopentadienes to produce exclusively the endo, anti adduct (84) (Scheme 34).162,’63Face selectivity in the inverse-electron-demand Diels-Alder reactions of 1,2,3,4,5-pentachloro-5-methoxycyclopenta-1,3-diene was constantly to the face syn to the methoxy Laser Aash photolysis and steady-state photolysis have been used to study 4 2cycloaddition of singlet oxygen with 1,4-dimethylnaphthalene.165 The reaction of imidazole tautomers with ethylene and singlet oxygen have been investigated by ab

+

+

420

Organic Reaction Mechanisms 1995

Me0 R = Me, CF3 X = 0, O(CH2)30 SCHEME 33

_____t

xylene, reflux

+

initio MO calculations. The diastereoselectivity in the singlet oxygen 4 2cycloaddition to chiral naphthyl alcohol derivatives has been investigated in debi1.167,168 The photochemical addition of singlet oxygen to bisdialine (85) yields predominantly the anti adduct (87) rather than the expected syn adduct (88). A stepwise mechanism involving the perepoxide (86) as intermediate is proposed (Scheme 35).169 AM1 calculations have been carried out on the reactants of the Diels-Alder addition of N-phenylmaleimide and N-methyltriazolinedione with dispiro[4.0.4.4]tetradeca11,13-dienes in order to study their steric, electronic, and electrostatic proper tie^.'^' Intramolecular Diels-Alder cycloadditions of internally sulfonyl-substituted tienes (89) yields bicyclic cycloadducts (90) and (91) with complete cis selectivity (Scheme 36).”’ The thermal intramolecular Diels-Alder reactions of N-substituted sulfoximi-

I 4 Addition Reactions: Cycloaddition

42 1

(87)

SCHEME 35

(89)

R = TBDMS

(90) 3 SCHEME 36

(91) 1

Organic Reaction Mechanisms 1995

422

doylnona-1,6,8-trienes and -deca-1,7,9-trienes produce diastereomeric mixtures of bicyclo-[4.3.0]nonanes and -[4.4.O]decane~.'~*The influence of alkyl substituents on the acid-catalysed intramolecular ionic Diels-Alder reaction of methylated analogues of (3E,8E)-undeca-l,3,8,10-tetraene has been rep01ted.I~~The intermediacy of ally1 cations and of 1,3-diene cation radicals in the 2 4-cycloadditions of undeca-l,3,8,10tetraene has been in~estigated.'~~ The intramolecular Diels-Alder reaction of decal ,7,9-trienylboranes (92) provides a highly stereoselective two-step decalin synthesis via the trans-cycloadduct (93) (Scheme 37).175

+

A modified MM2 force field method has been developed to reproduce the selectivities of Lewis acid-catalysed Diels-Alder reactions of chiral acrylates to 1,3dienes. 176 The Diels-Alder reaction of (3R,5S)-3-benzoyloxy-2,2,6,6-tetramethyl-5heptyl acrylate (94) with cyclopentadiene in the presence of TiCl4.(ArnHg),-comp1exed Lewis acids produce the R-isomer (95), whereas in the presence of TiC14 the S-isomer (96) predominates (Scheme 38).177The structure of the complex (97) proposed to be the intermediate in the Ti-TADDOLate-catalysed Diels-Alder reactions with cyclopentadiene has been determined by X-ray diffraction. 78 The reactivity and stereoselectivities of hetero-Diels-Alder additions to furan have been investigated by ab initio calculation^.'^^ The Diels-Alder reaction of furan with methyl acrylate is strongly dependent on pressure.'8o An ab initio study of the DielsAlder addition of furan with cyclopropenone indicates a stabilizing interaction between the ether oxygen and the carbonyl carbon makes the ex0 product the thermodynamic and the kinetic product.18' The furan analogue of o-quinodimethane (98) undergoes Diels-Alder addition with unsymmetrical quinones (99) to yield cycloadducts (100)

423

14 Addition Reactions: Cycloaddition 0

JO

hPO '

Ph2Hg.2TiC14

(94)

t

(97)

SCHEME38

(Scheme 39).1823-Substituted 5-methylene-2(5H)-furanones react with butadiene to produce 1,2- and 1,cadducts through a common biradical inte~mediate.'~~ The intramolecular Diels-Alder reaction of chiral N-substituted Mr y la m in e s with maleic anhydnde produces tricyclic adducts with five chiral centres.'84 The furan derivatives, (E,Z)- and (Z,E)-fulgides (101) and (103), in toluene at room temperature undergo photochemical isomerization to the (E,E)-fulgide (102) followed by intramolecular 2 4-cycloaddition to give the adduct (104) (Scheme 4O).Is5 A PM3 semiempirical MO method has been used to study the competition between Michael addition reactions and Diels-Alder reactions of 1-methyl-2-( 1-substituted-

+

14 Addition Reactions: Cycloaddition

425

viny1)pyrroles with DMAD.'86 However, the PM3 method has been shown to be unreliable for predicting the reactivities and selectivities of cyanoethylenes in DielsAlder reactions with pyrr01e.'~~3,3-Dihydro-lH-thien0[3,4-c]pyrrole 2,2-dioxides (105) react with DMAD to yield the cycloadduct (106), which reacts further with DMAD to produce a number of polycyclic cycloadducts (107) and (108) as outlined in Scheme 41.'88

,

E

E = CO2Me

ww

SCHEME 4I

Kinetic studies on the influence of substituents on the reactivity and stereoselectivity in the Diels-Alder cycloadditions of para-substituted 6-phenyl-6-methylfulveneshas been reported. 89 5-(Alkylaminomethylene)-6-methyleneperhydropyrimidine-2,5diones (109) with tropone yield 4 2-cycloadducts (110), which rearrange firther to the final adducts, 2,5-ethanopyridoquinazoline(1 1l), cycloheptaquinazoline (1 12), and azocine (113) (Scheme 42). 190 The Diels-Alder reactions between pyranobenzoquinones (114) and 1-azadienes produces the unstable cycloadduct (115), which is readily oxidized to the pyranoquinolinequinone (1 16) which dehydrates to the quinone (1 17) (Scheme 43).19' A review of the diastereofacial selectivity in Diels-Alder reactions has been p r e ~ e n t e d . 'Ab ~ ~ initio calculations on the Diels-Alder addition of ethylene to 5-

'

+

Organic Reaction Mechanisms 1995

426

YHR

?

tropone

t

RNH2, 1,4-dioxane A I

Me

(109) I

R

0

I Me

I Me

0

I Me

0

NMe2 0

@

*0

p-TSA

0

(117)

SCHEME 43

OH

0

427

14 Addition Reactions: Cycloaddition

substituted cyclopenta-1,3-dienes preclude many of the reported rationalizations of the origin of n-facial se1e~tivity.l~~ In the particular case of 5-phenylthiocyclopentadiene with electron-withdrawing dienophiles, the n-face selectivities are shown to be enhanced by the reactivity of the dien0phi1es.l~~ Also, a semiempirical AM1 method successfully reproduces the facial selectivities and relative reactivities for the DielsAlder reactions of maleic anhydride with C(5)-substituted cyclopentadiene~.'~~~'~~ The n-facial selectivity in the Diels-Alder reactions of [3.3]orthoanthracenophanes with electron-deficient dienophiles is controlled by the adjacent aromatic ring system.'" 1@Substituted buta-l,3-dienes undergo uncatalysed Diels-Alder addition with sugarderived nitroalkenes having D-galacto configurations with complete regioselectivity and diastereofacial specificity.'98 In the presence of TiC13, the asymmetric Diels-Alder reaction between (E)-2cyanocinnamates and butadiene proceeds with high diastereoselectivity.'99 exoSelective Diels-Alder reactions between cyclopentadiene and a,P-unsaturated ketones have been achieved by using the complex aluminium tris(2,6-diphenylpheno~ide).~~~ Transition metal-catalysed intramolecular Diels-Alder reactions of tethered dieneallenes (1 18) provide a high-yield stereospecific synthesis of angularly substituted bicyclic adducts (119) (Scheme 44).201The Diels-Alder cycloaddition of 4-vinyl- 1,2isothiazoline-3-one-1-oxides shows high diastereoselectivity via an unusual exo,syn transition state.202A diastereoselective Diels-Alder reaction between cc,j-unsaturated ketones (120) and isoprene has been developed to prepare substituted cyclohexenes via a five-membered cyclic oxocarbenium ion (121) (Scheme 45).203 Unstable phosphaalkene-Mo(CO)s (122) complexes undergo Diels-Alder reactions with electron-rich 1,3-dienes to yield cycloadducts (123) with high stereo- and regioselectivity (Scheme 46).204 The Diels-Alder reactions of trichlorophosphaethene proceed with normal electron demand.205 Miscellaneous Cycloadditions Ab initio MO theory has been used to investigate the transition structures for the trimerization of acetylene and the addition of ethylene and acetylene to formylketene.206The cyclotrimerization of peduoroalkyl- and peduorooxaalkyl-acetylenes has been studied.207Cobalt-mediated 2 2 2-cycloadditions of alkynes to furans and thiophenes (124; X = 0 and X = S) yield the propellenes (126) rather than the expected cycloadducts (125) via an en01 ether migration (Scheme 47).208 The scope and stereoselectivity of nickel-catalysed homo-Diels-Alder reactions between norborna-

+ +

(119) SCHEME 44

98%

428

Organic Reaction Mechanisms 1995 1

(120) R = Pr‘, Bur, Me, Ph

JAMe

4

01

-

TsOH

Me

.M e

SCHEME 45

SCHEME 46

429

14 Addition Reactions: Cycloaddition SiMe3

q : zx ...'

CpCoLz, BTSMA

O

L=CO(hv)

*

\

0

m

S

i

M

'

e

3

cocp SiMe3

(125)

(124)

x=o,s

SCHEME 41

R1

"iNL0 I

\

SCHEME 48

+ +

diene and various dienophiles has been studied.209An extended 3 3 2-cycloaddition between a carbonyl oxide, a nitrone, and an aldehyde produces the novel 3,4-dihydro-l,2,5,7,4-tetraoxazocine(127) as outlined in Scheme 48.'" The regiochemical and stereochemical outcomes of intramolecular 4 3-cycloaddition reactions of alkoxyallylic sulfones with TiC14 have been shown to be dependent on the allylic cation stereochemistry.21 The N-substituted oxyallyl cation (128) formed from a,a-phthalimidoyl dibromide readily undergoes 3 + 4-cycloaddition with furan and cyclopentadiene to form cycloadducts (129) and (130) (Scheme 49).212

+

Organic Reaction Mechanisms 1995

430 0

NPhth

(129) SCHEME 49

The rates of 4 + 4- and 4 + 2-dimerization of furan-based o-quinodimethanes are retarded by a-methyl substitution. This result supports a two-step mechanism involving rate-determining formation of a diradical intermediate followed by rapid cyclization of the diradicaL213 The fulgides, 3,4-bis(9-anthrylmethylene)tetrahydrofuran-2,5-dione (131; X = 0) and the related 5-dicyanomethylene derivative [132; X = C(CN),] undergo intramolecular 4 4-photo-cycloaddition to the adducts (133; X = 0) and [133; X = C(CN)?], respectively, on exposure to white light (Scheme Transition metal-catalysed intramolecular 5 2-cycloadditions between vinylcyclopropanes and alkynes provide a facile synthesis of cycloheptadienes (134) (Scheme 51).’15 The highly strained bicyclo-annelated benzene trisbicyclo[2.1.llhexabenzene (136) was synthesized by base treatment of 2-chlorobicyclo[2.1.l]hex-2-ene(135) (Scheme 52); ab initio calculations disfavour the intermediacy of bicyclo[2.1.l l h e ~ y n e . ~ ’ ~ The Rh,(OA~)~-catalysedcycloaddition of ethyl diazoacetate with 1,2-methylenedioxybenzene gives the corresponding cycloheptatnenes (137) and (139), while the reaction with 1,2-dimethoxybenzene produces a stable norcaradiene (138) (Scheme 53).’17 3-Benzyl(dimethylsila)prop- 1-enes undergo intramolecular meta-photo-cycloaddition where the heteroatom in the linking tether controls the cyclopropane ring formation.218 The meta-photo-cycloaddition of monosubstituted 4-substituted 5-phenylpent-1-ems always prefers 2,6-addition whereas 1,3-addition is preferred with disubstituted compounds.2193220 A nitrile substituent forces the anisole bichromophore (140) to undergo an intramolecular ortho arene-alkene photo-cycloaddition to the cycloadduct (141) which undergoes thermal electrocyclic ring opening to the bicyclo[6.3.0]undecatriene (142) followed by photochemical disrotatory ring closure to the tricyclic adduct (143) (Scheme 54).’”

+

+

14 Addition Reactions: Cycloaddition

X = 0, (13') C(CN)2

/white

43 1

light

J X

(133) SCHEME 50

Me AgOTf [RhCI(PC13)3] (0.5 rnol%), (0.5 mol%) PhMe* 100 T, 20 111

&

Me02C

---

Me02C'

(134) SCHEME 51

43 2

Organic Reaction Mechanisms 1995

Bu'OK, Bu'Li

*

THF, pentane 10 mol% Ni(Cp)z -78 to 35 "C

SCHEME 52

'n

(137)

M e O D Me0

(138)

N2CHC02E

+

Rhz(OAc)4, r.t.

R

C02Et

Me0 M e O u o 2 E t

SCHEME 53

CN

o,^c"" OMe

I

M e Me

hv MeCN

M&

Me I

Me

I

A

r

CN

hv

Me0

Me

H

L

(142)

(143) SCHEME 54

14 Addition Reactions: Cycloaddition 1

r

(144)

433

SCHEME 55

(145)

A novel homo-Cope rearrangement reaction has been reported for the thermolysis of the endo,endo-cycloadduct (144) leading to compound (145) (Scheme 55).222 References 1

2 3 4

5 6

7 8 9

10

11 12

13 14

15 16

17

'

18

'

19

2o

21

'* 23

Mattay, J. and Griesbeck, A. (Eds), Photochemical Key Steps in Organic Synthesis. A Practical Guide to Photochemical Cycloadditions, VCH, Weinheim, 1994. Patalakha, A. E., Vasil'ev, N. V, and Buzaev, A. V, Khim. Fiz., 13, 65 (1994); Chem. Abs., 122, 80553 (1 995). Hu, X., Daxue Huaxue, 8, 29 (1993); Chem. Abs., 122, 9265 (1995). Chen, L., Chen, G., and Fu, X., Wuli Huaxue Xuebao, 10,680 (1994); Chem. Abs., 121,280033 (1994). Marcus, R. A., 1 Am. Chem. SOC.,117,4683 (1995). Kim, T., Sarker, H., and Bauld, N. L., 1 Chem. SOC.,Perkin Trans. 2, 1995, 577. Graziano, M. L., Iesce, M. R., Cermola, F., Ialongo, G., and Giordano, F., 1 Chem. Res. (S), 1995, 176. Takahashi, Y., Ando, M., and Miyashi, T., 1 Chem. SOC.,Chem. Commun., 1995, 521. Smart, R. F! and Wagner, F! J., Tetrahedmn Lett., 36, 5131 (1995). Bradford, C. L., Fleming, S. A., and Ward, S. C., Tetrahedron Lett., 36, 4189 (1995). Broeker, J. L., Eksterowicz, J. E., Belk, A. J., and Houk, K. N., 1 Am. Chem. SOC.,117, 1847 (1995). Andrew, D., Hastings, D. J., and Weedon, A. C., 1 Am. Chem. SOC.,116, 10870 (1994). Adamson, G., Beckwith, A. L. J., Kaufmann, M., and Willis, A. C., 1 Chem. SOC.,Chem. Commun., 1995, 1783.

Chung, W . 3 , Liu, Y. D., and Wang, N.-J., 1 Chem. Soc., Perkin Trans. 2, 1995, 581. Chung, W.-S., Wang, N.-J., Liu, Y.-D., Leu, Y.-J., and Chiang, M. Y., 1 Chem. SOC.,Perkin Trans. 2,1995, 307.

Hyatt, J. A. and Raynolds, €? W., Org.React., 45, 159 (1994). Ali, Sk. A., Muqtar, M., and Al-Huiini, A. H., 1 Chem. SOC.,Perkin Trans. 2, 1995, 1001. Hosoya, T., Hasegawa, T., Kuriyama, Y., and Suzuki, K., Tetrahedmn Lett., 36, 3377 (1995). Zemribo, R. and Romo, D., Tetrahedron Lett., 36, 4159 (1995). Concepcion, A. B., Maruoka, K., and Yamamoto, H., Tetmhedmn, 51, 401 1 (1995). Lopez, R., Suirez, D., Ruiz-Lopez, M. F., Gonzalez, J., Sordo, J. A,, and Sordo, T. L., 1 Chem. Soc., Chem. Commun., 1995, 1677. Croce, I? D., Femccioli, R., and La Rosa, C., Tetrahedron, 51, 9385 (1995). Dehmlow, E. V, Bollmann, C., Neumann, B., and Stammler, H.-G., Liebigs Ann. Chem., 1995, 1915.

26

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27

Yamazaki, S., Tanaka, M., Inoue, T., Morimoto, N., Kumagai, H., and Yamamoto, K., 1 Org. Chem., 60,

28

Bravo-Zhivotovskii, D., Zharov, I., Kapon, M., and Apeloig, - Y., 1 Chem. SOC.,Chem. Commun., 1995,

24

25

(1995).

6546 (1995). 1625.

29 30 31

32 33 34

Temciuc, E., Hornfeldt, A,-B., Gronowitz, S., and StSllhandske, G., Tetrahedmn, 51, 13185 (1995). Neumann, F. and Jug, K., 1 Phys. Chem., 99, 3511 (1995). Jursic, B. S. and Zdravkovski, Z., THEOCHEM, 332, 127 (1995); Chem. Abs., 122, 313971 (1995). Jursic, B. S. and Zdravkovski, Z., THEOCHEM, 333, 209 (1995); Chem. Abs., 122, 313975 (1995). Wijnen, J. W., Steiner, R. A,, and Engberts, J. B. F. N., Tetmhedron Lett., 36, 5389 (1995). Davies, D., Spagnolo, P., and Zanirato, F!, 1 Chem. SOC.,Perkin Trans. I , 1995, 613.

Organic Reaction Mechanisms 1995

434 35

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Kanemasa, S., Yuki Gosei Kugah Kyokuishi, 53, 104 (1995); Chem. Abs., 112, 159829 (1995). 37 Mancera, M., Roffk, I., and Galbis, J. A., Tetrahedron, 51, 6349 (1995). 38 de Blas, J., Carretero, J. C., and Dominguez, E., Tetruhedron: Asymmehy, 6, 1035 (1995). 3y Annunziata, R., Benaglia, M., Cinquini, M., Cozzi, F., and Raimondi, L., J Org. Chem., 60,4697 (1995). 40 Gravestock, M. B., Paton, R. M., and Todd, C. J., Tetrahedron: Asymmehy, 6, 2723 (1995). 4 ' Sustmann, R., Sicking, W., and Huisgen, R., 1 Am. Chern. Soc., 117, 9679 (1995). 42 Huisgen, R., Fisera, L.,Giera, H., and Sustmann, R., 1 Am. Chem. Soc., 117, 9671 (1995). 43 Kansui, H. and Kunieda, T., Tetrahedron Lett., 36, 5899 (1995). 44 Berezina, T. A,, Remikov, V A,, Mamatyuk, V I., Butakov, P. A,, Gatilov, Yu. V, Bagryanskaya, I. Yu., and Volodarsky, L. B., In? Akud. Nuuk, Ser Khim., 1994, 894; Chem. Abs., 122, 132356 (1995). 45 Aurich, H. and Koster, H., Tetruhedron, 51, 6285 (1995). 46 Fredrickson, M., Grigg, R., Rankovic, Z., Thomton-Pett, M., Redpath, J., and Crossley, R., Tetruhedrun, 36

51,6835 (1995).

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48

Cordero, F. M., and Brandi, A,, Tetrahedron Lett., 36, 1343 (1995). de March, F?, Figueredo, M., Font, J., and Monsalvatje, M., Recl. Trav. Chim. Pays-Bas, 114, 357

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52

53

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'*

59 60

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73

Langolis, N., Van Bac, N., Dahuron, N., Delcroix, J.-M., Deyine, A,, Gnffart-Bmnet, D., Chiaroni, A,, and Riche, C., Tetruhedmn, 51, 3571 (1995). Chanet-Ray, J., Channier-Januario, M. O., Vessiere, R., and Zuccarelli, M., 1 Hetemcycl. Chem., 31, 1667

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Shu, L.-H., Wang, G.-W, Wu, S.-H., Wu, H.-M., and Lao, X.-F., Tetruhedron Lett., 36, 3871 (1995). 75 Cooper, D. M., Grigg, R., Hargreaves, S., Kennewell, P., and Redpath, J., Tetrahedron, 51, 7791 (1995). 76 Bonnet-Delpon, D., Chennoufi, A., and Rock, M. H., Bull. SOC. Chim. Fr, 132, 402 (1995). 77 Galley, G., Liebscher, J., and Patzel, M., 1 Org. Chem., 60, 5005 (1995). Pyne, S. G., Safaei-G., J., and Koller, F., Tetrahedron Lett., 36, 2511 (1995). 79 Padwa, A., Meske, M., and Ni, Z., Tetruhedron, 51, 89 (1995). so Patti, A,, Nicolosi, G., Piattelli, M., and Sanfilippo, C., Tehahedmnt Asymmehy, 6, 2195 (1995). 81 Galley, G., Patzel, M., and Jones, P. G., Tefrahedmn,51, 1631 (1995). a2 L'abbC, G., Francis, A,, Dehaen, W., and Toppet, S., 1 Chem. Soc., Chem. Commun.,1995, 67. 83 Kende, A. S. and Journet, M., Tetruhedron Lett., 36, 3087 (1995). 74

''

14 Addition Reactions: Cycloaddition 84

43 5

McCullough, K. J., Mori, M., Tabuchi, T., Yamakoshi, H., Kusabayashi, S., and Nojima, M., 1 Chem.

Soc., Perkin Trans. 1, 1995, 41. 85 86

87 88

89

Bussenius, J., Keller, M., and Eberbach, W., Liebigs Ann. Chem., 1995, 1503. Sharma, P. K. and Warkentin, J., Tetrahedron Lett., 36, 7591 (1995). Hunig, S. and Schmig M., Liebigs Ann. Chem., 1995, 1801. Hoffman, F!, Hiinig, S., Walz, L., Peters, K., and von Schnering, H.-G., Tetrahedron, 51, 13197 (1995). Bemardi, F., Celani, F!, Olivucci, M., Robb, M. A,, and Suzzi-Valli, G., 1 Am. Chem. Soc., 117, 10531 (1995).

90

" y2

93

94 95 96

y7 98

99

loo lo'

lo'

lo'

Apeloig, Y. and Matzner, E., 1 Am. Chem. SOC.,117, 5375 (1995). Cramer, C. J. and Barrows, S. E., 1 Org. Chem., 59, 7591 (1994). Jursic, B. and Zdravkovski, Z., 1 Chem. Soc., Perkin Trans. 2, 1995, 1223. Jursic, B. S. and Zdravkovski, Z., 1 0%.Chem., 59, 7732 (1994). Mangion, D., Borg, R. M., and Emrngton, W., 1 Chem. SOC.,Chem. Commun., 1995, 1963. Rese, M., Dern, M., Lucking, K., and Sustmann, R., Liebigs Ann. Chem., 1995, 1139. Lucking, K., Rese, M., and Sustmann, R., Liebigs Ann. Chem., 1995, 1129. Sola, M., Ventura, M., Segura, C., and Duran, M., 1 Chem. SOC.,Perkin Tmns. 2, 1995, 605. Mulzer, J. and Melzer, K., Angew. Chem., Int. Ed. Engl., 34, 895 (1995). Froese, R. D. J., Organ, M. G., Goddard, J. D., Stack, T. D. I?, and Trost, B. M., 1 Am. Chem. Soc., 117, 1093 1 (1 995). Fabian, W. M. F. and Kollenz, G., THEOCHEM, 119, 219 (1994); Chem. Abs., 122, 9276 (1995). Dey, P. D., Sharma, A. K., Rai, S. N., and Mahajan, M. I?, Tetrahedron, 51, 7459 (1995). Karakasa, T. and Satsumabayashi, S., Nippon Shika Daigaku Kiyo, @pan Kyoiku-kei, 23, 79 (1994); Chem. Abs., 122, 80477 (1995). Karakasa, T. and Satsumabayashi, I., Nippon Shika Daigaku Kiyo, @pan Kyoiku-kei, 24, I 17 (1995); Chem. Abs., 123, 111267 (1995). Wada, E., Pei, W., and Kanemasa, S., Chem. Lett., 1994, 2345. Valderrama, 3. A,, Spate, M., Dona, R., and Tapia, R., 301.SOC.Chil. Quzm., 40, 105 (1995); Chem. A h . , 122,290129 (1995).

'06

lo' lo' 'lo 111

112

1 I4

'I5

Amaud, R., Chavant, I? Y., Molvinger, K., and Vallee, Y., 1 Chem. SOC.,Chem. Commun., 1995, 1897. Wilker, S. and Erker, G., d Am. Chem. SOC.,117, 10922 (1995). Yueh, W. and Bauld, N. L., 1 Chem. SOC.,Perkin Tmns. 2, 1995, 871. Faita, G. and Righetti, I? I?, Tetrahedron, 51, 9091 (1995). Cativiela, C., Dillet, V., Garcia, J. I., Mayoral, J. A,, Ruiz-Lopez, M. F., and Salvatella, L., THEOCHEM, 331, 37 (1995); Chem. Abs., 122, 213343 (1995). Otto, S. and Engberts, J. B. F. N., Tetrahedron Lett., 36, 2645 (1995). Engberts, J. B. F. N., Pure Appl. Chem., 67, 823 (1995). Blokzijl, W. and Engberts, J. B. F. N., ACS Symp. Ser, 1994, 568; Chem. Abs., 122, 290133 (1995). Assfeld, X., Ruiz-Lopez, M. F., Garcia, J. I., Mayoral, J. A,, and Salvatella, L., 1 Chem. Sac., Chem. Commun., 1995, 1371. Breslow, R. andZhu, Z., 1 Am. Chem. Soc., 117, 9923 (1995). Oikawa, H., Katayama, K., Suzuki, Y., and Ichihara, A,, 1 Chem. SOC., Chem. Commun., 1995, 1321. Meekel, A. A. F,! Resmini, M., and Pandit, U. K., 1 Chem. SOC.,Chem. Commun., 1995, 571. Yli-Kauhaluoma, J. T., Ashley, J. A,, Lo, C.-H., Tucker, L., Wolfe, M. M., and Janda, K. D., 1 Am. Chem. SOC.,117, 7041 (1995).

Alvira, E., Cativiela, Garcia, J. L., and Mayoral, J. A,, Tetrahedron Lett., 36, 2129 (1995). 120 Chung, W.-S., and Wang, J.-Y., 1 Chem. Soc., Chem. Comrnun., 1995, 971. Breitkopf, V., Hopf, H., K l h e r , F.-G., Witulski, B., and Zimney, B., Liebigs Ann. Chem., 1995, 613. 122 Buback, M., Abbelin, J., Hubsch, T., Ott, C., and Tietze, L. F., Liebigs Ann. Chem., 1995, 9. 123 Galley, G., Mugge, C., Jones, P. G., and Patzel, M., Tetrahedron: Asymmetry, 6, 2313 (1995). 124 Corey, E. J., Sarahar, S., and Lee, D.-H., 1 Am. Chem. Soc., 116, 12089 (1994). 125 Barluenga, J., Tom&, M., Sukez-Sobrino, A,, and Lopez, L. A., 1 Chem. Soc., Chem. Commun., 1995, 1785.

126

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12* 129 I3O 13'

Adam, W., Glaser, J., Peters, K., and Prein, M., 1 Am. Chem. Sac., 117, 9190 (1995). Kitamura, T. and Yamane, M., 1 Chem. Soc., Chem. Commun., 1995, 983. Buszek, K. R., Tetrahedron Leu., 36, 9125 (1995). Jursic, B. S. and Zdravkovski, Z., THEOCHEM, 121, 85 (1994). Jursic, B. S. and Zdravkovski, Z., 1 Phys. 0%.Chem., 7, 641 (1994). Barluenga, J., Sordo, T. L., Sordo, J. A., Fustero, S., and Gonzalez, J., THEOCHEM, 121, 63 (1994); Chem. Abs., 122, 105063 (1995). Tietze, L. F., Hubsch, T., Ott, C., Kuchta, G., and Buback, M., Liebigs Ann. Chem., 1995, 1.

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Linkert, F., Laschat, S., and Knickmeier, M., Liebigs Ann. Chem., 1995, 985. L. F. and Schulz, G., Liebigs Ann. Chem., 1995, 1921. Jeon, I?, Lee, Y. Y.,and Goo, Y. M., 1 Korean Chem. Sac., 38,676 (1994); Chem. Abs., 122,9275 (1995). Chavant, I?-Y. and Vallee, Y., 1 Chem. Res. (S), 1995, 204. Eberlin, M. N., Morgon, N. H., Yang, S. S., Shay, B. J., and Cooks, R. G., 1 Am. Sac. Muss Spechorn., 6, 1 (1995); Chem. Abs., 123, 111355 (1995). Frenzen, G., Geminghaus, C., Meyer-Dulheuer, C., Paulus, E. F., and Seitz, G., Liebigs Ann. Chem., 1995,

134 Tietze,

13' 13'

I37

139

I4O 14'

142

143

'41 146 147 14'

'49

lS0 151

'sI

'53

1313.

Beihss, U. and Ledderhose, S., 1 Chem. Sac., Chem. Commun., 1995,2137. Jursic, B. S., Dzravkovski, Z., and Whittenburg, S . L., 1 Phys. Org. Chem., 8, 753 (1995). Jursic, B. S., 1 Chem. Sac., Perkin Tmns. 2, 1995, 1217. Jursic, B. S. and Coupe, D., 1 Heterocycl. Chem., 32, 483 (1995). D'Auria, M., Tetrahedron Lett., 36, 6567 (1995). Surez, D., Sordo, T. L., and Sordo, J. A,, 1 O x . Chem., 60, 2848 (1995). Suarez, D., Iglesias, E., Sordo, T. L., and Sordo, J. A,, Tetruhedron, 51, 12661 (1995). Capozzi, G., Fratini, I?, Menichetti, S., and Nativi, C., Tetmhedron Lett., 36, 5089 (1995). Jursic, B. S. and Zdravkovski, Z., 1 Org. Chem., 60,3163 (1995). Palacios, F., de Heredia, I. l?, and Rubiales, G., 1 Org. Chem., 60,2384 (1995). Sola, M., Mestres, J., Marti, J., and Duran, M., Chem. Phys. Lett., 231, 325 (1994); Chem. Abs., 122, 159902 (1 995). Banks, M. R., Cadogan, J. I. G., Gosney, I., Hodgson, I? K. G., Langridge-Smith, I? R. R., Millar, J. R. A,, Parkinson, J. A,, Sadler, I. H., and Taylor, A. T., 1 Chem. Sac., Chem. Cornmun., 1995, 1171. Linssen, T. G., Diirr, K., Hanack, M., and Hirsch, A,, 1 Chem. Sac., Chem. Commun., 1995, 103. Jursic, B. S. and Zdravkovski, Z., 1 Phys. Org. Chem., 7, 634 (1994). Jursic, B. S. and Zdravkovski, Z., THEOCHEM, 1995, 331, 229; Chem. Abs., 122, 238994 (1995). Jursic, B. S., 1 0%.Chem., 60, 4721 (1995). Jursic, B. S. and Zdravkovski, Z., THEOCHEM, 332, 39 (1995); Chem. Abx, 122, 290101 (1995). Jursic, B. S. and Zdravkovski, Z., Glas. Hem. Tehnol. Maked., 13, 55 (1994); Chem. Abs., 122, 238986 (1 995).

I6O

Turchi, S., Giomi, D., and Nesi, R., Tetruhedron, 51, 7085 (1995). Rao, M. V B., Satyanarayana, J., Ila, H., and Junjappa, H., Tetrahedron Lett., 36, 3385 (1995). Padwa, A., Coats, S. J., and Semones, M. A,, Tetrahedron, 51, 6651 (1995). Nemoto, H., Satoh, A., and Fukotomo, K., Tetrahedron, 51, 10159 (1995). Saltiel, J., Dabestani, R., Sears, D. F., McGowan, W. M., and Hilinski, E. F., 1 Am. Chem. Soc., 117,9129 (1995).

led

16'

Marchand, A. P., Zope, U. R., Burritt, A., and Bott, S. G., Tetrahedron, 51, 9319 (1995). Marchand, A. P., Shukla, R., Bunitt, A., and Bott, S. G., Tetmhedron, 51, 8733 (1995). Burry, L. C., Bridson, J. N., and Burnell, D. J., 1 Org. Chem., 60, 5931 (1995). Aubry, J.-M., Mandard-Cazin, B., Rougee, M., and Bensasson, R. V, 1 Am. Chem. Soc., 117, 9159 (1995).

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Jursic, B. S. and Zdravkovski, Z., 1 0%.Chem., 60,2865 (1995). Adam, W , Peters, E. M., Peters, K., Prein, M., and von Schnering, H. G., 1 Am. Chem. SOC.,117, 6686

(1995).

Adam, W. and Prein, M., Tetruhedron, 51, 12583 (1995). Delogu, G., Fabbri, D., Fabris, F., Sbrogib, F., Valle, G., and De Lucchi, O., 1 Chem. Sac., Chem. Cornmun., 1995, 1887. Paquette, L. A., Branan, B. M., Rogers, R. D., Bond, A. H., Lange, H., and Gleiter, R., 1 Am. Chem. Sac., 117, 5992 (1995). Clasby, M. C., Craig, D., Slawin, A. M. Z., White, A. 1. P., and Williams, D. J., Tetrahedron, 51, 1509 (1995).

172 Craig,

D., Geach, N. J., Pearson, C. J., Slawin, A. M. Z., White, A. J. P., and Williams, D. J., Tetrahedron,

51, 6071 (1995).

D.B. and Gassman, P. G., 1 0%.Chem., 60, 977 (1995). Gassman, P. G., Mad. Methodol. Org. Synth., Proc. Int. Symp. Org. React., 1992, 11; Chem. Abs., 122,

173 Gorman, 174

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Singleton, D.A. and Lee, Y.-K., Tetrahedron Len., 36, 3473 (1995). de Pascual-Teresa, B., Gonzalez, J., Asensio, A,, and Houk, K. N., 1 Am. Chem. SOC., 117,4347 (1995). 177 Kadota, I., Kobayashi, K., Asao, N., and Yamamoto, Y.,1 Chem. SOC.,Chem. Cornmun., 1995, 1271. 17* Gothelf, K. V; and Jergensen, K. A,, 1 Org. Chem., 60, 6847 (1995). 179 Jursic, B. S. and Zdravkovski, Z., THEOCHEM, 331, 215 (1995); Chem. Abs., 122, 238993 (1995).

'71

176

14 Addition Reactions: Cycloaddition

43 7

Zhulin, Y M., Koreshkov, Y.D., Kel'tseva, M. Y, and Bogdanov, Y S., Dokl. Akud. Nauk, 338, 344 (1994); Chem. Abs., 122, 213333 (1995). Bachrach, S. M., 1 Org Chem., 60, 4395 (1995). A1 Hariri, M., Pautet, F., Fillion, H., Domard, M., and Fenet, B., Tetrahedron, 51, 9595 (1995). de Echagiien, C. 0. and Ortufio, R. M., Tetrahedron Lett., 36, 749 (1995). 184 Zylber, J., Tubul, A., and Brun, P., Tetrahedron: Asymmehy, 6, 377 (1995). Heller, H. G., Hughes, D. S., Hursthouse, M. B., Levell, J. R., and Ottaway, M. J., 1 Chem. SOC.,Chem. Commun., 1995, 837. Domingo, L. R., Jones, R. A,, Picher, M. T., and Sepulveda-Arques, J., Tetrahedron, 51, 8739 (1995). Jursic, B. S. and Zdravkovski, Z., 1 Heterocycl. Chem., 31, 1429 (1994). 188 Ando, K., Kankake, M., Suzuki, T.,and Takayama, H., Tetrahedron, 51, 129 (1995). Gugelchuk, M. M., Chan, I? C.-M., and Sprules, T. J., 1 (3%. Chem., 59, 7723 (1994). 190 Kobayashi, T., Ikuno, K., Noguchi, M., and Kakehi, A,, 1 Chem. Soc., Perkin Trans. 1, 1995, 1453. 19' Zuloaga, F., Tapia, R., and Quintanat, C., 1 Chem. Soc., Perkin Trans. 2, 1995, 939. I 92 Coxon, J. M. and McDonald, D. Q., Adv. Detailed React. Mech., 3,131 (1994); Chem. Abs., 121,280022 (1994). Iy3 Poirier, R. A., Pye, C. C., Xidos, J. D., and Bumell, D. J., 1 Urg. Chem., 60, 2328 (1995). 194 Ishida, M., Kakita, S., and Inagaki, S., Chem. Lett., 1995, 469. 195 Werstiuk, N. H. and Ma, J., Can. 1 Chem., 72, 2493 (1994). 196 Adam, W., Jacob, U., and Prein, M., 1 Chem. Soc.. Chem. Commun., 1995, 839. 197 Mataka, S., Ma, J., Thiemann, T., Rudzinski, J. M., Sawada, T., and Tashiro, M., Tetrahedron Lett., 36, 6105 (1995). Iq8 Serrano, J. A,, Caceres, L. E., and Romh, E., 1 Chem. Soc.. Perkin Trans. I , 1995, 1863. 19' Cativiela, C., Avenoza, A,, Paris, M., and Peregrina, J., 1 O x , Chem., 59, 7774 (1994). Maruoka, K., Imoto, H., and Yamamoto, H., 1 Am. Chem. Soc., 116, 12115 (1994). Wender, P. A,, Jenkins, T. E., and Suzuki, S., 1 Am. Chem. SOC., 117, 1843 (1995). 202 Bell, A. S., Fishwick, C. W. G., and Reed, J. E., Tetmhedron Left., 36, 7713 (1995). 203 Sammakia, T.and Berliner, M. A., 1 Org. Chem., 60, 6652 (1995). Trauner, H., de la Cuesta, E., Marinetti, A., and Mathey, E, BUM SOC. Chim. Fr., 132, 384 (1995). ' 0 5 Teunissen, H. T., Hollebeek, J., Nieuwenhuizen, F! J., van Baar, B. L., de Kanter, F. J. J., and Bickelhaupt, F., 1 Urg. Chem., 60, 7439 (1995). '06 Wagenseller, F! E., Bimey, D. M., and Roy, D., 1 Org. Chem., 60, 2853 (1995). '07 Batizat, D. V, Glazkov, A. A,, Ignatenko, A. V, Yarosh, A. A,, and Ponornarenko, V. A,, Izv. Akad. Nauk, Ser Khim., 1994, 1789; Chem. Abs., 123, 55188 (1995). 208 Boese, R., Harvey, D. F., Malaska, M. J., and Vollhardt, K. P. C., 1 Am. Chem. SOC.,116, 11153 (1994). 2oy Lautens, M., Edwards, L. G., Tam, W., and Lough, A. J., 1 Am. Chem. Soc., 117, 10276 (1995). 210 Satake, S., Ushigoe, Y., Nojima, M., and McCullough, K. L., 1 Chem. SOC., Chem. Commun., 1995, 1469. Harmata, M., Gamlath, C. B., Barnes, C. L., and Jones, D. E., 1 Urg. Chem., 60, 5077 (1995). 212 Walters, M. A., Arcand, H. R., and Lawrie, D. J., Tetrahedron Lett., 36, 23 (1995). 213 Leung, M. and Trahanovsky, W. S., J. Am. Chem. Soc., 117, 841 (1995). 214 Heller, H. G. and Ottaway, M. J., J. Chem. Sac., Chem. Commun., 1995, 479. 215 Wender, P. A., Takahashi, H., and Witulski, B., 1 Am. Chem. Soc., 117,4720 (1995). Frank, N. L., Baldridge, K. K., and Siegel, J. S., 1 Am. Chem. Soc., 117, 2100 (1995). 2'7 Matsumoto, M., Shiono, T., Mutoh, H., Amano, M., and Arimitsu, S., J. Chem. SOC., Chem. Commun., 1995, 101. Blakemore, D. C. and Gilbert, A., Tetrahedron Left., 36, 2307 (1995). 219 Barentsen, H. M., Sieval, A. B., and Cornelisse, J., Tetrahedron, 51, 7495 (1995). Barentsen, H. M., Talman, E. G., Piet, D. F!, and Cornelisse, J., Tetmhedron, 51, 7469 (1995). 221 Nuss, J. M., Chinn, J. P., and Murphy, M. M., 1 Am. Chem. SOC.,117, 6801 (1995). 222 Hochstrate, D. and Klirner, F.-G., Liebigs Ann. Chem., 1995, 745.

CHAPTER 15

Molecular Rearrangements A . W. MURRAY Department of Chemistry. University of Dundee Aromatic Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Benzene Derivatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Heterocyclic Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sigmatropic Rearrangements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [3.3 ].Migrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Claisen and related rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . Cope and related rearrangements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . [2,3 ]-Migrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [ 1,3 ]-Migrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [ 1.5 ].Migrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrocyclic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anionic Rearrangements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cationic and Related Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . Rearrangements in Natural-product Systems . . . . . . . . . . . . . . . . . . . . . . . Rearrangements Involving Electron-deficientHeteroatoms . . . . . . . . . . . . . . Rearrangements Involving Organometallic Compounds . . . . . . . . . . . . . . . . Rearrangements Involving Ring Opening . . . . . . . . . . . . . . . . . . . . . . . . . Isomerizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tautomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

439 439 450 462 462 462 471 476 483 486 487 490 498 505 519 523 527 530 539 540 542

Aromatic Rearrangements

Benzene Derivatives The kinetics of the Fischer-Hepp rearrangement of N-nitrosodiphenylamine in anhydrous hydrochloric acid have been studied’ in methanol.toluene . 1,2.Diphenylhy . drazine has been reported’ to rearrange exclusively to o-semidine in the presence of square-planar rhodium(1) complexes. The authors have proposed that the rearrangement involves the initial coordination of 1 Zdiphenylhydrazine as a bidentate ligand to rhodium(1) when steric constraints place the phenyl rings of coordinated substrate into the perfect position to allow the exclusive formination of o-semidine via a mechanism similar to the acid-catalysed benzidine rearrangement. Treatment of N-aryl-Nmethoxyacetamides bearing strong electron-donating groups on the aryl ring. with A1C13-Me2S. has been shown3 to result in heterolytic cleavage of the N - 0 bond and

.

Organic Reaction Mechanisms 1995 . Edited by A . C . Knipe and W. E. Watts 0 1997 John Wiley & Sons Ltd

439

Organic Reaction Mechanisms 1995

440

introduction of a methylsulfanyl group at the ortho orpara position of the aryl ring. The photochemical rearrangement of o-phenylhydroxylamine has been studied4 and 0aroyl-N-acetyl-N-(2,6-dimethylphenyl)hydroxylamineshave been rearranged5 in acetwhich, in onitrile to 1,5-dimethyl-5-aryloxy-6-N-acetyliminocyclohexa-l,3-dienes, aqueous solution, produce m-aroyloxy- and m-hydroxy-2,6-dimethylacetanilidesin an H+-catalysed reaction, and the corresponding para products in a non-catalysed reaction. Trapping results have determined6 the nature of the nitrenium-carboxylate ion-pair intermediates in the hydrolysis of these hydroxylamines. A novel type of rearrangement has been reported’ to occur when aromatic bis(imides), which are usually chemically inert, are treated with alkali metal hydroxides in alcohols. A likely mechanism for this rearrangement is shown in Scheme 1, where the first step of the reaction is similar to the benzilic rearrangement to which it is vinylogous. The Smiles rearrangement of a-aminodiphenyl ethers has been reviewed8 and the cyclization of 4-chloro-2,3,5,6-tetrafluoro-2’-amino-substituted diphenyl ethers to phenoxazines has been studied.’ A Smiles rearrangement has been utilized” in a novel approach to 1-awl- 1H-4,l ,2-benzoxadiazinesYand chromium tricarbonylpromoted @so-Smilesrearrangements of 0-phenyl to N-phenyl derivatives of ephedrine and pseudoephedrine have been reported” (Scheme 2). Mechanistically informative Brsnsted plots for two examples of Smiles photo-rearrangements that are regiospecific for the ring position meta to a nitro group have been presented.” The reaction of thioquinanthrene (1) with alkali metal alkanethiolates has been found13 to proceed via the Smiles rearrangement of 3’-quinolinethiolate (2) to 4’-quinolinethiolate (3) to give 4,4’-dialkylthio-3,3’-diquinolinylsulfides (4) as the final products, and the reaction of 4-nitro-8-hydroxyquinolinewith (diacetoxyiodo)benzene has been shown to afford aryliodonioquinoline-8-olates(5). Subsequent thermal migration of the aryl group from

RSNa

SR

SR’

(4)

(3)

441

15 Molecular Rearrangements

N-u

-

\ /

‘0

w

0

\O

SCHEME 1

Me

I

BuLi

I

-

-Cr(C0)3

1 SCHEME 2

iodine to oxygen and photochemical migration from oxygen to nitrogen have been postulatedI4 to account for the formation of the intensely coloured arylquinolinium8-olates (6) (Scheme 3), the ultimate products of this reaction. New heterocyclic ring-annulated azepines have been prepared15 in good yields by capturing didehydroazepines intramolecularly with an amino group, during the photolysis of 2-(w-aminoalkyl)phenyl azides. The Fries rearrangement of phenyl acetate, p-tolyl acetate, and phenyl benzoate has been investigated16 using the H-form of various zeolites as catalysts, and the Fries rearrangement of acyloxynaphthalene to the corresponding hydroxynaphthyl ketones

442

Organic Reaction Mechanisms 1995

rt+

-

0-

0 I

SCHEME 3

has been shown" to proceed smoothly using a catalytic amount of scandium trifluoromethanesulfonate. The photo-Fries rearrangement of naphthyl acetate in supercritical carbon dioxide has been used" to probe the existence of supercritical solvent-solute clusters. The photo-Fries rearrangement of 2,2,2-trichloroethyl-3,5bis(benzoy1oxy)benzoate has been investigated,19 and the rate constants for the [ 1,3]and [ 1,5]-sigmatropic hydrogen shifts in the ground state of the photo-Fries rearranged intermediates of phenyl acetate, produced by laser flash photolysis, have been measured directly.20 It has been shown21 that, in a homogeneous solution, the photo-Fries rearrangement of 2,5-disubstituted phenyl acetates yields o-hydroxyacetophenones as major products, and a new approach to the synthesis of 7,8-dioxygenated tetrahydroisoquinoline alkaloids, based on the photo-Fries rearrangement of esters derived from 3-hydroxy-4-methoxyphenylacetonitrile, has been reported.22Pinacolone photolysis in the presence of phenols has led to phenyl acetates and hydroxyacetophenones. The process has been explained23by Nomsh type I cleavage and subsequent hydrogen abstraction from the phenol by the t-butyl radical to give rise to acyl-aryloxy radical pairs which recombine, thus constituting an intermolecular photo-Fries rearrangement. It has been shown24that the solid P-cyclodextrin complex of benzyl

443

15 Molecular Rearrangements

phenyl sulfone, upon irradiation, undergoes a unique intramolecular rearrangement yielding exclusively o-methyldiphenyl sulfone. A kinetic study of the acid-catalysed cleavage of phenylthioacetic acid by sodium perborate has been undertaken.25A mechanism involving an intramolecular Pummerertype rearrangement, followed by cleavage, has been suggested to account for the formation of thiophenol in the process. A facile two-step preparation of oaryloxyphenols has been described26 in which the key step is the intramolecular trapping of an a-keto sulfonium salt prepared by Pummerer rearrangement of a symmetrical 0-hydroxyaryl sulfoxide to give an orthoquinone mono(monothioaceta1). Treatment of p-sulfinylphenol derivatives (7; R = H) with trifluoroacetic anhydride has initiated2’ a Pummerer-type rearrangement on aromatic rings and concomitant desulfurization to give 1 : 1 mixtures of the corresponding p-quinones (8) and p dihydroquinones, while similar treatment of p-(phenylsulfiny1)phenyl ethers (7; R = alkyl) has yielded protected dihydroquinone derivatives (9), presumably via the direct @so substitution of the sulfinyl group by a trifluoroacetoxy group.28The recently reported29 Pummerer-induced rearrangement of aryl amido sulfoxides with trifluoroacetic anhydnde represents a highly efficient method for the synthesis of oxindole and tetrahydroisoquinoline ring systems. The details of this new rearrangement are summarized in Scheme 4.A novel preparation of 1,3-oxathiane derivatives through the Pummerer rearrangement of y,b-unsaturated sulfinyl compounds has been described3* and a plausible mechanism for the process has been outlined (see Scheme 5). The presence of an o-hydroxymethyl group in aryl methyl sulfoxides has been found3lS3’ to ensure the exclusive formation of chloromethyl sulfides, mediated via an intramolecular

6 4 -

0

0 0

II II

CF3COCCF3 R=H

s-0 I

+

0

s-o-

CF3CO

IW

R

R’

(7)

1

\

R = alkyl

I

OCOCF3

0

OCOCF3

444

Organic Reaction Mechanisms 1995 Ar

Ar

I

-CF,CO*H

I

R

.-' I R

I R

SCHEME 4 H

J SCHEME 5

f

15 Molecular Rearrangements

445

attack, to yield an alkoxysulfonium salt (see Scheme 6), thus preventing the formation of siloxymethyl sulfides via a sila-Pummerer rearrangement. The 1,a-migration of the phenyl group in the acid-catalysed rearrangement of 4hydroxy-4-phenylcyclohexa-2,5-dienonehas been compared with that of the migration of the ethyl (or vinyl) group in 4-hydroxy-4-ethyl(or vinyl)cyclohexa-2,5-diene.The slower phenyl group migration is considered to be due to the electronic cloud overlap between the phenyl group and protonated dienone in the transition state.33 Azaspirodienones (1l), synthesized via intramolecular cyclization of p-hydroxybenzylacetoximes (lo), have been t r an ~ f o r m edinto ~ ~ quinolines (12) via a dienone-phenol rearrangement, while thermal cyclization of p-benzoquinone imine derivatives (13) has yielded spirodienone diazacarbocycles, such as (14), which have been converted35into diazepine (15) via a dienonephenol rearrangement. The photochemical behaviour of 5,5-diphenylcyclohexa-1,3-diene has been inve~tigated~~ and the significant role played by spin-orbit coupling and symmetry in controlling the mode of phenyl migration and ring contraction has been delineated. One of the major products 4,6,7-trimethyl-l(2’,2’,2’-trinitroethylnaphthalene(18), obtained on photolysis of 1,4,6,7-tetramethyl-r1-nitro-t-4-trinitromethyl-1,4-dihydronaphthalene(16), has been postulated37 to arise via 1,4,6,7-tetramethyl-t-2-nitro-r1-trinitromethyl-1,2-dihydronaphthalene (17), as shown in Scheme 7. AM1 calculations with full geometry optimization have been carried out3* for polyfluorobenzenes and their protonated forms. A mechanism (part of which is outlined in Scheme 8), involving ips0 protonation of biphenyl followed by 1,2-migration of a phenyl group via the novel phenonium ion (19) and rearomatization, has been postulated39to explain the results of a labelling study of the acid-catalysed degenerate isomerization of biphenyl. A comprehensive study has been undertaken4’ of the structure and reactivity of free arylium ions, while two stable isomers of the benzenium ion, the most stable of which appears to be the face-centred n-complex, have been identified41 by CIDMS. Cram’s phenonium ion (20) has been obtained by the independent route of protonation of benzocyclobutene under superacidic stable-ion conditions, and shown42to be de fact0 a spirocyclopropylbenzeniumion and not a nonclassical carbocation. A novel rearrangement has been observed43 during the synthesis of poly(phtha1idylidenearylenes) by the Friedel-Crafts self-condensation of 3-aryl-3-chlorophthalides. Thus monomers containing substituents at the 4- and 6-position of the phthalide ring were found to rearrange in the course of the polymer synthesis. Trifluoroacetic acidcatalysed rearrangement of 1,Cdihydro- 1,5,8-trimethoxy-1,Cethenonaphthalene has been shown to produce precedented products of bicyclic rearrangement along with 2,4’,5-trimethoxybiphenyl,the product of a remarkable retro-Friedel-Crafts protodealkoxyalkylative fragmentation of the bicyclic system44 (Scheme 9), while a 14C tracer study has e ~ t ab l i s h e dthe ~ ~ likely pathways that operate in the acid-catalysed rearrangement of 1,4-dihydro-1-methoxy-1,Cethenonaphthalene and its 5,6,7,8-tetrahalogeno derivative into the corresponding 3,4-dihydro-l,4-ethenonaphthalen-2( 1H)ones. Exposure of u-tocopherol (21) to nitric oxide in air-saturated cyclohexane has been reported to lead to a complex mixture of products, one of which has been identified46 as the novel 2,3-dimethyl-4-acetyl-4-hydroxy-5-nitrosocyclopent-2-enone

Organic Reaction Mechanisms 1995

446

1

M€!o*c&uMe HO

OH

/

derivative (22). It has been demon~trated~~ that 2,6-dimethoxycinnamic acid ethyl ester undergoes an interesting rearrangement to afford the same calix[4]resorcinarenes as those obtained from the 2,4-dimethoxy isomer. Cyclo-condensation of 2-alkylresorcin01s with 1,3,5-trioxane has produced4*both calix[4]resorcinarene and calix[6]resorcin-

I5 Molecular Rearrangements

he (18)

447

8

he

SCHEME 7

/

arene, the latter being isomerized to the former on prolonged heating in acid. An intermolecular migration of sulfonyl groups in 1,3-bis(triflate) and 1,3-bis(rnesylate) derivatives of p-t-butylcalix[4]arene has been found to take place49 in the presence of both a palladium catalyst and chloride. A report has appeared'' on the synthesis of

Organic Reaction Mechanisms 1995

448

@

H+

___)

+OMe

OMe

M e 0 - - -H

qoMe

Me0

-H+

OMe

Me ~.

OMe

OMe SCHEME 9

topologically chiral catenanes bearing sulfonamide units. Flash vacuum pyrolysis of 1,2-dialkoxybemenes (23) has been shown to yield 0-hydroxy carbonyl compounds whose formation can be rationalized5’ by the radical pathways outlined in Scheme 10, while 1-alkyl-4-hydroxyoxindoleshave been obtained” by a 1,3-migration of the hydroxyl group on irradiation of 1-alkyl-3-hydroxyindoles in degassed solutions. A free-radical mechanism has been suggested53to account for the products observed on thermolysis of ketoxime arenesulfonates, and 1,2-radical rearrangements of aryl, k a n y l , and thiophenyl groups from carbon to nitrogen, using azido groups as radical precursors, have been observed for the first time.s4 The 1,2-aryl rearrangement has been applied to the synthesis of phenanthridine derivatives from 6-fluorenyl aides. 1A5,3AsBenzodiphospholes (24), on heating, have been reported” to undergo a phosphoranephosphane rearrangement, (24) -+(25), which results from the migration of a phenyl ring and formation of a biphenyl moiety at the ylidic phosphorus atom. An interesting rearrangement involving a novel 1,Chydrogen shift from a carbon of an aromatic nucleus to an sp2 silicon atom of a silicon-carbon double bond has been postulateds6

15 Molecular Rearrangements

449

1

-R2cn, R‘

SCHEME 10

heat

1.4-H

for the conversion of 1-naphthyl-1-methylsilane (26) into 1-methyl-1-sila-acenaphthene (27). A mechanistic study of the thermal cyclo-isomerization of 1,4-diphenylbut-l-en-3yne has been ~ndertaken,~’ and a double-labelling experiment has demon~trated~~ that a 1,%-sty1371 migration is involved in the process. Ab initio quantum mechanical methods have been employed59to study [4]paracyclophane and its Dewar benzene isomer. This study indicated that the boat-shaped benzene, with the same geometry as [4]paracyclophane, has the same magnetic susceptibility as the hypothetical cyclohexatriene.

Organic Reaction Mechanisms 1995

450 Heterocyclic Derivatives

5,5-Dimethy1-3-phenyl-1-pyrroline-1-oxide (28) has been found6’ to undergo an unprecedented acid-catalysed 1,3-0xygen migration to give the 1-pyrroline (29), and a base-catalysed 1,2-0xygen migration to give the pyrroldin-2-one (30). When heated in an alcoholic solvent, 4-substituted 3-aroyl-1-alkylpyrrolidines (31) have been found61 to afford 4-substituted 1-alkyl-2-aryl-3-methylpyrrolederivatives (32) by a thermally induced retro-Michael addition (Scheme 1l), and the thermal rearrangement of 2,5diaryl-3,3,4,4-tetracyanopyrrolidineshas been studied.62 The tosyl group of 3,4disubstituted 2-tosylpyrroles has been easily transferred from the 2- to the 5-position by treatment of these compounds with trifluoroacetic acid.63A possible mechanism for this rearrangement is shown in Scheme 12. The rearrangement of some N-substituted pyrrolo[3,4-c]pyrroles to the corresponding pyrrolo[3,4-c]pyridines has been reported.64 The mechanism outlined in Scheme 13 has been postulated6’ for the acidcatalysed rearrangement of 1-arylindoles to SH-dibenz[b,flazepines, and the formation of 1,2,3,4-tetrahydro-j-carbolinein the Pictet-Spengler reaction has been studied66 using an MNDO approach. Ph

Ph base

Me M

eH a o

SCHEME 11

OH

45 1

15 Molecular Rearrangements

J

H

SCHEME 12

I

Ph

I

Ph

I

ox

Ph

i

-xo-

SCHEME 13

A convenient synthesis of the coffee and caramel flavour component 2-methylfuran3(2H)-one has been developed6’ by acid-catalysed rearrangement of 2-methoxy-2methyltetrahydrof-3-one (Scheme 14). Semiempirical MO calculations have been used6*to explain the formation of (37)as the product obtained from the reaction of 4acylfuran-2,3-diones (33) with ketenimines (34). The rearrangement of the primary

Organic Reaction Mechanisms I995

452

H+

OMe

Me

H

SCHEME 14

cycloadduct (35) via intermediate (36) appears to be the most feasible pathway. Condensation of amidines with 2-amino-3-cyanofUrans (38) has been reported69 to yield 2-substituted 4-aminopyrrolo[2,3-4pyrimidines by a ring opening-ring recyclization sequence of reactions (see Scheme 15) by which the starting furan 2-amino nitrogen becomes the pyrrole nitrogen of the final product, and one of the amidine nitrogens becomes N(l) of the fused pyrimidine ring. During the photo-reaction of thiobenzamide with substituted furans (39), transformation of the furans to pyrroles (Scheme 16) was found to in preference to p-benzoylation, while photoirradiation of 3-alkoxy-6-chloro-2-(2'-furyl)-4-oxo-4H-1-benzopyrans(40) has led to the formation of methyl 8-chloro-1O-oxo-2-phenyl-2,3,4,1O-tetrahydropyrano-

453

15 Molecular Rearrangements

SCHEME 15

SCHEME 16

[3,2-b][ llbenzopyran-3-yl acetate (45). It was p ~ s t u l a t e d that ~ ~ the reaction proceeds through the formation of 8-chlor0-4-phenyl-3a,4,6,11 b-tetrahydrofuro[2’,3’ : 4,5]pyrano[3,2-b]benzopyran-6-one(41), which subsequently undergoes a ring contraction-ring expansion mechanism to give the cyclopropanecarbaldehyde (42) followed by its rearrangement to ketene (44) via the carbene (43) to furnish ester (45). In addition to the expected substitution product (47), the unexpected product (48) was also obtained from the reaction of 3-bromo-2-nitro-benzo[b]thiophene with various mines. The formation of (48) represents a novel aromatic nucleophilic substitution reaction and a number of alternative intermediates, e.g. (46), have been proposed7’ to account for the observation.

454

Organic Reaction Mechanisms 1995

Ph

OCHzPh 0

0

H

t

R=H

1

3-Acetyl-2-pyrazolines have been to 3-methyl-4(1H)-pyridazinones. The mechanism of the themolytic ring opening of 5-azido-4-formyl-3-methyl1phenylpyrazole to yield (4-cyanopyrazol-3-ylmethy1)pyrazoleshas been in~estigated,~~

I5 Molecular Rearrangements

455

and lH-pyraz0[3,4-dlthiazole-5-carbonitriles(51) have been obtained75by treating 4unsubstituted 5-aminopyrazoles (49) with Appel's salt (50) at room temperature in the presence of 2,6-dimethylpyridine. The mechanism of the thermal rearrangement of 1,4dinitroimidazole to 2,4-dinitroimidazole has been interpreted76as a [ 1,5]-sigmatropic type shift, and the rearrangement of 1-(dimethylsulfmoyl)-5-imidazolecarboxaldehyde to the corresponding 4-carboxaldehyde has been considered to proceed by the pathway outlined in Scheme C1

R'

1

(49)

\

OHC

-4) CI

-

R2

OHC

-4-$

- 4.-

S02NMe2

Nu-

R'

2

OHC -

/

OHC

SCHEME 17

A frequency descriptor-aided study78has been made of the rearrangement of l-oxa2-moles. 5-Azidoisoxazoles containing an unsaturated group in the 4-position have been found to rearrange by two discrete processes to yield, either bicyclic isoxazoles which result from direct attack of the a i d e (or nitrene) on the unsaturated group, or

456

Organic Reaction Mechanisms 1995

0

SCHEME 18

monocyclic pyrroles and pyrazoles which result from ring opening followed by bond reorganization and subsequent ring closure.79Naphth12,l -dJisoxazoles, 1llbenzofuro[6,7-dJisoxazoles, -[5,4-d]diisoxazoles, and 1,2-benzisoxazoles have been prepared8' by the thermal decomposition of dimethyl 2-[5-aryl(or fury1 or alkenyl)]-3methylisoxazol-4-yl)-2-oxo-1-diazoethylphosphonatesthrough a tandem Wolff rearrangement-benzannulation sequence. It has been demonstrated*' that the thermal rearrangement of spirocyclopropaneisoxazolidinescan be utilized in an intramolecular fashion to lead to interesting bicyclic tetrahydropyridones with high selectivity. NBenzoylamino acids have been found to react with excess oxalyl chloride followed by addition of alcohols to afford 4-substituted 2-phenyloxazole-5-carboxylates82 (Scheme 18). A novel rearrangement of the oxazolidin-2-thione (52) to 1,3-oxazin-4-one (53), which involves attack of the side-chain hydroxyl on the thiocarbonyl group, has been

457

15 Molecular Rearrangements

reported.83 and an interesting oxazoline to thiazoline conversion, which involves thiolysis of oxazolines with H2S in methanol-triethylamine and subsequent cyclodehydration of the corresponding thioamide (Scheme 19), has been achieved.84 A straightforward two-step sequence capable of converting simple thiazoles into different sets of ring-expanded N,S-heterocycles of various ring sizes has been developed85(Scheme 20), and a novel rearrangement has been discovered86during an investigation of the lithium-bromine exchange reaction of bromothiazole derivatives and their subsequent reactions with various electrophiles. The 1,4-dipolar cycloaddition of 3-phenyl-7[~-phenyl(carbamoyl)]-5,6-dihydroimidazo[2,1-b]thiazolium betaine (54) with a series of aliphatic alkylating agents have been found to yield a variety of new ring-expanded cycloadducts such as (55).87

SCHEME 20

4-Alkyl-substituted 4H-1,2,4-triazoles have been found to undergo thermal rearrangement to the corresponding 1-alkyl-substituted triazoles in the crystalline in the presence of dimethyl state,88while pyrolysis of 4-aryl-5-amino-l,2,3-triazolines acetylenedicarboxylate has produced" 1-aza-l,3-dienes and 2-pyrrolines via the intermediacy of 2-aminoaziridines. Phosphonium bromides (56) on treatment with base have been found to afford the stable phosphorylides (57), which upon refluxing in xylene give good yields of pyrazolo[4,3-dJ(2,3)-benzodiazepines(58) via a Dimroth-

Organic Reaction Mechanisms I995

458

like rearrangement." 2-(Benzotriazol-1-yl)enamines (59), readily available from lithiated 1-(arylmethyl)benzotazole and nitriles, have been found to undergo facile rearrangement to 2,4-diarylquinazolines. A plausible mechanism for this novel rearrangement" is shown in Scheme 21.

R R4 R'

3 \

m

R

2

1

NH

R' SCHEME 21

-

R3m R4

\

R'

NH2

15 Molecular Rearrangements

459

-

-

hv

-PhCN

+ZH

SCHEME 22

Desilylation of N-trimethylsilylmethyl-1,2,5-oxadiazolium salts and deprotonation of the N-methyl analogues have been shown to initiate ring expansion to 6H-1,2,5oxadiazine~.~'The photochemical behaviour of 1,2,4- and 1,2,5-0xa&azoles has been reviewed,93 and the irradiation of 3-(acetylamino)-4-phenyl-1,2,5-oxadiazolehas been developed94as a new methodology for the synthesis of 3-substituted 1,2,4-oxadiazoles (Scheme 22). A study has been made95 of the mechanism of formation of 1,3,4thiadiazol-2(3H)-ones during the reaction of hydrazonoyl halides with 1,3,4oxadiazole-2(3H)-thiones. The Boulton-Katritzky rearrangement of 5-(cyanoimin0)1,2,4-thiadiazolines has been reported,96 and the rearrangement of 5-amino-l,2,3thiadiazole-4-carbothioamides(60) to (61) via ring cleavage has been studied9' by NMR.

The thermal rearrangement of 1-alkoxy-5-aryltetrazolesto 3-alkyl-5-aryltetrazole1oxides has been i n ~ e s t i g a t ed . ~ ~ The hydrolysis of 2-chloro-3,5-dinitropyndine (62) to the 2-pyridone (64) has been shown to proceed through the remarkable intermediate (63), whose formation and disappearance have been followed separately in a number of mixed solvents.992,4,4,6Tetraaryl-4H-thiopyrms (65) have been found to react smoothly with chlorine to yield the corresponding 3,5-dichloro derivatives. However, with longer reaction times and higher temperatures, trichloro derivatives (66) were found to be the major products and their formation was explainedIoOby the mechanism outlined in Scheme 23. A mechanism involving a 'benzva1ene'-type intermediate has been proposed"' to explain the first reported thermal rearrangement reaction of a phthalazine to a quinazoline, while a plausible explanation for the formation of products (68) from the pyrolysis of N-( 1-phthalazinyl)-N-cycloalkylidenehydrazines (67) has been proposed"' (Scheme 24). Photochemical transformations of pyrazolopyridazine (69) have been rep~rted,"~a novel thermal rearrangement in the pyrido[ 1,2-a]pyrirnidine series has been ob~erved,''~and 2-oxo-3-phenylisoxazolo[2,3-a]pyrimidinesupon heating in

460

Organic Reaction Mechanisms 1995

HO-

J

Ar Ar

Ar

SCHEME 23

water or ethanol have been found to undergo ring opening followed by decarboxylation to yield phenylpyrimidylmethanol and phenylpyrimidyl methyl ethers."' Unprecedented transformations of 1,3-dialkyl-5-formyluracilsto 1,3-dialky1-7hydroxyquinazolines have been observedIo6during the treatment of the former with a series of carbanion precursors such as ethyl acetoacetate and the like, while a new type of rearrangement has been added to those already known for the glycol half-ethers

I5 Molecular Rearrangements

46 1

mCN

H7 I?

of uric acid.'07 Fervenulone (70) has been shown to undergo an unprecedented and facile ring contraction'08 (Scheme 25) upon attempted N-alkylation with I-butyl bromoacetate. Alper et al.'09 have established that a variety of suitably substituted 1,3thiazanes are able to undergo a unique iridium-catalysed disproportionation reaction to give thiazines in moderate to good yields. As illustrated by the simplified scheme (71) 3 (72) -+ (73), chromium(0)-promoted 6 2-cycloaddition-thallium(III)-mediated oxidative rearrangement of N-substituted azepines has afforded'" a novel and efficient entry into tropane alkaloid building blocks. It has been postulated" that flash vacuum pyrolysis of 2,3-dihydro-l,4diazepines involves interaction of the saturated portion of the molecule with the vinamidine system and causes [1,5]-hydrogen shifts, while at higher temperatures ring contraction to yield pyrazines has been established as the main pathway. Microwave heating of pyrrolo- and pyrido-[2,l-c][ 1,4]benzodiazepinediones in boiling phosphorus oxychloride has produced a new rearrangement' l2 leading to cyclopenta[b][1,4]benzodiazepines and tetrahydrodibenzo[b,fl[1,4]diazepines. A mechanism based on tightly bound ion pairs and transfer of the CH2CH2C(0)C (Me)=CH2 moiety to the nitrogen centre has been p r o p ~ s e d ' ' ~ for the thermal rearrangement of (2-oxyethylmethacryl)pentachlorocyclotriphosphazene (74) to (75).

+

'

462

Organic Reaction Mechanisms 1995

Br/’C02Buf

CO~BU‘

SCHEME 25

(74)

(75)

Sigmatropic Rearrangements [3,3]-Migrations Ciaisen and related rearrangements An account which details the insights, arguments, and events which have shaped our current vision of the nature of the transition states of pencyclic reactions has appeared.’14 A quantum chemical study’” has been made of the Claisen rearrangement, and the Claisen rearrangement of chorismate to prephenate, and models for the catalysis of this reaction by the enzyme chorismate mutase, have been studied’I6 using

I5 Molecular Rearrangements

463

Hartree-Fock and density functional theories. A simple and generalized method which gives more detailed information than that from the Woodward-Hofiann rule and the usual molecular theories has been developed’ l 7 for investigating non-adiabatic transitions in photochemical [i,/l-sigmatropic rearrangements. A new treatment of solvation effects on the Claisen rearrangement has been reported,*18a factor analysis of solvent effects on reactions has been applied”’ to the Claisen rearrangement, and a hybrid, explicit solvent and continuum model has been described and used’” to study the acceleration of the Claisen rearrangement of allyl vinyl ether in aqueous medium. Sehgal et a1.’” have carried out a combined quantum mechanical and statistical mechanical investigation and provided computational evidence of substitution patterns that can amplify the solvent effect on Claisen rearrangements in water. A new chiral Lewis acid for the asymmetric Claisen rearrangement has been designed. The Claisen rearrangement of 6-methoxyallyl vinyl ether has been catalysed by a soluble diarylurea. Evidence has been presentediz3to show that the urea stabilizes a dipolar transition state by hydrogen bonding. A metal-mediated one-pot synthesis of cyclopentanones from allyl vinyl ethers via a tandem Claisen rearrangement and hydroacylation has been reported,’24 an improved procedure for the Pd(I1)-catalysed Claisen rearrangement via in situ enol ether exchange has been described, while the Pd(I1)-catalysed Claisen rearrangements of the geometrical isomers of crotyl en01 ether have been shown to exhibit identical anti diastereoselection,lZ6 in marked contrast to the high stereospecificity observed in the thermal rearrangements. Several cases of significant enhancement in the diastereoselectivity of the acyclic Claisen rearrangement of cyclohexenyl allyl ethers, governed principally by remote asymmetric centres, have been observed when Lewis acid catalysts are empl~yed”~ rather than the usual thermal rearrangement conditions. A convenient synthetic route to 8,E-unsaturated P,j-difluoro-a-keto esters has been developedIz8by utilizing the Claisen rearrangement of allyl-substituted difluoroenol pyruvyl ethers, while difluoroallylic alcohols have been found to undergo a range of Claisen and related [3,3]-sigmatropic rearrangements to yield 0-fluorocarbonyl and P,P-difluorocarbonyl deri~atives.’’~ The enantioselective synthesis of an oxataxane derivative via a tandem intramolecular 2 2-cycloadd~tionand [3,3]-sigmatropic rearrangement of an allenyl ether has been des~ribed’~’ (Scheme 26), and a new synthesis of retinal and various poly-unsaturated carbonyls has been pr~posed’~’ which involves a Pd(0)-catalysed vinylogous acetylenic Claisen rearrangement.

’’

’”

+

SCHEME 26

Organic Reaction Mechanisms I995

464

The suitability of the Claisen ring-expansion protocol for the construction of crenulide diterpenes has been established,' 32 and the sesquiterpene ceratopicanol has been s y n t h e s i ~ e d' ~ by~ a route based on a Claisen rearrangement and radical cyclization. Convenient two-step syntheses of seselin and angelicin derivatives have been achieved'34 using a tandem Claisen rearrangement and Wittig reaction. The thermal rearrangement of ally1 aryl ethers (76) generated in situ from hydroquinone and conjugated polyenols has afforded 2 , 3 - d i h y d r o b e n z o f o l ~ 'such ~ ~ as (77), while 1-enes (78) have successive Claisen rearrangements of 2-aryloxymethyl-3-aryloxypropled'36 to the corresponding 2-(o-hydroxyaryl)methyhyl-3-(o-hydroxyaryl)-prop-l-enes (79).The effect of substituents on the phenyl ring on the caesium fluoride-mediated Claisen rearrangement of phenyl propargyl ethers has been studied.137Polyheterocycles such as 7a-methyl-2-phenyl-l3,13a-dihydro-7aH-furo[3,2-a : 5,4-h']bis[ llbenzopyran4-ones have been ~ y n t h e s i z e d ' by ~ ~ a series of sequential [3,3]-sigmatropic rearrangements of 7-(4-aryloxybut-2-yn-1-yloxy)[l]benzopyran-4-ones, while hitherto ' ~ ~the unreported 3H-pyrano[2,3-c]quinolin-5(6H)-ones(81) have been sy n th e ~ iz e dby thermal [3,3]-sigmatropic rearrangement of 3-propargyloxyquinolin-2-ones (SO) and subsequent acid-catalysed cyclization (Scheme 27). A study has been made'40 of the solvent dependence of ips0 versus ortho selectivity in the reductive iodonio-Claisen rearrangement of allenyl(p-methoxypheny1)iodane.

-

Me

Me

Me

t

(77)

Me

The chelation-controlled ester enolate Claisen rearrangement has been shown to yield trisubstituted(2)alkenes with high selectivity as a result of heteroatom-enforced control over the conformation of the transition state. In this way y,b-(Z)-unsaturated carboxylic

15 Molecular Rearrangements

i

465

-

Me

.Me

L

I

Me (80)

0

-

___)

I

Me

R

S

'N

R

2

I

Me (81)

SCHEME 27

acids, with outstanding stereocontrol at the a$-stereogenic centre as well as in the alkene double bond, have been ~repared.'~' The ester enolate Claisen rearrangement of chelated N-protected amino acid allylic esters has resulted in the formation of aalkylated y,b-unsaturated amino acids in good yields and in a highly diastereoselective fashion.142,143 A simple stereoselective synthesis of ethy1(42)-4-cyanoalk-4-enoates via the Johnson-Claisen rearrangement of 3-hydroxy-2-methylenealkanenitriieshas been described,'44while a Johnson-Claisen rearrangement of the chiral intermediate (82) has been used145as a key step in a synthesis of both the (3R)-( -)- and (3S)-(+)-A factors. The Johnson variation of the Claisen rearrangement has also been used'46 to introduce the C(8) side-chain of the pyran nucleus of pseudomonic acid A regio- and stereoselectively. The use of a tandem Ireland-Claisen rearrangement followed by an in situ silicon-mediated epoxide fragmentation has provided an efficient entry to 1,3-dienes containing an E double bond and an exo-methylene group.'47 An enantioselective total synthesis of p-elemene and fuscol based on an enantio-controlled Ireland-Claisen rearrangement has been described,148 and the p-lactone enzyme inhibitors (-)ebelactone A and (-)-ebelactone B have been prepared'49 using a series of three boron enolate aldol reactions coupled with a remarkable Ireland ester enolate Claisen rearrangement, A novel stereo-controlled route to 5-oxaprostaglandin intermediates has used'50 a sequence of 1,2-0-0-silyl migration, Claisen rearrangement, and SN2'displacement. Acetoacetates, easily prepared from substituted p-quinols, have been found to undergo a Carroll rearrangement under mild conditions to afford substituted arylacetones and related derivatives."' Enders et ~ 1 . have ' ~ ~ reported on a highly diastereo- and enantio-selective synthesis of sterically demanding functionalized

466

Organic Reaction Mechanisms 1995

ketones (85) with adjacent quaternary and tertiary centres, starting from P-hydrazono esters (83). The key step is the stereoselective [3,3]-sigmatropic Carroll rearrangement of the hydrazono ester dienolate (84). The chiral auxiliary used in this rearrangement is (5)-1-amino-2-methoxymethylpyrrolidine,and the ketones (85) are obtained after reductive work-up and oxidative cleavage of the auxiliary. A Claisen orthoester rearrangement has been used'53 to prepare (2,)-isositsirikine and (2,)-geissoschizine derivatives possessing the right oxidation state at C( 17). A mild, regioselective ketal Claisen rearrangement promoted by triisobutylaluminium has been reported,154 and a new ketal Claisen rearrangement for C(S)-unit elongation has been established and A new sequence for the applied to the synthesis of a sarcophytol A inte~mediate.'~~ highly stereoselective synthesis of trisubstituted y,d-unsaturated acids has been d e ~ c r i b e d . It ' ~ consists ~ of a ketal Claisen rearrangement of a terpene allylic alcohol with 2,2-dimethoxy-3-methylbutan-3-ol,and subsequent oxidative cleavage of the resulting a-ketol.

coy

Me

0

SCHEME 28

The aromatic amino-Claisen rearrangement of N-alkenyl-2,5-dimethoxyanilineshas been studied,'57 an amino-Claisen rearrangement has been observed'58 in substituted N-(2-propynyl)anilines on electron impact, and new tetrahydroazocinoquinones and

467

15 Molecular Rearrangements

N x SePh o SCHEME 29

dihydroazepinoquinones have been prepared’59by the amino-Claisen rearrangement of 4-(2-vinyl-azetidino or -aziridino)-5-methoxy-1,2-benzoquinones (Scheme 28). The utility of [3,3]-sigmatropic rearrangements of hydroxylamine derivatives has been exemplified’6o by the rearrangement of N-phenyl-0-acylhydroxylamines,N,Odiacylhydroxylamines, and N-acylhydroxylamine-0-carbamates.Evans et al.16’ have reported the use of a novel Claisen rearrangement to prepare the highly strained Nbenzyloxycarbonyl-substitutedlactam (88). It involves the Claisen rearrangement of the ketene aminal(87) which was generated by in situ elimination of the selenoxide derived from (86) (Scheme 29). A zwitterionic Claisen rearrangement has been developed for optically active N-allylpyrrolidines using a two-phase system (Scheme 30), and the inherent 1,Zasymmetic induction has been investigated’62for the generation of a new carbon-carbon bond adjacent to a chiral carbon-oxygen function. The y-lactam portion of the non-protein neurotrophic factor (+)-lactacystin has been constructed stereoselectively from D-glucose using the allylic tichloroacetimidate rearrangement as the key reaction,’63 and (2-cyclopropylideneethyl)acetimidates (89) have been found’64to undergo a thermally induced, or palladium(I1)-catalysed, aza-Claisen rearrangement to 1-ethenylcyclopropyl acetamides (90), thus providing convenient precursors to 1aminocyclopropanecarboxylic acids (91). Inverse regioselectivity in the cycloaddition of diazomethane and diphenyldiazomethane to methyl acetyloxyimino(cyano)acetate

C02H

I\/

R (89)

Organic Reaction Mechanisms 1995

468

Ph

R=

2

’ 0 -

J

c,-

base -HC1

SCHEME 30

(92) has led165to the specific evolution of the transient triazoline (93), which by an eventual [3,3]-sigmatropic transposition yields imines (94) (Scheme 3 1). An unusually

facile thermal aza-Claisen rearrangement’66has been used in a stereospecific synthesis of novel 2’,3’-dideoxynucleoside precursors, and the asymmetric synthesis of an allylic azide combined with the facility of its [3,3]-sigmatropic rearrangement has provided’67 a simple strategy for the synthesis of conduramine E. Generated in situ,the parent ally1 vinyl sulfonium ion (95) has been found to undergo a rapid thio-Claisen rearrangement16*(Scheme 32), while 1,8-bis(allylthio)naphthaIene

-

NckdocoMe R’R2CN2 Me02C

(92)

(93)

SCHEME 31

-I

n

15 Molecular Rearrangements

469

-

I

OMe SCHEME 32

qs P s-0

(97)

L

SCHEME 33

monoxides (96) have been o b ~ e r v e d ' ~to~undergo ~ ' ~ ~ consecutive [2,3]-sulfur-sulfur and thio-Claisen rearrangements to afford 2-allylnaphtho[1J3-cdI-1 ,a-dithioles (97) (see Scheme 33). A diastereoselective thio-Claisen rearrangement of S-allylic a-silyloxyketene dithioacetals has been r e ~ 0 r t e d . l ~ An ~ ab initio study17* of the thermal fragmentation of N-(acyloxy)pyndine-2-thiones has indicated that a [3,3]-sigmatropic process initiates the radical fragmentation, and S-allyl-, S-propargyl-, and S-methallylthioiminium salts derived from methyl 1-benzyl-5-thioxoprolinatehave been found to undergo a facile thio-Claisen rearrangement which has provided easy access to 4substituted thioxoprolinate~.'~~ A one-pot synthesis of allyl dithioesters has been achieved by employing a tandem condensation-alkylation-sigmatropic rearrangement sequence,174,175 and it has been that 0-substituted allyl N-acylmonothiocarbamates (98) spontaneously undergo [3,3]-sigmatropic rearrangement to Ssubstituted allyl N-acylmonothiocarbonates (99) which, on further heating, undergo a [1,3]-sigmatropic shift to yield (100). A highly stereoselective synthesis of Z or E

Organic Reaction Mechanisms 1995

470

double bonds in 10-membered thiolcarbonates has been achieved by the [3,3]sigmatropic ring expansion of eight-membered thionocarbonates which proceeds through a chair-like transition state.'77 The methodology has been used to provide a unique stereoselective synthesis of ( -)-yellow scale pheromone. A similar [3,3]sigmatropic ring expansion of alkynyl cyclic thionocarbonates (101) has been used'78 to prepare medium-sized heterocyclic allenes (102) (Scheme 34), and further applied to the synthesis of the antifungal constituent of Sapium japonicum. FurfUryl sulfides (104) have been prepared readily via extrusion of COS from the corresponding xanthates (103). Cross-over experiments have indicated that the reaction probably proceeds intermolecularly via ion pairs than via an energetically unfavourable [3,3]-sigmatropic route. 179 ,R'

R' C'

R : H

SCHEME 34

A selenoaldehyde, a selenoketone, and telluroaldehydes have all been generated18' by the [3,3]-sigmatropic rearrangement of ally1 alkenyl selenides and tellurides, respectively.

15 Molecular Rearrangements

47 1

Cope and related rearrangements

IGLO computations have revealed'" the aromatic character of the transition structures for the Cope rearrangement of hexa-1,5-diene and, in addition, high-level ab initio calculations have favoured a synchronous, concerted mechanism via intermediates not having significant diradicaloid character for the rearrangement. Moreover, a reinvestigation' 82 of the Cope rearrangement using multi-reference perturbation theory has shown that the Dewar-type diradicaloid stable intermediate does not occur as a minimum in the potential surface and that the aromatic transition state moves to shorter bond lengths. Evidence for competitive and diradical processes has been obtained'83 during the rearrangement of the Diels-Alder adducts of cyclic 1,3-dienes to norbornadienes [see (105) -+ (106)l. An ab initio study of the use of kinetic isotope effects as a guide to transition state geometries for the Cope rearrangement has been ~ n d e r t a k e n , 'and ~ ~ Hine's D values (the double-bond-stabilizing abilities of diverse groups) have been shown to have a semi-quantitative predictive value in determining the position of equilibrium in Cope rearrangement^.'^^ An ab initio MO study'86 has been made on the thermal rearrangements of bicyclo[5.1.O]octa-2,4-dieneand its 8-oxa, 6-oxa and 6,8-dioxa derivatives and an oxa-Cope rearrangement route has been reported' 87 as a competitive alternative to previously published sphingosine syntheses. Semiempirical AM1 SCF MO calculations have shown188that the activation energy for the degenerate Cope rearrangement of hypostrophene is greater than that for comparable rearrangements of bullvalene, barbaralane, and semibullvalene, while a systematic search has been made for substituted semibullvalenes that can provide suitable substrates for a laser pulse-mediated Cope r e a ~ ~ a n g e m e n t. ' ~ ~

The application of [3,3]-sigmatropy to the enantioselective synthesis of natural products containing bridgehead unsaturation has been re~iewed.'~'The [3,3]-Cope rearrangement of the pheromone (107) of the marine brown alga Ectocurpus siliculosus to cyclophepta-1,4-diene (108) has been established'" as the fastest known reaction for the spontaneous inactivation of a pheromone, and it has been shown that cyclohexa-2,4dienones behave as the 4n component during their pericyclic reaction with cyclohexa-

472

Organic Reaction Mechanisms 1995

1,3-diene and cycloheptatriene. The adducts of these additions have been isolated and their Cope rearrangements studied.192 Treatment of 2-allyl-1,2-dihydroindo1-3-ones (109) with phosphorus ylides has afforded 3-indole acetates (110) in good yields by a tandem Wittig reaction and an aromatization-induced Cope rearrangement.'93 The first oxy-Cope rearrangement involving the endocyclic double bond in a 7oxanorbomenic system has been d e ~ c r i b e d . An ' ~ ~anionic oxy-Cope rearrangement of (111) has been developed'95 (Scheme 35) to produce enantiomerically pure keto ester (112), which has been structurally modified to yield a 1 : 1 mixture of (-)-vulgarolide and its anomer, while the anionic oxy-Cope rearrangement of bicyclo[2.2.2]octadienols has served'96 as a key step for the construction of substituted bicyclo[5.3.1]undecenones, thus providing a novel entry to the AB ring system of the taxane diterpenes (Scheme 36). A tandem oxy-Cope-transannular ring-closure route to polyquinanes (Scheme 37) has been described,197and the diastereoselective synthesis of cis-l,2dialkenylcyclopropanols (1 13), and their subsequent oxy-Cope rearrangement, has provided'98 stereoselective syntheses of fused bicyclic compounds, such as bicyc10[5.4.0]undecanes,which have several sites for further structural elaboration (Scheme 38). Ab initio calculations have indicated199that the anionic aza-Cope rearrangement of the l-azahexa-l,5-dienyl anion (114) to the 3-azahexa-l,5-dienyl anion (115) probably proceeds by an exothermic, stepwise process with a relatively low activation energy. The 3-aza-Cope rearrangement has been identified*'' as a convenient route to higher branched aliphatic aldehydes from telomers of isoprene with secondary amines. A tandem imine-enamine equilibrium-3-aza-Cope-Mannich reaction (Scheme 39) has been explored2" to assemble chiral 4-hydroxy-4-alkylcyclopentenones,and a novel

473

15 Molecular Rearrangements

L

OSEM

L

(111)

OSEM

0-

J

SEM = trimethylsilyl enol ether

SEMO

w\

Me

Me

-

Me

‘0-

R Me

OH

W = H, OR, SR SCHEME 36

synthetic approach to carbapenems utilizing an aza-Cope-Mannich cyclization has been described202(Scheme 40). The zinc chloride-promoted 3-aza-Cope rearrangement of benzoyl-substituted heterocyclic ketene aminals has been reported203(Scheme 4 l), and a new synthesis of desoxyeseroline, which involves the [3,3]-sigmatropic rearrangement of bis(enamine) (116) into the suitable precursor (117), has been

474

Organic Reaction Mechanisms 1995

-

TM so

I7

0-

TMSO

c--

H

OH

SCHEME 37

Me

475

15 Molecular Rearrangements

1

aza-Copc

SCHEME 39

+ BuTvle2SiO

Bu'MeISiO

M % e7

-C1-

___)

OSiMezBu'

OSiMezBu'

C02Me

Bu'MezSiO CHO

C02Me

-

C02Me

me^ ~7

Bu'Me2SiO

OSiMe2Bu'

C02Me

SCHEME 40

presented.204Variable-temperatureNMR spectroscopy and X-ray crystallography have been employed205to study the stereochemistry of 2-cyano-3,3-dimethyl-l-phenylpyrazolidin-5-one (118) which thermally rearranges to 2,3-dihydro-2,2-dimethylpyrimido[] ,2-a]benzimidazol-4(lH)-one (1 19). An ab initio investigation of the phospha-Cope rearrangement converting 1,6diphosphahexa-1,S-diene into 3,4-diphosphahexa-1,S-diene, has been undertaken,2°6 and the use of the [3,3]-sigmatropic selenocyanate to isoselenocyanate rearrangement has led to the first synthesis of vinyl isoselen~cyanates~~~ [see (120) + (121)l.

Organic Reaction Mechanisms 1995

476

ZnCll

-ZnC12

SCHEME 41

NCSe\

-

[2,3]-Migrations

A method for determining Huckel-Hubbard parameters has been extended to analyse the stereochemistry of [2,3]-sigmatropic rearrangements,208 and a review which outlines the synthetic scope, stereochemistry, and mechanistic aspects of the [2,3]Wittig rearrangements has appeared.209A [2,3]-Wittig rearrangement using glucose as a chiral auxiliary has been reported,210 an asymmetric [2,3]-Wittig approach to the formal synthesis of (+)-brefeldin-A has been published,21 and the [2,3]-Wittig rearrangement of the propargylic ether of B-( 1-alkoxymethyl)allyl alcohol has been found to proceed with a high degree of either 1,4-syn or 1,4-anti selection, depending on the choice of alkoxy group and solvent.212 The [2,3]-Wittig rearrangement of

’

15 Molecular Rearrangements

477

trimethylsilylpropargyl ethers of k a n o i d glycals derived from D-mannose and Lgulonic y-lactone has been used213to afford cis-2,5-disubstituted dihydrofurans with predominant etythro selectivity, while the Wittig rearrangement of 3-furylmethyl ethers (122) has been found to proceed efficiently to yield either 3-methyl-2-furylmethanols (123) or 3-furylethanols (124), depending on the basicity of the butyllithium used.’I4 Ally1 alcohols (126), prepared by addition of lithium vinylcuprates to (R)-2,3-0isopropylideneglyceraldehyde (125) have been converted into 3,4,5-trimethoxybenzyl ethers (127) by a one-pot desilylation-alkylation. After deprotonation, these benzyl ethers have been observed215to undergo a [2,3]-sigmatropic Wittig rearrangement with complete 1,3-chirality transfer and good diastereoselectivity to afford homoallyl alcohols (128). The diastereoselective [2,3]-Wittig rearrangement of the oxazoline ether of a bis(ally1ic) tertiary alcohol has been described,216and the strategy successfully and other used2I7 to synthesize (2E,4E)-4,6,10,12-tetramethyltrideca-2,4-dien-7-one closely related analogues which serve as sex pheromone components of female Matsucoccus pine scales. Compounds containing a CF2 group in mid-chain have been obtained’l8 from the [2,3]-sigmatropic rearrangement of 3,3-difluoro-2-alkylalken-lols, and a-hydroxy-y-amino acids having y-turn conformational features have been produced2I9by a stereoselective [2,3]-Wittig rearrangement of enantiomerically pure 4aminoallyloxyacetates. The diastereoselective and enantioselective synthesis of Bsubstituted y,h-unsaturated a-hydroxy ketones has been accomplished via the [2,3]Wittig rearrangement of a-allyloxy ketone hydrazones:20 and this methodology has been extended2” to the synthesis of ( - )-oudemansin starting from crotyloxyacetaldehyde hydrazone. The reaction of singlet carbene with 2-methylbut-3-en-2-01 has been found to lead to several products, including 4-methylpent-3-en-1-01, whose formation has been explained”’ as the result of the [2,3]-sigmatropic rearrangement of an ylide intermediate (Scheme 42). A variety of substituted benzocyclopentenones have been synthesized by the rhodium(I1)-catalysed reaction of a-diazo ketones bearing tethered alkyne units. The results obtained in all cases have pointed to a mechanism which involves addition of the rhodium-stabilized keto-carbenoid to the acetylenic n-bond to give a new rearranged vinyl-carbenoid. In the case223where an ether oxygen is present on the backbone of the vinyl-carbenoid, the resulting oxonium ylide (129) undergoes a [2,3]-shift to give the rearranged product (130) (Scheme 43).

Sigmatropic rearrangements of sulfur and nitrogen allylic ylides have been studied by ab initio method^."^ The first example of an acyclic aza-[2,3]-Wittig rearrangement has been presented, and its application to the synthesis of unnatural amino acids has been described225(Scheme 44). N-Alkylation of a series of 2-ketoaziridines, followed

Organic Reaction Mechanisms I995

478 0

4

OH

H

R

+

MeA Me -0

Me

?Me

OMe

a

Me

Me

d 0 ’

MeAMe -0

SCHEME 42

0

(129) SCHEME 43

R

479

15 Molecular Rearrangements

by Wittig olefination, has generated intermediate vinylaziridines which have been found to rearrange by an aza-[2,3]-Wittig process to create a new carbon-carbon bond with concomitant ring opening of the aziridine, thus affording unsaturated p i p e r i d i n e ~ , ~ ~ ~ ' ~ ~ ' of indolizidines and indeed, the key step in the recently r e p ~ r t e d ~total ~ ' , ~syntheses ~~ 209B and 209D has involved just such as aza-[2,3]-Wittig rearrangement of vinylaziridines to tetrahydropyridines (Scheme 45). Gawley et al.230have established that both [2,3]-anionic and ylide rearrangements of unstabilized a-lithio-mines occur with inversion of configuration at the metal-bearing carbon and that [1,2]- and [2,3]mechanisms compete in the aza-Wittig rearrangement. Ammonium benzylides generated from salts (131; R = H, Cl), have been shown23' to undergo, in addition to the expected [2,3]-reamgement, a new [1,4]-rearrangement (Scheme 46), while trans2-methyl-3-(substituted-phenyl)-1,2,3,4-tetrahydroisoquinolinium2-methylides have been to undergo predominantly a [2,3]-sigmatropic rearrangement. With the cis-ylides, an intramolecular Hofinann degradation was the single pathway. An efficient enantioselective synthesis of the azabicyclo[6.3.O]undecane (133) from (9prolinol has been described.233The key step in the route to (133) was the intramolecular generation and rearrangement of the spiro-fused bicyclic ylide (132) from a copper carbenoid.

4"Ph

Ph

I

BbC

BbC

SCHEME 44

\/Me SCHEME 45

480

Organic Reaction Mechanisms 1995

1

CN I

CN I

SCHEME 46

The effectiveness of ab initio calculations in the elucidation of reaction paths and solvent effects on the [2,3]-sigmatropicrearrangement of allylic sulfoxides to sulfenates has been determined,234and this study has been extended235to investigate the origin of the observed control of olefin geometry by analysing the constituent interactions in the alternative transition structures for the rearrangement. (4-y-Hydroxy sulfoxides (136) have been prepared236 in good yield from simple aldehydes (134) and chiral bis(su1foxide) (135) in a one-pot procedure based on a Knoevenagel condensation, subsequent prototropic shift and [2,3]-sigmatropic sulfoxide-sulfenate rearrangement (Scheme 47). Sulfenic acid (138), obtained on thermolysis of thiosulfinic S-ester (137), has been found to afford 1,3-oxathiolane S-oxide (139) by a process which can be regarded as a 'reverse' [2,3]-sigmatropic rearrangement.237Pyne and co-workers238~23y have shown that allylic sulfoximines (140) undergo a novel and efficient Pd(0)catalysed allylic sulfoxide to allylic sulfinamide rearrangement, (140) +.(141), but ab initio calculations on the [2,3]-sigmatropic shift of allylic sulfoximines and sulfilimines have indicated240that a substantial kinetic barrier exists for the former relative to the

(-"-

Tol.,

R1

+

)-CHO

R2

2-O

R1

R2 J - k O T O l

To1

(134)

(135)

0

(136)

SOTol

0

SCHEME 47

48 1

15 Molecular Rearrangements

R+ TsN-s, I/

0

Ph

-

R-

SOPh NTs I

latter. It has been shown that the chiral rhenium Lewis acid [$-CpRe(NO)(PPh,)]+ can serve as a readily recycled auxiliary for the conversion of achiral symmetrical diallyl and dipropargyl sulfides into chiral rearranged sulfides of high enantiomeric purity. In particular, alkoxide bases have been used to deprotonate the cationic adducts to sulfur ylides which undergo rapid [2,3]-sigmatropic bond shifts at - 80 0C241(Scheme 48). Rhodium(I1) acetate-catalysed cyclization of methyl 2-diazo-5-[2-methoxy-5(2-phenylsulfanylethylidene)tetrahydro-2Hpyran-4-yl]-3-oxopentanoatehas been shown242to proceed through the [2,3]-sigmatropic rearrangement of a nine-membered cyclic ally1 sulfonium ylide, to afford a cis-2-oxa-9-vinyldecalin derivative, the basic AB ring skeleton of vernolepin, and highly substituted cyclohexanones such as (142) have been prepared in a similar m a r ~ n e ?as ~ ~shown in Scheme 49. Sommelet-Hauser products have been established244as the sole products obtained from the rearrangement of S-methylbenzylsulfonium S-alkylides in non-basic media, while Sommelet-Hauser and Stevens products were obtained from the rearrangement of 1-phenyl-3,4-dihydro1H-2-benzothiopyranium2 - m e t h ~ l i d e sNovel . ~ ~ ~ chiral ferrocenyl selenides have been prepared and shown to be good reagents for the asymmetric synthesis of c h i d allylic alcohols by [2,3]-sigmatropic rearrangement of the corresponding ~ e l e n o x i d e s ~ ~ ~ (Scheme 50), and an asymmetric [2,3]-sigmatropic rearrangement of the chiral cinnamyl(ferroceny1)selenimide (143) to produce the corresponding optically active allylic amine (144) with high enantioselectivity has been accomplished.247Similarly, when the chiral ferrocenyl telluride (145) was treated with an imination agent under various conditions, the chiral amine was isolated with even higher enantio~electivity.~~~ This observation was in sharp contrast to the result of [2,3]-sigmatropic rearrangement of chiral allylic ferrocenyl telluroxides where the formation of allylic alcohols of only low enantioselectivities was observed.249The first reported example of enantioselective carbenoid addition to chalcogen atoms of prochiral organic chalcogenides, and the

482

Organic Reaction Mechanisms 1995

R2 SCHEME 48

0

R' R'

R402c*R2

SCHEME 49

F

S

e

F

\\0f

- @(==

OSeFc*

--Q6

SCHEME 50

chirality transfer from the resulting chiral chalcogen ylide via [2,3]-sigmatropic rearrangement has provided250a new methodology for carbon-carbon bond formation with chiral induction at both carbon centres (Scheme 51). C02Et

N=N=C,

/

H

ML*

M = Cu, Rh

*LM=C,

CO2Et

/

H

Ph-f+ph P-CO2Et

PhY-(!i!--COzEt I H

I H

SCHEME 51

15 Molecular Rearrangements

483

The [2,3]-Wittig sigmatropic rearrangement of distannyl- and silylstannyl-substituted diallyl ethers has been achieved25' using LDA; in certain cases252the rearrangement was found to be followed by a spontaneous anionic oxy-Cope rearrangement. The stereoselective synthesis of y,d-unsaturated a-hydroxyphosphonates via the [2,3]-Wittig sigmatropic rearrangement of a-allyloxyphosphonates has been reported,253and the facile and highly stereoselective [2,3]-Wittig rearrangements of chirally-modified phosphorus-stabilized anions have been An in-depth of the mechanism of the p-(phosphat0xy)alkyl radical migration has shown that phosphoranyl radicals are not intermediates in this rearrangement. The study has shown that the migration is intramolecular and proceeds through competing [ 1,2]- and [2,3]-pathways, and does not involve fragmentation to a cage pair followed by recombination.

CH2CHO (146)

X=0,5

SCHEME 52

[I, 31-Migrations An ab initio study has been made of the allene effect in [ 1,n]-sigmatropic hydrogen

shifts.257Although benzyl and naphthylmethyl vinyl ethers have been found to be inert to lithium perchlorate in diethyl ether, hetero-aromatic methyl vinyl ethers, such as 2fury1 and 2-thienylmethyl vinyl ethers (146), have been found to undergo formal [ 1,3]rearrangement in that medium258(Scheme 52). The electron-transfer photochemistry of vinylcyclopropane systems (147) and (148) has been found to proceed via strainreleasing reactions of their radical cations. These rearrangements have been described259 as sigmatropic shifts with inversion of configuration at the carbon receiving the migrating hydrogen. The energetics of the [ 1,3]-hydrogen shift in formyland diformyl-phosphine have been determined260by ab initio methods, and secondary alkyl(cl-ethoxyethenyl)phosphines, prepared by the palladium-catalysed cross-coupling of alkyl(trimethy1silyl)phosphines with (a-bromoetheny1)ethyl ethers, have presented the first example of compounds which undergo a reversible intramolecular [ 1,3]-shift of hydrogen in a phosphorus-carbon-carbon triad.261

Me

(147)

484

Organic Reaction Mechanisms 1995

A facile [1,3]-shifl of a methoxy group has been shown261 to interconvert imidoylketene (149) and ketenimine (150), and the first direct evidence for the vinylketene-acylallene rearrangement, ( E l ) $ (152), using alkoxy- and (dialkylamino)vinylketene precursors and the corresponding allenecarboxylic acid derivatives, has been reported.263Direct dynamics calculations have been carried out on the formal [1,3]-sigmatropic migration that interconverts bicyclo[3.2.0]hept-2-ene and norbornene, and these calculations264have shown that the transformation occurs with a preference for inversion of configuration at the migrating carbon. A stereochemical analysis of the fragmentation of 2-oxabicyclo[3.2.O]hepteneto furan and ethene has led to the conclusion265that a sigmatropic [ 1,3]-carbon shiR proceeding with inversion of the migrating carbon, followed by a stereospecific retro Diels-Alder reaction, is the major pathway for this reaction. Direct photolysis of 1-methyl-1-silabicyclo[2.2.llhept2-ene (153) in alcohols has resulted266in the [1,3]-migration of C(7) to produce 3alkoxy-3-methyl-3-silabicyclo[4.1 .O]heptanes (154). The thermal isomerization of cycloocta[dlpyridazine (155) in non-polar solvents to the barreleno[dJpyridazine (156) has been explained267by invoking a formal [1,3]-carbon migration. A kinetic study of the thermal rearrangement of 2-(trifluoromethy1)-1-vinylcyclopropane to 3and 4-(trifluoromethyl)cyclopentenes has been undertaken.268A theoretical study of the photochemical behaviour of vinylcyclopropanes has indicated269that the photorearrangement to cyclopentenes is completely stereospecific and proceeds via a concerted process. On the other hand, a recent ~ a p e ? ~has ' shown that the thermal isomerization of (1S,2R)-l-(E-styryl)-2-phenylcyclopropaneto 3,4-diphenylcyclopentenes can be viewed as processes passing though alternative kinetically competitive diradical transition structures, rather than controlled by orbital-symmetry considerations. The allylidenecyclopropane to methylenecyclopentene thermal isomerization has

485

I5 Molecular Rearrangements

I

CF3

(155)

phneMe Ph

_._t

Ph/

'Ph

Ph

Ph

SCHEME 53

been subjected to a detailed theoretical e~amination,~~' and it has been concluded272 from a study of the direct photochemistry of 1-anisyl-2-phenyl-3-methyl-3-isobutenylcyclopropene that bond b scission operates to a greater extent in the reaction mechanism than formation of bond a (Scheme 53). The activation barrier for the [1,3]phosphorus migration in 1,3,5-triphosphabicycIo[2.1.O]pent-2-ene has been estimated273as being considerably smaller than the barrier for [ 1,3]-carbon migration of the corresponding hydrocarbon. It has been shown that the intramolecular photochemical reaction of 0-alkenyl thiocarbamates yields photo-products in which the photo-processes are defined by the length of the carbon chain between the oxygen and the alkenyl group attached to the thiocarbamate. Photolysis of 0-allylthiocarbamates which have one carbon between the oxygen and the alkenyl group was found to promote a concerted [ 1,3]-allyl migration leading to S-allylthio~arbamates~~~ (Scheme 54). It has been suggested275that the photochemical [1,3]-stannyl migration of 3-aryl-substituted allyltins, (157)s (158), involves photo-excitation of the cinnamyl 7c system and proceeds intramolecularly via an orbital-symmetry-allowed concerted [ 1,3]-sigmatropic mechanism as has been proposed in germyl migration. A new silene-to-silene thermal rearrangement, which involves the [1,3]-shifts Me3% and Me3Si0 groups that are attached to the siliconcarbon double bond of silenes, has been observed.276

486

Organic Reaction Mechanisms 1995 R'

R2

SCHEME54

[I, 51-Migrations The involvement of a [ 1,5]-sigmatropic shift via [ 1,5,] geometry from a higher excited state has been invoked277to explain the photo-cyclization of an o-alkenylbenzaldehyde (159) to a benzocyclobutenone (160) (Scheme 55). [ 1,5]-Hydrogen shift products (162) and (163) were obtained in addition to the usual fragmentation product when 7-ethyl-7methylbicyclo[3.2.0]hept-2-ene (161) was subjected to gas-phase pyrolysis.278An investigation of substituent effects in the homodienyl[ 1,5]-hydrogen shift in vinylaziridines [see proposed transition state (164)] has shown that the rearrangement is affected by substituents at both the rearrangement origin and terminus.279 A theoretical study of the cyclization of a-iminothioaldehydes to dihydrothiazoles has been undertaken.28oa-Oxy- and a-thio-substitutedradicals, e.g. (165), derived from the [ 1,5]-shift of samarium diiodide-generated vinyl radicals,28' have been hrther rearranged to alcohols and thiols through a Wittig rearrangement (Scheme 56). It has been suggested282that the iron(II1)-mediated rearrangement of 1,2,4-trioxanes (166) to 1,2-diol mono-esters (168) involves reduction of (166) to an oxyl radical (167) followed

487

I 5 Molecular Rearrangements 0

&Ph \

c//o U \

Ph

\P

Phh

\

Ph

(159)

SCHEME 5.5

x=o,s

J XH

SCHEME 56

R Fe3+

Me Me

Me

(165)

Me Me

R

-

___)

Me Me

Me Me

by a [1,5)-hydrogen-transfer sequence similar to that implicated in the molecular mechanism of action of the antimalarial artemsinin. Miscellaneous

It has been that the thermal rearrangement of enantio-enriched a-ally1 and atrimethylsilylpropargyl a-hydroxyimines (169) proceeds with a complete 1,2-transfer of chirality. Moreover, the [1,2]-shift was shown to be suprafacial and to proceed with inversion of configuration. The synthetic value of the rearrangement has been highlighted284by its use in the synthesis of (170), an advanced intermediate in the synthesis of (- )-perhydrohistrionicotoxin. The formation of the hydantoin biotransformation product (172) of alosetron (171) has been shown285to proceed via a [1,2]migration of the tricyclic lactam moiety which occurs with retention of both hydrogens in the C(7’)-methylene group. The thermal rearrangement of endoperoxide (173) to

Organic Reaction Mechanisms 1995

488

OMe

I

(169) R = CH2CH=CH2, CH2C=CSiMe3

Me

(174) and (175) has provided286an example of a bicyclic endoperoxide leading to the direct formation of an enedione system by consecutive carbon-carbon cleavage and [ 1,2]-hydrogen (or [1,2]-alkyl) migration. An I80-labelling study287 of the 8(nitroxy)alkyl and 0-(trifluoroacetoxy)alkyl radical migrations has shown that these migrations OCCUT to a greater extent through the [1,2]-shift pathway as opposed to a [2,3]-shiR mechanism. The thermal isomerization of olefins to carbenes via a [ 1,2]-silyl shift (Scheme 57) has been examined both by experiment and by theory.288The study

Me&*,'

0-y Ph

-

Me@ Ph

+

Me

.,oT

.,%"

'2

0

Ph'

0

15 Molecular Rearrangements

489

- 3

MqSi?I

Me2Si

SCHEME 57 R' H-} 0

b@

R40 R3 (176)

J

SCHEME 58

has shown that, for silyl migration, the transition state was late and was actually the carbene, whereas for carbon migration, the transition state was early and considerably higher in energy than the resulting carbene. Lithioalkynyltriorganoborates(177) derived from propargylic acetals (176) have been found to rearrange in the presence of BC13, to homopropargylic alcohols (180) free of the corresponding allenic isomers. From a mechanistic point of view, these results have been explainedzE9by the intermediate formation of an allenylboron compound (178) as shown in Scheme 58, where the ate complex (177) has rearranged in the presence of BC13 with one R group migrating from boron to the adjacent carbon with concomitant elimination of the complexed acetal moiety. Addition of the carbonyl species (179) to the allenylborane affords, after oxidation via a usual allylboration type reaction, the alcohol (180). Kocienski and cow o r k e r ~have ~ ~ ~demonstrated the value of the Cu(1)-mediated [ 1,2]-metallate rearrangement for the connective and stereoselective synthesis of alkenyl metals from a-heteroalkenyllithiums and alkyllithiums and utilized this methodology for the syntheses of the C( 16)-C(23) fragment of FK-506, ja~pamide,~"and (3R,4R)l~ffariolide.~~~ Ab initio and semiempirical MO theory has been usedz937z94 to explore the ion-pair and lithium-catalysedpathways in the Stevens rearrangement of alkylammoniumylides to amines. In every case studied, the stepwise free-radical pathway was predicted to be the favoured mechanism for the rearrangement. Enantio-pure 1,3,4,6,11,11a-hexahydro[1,4]0xazino[4,3-b]isoquinolines have been prepared295by a cyclization rearrangement of L-serine-derived diazo esters. 2-Phenylhexahydroazeto[1',2', 1,2lpyrido[3,4-b]

490

Organic Reaction Mechanisms 1995

indoles, on oxidation with MCPA, have been observed to undergo ring expansion by a [1,2]-Meisenheimer rearrangement.296 The spin-orbit coupling components of the effective one-electron Hamiltonian operator, with the inclusion of symmetry, have been used to investigate the photochemical behaviour of the di-x-methane rearrangement in cyclic and acyclic non-conjugated systems.297The cyclopropanolactone (182) has been prepared298by the di-n-methane rearrangement of the 4-benzylfuran-2(5H)-one system (181).

In solution, 9,10-dihydro-9,1O-ethenoanthracene-11,12-bis(diphenylmethanol) (183) has been found to undergo a di-n-methane photo-rearrangement to (1134):~~whereas irradiation of its crystalline complexes led to a novel dehydration reaction to yield (185).

Several novel examples of the oxa-di-x-methane rearrangement in P,y-unsaturated aldehydes have been observed,300and a new photochemical synthesis of cyclopropanecarboxylic acids present in pyrethroids has been achieved3" by utilizing the aza-dix-methane rearrangement.

Electrocyclic Reactions It has been noted that diastereotopic protons have different kinetic isotope effects in a variety of concerted pericyclic reactions. Moreover, these differences follow a pattern that makes it possible to use the IN and OUT protons as probes for the properties of the transition states.302The transition structures for the disrotatory electrocyclizations of a variety of 1-substituted hexa-1,3,5-trienes have been located303using ab initio MO calculations, and appreciable electrostatic acceleration of the electrocyclization of hexa-

1.5 Molecular Rearrangements

49 1

1,3-cis-5-triene to cyclohexa-l,3-diene by Li+ complexation has been predicted at the theoretical level, and shown to occur e~perimentally.~'~ In addition to its described perk and regio-selectively, the electrocyclic ring closure of (8E,13E)-12-t-butyl-l1,7retroretinal has also been found to be torquo-selective, leading exclusively to the (1OE)-alkylidenecyclobutana1.305The experimental results have been explained by an ab initio study of transition structures. A kinetic study306has been made of the ring closure of unstabilized bis(ketenes) to cyclobutenediones, and at 200 "C the diepoxide (186) derived from perfluoro-3,4-dimethyl-2,4-dienehas been found to undergo an unprecedented rearrangement to the corresponding 1,4-dioxine derivative (187). This rearrangement can be described3" either as proceeding in a concerted manner or via radical intermediates (Scheme 59).

F3cHcF3 0

)*'

F

OFF CF3 CF3

SCHEME 59

The observed cyclization of 1-azatrienes,formed in situ by simply mixing the t-butylsubstituted cr,b-cis-dienal with a primary amine, represents a useful method for the preparation of 1,2-dihydropyridines.The reactivity profile and activation parameters for the cyclization have been determined308and the mechanism shown to correlate well with the classical concerted disrotatory mode of electrocyclizations. Deprotonation of 4-azahepta-1,3,6-trienes(188) using LDA has been found to yield 4-azaheptatrienyllithium compounds (189), which on warming to room temperature undergo a 1,7electro-cyclization309to afford 3-azacycloheptadienyllithium compounds (190). Subsequent treatment of (190) with various electrophiles has provided access to several substituted 4,5-dihydroazepines (191). The facility of N-aziridinyliminoureas (192) for the synthesis of 1,2,4-triazole-f%sedheterocycles (193) via electro-cyclizationshas been achieved3" under mild conditions, and an unusual electrocyclic transformation of the azabicyclo[7.3. llenediyne dynemicin core analogue (194) to (195) has been observed3" during treatment of (194) with excess bromine.

Organic Reaction Mechanisms 1995

492

E I

R

(191) 7

N/N

Me

Ph,P, CC14, Et,N

0

_____)

ANAN/R H

H

(192)

P OMe /

OMe

Br

15 Molecular Rearrangements

493

to investigate the Ab initio and force-field calculations have been carried torquo-selectivity of ring openings of cyclobutenes with substituents which sterically influence the selectivity, and a theoretical study has predicted3’ that electron donors have larger outward rotation preferences than electron acceptors in thermal ring openings of cyclobutenes. A number of unusual rearrangements of 4-alkyl-4hydroxycyclobutenones, in which the alkyl group bears a heteroatom at its 2-position, e.g. (196; X = heteroatom), have been reported. The authors3I4have envisaged that thermolysis of such compounds would result in stereospecific electrocyclic ring opening to the cis-vinylketene (197), followed by intramolecular attack of the heteroatom on the ketone moiety to give (198) which would lead directly to the macrocycle (199). A direct one-step conversion of diisopropyl squarate into unsaturated diquinanes has been uncovered315an4 as shown in Scheme 60, the route is thought to utilize two consecutive conrotatory processes, the first being 4n and the second 871. Similar successive electrocyclic rearrangements, initiated by the addition of a lithiated cyclopropenone acetal to a squarate ester, have been r e p ~ r t e dl 6. ~ Pentacyclo[6.5.0.043’2.05~’0.09~13]trideca-2,6-diene (200) has been observed to undergo asymmetry-forbidden thermal 2 2-cycloreversion of its cyclobutane ring to afford a cis,czsoid,cis-[2.2,l]tricyclic tetraene (201), which subsequently undergoes an intramolecular Diels-Alder cycloaddition to (202).3l7 The selectivity observed in rhodium(I1)catalysed rearrangements of cycloprop-2-ene-1- carboxylates has been accounted for3’ by a mechanism in which attack of the electrophilic Rh(I1) species is considered to be concerted with disrotatory ring opening of the incipient cyclopropyl cation. Thermal and silver ion-induced electrocyclic ring opening of cyclohexa-annulated [5.3.llpropellanes have provided3I9 ABC ring analogues of taxol, and 4-(trans-1,2-dicarbo-

+

OH

(199)

Organic Reaction Mechanisms I995

494

Me

H3C=C,

Li

0-

SCHEME 60

methoxy-2-iodoviny1)-5 -methyl-6,7-dicarbomethoxy-4,5-dihydrothieno[2,3-c]quinoline has been isolated32oas an unexpected 2 2-cycloaddition product from the reaction of 4-methyldithieno[3,4-b : 3’,2’-d]pyridinium iodide with 2 equiv. of dimethyl acetylenedicarboxylate. The thermal rearrangement of azulenes with dimethyl acetylenedicarboxylate in supercritical carbon dioxide has been studied.321The isomerization of 6(1,l -dimethylethoxy)-2H-pyran-3-oneto 4-( 1,l-dimethylethoxy)-5-hydroxycyclopent2-enone has been as a key step in the preparation of 2-bromo-5-[(1,1dimethylethyl)dimethylsiloxy]-4-hydroxycyclopent-2-enone, a potential intermediate for the synthesis of neocarzinostatin and kedarcidin chromophores. In addition to normal electrocyclic B-ring opening, la-hydroxyprovitaminD (203)has been found to undergo a new photochemical isomerization cascade initiated by I, 10-bond cleavage. This new isomerization, which becomes the major pathway when a methyl group is present in the lp-position, has been proposed323 to involve a 6n photochemical conrotatory electrocyclic reaction, (204) + (205), and a typical intramolecular photochemical n4s xza cycloaddition, (205) -+ (206). A comparative study has been made324on the energetics and mechanism of the ene reaction. The ene reaction of maleimide and 1-alkenes has been studied by both semiempirical and ab initio methods, and the information obtained has aided the

+

+

495

15 Molecular Rearrangements Me..,,,,

R30

X

synthesis of suitable transition-state analogues with the ultimate purpose of generating an antibody against the transition state.325The regioselectivity of the ene dimerization of 8-chlorobicyclo[5.1.O]oct-l(8)-ene has been described.326The singlet oxygen ene reaction of chiral cyclohexadienes has been shown to proceed with high regio- and diastereo-selectivity through control by a combination of electronic and steric interactions.327 On photo-oxygenation, aryl vinyl sulfides (207), with powerful electron-accepting substituents in the para-position, have been found to undergo predominantly:28 the ene reaction to (208). An unusual acid-catalysed rearrangement of cyclodecene-1,4-diones such as (209) to five-membered spiro-y-lactones (210) has been cla~sified~~' as an ene-type process, and the stereoselective formation of six carbon-carbon bonds and four rings in a one-pot cascade ene-type 2 + 2 + 2 then 4 + 2sequence has been achieved330from an acyclic polyunsaturated precursor bearing three uncontrolled centres, using a cobalt(1) catalyst. The discovery of an effective metallo+me-allene reaction from polysubstituted e n y n e ~ ~has ~ ' represented a new and promising way to generate polysubstituted cyclopentylmethylzinc derivatives under mild cyclization conditions, while the

Organic Reaction Mechanisms 1995

496

synthesis of polysubstituted tetrahydrofurans has been made available by a new zincene-allene reaction.332 Details of inter- and intra-molecular imino ene reactions involving N-alkyl, N-acyl, and N-sulfonyl imines or iminium ions have been presented333with particular emphasis on the regio- and stereo-chemical issues accompanying these processes. The same group334 has developed a synthesis of (-)-papuamine by utilizing a novel but apparently general type imino ene reaction of allenylsilanes (Scheme 6 l), while further studies on novel intramolecular ene reactions of allenylsilanes have been reported.335 A kinetic study336of the thermal isomerization of gaseous cis-cyclooctene has indicated that the formation of octa-1,7-diene in the reaction probably proceeds by a concerted retro-ene pathway. Formation of 5-aryl-4-methylhex-5-en-2-ones(214) by heating 4-aryl-4-methylhex-5-en-2-ones (21 1) in acid has been explained337by the route depicted in Scheme 62, where an intramolecular ene reaction of the enol tautomer H

-

1. PhCHZNH2 2. SnC14

H

NHCHZPh

I

phc SiMezPh

SiMezPh SCHEME 61

497

15 Molecular Rearrangements

oMe A Mer

ArMe

G

M

e

Me Me Ar

SCHEME 62

(2 12) provides acetylcyclopropanes (213) which undergo a retro-ene reaction to furnish the rearranged enone. A similar rearrangement has been extended to a formal synthesis of B-cuparenone. The exploitation of a retro-ene reaction of alkynylsulfinic acids (216), generated by aluminium amalgam reduction of alkynyl P-keto sulfones (215), has provided338 a simple, high-yielding, and versatile mode for the synthesis of trisubstituted allenes (217). Labelled allylsulfinic acids have been observed to undergo spontaneous decomposition with y-syn deuterium a fact that is consistent with a concerted retro-ene mechanism for the process (Scheme 63). It has been shown340 that benzothiophenethiol and benzofuranthiol (218; X = S and 0, respectively), react under non-radical conditions with electron-rich alkenes to yield

R’

so

:’3 0-

5

0-

5

H /

0 II

o//s Me

SCHEME 63

498

Organic Reaction Mechanisms 1995

Me

Ph

I

I

SCHEME 64

products derived from a retro-hetero-ene reaction in which the aromatic thiols behave as the hetero-ene reagent (Scheme 64).

Anionic Rearrangements The various rearrangements of ethyl, ethenyl, and ethynyl anions, as well as the stabilities of these anions towards spontaneous electron loss, has been studied at the Gaussian-2 The isomerization of [(3-t-butyl-l -bicycle[ 1.1.l]pentyl)methyl]lithium (219) to 4-t-butyl-2-methylidene-4-pentenyllithium (221) via [(l-t-butyl-3methylidenecyclobutyl)methyl]lithium (220) has been found to involve a very rapid initial ring opening of (219) to (220) followed by a slow isomerization of (220) to (221).342A study has been made 343 of the solvent dependence of enantioselectivity for the base-catalysed prototropic rearrangement of 1-methylindene to 3-methylindene, and a general method for the catalytic asymmetric synthesis of chiral amines via a 1,3proton transfer reaction of imines has been d e v e l ~ p e dA. ~theoretical ~ study of the rearrangement of ketenimine to acetonitrile has predicted345that the rate-determining step in the rearrangement is the 1,2-hydrogen transfer of the imine hydrogen to the adjacent carbon to produce vinylnitrene. The base-catalysed rearrangement of 0propargyl ketoximes (222) to N-( 1 -alkenyl)acrylamides (225) has been visualized346to proceed as shown in Scheme 65, where the key step is the rearrangement of the intermediate allenyl carbanion (223) to enolate (224), which then predictably transforms into N-( I-alkeny1)acrylamide (225). BF3-complexed N-allyl- and N-

499

15 Molecular Rearrangements

R21Nx/ R'

H

(225) SCHEME 65

benzyl-tetrahydroisoquinolines have been found to react with s-BuLi in an anionic rearrangement to afford 1-substituted tetrahydroisoq~inolines,~~~ and a PotierPolonovski rearrangement sequence has been to establish the carbamoyl enamine structure of the naturally occurring sulfonamide ( - )-altemicidin. Intramolecular nucleophilic attack at the ct-carbon of cyclopropanone Favorskii intermediates by enolate anions has provided a novel, flexible entry to hnctionalized tri- and tetra-cyclic systems.349The Favorskii rearrangement of 3-bromo-4-0x0-1-0xyl2,2,6,6-tetramethylpiperidinehas been used3" as a convenient route to esters of 1-0xyl2,2,5,5-tetramethylpyrrolidine-3-carboxylicacid, and a study of the Favorskii radical has been rearrangement of 3-bromo-4-oxo-2,2,6,6-tetramethylpiperidin-l-oxyl described.351The latter reaction has resulted in a viable alternative method for the direct synthesis of saturated pyrrolidine derivatives. A total synthesis of hinesol and agarospirol via a retro-benzilic acid rearrangement has been reported.3523353 Trapping experiments have shown3s4 that anionic ring opening of the C( 1)-C(2) bond in benzylidenebenzocyclobuten-ols and -ones can best be explained as occurring Me

% -Br\

R@-Me

Ye

\

- R&xMe \

SCHEME 66

/ j

500

Organic Reaction Mechanisms 1995

via carbon-carbon cleavage resulting in vinyl anions, rather than via oxyanionpromoted electrocyclic ring opening to an alkoxy o-quinodimethane. A plausible reaction mechanism has been proposed355for the electrolytic reduction of 2-( 1-bromo1-methylethyl)benzohans to 2,2-dimethylchromenes (Scheme 66), while metallation of cyclic carbamate (226) has been found to lead to a 3-hydroxytetrahydroh (227) via a metallation-ring-opening sequence356(Scheme 67). cr-Ethylidenecycloalkanones have been reported to undergo ring enlargement to P-alkylidenecycloalkanoneswith

-

Cbm-0

n-BuLilTMEDA ClCONPr'2 Et3N

o m co

<

OMe

OMe (226) Cbm = CONPr'2

%

Pri2N(CO)0

j-4

Cbm-0

-0

SCHEME 67

SCHEME 68

OMe

50 1

15 Molecular Rearrangements

J

R: R2-Si-OL R2-Si-0 R:

\

R: R2-Si-0

R:

4

-d


/ \ SCHEME 69

high stereoselectivity upon treatment with trimethylstannyllithium-aldehyde equivalent-Lewis acid; the rearrangement has been represented357by the pathway outlined in Scheme 68. The mechanism of the potassium t-butoxide-induced rearrangement of 1,8,9,10,11,1 1-hexachloro-3~,6a-dihydroxytricyclo[6.2.1 .02’7]undeca-4,9-diene has been re-inve~tigated.~~~ The generality of the unusual Pd(0)-catalysed 1,2-silicon shift of silicon-substituted vinyloxiranes (228) to a-trialkylsilyl-B,y-unsaturated aldehydes has been investigated. The rearrangement appears to depend on the size of the trialkylsilyl group, and a number of the vinyl epoxides were found to yield the corresponding silyldienol ethers (229) resulting from a Brook rearrangement which involved an intramolecular 172-migrationof silicon from carbon to oxygen with elimination of palladium359(Scheme 69). The Brook rearrangement of 1,2-disilylated titanium-I,2-diolates (230) leading to the formation of C,O-disilylenol ethers (231) has been shown360to compete with the McMuny deoxygenation pathway to (232) (Scheme 70), while treatment of B-hydroxyacyldimethylphenylsiianeswith potassium fluoride in DMSO has been shown to afford 1,3-diols stereoselectivelyvia migration of the phenyl group from silicon and subsequent Brook rearrangement of the silyl group from carbon to oxygen36’ (Scheme 71). The formation of alkyl silyl mixed acetals (234) on treatment of benzoates or formates with t-butyldimethylsilyldibromomethyllithium has been explained362by invoking a 1,3-rearrangement of the silyl group from carbon to oxygen in the intermediate P-oxidosilane (233). New rearrangements of 2,3-epoxy-3(trialkylarylsily1)propan- 1-01s have been reported363 and include the conversion of silylepoxypropyl mesylates (235) with sodium iodide to give cyclopropane derivatives (237) as the result of a 1,3-migration of the triphenylsilyl group from carbon to oxygen followed by intramolecular displacement of the mesyloxy group [see (236)l. A strategy has been developed364whereby transmetallation of silyl ethers of stereochemically defined vinyl-, epoxy-, and cyclopropyl-stannanes undergo 1,Csilyl migration from carbon to oxygen to generate a variety of (a-vinyl-, epoxy-, and cyclopropyl-silanes,

502

-

R'C02R2

Bu'Me2SiCBr2

I

Li

Organic Reaction Mechanisms 1995 R20 SiMe2Bu' L i O w B r R' Br (233)

\ E

R20, Bu'MezSiO H R'

B

r

cE+-

R20 Li B u t M e z S i O H B r R'

Br

Br

(234)

and hetero- and homo-bimetallic compounds which cannot be readily prepared using existing methodology. The first direct observation of the 1,3-migration of a silyl group from oxygen to carbon has been made365using NMR spectroscopy, and an anionic species such as (239) has been invoked366in the novel 1,3-0xygen to carbon migration of a silyl group M M I I R W S i M e 3 Me@

R

McMurry reaction

(230)

i

RHsiMe3

Me3Si

R

(232)

Brook rearrangement

M I

Me$i R + T i M CR3

-

R (231)

SCHEME 70

503

15 Molecular Rearrangements

SCHEME 71

accompanying the deacylation of (238) to (240). a-Chiral crotylsilanes have been prepared367by a retro-( 1,4)-Brook rearrangement, while facile access to specifically acylated aromatic systems has been achieved368by utilizing the procedure outlined in Scheme 72.

Benzyl carbanions with a dialkoxyphosphonyloxy substituent have been rearranged to optically active a-hydroxyphosphonatesby a process which is related to the Brook rearrangement.369Phosphonate-stabilized anions derived from a variety of cyclic p-

504

Organic Reaction Mechanisms 1995

@/

YSiMe' Bur- C -Li C5N

/

-0

0

But 0

0

SCHEME 72

ketophosphonates have been shown to react with dimethyl acetylenedicarboxylate to afford 4 2 ring-expansion products,370while intermediates arising from the addition of the lithium anion of dialkyl phosphites to acid chlorides have been found to produce rearranged tetraalkyl phosphonophosphatesin addition to tetraalkyl 1-hydroxybis(phosphonates).3 A novel base-catalysed rearrangement of 2,5-diaryl-1,Cdithiins to 1,4-dithiahlvenes has been reported,372and the synthesis of thiophenes starting fiom allenyl sulfones via intermediate formation of a,a-unsaturated sulfines has been described373(Scheme 73). Substituted hexa-l,3,5-trienes have been prepared in excellent yields and with good stereoselectivity from diallylic sulfones employing a modified Ramberg-Backlund reaction.374 A novel Ramberg-Backlund approach to the synthesis of 1-amino-4-

+

'

2

os*R j

R2

S02T0l-p

R2

R3

SCHEME 73

01-P

-

R ~ ~ s o 2 T o ~ + , R2

R'

505

15 Molecular Rearrangements

substituted cyclopentenes has been described375and applied to the synthesis of the trans isomer of the carbocyclic nucleoside carbovir and a decarboxylative RambergBacklund rearrangement has been observed376in some isopropylsulfonyl carboxylic esters. Enantiomerically enriched thiols have been prepared by rearrangement of racemic carbonodithioic 0,s-dialkyl esters catalysed by optically active pyridine-Noxides, followed by reaction of the resulting carbonodithioic S,S,-dialkyl esters with 2aminoethano~.~~~ Cationic and Related Rearrangements A review3" has appeared on ion pairs and ion-molecule pairs in solvolytic substitution, elimination and rearrangement reactions, and low-barrier isomerization processes in radical cations have been reviewed.379An ICAR programme for the elucidation of carbocationic rearrangement mechanisms has been described,380and potential control of carbocation rearrangements in the fitter reaction has been achieved.381 that primary (CH2X+) and secondary Ab initio MO calculations have (RCHX+) carbocations in which X = CHO, CHS, CONH2, and CSNH2, have a cyclic structure involving an oxiranyl or thiiranyl ring while, according to ab initio c a l ~ u l a t i o n s(241) ~ ~ ~ and (242) have been established as the more stable structures of the C2H21+cation. A theoretical study384has been made of the CI2Ht7ion potentialenergy surface in the 2,3-dimethy1-3-phenyl-2-butyl cation region, and theoretical and experimental evidence385has been obtained for unsymmetrical bridging in the cations derived from 2-t-cumyl-2-adamantanol and 2-isopropenyl-2-phenyladamantane in magic acid solution. H

\

c-C-I

/

'

H

(241)

A review on the reactivity of iron(II1) chloride in various reactions has included386its use in promoting the pinacol rearrangement. The solid-solid chemical reaction of benzopinacol with p-toluenesulfonic acid to give a quantitatively proton-catalysed pinacol rearrangement with the formation of triphenylacetophenone in the absence of solvent has been studied387using atomic force microscopy measurements and known crystal structure data. On treatment with thionyl chloride and pyridine, tertiary alcohols such as (243) have been found to yield octahydr~naphthalenes~~~ (244), and lithium triethylborohydride has been found to react with the triisopropylbenzenesulfonateester of 2-methoxy-5,5-dimethyl-2-vinylcyclohex-3-en-l-01 (245) to afford 8-methoxy-6,6dimethylspiro[2.5]oct-4-ene (246). Labelling studies389have revealed that this novel cyclopropane-forming reaction proceeds with retention of configuration at the newly formed quaternary centre. Reaction of a$-unsaturated esters with nitronium tetrafluoroborate has afforded products of skeletal cationic rearrangements, suggest-

Organic Reaction Mechanisms I995

506

ing390 the intermediacy of highly reactive a-carbonyl cations, and treatment of aethenyl-cr-phenylbenenemethanolwith iodine and silver acetate in either acetic acid or benzene has been found to yield 1,2-diphenyl-3-iodopropan1-one.391 An unusual neopentyl rearrangement has been observed392during the solvolysis of 5(l’,l’-dimethylethyl)-5-hydroxy-5~-lO-bromodibe~o[a,~cycloheptene. The acid-catalysed ring opening of tosylated and acylated t-butylaziridines (247) has been shown to generate carbocations (248) which rearrange by a neopentyl rearrangement to carbocations (249) from which the final products are derived.393 Both carvenone (251) and the P,y-unsaturated ketone (252) have been obtained394in high optical purity from the treatment of (+)-a-3,4-epoxycarane (250) with TMSOTf. It

R = Ph, CHzPh Z = Ts. COPh

Me

Me

I5 Molecular Rearrangements

507

has been discovered395that several compounds of the structure (253) rearrange to form (255) as the dominant products, in a reaction which is dependent on the configuration of the initially formed epoxide-opened cyclopropylcarbinyl cation intermediate (254). Iodination of selected 1-allyl(or 1-benzyl)cyclopropenes containing electron-donating groups has been reported to lead to 2-iodo-14odomethyl-1-vinyl or 1-arylcyclopropanes. It was proposed396 that the mechanism involves electrophilic addition to the cyclopropene n-bond and cyclization to a spiro-fused cyclopropylmethyl cation, followed by opening of the derived cation by halide. A facile method for the synthesis of highly functionalized seven-membered ring systems that uses readily available carbohydrates as stereospecific templates has been developed397(Scheme 74). The first example of asymmetric dihydroxylation of cyclopropylidene derivatives (256) followed by enantiospecific 1,2-rearrangementof the resultant diols (257) to give optically active cyclobutanones (258) has been reported,398and the methodology has been used in a formal total synthesis of ( - )-filiformin. Exploratory studies399on the photo-reactions of 1,l-diphenylspiropentanes have provided unprecedented examples of photochemically induced radical cation skeletal rearrangements of spiropentanes to methylenecyclobutanes. Cyclopropylacylsilanes (259) have been found to react with acid to afford the corresponding cyclobutanones (260) or 2-silyl-4,5-dihydrofuranderivatives (261) (Scheme 75), depending on the nature of the substituents on the three-membered ring and the acid used.400

The stereospecific ring contraction of bromohydrin (262) has afforded aldehyde (263) as the sole pr~duct.~'' A sequence for the synthesis of vicinally substituted cyclopentanones of the type (266) has been developed4" starting from acyclic ketones (264). The key step is thought to involve a stereospecific pinacol-type rearrangement of the cyclobutane ring embodied in oxabicyclo[3.2.0]heptanes (265) involving exclusive migration of the stereo-electronically disfavoured cyclobutane bond (Scheme 76). A similar methodology has been used to synthesize functionalized spiro[4.n] systems.403

508

Organic Reaction Mechanisms 1995

NaOH

0-

OH

(262)

(263)

1

Lewis acid

0

(25%

t

' Y S i M e 3

OH

OH

\

R

1 R

R 4 s i M e 3

+OH

OH

it

OH

R

0

509

15 Molecular Rearrangements

R'

OEt

0

SCHEME 76

A new sequence of cationic reactions that converts cyclic silyl acyloins and oalkynyl acetals into polycyclic enediones has been reported.404This new ring-enlarging annulation is outlined in Scheme 77. 2,3,4-Trisubstituted 4-hydroxycyclobut-2-enones have been found to undergo Lewis acid-facilitated ionization to cyclobutenyl cations which have been trapped by trialkylsilanes in a regioselective sense.4o5Thermolysis of the resulting cyclobutenones has afforded phenols in high yields. A new strategy based

o r b

+

TMSoHoTMs -

R'/R2

X

M

M = TMS or BF3

P-,-d R'

SCHEME 77

R'

510

Organic Reaction Mechanisms 1995

on the iodonium ion-mediated ring expansion of olefinic cyclobutanols has been disclosed406for the synthesis of iodoalkylated cyclopentanoids, while the rearrangement of 4-alkynyl-4-hydroxycyclobutenones(267) with hypoiodite has provided a route to iodomethylenecyclopentene-1,3-diones (269) from squaric acid. In this latter case, the results have been explained4" by positive iodine transfer from a hypoiodite moiety in (268) to an alkyne terminus and concomitant 1,2-acyl migration. Substituted cyclobutanones have also been converted into cyclopentanones by using the CH212SmIz system?08 On treatment with MgBr,, 8-spirolactones of the type (270; n = I , 2) have been observed409to undergo ring enlargement to the y-lactones (271), whereas the P-spirolactones (270; n = 2) show diastereoselective p-elimination to form the p,yunsaturated acids (272). Labelling experiments410have shown that the acid-catalysed transannular rearrangement of cyclodec-5-ynone (273) to bicyclo[4.4.0]dec-l(6)-en-2one (275) proceeds through a four-membered-ring intermediate (274) and that carboncarbon bond formation occurs before carbon-oxygen bond formation (Scheme 78).

R

4

Oxonium ion-initiated pinacolic ring expansion reactions have been applied4" to the enantioselective synthesis of spirocyclic sesquiterpene ethers. Investigation of an apparent 6-end0 dig cyclization of o-ethynylarylbenzylic alcohols (276) has revealed an

I5 Molecular Rearrangements

511

J SCHEME 78

unusual acid-catalysed rearrangement of the initially formed benzofuran derivative (277) to pyran (281). A plausible mechanism for the rearrangement is shown4I2 in Scheme 79 and involves an initial protonation of (277) followed by intramolecular cyclization of the ortho-carbonyl group to form spiroacetal (278). Ring expansion by a 1,2-oxygen shift would then result in formation of cation (279) which could undergo proton loss to produce (280). This intermediate could then proceed to the final product by a [ 1,5]-hydrogen shift and a subsequent cycloreversion. A mechanistic rationale for the lead tetraacetate-induced oxidative rearrangements of unsaturated diols (282; n = 1) and (282; n = 2) leading to the tetrasubstituted cyclohexane and cycloheptane derivatives (283) and (284) has been presented,413and is outlined in Scheme 80. Irradiation of 4-aryl-4-alkylhex-5-en-2-ones adsorbed on montmorillonite K- 10 in a commercial microwave oven has furnished414 multi-alkylated naphthalenes (Scheme 8 1). It has been shown4I5 that reaction of 1,3,5-tri-t-butylcyclopentadiene with dichloroketene results in a complex cationic rearrangement, while treatment of the adduct between the acyl nitroso intermediate from (R)-a-hydroxyphenylacetohydroxamic acid and cyclopentadiene with dilute acid has provided4I6 a high yield of the cyclopentene hydrochloride (285) (Scheme 82). 1 ,CDialkylated 2,3-diazabicycl0[2.2.l]hept-2-enes with stereo-labels at the C(7) position have been prepared417 for the first time by way of a highly diastereoselective intramolecular cyclization of stereo-labelled y,h-unsaturated tosylhydrazones under acidic conditions. The pathway outlined in Scheme 83 has been proposed4I8to explain the formation of 2,5-dimethyl5-silahex-1-ene-3,5-sultone (287) from the sulfonation of 1,1,3-trimethyl-l-silacyclopent-3-ene (286) with sulfur trioxide. A new stereoselective route to chiral spiro compounds has been developed4I9 (Scheme 84), and a perhydroisoindol-4,5-diolderivative (288) has been transformed into a perhydrocyclopenta[c]pyrrole (289) by a new tandem ring contractionautoxidation reaction. A plausible mechanism for this reaction is outlined4” in Scheme 85. Two rearranged ketones (292) and (294) have been isolated421when meso-

512

Organic Reaction Mechanisms 1995 OH

I

I

R

(276)

% % -H+

f--

R H

/

R H

1. 1.5-H shift 2. Cycloreversion

SCHEME 79

2,3-diallyl-2,3-dimethyl- 1,Cdioxane (290) was treated with titanium tetrachloride. Clearly, cleavage of (290) giving (292) involves the migration of one allylic group [see transition structure (291)], while the formation of (294) arises by migration of one of the methyl groups [see transition structure (293)l. In either case, the 0-C and C-C bonds involved have the antiperiplanar relationship appropriate for 1,2-migration. In a similar pinacol-like 2,3-diallyl-2,3-dialkyl-l,4-dioxanes(295) have been transformed into acyldivinylcyclopentanes (296). The effect of the medium on the rate of rearrangement of 2,3,3-trimethylbenzobicycl0[2.2.l]hepten-2-y1 cations has been studied423and a recent study424has confirmed that the non-classical form of the 2-norbornyl cation is the only stable form in the gas

Pb(OAc)3

I

OAc

SCHEME 80

SCHEME 81

514

Organic Reaction Mechanisms I995

SCHEME 82

J -=) M e

4%.

Me

Me

so3

=$LP si,'

Me'

0

"Me (287) SCHEME 83

Mefl Si,

Me'

Ir

"Me

515

15 Molecular Rearrangements

N-BOC

@N-Boc Ph

Ph

SCHEME 85

-+ -

//

(295)

r

'Tic14

(293)

0

-

(294) 1

Organic Reaction Mechanisms 1995

516

@ \ / R

-& \ /

R

0

gh 0

020Et

~

\I

OS020Et

R

0

\\

phase and in solution. The exceptional preference for endo attack of water during the nitrous acid deamination of spiro(bicyclo[2.2.l]heptane-7,l’-cyclopropan)-endo-2m i n e has been attributed425to the intervention of the bridged norpinyl cation which is stabilized by the spiro-annellated cyclopropane ring. The effect of electronwithdrawing substituents on the rearrangement of the bicyclo[3.1.l]hept-2-y1 skeleton to the bicyclo[2.2.l]hept-2-yl skeleton has been explored426and the driving force of the unusual montmorillonite K10-catalysed 1,2-rearrangernent of 6,7-dithiabicyclo[3.1.1]heptane 6-oxide to a 7,8-dithia-6-oxabicyclo[3.2.lloctane is considered to be the release of the ring strain of the bicyclo[3.1.1]heptane system by ring expansion.427The details of the nitroxylation of 2-nitroxy-endo-tetrahydrodicyclopentadienewith nitric acid has been studied, and a bridged carbocation has been suggested428as the intermediate responsible for the parallel and irreversible formation of 2,6-dinitroxyendo-tetrahydrodicyclopentadiene and 2,7-dinitroxy-1,7-trimethylenenorbornane. A general method for the one-pot transformation of cycloolefins into cr-ethoxysulfosubstituted ketones based on S03-mediated nitrosation by ethyl nitrite has been developed. When applied429to benzonorbornadiene derivatives such as (297), this process has yielded products of Wagner-Meerwein rearrangement (298), in addition to non-rearranged ketones (299). The electron-transfer photo-sensitized reaction of quadricyclanone (300) with methanol has been shown to produce a single product, 7-syn-methoxybicyclo[2.2.l]hept-5-en-2-one (301) via nucleophilic attack of methanol on the radical cation of (300). The structure of the product and the stereochemistry of the methoxy group has revealed430that the radical cation is captured by backside attack of methanol on one cyclopropane function followed by a specific cyclopropylcarbinyl to butenyl rearrangement. On treatment with acid, the 7-oxa-2,3-dimethylenenorbornene derivative (302) has been found to afford (303) by a rearrangement which is thought431to proceed by the pathway outlined in Scheme 86, and N-chloro derivatives of the 7-azabenzonorbornadiene ring system have been found to undergo a silver(1)assisted rearrangement with participation of etheno- (in the syn-chloro series) or benzo(in the anti-chloro series) z - e l e ~ t r o n sThe . ~ ~first ~ photo-sensitized skeletal rearrange-

15 Molecular Rearrangements

517

SCHEME 86

ment of organosilicon compounds has been observed433 during the irradiation of silanorbornadienes using 9,lO-dicyanoanthracene as a sensitizer. Oxidation of 2,3,5,6-tetramethoxybenzobarreleneby dimethyldioxirane has been to afford the benzonorcaradiene endo-2-ester stereoselectively by a WagnerMeenvein rearrangement, but this isomer is smoothly rearranged to the exo-2-isomer by a norcaradiene-tropylidene valence isomerization. A study has been made43s of the neopentylic versus skeletal rearrangement in the reaction of 7-t-butyldibenzobicyclo[2.2.2]octatriene and its 8-carbomethoxy derivative with chlorine. The regio- and stereo-selectivity of the addition of bromine to exo- and endotricyclo[3.2.1.02’4]octanehas been investigated,436while the bromination of exo- and endo-tricyclo[3.2.1.0234]oct-6-ene has been shown to be initiated at the double bond,437 in complete contrast to the reaction with acid where reaction is found to be initiated preferentially at the cyclopropane. The tricyclo[4.1.0.0”3]heptyl cation has been described438as being remarkably stabilized compared with its parent compound, and a recently reported cyclopropylcarbinyl rearrangement of tricycl0[5.3.1.0’,7]undecanols has opened up a facile route to the bicyclo[5.3.l]undecenol ring system.439 Rearrangement of the 1-adamantyl-3-noradamantylmethylradical to the 1,2’-biadamantyl radical has been found to compete with hydrogen abstraction from the solvent.440 The acid-catalysed cationic rearrangement of tetracyclo[4.3.0.02~904~8]nonane skeleton to substituted brendene derivatives has been studied,441and the acid-promoted rearrangement of pentacyclo [5.4.0. OZx6.0.331O . Os,g]undecane-derivedpinacols has been investigated442with the aim of evaluating steric versus stereo-electronic effects on the

Organic Reaction Mechanisms 1995

518

pinacol rearrangement of structurally complex 1,2-diols. The results of such a study have shown that the cyclobutane ring displays higher migratory aptitude [via C(7)-C(8) a-bond migration] than an endo-norbomyl group [whose migration would involve a 1,2-shift of the C(8)-C(9) 0-bond] in the protonated pinacol substrate. The Meyer-Schuster rearrangement of y-sulfur-substituted propargyl alcohols using polyphosphoric acid trimethylsilyl ester has produced443a convenient synthesis of a$unsaturated thio esters, and a Meyer-Schuster-type rearrangement is the key step in the cycloaromatization of 6,7-benzobicyclo[8.3 .O]trideca-6,1O-diene-3,8-diyne-l,5di01s.~~~ A new version of the Pummerer-type fluorination has been appliedM5to the synthesis of oligo-fluorinated compounds, and an unusual non-oxidative Pummerer rearrangement of y -trifluoro-/3-amino sulfoxides has been reportedu6 in which migration of the p-tolylthio group to the nitrogen atom provides the corresponding a-sulfenamidotrifluoroacetates. The first highly asymmetric Pummerer-type cyclization of chiral, nonracemic p-amid0 sulfoxides, leading to enantiomerically enriched /3-lactams, has been described447(Scheme 87), while stereoselective deprotonation of the a-proton from both acyclic and rigid cyclic sulfoxides has been observed4* in a silicon-induced Pummerer-type reaction. Reaction details and mechanistic proposals have been presentedm9 for a sulfinate-sulfone Pummerer rearrangement. The reaction of 2vinylcyclopropyl sulfoxides (lacking an a-hydrogen) with acetic anhydnde has provided cyclic or acyclic conjugated dienes via butadienylthionium ions.450A twocarbon homologation of aldehydes and ketones has been achieved4” by using a sequence involving the formation and the subsequent Pummerer-type ring fission of 5,6-dihydro-4H-1,3,4-thiadiazine rings possessing methylsulfonyl functionality at C(2) (Scheme 88), and a convenient synthesis of 1-benzenesulfonyl-4-keto-8-methoxy-

~

N

H

R

I SCHEME 87

519

15 Molecular Rearrangements

H

1

V"R'

H

R2 = H

SCHEME 88

1,2,2a,3,4,5-hexahydrobenz[cdjindolehas been described452based on an intra-homoacylation via a Pummerer intermediate. A sequence involving a Pummerer-type rearrangement, difluorocarbene formation, electrophilic addition of the carbene to the oxygen atom of ethers leading to oxonium ylides, and trapping with phenylselenenyl acetate has been proposed4" to account for the formation of w-[difluoro(phenylseleno)methoxy]alkyl acetates on treatment of difluoromethyl phenyl selenoxide with acetic anhydride. The vinylogous Wolff rearrangement of /?,punsaturated cr-diazo-/?-keto esters has opened up a novel route for the preparation of substituted m a l~ n a te s:~and ~ a stereoselective total synthesis of camphorenone from bicyclo[3.2.l]oct-6-en-2-one, based on a one-step diazo transfer followed by a Wolff rearrangement, has been outlined.455The photolysis of 2-diazoindan-l,3-dione has been to lead to ketene formation via the Wolff rearrangement, and the thermal decomposition of dimethyl 1-diaz0-2-0~0-(2-N,N-disubstituted aminopheny1)ethylphosphonates has been shown to proceed to 2-oxoindolinium enolates by way of a Wolff rearrangement followed by an attack of the nitrogen atom on the intermediate ketene moiety.457An improved synthesis of RG-14893, a high-affinity leukotriene B4 receptor antagonist, has been achieved458via a photochemical Wolff rearrangement. Rearrangements in Natural-product Systems

Studies using '3C-labelled mevalonates have verified4s9that preferential labelling in the farnesyl diphosphate-derived portion, and a 1,2-migration of the C( 19)-methyl group originating at C(6) of mevalonate, occur in the biosynthesis of heteroscyphic acid A, and an NMR study46ohas identified the occurrence of 1,2- and 1,3-hydride shifts in the biosynthesis of (+)-cubenene and (+)-epicubenol by cell-free extracts of cultured cells of Heteroscyphus planus. Methyl 7-0x0-5,8,11,13-abietatetraen-l8-oatehas been reduced to the corresponding 7-hydroxy compound, which has been found to rearrange into methyl 7-isopropyl-1,l0-dimethyl-1,2,3,4-tetrahydroanthracene1-carb~xylate.~~'

520

Organic Reaction Mechanisms 1995

Lactone (304), easily prepared from hydroxy-b-ionone, has been transformed into the Ziegler intermediate (305) in the forskolin synthesis by a straightforward strategy involving two new rearrangements,"62 and (+)-grindelic acid has been synthesized by a stereo-controlled oxonium ion-activated pinacol ring expansion.463A study has been made464of the acid-catalysed rearrangement of parthenin and its derivatives, and (-)a-cedrene (306) has been rearranged for the first time into isomeric compounds with the zizaene (307) and patchoulene (308) skeletons. The possible mechanisms of these

Me.,

-

1. HS03F,

SOzFCI

+

2. MeOH

Me

PMe M Me

e

Me'

carbocationic rearrangements have been studied465 by methods of molecular mechanics. The rearrangement of (-)-fl-caryophyllene with sulfuric acid in diethyl ether has been re-investigated, and a previously unknown rearrangement, involving protonation of the exocyclic double bond followed by transannular ring closure, has been identified466as the main reaction. A new strategy for the synthesis of the taxane diterpenes has involved467the formation of the eight-membered /?-ring of taxol by a semi-pinacol rearrangement, and an interesting pinacol rearrangement involving 7-epi6a-tosylateltriflate derivatives of taxol has been described46* which affords fivemembered C-ring-containing analogues. In the presence of BF3.0Et2 or HC1, 3fl,4pepoxy-D : A-friedoolean-7-one has been found to rearrange to D :A-fnedoolean-3,7di0ne.4~~ The influence of hydroxyl groups of different stereochemistries at C(12) of ent-15,16-epoxybeyeranes has been reported,47oand the rearrangement reactions of these compounds with acetoxy substituents at C(12) have been carried out by treatment with ruthenium acetylacetonate. In the latter study, the stereochemistry of the acetoxy group has been shown to have a decisive influence on the course of the rearrangement. Thus, an axial substituent was shown to aid in the stabilization of intermediate

52 1

15 Molecular Rearrangements

SCHEME 89

structures derived from an electron deficiency at C(15), thus allowing the formation of 8(15 -+9)-abeo and 8(14 -+ 9)-, 13(12 -+ 16)-di-abeo compounds.471 On the other hand, an equatorial acetoxy group at C(12) blocked the possible skeletal rearrangements. A new approach to steroid thiols has been achieved472using a dienthionthiophenol rearrangement of 3-thio~o-A'~~-steroids, and racemic 11by14/l-dihydroxyestrone has been prepared from 6-methoxytetralone by a route which involves a novel 1,3-rearrangement of an allylic nitro (Scheme 89). The reduction of 1,6dioxaspir0[4S]decan-10-yl methanesulfonate derivatives of steroids with DIBAH has provided474 a new method for the synthesis of steroidal cis- and trans-fused tetrahydropyrans (e.g. Scheme 90). A full account of synthetic and mechanistic studies on the use of dipent-4-enyl acetals as effective acetal-transfer agents in carbohydrate chemistry has appeared. It was that the reactions can be promoted under neutral conditions by iodonium dicollidine perchlorate or an N-halosuccinimide. A detailed study476of non-acidic, iodonium-induced Ferrier-type rearrangements has helped to classify mechanistic aspects of the Ferrier reaction. A general procedure for the synthesis of new methylfuranosides, fused with a cyclopropane ring carrying a hydroxymethyl sidechain, has been developed477by a one-pot lY2-di0lmonosulfonate rearrangementcyclopropanation reaction under simple and mild reaction conditions. C-Glycosylation

522

Organic Reaction Mechanisms 1995

Me

Me k C

J Me

SCHEME 90

of 2,3,4,6-tetra-0-benzyl-~-D-glucopyranosyl fluoride and 2-acetylphloroglucinol 3,sbis(alky1 ether) in the presence of BF3.0Et, has been found to afford p-C-glucosides via an 0 -+C-glycoside rearrangement.478 A ring-expansion protocol has been developed479for the conversion of readily available furanosylated indolocarbazoles into the corresponding pyranosylated analogues; see (309)- (310). Importantly, the ring expansion has been found to proceed regio- and stereo-selectively to products suited for the synthesis of staurosporine and its congeners. 4'-Thionucleosides have been prepared via an in situ pyranose-furanose rearrangement.480

An oxidative rearrangement of isostrychnic acid which involves the transformation of the strychnine skeleton into the heteroyohimbane series has been reported,481and an investigation of the conversion of the secodaphnane skeleton into the daphnane

15 Molecular Rearrangements

523

A new rearrangement of an Aspidosperma alkaloid has skeleton has been carried produced the first biomimetic entry into the goniomitine skeleton.483 Rearrangements Involving Electron-deficient Heteroatoms

A comparative kinetic and stability study484has been undertaken of the isomerism and Beckmann rearrangement reactions of a-benzil monoxime. The role of alcohols on lactam selectivity in the vapour-phase Beckmann rearrangement has been investigated,485 and vapour-phase Beckmann rearrangements have been performed486 on silica-supported tantalum oxide catalysts. Beckmann rearrangements of cyclohexanone oxime have been carried out on the external surface of zeolite cry~tals,4~’ on silica monolayers prepared on y-Al203, Zr02, and Ti02,488and under dilute acid conditions in micellar media.489The Beckmann rearrangement of oximes has been catalysed with tetrabutylammonium perrhenate and trifluoromethanesulfonic acid.490The Beckmann rearrangement has been utilized to prepare 2,6-disubstituted 5-aminopyrimidin-4-ones from 2,6-disubstituted 5-acetylpyrimid-4-one ~ x i m e s and ~ ~ lsubstituted benzoxazoles fiom o-acylphenol 0ximes.4~’It has also been used to prepare 2,2-dimethylbenzoxazepinones from 2,2-dimethyl-4-chromanone~ x i m e sand ~ ~(f)-anti-N-benzyl-3~ amino-4-hydroxyhexahydroazepine, a key intermediate for the synthesis of racemic balanol and its analogues, fiom the syn-oxime of 3-ethoxycyclohex-2-en-1-one.494The Beckmann rearrangement has been used495to achieve a simple and efficient method for the preparation of conformationally constrained aminomethylene gem-diphosphonate derivatives. A theoretical study496has confirmed that the loss of HCN from metastable hydrazonium cations can be better rationalized in terms of a gas-phase Beckmann rearrangement than by a 1,2-cis-elimination, and a detailed exploration of the [CH4NO]+ potential-energy surface has confirmed497that the classical gas-phase Beckmann rearrangement represents the easiest way of transforming protonated oximes and their isomers into products. Hydroxylamine-0-sulfonicacid has been found to react with alicyclic ketones over Si02 under microwave irradiation to afford amino acid salts which cyclize in high yield to the corresponding lactams after work-up in basic medium!98 Triazidochlorosilane (produced in situ from SiCb-NaN3) has been discovered as a new and efficient reagent for the direct conversion of ketones or cr$unsaturated ketones into the corresponding tetrazole derivatives. It was proposed499that the reaction proceeds via the formation of d o x y azide (311) and subsequent formation of gem-diazidoalkane (312), which then undergoes a rearrangement similar to the Beckmann rearrangement with predominant migration of the aryl group yielding the imidoyl azide (313), followed by cyclization to the tetrazole derivative (314) (Scheme 9 1). 1,2-Migration of hydrogen and methyl to electron-deficient nitrogen in 3,3disubstituted 1-methyl-5-0~0-4,5-dihydro-3H-[ 1,2,4]triazolium cations have been compared by means of ab initio MO calculations,500and the preference for hydrogen migration appears to result from stabilization of the transition state by the nonmigrating substituent. The kinetics of the Curtius rearrangement of the isomeric 3(4)azidocarbonyl-4(3)-methylfuroxans to a new series of aminofiroxans have been studied.”’ The rearrangement has been shown to proceed faster at the 3- than at the 4-

524

Organic Reaction Mechanisms 1995

-N2

/

J

N-N N-N

RR A N J I Ar

c--

N3 )C=N-Ar

R

SCHEME 91

position, and to be favoured by an electron-withdrawing substituent at the second ringcarbon atom. 2-Carbethoxy-3-(5-imidazolyl)indoles, when subjected to a tandem, modified Curtius rearrangement-intramolecular electrocyclization, has been shown to afford p y n d ~ n e s , ~key ~ *intermediates in the synthesis of analogues of the naturally occurring cytotoxic a-carbolines, grossularines-1 and -2. A Curtius rearrangement has been used to achieve the selective synthesis of h.uns-2-(indol-3-yl)cyclopropylamines?O3 and it constitutes a key step in a recently reported504asymmetric synthesis of (1'S,2'R)-cyclopropylcarbocyclic nucleosides. Cyclopropanation of chiral bicyclic lactams (315), followed by removal of the chiral auxiliary and a modified Curtius rearrangement employing diphenylphosphoryl azide-Bu'OH, has led505 to novel aminocyclopropyl lactones (316) in > 99% ee (Scheme 92). Novel transformations, including a rearrangement analogous to the Hohann reaction of primary carboxamides, have been reported506 for the reaction of N-substituted amidines with (diacetoxyiodo)benzene.An intramolecular cross-over experiment has shown that the

(316)

SCHEME 92

525

15 Molecular Rearrangements

R102CR + OR'

-

RC02R1+N2

SCHEME 93

formation of esters from the thermal decomposition of N,N-diacyl-N,N-dialkoxyhydrazines is consistent with a three-centred rearrangement process507(Scheme 93). 'H NMR spectroscopy has been used to monitor the formation of 1,4benzoxazepinones and their [ 1,5-d]t~trazOlO analogues from the azidotrimethylsilanemediated Schmidt rearrangement of flavanone precursors,5o8and the mechanism of the same rearrangement of thioflavanone and thiochromanone precursors to benzothiazepinone derivatives has been studied."' The first known example of an asymmetric Schmidt reaction using chiral azido alcohols has been used5" to provide an effective approach to the synthesis of multi-functional lactams, and a mechanistic analysis5' has suggested that the intramolecular Schmidt reaction of alkyl azides and ketones proceeds via an intermediate azidohydrin which rearranges directly to the amide, possibly under stereo-electronic control. 5-Azido-2,3,4-tri-0-benzoyl-5-deoxy-~-xylose diethyl dithioacetal (317) has been reported5" to undergo smooth Lewis acid-catalysed demercaptalation to afford the unstable aldehydo azide (318) which, in the presence of Lewis acids, yields the tribenzoate of 1,5-dideoxy-l,5-irnino-D-xylono~actam (319) via an apparent intramolecular Schmidt rearrangement. The intermolecular Schmidt reaction of aliphatic azides with carbocations (Scheme 94) has been described,513 and a novel sequence for the conversion of triisopropylsilyl enol ethers (320) via aazido triisopropylsilyl ethers (321) into the corresponding caprolactam derivatives (322)

roBz I

- -B

i

O

Bzo 0)

h

OSi Pr'2

R

X

(320)

X = CH?. 0. S

-

-KO+

BzO

Tic14

CH2N3

(317)

T

(3181

(3191

0

526

Organic Reaction Mechanisms 1995

SCHEME 94

via a photo-induced Schmidt rearrangement has been d e ~ e l o p e d . ~The ' ~ Schmidt rearrangement of methyl furoxanyl ketones and furoxancarboxylic acids has been shown to represent a convenient method for the preparation of aminofi~oxans.~'~ A study has been made of the Schmidt-type rearrangement of pentacyclo[5.4.0.02~6.03~'0.0579]undecan-8-one. An unusual 'double Schmidt' rearrangement, that results in the formation of a pentacyclic urea, has been rationalized516by invoking the formation of an intermediate tetrazole which undergoes subsequent acylation with concomitant Huisgen rearrangement. The Baeyer-Villiger oxidation of 4-formyl-P-lactams with mCPBA has been established5" as a convenient method for the preparation of 4-formyloxy-P-lactams, and the Baeyer-Villiger rearrangement of steroidal cr-substituted P-spirocyclobutanones has been studied.518An unusual outcome of the Baeyer-Villiger reaction of truns-3/?hydroxy-4,4,1O~-trimethyl-9-decalone(323) with CF3C03H has been described5' where the initially formed hydroxy lactone (324) undergoes acid-catalysed cleavage of the lactone C-0 bond and rearrangement to form a 7-oxabicyclo[2.2.1]heptane (325). A Baeyer-Villiger oxidation has been used as a key step in the stereoselective synthesis of rare D- and L-mono- and -di-saccharides of 5-deoxyhexofuranosiduronicacids.520An active-site model for enzyme-catalysed Baeyer-Villiger reactions has been proposed and validated5'l by transformation of the tricyclic ketone (326). Ring expansion of (326) with a number of organisms was enantioselective. The Baeyer-Villiger oxidation of some 2- and 3-substituted cycloalkanones using myristic acid and H202has been

Me

Me

527

15 Molecular Rearrangements

-A

MezSljf $. 0

+

Ph-E

Roo-

?R

R'OH

J

XMe2

4--'

SCHEME 95

catalysed by Candida antarctica l i p a ~ ethe , ~ application ~~ of enzymic Baeyer-Villiger oxidations of 2-substituted cycloalkanones to the total synthesis of (R)-(+)-lipoic acid has been reported,523and enzymatic Baeyer-Villiger oxidations of some bicyclo[2.2.1]heptan-2-ones using monooxygenases from Pseudomonas putida NCIMB 10007 have been in the preparation of a precursor of the growth regulator agent azadirachtin. A phenyldimethylsilyl group attached to carbon has been converted into a hydroxy group, with retention of configuration at the migrating carbon, by protodesilylation to remove the phenyl ring from the silicon atom, followed by oxidation of the resulting hnctionalized silicon atom using peracid or H202525(Scheme 95). Rearrangements Involving Organometallic Compounds Some unusual chemistry involving boron migrations that result from the juxtaposition of boron and zirconium in the same molecule has been presented,526and a new directed synthesis of enol borates from the reaction of acid chloride and gem-borazirconocene alkanes has been reported.527Zirconacyclopentanes have been found to react with acid chlorides in the presence of a catalytic amount of CuCVLiCl to yield five-membered carbocyclic ring compounds528(Scheme 96). This type of intramolecular nucleophilic attack of zirconium compounds on the carbonyl group is considered to be unprecedented. A stoichiometric study of aldopentose rearrangement processes catalysed by enantiomeric chromium(II1) complexes of the optically active 5,5,7,12,12,14hexamethyl- 1,4,8,11-tetraazacyclotetradecane ligand has been described.529

528

Organic Reaction Mechanisms 1995

Pentacarbonyl[(+)- and ( - )-menthyloxycarbene] complexes of chromium have been found to react with 3,3-dimethylbut-1-yne diastereoselectively to give optically active (naphthalene)Cr(C0)3 complexes which, upon warming, undergo an intramolecular haptotropic migration of the metal The conversion of 2-alkenylcyclopropylcarbene-chromium complexes into 5-alkenylcyclopent-2-enoness3’ has been shown to proceed with retention of configuration in the absence of steric interactions which suppress the preferred reacting conformation. The first example of the direct protonation of a nitride group to an amide has been observed in a molybdenum complex.532 Boratropic rearrangements in tris(pyrazoly1)borate molybdenum mononitrosyl complexes have been inve~tigated,’~~ and the clean irreversible thermal transformation of $-acyl-isocyanide complexes into their q2-iminoacyl-carbonyl derivatives has been documented for the first time.s34 A plausible mechanism for the spontaneous isomerization of symmetric M(,u-NO)~Mlinkages to (ON)M=N=M=O groupings in bismetallic species has been proposed53s (Scheme 97). A molybdenum hexacarbonyl-catalysed cyclo-isomerization of acyclic alkynyl alcohols to endocyclic enol ethers and thence y-butyrolactones (Scheme 98) has been employed536as a key step in the enantiospecific synthesis of (+)-(4S,Ss)-muricatacin. A kinetic study has been presented537of the skeletal rearrangement and acetylide migration in the buttertly cluster complexes of the type C ~ W O S ~ ( C1(C=CCH20Me). O)~ 0-Acyl and 0-phosphonyl cyanohydrin derivatives of the tricarbonyliron complex of hexa-2,4-dienal have been found to undergo regio- and stereo-selective 1,5-~ubstitution reactions with several heteroatomic nucleophiles giving, with 1,2-migration of the Fe(CO)3 group, predominantly either E,E or E,Z products by appropriate selection of solvent or acid catalyst.s38 A large variety of N, 0-, and S-containing heterocyclic compounds have been found to undergo carbonylative ring expansion when exposed to carbon monoxide in the presence of transition metal complexes.s39 Ruthenium hydrido-alkynyl complexes have been e~tablished’~~ as feasible intermediates in the transition metal-promoted isomerization of alk-1-yne complexes to their vinylidene isomers. A novel transformation reaction of l-(propa-l,2-dienyl)cyclopropanolsto hydroquinone derivatives has been developed541by utilizing the interaction between propa1,2-diene and octacarbonyldicobalt. Diethyl 2-acetylamino-2-methylpropanedioate, coordinated to a hydrophobic vitamin BI2 covalently bound to a peptide lipid, has been found to undergo a carbon skeleton rearrangement542 to afford diethyl 2-

M = CpMR (M’ = Mo, W; R = CH2SiMe3, CH2CMe3,CH2CMe2Ph)

529

15 Molecular Rearrangements

SCHEME 98

acetylaminobutanedioate in the single-walled vesicle of N,N-bis(hexadecyl-W-(6sulfohexanoy1)-L-alaninamide under photolysis conditions. A study543of the reactions of (3-furylmethyl)cobaloxime (327) with dienophiles such as dimethyl acetylenedicarboxylate has unearthed an interesting 1,Ccycloaddition and concomitant 1,3migration of the cobaloxime moiety, thus opening up a new synthetic strategy for the syntheses of oxabicyclo[2.2.llsystems (Scheme 99). A mixture of methyl iodide and formic acid has proved544to be an extremely effective promoter-solvent combination for the transition metal-catalysed conversion of methyl formate into acetic acid. A palladium-catalysed rearrangement of (a1koxy)oligosilanes via silylene transfer has been reported,545 and the rearrangement of a dipalladiumacetylene adduct to a vinylidene-bridged complex has been carried out under Lewis acid catalysis.546Ally1 propynyl ethers (328) have been found to undergo cyclo-rearrangement to 3oxabicyclo[4.1.O]hept-Cenes (331) on brief treatment at room temperature with a catalytic amount of PtC14. It was indicated547that the transformation of (328) to (331) probably involves platinum-allene intermediates (329) and (330) (Scheme 100). The reversible spontaneous isomerization between q’-allenyl- and q I-propargyl-platinum complexes has been reported and suggested548to proceed via pseudo-rotation of a fivecoordinate q3-allenyl/propargylintermediate.

C02Me C02Me

SCHEME 99

Organic Reaction Mechanisms I995

530 RCrCCH20CH*CH=CHR’

RCH=C=CHOCH2CH=CHR’

(328) H

SCHEME 100

Rearrangements Involving Ring Opening

A recent study549has shown that the rearrangement mode of (dihalocyclopropy1)methyleneamines to halopyrroles depends on the nature of the halogen atoms on the cyclopropane ring and the reaction medium as well as on the additives. I-Sulfenylsubstituted 2-vinylcyclopropanes containing a methoxycarbonyl or a cyan0 group at C(1) have been isomeri~ed~’~ in the presence of a sulfonic acid to 6-sulfenyl-a,p-y,6unsaturated carboxylic esters and nitriles via a C(I)-C(2) bond fission and an intramolecular 1,5-sulfenyl shift. Evidence supportive of a non-carbenoid mechanism has been presented5” for the unusually efficient photochemical conversion of substituted 3,3-dimethyl-1-(trimethylsilyl)cyclopropenes (332) into the corresponding allenes (333).

p

Me \

/c=c=c’SiMq

Me

MelSi (332)

(333)

Tris(pentafluoropheny1)boron has been used’” as an efficient catalyst in the stereoselective rearrangement of epoxides and, under forcing conditions with base, p menth- 1-en-4(8)-oxide has been rearranged553to p-mentha- 1,8-dien-4-01. 2-Methyl-2vinyl-3-alkyloxiranes (334) have been shown to undergo facile 1,2-alkylmigration with inversion of configuration leading to 2-methyl-2-vinylalkanals(335), thereby establishing an acyclic quaternary carbon in high yield and optical ~ u r i t y . ”An ~ enantioselective

(334)

(335)

53 1

15 Molecular Rearrangements

-

T M S ~

Tic14

‘b

Me

Me

OR1

OR2 CHO OR’

SCHEME 101

synthesis of the highly fictionalized bis(tetrahydrokan) sub-unit of asteltoxin has been accomplished,sss in which a sterically congested quaternary centre has been constructed by the Lewis acid-catalysed rearrangement of an epoxy silyl ether (Scheme 101). Total chirality transfer has been achieveds56 in a palladium(0)-catalysed rearrangement of silicon-substituted vinyloxiranes to aldehydes. The strategic sequential use of two Sharpless epoxidations in combination with epoxy diazo chemistry has constituteds5’ a flexible synthesis of 6-hydroxy-y-lactones which has been extended to the synthesis of (4R,SR)-rnuricatacin and its 4R,5S epimer. The observeds58formation of the teurilene-related meso-compound (337) from the chiral diepoxide (336) is one of the few synthetic examples of an epoxide cascade involving intermolecular attack of a water molecule (Scheme 102). The formation of spiro(azetidine-3,3’-pyrrolidine)derivatives (340) from oxidation of the monocarboxylates of 3-methylidene-B-lactams (338) has been explained559 by postulating the transformation of the methylidene-B-lactam into an oxirane (339) and a partial fragmentation to an imine. Acylation of the imine by the ester group of (339) and subsequent rearrangement would produce (340). The reaction of singlet oxygen with chiral alkoxyallylstannanes has been found to provide a new route for the . ~ ~ ~ formation is considered to stereoselective synthesis of 1 , 2 - d i o ~ o l a n e s Product proceed through ring opening of an intermediate perepoxide upon migration of the stannyl group, and has been shown to be favoured by the presence of an electrondonating group and by steric factors which can suppress the more typical hydrogen-ene reaction which produces ally1 hydroperoxides. The facile rearrangement of 2-thioalkyl3-aryloxiranes (341) containing strong electron-donating substituents in the aromatic Me0

H I

H-0 :

-

H20, P-TsOH

Me

SCHEME 102

Organic Reaction Mechanisms 1995

532

H

A Ph rJ%

CO2R

(339) Ar

FNlr

(340)

Ph

r

0-

0-

1

I

(341) SCHEME 103

ring has been found to proceed561with migration of the thioalkyl substituent (Scheme 103). Rearrangement of homochiral2,3-epoxy-aminesby treatment with TMSOTf has yielded 3-trimethylsilyloxy-1,2-miridinium triflates, which were found to undergo efficient regiospecific ring opening at C( 1) with amino acid ester nucleophiles to yield N-(2-amino-3-hydroxyalkyl)-substitutedamino acid esters.562 A study has been directed563to the problem of delineating the factors which are responsible for controlling the direction of the ma-Payne rearrangement of activated 2aziridinemethanols and 2,3-epoxyamines under basic conditions, and a regio- and stereo-selective synthetic route to diastereomericallypure 1,2-amino alcohols via a onepot aza-Payne rearrangement-epoxide ring-opening reaction of 2-aziridinemethanols has been reported564(Scheme 104). The mechanism of the rearrangement of bicyclic 2methoxy- 1-arylsulfonylaziridines (342) to imines (343) and enamides (344) has been discussed.565Fulleroaziridines have been rearranged to fulleroo~azoles~~~ in boiling tetrachloroethane, and the reaction of N-arylsulfonylaziridines with (dimethylsulfonium)(ethoxycarbonyl)methylide has proved to be a fairly general approach for the synthesis of azetidines bearing an ethoxycarbonyl f~nctiona1it-y.~~’ N-Arylamino-1,3Me

+-$

Me Me0

NR

(342)

M R;$e

M $+ -e

Me

/

Me OMe

(343)

OMe

(344)

NHR

15 Molecular Rearrangements

533

SCHEME 104

diazabuta-l,3-dienes have been shown to undergo regioselective additions with haloketenes to yield 3-aryl-5-(N-arylamino)-2-methylthio-6-phenyl-4(3~-p~midinones via an aziridine intermediate,568and an aziridinium imide has been directly observed569 during the reaction of N-substituted 1,2,4-triazoline-3,5-dionesand trans-cyclooctene. An unexpected rearrangement of a bicyclo[3.2.lloctane to a bicyclo[2.2.2]octane occurring via an aziridinium ion has been observed570during an attempt to prepare the core skeleton of sarain A, and 2-azabicyclo[2.2.l]hept-5-en-3-onehas been converted5" into its enantiomer by a five-step sequence incorporating a skeletal rearrangement mediated by anchimeric assistance of the nitrogen atom (Scheme 105). The synthesis of a 2H-azirine by 1 +2-cycloaddition of a phosphinocarbene with a nitrile, and its ring expansion to a 1,2A5-azaphosphete,have been reported.572 The formation of the same cyclic ethers (348) and (349) from the sulfenylation of unsaturated alcohols (345) and from acid-catalysed phenylthio migration reaction of diols (346) via the same episulfonium ion intermediate (347) has been explained573by kinetic and thermodynamic control. Episulfonium ions have also been postulated574as intermediates in the rearrangement of a series of 1,n-diols (n=2-12) in which one hydroxyl group has an adjacent phenylthio group. A novel rearrangement of a cyclobutane to a cyclopropane in the presence of ZnBr2 under reversible conditions has been discovered575(Scheme 106). Unusual diradical intermediates arising from ring opening have been proposed576 to account for the enantiospecific formation of pyranoquinones from the thermolysis of 4-p-0~01,6enynyl)-4-hydroxycyclobutenones,while pyran-2-ones (350) bearing pendant alcohols

(348)

(349)

Organic Reaction Mechanisms I995

534

p-MeOChH&Hz: base

& N\

~

Br&

*\R

R

R = p-MeOC6HdCH2

J

O D H SCHEME 105

/COzR‘

I;)v( C02R‘

PhSe, R3Si

C02R’

H

SCHEME 106

have been found to undergo conversion to dihydropyrans (351) via irradiation in methanol followed by stirring in the presence of a catalytic amount of HCl. It has been proposed577that this process requires the intervention of a prior skeletal rearrangement of the starting pyran-2-one to place the hydroxyalkyl substituent at C(4), along with temporary incorporation of methanol (Scheme 107). An oxetane intermediate has been invoked578to account for the formation of 3-hydroxy-2,2’-dimethyl1,1’-dimethoxypropane from the treatment of prenol under direct anodic-oxidation conditions. The unexpected formation of a substituted oxazole has been reported579during the rearrangement of substituted 3-azidoazetidines. The mechanism described in Scheme 108 has been proposed5” to account for the formation of 4-imidazolin-2-ones (353) from the reaction of 3-amino-1-hydroxyazetidin-2-ones (352) with p-toluenesulfonyl chloride in the presence of a tertiary mine. Treatment of 1,2-thiazetidine-1,I-dioxides

535

15 Molecular Rearrangements

C02H

Me0 /

Me0

M e 0 Me

Me

1

-MeOH

Me SCHEME 107 H RCONH

OH

(352)

J dR' RcoNKNH c-

0

(353) SCHEME 108

RCoY\

JC 0

ON

536

Organic Reaction Mechanisms 1995

-

R

?HI N

1

f

(354)

Ph'

(355)

(354), bearing a poor migratory substituent at C(3), with Lewis acids has been reportedsp1to provide trans- 1,2,3-0xathiazolidine-2-oxides(355)and/or cis-aziridines (356)via C-S bond cleavage and re-cyclization. The i%ee-radicalreaction of endo-bromopropylbicyclo[4.2.0]oct-2-en-7-ones(357) has been shown to lead to a deep-seated rearrangement and formation of the bridged tricyclic ketonesp2(358)(Scheme 109). Mechanistic studies583of the ring expansion of isatylidenes to quinolines have shown that the process proceeds through a benzylidene intermediate which undergoes nucleophilic cyclization to afford the six-membered heterocycle. A study584has been made of the kinetics and mechanism of the reversible isomerization of aspartic acid residues in tetrapeptides. The reaction has been shown to involve the reversible formation of an aminosuccinimide intermediate. It has been 1Hreportedsp5 that the reaction of tosyl azide with 2-phenylsulfanyl-2,3-dihydroindan-l,3-dione (359)in HMPA gives the ring-expanded hydroxybenzopyran (363),the formation of which has been ascribed to preferential fragmentation of the corresponding 4,5-dihydro-lH-triazole (360)to give zwitterion (361).This intermediate then leads to the benzopyran (363) through a ring-cleavage rearrangement of the initially formed oxirane (362). A transformation of some 5,lO-secosteroidal a,Bunsaturated oximes to the corresponding 1,3-dioximes has been reported.586 The favoured route for the conversion is one involving an isoxazoline intermediate formed by intramolecular attack of the oxime hydroxy group at the C(3) centre (Scheme 110). Thermal cyclization of 3-benzyl-2,2-dimethylpenta-3,4-dienal hydrazone derivatives, has leading to the formation of 5-benzyl-4,4,6-trimethyl-l,4-dihydropyridazine~,~~~ been shown to support an earlier hypothesis about the reaction mechanism of pyridazinone formation of this process as outlined in Scheme 111. Synthesis of the 13C-enrichedhydroxynaphthoquinone (364)and its rearrangement to (365) have provided data5@ in agreement with the mechanism for the Hooker oxidation. A possible mechanistic rationale which accounts for the remarkable one-step samarium(I1) iodide-induced transformation of aldehydo methyl pyranosides into functionalized cyclopentanes has been depicted589as proceeding by the pathway set out

531

I 5 Molecular Rearrangements

(357) 111

c1

SCHEME 109

(359)

(361)

1

538

Organic Reaction Mechanisms 1995

&\

0

NH2

HO”

J

/

SCHEME 1 10

* = I3C enrichment

J SCHEME 11 1

539

15 Molecular Rearrangements

-

BnO OMe

BnO OMe

OMe

SCHEME I 13

in Scheme 112. Finally, the reaction of 2-methyl-1-vinyl-l,2,3,4-tetrahydroisoquinolines with dimethyl acetylenedicarboxylate has been reported590to yield 3-benzazecine esters, the formation of which has provided a new example of ring expansion by four atoms to access ten-membered rings, as shown in Scheme 113.

Isomerizations The effect of hydroxide ion on the Z to E thermal isomerization of azobenzene derivatives has been studied,591and the first examples of Lewis acid-promoted E to 2 isomerization of carbonyl-conjugated nitrones have been reported.592

540

Organic Reaction Mechanisms 1995

Cyclophanes (366), which contain a triple bond in the meta bridge, have been transformed593to allenes (367) by the action of bases or acids. A further isomerization yielded the dienes (368) with an E,Z or Z,Z configuration.

Tautomerim The acidity and keto-enol tautomerism of a series of symmetrical and unsymmetrical /jdiketones have been investigated in aqueous solutions,594and a detailed study595has demonstrated the effectiveness of the fluorenyl group in increasing enol stability and ketone acidity. A theoretical study of tautomerism in the reduced forms of 1,4disubstituted anthraquinones has been undertaken,596and a quantitative description of proton dissociations and tautomeric equilibria of apigeninidin (369) in solution has been reported.597 (R)-N-acetyl-[fi-H-2(l)]-dopamine has been found to undergo an enzyme-catalysed oxidative tautomerization to a quinone methide with loss of the benzylic hydrogen atom.598A study has been made599of ring-chain tautomerism in both 3-hydroxyisoindolin-l-ones and o-acylbenzamides, and ring-chain tautomerism has provided a route to 7a-hydroxy-3a-methyl-2,7-dioxoperhydrobenzofuran.600

Imine-enamine tautomerism in dihydroazolopyrimidines has been reviewed,60' and reviews have appeared on the tautomerism and isomerism of a variety of diverse heterocyclic compound^.^^^^^^^ A detailed study has been made of the effects of substituents and solvents on the tautomer ratios between the hydrazone imine and diazenyl enamine forms in para- and rneta-substituted 3-(arylhydrazono)methyl-2-oxo1,2-dihydroquino~alines.~~~~~ The tautomeric conditions of the primarily formed dihydropyridazine, produced during the cycloaddition of azolyldienes to dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate, have provided an explanation607for the formation

54 1

15 Molecular Rearrangements

and (E)-azolylvinyl-substituted pyridazines in the of the hitherto unknown (3cycloaddition. Semiempirical and ab initio calculttions have been performed on pyrazoles with 3- or 5-cationic substituents such as NH3, with the aim of discovering the effect of such substituents on the tautomeric equilibrium of these compounds.608 Proton-transfer phenomena for the 2-hydroxypyridine system in the cation ground state have been studied609by zero-kinetic-energy photoelectron spectroscopy. NMR studies have been used to investigate the tautomerism of N-(2-hydro~ybenzylidene)anilines~~~ and of 2-a~ylaminopyridines,6~~ while a spectroscopic and theoretical study has been Ab carried out on a number of representative aromatic a-hydroxy-carbaldehyde initio studies have been made of the tautomerism and protonation of 7-aminopyra z ~ l o p y r i m i d i n ein~the ~ ~ gas phase and in aqueous solution, and of the tautomerism of neutral and protonated 6-thi0guanine~~~ in the gas phase and in aqueous solution. MO studies have been carried out on the prototropic tautomerism and protonation of 2t h i ~ p u r i n e ,and ~ ~ ~aqueous solvation effects on the prototropic tautomerism of 2thiocytosine have been studied.616A detailed report has appeared on the tautomerism of 2,5-dimercapto-1,3,4-thiadia~oles,~~’ An intramolecular 1,3-chlorine migration in the triad ‘carbon-carbon-sulk’ with nucleophilic solvent or catalyst assistance has been proposed61 as a mechanism for the perfluoro-2-methylpent-2-ene-3-sulfenyl chloride (370)~2-chloroperfluoro-2-methylpentane-3-thione (371) tautomerism.

Se

I

R3C=CCH2Br

542

Organic Reaction Mechanisms I995

Variable-low-temperatureNMR studies of lithium 1-alkoxyeneselenolates (372) have disclosed619that the equilibrium between the selenoxo form (372) and the eneselenol form (373) lies far over on the side of the latter species which acts mainly as a carbon nucleophile in its reaction with propargylic bromides, thus leading directly to allenic selenoates (374). Picosecond laser-flash photolysis has been employed620to study intramolecular electron-transfer and spin-state interconversions in a valence tautomeric cobalt complex containing a semiquinone anion as ligand. Finally, although little is known about the factors which favour the intramolecular proton transfer within a transition metal complex [from coordinated dihydrogen to a co-ligand which acts as the GM(H)(HL)(L),an instance has recently been reported6*’ base, viz. M(V’-H~)(L)~ (M = Os, L = quinoline-8-thiolate) where both tautomers have been observed simultaneously. References Petrisko, M. and Pasek, J., Chem. Prum., 45, 17 (1995).

’ Davies, C. J., Heaton, B. T., and Jacob, C., 1 Chem. Sac., Chem. Commun., 1995, 1177. ’

ti

lo I

I’

I’

14

I’ l6

17

Is l9

2o

’’ 23 24 25

*’

26

”

Matsumoto, K., Kato, M., Sakamoto, T., and Kikugawa, Y., 1 Chem. Res. (S), 1995, 34. Ha, E. K., Chae, W. K., and Park, B. S., Bull. Korean Chem. Sac., 16, 899 (1995). Fishbein, J. C. and McClelland, R. A,, 1 Chem. Sac., Perkin Tmns. 2, 1995, 653. Fishbein, J. C. and McClelland, R. A,, 1 Chem. SOC., Perkin Trans. 2, 1995, 663. Langhals, H. and Unold P. von, Angew. Chem., Int. Ed. Engl., 34, 2234 (1995). Gerasimova, T. N. and Kolchina, E. F., Usp. Khim., 64, 142 (1995). Kolchina, E. F. and Gerasimova, T. N., Im. Akad. Nauk, Sex Khim., 1993, 110 I . Garanti, L., Molteni, G., and Zecchi, G., 1 Chem. Rex (S), 1995, 276. Davies, S. G . and Hume, W. E., Tetmhedron Lett., 36, 2673 (1 995). Wubbels, C. G., Cotter, W. D., Sanders, H., and Pope, C., 1 Org. Chem., 60, 2960 (1995). Pluta, K., 1 Heterocycl. Chem., 32, 1245 (1995). Georgantji, A. and Spyroudis, S., Tetruhedron Lett., 36, 443 (1995). Murata, S., Miura, M., and Tomioka, H., 1 Chem. Sac., Chem. Commun., 1995, 1255. Vogt, A,, Kouwenhoven, H. W., and Prins, R., Appl. Catal. 123, 37 (1995). Kobayashi, S., Moriwaki, M., and Hachuja, I., 1 Chem. Sac., Chem. Commun., 1994, 1527. Andrew, D., Islet, B. T. D., Margaritis, A,, and Weedon, A. C., 1 Am. Chem. Sac., 117, 6132 (1995). Moon, J. M., Jeon, I. C., and Kim, S. S., Bull. Korean Chem. Sac., 16, 6 (1995). Arai, T., Tobita, S., and Shizuka, H., 1 Am. Chem. Sac., 117, 3968 (1995). Suau, R., Tores, G., and Valpuesta, M., Tetrahedron Lett., 36, 1311 (1995). Suau, R., Valpuesta, M., and Torres, G., Tetruhedron Lett., 36, 1315 (1995). Jimenez, M. C., Leal, F!, Miranda, M. A,, and Tomos, R., 1 Chem. Sac., Chem. Commun., 1995, 2009. Pitchumani, K., Velusamy, P., Banu, H. S., and Srinivasan, C., Tetvahedron Left., 36, 1149 (1995). Kabilan, S., Krishnasamy, K., and Sankar, P., Oxid. Commun., 17, 264 (1994). Jung, M. E., Jachest, D., Khan, S. I., and Kim, C., Tetrahedron Lett., 36, 361 (1995). Akai, S., Takeda, Y., Iio, K., Yoshida, Y., and Kita, Y., 1 Chem. Sac., Chem. Commun., 1995, 1013. Akai, S., Iio, K., Takeda, Y., Ueno, H., Yokogawa, K., and Kita, Y., 1 Chem. Sac., Chem. Commun., 1995, 2319.

29

30

Kuethe, J. T., Cochran, J. E., and Padwa, A., 1 Org. Chem., 60, 7082 (1995). Abe, H., Itani, J., Masunari, C., Kashino, S., and Harayama, T., 1 Chem. SOC.,Chem. Commun., 1995, 1197.

31

32 33

34

” 36 37

Findlay, J. B. C., Fishwick, C. W. G., Kersey, 1. D., and Ward, P., Tetrahedron Left.,36, 2299 (1995). Kersey, I. D., Fishwick, C. W. G., Findlay, J. B. C., and Ward, P., Tetrahedron, 51, 6819 (1995). Seong, J. H. and Paik, Y.-S., 1 Koreun Chem. SOC.,38, 924 (1994). Kusama, H., Uchiyama, K., Yamashita, Y., andNarasaka, K., Chem. Lett., 1995, 715. Kobayashi, M., Uneyama, K., Hamada, N., and Kashino, S., 1 Org. Chem., 60, 6402 (1995). Su, M.-D., 1 Org. Chem., 60, 6621 (1995). Eberson, L., Hartshom, M. F!, Robinson, W. T., and Timmermanvaughan, D. J., Acta Chem. Scand., 49, 571 (1995).

15 Molecular Rearrangements

543

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39

\--

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I9O 19'

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226 227

z28 229 230 23' 232

233

234

23s 236

237 238

239 240 241

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548 299

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2033.

338

Baldwin, J. E., Adlington, R. M., Crouch, N. l?, Hill, R. L., and Laffey, T. G., Tetrahedron Lett., 36, 7925 (1995). \

33y

I

Hiscock, S. D., Isaacs, N. S., King, M. D., Sue, R. E., White, R. H., and Young, D. J., 1 0%.Chem., 60, 7166 (1995).

340 341 342

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348 34y

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15 Molecular Rearrangements

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350 35 I

”’

550

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402

403

I5 Molecular Rearrangements 45'

452 453 454

551

Shimada, K., Otaki, A., Yanakawa, M., Mabuchi, S., Yamakado, N., Shimoguchi, T., Inoue, K., Kagawa, T., Shoji, K., and Takikawa, Y., Chem. Lett., 1995,925. Stamos, I. K. and Kotzamani, H. K., 1 Heterocycl. Chem., 32,947 (1995). Uneyama, K., Maeda, K., Tokunaga, Y., and Itano, N., 1 Org. Chem., 60,370 (1995). Ceccherelli, P., Curini, M., Epifano, F., Marcotullio, M. C., and Rosati, O., Synth. Cornmun., 25, 301 (1995).

455

456

457 458 459 460

461

462 463 4M

465

466 467 468 469 470

Uyehara, T., Takehara, N., Ueno, M., and Sato, T., Bull. Chem. SOC.Jpn, 68,2687 (1995). de Lucas, N. C., Andraos, J., Netto-Ferreira, J. C., and Scaiano, J. C., Tetrahedron Lett., 36,677 (1995). Chantegrel, B., Deshayes, C., and Faure, R., Tetrahedron Left., 36,7859 (1995). Pendrak, I. and Chambers, P. A., 1 Org. Chem., 60,3249 (1995). Nabeta, K., Ishikawa, T., Kawae, T., and Okuyama, H., 1 Chem. Sac., Chem. Commun., 1995,681. Nabeta, K., Kigure, K., Fujita, M., Nagoya, T., Ishikawa, T., Okuyama, H., and Takasawa, T., 1 Chem. Sac., Perkin Tmns. I , 1995, 1935. Matsumoto, T., Takeda, Y., Soh, K., Sakamoto, M., and Imai, S . , Bull. Chem. Sac. Jpn, 68,2349 (1995). Leclaire, M., Pericaud, F., and Lallemand, J. Y., 1 Chem. Sac., Chem. Cornmun., 1995,1333. Paquette, L. A. and Wang, H.-L., Tetmhedron Lett., 36,6005 (1995). Dhillon, R. S. and Battu, R. S., Indian 1 Chem., 34B,964 (1995). Polovinka, M. €?, Korchagina, D. V, Shcherbukhin, V V, Gatilova, Y. V, Rybalova, T. V, Zefirov, N. S., and Barkhash, V A., Tetmhedron Lett., 36, 8093 (1995). Fitjer, L., Malich, A,, Paschke, C., Kluge, S., Gerke, R., Rissom, B., Weiser, J., and Noltemeyer, M., 1 Am. Chem. Sac., 36,9180 (1995). Magnus, P., Diorazio, L., Donohoe, T., Giles, M., F'ye, I?, Tarrant, J., and Thom, S., 1 Chem. Sac., Chem. Comrnun., 1995, 1935. Chen, S.-H., Huang, S., and Roth, G . I?, Tetrahedron Lett., 36,8933 (1995). Datta, S. K., Gosh, S. K., Majumdar, K., and Das, S., Indian 1 Chem., 34B,960 (1995). Duefias, J., Garcia-Granados, A,, Martinez, A,, Onorato, E., and P m , A,, 1 Org. Chem., 60, 2170 (1995).

471 472

473 474 475

476

477 478

Duefias, J., Garcia-Granados, A,, Martinez, A,, and Parra, A,, 1 0%.Chem., 60,7552 (1995). Moller, S., Weiss, D., and Beckert, R., Liebigs Ann. Chem., 1995,1397. Barlaam, B., Boivin, J., Elkaim, L., Eltonfarr, S., and Zard, S . Z., Tetmhedron, 51, 1675 (1995). Dorta, R. L., Freire, R., Martin, A., and Sdrez, E., Tetrahedron Lett., 36, 7309 (1995). Madsen, R. and Fraser-Reid, B., 1 Org. Chem., 60,772 (1995). Ldpez, J. C., Gbmez, A. M., Valverde, S., and Fraser-Reid, B., 1 0%.Chem., 60,3851 (1995). Kawana, M. and K d a r a , H., Synthesis, 1995,544. Kumazawa, T., Ohki, K., Ishida, M., Sato, S., Onodera, J. I., and Matsuba, S., Bull. Chem. Sac. Jpn, 68, 1379 (1995).

479 480

481 482 483

484 485 486

487 488 489 490

491 492

493 494

495 496

497 498 499

Stoltz, B. M. and Wood, J. L.,Tetrahedron Lett., 36,8543 (1995). Jandu, K. S. and Selwood, D. L., 1 Org. Chem., 60,5170 (1995). Teuber, H. J. and Lahnstein, O., 1 Prakt. Chem., 337,456 (1995). Heathcock, C. H. and Joe, D., J Org. Chem., 60, 113 1 (1 995). Lewin, G., Schnaeffer, C., and Lambert, P. H., 1 Org. Chem., 60,3282 (1995). Assouz, A. S. P., Spectrosc. Lett., 28, 1 (1995). Kitamura, M. and lchihashi, H., Stud. Surl: Sci. Catal., 90,67 (1994). Ushikubo, T. and Wada, K., 1 CaraL, 148, 138 (1994). Yashima, T., Miura, K., and Komatsu, T., Stud. Su$ Sci. Catal., 84, 1897 (1994). Katada, N., Tsubouchi, T., Niwa, M., and Murakami, Y., Appl. Caral., 124, 1 (1995). Jha, B. K. and Kulkami, B. D., Ind. Eng. Chem. Res., 34, 3826 (1995). Kusama, H., Yamashita, Y., and Narasaka, K., Bull. Chem. SOC.Jpn, 68,373 (1995). Yamamoto, Y. and Ogawa, Y., Yakugaku Zasshi, 115,256 (1995). Bhawal, B. M., Mayabhate, S. €?, Likhite, A. I?, and Deshmukh, A. R. A. S., Synth. Commun.,25,33 15 (1995). Levai, A., Toth, G., Halasz, J., Timar, T., Frank, L., and Hosztafi, S., Heterocycles, 38, 305 (1994). Hu, H., Jagdmann, G. E., Hughes, €? F., and Nichols, J. B., Tetrahedim Lett., 36,3659 (1995). Yokomatsu, T., Yoshida, Y., Nakabayashi, N., and Shibuya, S., 1 Urg. Chem., 59,7562 (1994). Nguyen, M. T., Int. 1 Mass Spectrom. Ian Processes, 136,45 (1994). Nguyen, M. T., Raspoet, G., and Vanquickenborne, L. G., 1 Chem. Sac., Perkin Trans. 2, 1995, 1791. Laurent, A,, Jacquault, P., Di Martino, J.-L., and Hamelin, J., 1 Chem. Sac., Chem. Cornmun., 1995,1101. El-Ahl, A.-A. S., Elmorsy, S. S., Soliman, H., and Amer, F. A,, Tetrahedron Lett., 36,7337 (1995). Kroemer, R. T., Gstach, H., Liedl, K. R., and Rode, B. M., Chem. Phys. L e a , 231,289 (1994). Ovchinnikov, I. V, Blinnikov, A. N., Makhova, N. N., and Khmelnitskii, L. I., Mendelem Commun., 1995, 58.

552

Organic Reaction Mechanisms 1995

Achab, S., Guyot, M., and Potier, P., Tetrahedron Lett., 36,2615 (1995). Vangveravong, S. and Nichols, D. E., 1 Org. Chem., 60,3409 (1995). 504 Zhao, Y., Yang, T., Lee, M., Lee, D., Newton, M. G., and Chu, C. K., 1 Org. Chem., 60, 5236 (1995). 505 Es-Sayed, M., Devine, P., Burgess, L. E., de Meijere, A., and Meyers, A. I., 1 Chem. Soc., Chem. Commun., 1995, 141. 506 Ramsden, C. A. and Rose, H. L., 1 Chem. Soc., Perkin Trans. I , 1995, 615. 507 Buccigross, J., Glover, S. .A,, Hammond, G. P., and Rowbottom, C. A,, Aust. 1 Chem., 48,353 (1995). 508 Kaye, P. T., Mphahlele, M. J., and Brown, M. E., 1 Chem. Soc., Perkin Tmns. 2, 1995, 835. SOY Kaye, P. T.and Mphahlele, M. J., Synth. Commun., 25, 1495 (1995). 510 Gracias, V, Milligan, G. L., and Aubt, J., 1 Am. Chem. SOC.,117, 8047 (1995). 511 Milligan, G. L., Mossman, C. J., and Aube, J., 1 Am. Chem. SOC., 117, 10449 (1995). 512 Noms, P., Horton, D., and Levine, B. R., Tetrahedron Lett., 36,781 1 (1995). 513 Pearson, W. H. and Fang, W., 1 Org. Chem., 60,4960 (1995). 514 Evans, I? A. and Modi, D. P., 1 Org. Chem., 60,6662 (1995). 515 Makhova, N. N., Blinnikov, A. N., and Khmelnitskii, L. I., Mendeleev Commun., 1995, 56. 516 Marchand, A. P., Sorokin, V. D., Rajagopal, D., and Bott, S. G., Heterocycles , 40, 223 (1995). 517 Alcaide, R., Aly, M. F., and Sierra, M. A., Tetrahedron Lett., 36,3401 (1995). 518 Paryzek, Z. and Blaszczyk, K., Liebigs Ann. Chem., 1995, 341. 519 Demnitz, E W. J., Philippini, C., and Raphael, R. A., 1 Org. Chem., 60, 5114 (1995). 520 Mereyala, H. B. and Guntha, S., Tetmhedmn, 51, 1741 (1995). 521 Kelly, D. R., Knowles, C. J., Mahdi, J. G., Taylor, I. R., and Wright, M. A., 1 Chem. Soc., Chem. Commun., 1995, 729. 522 Lemoult, S. C., Richardson, P. F., and Roberts, S. M., 1 Chem. SOC.,Perkin Trans. I , 1995, 89. 523 Adger, B., Bes, M. T., Grogan, G., McCague, R., Pedragosa-Moreau, S., Roberts, S. M., Villa, R., Wan, €? W. H., and Willetts, A. J., J. Chem. SOC., Chem. Commun., 1995, 1563. 524 Gagnon, R., Grogan, G., Roberts, S. M., Villa, R., and Willetts, A. J., 1 Chem. Soc., Perkin Trans. I , 1995, 1505. 525 Fleming, I., Henning, R., Parker, D. C., Plant, H. E., and Sanderson, I? E. J., 1 Chem. Soc., Perkin Trans. I , 1995, 317. 526 Pereira, S. and Srebnik, M., 1 Org. Chem., 60,4316 (1995). 527 Zheng, B. and Srebnik, M., Tehahedron Lett., 36, 5665 (1995). 528 Takahashi, T., Kotora, M., and Xi, Z., 1 Chem. SOC.,Chem. Commun. 1995, 1503. 529 Eriksen, J., Monsted, L., and Mmsted, O., Acta Chem. Scand., Ser B, 49, 713 (1995). 530 Dotz, K. H., Stinner, C., and Nieger, M., 1 Chem. Soc., Chem. Commun., 1995, 2535. 53 I Hemdon, J. W., Hill, D. K., and McMullen, L. A,, Tetrahedron Left.,36,5687 (1995). 532 Adachi, T., Hughes, D. L., Ibrahim, S. K., Okamoto, S., Pickett, C. J., Yabanouchi, N., and Yoshida, T., 1 Chem. Soc.. Chem. Commun., 1995, 1081. 533 Cano, M., Heras, J. V., Monge, A,, Pinilla, E., Santamaria, E., Hinton, H. A., Jones, C. J., and McCleverty, J. A,. 1 Chem. SOC..Dalton Tmns.. 1995. 2281. 534 Pizzko, A., Shnchez, L., Altmann,’M., Monge, A,, Ruiz, C., and Carmona, E., 1 Am. Chem. Soc., 117, 1759 (1995). 535 Legzdins, P., Young, M. A,, Batchelor, R. J., and Einstein, F. W. B., 1 Am. Chem. SOC.,117, 8798 (1995). 536 Quayle, F!, Rahman, S., and Herbert, J., Tetrahedmn Letf.,36,8087 (1995). 537 Su, F!-C., Chiang, S.-J., Chang, L.-L., Chi, Y., Peng, S.-M., and Lee, G.-H., Organometallics, 14, 4844 (1995). 538 Takemoto, Y., Yoshikawa, N., and Iwata, C., 1 Chem. Soc., Chem. Commun., 1995, 631. 53y Khumtaveepom, K. and Alper, H., Acc. Chem. Res., 28, 414 (1995). 540 de 10s Rios, I., Tenorio, M. J., Puerta, M. C., and Valerga, I?, 1 Chem. Soc., Chem. Commun., 1995, 1757. 541 Iwasawa, N., Owada, Y., and Matsuo, T., Chem. Lett., 1995, 115. 542 Murakami, Y., Hisaeda, Y., Ogawa, A,, and Ohno, T., 1 Chem. SOC.,Perkin Trans. 2, 1995, 189. 543 Tada, M., Mutoh, N., and Shimizu, T., 1 Org. Chem., 60, 550 (1995). 544 Cheong, M., Bae, S., and Lee, K. B., 1 Chem. SOC.,Chem. Commun., 1995, 1557. 545 Tamao, K., Sun, G. R., and Kawachi, A., 1 Am. Chem. SOC.,117, 8043 (1995). 546 Kluwe, C. and Davies, J. A., Organometallics, 14, 4257 (1995). 547 Blum, J., Beer-Kraft, H., and Badrieh, Y., 1 Org. Chem., 60 5567 (1995). 548 Ogoshi, S., Fukunishi, Y., Tsutsumi, K., and Kurosawa, H., 1 Chem. SOC.,Chem. Commun., 1995,2485. 549 Kagabu, S., Tsuji, H., Kawai, I., and Ozeki, H., BUN. Chem. SOC. Jpn, 68,341 (1995). Kataoka, T., Matsumoto, H., Iwama, T., and Shimizu, H., Chem. Lett., 1995, 459. 551 Kirms, M. A,, Salcido, S. L., and Kims, L. M., Tetrahedron Lett., 36, 7979 (1995). 552 Ishihara, K., Hanaki, N., and Yamamoto, H., Synlett., 1995, 721.

502 503

15 Molecular Rearrangements 553

554

555 556

557 558

559 560 561

563 5M

565 566

567 569 570

57’

572

573 574

553

Roy, A., Gurudutt, K. N., and Rao, S., Indian 1 Chem., 34B, 636 (1995). Jung, M. E. and Damico, D. C., 1 Am. Chem. Sac., 117, 7379 (1995). Raman, J. Y,Lee, H. K., Vleggaar, R., and Cha, J. K., Tetrahedron Left,36, 3095 (1995). Lebideau, F., Aubert, C., and Malacria, M., Tetrahedron: Asymmee, 6, 697 (1995). Vanaar, M. P. M., Thijs, L., and Zwanenburg, B., Tetrahedron, 51, 11223 (1995). Lindel, T. and Franck, B., Tetrahedron Left.,36, 9465 (1995). Johner, M., Rihs, G., Giirtler, S . , and Otto, H.-H., Helv. Chim. Acta, 77, 2147 (1994). Dussault, P. H. and Zope, U. R.,Tefmhedron Left., 36, 2187 (1995). Makosza, M. and Sypniewski, M., Tetrahedron, 51, 10593 (1995). Liu, Q. Y., Marchington, A. P., Boden, N., and Raper, C. M., Synletf., 1995, 1037. ibuka, T., Nakai, K., Habashita, H., Hotta, Y., Otaka, A,, Tamamura, H., Fujii, N., Mimura, N., Miwa, Y., Taga, T., Chounan, Y., and Yamamoto, Y., 1 Org. Chem., 60, 2044 (1995). Nakai, K., Ibuka, T., Otaka, A., Tamamura, H., Fujii, N., and Yamamoto, Y., Tetrahedron Left,36, 6247 (1995).

Semenov, Y P., Zh. 0%.Khim., 30, 59 (1994). Averdung, J., Mattay, J., Jacobi, D., and Abraham, W., Tetrahedron, 51, 2543 (1995). Nadir, U. K. and Arora, A., J. Chem. Sac., Perkin Trans. 1 , 1995, 2605. Dey, F! D., Sharma, A. K., Rai, S . N., and Mahajan, M. P., Tefmhedron, 51, 7459 (1995). Poon, T. H. W., Park, S . H., Elemes, Y., and Foote, C. S., 1 Am. Chem. Sac., 117, 10468 (1995). Griffith, D. A. and Heathcock, C. H., Tetrahedron Left.,36, 2381 (1995). Palmer, C. E and McCague, R., 1 Chem. Soc., Perkin Tmns. I , 1995, 1201. Alcaraz, G., Wecker, U., Baceiredo, A,, Dahan, F., and Bertrand, G., Angew Chem., Inf. Ed. Engl., 34, 1246 (1995).

Bird, P., Eames, J., Fallis, A. G., Jones, R. V. H., Roddis, M., Sturino, C. F., O’Sullivan, S . , Warren, S . , Westwell, M. S., and Worrall, J., Tefmhedron Lett., 36, 1909 (1995). Djakovitch, L., Eames, J., Jones, R. V H., McIntyre, S . , and Warren, S . , Tetrahedron Left., 36, 1723 (1995).

575

Yamazaki, S., Tanaka, M., Inoue, T., Morimoto, N., Kumagai, H., and Yamamoto, K., 1 Org. Chem., 60, 6546 (1995).

576 577 578

579

5E2 583

584 585 586

587

”*

589

590 591

5y2 5y3

594 595

596

597 598 599

601

602 603

Xiong, Y., Xia, H., and Moore, H. W., 1 Org, Chem., 60, 6460 (1995). Chase, C. E., Jarstfer, M. B., Arif, A. M., and West, F. G., Tefmhedron Lett., 36, 8531 (1995). Maki, S., Konno, K., and Takayama, H., Chem. Lett., 1995, 559. Marchand, A. P., Rajagopal, D., and Bott, S . G., 1Heterocycl. Chem., 32, 1409 (1995). Li, X., Niu, C., and Miller, M. J., Tetrahedron Left., 36, 1617 (1995). Kataoka, T. and Iwana, T., Tetrahedron Left, 36, 5559 (1995). Dowd, I?, Zhang, W., and Mahmood, K., Tefrahedron, 51, 39 (1995). Morales-Rios, M. S., Martinez-Galero, N. X., Loeza-Coria, M., and Joseph-Nathan, I?, 1 0%.Chem., 60,

6194 (1995). Capasso, S., Kirby, A. J., Salvadori, S., Sica, F., and Zagari, A,, 1 Chem. Sac., Perkin Tmns. 2,1995,437. Benati, L., Calestani, G., Montevecchi, P. C., and Spagnolo, F,! 1 Chem. Sac., Perkin Tmns. 1,1995, 1381. Lorenc, L., PavloviC, V., BjelakoviC, and MihailoviC, M. L., 1Chem. Res. (S), 1995, 468. Marek, R., Potizek, M., and Sapik, M., Tetrahedron Lett., 36, 8101 (1995). Lee, K., Turnbull, F!, and Moore, H. W., J Org. Chem., 60, 461 (1995). Chtnede, A,, Pothier, F!, Sollogoub, M., Fairbanks, A. J., and Sinay, F!, 1 Chem. Sac., Chem. Commun., 1995, 1373. Bamatraf, M. M. M., Vernon, J. M., and Wilson, G. D., 1 Chem. Sac., Perkin Trans. I , 1995, 1647. Sanchez, A. M., and de Rossi, R. H., 1 Org. Chem., 60,2974 (1995). Kanemasa, S. and Tsuruoka, T., Chem. Lett., 1995, 49. Cao, D., Kolshom, H., and Meier, H., Tetrahedron Lett., 36,7069 (1995). Bunting, J. W., Kanter, J. F!, Nelander, R., and Wu, Z., Can. 1 Chem., 73, 1305 (1995). Harcourt, M. F! and More O’Ferrall, R. A,, 1Chem. Sac., Perkin Tmns. 2, 1995, 1415. Morley, J. O., 1 Phys. Chem., 99, 5956 (1995). Costantino, L., Rastelli, G., Rossi, M. C., and Albasini, A., 1 Chem. SOC.,Perkin Trans. 2, 1995, 227. Peter, M. G. and Men, A,, Tetrahedron: Asymmefry, 6, 839 (1995). Nishio, T. and Yamamoto, H., 1 Heterocycl. Chem., 32, 883 (1995). Langschwager, W. and Hoffmann, H. M. R., Liebigs Ann. Chem., 1995, 797. Desenko, S . M., Khim. Geterotsikl. Soed. 11, 1995, 147. Kurasawa, Y., Takada, A,, and Kim, H. S., Heterocycles, 41, 1805 (1995). Kim, H. S . , Heterocycles, 41, 2057 (1995). Kim, H. S. and Okamoto, Y., 1 Heferocycl. Chem., 32, 445 (1995).

554

Organic Reaction Mechanisms 1995

608

Kim, H. S. and Okamoto, Y., 1 Heterocycl. Chem., 32, 531 (1995). Kim, H. S. and Okamoto, Y., 1 Heterocycl. Chem., 32, 671 (1995). Kotschy, A,, Hajbs, G., and Messmer, A., 1 0%.Chem., 60,4919 (1995). Elhammadi, A,, Elmouhtadi, M., Notario, R., Werner, A,, and Elguero, J., 1 Chem. Sac., Perkin Tmns. 2,

‘09

Ozeki, H., Cockett, M. C. R., Okuyama, K., Takahashi, M., and Kimura, K., 1 Phys. Chem., 99, 8608

610

Zheglova, D. K., a n d i n , V, and Koltsov, A. I., 1 Chem. Res. (S), 1995, 32. Katritzky, A. R. and Ghiviriga, I., 1 Chem. Sac., Perkin Trans. 2, 1995, 1651. Alarcon, S. H., Olivieri, A. C., Labadie, G. R., Craven, R. M., and Gonzalezsierra, M., Tetrahedron, 51,

‘05

‘06

607

61 I

612

613 614 615 616 617 618 619

620 621

1995, 379. (1995).

4619 (1995).

Orozco, M. and Luque, F. J., 1 Am. Chem. Soc., 117, 1378 (1995). Alhambra, C., Luque, F. J., Estelrich, J., and Orozco, M., 1 0%.Chem., 60, 969 (1995). Contreras, J. G. and Alderete, J. B., THEOCHEM, 334, 223 (1995). Contreras, J. G. and Alderete, J. B., 1 Phys. Org. Chem., 8, 395 (1995). Amiel, P., Mahamoud, A,, Brouant, P., Galy, J. I?, Barbe, J., Karolak-Wojciechowska, J., and Posel, M., Can. 1 Chem., 73, 1258 (1995). Popkova, V Ya., Anisimov, V M., Dolenko, G. N., Semenenko, M. N., and Fedoseev, V M., 1 Chem. Sac., Perkin Trans. 2, 1995, 1375. Kanda, T., Ezaka, T., Murai, T., and Kato, S., Tetmhedron Left.,36, 2807 (1995). Adams, D. M., Li, B. L., Simon, J. D., and Hendrickson, D. N., Angew. Chem., Znt. Ed. Engl., 34, 1481 (1995).

Schlaf, M. and Moms, R. H., 1 Chem. Sac., Chem. Commun., 1995, 625.

Author Index In this index bold figures relate to chapter numbers, roman figures are reference numbers

Aaby, K.,8 , 2 4 Abbas, I.M., 15, 95 Abbass, I.M., 14, 56 Abbelin, J., 14, 122 Abbott, D.A., 1, 102 Abbott, D.E., 11, 107 Abbotto, A., 11, 26 Abd Elhafez, F.A., 1,86a Abdallah, M.A., 14,56; 15, 95 Abdelaal, S.M., 15, 77 Abdelaziz, N.A., 3, 187 Abdrakhmanov, 1.B.. 15, 157 Abduljaber, M.H., 10, 78 Abe, H., 7. 58; 15, 30 Abe, T., 3, 65 Abelt, C.J., 4, 96 Abiko, T., 15, 242, 243 Ablelom, T., 6, 82 About-Jaudet, E., 15, 255 Aboutayab, K., 3, 135 Abraham, W., 6.57; 14, 35; 15, 566 Abrash, S.A., 12, 43 Abu-Hasanayn, F., 11, 61 Abu-Raqabah, A,, 4, 6 Achab, S., 15, 502 Achmatowicz, R., 15,363 Acuner Tunca, A., 1 . 4 Adachi. T., 15, 532 Adam, W., 3, 204; 4, 126, 236, 238; 5, 103, 139, 143145, 160, 168; 10, 32; 14, 126, 167, 168, 196; 15, 328,417,434 Adamczyk, M., 15, 83 Adamo, C., 4, 12 Adamowicz, L., 11, 13 Adams, D.M., 15, 620 Adarnson, G., 14, 13 Adcock, J.L., 5, 196 Adcock, W., 1, 153; 3, 104, 173

Adediran. S.A.. 2, 84

Adger, B., 5, 151; 15, 523 Adinarayana, M., 5, 27 Adlington, R.M., 15, 338 Adolfsson, H., 10, 19 Afanasyev, V.N., 11, 121 Afriyie, Y.,15, 336 Agarrabeitia, A.R., 15, 301 Agarwal, D.D., 13,45 Aggarwal, R., 2, 172 Aggarwal, V.K., 1, 110; 11, 80 Ahamed, B.K.A., 5 , 4 4 Ahbala, M., 3, 174 Ahlbrecht, H., 11. 18 Ahlers, W., 9, 52 h m a n , J., 15, 228, 229,279 Ahmed, F., 5, 73 Ahmed, G.A.-W., 10.79 Ahrweiler, M., 15, 434 Akai, S., 15, 27, 28, 419 Akar, A., 1, 4 Akasaka, T., 6, 98 Akazome, M., 3, 155 Akcakaya, N., 5, 50 Akita, H., 11, 106 Akita, T.. 4, 56 A1 Dulayymi, A.R., 6, 33 A1 Dulayymi, J.R., 6, 33 A1 Hariri. M., 14, 182 Al-Ajlouni, A.M., 5, 101 Al-Awadi, N.A., 2, 79; 12, 22, 26 Al-Gurashi, M.A.M.R., 10,45 Al-Husaini, A.H., 14, 17 Al-Lohedan, H.A., 2, 122; 7, 46, 86; 15, 99 Al-Omm, EA., 2, 79; 12, 22 Alagona, G., 11, 109 Alarcon, S.H., 15,612 Albasini, A,, 15, 597 Alberti, A., 4, 9 Albini, A., 4, 91-93; 7, 54 Albrecht, K., 4,249 Albu, C., 2, 124

555

Alcaide, B., 10, 26 Alcaide, R., 15, 517 Alcaraz, G., 6, 47; 15, 572 AlcBzar, V., 13, 8 1 Alcudia, F., 15, 236 Alder, R.W., 6, 90 Alderete, J.B., 15, 615, 616 Aldridge, D.C., 2, 50; 12, 73 Aleksandrov, G.G., 7, 105 Aleksiev, D.I., 13, 26 Alexiev, D.I., 13, 93 Alfassi, Z.B., 4. 3 8 , 3 9 Alhaji, N.I., 5, 3 1 Alhaji, N.M.I., 1, 147; 5, 10 Alhambra, C., 1 5 , 6 1 4 Ali, M., 1, 7a, 7b Ali, M.M., 4, 75, 76 Ali, Sk.A., 14, 17 Alifanov, E.N., 7, 109 Allen, A.D., 1, 12a, 12b; 10, 96; 15,306 Allen, C.W., 15, 113 Allen, D.A., 13, 82 Allen, P.R., 6, 90 Allen, W.D., 10, 6 4 Allin, S.M., 11.66 Allouche, A., 6,79; 10, 110 Almansour, A.I., 10, 44 Ahajar, M.S., 4, 22 Alonso, J.J.P.,11, 30 Alper, E., 1, 123 Alper, H., 13,41, 55; 15, 109, 539 Altmann, M., 15, 534 Alvarez Martinez, R., 9, 67 Alvarez-Builla, J., 1,36 Alvarez-Larena, A., 1, 168 Alvarez-Macho, M.P., 5, 14, 22 Alvemhe, G., 13, 24 Alvira, E., 14, I19 Aly, M.F., 15,517 Amadji, M., 13, 16

556 Amann, C.M.. 2, 51 Amano, M., 14, 217 Amatore, C., 4, 116, 117; 7, 1 I; 10,3 Amer, A,, 15, 102 Amer, F.A., 15, 499 Amiel, P., 15, 617 Amrollahnadjdabadi, A,, 3, I37 Aniyes, T.L., 1, 9b; 9, 27 Anand, N., 15, 173 Ananda, S., 5, 120 Anastasi, C., 5, 170, 171 Anaud, R., 15. 280 Ancel, J.-E., 9, 16 Anders, E., 11, 90 Andersen, K.K., 2, 215 Andersen, M.L., 15, 372 Anderson, D.J., 15, 79 Anderson, G.B., 9, 42 Anderson, J.C., 15, 225 Anderson, M.A., 4, 237 Anderson, P.D.J., 9, 56; 15, 41 Anderson, I., 2, 169 Ando, H., 8, 42 Ando, K., 14, 188 Ando, M., 1, Sob; 3, 177; 14, 8 Ando, W., 6, 98 Andraos, J.. 15, 456 Andres, J., 1, 150; 5, 217 Andres, J.L., 12, 42; 15, 184 Andrew, D., 4, 234, 235; 14, 12; 15, 18 Andrews, S.R., 9, 61 Andrianov, V.G., 5,45, 46 Andrieux, C.P., 4, 213 Andrievsky, A.M., 8, 9 Andrijewski, G., 5, 48 Antin, Z., 2, I17 Anfinogenov, V.A., 2, 103; 5, 152 Anghcl, D.F., 2, 124 Anglada, J.M., 6, 9 Anh, N.T., 1, 84; 13, 69 Anies, C., 3, 39 Anisimov, V.M., 15, 618 Anker, D., 13, 24 Annunziata, R., 14, 39 Anouti, M., 7, 30 Anslyn, E., 1, 61b Anslyn, E.V., 1, 129; 11, 33 Antalik, M., 2, 107 Antelo, J.M., 5, 1 18; 11, 139I42 Antipin, IS., 2, 13 Aoki, I., 1, 159; 5, 200 Auuad, E., 7,57 Apaydin, G., 2, 156; 12, 41 Apeloig, Y., 4, 249; 6. 101; 12, 76; 14, 28, 90 Apostolova, E.S., 5, I8 1

Author Index Arai, T., 15, 20, 394 Araneo, S., 3, 171 Arasasingham, R.D., 2, I18 Arbelot, M., 10, 110 Arcand, H.R., 14, 212 Arce, F., 5, 118; 11, 139-142 Arcelli, A,, 2, 116; 10, 54 Arduengo, A.J., 6, I9 Arends, I.W.C.E., 3, 64 Arey, J., 3, 202 Arienti, A., 8, 32 Arif, A.M., 15, 241, 577 Arimitsu, S., 14, 217 Ariza, X., 1, 100; 11, 103 Arjona, 0.. 15, 194 Annesto, D., 1, 162; 15, 300, 301 Armstrong, B.M., 6, 5 Armstrong, K.B., 1, 3a Armstrong, P.L., 15, 166 Arnaud, R., 3, 143; 13, 83; 14, 106 Arnett, E.M., 4, 21; 9, 6; 11, 110 Arnold, D.R., 4, 90 Arnone, A,, 15, 446 Arnone, C., 2, 106; 7, 77 Arora, A,, 10, 36; 15, 567 Arseniyadis, S., 15, 413 Arthur, L.G., 6, 20 Asa, N., 13, 53 Asada, D., 6, 94 Asahara, M., 6, 99 Asao, N., 1, 104; 14, 177 Asao, T., 9, 36, 37 Ascanio, J., 3, 73; 12, 29, 30 Aschi, M., 8, 31; 9, 18 Aschmann, S.M., 1, 165; 3, 92, 202, 203 Asensio, A., 14, 176 Asensio, G., 1, 91; 4, 190 Ashby, E.C., 4, 88, 107-109; 6 , 32; 10, 74 Ashley, J.A., 14, 118 Ashton, P., 15, 82 Ashworth, P., 15, 291 Asmus. K.-D., 3, 89 Assad, A.N., 11, 62 Assercq, J.-M., 15, 196 Assfeld,X., 14, 114 Assouz.A.S.P., 15,484 Asuncion, L.A., 15, 270 Atalla, A.A., 1, 40; 3, 75; 4, 75, 16; 15, 53 Atherton, J.H., 7, 100; 11, 53 Atherton, M., 8, 12 Atkinson, R., 1, 165; 3, 92, 202, 203 Atkinson, R.S., 6, 59; 13, 3338 Atroshchenko, Yu.M., 7, 97, 98, 107, 108

Attina, M., 8, 3 I : 9, 18 Atwell, G.J., 2, 80 AubC, J . , 1, 120; 15, 510, 51 I Aubert, C., 15,330,359, 556 Aubry, J.-M., 5, 167; 14, 165 Aune, J.-P, 4, I 15 Aune, M., 15,343 Aurich, H.. 14, 45 Austen, S.C., 15, 277 Austin, R.E., 15, 196 Autera, J.R., 15, 76 Autrey, T., 3, 66 Aveline, B.M., 4, 262 Avenoza, A,, 14, 199 Averdung, J., 15, 566 Avila, D.V., 3, 88; 4, 37 Axelsson, A,-K., 10, 116 Axenrod, T., 15, 76 Axon, J.R., 3, 151 Ayah, N.L., 11, 147 Aycard, J.-P., 6, 79 Ayoko, G.A., 10.45 Azam, S., 2, 90 Azran, C., 13, 109 Azzena, F., 10, 16 Ba-Saif, S.A., 2, 62 Babayan, A.T., 12, 17 Baceiredo, A,, 6, 47, 96; 15, 572 Bach, R.D., 12,42; 15, 184 Bachi, M.D., 3, 148 Bachrach, S.M., 14, 181; 15, 206, 260, 273 Baciocchi, E., 3, 110, 165; 5, 76, 80; 8, 5 Back, T.G., 13, 101 Backhaus, D., IS. 220,221 Backvall, J.-E., 15, 395 BaCskdy, G.B.. 1, 1 I ; 4, 254; 15,345 Badawi, M., 15, 102 Badca, F., 15, 435 Badrieh, Y., 15, 547 Bae, S., 15. 544 Baerends, E.J., 12, 8 Bagno, A,, 2, 208 Bagryanskaya, I.Yu., 14,44 Bai, T.S.J., 1, 49; 5, 113 Bailey, P.S., 5, 128 Bailey, W.F., 15, 342 Baird, M.S., 6, 33; 15, 396 Bakavoli, M., 14, 5 1 Bakhmutov, Yu.L., 5, 182 Bakhtiar, R., 9, 1.5 Bakke, J.M., 5, 90; 8, 24, 25 Bakker, B.H., 8, 50; 13, 60: 15.41 8 Bakry, R.S., 7, 96 Bakulev, V.A., 15. 97 Balasubramanian, K.K., 15, 258

557

Author Index Balazs, L., 14, 70 Balhuena, P.B., 10, 94 Balci, M., 15, 434 Baldea, I., 5, 1 Baldridge, K.K., 14, 216 Baldwin, J.E., 2, 169: 15, 270, 338 Ball, J.C., 3, 87 Ballesteros, R., 1, 91; 4, 190 Ballistreri, F.P., 5, 72 Bally, T., 4, 142, I43 Balog, A,, 1, 121: 15, 404 Balon, M., 5, 1 1 I Bamatraf, M.M.M., 15, 590 Bambridge, K., 1, 140 Baneqee, A.K., 15, 388 Banerji, K.K., 5, 3, 6, 12 Banerki, K.K., 5, 117 Banert, K., 15, 207 Banks, J.T., 3, 15, 90: 5, 142 Banks, M.R., 14, 150 Bantle, G., 3, 162 Banu, H.S., 15, 24 Banwell, M.G., 9, 73: 15, 319 Bao, B., 10, 92 Bar, N., 5, 199 Bar, T., 15, 187 Barhe. J., 15, 617 Barcock, R.A., 7, 84 Bardan, A.A.EI, 10, 93 Bardia, M.F., 12, 67 Barentsen, H.M., 14, 219, 220 Bargon, J., 4, 185 Barker, E., 6, 59; 13, 36-38 Barkhash, V.A., 9, 74; 15, 465 Barkley, R.M., 4, 87 Barlaam, B., 15,473 Barletta, G.L., 1, 78; 11, 126 Barlow, S.J., 8, 28 Barluenga, J., 14, 125, 131 Barnabas, EA., 1, 144 Barnes, C.L., 14, 21 1 Barnes, J.R., 3, 127 Barnett, D.J., 2, 222 Baron, A., 3, 105 Barone, V., 4, 12 Barr, D.A., 14, 71 Barrahass, S., 2, 21 7 Barrat, M.D., 4,193 Barrett, A.G.M., 13, 96 Barrows, S.E., 9, 71; 14, 91 Barry, J., 5, 183 Bartberger, M.D., 3, I6 I Barth, T., 4, 164 Bartl, J., 9, 34 Bartlett, R.J., 9, 13 Bartnik, R., 6, 84 Bartoletti, A., 2, 132 Barton, D.H.R., 6, 40 Barton, G.J., 2, 169 Barton, T.J., 6, 81: 15, 288 Bartsch, M., 15, 221

Barvian, M.R., 4, 87 Basak, M., 11, 99 Basavaiah, D., 15, 144 Baskaran, S., 14, 54 Basu, N., 10, 35 Batchelor, R.J., 15, 535 Batizat, D.V., 14, 207 Batra, R., 3, I , 163 Batsanov, A.S., 3, 31 Batt, L., 3, 186 Battacharjee, G., 1, 43 Battu, R.S., 15, 464 Baudrillard, V., 11, 70: 15, 365 Baudy-Floc’h, M., 10, 17 Bauer, J.A.K., 15, 277 Bauer, L., 15, 77 Bauld, N.L., 4, 124, 125: 14, 6, 108 Baumann, L., 15,267 Baumgarten, M., 4, 217 Bayly, C.I., 13, 22 Bazureau, J.P., 14, 69 Beake, B.D., 5, 107 Beaudoin, S., 1, 103: 11, 148 Bechaus, H.D., 3, 144 Becher, J., 15, 74 Beck, A.K., 1, 100: 11, 103 Beck, F., 5, 186 Beckert, R., 15,472 Beckhaus, H.-D., 4, 16-18 Beckwith, A.L.J., 3, 84, 151; 14, 13 Bedat, J., 5, 218, 220 Bedovskaya, L.A., 4, 169 Beer-Kraft, H.. 15, 547 Begley, M.J., 3, 31 Begtrup, M., 15, 74 Begue, J.-P., 10, 29: 15, 218 Behera, G.B., 1, 29, 30 Behrens, K., 15, 367 Behrens, R., 15, 76 Beichert, P., 3, 93 Beifuss, U., 14, 139 Bekarek, V., 10, 88 Belal, S.F., 7,96 Beletskaya, I.P., 7, 67; 15,26 1 Belevski, V.N., 4, 169 Belik, A.V., 15, 78 Belikova, N.A., 15, 381 Belk, A.J., 14, 11 Bell, AS., 14, 202 Bell, R., 15, 291 Bell, R.L., 11, 118 Bellos, K., 9, 23: 15, 393 Bellucci, G., 13, 1, 10 Belmeliani, A,, 4, 251 Belohradsk, M., 7,36 Belopushkin, S.I., 4, 169 Belousova, LA., 2, 46 Belyakov, V.A., 3, I9 I Benaglia, M., 14, 39

Benassi, R., 5, 158 Benati, L., 6, 30: 15, 585 Benayoud, F., 10, 29 Bencheqrous, M., 3, 162 Bencsura, A,, 3, 147: 4, 44 Benderskii, V.A., 11, 119 Benhardsson, A,, 4, 230 Benhida, R., 3, 137 Bennet, A.J., 1, 9a; 9, 40 Bennetau, B., 11, 88 Bennett, S.M., 3, 169 Bensadat, A,, 13, 83 Bensasson, R.V., 5, 167; 14, 165 Bentley, J., 4, 58 Bentley, T.W., 2, 67; 9, 88; 10, 112 Bently, J., 4, 205 Beranek, I., 3, 107 Berestovitskaya, V.M., 2, 223 Berezina., T.A.., 14., 44 Berg, U., 1, 154; 5, 197: 10, 59,71 Bergmann, B., 4, 192 Bergmeier, S.C., 6, 58 Bergmeier, S.S., 10, 37 Bergon, M., 2, 68: 12, 1 Bergonzi, C., 2, 68: 12, 1 Berinstain, A.B., 3, 129 Berkes, D., 5, 199 Berliner, M.A., 14, 203 Bernad, P.L., 1, 88; 11, 98 Bernal, M.K., 7,40 Bemardi, A,, 1, 51, 69 Bernardi, F., 14, 89 Bernardinelli, G., 6, 53 Bernasconi, C.F., 10, I , 2; 11, 115: 12, 2, 3; 13, 90-92 Berndt, A,, 6, 82 Bemhardsson, A,, 3, 48 BerrBe, F., 14, 66 Bemsford, D.J., 11, 38 Bershadsky, Y., 4, 162 Bersohn, R., 3, 97; 5, 173 Berson, J., 4, 227 Bertune, M., 9,50: 15,382 Bertran, J., 8, 3; 1 0 , 7 2 Bertrand, G., 6 , 47, 96; 15, 512 Bertrand, M.P., 3, 149 Bertrand, P., 15, 213 Bes, M.T., 5, 151; 15, 523 Besemer, A.C., 3, 172; 5, 106 Beslin, P., 15, 171 Besseris, G.J., 12, 34 Bestmann, H.J., 15, 55 Bethell, D., 7,9 Beugelmans, R., 3, 137; 4, 1 13; 7, 48-50 Bhat, K.I., 5, 33, 34 Bhatnagar, P., 5, 99 Bhattacharyya, S., 7,62

Author Index Bhawal, B.M., 15,492 Bian, N., 6 , 20 Bianchini, R., 13, I Bibas, H., 15, 263 Bickelhaupt, F., 14, 205 Bickelhaupt, EM., 12, 8 Biehl, E., 7, 42 Biehl, H., 5, 172 Bielinyte-Williams, B., 13, I04 BienaymC, H., 9, 16; 15, 131 Bieniecki, A,, 12, 12 Bierbaum, V.M., 11, 112 Bigi, F., 8 , 32, 46 Bilkis, I.I., 4, 81, 223: 5, 206: 7, 15 Rillot, L., 3, 39 Binmore, C., 3, 29 Binmore, G.T., 3, 104 Bird, C.W., 15, 205 Bird, P., 15, 573 Birney, D.M., 14,206 Bitter, I., 14, 70 Bittner, J., 5, 172 Biurrun, C., 10, 26 BjelakoviC, M., 15, 586 Blache, Y., 11, 92 Black, J.R., 10, 44 Black, K.A., 15, 302 Blacklock, T.J., 2, 16 Blackstock, S., 4, 61 Blackstock, S.C., 4, 99, 165 Blackwood, M.E., 4, 204 Blakemore, D.C., 14, 218 Blanch, R.J., 6, 20 Blandamer, M.J., 2, 81, 102 Blask6, A,, 2, 118, 131, 132: 10, 98 Blaszczyk, K., 15, 518 Blechert, S., 4, 94, 130 Bleisch, T.J., 2, 148 Blinnikov, A.N., 15, 501, 515 Blokhim, I.V., 7, 97 Blokzijl, W., 2, 102; 14, I13 Bloodworth, A.J., 3, 166; 15, 282 Blucher, W.G., 8 , 22 Bluni, J., 15, 547 Boach, R.D., 5, IS9 Boaz, N.W., 10, 18 Bobal, P., 2, 44 Bobica, C., 2, 124 Bobyleva, A.A., 15, 381 Bochkova, M.M., 5, 36 Bock, C.W., 15, 186 Bock, H., 4, 166; 9, 91 Bodalski, T., 15, 64 Boden, N., 15, 562 Rodiguel, J., 7, 10 Bodnar, P.M.. 1, 107 Boeckman, R.K., 15, 127 Boclens, M., 13, 29

Boeriu, C., 5, 192 Boese, R., 14, 208 Boeykens, M., 15.67 Bofill, J.M., 6, 9; 11, 128 Bogaert, P., 3, 23 Bogdanov, V.S., 14, 180; 15, 104 Bogdanowicz-Szwed, K., 1, 24: 2, 87 Bogomolov, A.Yu., 13, 25 Bohac, A,, 1, 100; 11, 103 Bohn, B., 5, 172 Bois-Choussy, M., 7, 50 Boissel, P., 4, 180 Boivin, J., 3, 43: 15, 473 Bojarski, A.J., 15, 66 Boland, W., 15, I9 1 Bollmaun, C., 6, 45; 14, 23; 15, 415 Bonati, L., 14, 67 Bonchio, M., 5, 72, 157 Boncic-Caricic, G.A., 12, 28 Bond, A.H., 14, 170 Bondarenkogheorghiu, L., 15, 329 Bonini, C., 5, 63 Bonitacic. M., 3, 89 Bonnet-Delpon, D., 10, 29: 14, 76: 15, 2 I8 Borden, W.T., 3, 25; 4, 229 Bordwell, EG., 2, 15; 4, 33, 34: 11, 24, 25, 75, 111 Borg, R.M., 14, 94 Borghi, R., 4, 188, 189 Borisov, Y., 4, 216 Borisov, Yu.A., 1, 1 1 1 ; 8, 49, 15,38 Borodkin, G.I., 8, 54 Borosky, G.L., 4, 110; 10, 76; 11,69 Bors, W., 3, 191 Borzilleri, R.M., 15, 333, 334 Bosch, E., 4, 138; 5, 105, 108 Bosch, I., 2, 63 Bosnich, B., 1, 64 Bosser, G., 7, 30 Boswell, G.E., 7, 31 Bott, S.G., 14, 162, 163; 15, 4 4 2 , s 16,579 Botta, B., 15, 47 Botta, M., 15, 47 Bottoni, A., 3, 94 Boubaker, T., 7,103 Bouhamra, W., 1, 123 Bouquant, J., 1 2 , 6 5 Bourdet, S., 7, 48, 49 Bourguignon, J., 5, 218, 220 Bourguignon, J.-J., 3, 168 Bourne, G., 14, 64 Bourrinet, L., 15, 395 BouteillerJ-C., 4, 68 Bouvier, J.-P., 15, 371

BouzBouz, S., 4, 85 Bowie, J.H., 11, 4 Bowman, R.W., 3, 36 Boyd, M.J., 2, 141 Boyd, R.J., 3, 196 Bozec-Ogor, S., 12, 74 Bozell, J.J., 15, 397 Bozzi, M., 2, 140 Brace, N.O., 2, 86 Bradamante, S., 11, 26 Bradford, C.A., 4, 244 Bradford,C.L., 14, 10 Bradley, J.C., 15, 354 Bradshaw, J.D., 7, 29 Brailovskii, S.M., 13, 52 Branan, B.M., 14, I70 Brandi. A., 5, 41; 14, 47; 15, 81 Brands, K.M.J, 15, 348 Brandt, B., 15, 336 Brard, L., 13, 50 Braslau, R., 3, 145 Brauman, J.I., 5, 28: 10, 64 Braun, M., 1, 90; 11, 97 Braverman, S., 11, 76a; 15, 373,435 Bravo, A,, 4, 72, 73, 74: 5, 140, 141 Bravo, P., 15,446 Bravo-Zhivotovskii, D., 12, 76; 14, 28 Brede, O., 4, 59, 172 Breitkopf, V., 14, 121 BrembilhA., 2, 129 Breslow, R., 1, 77, SOc, 61a-c, 79b; 2, 163: 11,57; 14, I 15 Brichford, N.L., 15, 119 Bricout, H.. 10, 7 Bridson, J.N., 14, 164 Brieva, R., 1, 105 Brillas, E., 4, 13 Bringmann, G., 2, 52 Britt, P.F., 4, 255 Brivba, K., 5, 143 Broadbent, B., 15, 291 Broeker, J.I.., 14, 1 L Brook, A.G., 15,276 Brouant, P., 15, 617 Brown, C.E., 3 , 4 1 Brown, D., 4, 246 Brown, M.E., 15, 508 Brown, R.S., 2, 2; 13, 2, 11, 13 Broxton, T.J., 7, 4 Bruche, L., 15,446 Bruckner, R., 15, 367 Bruice, T.C., 2, 118, 181, 182 Bruix, M., 15, 43 Brun, P., 14, 184 Brunck, J.S., 11, 82 Bruncko, M., 13,95 Brunckova, J., 2, 44

Author Index Brunel, Y., 4, 12; 8, 11 Brunow, G., 15, 325 Brzezinski, B., 11, 124 Buhack, M., 14, 122, 132 Buccigross, J., 15, 507 Buchachenko, A.L., 3, 8 Buchanan, A.C., 4, 255 Buchholz, H.A., 9, 59 Buchwald, S.L., 1, 27; 5, 209; 7, 116 Buck, K., 14, 35 Buegler, S., 15,449 Buisman, G.J.H., 12, 8 Bukovska, A,, 10, 25 Bukowski, W., 5, 75, 81 Bulai, A.K., 15, 62 Bulusu, S., 15, 76 Bumagin, N.A., 7, 67 Buncel, E., 2, 147, 188, 201 ; 7, 94 Bunker, C.E., 4, 84 Bunnelle, W.H., 5, 131 Bunting, J.W., 15, 594 Buntkowsky, G., 4, 239 Bunton, C.A., 2, 13I , 132, 203; 5, I 10;in, 98 Burgers, P.C., 6, 13 Burgess, L.E., 15, 505 Burghardt, A,, 4, 178 Burk, M.J., 1, 157 Burke, L.A., 15, 92 Burnell, D.J., 14, 164, 193 Burrichter, A,, 2, 35 Burritt, A,, 9, 77, 7X; 13,62, 63; 14, 162, 163; 15, 436, 437, 442 Buny, L.C., 14, 164 Buryak, A.A., 2, 214 Buscemi, S., 15, 93, 94 Buschmann, J., 12, 62 Busfield, W.K., 3, 123, 124 Bushmelev, V.A., 15, 423 Buss, A.D., 15, 145 Bussenius, J., 14, 85 Buszek, K.R., 7, 120; 14, 128 Butakov, P.A., 14, 44 Butkus, E., 1, 154; 5, 197; 13, I04 Butler, R.N., 15, 92 Butler, T.N., 7, 65 Butts, C.P., 8 , 13, 14 Buxton, P.C., 7, 114, 1 15; 12, 69 Buzaev, A.V., 14, 2 Bytheway, I., 6, 40 Cabal, J., 2, 146 Caballol, R., 4. 232 Cahezas, N., 2, 165 Cable, K.M., 15, 285 Cahrera, M., 2, 6 Cacace, F., 8 , 31

559 Ciceres, L.E., 14, 198 Caddick, S., 3, 135; 15, 322 Cadogan, J.I.G., 14, 1 50 Caffrey, P., 2, 172 Cagle, PC., 15, 241 Cai, K., 5, 16 Cai, W., 15, 128 Cai, Z., 15, 351 Cai, Z.-W., 3, 19 Cainelli, G., 1, 20, 21 Cakniak, O., 15,434 Calabrese, J.C., 15, 391 Calado, A.R.T., 10, 89 Calestani, G., 6, 30; 15, 585 Calirnan, V., 15, 273 Calleja, F.J.B., 15, 43 Callier-Duhlanchet, A.-C. 3, 43,44 Calvani, F., 10, 16 Calvert, J., 8 , I S Calven, J.G., 3, 201 Calzada, E., 5, 203 Camp, D., 4, 139 Campagna, S., 15,230 Camperstrini, S., 5, 157 Canipos, P.J., 9, 62; 15, 383 Camps, P., 12, 67 Cannell, R.J.P., 15, 285 Cano, M., 15, 533 Cantin, M., 3, 46 CdO, D., 15, 593 Cao, x.-P.,15,374 Cao, X.P., 12, 75 Capasso, S., 15, 584 Capdevielle, P., 15, 159 Capella, L., 3, 40; 15, 281 Caple, R., 13, 4 Capon, B., 1, 135 Capozi, G., 12, 37; 14, 146 Capriati, V., 1, 26 Caralp, F., 3, 133 Caravaniez, D., 1, 94; 11, 100; 13, 99 Carbonetti, A,, 15, 47 Carboni, B., 3, I 1 I ; 15, 289 Cardellini, L., 3, 29 Cardin, C.J., 4, 246 Carey, A,, 7, 43, 44 Carey, A.R.E., 1, 132 Carilla, J., 4, 13 Cariou, M., 4, 158 Carlsen, P.H.J., 15, 88 Carlson, R, 10, 116 Carmona, C., 5, 11 1 Carmona, E., 15, 534 Caronna, T., 15, 94 Carpenter, B.K., 4, 42; 15, 264 Carpentier, J.-F., 10, 7 Carr, M.B., 2, 173 Carr, R.A.E., 11,66 Carretero, J.C., 14, 38 Carrie, D., 15, 289

Carrie, R., 15, 165 Cartwright, D., 7, 93; 10, 102 Casado, F., 4, 120; 7, 14, 53 Cascaval, D., 2, 29 Casey, C.P., 13, 40 Castanet, Y.,13, 42 Castedo, L., 7, 119 Castejon, H., 11, 11 Castell, 0..4, 232 Castells, J., 11, 128 Castro, E.A., 2, 6, 7 Castro, M.C., 11, 141 Casuscelli, E, 12, 64 Catalani, L.H., 4, 261 Cativiela, C., 1, 163; 14, 110, 119, 199 Caubire, P., 7, 10; 11, 91 Ceccerelli, P., 15,454 Cegan, A., 1 , 4 7 Celani, P., 14, 89 Cerfontain, H., 8, 50; 13, 60: 15,418 Cermola, F., 14, 7 Cervera, M., 4, 120: 7, 14, 53 Cervilla, A., 5, 207 Cevasco, G., 2, 28; 1 2 , 4 Cha, J.K., 15, 198, 555 Chae, W.K., 15, 4 Chdhoua, L., 1 0 , 5 7 Chai, W., 14, 62 Chakd, A.M., 8, 30 Chalier, F., 4, 162 Chamberlin, R.A., 7, 19 Chambers, P.A., 15, 458 Chambers, R.D., 8 , 7, 12; 15, 307 Chan, A.S.C., 5, 208 Chan, K.P., 15, 101 Chan, P.C.-M., 14, 189 Chan, T.-L., 15,374 Chan, T.H., 6, 51; 11, 73a Chand, K., 15, 71 Chanet-Ray, J., 14, 50 Chang, B.D., 10, 105 Chang, C.-S., 1, 71, 72; 11, 40,44 Chang, G.-G., 7, 47 Chang, LW., 9, 28 Chang, L.-L., 15, 537 Chang, S.-Y., 3, 13 Chang, S.I., 2, 133 Chanon, M., 10, 7 I, 1 10 Chantegrel, B., 15, 80, 457 Chapat, J.-P., 11, 92 Charrnier-Januario, M.O., 14, 50 Chase, C.E., 15, 577 Chastanet, J., 7, 48 Chateauneuf, J.E., 6, 48 Chatgilialoglu, C., 3, 79, 81; 4, 49 Chatterlee, J., 3, 127

Author Index Chatterjee, M., 10, 27 Chatterjee, P., 15, 139 Chattopadhyay, S., 4, 266 Chaudhary, R.B., 5, 24 Chaudhry, A., 10,48 Chavant. PY., 14, 106, 136 Chavignon, O., 11,92 Chcesemann, J.R., 4, 14 Chellamani, A,, 5, 10, 31 Chellamani.A., 1, 147 Chelucci, G., 6, 18 Chen. B., 7, 28 Chen, B.-L., 1, 166 Chen, C.-C., 2, 154; 5, 208 Chen, C.-S., 15, 326 Chen, G., 12, 46; 14, 4 Chen, G.-J., 12, 51 Chen, G.S., 15, 240 Chen. J., 4, 90; 5, 132; 10, 52; 15, 326 Chen, L., 14, 4 Chcn, L.-T., 12, 5 1 Chen, M., 5, 16 Chen, P., 4, 136 Chen, Q., 15, 266 Chen, Q.-Y., 6, 25 Chen, S.-H., 15, 468 Chen, T., 4, 19 Chen, T.-F., 5, 55 Chen, W., 2, 88 Chen, Y., 5, 147 Chen, Y.-T., 1, 78; 11, 126 Chen, Y.J.. 12, 5 Chen, Y.P., 15, 80 Chenard, B.L., 7, 65 ChknedC, A., 15, 589 Cheng, J.T., 1, 78; 11, 126 Cheng, K.-L., 4, 196 Cheng, M.-C., 5, 208 Chennoufi, A,, 14, 76 Cheong, D.-Y., 2, 42, 43; 10, I07 Cheong, J.H., 3, 33 Cheong, M.. 15, 544 Cherevach, T.V., 10, 87 Cherkasova, K.L., 15, 104 Cherneva, D.R., 5, 135 Chernykh. V.P., 2, 214 Chi, Y., 15, 537 Chiacchio, U., 12, 64 Chiang, M.Y., 14, 15 Chiang, S.-J., 15, 537 Chiappe, C., 13, 1, 10 Chiaroni, A,, 14, 49 Chiba, T., 15, 247, 249 Chida, N., 15, 163 Chimichi, S., 1, 130 Chimni, S.S., 15, 106 Chin, C.P., 10, 82 Chin, W.S., 12, 31 Chinn, J.P., 14, 221 Chistyakov, A.C., 7, 106

Chkanikov, N.D., 1, 111 Chnst, K., 2, 112 Cho, B.R., 4, 118; 12, 9, 16 Cho, C.M., 6, 71 Cho, J.-K., 4, 176 Choi, I., 6 , 67 Choi, K.-N., 2, 133 Choi, S.-Y., 3, 20 Choo, D.-J., 1, 68; 11,29 Chou, P.T., 4, 182; 11, 123 Chou, S.-Y., 2, 49 Chounan, Y., 15, 563 Choung, W.-K., 11, 51 Chow, A., 11, 15 Chow, H.F.. 12, 75; 15, 374 Chow, Y.L., 3, 179 Christensen, L.K., 15, 74 Christensen, T.B., 4, 222 Christi, M., 10, 112 Christl, M., 9, 88; 13, 5 Chu, C.K., 15, 504 Chuchani, G., 2, 158; 12, 2325, 27 Chuche, J., 12,65 Chung, C.K., 3, 18 Chung, D.S., 12, 58 Chung, J.-U., 5, 100 Chung, K.H., 12, 58 Chung, W-S., 14, 14, 120 Chung, W.-S., 14, 15 Chuo, C.-M., 5, 4 Chupakhin, O.N., 7, 105 Chyall, L.J., 4, 182 Cicchi, S., 5, 41 Cieplak, A.S., 13, 67 Ciganek, E., 12, 60; 15, 391 Cinquini, M., 14, 39 Cirillo, P.F., 1, 106 Clark, B.P., 1, 140 Clark, C.I., 3, 173 Clark, J.H., 8, 28 Clark, J.S., 15, 233 Clark, K.B., 3, 64 Clarke, C.A., 5, 203 Clary, S., 2, 137 Clasby, M.C., 14, 171 Class, Y.J., 15, 146 Clayden, J., 7, 59 Clegg, W., 5, 155, 156 Cleland, W.W., 2, 179 Clement, N., 2, 140 Clennan, E.L., 5, 162 Clerici, A., 5, 68 Clerici, L., 5 , 68 Clifton, I.J., 2, 169 Clive, D.L.J., 3, 46; 15, 133 Clough, J.M., 11, 93 Coats, S.J., 14, 159 Cobb, J., 15. 205 Coca, G.P., 11, 30 Cochard, S., 3, I 1 1 Cochran, J.E., 15, 29

Cockayne, G.A., 2, 24 Cockett, M.C.R., 15, 609 Coe, P.L., 11, 87 Cohen, T., 15, 271 Coker, A., 11, 122 Coldham, I., 15, 226, 227 Colella, S.M.A., 6, 20 Collignon, N., 15, 255 Collington, E.W., 11, 66 Collins, I., 15, 161 Collis, A.J., 15, 226, 227 Collman, J.P., 5, 28 Colombini, M., 10, 15 Colomvakos, J.D., 15, 306 Colson, A.-O., 4, 45 Colton, R., 7, 4 Combellas, C., 4, I 16; 7, 11 Cornpain, P., 15, 283, 284 Compton, R.G., 7, 9 Concellbn, J.M., 1, 88; 11, 98 Concepcion, A.B., 14, 20 Connors, R.V., 1, 77; 11, 57 Conol, D.A., 4, 127 Consiglio, G., 2, 106; 7, 77 Conte, V., 5, 72, 157 Conti, F., 3, 130 Contreras, J.G., 15, 615, 616 Cook, C.E., 13, 82 Cooks, R.G., 14, 137 Cooksy, A.L., 4, 10, 11 Coombes, R.G., 3, 127 Coon, M.J., 2, 175 Cooney, J.J.A., 7, 59 Cooper, D.L., 8, 1 Cooper, D.M., 14, 75 Cooper, H.J., 4, 181 Corchnoy, S.B., 3, 202 Cordero, F.M., 14,47; 15, 8 I Corelli, E, 15, 47 Corey, E.J., 5, 60, 93, 126; 13, 47,48; 14, 124; 15, 148 Cork, D.G., 7, 45 Corlay, H., 14, 59 Corma, A., 5. 66, 207 Cornelisse, J., 11, 134; 14, 219,220 Corvaja, C., 3, 130 Cossy, J., 3, 49; 4, 85 Costantino, L., 15, 597 Cotarca, L., 2, 160; 4, 77 Cotter, W.D., 7, 52; 15, 12 Coull, I.C., 15, 166 Counioux, J.J., 5, 119 Coupe, D.. 14, 142 Courtemanche, G., 15, 33 1 Coustard, J.-M., 9, 96 Couturier, M., 11, 65; 13, 84 Cox, B.G., 9,30 Cox, P.B., 3, 152 Coxon, J.M., 1, 152; 5, 195; 9, 77, 78; 13, 62, 63; 14, 192; 15,436,437

Author Index Cozzi, F., 14, 39 Craig, D., 14, 171, 172 Cram, D.J., 1, 6Sh, 86a Cramail, H., 9, 25; 13, 30 Cramer, C.J., 9, 71; 14, 91; 15, 118 Crampton, M.R., 7, 19, 100; 11,53

Cravero, R.M., 15, 612 Creary, X., 2, 82; 9, 47 Cremer, D., 6, 26; 9, 14, 85; 15,438 Cremonese, F., 3, 130 Cremoni, M.A., 4, 189 Cressman, E.N.K., 1, 102; 11, 107 Crestoni, M.E., 9, 19, 20 CrCvisy, C., 11, 65; 13, 84 Crich, D., 3, 10, 1 I ; 13, 95; 15, 256,287 Croce, P.D., 14, 22 Cronkhite, J.M., 5, 174 Crooks, P.A., 15, 82 Crossley, R., 14, 46 Crotti, P., 10, 15, 16, 33 Crouch, N.P., 15.338 Crowley, P.J., 15, 147 Crozet, M.P., 3, 175; 4, 114, I15 Crucianelli, M., 15, 446 Cruciani, P., 15, 330 Crudden, C., 15, 109 Crugeiras, J.. 11, 139, 141 Csanidi, J.J., 12, 66 Csizmadia, I.G., 1, 135 Cui, J.-X., 1, 146; 5, 83 Cullis, P.M., 10, 40 Cullum, N.R., 7, 76 Cunje, A,, 9, 50; 15, 382 Curci, M., 10, 23 Curci, R., 5, 82, 136 Curini, M., 15, 454 Curran, D.P., 1, 121; 3, 4, 82; 15, 123,404 Currie, K.S., 8, 40 Currie, M., 11, 132 Cushman, M., 5, 42; 15, 366 Custodio, R., 7, 11 1 Cuza, O., 1, 94; 11, 100; 13, 99 Cynkowska, G., 15, 82 Cynkowski, T., 15, 82 Cyr, D.M., 10, 62 Czamik, A.W., 2, 148 Czamota, G., 2, 159 Czarnik, A.W., 2, 137 Czarnota, G., 12, 71 Czuh, P., 13, 106 d’Acunzo, F., 3, 165; 5, 76 D’Arrigo, M.C., 1, 5 5 , 56; 11, 45

561 D’Auria, M., 14, 143 d’kchia, M., 15, 46 D’Souza, M.J., 2, 67; 10, 13, 77, 106 D’hooge, B., 15, 75 Daasbjerg, K., 4, 106, 222; 10, 73 Dabestani, R., 14, 161 Dahan, F., 6, 47, 96; 15, 572 Dahuron, N., 14, 49 Dai, S., 4, 142 Dailey, W.P., 6, 2, 3 Dainty, R.F., 8, 47 Dalal, N., 4, 241 Dalko, P.I., 3, 5 Daly, K.M., 15, 92 Damavarapu, R., 15, 76 Damico, D.C., 15,554 Damm, W., 3, 1 Damrauer, R., 11, 74 Dang, H . 3 , 3, 99 Danisov, E.T., 3, 101 Dankova, E.F., 15, 97 Danovich, D., 4, 176, 177 Dantanarayana, A.P., 15, 196 Dart, M.J., 1, 67; 11, 28 Das, A.K., 5, 88 Das, M., 5, 88 Das, S., 15, 469 Dash, P.K., 1, 29, 30 Dash, S., 5, 20, 21 Dasopoulos, P.C., 2, 90 Dasse, O.A., 15, 141 Datta, S.K., 15, 469 Dau, M.E.T.H., 2, 53 Daub, J., 4, 199, 218 Dauhan, I?, 2, 53; 10, 38 Dave, V., 2, 200; 9, 21; 12, 20 David, D.M., 14, 5 1 David, F., 4, 172 Davidse, P.A., 6, 86 Davidson, E.R., 15, 182, 271 Davidson, M.M., 15, 120 Davidson, V.L., 5, I88 Davies, A.G., 4, 155, 186 Davies, C.J., 15, 2 Davies, D., 14, 34 Davies, I.W., 10, 51 Davies, J.A., 15, 546 Davies, J.W., 10, I 1 Davies, M.J., 4, 65, 66 Davies, M.S., 4, 193 Davies, S.G., 11, 64, 93, 94 Davis, A.P., 1, 65a Davis, F.A., 11, 143 Davoust, D., 11, 70; 15, 365 Denny, W.A., 2, 80 De Almeida, M.V., 6, 40 De Angelis, F., 6, 46 de Armda Campos, I.P., 4, 261 de Bertorello, M.M., I, 133; 2, 96

de Blas, J., 14, 38 de Conciliis, M.A., 5, 72 de Echaguen, C.O., 14, 183 de Graauw, C.F., 5, 194 de Heredia, I.P., 14, 148 de Kanter, F.J.J., 11, 14; 14, 205 De Kimpe, N., 3, 23; 13, 29; 15, 67 de Koning, L.J., 11, 3; 12, 8 de la Cuesta, E., 14, 204 de la Rosa, J., 11, 54 de la Vega, D., 3, 105 de Lera, A.R., 15, 305 de 10s Rios, I., 15, 540 de Lucas, N.C., 15, 456 De Lucchi, O., 14, 169 de March, P., 14, 48 de Meijere, A,, 4, 147; 11, 23; 15, 505 de Mendoza, J., 13, 81; 15,49 de Menorbal, L.C., 5, 64 De Neef, A,, 6, 80 de Nooy, A.E.J., 3, 172; 5, 106 de Pascual-Teresa, B., 14, 176 de Rege, F.M.G., 7, 116 De Riggi, I., 3, 149 De Rosa, M.C., 15, 47 de Rossi, R.H., 2, 144; 7, 32; 15,591

De Schryver, F.C., 4, 217 De Smaele, D., 3, 23 de Vargas, E.B., 7,32 de Vries, J.G., 15, 344 de Waishaum, R.G., 2, 95 Debouzy, J.-C., 11, 92 Declerq, D., 4, 2 17 Decroix, B., 5, 199 Deffieux, A,, 9, 25; 13, 30 Degueil-Castaing, M., 3, 141 Dehaen, W., 6, 39; 14, 82; 15, 74,75 Dehmlow, E., 6, 45 Dehmlow, E.V., 14, 23; 15, 415 Deka, M., 5, 46 Del Rosso, F., 2, 132 Delalu, H., 5, 119 Delanghe, P.H.M., 1, 160; 5, 198; 15, 364 Delaude, L., 1, 5Oc Delcroix, J.-M., 14, 49 Dell’Erha, C., 1, 130; 11, 129, 130 Della, E.W., 9, 76; 10, 12; 15, 342 Delogu, G., 14, 169 Delogu, P., 2, 160; 4, 77 Deluca, J.P., 15, 222 Demnitz, F.W.J., 15, 5 19 DeMore, W.B., 3, 194

Author Index

562 Deniura, T., 7, 24-26 Denchuk, D.V., 3, 58 Deng, L., 6, 83 DeNinno, M.P., 5, 129 Denisov, E.T., 3, 7, 192 Deniz, A.A., 10, 86 Denmark, S., 15. 254 Denmark, S.E., 7, 73 DePinto, J.T., 6, 4 DePuy, C.H., 11, 112 Deraniyagala, S.A., 2, 54 Derbesy, G., 2. 205 Derewenda, Z.S., 2, 166 Dereza, L.I., 7, 79 Dern, M., 4, 129; 14, 95 Derrick, P.J., 4, 181 DCsauhry, L., 3, 168 Desenko, S.M., 15, 601 Deshayes, C., 15, 80,457 Deshmukh, A.R.A.S., 15, 492 DeShong, P., 15, 146 Deshpande, A.K., 4, 107-109; 6, 32 Deshpande, S.R., 2,26 DeSimone, R.W., 5, 161 Deslongchamps, P., 11, 65; 13, 84

Desmazeau, I?, 15,420 Desper, J.M., 1, 61a Detty, M.R., 5, 114 Deufel, T., 15, 286 Devadoss, C., 3,66; 9, 63 Devaney. A.C., 2, 67 Deveva, M., 5, 135 Devine, P., 15, 505 deVisser, S.P., 11, 3 Devitt, PG., 1, 115 Dey, P.D., 14, 101; 15, 568 Deyine, A,, 14, 49 Dezi, E., 10, 8 Dhawan, S.N., 15,71 Dhillon, R.S., 15, 464 Di Blass, S., 4, 7 Di Bussolo, V., 10, 15 di Furia, R, 5 , 72, 157 Di Martino, J.-L., 15, 498 Di Nardo, A.A., 4, 37 Di Profio, P., 2, 132 Di Vitta, C., 15, 376 Diana, M.B., 15, 377 Diaz, A,, 1, 36 Diaz-de-Villegas, M.D., 1, 163 Didiuk, M.T., 13, 49 Dienes, Z., 13, 9 Dieter, R.K., 7, 60 Diez, A,, 5, 146 Digits, J.A., 1, 33 Dikanov, S.A., 4, 53 Dikshit, D.K., 15, 173 Dillel, V., 8, 3; 10, 72; 14, 110

Dimov, D., 11, 95; 13, 110

Dimroth, P., 2, 161 Ding, J., 7, 85; 8, 4 Ding, L., 5, 16 Ding, Y., 1, 63 Dinnocenzo, J.P., 4, 127, 176 Dinol, A.. 5 , 82, 136 Dinulescu, I.G., 15, 435 Diorazio, L., 15,467 Dix, E.J., 6 , 88 Dixon, B.R., 15, 148 Dixon, R.P., 2, 25 Djakovitch, L., 15, 574 Dmitrieva, M.A., 10, 30 Dneprovskii, A S . , 3, I06 Dnzhd, L.P., 2, 109 Do Amaral, L., 1, 45 Do, J.Y., 3, 16; 15, 54 Dodd, R.H., 2. 53; 10, 38 Dodds, D.R., 5, 79 Doering, W. von E., 6, 42 Dohle, M., 15, 189 Dohrmann, J.K., 4, 192 Dolbier, W., 15, 268 Dolbier, W.R., 3, 161 Dolenko, G.N., 15, 618 Dolliver, D.D., 2, I10 Dolphin, D., 13, 85 Domard, M., 14, 182 Domingo, L., 11, 128 Domingo, L.R., 11, 19; 14, 186

Domingo, L.S., 13, 108 Dominguez, A,, 2, 165 Domingucz, E., 14, 38 Dominguez, R., 12, 27 Domingucz, R.M., 2, 158; 12, 23,24

Dona, R., 14, 105 Dong, G.-X., 6, 51 Dong, L., 7, 57 Dong, Z., 15, 238, 239 Donohoe, T., 15,467 Donovan, T.A., 7, 57 Donya, A.P., 2, 83 Doolen, R., 4, 105 Doona, C.J., 5, 58 Dorokhov, V.A., 15, 104 Dorrity, M.J., 14, 71 Dorta, R.L., 15, 474 Dory, Y.L., 11, 6.5; 13, 84 Dotz, K.H., 15, 530 Douadi, T., 4, 158 Doughty, A,, 1, 11; 4, 254; 15, 345

Dowd, P., 3, 28, 13 I ; 15, 582 Doyle, TI., 8, 39 Doyon, J., 15, 3 15 Draghici, C., 15, 392 Dress, R.K., 11, 77 Drewes, R., 15, 265 Driess, M., 6, 102 Drozd, V.N., 7, 95. 106

Dryfe, R.A.W., 7, 9 Du, X., 3, 178; 4, 90 Du, X.-M., 4, 95, 96 Dua, S.. 11, 4 Duan, X., 12, 48 Dubinina, T.V., 9, 90; 15, 428 Dubinsky, LA., 3, 147; 4, 44 Dubois, L., 1, 156; 2, 53; 10, 38

Duca, J.S., 4, 212; 7, 8 Duefias, J., 15, 470, 471 Duerr, B.F., 2, 148 Duffield, G.L., 7, 100; 11, 53 Duffy, J.L., 1, 67; 11, 28 Duffy, K.J., 6, 29 Dugave, C., 11, 65; 13, 84 Dugudy, G., 5, 204 Duharnel, L., 9, 16 Duhamel, P., 9, 16 Dujardin, G., 13, 79 Dulcire, J . 2 , 3, 55 Dumez. E., 3, 55 Dumitrascu, A,, 2, 29 Duncan, D.C., 5, 74 Dunford, B., 5, 221 Dunn, E.J., 2, 147 Dunyakhin, V.A., 5, 133 Dupas, G., 5 , 218, 220 Dupius, M., 15, 182 Durdn, M., 14. Y7, 149 Dun, K., 14, 151 Durrant, M.L., 10, 1 1 : 15,432 Durbt, T., 15, 354 Duschek, F., 5, 143 Dussault, P.H., 15, 560 Dust, J.M., 7, 35, 94 Dutson, S.M., 2, 110 Dutt, M., 7, 42 Dvies, S.G., 15, 11 Dvinskikh, S.V., 4, 239 Dvorko, G., 10,95 Dvorko, G.F., 10, 87 Dyall, L., 6 , 39 Dyer, P., 6, 96 Dyker, G., 5, 137 Dziegiec, J., 5, 46, 48, 49 Dzravkovski, Z., 14, 140 Dzurilla, M., 15, 176 Eaborn, C., 10, 44, 45 Eames, J., 15. 573, 574 Easton, C.J., 2, 138 Eastwood, F.W., 3, 150 Eaton, P.E., 9, 84 Eberbach. W., 14. 85 Eberlin, M.N., 14, 137 Eberson, L., 4, 60, 62, 149154: 8 , 13-16; 15,37

Ebert, G.W., 7, 57 Echavarren, A.M., 15, 49 Echevarrkd, G.R., 1, 16 Eckert, G., 4, 101

563

Author Index Eckrich, R., 15, 317 Edwarda, L.G., 14, 209 Edwards, PJ., 13, 36, 38 Efremov, D.A., 2, 223 Egerer-Sieber, C., 15, 55 Egle, I., 15, 306 Eguchi, S., 15,407 Eguchi, T., 5, 219 Eilbracht, P., 15, 124 Einstein, F.W.B., 15, 535 Eisenbeis, S., 15, 31 1 Eklund, J.C., 7, 9 Eksterowicz, J.E., 14, 11 El Khatih, M., 5, 119 El Oualja, H., 4, 78 El Seoud, O.A., 2, 48 El Walily, A.F., 7, 96 El-Abbady, S.A., 14, 63 El-Ahl, A.-A.S., 15,499 El-Nabi, H.A.A., 15,262 El-Nagdi, M.H., 12, 26 Elango, K.P., 5, 87, 116 Eldin, S., 1, 32, 33; 10, 109 Elemes, Y., 13, 32; 15, 569 Elguero, J, 15, 608 Elhafez, F.A.A., 1, 65b Elhammadi, A,, 15, 608 Eliel, E.L., 11, 81 Eliseenkov, E.V., 3, 106 Elkaim, L., 15,473 Ellinger, Y.,4, 180 Ellis, M.J., 15, 11 1 Elmorsy, S.S., 15, 499 Elmouhtadi, M., 15, 608 Elsey, G.M., 9, 76; 10, 12 Eltoneam, s., 15, 473 Emanuel, O.N., 4, 52; 5, 175, 176 Emori, E., 15, 394 Emoto, S., 1, 50a Emrich, R., 5, 180 Enas, J.D., 8, 27 Enders, D., 15, 152, 220, 221 Endo, T., 10, 20; 12, 21; 13, 27 Endo, Y., 15, 160 Enfedaque, J., 11, 54 Engberts, J.B.F.N., 2, 81, 102; 14, 33, 11 1-1 13 Engell, K.M., 1, 117 Engehdnn, G., 4, 157 Engels, B., 4, 29 Engler, T.A., 14, 62 Engman, L., 3, 193 Enriquez, R.G., 1, 17 Epifano, F., 15,454 Erabi, T., 9, 38 Ericsson, A.M., 15, 395 Eriksen, J., 15, 529 Eriksen, T.E.. 3, 98; 4, 160, 161 Erker, G., 9, 52; 14, 107

Errirngton, W., 14, 94 Es-Sayed, M., 15, 505 Eshelby, J.J., 15, 147 Espenson, J.H., 5, 101, 102 Espin, M., 4, 120; 7, 14 Estelrich, J., 15, 614 Estieu, K., 15, 164 Eto, M., 14, 25; 15, 179 Etzkorn, M., 4, 145 Eustace, S.J., 2, 208 Evans. D.A., 1, 67; 11, 28 Evans, D.H., 7, 12 Evans, G.R., 1, 110; 11, 80 Evans, P.A., 3,42; 15, 161, 5 14 Evanseck, J.D., 15, 303 Eventova, I., 10, 2; 12, 3; 13, 91, 92 Evin, O.O., 1, 98 Ezaka, T., 15, 619 Ezell, M.J., 3, 93 Ezqucrra, J., 15, 132 Fabbri, D., 14, 169 Fabian, l., 5, 71 Fabian, J., 9, 72 Fabian, M.A., 1, 3a Fabian, W.M.F., 14, 100; 15, 68 Fabris, F., 14, 169 Fadda, A.A., 7 , 4 2 Fagnoni, M., 4, 93 Fahmy, A.M., 4, 7 5 , 7 6 Fahr, A,, 3, 63; 4, 264 Fairbanks, A.J., 15, 589 Fairhurst, R., 15. 31 1 Faita, G., 14, 109 Fajari, L., 4, 13 Fallis, A.G., 15, 573 Falvey, D.E., 9, 42 Famini, G.R., 2, 55 Fan, H., 6 , 43 Fan, J.-S., 2, 154 Fan, W.-Q., 11,90 Fan, X., 1, 92 Fang, D.-C., 12, 56 Fang, J.-M., 3, 35 Fang, W., 9, 24; 15, 513 Fang, W.-H., 1, 31 Fang, X., 4, 40 Fanwick, P.E., 15, 366 Farahat, M., 5, 73 Farina. V., 7, 64 Farley, R., 4, 203 Famsworth, D.W., 12, 14 Fasani, E., 4, 91; 7, 54 Fau, S., 6 , 82 Faure. R., 15, 422,457 Fauve, R., 3, 55 Favero, L., 10, 15, 33 Filwcett, J., 1, 62; 13, 34, 35 Federsel, H.J., 15, 85

Fedevich, M.D., 5, 153 Fedoseev, V.M., 10, 108: 15, 618 Feit, B.-A,, 11, 125 Fekete, Z., 3, 114 Feldman, P.L., 15, 108 Fendel, W., 9, 89; 15, 426 Fenet, B., 14, 182 Feng, W., 12, 57 Fensome, M., 7, 115 Ferey, V., 1. 53 Ferguson, J.R., 7, 93; 10, 102 Fernindez, I., 11, 59; 13, 89 Ferntindez, P., 11, 59; 13, 89 Fernandez-Castafio, C., 6 , 28 Fernandez-G., J.M., 1, 17 Feroci, M., 6 , 46 Ferraccioli, R., 14, 22, 67 Ferreira, J.A., 6 , 40 Ferrer, M., 5, 146 Fiandri, L.G., 5, 158 Fiaud, J.-C., 1, 156 Ficeri, V., 15, 176 Fiddler, W., 11, 147 Fiedler, A,, 11, 86 Field, L.D., 11, 17 Fievre, A,, 15, 141 Figueredo, M., 14, 48 Fikes, L.E., 2, 137 Fildes, M.J., 3, 127 Filimonov, V.D., 5, 152 Filipkowski, M.A., 3, 34 Filippi, A., 7, 3; 9, 64; 15, 40 Filippini, M.-H., 1, 75 Fillion, H., 14, 182 Filzen, G.F., 15, 256, 287 Findeisen, M., 6, 70; 15, 58 Findlay, J.B.C., 15, 31, 32 Finet, J . 2 , 4, 162 Finlayson-pitts, B.J., 3, 93 Finn, M.G., 6 , 72 Finneman, J.I., 9, 31 Finney, N.S., 5, 191; 6, 55 Fischer, H., 3, 107-109 Fischer, J.W., 2, 60 Fisera, L., 14, 42 Fishbein, J.C., 1, 34; 2, 69, 7 0 9, 31, 44,46; 10, 57; 15, 5 , 6 Fisher, P.V., 2 , 51 Fisher, R., 4, 253 Fishpaugh, J.R.,15, 196 Fishwick, C.W.G., 14, 202; 15, 31, 32 Fitjer, L., 15, 466 Fitzen, G.F., 3, 10 Flanagin, L.W., 10, 94 Flannery, C.A., 9, 28 Fleet, G.W.J., 7, 9 Flcischcr, J.M., 1, 2hb Fleischer, R., 11, 23 Flemes, Y., 13, 31

564 Fleming, I., 15, 525 Fleming, S., 13, 98 Fleming, S.A., 4, 244; 14, 10 Fletcher, R.J., 3, 31; 4, 121, 263 Florent, J.-C., 15, 201 Florio, S., 1, 26; 11, 73b Floss, H.G., 2, 161 Flowers, R.A., 4, 21; 9, 6; 11, 110 Foces-Foces, C., 6, 28 Fogg, J.A., 13, 22 Fokin, A.V., 1, 1 1 1 Folkerts, A., 15, 267 Foloppe. M.-P., 15, 112 Font, J., 14, 48 Fontana, A., 1, 127; 11, 114 Fontana, F., 3, 171; 4, 72-74; 5, 140, 141 Fontecave, M., 4, 12 Foote, C.S., 5, 164; 13, 31, 32; 15,569 Foray, C.S., 4, 112 Forlani, L., 7, 20 Forman, F.W., 7, 68 Fornarini, S., 9, 19, 20 Fornes, V., 5, 207 Foroudian, H.J., 2, 203 Forrester, A.R., 15, 60 Forsterling, H.-D., 5, 54 Forsyth, D.A., 9, 79; 15, 385 Fort, Y., 7, 10; 11, 91 Fouch, R.A., 1, 66 Foulds, G.J., 8, 13 Fouquet, E., 3, 121 Fouroudian, H.J., 5, I 10 Fraenkel, G., 11, 15 Fraile, J.M., 5, 64 Francis, A,, 14, 82 Francis, M.B., 13, 66, 71 Franck, B., 15, 558 Frank, L., 15, 493 Frank, N.L., 14, 216 Franklin, J., 5, 183 Franklin, R., 1, 110; 11, 80 Frankowski, A,, 15, I03 Franz, J.A., 3, 66; 4, 22 Fraser-Reid, B., 2, 113; 15, 475,476 Fratini, P, 12, 37; 14, 146 Freccero, M., 4, 92 Fredrickson, M., 14, 46 Freire, R., 15, 474 Frejaville, C., 4, 68 Fremy, G., 13, 42 Frenking, G., 6, 82 Frenna, V., 1,48; 2, 106; 7, 17 Frenzcn, G., 14, 138 Frey, J., 1, 13 Friedman, A.E., 5, I14 Friedrich, D., 15, 316

Author Index Friesen, R.W., 13, 22 Frimer, A.A., 5, 169 Frinault, T., 3, 137 Fringuelli, F., 1, 70; 11,41 Frish, M.J., 4, 14 Fritch, P.C., 15, 84 Froese, R.D.J., 14, 99 Frohaug, A.E., 5, 90 Frohlich, L., 15, 327 Frohlich, R., 9, 52 Fronczek, F.R., 8, 27 Fronza, G., 4, 72 Fry, J.L., 9, 57, 79; 15, 384, 385 Fu, G.C., 1, 101; 3, 52 Fu, P-F., 13, SO Fu, T.Y., 15, 299 Fu, X., 12, 46; 14, 4 Fu, X.-Y., 12, 51, 53, 56 Fu, Y., 3, 195 Fuchikami, T., 4, 26 Fuchs, PL., 11,60; 13, 103 Fuhrer, H., 15, 329 Fuji, K., I, 137; 11, 34 Fujii, N., 15, 563, 564 Fujimori, C., 15, 447,448 Fuiimoto, T., 11, I13 Fujimura, 0.. I , 101 Fujio, M., 4, 207; 10, 79-81, 84, 85, 96 Fujioka, H., 15, 419 Fujisaki, S., 5, 109 Fu.jisawa, T., 11, 137 Fujita, M., 3, 155; 7, 66; 15, 460 Fujita, S., 15, 448 Fujita, T., 15, 274 Fujita, Y., 13, 75 Fujiwara, J., 15, 357 Fujiwara, K., 15, 136 Fujiwara, M., 8, 42 Fukaya, H., 3, 65 Fukotomo, K., 14, 160 Fukumoto, K., 2, 101; 15, 398,406 Fukunishi, Y., 15, 548 Fukute, Y., 15, 400 Fukuzawa, S., 15, 246,408 Fukuzumi, S., 5, 21 2; 9, 17; 13, 75 Fulloon, B., 15, 262 Fulop, V., 2, 169 Fiilscher, M.P., 6, 6 Fulton, K.L., 8, 13 Funabiki, K., 13, 86 Funakoshi, Y., 2, I30 Furet, N., 4, 85 Furstner, A,, 15, 360 Furukawa, N., 15, 169, 170 Furusawa, G.-I., 4, 104 Furuta, S., 15, 445 Fuss, M., 9, 83

Fustero, S., 14, 13 I Caber, A.M., 4, 75, 76 Gable, R.W., 15, 319 Gabnelson, K.D., 2, 120 Gabor, B., 15, 360 Gacs-Baitz, E., 15, 47 Gadgil, V.R., 15, 442 Gadosy, T.A., 2, 140, 142 Gagnon, R., 15,524 Gai, H., 5, 91 Gaidukevich, A.N., 2, 213 Gairola, P., 1, 43 Gajewski, J.J., 15, 119, 271 Gal, D., 2, 160; 4, 77 Galan, B.C., 3, 128 Galbis, J.A., 14, 37 Gale, D.J., 7, 22 Gallagher, J.D., 15, 186 Gallagher, T., 10, SO, 51 Gallardo, l., 4, 120; 7, 14 Gallego, M.G., 15, 301 Galletti, P., 1, 21 Galley, G., 14, 77, 81, 123 Gallgher, R.T., 4, 181 Galli, C., 3, 165; 4, 117; 5, 76; 8, 5; 10, 3 Gallo, G., 10, 71 Gallou, F., 3, 47 Galtier, C., 11, 92 Galy, J.P., 15, 617 Gamlath, C.B., 14, 211 Gancarz, R.. 1, 114 Cani, D., 2, 167, 190 Ganter, C., 1, 100; 11, I03 Gao, J., 2, 157; 12, 40; 15, 1L1

Y.,5, 54; 13, 5 1 Gapanova, R.G., 10, 22 Garanti, L., 15, 10 Garcia Blanco, F., 1, 16 Garcia Fraile, A,, 9, 67 Garcia Martinez, A,, 9, 67 Garcia del Vado, M.A., 1, I6 Garcia, J.G., 8, 27 Garcia, J.I., 5, 64; 14, 110, I14 Garcia, J.L., 14. 119 Garcia-Granados, A,, 15, 470, 47 1 Garcia-Navio, J.L., 1, 36 Garcia-Raso, A,, 3, 77 Gardelli, C., 10, 15, 16, 33 Garden, S.J., 5, 142 Gareau, Y., 3, 59 Garner, P.P., 3, 152 Garrity, PM., 10,44 Gasper, S.M., 9, 63 Gassman, P.G., 9, 10. 49; 10, 10; 14, 173, 174 Gastaldi, S., 3, 149 Gasteiger, J., 2, 65 GdO,

565

Author Index Gates, R.A., 11, 147 Gatilov, Y.V., 9, 74; 14, 44; 15,465 Gaul, M.D., 15, 127 Gauss, J., 9, 83 Gautun, O.R., 10, 34; 15, 88 Gawley, RE., 1, 100; 11, 103; 15, 230 Ge, C.-S., 6, 43,44 Geach, N.J., 14, 172 Gebicki, J., 15, 103, 379 Gehre, M., 2, 159; 12, 71 Geib, S.J., 1, 121 Gellis, A., 4, I15 Gen-Hou, L., 3, 197 Genaev, A.M., 15,423 Gennari, C., 1, 51, 52,69; 11, 42 Gentili, P., 4, 117; 10, 3 Georgantji, A., 15, 14 George, P., 15, 186 Georgieva, A., 13, 29; 15, 67 Georgiou, D.G., 4, 206 Gerasirnov, P.V., 13, 25 Gerasimova, T.N., 15, 8, 9 Gerke, R., 15, 466 Germain, G., 1, 168 German, E.D., 4, 209, 210, 21 1 Germani, R., 2, 132 Gerninghaus, C., 14, 138 Gerratt, J., 8, I Gers-Muller, R., 5, 172 Gersmeier, A., 15, 124 Gerson, F., 4, 147, 148 Gerster, M., 3, 122, 159 Gescheidt, G., 4, 145, I86 Gesenberg, C., 15, 265 Gesheidt, G., 4, 144, 199, 218 Gesser, J.C., 1, 143; 13, 74 Gesson, J.-P., 15,213 Getoff, N., 4, 215 Ghdrbaoui, T.,3, 137; 4, 113 Gheorghui, M.D., 15, 39 Gherghel, L., 4, 217 Ghio, C., 11, 109 Ghiro, E., 3, 162 Ghiviriga, I., 7, 84; 11, 89; 15, 61 1 Ghobsi, A,, 13, 83 Ghosh, K.K., 2, 71-73, 128 Ghosh, S., 2, 71-73; 9, 39; 15, 402,403 Ghosh, S.K., 15, 138 Giacomini, D., 1, 20, 21 Giannopoulos, T., 7, 93; 10, 102 Gibson, N.J., 15, 60 Gibson, S.E., 11, 83 Giera, H., 14, 42 Gierczyk, B., 7, 104 Giese, B., 3, 1, 158, 163

Giesen, D.J., 15, 118 Giesselmann, F., 15, 251, 252 Giessner-Prettre, C., 9, 16 Giglio, A,, 11, 129 Gil, S., 11, 19 Gilbert, A,, 14, 21 8 Gilbert, B.C., 4, 65, 66, 203; 5, 35; 7, 7 Gilbert, R.G., 3, 60 Giles, M., 15, 467 Gilinsky-Sharon, P.,5, 169 Gillard, A,-C., 15, 112 Gille, L., 4, 63 Gilloir, F., 15, 359 Gimarc, B.M., 15, 188 Gindin, V., 15, 610 Giomi, D., 14, 157 Giordano, F., 14, 7 Giorgi, J.B., 2, 139, 145 Girard, P., 3, 134 Gitis, S.S., 7, 97, 98, 107-109 Giurgiu, M., 5, I Gjerlgv, A,, 15, 74 Gladysz, J.A., 15, 241 Glasare, G., 15, 85 Glaser, J., 14, 126 Glaser, R., 7, 2; 15, 240 Glass, R.S., 4, 100 Glass, T.E., 15, 278 Glaz, A.I., 7, 107, 108 Glazkov, A.A., 14,207 Gleiter, R., 9, 92; 14, 170 Glendenning, L., 11, 17 Gloanola, M., 3, 57 Glover, S..A., 15, 507 Gluchowski, C., 15, 196 Glukhovtsev, M.N., 9, 55; 10, 65,66 Glusker, J.P., 15, 186 Gnaim, J.M., 8, 8 Gnappi, G., 8, 32 Gobbi, A,, 10, 97 Goddard, J.D., 14, 99 Goddard, R., 11, 68; 13, I 1 1; 15, 219 Goerlich, J.R., 6, 19 Goez, M., 4, 101 Gogoll, A,, 15, 343 Goh, J.B., 15, 364 Gold, M.A., 2, 8 Goldberg, N., 11, 86 Goldenberg, V.J., 3, 100 Goldstein, D.M., 15, 278 Golik, N.Yu., 2, 213 Goller, K., 4, 236 Golovina, N.A., 5, 179 Golovko, N.N., 1 0 , 9 5 Golsch, D., 5, 143 Gbmes, A.M.E.A.N.F.,8, 2 G h e z , A.M., 15,476 Gonzalez, C., 7, 119; 12, 42; 15, 184

Gonzilez, J., 14,21, 131, 176; 15, 114 Gonzalez, J.J., 15, 49 Gonzilez, R.R., 11, 30 Gonzalez-Lafont, A,, 8, 3; 10, 72 Gonzalezsierra, M., 15, 612 Goo, Y.M., 14, 135 Goodman, J.L., 4, 98; 6, 10, 88 Goodman, J.M., 1, 51, 69 Goosen, A,, 1, 25; 4, 82 Gopalakrishnan, M., 5, 1 1 , 13, 96 Gorath, G., 9, 32 Gordon, M. 6, 81 Gordon, M.S., 9, 15; 12,44; 15,288 GorC, J., 15, 283, 284 Gorelik, M.V., 8, 9, 26 Gorgenyi, M., 4, 253 Gorman, D.B., 14, 173 Goryachii, V.D., 2, 214 Gosh, S.K., 15, 469 Gosney, I., 14, 150 Gothelf, K.V., 14, 178 Goti, A., 5, 41 Goto, M., 10, 79, 81 Goto, N., 10, 80 Goto, s., 1, 99 Gotor, V., 1, 105; 2, 168 Gottlieb, H., 15, 435 Goulding, C.W., 2, 34 Goumont, R., 7, 101. 103; 11, 63; 12, 13 Gowda, N.M.M., 5, 34, 120 Gracias, V., 15, 510 Graff, A., 1, 61c Grampp, G., 4, 224 Granados, A., 2, 144 Grand, A., 4, 12, 232 Grandberg, 1.1.. 15, 65 Grandjean, D., 15, 31 1 Granicher, C., 15, 3 18 Granucci, G., 4, 180 Gratchev, M.K., 10, 113 Gravestock, M.B., 14, 40 Graziano, M.L., 14, 7 Grebenshchikov, S.Y., 11, I19 Grech, E., 11, 124 Grech, J.M., 13, 64 Green, D.L.C., 11, 131 Green, R.E., 10, 40 Greenberg, A., 15, I86 Greenberg, M.M., 3, 26; 4, 87 Greenop, M.W., 8, 18 Greenwood, P.F., 4, 181 Greer, M.L., 4, 61 Gregory, G.S., 7, 69 Grehan, B., 15, 396 Grchn, L., 2, 21 1

566 Greifenberg, S., 15, 150 Grevy, J.-M., 2, 187 Gricc, D.I., 3, 124 Griebenour, N., 15, 219 Cries, S., 5, 180 Gricsbaum, K., 1, 5 Griesbeck, A,, 14, 1 Griesbeck, A.G., 15, 286 Griffart-Brunet, D., 14, 49 Griffith, D.A., 15, 570 Grigg, R., 13,44; 14,46, 71, 72, 75 Grissom, C.B., 4, 237 Grissom, J.W., 4, 243 Gritsan, N.P., 1, 112, 113; 4, 194 Grogan, G., 5, 151; 15,523, 524 Groger, S., 2, 161 Grohmann, K.G., 11, 71; 15, 349 Gronchi, G., 4, 162 Gronert, S., 10, 21, 49; 12, 38, 39 Gronowitz, S., 14, 29; 15, 320 Gros, P., 11, 91 Groschl, D., 15, 5 I Grosjean, D., 5, 134 Grosjean, E., 5, 134 Gross, M.F., 6, 72 Grubbs, R.H., 1, 101 Grudtsyn. Yu.D., 7 . 9 7 Grurndnn, A,, 15, 375 Grundemann, E., 7, 102; 15, 96 Grunwell, J.R., 15, 410 Gruttddauria, M., 1, 48, 130 Grzegozek, M., 7, 38 Gstach, H., 15, 500 Gu, H., 5, 138 Gu, J.-M., 13, 75 Guardado, P., 5, I I I Guarnieri, A,, 4, 117; 10, 3 Gueiffier. A,, 11, 92 Guennouni, N., 3, 111 Guerra, M., 4, 47, 48 Guerrera, E, 7, 78; 15, 72 Guerrero-de la Rosa, V., 15, 236 Guerret, O., 6, 96 Guesnet, J.-L., 11, 88 Gugelchuk, M.M., 14, 189 Guillemet, M., 10, 17 Guillot, N., 3, 134 Guindon, Y., 3, 162 Guinn, D.E., 15, 196 Guir, F., 2, 183 Guitian, E., 7, 119 Gulea-Purcarescu, M., 15, 255 Gulzar, M.S., 2, I67 Gunawardena, G.U., 4, 243 Gunderrnann, K.D., 1 0 , 9 3

Author Index Gung, B.W., 1, 66; 13, 66, 70, 71 Cunnersen, J.N., 7, 57 Guntha, S., 15, 520 Guo, J., 3, 125 Guo, Q., 3, 181 Guo, X., 6, 49 Guo, Z.R., 12, 72 Gupta, S.C., 15, 71 Gurtler, C.F., 4,130 Giirtler. S., 15, 559 Gurudutt, K.N., 15, 553 Gurvich, V., 15, 105 Gus’kov, A.K., 10, 25 Gusel’nikov, L.E., 15, 56 Guseva, V.V., 15, 200 Gushurst, A.J., 1, 26b Guthier. K., 4, 256, 257; 6, 34 Guthrie, J.P., 1, 60h Gutman, D., 3, 147; 4, 44 Gutsche, G.J., 6, 1 1 Gutsev, G.L., 11, 13 Guyot, M., 15, 502 Guzman-Perez, A,, 5, 93; 13, 47 Gyul’nazaryan, A.Kh., 12, 17 Ha, C., 3, 34 Ha, D.-C., 11, 51 Ha, E.K., 15, 4 Haag, R., 11, 23 Haak, M., 15, 387 Habashita, H., 15, 563 Haberlield, P., 10, 75 Habicher, W.D., 5, 39 Hachemi, M., 15, 174, 175 Hachiya, I., 1 , 59; 8, 44 Hachuja, I., 15, 17 Hadjiarapoglou, L.P., 5, 139 Hadzialic, G., 6, 86 Hagen, J.P., 15, 185 Haghjoo, K., 1 , 7 8 ; 11, 126 Hagiwara, T., 3, 115; 13, 94 Hahn, H.G., 15, 237 Hahn, I S . , 5, 214 Hahn, J.M., 13, 68a Haimova, M., 13, 29 Haire, D.L., 4, 69, 70 Hajdu, J., 2, 169 Hajipour, A.R., 10, 39 Hajds, G., 15, 607 Hakamata, H., 15, 398 Hakansson, M., 15, 88 Halama, A,, 1, 47 Halasz, J., 15, 493 Hales, N.J., 15, 44, 45 Hall, C.D., 2, 34; 12, 70; 13, 80 Hall, M.B., 6, 40 Halle, J., 12, 13 Hallk, J.-C., 7, 101, 103; 11, 63

Halpern, A.M., 12, 47 Hamada, K., 2, 204 Hamada, N., 15, 35 Hamana, H., 3, 115; 13, 94 Hamelin, J., 14, 69; 15, 498 Hamilton, A.D., 2, 25 Hammerich, O., 15, 372 Hammerschmidt, F., 15, 369 Hammond, G.P., 15, SO7 Hammond, R.C., 7, 7 Hamon, D.P.G., 3, 1.53 Hampel, F., 15, 55 Hams, K.J., 2, 161 Han, W., 11, 143 Hanack, M., 9, 69; 14, 151 Hanai, R., 3, 154 Hanaki, N., 15, 552 Hanawa, T., 2, 143 Handfel, H., 12, 74 Handlon, A.L., 1, 10 Hanhinen, P., 15, 1.53 Hankin, J.A., 11, 74 Hanninger, A., 15, 369 Hans-Heinrich, L., 11, 120 Hansen, H.-J., 4, 148; 15, 321 Hansen, K.B., 6, 55 Hansen, P.E., 9, 60 Hanson, C., 8, 17 Hanson, G.R., 4, 139 Hanson, J.R., 13, 46, 56 Hanson, P., 4, 203; 7, 7 Hapiot, P., 3, 174 Happer, D.A.R., 10, 44 Harada, N., 5, 130 Harada, S., 3, 154 Haraguchi, K., 3, 12, 156 Harano, K., 14, 25, 53; 15, 179 Harayama, T., 15, 30 Harbach, J., 11, 18 Harcourt, M.P., 1, 126; 15, 595 Harder, S., 10, 63 Hareau-Vittini, G., 15, 292 Harger, M.J.P., 2, 185; 10, 48 Hargreaves, S., 14, 71, 75 Harlos, K., 2, 169 Harmata, M., 14, 211; 15, 240 Harnish, R., 3, 190 Harper, T.G.P., 1, 1.57 Harpp, D.N., 2, 205 Harren, J., 15, 50 Harrer, H.M., 3, 204 Harris, EM., 9, 61 Harris, J.M., 10, 55 Harrowven, D.C., 8, 47 Harsanyi, M.C., 4, 1 19 Hart, D.J., 1, 37; 5, 202 Hartmann. M., 15, 196 Hdrtahorn, M.P., 4, 1.50-154; 8, 13-16; 15. 37 Hartung, J., 3, 47

567

Author Index Haitwig, J.F., 7, 61 Hartz, N., 2, 35 Harusawa, S., 15, 177, 178, 296 Harvey, D.F., 14, 208 Harvey, J.N., 15, 168 Harvey, R.G., 8, 43 Hase, T.,15, 325 Hase, W.L., 10, 67, 68 Hasegawa, T., I, 42; 4, 245; 12. 63; 14, 18; 15,444 Haseltine, J., 8, 39 Hashimoto, N., 7, 45 Hashimoto, Y., 11, 138 Hashizume, K., 7, 45 Hassler, C., 3, 158, 163 Hassoon, S., 4, 86 Hastings, D.J., 4, 235; 14, 12 Hatae, N., 15, 130 Hatakenaka, K., 15, 433 Hatanaka, M., 14, 57 Hatano, K., 15, 232, 245 Hatsui, T., 15, 352, 353 Hauffe, G., 13, 24 Hausen, H.-D., 4, 201 Hausinger, R.P., 2, 173 Havlas, Z., 9, 91 Havlicek, V., 15, 100 Hawkins, G.D., 15, 118 Hay, A S . , 15, 101 Hayase, S., 9, 38 Hayase, T., 1, 87 Hayashi, A., 8, 33 Hayashi, T., 13, 43 Hayes, R.F., 15, 113 Haynes, R.K., 11, 17, 39; 13, 77 Hays, D.S., 3, 52 Hazlewood, C., 4, 65, 66 He, C., 5, 154 He, F.C., 15, 117, 208 He, H.-M., 15, 366 He, H.-Y., 4, SO He, W., 15, 132 Head, N.J., 9, 58, 94; 15, 42 Headley, A.D., 2, 55 Heagy, M.D., 9, 29, 95 Heaney, H., 7, 1 14, 115; 12, 69; 15, 44, 45 Heard, G.L., 15, 293, 294 Heathcock, C.H., 15, 482,570 Heaton. B.T., 15, 2 Heherger, K., 2, 160; 3, 113; 4, 77 Hebgen, I?, 4, 256,257; 6, 34 Hecht, E.A., 5, 74 Hegbom, I., 8 , 24, 25 Heiher-Langer. I., 2, 217 Heidenfelder, T., 4, 126 Heiland, K., 3, 123 Heimer, N.E., 15, 77 Heinze, J., 4, 144-146, 179

Heller, H.G., 14, 185, 214 Helmchen, G., 10, 6 Heming, X., 2, 64 Hemnan, R.G., 10, 99 Hendrickson, D.N., 15, 620 Hendrickson, W.H., 3, 185 Hengge, A.C., 2, 3, 179 Henke, H., 1, 5 Henley, R.L., 5, 25 Henning, R., 15, 525 Henninger, J., 9, 54 Heras, J.V., 15, 533 Herberg, C., 3, 144; 4, 16 Herbert, J., 15, 536 Herbst, A., 11, 125 Herek, J.L., 4, 228 Herges, J., 4, 144 Herges, R., 4, 145; 13, 19 Herlinger, E., 4, 7 1 Hern&ndez.V.T.,11, 30 Herndon, J.W., 15, 531 Herrmann, J., 2, 2 18 Herrmann, R., 9, 80, 87; 15, 425 Hemnann, W.A., 5. 103 Herschlag, D., 2, 194 HervCs, P., 11, 144 Hess, R.A., 2, 3 Hewlins, S.A., 9, 5 1 ; 13, 59; 15, 390 Hewson, A.T., 15, 166 Hibbert, E, 11, 122 Hidaka, Y., 3, 70, 71 Hidalgo, J., 5, I 1 1 Hiebert, T., 1, 9a; 9,40 Higashihard, T., 3, 70, 7 1 Higashiura, M., 15, 298 Hilbi, H., 2, 161 Hildenbrand, K., 4, 67 Hilinski, E.F., 14, 161 Hill, C.L., 5, 74 Hill, D.K., 15, 53 I Hill, R.L., 15, 338 Hillier, I.H., 15. I20 Himeda, Y., 14, 57 Hinton, H.A., 15, 533 Hirai, K., 6, 12, 92; 13, 75 Hirarna, M., 8 , 33 Hiran, B.L., 1, 145; 5, 40 Hiratani, K., 15, 136 Hirayama, M., 4, 197, 198 Hirokawa, J.H., 10, 62 Hirota, S., 2, 130 Hirsch, A,, 13, 8; 14, I5 1 Hirst, J., 7, 9 Hiruta, K., 4, 240 Hisaeda, Y., 15, 542 Hisano, T., 15, 179 Hiscock. S.D., 15, 339 Hitchcock, PB., 13, 46, 56 Hitchcock, S.A., 7, 69 Hiyama, T., 15, 445

Hiyashi, R.K., 10, 14 Hizatate, S., 15, 160 Ho, D., 15, 102 Ho, D.M., 15,277 Ho, T.-I., 4, 196 Ho, T.-L., 2, 136 Ho, 2.. 2, 149 Hoberg, J.O., 15, 397 Hochemer, R.H., 2, 36 Hochstrate, D., 14, 222; 15, 183 Hodgson, P.B., 15, 233 Hodgson, P.K.G., 14, 150 Hodnett, B.K., 7, 44 Hoff, A.J., 4, 194 Hoffman, P., 14, 88 Hoffman, R.E., 11, 5 Hoffmann, G., 5, 67 Hoffmann, H.M.R., 2, 36; 15, 600 Hoffmann, R.W., 11, 18, 77 Hofling, R., 2, 159; 12, 71 Hofmann, J., 4, 256-258; 6, 34, 70; 15, 57, 58 Hogan, G., 2, 2 16; 12, 6 Hogen-Esch, T.E., 11, 95; 13, 110 Hogstrom, C., 15, 85 Hokai, N., 3, 80 Holcman, J., 4, 215 Holland, P.M., 2, 131 ; 10, 98 Hollebeek, J., 14, 205 Hollinshead, J.H., 15, 44, 45 Hollis, T.K., 1, 64 Holmes, A.B., 15, 161 Holmes, J.L., 4, 15 Holy, P., 7, 36 Homann, K.-H., 4, 256-258; 6, 34; 15, 57 Homer, J.H., 3, 21 Homes, D.L., 2, 56 Hon, Y.S., 12, 5 Honda, M., 15, 400 Honda, T., 15, 214 Honda, Y.,3, 50 Hondelmann, U., 2, 65 Hondo, T., 3, 116 Hong, B.-C., 3, 83 Hong, S., 12, 54 Hong, S.-G., 2, 92; 12, 52, 53 Hong, S.H., 12, 57 Hootele, C., 14, 55 Hopf, H., 14, 121 Hopkinson, A.C., 9, SO; 15. 382 Horan, C.J., 7, 2 Horikawa, H., 15, 202 Horiuchi, Y., 15, 361 Horner, J.H., 3, 32, 34; 4, 30 Hornfeldt, A.-B., 14, 29; 15, 320 Hornwell, D.C., 3, 24

Author Index Horoba, E., 2, 29 Horspool, W.M., 1, 162; 15, 301 Horton, D., 15, 5 12 Hoshino, M., 15, 427 Hosomi, A,, 3, 116 Hosoya, T., 14, 18 Hosztafi, S., 15, 493 Hotema, M., 2, 110 Hotfman, R.V., 2, 88 Hotta, Y., 15, 563 Houk, K.N., 1, 152; 2, 156; 5, 195, 215; 12, 35, 36,41; 13, 68b; 14, 1 I , 176; 15, 114, 116,302, 303,3 12, 313 Houmam, A., 3, 174 Houser, J.J., 9, 60 Houser, M., 6, 24 Hoveyda, A.H., 13, 49 Howarth, J.A., 1, 54 Howell, J.A.S., 9, 22 Hoyer, K., 12, 68; 15, 409 Hoz, S, 2, 201 Hoz, S., 13, 109 Hrovat, D.A., 3, 25 Hsia, K.Y., 7, 9 Hsieh, S.-J., 9, 28 Hsieh, Y.-T., 1, 2; 11, 101 Hsu, K.-J., 3, 194 Hu, C.-H., 4, 252 Hu, H., 15, 494 Hu, K., 7, 12; 10, 92 Hu, S., 4, 204 Hu, W-P., 10, 61 Hu, X., 14, 3 Hua, I., 2, 36 Huang, H., 2, 148 Huang, H.H., 12, 31 Huang, L.W., 1, 166 Huang, M.B., 4, 29 Huang, Q.-Z., 2, 126 Huang, S., 15, 468 Huang, S.-T., 1, 33 Huang, X., 1, 9a; 3, 97; 5, 173; 9, 40 Huang, Z.-T., 15, 203 Huben, K., 15, 103 Huber, R.S., 6, 66 Huber, T., 15, 124 Hiibsch, T., 14, 122, 132 Huda, S.N., 15, 396 Hudhomme, P., 5, 204 Hudson, A,, 4, 9 Huet, F., 15, 401 Hughes, D.L., 15, 532 Hughes, D.S., 14, 185 Hughes, P.F., 15, 493 Hughes, P.J., 2, 202; 10, 101 Huh, C., 2, 111; 4, 207; 10, 83 Huh, T.-S., 2, 32

Huie, R.E., 3, 198 Huisgen, R., 14, 41,42 Huizer, A.H., 6, 78 Hulme, A.N., 15, 149 Hulme, C., 3, 126 Hume, W.E., 11, 94; 15, 11 Hung, A.-W., 1, 71, 72; 11, 40, 44 Hhnig, S., 14, 87, 88 Hunziker, R., 15, 321 Hurley, M.D., 3, 95 Hurley, T.B., 2, 197 Human, B.T., 2, 185 Hursthouse, M.B., 14, 185 Huskens, J., 5, 194 Hutchinson, J., 8, 7 Hutte, S., 13, 1 1 1 Hwang, B.K., 2, 174 Hwu, J.R., 1, 166 Hyashi, R.K., 4, 163 Hyatt, J.A., 14, 16 Hyun, Y.-L., 5, 188 Hutte, S., 11, 68 Ialongo, G., 14, 7 Ibata, T., 7, 24-26 Ibrahim, S.K., 15, 532 Ibuka, T., 15, 563, 564 Ichihara, A,, 14, 116 Ichihara, K., 7, 83 Ichihashi, H., 15, 485 Ichikawa, T., 4, 167 Ichioka, M., 15, 244 Iesce, M.R., 14, 7 Iglesias, E., 2, 134; 11, 56; 14, 145 Iglesias, M., 5, 66 Ignaczak, M., 5 , 4 5 , 4 8 Ignatenko, A.V., 14, 207 Ihara, M., 2, 101 lio, K., 15, 27, 28 Ijadi-Maghsoodi, S., 6, 81; 15, 288 Ikeda, H., 4, 102 Ikeda, K., 3, 37 Ikeda, S.Y., 15, 352 Ikemi, Y., 14, 65 Ikuma, K., 15, 52 Ikuuo, K., 14, 190 Ila, H., 14, 158 Imai, R., 15, 419 Imai, S., 15, 461 lmming, P., 15, 267 Imnch, J., 2, 107 Imoto, H., 14, 200 Imrich, J., 15, 176 Inagaki, S., 14, 194 Inazu, T., 12, 15 Inchley, P., 5, 78 Indolese, A.F., 13, 54 Inesi, A,, 6, 46

Ingold, K.U., 3, 41, 88, 90; 4, 37; 5, 142 Ingrosso, G., 13, 10 h o e , K., 4, 55, 57 Inomata, K., 15, 63 Inoue, K., 15, 451 Inoue, T., 14, 27; 15, 575 Insausti, M.J., 5, 22 Insawa, M., 2, 153 Ioannou, G.I., 4, 206 Ioele, M., 3, 165; 5, 76 IoRe, A., 4, 177 Ionica, I., 15, 435 Iozawa, T., 5, 222 Irie, S., 11, 106 Iriyama, H., 3, 37 Irk, S., 7, 18 Imgartinger, H., 5, 180; 9, 92 lrvine, J., 11, 132 Isaacs, N.S., 15, 339 Isdev, A.N., 1, 83 lseki, K., 6, 94 Ishibashi, H., 3, 37 Ishibashi, T., 4, 133; 8, 23 Ishida, A,, 4, 170, 171 Ishida, H., 15, 323 Ishida, M., 14, 194; 15,478 Ishida, Y., 2, 101 Ishiguro, K., 5, 163 Ishihara, K., 2, 20; 15, 552 Ishihara, T., 13, 86 Ishii, A,, 15, 427 Ishii, H., 15, 137 Ishikawa, K., 15, 21 1 Ishikawa, S., 7, 37 Ishikawa, T., 15, 137, 459, 460 Ishikubo, A,, 2, 15 I Ishimaru, M., 2, 21 Ishimura, A S . , 4, 233 Ishitani. H., 1, 18 Ishiyama, T., 3, 53; 7, 70 Ishizaka, H., 15, 323 Islet, B.T.D., 15, 18 Ismagilov, R.F., 3, 58 Ismail, J., 13, 21 Isobe, H., 3, 117; 6, 50 Itani, J., 15, 30 Itano, N., 6, 27; 15, 453 Itasaka, M., 4, 197, 198 Itaya, T., 7, 71 Ito, M., 11, 96 Ito, O., 3, 9; 4, 83 Ito, S., 9, 36, 37 Ito, T., 15, 140, 450 Ito, Y., 6, 99 Ito, Y.N., 1, 100; 11, 103 Itoh, D., 3, 116 Itoh, H., 3, 78 Itoh, T., 7, 92 Itoh, Y., 3, 12 Itzhaky, H., 2, 176

Author Index Iuliano, A., 1, 97: 11, 102 Ivanova, S., 13, 26 Ivanova, S.M., 13, 93 Iwama, T., 15,450, 550 Iwamoto, H., 15, 275 Iwamura, H., 4, 55-57 Iwana, T., 15, 581 Iwasaki, F., 15,433 Iwasaki, T., 15, 202 Iwasawa, N., 15, 541 Iwata, C., 15, 538 Iwata, M., 1, 50a Iyanar, K., 5, 132 Iyoda, M., 4, 80 lzawa, Y., 15, 52 Jahin. I., 1, 23 Jabn, E., 2, 173 Jachest, D., 15, 26 Jackson, R.F.W., 5, 155, 156 Jacob, C., 15, 2 Jacob, U., 14, 196 Jacobi, D., 15, 566 Jacohsen, E.N., 5, 29, 191; 6, 55, 61 Jacobsen, N.W., 14, 64 Jacobson, D.B., 9, 15 Jacquault, P., 15, 498 Jagannadham, V., 9, 27 Jagdmann, G.E., 15, 493 Jaglid, U., 10, 46 Jagner, S., 15, 88 Jahangiri. G.K., 1, 141 Jaime, C., 3, 149 .lain, I., 5, 43 Jain, N.F., 1, 106 Jain, S., 15, 173 Jain, S.L., 1, 145; 5, 40 Jalali-Heravi, M., 2, 54 Jameson, R.F., 4, 7 I Janda, K.D., 2, 177; 14, 118 Jandu, K.S., 15, 480 Jang, B.-M., 2, 104 Jang, E.G., 6, 43, 44, 91 Jang, S.-B., 7, 72 Jankowski, P., 15,291 Jankowski, S., 2, 186 Jannin, M., 14, 73 Janoschek, R., 6, 102 Janowski, M., 13, 23 Janzen, E.G., 4, 69, 70 Jarczewski, A,, 11, 124 Jarowicki, K., 15, 290 Jarrett, S., 15, 141 Jarstfer, M.B., 15, 577 Jasiohedzi, W., 13, 23 Jastrzebski, J.T.B.H., 1, 19; 11, 46, 47 Jayamma, Y., 10, 27 Jayasuriya, K., 15, 76 Jedrzejczak, M., 2, 108 Jefferson, E.A., 1, 124; 6, 43

569 Jefferson, G.R., 11, 83 Jefford, C.W., 5, 94 Jencks, W.P., 1, 32, 33,9b; 10, 109 Jenkins, H.D.B., 2, 10 Jenkins, I.D., 3, 123, 124; 4, 139 Jenkins, P.R., 1, 62 Jenkins, T.E., 14, 201 Jensen,F., 15, 257 Jeon, I.C., 15, 19 Jeon, P., 14, 135 Jernigan, M.T., 11, 81 Jesorka, A,, 4, 241 Jha, B.K., 15, 489 Ji, X., 8, 45 Jia, H., 7, 28 Jian, W., 1, 39 Jiang, J., 15, 91 Jiang, X.-B., 5, 62 Jiang, X.-R., 1, 63 Jiang, X.Y., 1, 92 Jiang, Z., 9, 47 Jiao, H., 15, 304 Jiao, H.J., 15, 181 Jiao, N.-X., 1, 146; 5, 83 JimCnez, A.I., 1, 163 Jimenez, L.S., 11, 79 Jimenez, M.C., 3, 67; 15, 23 Jimoto, T., 7, 99 Jin, J., 10, 114; 15, 335 Jin, Q.. 11, 95; 13, I10 Jin, Y.N., 15, 427 Jin, Z., 11, 60; 13, 103 Jing, C., 2, 91 Jing, Ch., 13, 105 Jing, N., 4, 259 Joe, D., 15,482 Joela, H., 4, 25 Johansson, L., 2, 208 Johner, M., 15, 559 Johnson, C.C., 3, 21, 32 Johnson, J.E., 2, 110 Johnson, K.E., 8, 48; 9, 9 Johnson, M.A., 1 0 , 6 2 Johnson, M.P., 2, 137 Johnston, K.P., 10, 94 Johnston, L.J., 4, 173 Jokela, R., 15, 153 Jonah, C.D., 1, 144 Jonas, J., 10,4; 11, 133 Jbnczyk, A,, 11, 55; 15, 231 Jones, C.J., 15, 533 Jones, D.E., 14, 21 1 Jones, D.W., 6, 41 Jones, G.B., 6, 66 Jones, J., 4, 254 Jones, M., 6, 20; 9, 90; 15, 428 Jones, P.G., 14, 81, 123 Jones, R.A., 13, 108; 14, 186 Jones, R.V.H., 15, 573,574

Jones-Hertzog, D.K.. 15, 234, 235 Jonnalagadda, S.B., 5, I23 Jonsson, M., 4, 160, I61 Jordan, F., 1, 78; 11, 126 Jergensen, K.A., 5, 84; 6, 54; 14, 178 Jorgensen, K.B., 15, 88 Jorgensen, W.L., 1, 26b, 26c; 9, 86; 15, 234, 235, 424 Joseph, R., 5 , 9 Joseph-Nathan, P., 15, 583 Joshi, S.N., 1, 145; 5, 40 Jouini, M., 3, 174 Journet, M., 14, 83 Jovanovic, S.V., 3, 129 Jubault, M., 5, 204 Jubian, V., 2, 25 Jug, K., 14, 30 Jugelt, W., 4, 157 Julia, L., 4, 13 Julia, M., 7, 59 Jun, J.-G., 15, 69 Jung, G., 3, 162 Jung, H.J., 2, 39 Jung, K.-Y., 5, 100; 7, 72 Jung, M.E., 15, 26, 554 Jung, W., 4, 100 Junjappa, H., 14, 158 Juntunen, S.K., 15, 395 Jursic, B., 14, 92 Jursic, B.S., 4, 19; 11, 117: 14, 31, 32,93, 129, 130, 140-142, 147, 152-156, 166, 179, 187; 15, 224 Just, G., 7, 82 Jwo, J.-J., 5, 47, 55, 57 Kabbara, J., 13, 98 Kabilan, S., 2, 219; 5, 23, 148, 149; 15,25 Kabuto, C., 2, 101 Kada, R., 2, 44 KBdas, I., 14, 70 Kadlecek, D.E., 9, 93 Kadota, I., 14, 177 Kady, LO.,2, 119, 149 Kagabu, S., 15, 549 Kagan, H.B., 1, 156 Kagawa, T., 15, 45 I Kahley, M.J., 9, 43 Kaim, W., 4, 200, 201 Kakehi, A,, 14,65, 190 Kakinuma, K., 5, 219 Kakita, S., 14, 194 Kako, M., 15, 433 Kakuma, S., 15, 433 Kalberg, C.S., 1, 157 Kalgutkar, R., 6, 20 Kallmerten, J., 15, 216 Kalra, B.L., 15, 336 Kalvoda, J., 15, 329

570 Kamala, V., 11, 72 Kaniata, K., 15, 61 KdmatSU, M., 3, 132 Kambanis, K.G., 3, 91 Kdmbe, N., 3 . 5 I , 132 Kameoka, C., 3, 37 Kaminskii, A.Ya., 7, 97, 98, 109 Kammel, T., 4, 236 Kamochi, Y., 5, 205 Kanavanoti, A., 2, 197 Kanda, T., 15, 619 Kaneko, C., 13, 18 Kaneko, K., 3, 30 Kaiiemasa, S., 11, 58; 13, 78; 14, 36, 52, 104; 15, 592 Kanematsu, K., 15, 130 Kang, B.-K., 2, 135 Kang, M.S., 2, 148 Kang, S.-K., 5, 100; 7, 72 Kang, S.-U., 15, 310 Kankake, M., 14, 188 Kanmi, S., 15, 349 Kansui, H., 14, 43 Kanter, J.P., 15, 594 Kanth, J.V.B., 1, 155; 5, 201 Kdplan, F., 6, 15, 16 Kapon, M., 12, 76; 14, 28 Kapoor, K.K., 15, 172 Kapoor, S., 1, 144 Kappe, C.O., 6 , 7 5 Kapturkiewicz, 4, 224 Kar, S., 3, 170 Karabet, F., 4, 79 Karadakov, P.B., 8, 1 Kdraiskakis, G., 2, 189 Kardkasa, T., 14, 102 Karaman, R.M., 10, 55 Karasevich, E.I., 5, 104 Karelson, M., 10, 90 Kdrfunkel, H.R., 13, X Karimi, S., 11, 71 Karlen, T., 13, 39 Karlstedt, N.B., 15, 261 Karlstriim, G., 3, 48; 4, 230 Karolak-Wojciechowska,J. 15, 617 Karoza, G.A., 15, 38 1 KdrpllIS. P.A., 2, 173 Karunakaran, C., 13, 15, 21 Karunakaran, IS.,5, 87, 116 Kas’yan, LJ., 10, 22 KdSa, s., 4, 25 Kasack, V., 4, 200 Kaaai, P.H., 4, 187 Kasaikina, O.T., 5, I79 Kase, N., 15, 178 Kaselj, M., 5, 196 Kashino, S., 15, 30, 35 Kasprzyk, G., 2, 159; 12, 71 Kasa, S.R., 12, 39; 15, 389 KasSara, s., 2, 138

Author Index Kassir, J.M., 15, 223 Kasuga, K., 15, 136 Katada, N., 15, 488 Katdo, Y., 5, 166 Kataoka, T., 9, 68; 11, 136; 15, 443,450,550, 581 Katayama, K., 14, I16 Kato, H., 2, 155 Kdto, M., 15, 3, 242, 243 Kato, N., 6, 73 Kato, S., 15, 619 Katouda, W., 3, 54 Katritzky, A.R.. 4, 241; 7, 84; 11, 89, 90; 13, 58; 15, 91, 61 I Katz, B., 3, 97 Kaufmann, M., 14, 13 Kaul, V.K., 15, 347 Kaupp, G., 15,387 Kautz, C.B., 9, 89; 15, 426 Kawabata, T., 1, 137; 11, 34 Kawachi, A,, 6, 99; 15,545 Kawae, T., 15, 459 Kawahigashi, M., 11, 136; 15, 443 Kawai, I., 15, 549 Kawai, Y., 4, 159 Kawakami, J.K., 4, 131 Kawakita, M., 9, 41 Kawamoto, T., 14, 61 Kawana, M., 15,477 Kawanishi, N., 15, 232 Kawano, H., 3, 70, 71 Kawano, N., 15,447,448 Kawasaki, H., 6, 12 Kawasaki, M., 2, 23 Kawasaki, T., 15, 193 Kawata, T., 11, 78 Kawatake, K., 11, 58; 13, 78 Kayano, A., 3, 155 Kayashila, T., 3, 154 Kaye, P.T., 15, 508,509 Kazin, V.N., 7, 23 Kazmaier, U., 15, 142, 143 Keana, J.F.W., 4, 54 Kearley, M.L., 4, 233 Keck, G.E., 1, 102; 11, 107 Kee, T.P., 1, 115 Keeffe, J.R., 1, 124 Keinan, E., 2, 176 Kel’tseva, M.V., 14, I80 Keller, M., 4, 18, 178; 14, 85 Kelley, S., 6, 24 Kellogg, B.A., 2, 2 Kellogg, R.M., 10, 3 I Kelly, B.J., 13, 33 Kelly, D.P., 9, 73 Kelly, D.R., 15, 521 Kelly, E.J., 2, 10 Kelly, T.R., 15, 86 Kelly-Rowley, A.M., 1, 129; 11,33

Kemme, A,, 13, 29 Kemmer, R., 9. 88; 10, I12 Kemp, D.S., 11, 108 Kenar, J.A., 6, 76 Kenda, B., 13, 97 Kende, A S . , 14, 83; 15, 348 Kennard, C.H.L., 14, 64 Kennedy, S.A., 9, 43.45 Kennewell, P., 14, 75 Kenso, S., I, 87 Kenttamaa, H.I., 4, 182, 183 Keong, P.-H., 15, 212 Keppens, M., 13, 29 Kersey, I.D., 15, 31, 32 Kessar, S.V., 15, 347 Kessels, R., I, 168 Keszler, A., 2, 160; 4, 77 Ketner, R.J., 10, 1; 12, 2; 13, 90,92 Ketrner, R.J.. 2, 197 Kevacher, V., 5, 220 Kevill, D.N.. 2, 67; 10, 13, 77, 78, 106 Khaikin, G.I., 4, 38, 39, 41 Khalilov, I.N., 15, 157 Khalizov, A.F., 3, 182, 183 Kham, M.A., 3, 186 Khamidova, E.A., 8, 9, 26 Khan, F.A., 1, IS3 Khan, I.M., 11, 20 Khan, M.I., 6, 10 Khan, M.N., 2, 5, 93, 94, 97, 99, 123 Khan, S., 13, 31; 15, 322 Khan, S.I., 15, 26 Khan,M.N., 2, 117 Khanchandani, R., 5, 6 Khiar, N., 11, 59; 13, 89 Khlebnikov, A.I., 2, 103 Khmelnitskii, L.I., 15, 501, 515

Khrustalev, V.N., 1, 8 1 Khrustalyov, V.N., 3, 58 Khumtaveeporn, K., 15, 109, 539 Khursan, K.L., 3, 182 Khursan. S.L., 3, 183 Kiddle, J.J., 11, 131 Kido, F., 15,242, 243 Kido, M., 1, 158 Kiefer, J.H., 12, 34 Kicfer, W., 5, 143 Kiesel, G., 1, 5 Kiesman, N.F., 7, 5 Kiesman, W.F., 3, 167 Kigure, K., 15. 460 Kihara, N., 10, 20 Kikuchi, T., 4, 159 Kikugawa, Y., 15, 3 Kilic, Y.. 5, 50 Kilkova, N.L., 7, 106 Kim, B.H., 4, 136

57 I

Author Index Kim, C., 15, 26 Kim, C.K., 2, I ; 10, 69, 70; 12,58

Kim, D.C., 15, 87 Kim, D.J., 15, 87 Kim, H., 15, 198 Kim, H.S., 4, 118; 15, 602606 Kim, J., 5, 77 Kim, J.-S.,2, 118; 11, 67; 13, 112 Kim, J.H., 7, 117 Kim, J.W., 15,77 Kim. M.S.. 6. 87 Kim, S., 3, 16, 27, 33; 6, 71; 15, 54 Kim, S.G., 3, 2 Kim, S.H., 10,79-81, 85 Kim, S.S., 3, 27, 86; 15, 19 Kim, T., 14, 6 Kim, T.-H., 2. 11 I , 133; 5, 100

Kim, T.R., 2, 100 Kim, W.K., 2. I , 39; 5, 51 Kim, Y., 1, 93 Kim, Y.J., 2, 104 Kim, Y.K., 12, 16 Kim.S.-J., 6, 7 Kimura, K., 15, 609 Kimura, N., 4, 2 14 Kinastowski, S., 13, 73 Kind, J., 7, 102 King, J.F., 2, 200; 9, 21; 12, 20, 72 King, K.D., 6, 1 I King, M.D., 15, 339 Kinoshita, H., 15, 63 Kirby, A.J., 2, 195; 7, 86; 15, 99, 584 Kirkhima, K., 9, 38 Kirms, L.M., 15, 55 1 K i m s , M.A., 15,55 1 Kirmse, W., 9, 80, 87, 89; 15, 425,426 Kirschenbaum, L.J., 2, 76; 4, 64 Kirste, B., 4, 157 Kirubasankar, P., 5, 23 Kise, H., 5, 222 Kisclyov, A S , 8, 43 Kishdn, 1, 155 Kishan, B.H., 5, 97 Kisielowski, L., 15, 55 Kistic, A.R., 3, 104 Kita, E, 4, 238 Kitd, Y., 1 5 , 2 7 , 28, 419,441, 448 Kitagaki, S., 15, 419 Kitagawa, H., 15, 61 Kitagishi, Y., 4, 27 Kitamura, M., 1, 95; 11, 104; 15. 485

Kitamura, T., 7, 88, 113; 10, 43; 12, 61; 14, 127 Kitayama, K., 13,43 Kitaygorodskiy, A., 4, 84 Kizil, M., 4, 263 Klar, M., 9, 89; 15, 426 Klamer, E-G., 14, 12 I , 222; 15, 183, 265 Klaukien, H., 4, 168 Kleijn, H., 1, 19; 11, 46, 47 Klein, A,, 4, 201 Kleindienst, T.E., 3, 200; 5, 178 Klemperer, W., 4, 10 Klier, K., 10, 99 Klimenko, L.S., 1, 112, 113 Klindert, T., 15, 267 Klinman, J.P., 5, 189, 190 Klipperstein, S.J., 3, 152 Kllotgen, S., 15, 309 Kloetstra, K.R., 1, 74 Klug, D.D., 9, 12 Kluge, R., 5, 67 Kluge, S., 15, 466 Kluger, R., 1, 80 Klumpp, G.W., 1, 89; 11, 14 Klunder, A.J.H., 13, 100 Kluwe, C., 15, 546 Km, C.K., 10, 9 Knaggs, A.R., 15, 285 Knastovski, S., 13, 72 Knauer, B., 5, 193 Knayazev, V.D., 3, 189 Kneisel, B.O., 15, 367 Knickmeier, M., 14, 133 Knight, J.G., 6, 62 Knoche, W., 2, 217, 218 Knopp, M., 15, 152 Knothe, L., 4, 146 Knowles, C.J., 15, 521 Knstian, P., 2, 107 Kniihl, G., 10, 6 Knyazev, V.D., 3, 147; 4, 44 Knyazev, V.N., 7, 95, 106 Kobayashi, K., 3, 160; 4, 56; 6.98; 9 , 4 1 ; 14, 177; 15, 48 Kobayashi, M., 15, 35 Kobayashi, N., 6, 12 Kobayashi, S., 1, 18, 58, 59; 2, 224; 8, 44; 11, 27; 13, 6; 15, 17 Kobayashi, T., 14, 190 Kobayashi, Y., 1, 73; 6, 94; 11, 31 Kobrina, L.S., 3, 14 Kobzev, S.P., 10, 24 Koch, R., 11, 90 Koch, S.A., 9, 33 Kocharyan, S.T., 12, 17 Kochevar, I.E., 4, 262

Kochi, J.K., 4, 123, 138, 156; 5, 105, 108 Kocienski, P., 15, 290-292 Kociolek, M.G., 2, 215 KoEovskS;, P., 13, 64 Kodama, K., 3, 37 Koen, M.J., 2, 221 Koertvelysei, T., 3, 114 Koga, K., 1, 57; 11, 36 Koga, N., 4, 55, 56 Koh, D., 15, 195 Koh, H.J., 10, 105 Koh, J.T., 1, 5Oc Kohori, K., 15, 63 Kolb, H.C., 5, 92 Kolbina, E.N., 15, 78 Kolchina, E.F., 15, 8, 9 Koliadima, A,, 2, 189 Kollcnz, G., 14, 100; 15, 68, 262 Koller, F., 14, 78 Kollman, P.A., 11, 109 Kolodiazhnyi, O.I., 5 . 127 Kolomiets, A.F., 1, 11 1 Kolonits, P., 15, 135 Kolshorn, H., 15, 593 Koltsov, A.I., 15, 610 Koltunov, K.Y., 9, 97 Komatsu, T., 4, 104; 15,487 Komisarski, S., 5 , 45, 48 Komissarov, V.D., 3, 182 Komiyama, M., 2, 151, 153, 196 Komuraiah, A,, 5, 97 Kondo, M., 1 5 , 4 1 9 Kondo, Y., 10, 91 Kondow, T., 10, 62 Konishi, H., 9, 38,41; 15, 48 Konno, K., 15,431,578 Konovalov, A.I., 2, 13 Konschin, H., 15, 324, 325 Koo, I.S., 2, 198 Kootiyama, Y., 11, 137 Kopeikin, V.V., 7, 23 Kopiske, C., 15, 360 Koppe, R., 4, 187 Koppel, I., 2, 21 1 Koppel, J., 2, 21 1 Korchagina, D.V., 9, 74; 15, 465 Korell, M., 4, 231 14, 180 Koreshkov, Y.D., Korodi, F., 7, 80 Kosonen, M., 2, 191 Kossmehl, G., 4, 157 Kostccki, M., 13, 72 Koster, H., 14, 45 Kotake, Y., 4, 7 0 Kothari, S., 5, 117 Kotila, S . , 15, 439 Kotora, M., 15, 528 Kotschy, A,, 15, 607

572 Kotzamani, H.K., 15, 452 Kouichi, Y., 9, 41 Kouwenhoven, H.W., 15, 16 Kovacs, P., 15, 13.5 Kovalenko, A.A., 2, 83 Kovesdi, I., 14, 70 Kovtoyuk, V.N., 3, 14 Kowalski, P., 8, 41; 15, 66 Kozanch, J.W., 3, 146 Kozlovskii, R.A., 10, 25 Kozlowski, P.M., 15, I82 Kraakman, PA., 6 , 78 Krafft, M.E., 15, 141 Kragol, G., 15, 441 Kramer, J.B., 13, 60; 15, 418 Krasodomska, M., 1, 24; 2, 87 Krasutsky, P.A., 9, 90; 15, 428 Krati.N., 2, 129 Kravchenko, 0.1., 11, 121 Krebs, A., 15, 143 Krechl, J., 1, 150; 5, 217 Kreher, R.P., 4, 20 Kresge, A.J., 1, 34, 124; 2, 14, 61 Krestov, G.A., 6 , 23 Krief, A,, 13, 97 Krieger-Beck, I?, 1, 5 Krishnan, K., 15, 337 Krishnasamy, K., 2, 219; 5, 148, 149; 15.25 Kroemer, R.T., 15, 500 Krogh-Jespersen, K., 6, 91 Krohn, K., 5, 193 Kroulik, J., 15, 100 Krstic, N., 15, 329 Krstic, V.V., 2, 58 Kruger, C., 15, 360 Kmsic, P.J., 4, 248 Krygowski, T.M., 7, 18 Kuberski, S., 15, 103 Kubicki, M.M., 14, 7 3 Kubota, M., 2, 20 Kubota, S., 4, 6 Kuchta, G., 14, 132 Kuck. D., 9, 20; 11, 23 Kudo, T., 5, 205 Kuethe, J.T., 15, 29 Kuhn, C., 15, 201 Kiihnle, F.N.M., 1, 100; 11, 103 Kulicke, K.J., 11, 21 Kulik, N.I., 10, 87 Kulishova, T.P., 7,21 Kuliya-Umdr, A.F., 2, 99 Kulkarni, B.D., 15, 489 Kulkarni. M.R., 2, 30 Kulkarni, V.R., 15, 370 Kuma, H., 14,61 Kumagai, H., 14. 27; 15, 575 Kumar, A., 2, 203; 5, 99, I10 Kumar, AS., 15, 328 Kumar, D., 15, 71

Author Index Kumar, G., 15, 347 Kumar, K.A., 15, 317 Kumar, I?, 5, 65 Kumar, P.P., 15, 337, 414 Kumar, R., 2, 33; 5, 9, 65 Kumar, S., 15, 106 Kumar, U.U., 5, 56 Kumaran, S.S., 4, 250 Kumazawa, T., 15, 478 Kumpegai, J., 4, 167 Kundu, A.K., 15, 139 Kunhara, H., 2, 20 Kunieda, T., 14, 43 Kunugi, A., 15, 355 Kuo, L.H., 15, 123 Kurdsawa, Y., 15, 602 Kurata, S., 7, 118 Kurbanbaev, R.M., 8, 49; 15, 38 Kuricheva, O.V., 5, 133 Kurihara, A,, 3, 51 Kurihara, T., 15, 177, 178, 296 Kurita, T., 7, 99; 11, I13 Kuriyama, Y., 4, 104, 140; 14, 18

Kuroboshi, M., 15, 445 Kuroda, A., 1, 137; 11. 34 Kurono, Y., 15, 232, 245 Kurosawa, H., 15, 548 Kusabayashi, S., 14, 84 Kusama, H., 1, 41; 15, 34, 490 Kushi, Y., 14, 61 Kuthan, J., 15, 100 Kutschy, P., 15, 176 Kuusela, S., 2, 150, 192 Kuwatani, Y., 4, 191, 245; 15, 444 Kuznetsov, A.M., 4, 209-21 1 Kuznetsova, M.G., 8, 9, 26 Kuzuhara, H., 1, 50a, 50b; 15, 477 Kwak, C.-G., 2, 104 Kwast, E., 7, 89 Kweon, J.-M., 2, 43; 10, 107 Kwetkat, K., 15, 25 I Kwon, D.-S., 2, 41 Kwon, H.-J., 2, 41 Kwon, K.-S., 2, 212; 9, 70 Kwon, K.S., 2, 100 Kwon, Y.-E., 11, 51 L'abbC, G., 6, 39; 14, 82; 15, 75 La Rosa, C., 14, 22 La Spina, A.-M., 13, 24 Laverne, J.A., 3, 62; 4, 265 Laali, K.K., 9, 60 Labadie, G.R., 15, 612 Labarta. A., 4, 13 Lachowska, M.. 2, 17 Lacrouts, P., 15, 145

Laev, S.S., 4, 81 Laffey, T.G., 15, 338 Lagercrantz, C., 4, 62, 202 Lahiri, S., 3, 170 Lahnstein, O., 15, 481 Lahti, P.M., 4, 233; 6, 20 Lai, D.K.W., 5, 59,215 Lai, M.-T., 3, 21 Laird, E.R., 1, 26c Lajis, N.H., 2, 5, 97 Lajunen, M., 10, I15 Lakin, M.T., 1, 19; 11, 47 Lakkaraju, P.S., 4, 96 Lakshman, M.K., 15, 368 Lallemand, J.-Y., 3, 39; 15, 462 Lam, J.F., 1. 80 Lam, J.Y.L., 2, 200; 9, 21; 12, 20 Lamartina, L., 7, 78; 15, 72 Lambert, P.H., 15,483 Lampard, C., 4, 121 Lamparth, J., 13, 8 Landais, Y., 3, 120 Landini, D., 1 0 , 9 7 Lanfranchi, M., 8, 46 Lang, F., 15, 86 Lange, H., 14, 170 Ldngers, S., 3, 69 Langhals, H., 15, 7 Langolis, N., 14, 49 Langridge-Smith, P.R.R., 14, 150 Langschwager, W., 15,600 Lanzalunga, O., 5, 80 Lao, X.-F., 14, 74 Lapin, Y.A., 15, 429 Lappas, A,, 4,4 Larka, E., 5, 77 Larock, R.C., I,74 Larouche, D., 3, 169 Larrow, J.F., 5, 29 Larsen, S., 15, 74 Laschat, S., 14, 133 Laskos, E., 15, 90 Lassacher, P., 15. 276 Laube, T., 9, 81 Laude, B., 14, 73 Laufer, A.H., 3, 63; 4, 264 Laurent, A., 13, 83; 15, 498 Lauricella, R., 4, 68 Lautens, M., 1, 160; 5, 198; 14,209; 15. 364 Lauterbach, G., 3, 190; 4, 79 Lavallke, J.-F., 11, 49 Lavrukhin, B.D., 15, 56 Lawrance, W.D., 6, 11 Lawrie, D.J., 14, 212 Laws, A.P., 2, 170, 171 Lawson, G.E., 4, 84 Laxmeshwar, N.B., 1, 28 Lay, PA., 4, I19

573

Author Index Layland, N.J., 2, 170 Lazar, L., 15, 67 Lazarou, Y.G., 3, 91 Lazny, R., 11.35 Lazzarini, E., 3, 82 Le Bideau, F., 15, 359 Le Drean, I., 13, 83 Le Gall, T., 1, 53 1.e Gouadec, G., 15, 201 Le Guevel, E., 2, 183 le Noble, W., 13, 68a le Noble, W.J., 5 , 196 Le Roux, C., 10, 41,42 Le, V.T., 1, 7a IeBras, G., 3, 199 LeGuyader, F., 2, 22 1 Leadley, P.F., 2, 172 Leal, P., 3, 67; 15, 23 Leardini, R., 3, 57 Lebbar, N.-E., 4, 116; 7, 11 Lebedev, Y u A , 6, 23 Leber, P.A., 15, 278 Lehideau, F., 15, 556 Lec, K.-I., 2, 104 Lechevallier, A,, 3, 137; 4, 113 Leclaire, M., 15, 462 Ledderhose, S., 14, 139 Lee, B.-S., 2, 1, 111; 10, 9, 69, 70, 105 Lee, B.S., 12, 58 Lee, C.-L., 5, 132 Lee, C.W., 13,41 Lee, D., 15, 504 Lee, D.-H., 14, 124 Lee, D.G., 5, 17, 91 Lee, E., 3, 18; 6, 67 Lee, E.K., 4, 1 1 8 Lee, G.-A,, 15, 326 Lee, G.-C., 2, 104 Lee, G.-H., 2, 154; 15, 537 Lee, H.-C., 1, 71, 72; 11, 40, 44 Lee, H.K., 15, 555 Lee, H.W., 4, 207; 10, 83 Lee,I., 2, l , 4 , 11,39, 1 1 1 ; 10, 9, 58, 69, 70, 83, 103, 105; 1 2 , 5 8 Lee, I.C., 10, 104 Lee, J., 3, 93; 15, 198 Lee, J.G., 1, 170 Lee, J.L., 15, 154 Lee, J.M., 10, 21, 49; 12, 38 Lee, J.P., 2, 209, 210 Lee, K., 9, 28; 15, 588 Lee, K.-J., 15, 310 Lee, K.B., 15, 544 Lee, K.H., 15, 314 Lee, M., 15, 504 Lee, N., 11, 48 Lee, S., 2, 174; 5, 131 Lee, S.-W., 2, 104

Lee, S.J., 12, 16 Lee, T.C.P., 5, 35 Lee, T.J., 3, 48; 4, 230 Lee, V.J., 5, 28 Lee, W.S., 15, 237 Lee, Y.-G., 9, 27 Lee, Y.-H., 2, 133 Lee, Y.-K., 14, 175 Lee, Y.R., 6 , 52 Lee, Y.Y., 14, 135 Lee-Ruff, E., 9, 50; 15, 382 Lefour, J.-M., 1, 84 Legzdins, P., 15, 535 Lehn, J.M. 2, 121 Lehnig, M., 4, 20, I68 Lei, M., 3, 25 Leis, J.R., 10, 56; 11, 144 Leistner, A,, 6, 57; 14, 35 Leito, I., 2, 21 1 Lemal, D.M., 4, 259 Lemoine, P., 1, 23 Lemoult, S.C., 5, 150; 15, 522 Lennartz, D., 15, 124 Lentini, M., 9, 19 Leon, I., 1, 17 Leonard, J., 13, 7 Leonenko, Z.V., 1, 1 12, 1 13 Lepoittevin, J.-P., 8, 10 Lerestif, J.M., 14, 69 Lerner, R.A., 2, 177 Leroy, V., 1, 37; 5, 202 Lesclaux, R., 3, 133 Leska, B., 7, 104; 11, 124 Leslie, D.R., 12, 7 Lesniak, S., 6, 84; 13, 83 Lessel, J., 1, 44 Lesueur, C., 3, 149 Leszczynski, L., 5, 49 Leu, J.R., 5, 47 Leu, Y.-J., 14, 15 Leue, V., 1, 69 Leung, M., 14, 21 3 Leung, M.K., 12, 75 Levai, A,, 15, 493 Levec, J., 5, 38 Levell, J.R., 14, 185 Levine, B.R., 15, 512 Levis, M., 1, 139; 4, 134, 135 Lew, C.S.Q., 1, 135 Lewin, G., 15, 483 Lewis, D.K., 15, 336 Lewis, K.D., 15, 185 Lewis, N., 4, 121 Lewis, R.T., 14, 59 Lewis-Brown, W., 3, 195 Ley, L., 3, 133 Leyes, A.E., 10, 2; 12, 3; 13, 91 Lhermitte, F., 3, 11 1 Li, B., 10, 86 Li, B.L., 15, 620 Li, G.-Z., 2, 126

Li, H., 5, 196 Li, J., 7,27, 28 Li, J.-S., 6, 51 Li, Q.-L., 2, 126 Li, Q.-M., 12, 56 Li, S.J., 7,60 Li, T., 2, 177 Li, W.-K., 11, 2; 15, 341 Li, X., 15, 580 Li, X.-Y., 9, 59; 15, 117, 208 Li, Y., 3, 125, 181; 12, 54; 13, SO; 15, 114 Li, Y.M., 1, 38, 39 Li, Z., 6, 61 Lianis, P.S., 15, 90 Liao, P.-Y., 2, 136 Liavona, L., 11, 98 Licause, J.F., 7, 31 Lickiss, P.D., 10, 45 Liebeskind, L.S., 7, 64 Liebscher, J., 14, 77 Liedl, K.R., 15, 500 Lightner, D.A., 2, 56 Likhite, A.P., 2, 26; 15,492 Likhotvorik, I.R., 9, 90; 15, 428 Lilla, G., 7,3; 9, 64; 15, 40 Lim, G.T., 6, 87 Lim, K.P., 3, 72; 4, 250 Lim, S., 1, 22; 13, 76 Lim, W.M., 2, 1, 39 Liman, M.D., 13,46, 56 Lin, C.-W., 5, 208 Lin, C.-Y., 4, 204 Lin, H.-P., 5, 47, 55, 57 Lin, J., 5, 103; 6, 81; 8, 51; 9, 43, 51; 13, 59; 15, 288, 390 Lin, L., 11, 84 Lin, M.C., 3, 85 Lin, S., 13,48 Lin, S.W., 12, 5 Lin, T.-Y., 5, 4 Lin, Y.-C., 5, 208 Lin, Y.-S., 10, 82 Lin, 2.-Y., 5, 5 Lincoln, S.F., 2, 138 Lind, J., 3, 98, 193; 4, 60, 160, 161 Lindel, T., 15, 558 Lindeman, S.V., 1, 81; 3, 58 Lindh, R., 3, 48; 4, 230 Lindqvist, O., 10, 46 Lineberger, W.C., 11, 112 Linert, W., 4, 71 Linker, T., 15, 327 Linkert, F., 14, 133 Linnert, H.V., 7,112 Linssen, T.G., 14, 151 Liotard, D.A., 15, 1 1 8 Lipina, E.S., 2, 223 Litvintsev, I.Y., 5, 75, 81 Liu, C., 6, 83

Author Index

574 Liu, H.-W., 3, 21 Liu, J.-X., 13, 53 Liu, K., 15, 348 Liu, K.-T., 10, 82 Liu, P., 2, 201; 3, 181 Liu, Q.Y., 15, 562 Liu, R.-S., 2, 154 Liu, S., 6 , 49; 8, 38 Liu, T., 5, 37 Liu, W., 6 , 40 Liu, W.-H., 1, 71; 11, 44 Liu, W.-Z., 2, 15; 11, 1 1 I Liu, X., 2, 19 Liu, X.-K., 1, 73; 11, 31 Liu, Y., 3, 181 Liu, Y.-C., 3, 179 I h , Y.-Z., 3, I15 Liu, Y.D., 14, 14, 15 Liu, Z., 6, 49; 15, 442 Liu, Z.-C., 3, 179 Livingston, A.B., 1, 67; 11, 28 Ljungstroem, E., 3, 69 Llamas-Botia, J., 6, 28 Llavona, L., 1, 88 Llera, J.M., 15, 236 Llewellyn, G., 10, 112 Llopis, E., 5, 207 I h y d , D., 15, 11 I Lluch, J.M., 8, 3; 10, 72 Lo Meo, P., 1, 48 Lo Moro, G., 13, 10 Lo, C.-H., 14, 118 LO, L.-C., 2, 177 Lobo, A.M., 15, 204 Lochon, P., 2, 129 Lock, J.D., 12, 72 Loeza-Coria, M., 15, 583 LoRe, A., 4, 176 Lofstriim, C.M.G., 15, 395 Lohray, B.B., 10, 27 Lomas, J.S., 3. 74; 9, 29; 10, 13; 15,440 Lombardozzi, A,, 10, 8 Lom~akova,V.I., 8, 9, 26 Loncharich, R.J., 1, 109; 11, 85; 12,59 Lonnberg, H., 2, 150, 191, 192 Lopata, A,, 3, 113 Lbpez, J.C., 15, 476 Lopez, L.A., 14, 125 Lopez, R., 14, 21 Lbpez, S., 4, 13; 15, 305 L6pez-Cabdhorra, F., 1, 79a; 11, 127, 128 Lbpez-Leonardo, C., 6, 28 Lord, M.D., 15, 41 1 Lorenc, L., 15, 329, 586 Loreto, M.A., 6, 60 Lorthiois, E., 15, 332 Lough, A.J., 14, 209; 15, 276 Loughlin, W.A., 11, 39

Louie, J., 7. 61 Louis, C., 14, 55 Lounasmaa, M., 15, 153 Lovell, S.W., 15, 185 Loveridge, T., 11, 93 Lowery, J.A., 9, 93 Lown, J.W., 14, 65 Lozano-Hemmer, R., 2. 139 Lu, L., 12, 5 Lu, X., 14, 58 Lubing, Y., 8, 52 Luca, C., 5 , 26 Lucarini, M., 3, 81 Lucassen, A.C.B., 11,76b Lucchini, V., 10, 5 ; 13, 87 Lucking, K., 4, 128, 129; 14, 95, 96 Ludwig, R.T., 4, 21; 9, 6; 11, 110 Luff, s., 4, 5 Luger, P., 12, 62 Lugtenburg, J., 4, 194; 11, 134 Luh, T.-Y., 1, 2; 11, 101 Lui, D.K.W., 5, 61 Luibrand. R.T., 1, 152; 5, 195 Luitjes, H., 1, 89; 11, 14 Lukach, A.E., 4, 11 1 Lukin, P.M., 15, 62 Lukovskaya, E.V., 15, 38 1 Lunazzi, L., 4, 188, 189 Lund, A,, 13, 39 Lund, H., 4, 106; 10, 73 Lund, T., 4, 106; 10, 73 Lunell, S., 4, 29 Luo, H., 5, 196 Luo, Y.-R., 4, 15 Luque, EJ., 15, 613, 614 Lusis, V., 7, 87 Lusztyk, J., 3, 41, 88, 90; 4, 37; 15, 306 Lutz, G., 4, 146 Luzkhov, V.B., 2, 27 Lyashchuk, S.N., 1, 14, 15; 2, 199 Lynch, G.C., 15, 1 I X Lynch, K.O., 14, 62 Lynch, V.M., 1, 129; 11, 33 Lyons, R.A., 3, 118, I 19 Lys, Ya.1.. 10, 108 Lyshchikov, A.N., 15, 62 Ma, B., 4, 84, 252; 15, 59 Ma, J., 1, 1221, 12b; 12, 32. 33; 14, 195, 197 Ma, K.-Q., 1, 146; 5, 83 Ma, L., 13, 85 Ma, M., 8, 48; 9, 9 Ma, Y., 8, 45 Ma, Z., 6, 81; 15, 288 MaGee, D.I., 11, 37 Mabic, S., 8, 10

Mahuchi, S., 15, 451 Macchia, F., 10, 15, 16, 33 Machacek, V., 1. 47; 7, 33 Machida, M., 15, 70 Machiguchi, T., 1,42; 12, 63 Mackie. J.C.. 1, 1 1 ; 4, 254; 15,345 Maclagan, R.G.A.R., 9, 78 Maddaluno, J., 9, I6 Madden, K.P., 4, 58 Maddock, J., 1, 110; 11, 80 Madjdabadi, A.A., 4, 1 I 3 Madkour, A.E.E.D., 11,62 Madsen, R.. 2, 11 3; 15,475 Maeda, K., 6, 27; 15, 453 Maerker, C., 9, 82 Maggi, R., 8 , 32, 46 Magnus, P., 3, 126; 15, 3 I I , 467 Magnuson, S.R., 15, 133 Mah-Arvela, P., 2, 59 Mahadevappa, D.S., 5, 120 Mahajan, M.P., 14. 101; 15, 568 Mahamoud, A., 1 5 6 I7 Mahdi, J.G., 15, 521 Mahler, H., 1, 90; 11, 97 Mahmood, K., 3, 131; 15,582 Mahnen, M.W., 2, 85 Mahon, M.F., 1, 110; 11, 80 Mahy, J.P., 6 , 1 Maia, A., 10, 97 Maia, H.L.S., 2, 2 I I Maicr, G., 5, 180 Maier, I., 15, 191 Maier, S., 15, 142 Maillard, B., 3, 141 Mainagashev, T.Ya., 1, I I2 Mains, G.J., 12, 43 Maity, D.K., 4, 266 Majetich, G., 8, 38 Majewski, M., 11, 35 Majima, T., 4, 170, 171 Majumdar, K., 15, 469 Majumdar, K.C., 15, 138. 139 Mak, T.C.W., 14, 64 Makarov, M.G., 10, 25 Makarova, O.N., 3, 183 Makhoul, M., 4, 79 Makhova, N.N., 15,501,515 Maki, S., 15,431, 578 Makosza, M., 7, 41, 89-9 1 ; 15,561 Maksimenko, N.N., 2, 199 Maksimov, B.N., 13, 17 Makurina, V.I., 2, 214 Malacria, M., 15, 330, 359, 556 Malandra, J.L., 9, 93 Mala\ka, M.J., 14, 208 Malcolm, E.A., 4, 255 Maldonado, J., 3, 175: 4, I14

575

Author Index Mali, R.S., 15, I34 Malich, A., 15, 466 Malinka, W., 15, 64 Malkova, N.N., 5, 152 Malkovd, O.V., 5, 45 Malone, J.F., 14, 71 Malone, M.E., 10, 40 Maloney, U., 6, 24 Malpass, J.R., lU, I I ; 15, 432 Maltese, M., 7, 81 Marnatyuk, V.I., 1, 112; 14, 44; 15,423 Mamon, R.E., 2, 195 Man’khoan, K., 13, 52 Manan, S.M., 13, 21 Mancera, M., 14, 37 Mandard-Cazin, B., 5, 167; 14, 165 Mangion, D., 14, 94 Manickdvasagar, R., 13, 46 Manickurn, T., 11,43 Manirnekala, A., 13, 15 Mann, J., 4, 246 Mann, M., 9, 72 Manna, L., 3, I10 Mannami, T., 9, 41 Manni, F., 2, 74 Mannschreck, A,, 5, 50 Manova, J., 7, 33 Mansuy, D., 5, 30; 6, 1 MdnZ, J., 15, 189 Mao, Y.-L., 5, 5 Marais, C.F., 4, 82 Maran, F., 3, 164 Maran, U., 10, 90 Marazov, A.V.. 13, 17 Marc, G., 15, 350 Marchal, J., 7, 10 Marchand, A,, 5, 119 Marchand, A.P., 14, 162, 163; 15, 3 17, 442,516,579 Marchetti, M., 15, 377 Marchington, A.P., 15, 562 Marco, J.-L., 13, 89 Marco, s.-l.,, 11,59 Marconi, E, 5, 80 Marcotullio, M.C., 15, 454 Marcus, R.A., 14, 5 Mareda, J., 9, 4 Marek, I., 15, 331, 332 Marek, R., 15, 587 Margaritis, A., 15, 18 Marguet, J., 4, 120 Marinetti, A,, 14, 204 Markaryan, N.D., 12, 17 Markiewicz, M., 5, 45 Markovic, D.A., 2, 77 Marks, T.J., 13, 50 Marley, H., 15, 375 Marlow, M., 6, 24 Marquart, A.L., 14. 6X Marques, C.A., 7, 63

Marquet, J., 7, 14, 53 Marsais, F., 15, 356 Marshall, J.A., 1, 103; 11, 148 Marshall, W.J., 6 , 19 Marston, G., 3, 128 Martell, J.M., 3, 196 Marti, J., 11. 128; 14, 149 Martin, A., 15, 474 Martin, C., 3, 73; 12, 29, 30 Martin, I., 2, 158; 12, 23, 25, 27 Martin, K., 8, 28 Martin, K.A., 2, 137 Martin, R., 4, 78, 144, 251 Martin, R.A., 11, 37 Martin, S.E., 12, 18 Martin, S.F., 15, 196 Martin, V.V., 4, 54 Martin-Esker, A.A., 3, 21 Martindornenich, A,, 15, 194 Martinez Alvarez, R., 9,69 Martinez, A., 10, 26; 15, 470, 47 1 Martinez, EN., 4, 30 Martinez-Galero, N.X., 15, 583 Martingale, L.J., 7, 9 Martins, M.F., 2, 48 Martiny, L., 5, 84 Maruoka, K., 11, 96; 14, 20, 200; 15, 122 Maruta, J., 5, 212; 9, 17 Maruthamuthu, P., 3, 198 Marx, D., 9, 11 Maryanoff, C.A., 15, 151 Marzorati,L., 15, 376 Masaki, A., 3, 188 Masaki, Y.. 1, 108; 4, 137; 6, 35 Masanet, J., 3, 133 Mason, K.G., 7, 115 MdSOfl, R.S., 9, 56; 15, 41 Massa, W., 6, 82; 15, 267 Massy-Westropp, R.A., 3, 153 Masuda, K., 15, 193 Masunari, C., 15, 30 Mata-Perez, F., 5, 14, 22 Mataka, S., 7,6; 14, 197; 15, 61 Mateos, A.F., 11, 30 Mathew, L., 2, 61 Mathew, T., 2, 79; 12, 22, 26 Mathews, J.E., 6, 66 Mathey, F., 14, 204 Matia, M.P., 1, 36 Matsson, O., 10, 59; 15, 343 Matsuha, S., 15, 478 Matsuda, I., 13, 55 Matsurnoto, H., 15, 450, 550 Matsumoto, K., 3, 12; 14, 65; 15, 3, 447

MdtSUrnotO, M., 5, 166; 14, 217 Matsumoto, T., 7, 1 18; 15, 46 1 Matsurnoto, Y., 4, 245; 15, 444 Matsuo, T.. 15, 541 Matsuoka, T., 14, 25, 53 Matsushita. M., 4, 6 Matsuya, Y., 7, 92 Matsuyama, K., 3, 184 Matsuzawa, T., 5, 219 Mdttay, I., 14. 1 ; 15, 566 Mattingly, P.C., 15, 83 Matuszewska, B., 12, 12 Matzinger, S., 6, 6 Matzner, E., 14, 90 Maude, A.B., 2, 62 MdUmy, M., 15, I S Y Maurel, F., 1, 84 Mavridis, J.M., 13, 31 Maxwell, B.J., 3, 45; 4, 31 May, B.L., 2, 138; 5, 17 Mayabhate, S.P., 15, 492 Mayhugh, D.R., 7, 69 Maynard, D.F., 15, 308 Mayoral. E.P., 1, 162 Mayoral, J.A., 5, 64; 14, 110, 114, 1 I9 Mayr, H., 9, 17, 32, 34, 35, 54 Mazagova, D., 2, 107 Mazaki, Y., 4, 56 Mazal, C., 10, 4; 11, 133 Mazza, C., 2, 139 Mazzieri, M.R., 12, 18 McAllister, M.A., 1, 12a; 15, 306 McCague, R., 5, 151; 15, 523, 571 McCamley, A., 5, 155 McCleland, C.W., 1, 25; 4, 82 McClelland, R.A., 1, 117; 2, 69, 70; 6, 86; 9, 2, 44, 46; 15, 5, 6 McCleverty, 15, 533 MeClinton, M.A., 15, 268 McCullough, K.J., 14, 84 McCullough, K.L., 14, 210 McDonald, D.Q., 14, 192 McDonald, R., 13, 11 McDougall, J.J.W., 5, 159 McGhee, W., 2, 112 McGibbon, G.A., 6, 13 McGowan, W.M., 14, 161 McGrath, P.,2, 2 16; 12, 6 McHoumadi, C., 15,420 Mcllroy, S., 15, 430 McIntyre, S., 15, 574 Mclver, C.D., 3, 200; 5, 178 McKee, M.L., 5 , 210; 6 , 5, 21; 13,57 McKenzie, M.J., 11,66

576 McLennan, D.J., 2, 80 McMahon, J.M., 1 5 , 9 2 McMahon, R.J., 6, 4 McManus, S.P., 10, 55 McMullen, L.A., 15, 53 1 McMurdie, N.,9, 75 McNab, H., 15, 111 Mcnvin, L.H., 2, 6 0 Meagley, R.P., 6, 69 Medio, M., 1, 91; 4, 190 Meduna, S.P., 14, 62 Meekel, A.A.P., 14, 117 Meekhof, A,, 4, 21; 9, 6; 11, I10 Meenal, K., 1, 49; 5, 113 Meersman, K., 6, 39 Meggers, E., 4, 94 Mehrotra, M.M., 15, 108 Mehta, G., 1, 153 Meier, H., 15, 51, 593 Meinike, T., 3, 102 Meinwald, J., 15, 216, 217 Meisel, D., 1, 144 Mel’nikov, A.I., 7, 98 Mele, A,, 4, 72 Mella, M., 4, 91-93; 7, 54 Melloni, G., 15, 377 Mellor, J.M., 13, 28 Mellouki, A., 3, 199 Melman, A,, 3, 148 Meloy, G.K., 6 , 15 Melzer, K., 14, 98 Mendiciano, M.E., 4, 61 Menendez, E., 1, 105 Meng, Q., 10, 60, 1 1 I ; 12, 10, 11

Menger, EM., 2, 120 Menichetti, S., 12, 37; 14, 146 Mentz, M., 2, 178, 180 Menzel, M., 6, 82 Merchan, EL., 1, 35; 13, 102 Mercier, M.-F., 14, 73 MerCnyi, G., 3, 98, 193; 4, 60, 160, 161 Mereyala, H.B., 15, 520 Merger, M., 9, 92 Merino, P., 1,35; 13, 102 Memll, G.N.. 12, 39 Merriman, G.D., 13, 28 Memtt, M.V., 9, 28 Mertens, H., 1, 5 Mertens, R., 4, 40 Merz, A,, 15, 598 Meske, M., 14, 26, 79 Messeguer, A,, 5, 146 Messrner, A,, 15, 607 Mestres, J., 14, 149 Mestres, R., 11, 19 Meth-Cohn, O., 8 , 53 MetL, P., 15, 215 Mevellec, L., 15, 401 Meyer, C., 15, 331, 332

Author Index Meyer, O., 15, 241 Meyer-Dulheuer, C., 14, 138 Meyers, A.I., 15, 505 Mezzina, E., 7, 20 Michael, J.V., 3, 72; 4, 250 Micklefield, J., 2, 161 Mieloszynski, J.-L., 10, 23 Mifsud, R.D., 3, 150 Migdal, W., 13, 23 Mihai, G., 15, 392 MihailoviC, M.L., 15, 329, 586 Mikami, K., 15, 209 Mikhailov, S.N., 2, 192 Mikhailov, V.A., 2, 109; 13, 14 Mikhaleva, A.I., 15, 346 Mikitenka, E.E., 2, 213 Mikroyannidis, J., 2, 189 Mile, B., 4, 193 Milin, D., 9, 4 Miljkovic, D.A., 12, 66 Millar, J.R.A., 14, 150 Millar, M.M., 9, 33 Miller, C.P., 15, 84 Miller, D.B., 13, 82 Miller, D.J., 6 , 63 Miller, D.M., 6, 8 Miller, M.J., 15, 580 Miller, P.C., 15, 254 Milligan, G.L., 1, 120; 15, 510, 51 I Mills, N.S., 9, 93 Mills, O.S., 9, 30 Mimura, N., 15, 563 Min, H., 8, 52 Minato, T., 1, 42; 12, 63 Minematsu, T., 15, 298 Minier, L.M., 15, 76 Minisci, F., 3, 171; 4, 72-74; 5, 140, 141 Minoshima, Y., 3, 184 Mioskowski, C., 1, 53 Mir, M., 4, 120; 7, 14 Miranda, M.A., 3, 67; 15, 23 Mishima, H., 9, 38 Mishima, M., 4, 191, 207 Mishnev, A,, 13, 29 Mishra, B.K., 1, 29, 30; 5, 20, 21 Misik, V., 2, 76; 4, 64 Misiti, D., 15, 47 Mitani, M., 3, 180 Mitchell, M.L., 6, I6 Mitchell, P.L., 13, 28 Mitchell, T.J., 3, 186 Mitchell, T.N., 15, 251, 252 Mitchell, W.L., 13, 64 Mitchenko, E.S., 7, 79 Mitsnhida, E., 6, 98 Mitsumori, T., 4, 55 Mittal, J.P., 4, 266, 267 Mituoka, T., 15, 400

Miura, K., 3, 116; 15,487 Miura, M., 7, 71; 15, 15 Miura, T., 1, 108; 4, 137 Minra, Y., 4, 26, 27 Miura., Y., 4, 28 Miwa, M., 6 , 85 Miwa, Y.,15, 563 Miyaji, M., 7, 88; 10, 43 Miyake, Y., 7, 45 Miyasaka, T., 3, 12, 156 Miyashi, T., 3, 177; 4, 102, 197, 198; 14, 8 Miyata, O., 3, 50 Miyauchi, H., 10, 28 Miyaura, N., 3, 53 Miyaura, W., 7, 70 Mizerski, T., 1, 60a; 11, 32 Mizobata, T., 6 , 68 MlinariC-Majerski, K., 15, 44 I Mloston, G., 6, 84 Moberg, C., 10, I9 Mocek, U., 2, 161 Modena, G., 10, 5; 13, 87 Modi, D.P., 15, 5 I4 Modro, A., 1 0 , 4 2 Modro, A.M., 10, 41 Modro, T.A., 2, 178, 180; 10, 42 Modro, T.M., 10, 41 Mohammed, S.Z., 15, 95 Mohan, H., 4, 266, 267 Mohiuddin, T.F., 1, 6 Moilliet, J.S., 8, 12 Moise, A., 4, 43 Mok, C.Y., 12, 31 Mokrosz, J.L., 15, 66 Mokrushin, V.S., 15, 97 Mokander, G.A., 1, 142 Moldovan, M., 2, 124 Molina, P., 6, 28 Moliner, V., 1, 150; 5, 217 Moller, S., 15, 472 Molloy, K.C., 1, 110; 11, 80 Molteni, G., 15, 10 Molvinger, K., 14, 106 Momoki, M., 4, 26 Momose, T., 15, 298 Moms, K.B., 2, 167 Monache, G.D., 15,47 Monflier, E., 13, 42 Monge, A,, 15, 533,534 Monguchi, T., 7, 6 Monhata, K., 15, 361 Monnier, K., 14, 73 Monnier, M., 6, 79 Monot, F., 2, 162 Monsalvatje. M., 14, 48 Mflnsted, L., 15, 529 Monsted, O., 15, 529 Monteil, F., 13, 55 Monteiro, L.S., 2, 21 1 Montenegro, L., 2, 134

Author Index Montevdlh, M., 2, 90 Montevecchi, P.C., 3, 40; 6, 30; 15, 281, 340,585 Montgomery, J., 14, 7 1 Moodie, R.B., 5, 107; 7, 34 Moody, C.J., 6, 63 Moon, J.M., 15, 19 Mooney, N.J., 9, 30 Moore, H.W., 15, 197, 314, 405, 576, 588 Mor, S., 15, 71 Moraglia, E., 3, 110 Morales-Rios, M.S., 15, 583 MorBn, J.R., 13, 81 Moran, M., 6, 53 Morawietz, J . , 6, 22 More O’Ferrall, R.A., 1, 126, 127, 132; 11, 114; 15,595 Morel, G., 14, 66 Moreno-Manas, M., 7, 53 Moresca, D., 1, 52; 11, 42 Moretti, N., 8, 32 Morgon, N.H., 7, I 1 1; 14, I37 Mori, M., 14, 84 Mori, T., 4, 132, 133; 8, 1921,23 Moriguchi, T., 12, 21; 13, 27 Morikawa, O., 9 , 4 1 ; 15,48 Morikawa, T., 3, 154 Morimoto, N., 14, 27; 15, 575 Morinaka, Y., 15, 155, 156 Morishima, K., 4, 170, 171 Morishima, S., 15, 399 Morita, N., 9, 36, 37 Moritz, R.J., 7, 39; 11, 135 Moriwaki, M., 8, 44; 15, 17 Moriyama, H., 15, 178 Morken, J.P., 13,49 Morkovnik, AS., 1, 81 Morkovnik, Z.S., 1, 81 Morley, J.O., 2, 220; 15, 596 Moro, G., 14, 67 Moro, S., 5, 157 Morokuma, K., 12, SO Morozova, O.B., 4, 239 Morrell, A., 3, 24 Moms, A.D., 3, 137 Morris, D.G., 4, 1 I1 Morris, H., 4, 3 Morris, R.A., 10, 62 Morris, R.H., 15, 621 Mortellaro, M.A., 2, 137, 148 Mortcnsen, J., 4, 146 Mortier, J., 11, 88 Morton, J.R., 4, I, 2, 5 Mortreux, A,, 10, 7; 13, 42 Murwick, T., 15, 315 Morya, Y., 3, 180 Morzherin, Y.Y., 15, 97 Mosimann, H., 13, 9 Moss, R.A., 6, 43, 44, 74, 91 Mosselhi, M.A.N., 14, 56; 15,

577 95 Mossman, C.J., 1, 120; 15, 51 I Motallebi, S., 13, 1 I Motherwell, W.B., 2, 221 ; 3, 134; 14,59 Motie, R.E., 2, 108 Motyakin, M.V., 4, 8 Moufid, N., 3, 157, 158 Mould, R.J., 15, 226, 227 Moulik, S.P., 5, 52 Moussonga, J.E., 12, 65 Moustafa, A.H., 14, 63 Moutiers, G., 2, 183 Moyroud, J., 11, 88 Mphahlele, M.J., 15, 508, 509 Mroczyk, W., 13, 73 Muceniece, D., 7, 87 Muchmore, C.R., 15, 79 Mudryk, B., 7, 39; 11, 135 Mugge, C., 14, 123 Mugnoli, A,, 11, 129 Mujashi, T., 15, 399 Mujata, J., 15, 398 Mukaiyama, T., 1, 58; 11, 27; 13, 6 Mukherjee, A,, 4, 204 Mukherjee, D.C., 5, 52 Mukherjee, K., 5, 52 Mulder, P., 3, 64 Muldowney, M.P., 6, 62 Mulhearn, D.C., 15, 260 Muller, P., 6, 53; 9 , 4 ; 15, 318 Muller, S.C., 4, 46 Muller, T., 6, 101 Miiller, T.J.J., 13, 54 Muller-Steffner, H.M., 1, I 0 Mulliez, M., 2, 187 Mullins, S.J., 15, 307 Mulzer, J., 12, 62, 68; 14, 98; 15, 150,409 Munoz, G., 2, 7 Munoz, M.A., 5, 11 1 Muytar, M., 14. 17 Murai, T., 15, 619 Murakami, Y., 15, 488, 542 Muraoka, H., 3, 51 Muraoka, O., 15, 298 Murata, M., 3, 53; 7, 70 Murata, S., 6, 38, 73, 85; 15, 15

Mure, M., 5, 189, 190 Murphey, J.A., 4, 263 Murphree, S.S., 14, 26 Murphy, C.K., 11, 143 Murphy, J.A., 3, 31; 4, 121, 122; 9, 51; 13, 59; 15, 390 Murphy, M.G., 1, 132 Murphy, M.M., 14,221 Murray, B.A., 1, 132 Murray, J., 4, 19 Murray, R.W., 5, 132, 138

Murtagh, L., 3, 162 Murthi, G.S.S., 11, 99 Murugesan, V., 5, 8 Musa, O.M., 4, 30 Musaev, D.G., 12, 50 Musgrave, R.P., 14, 64 Muskatirovic, M.D., 2, 57, 58; 12,28 Mustafi, D., 2, 85 Mustafin, A.G., 15, 157 Mutoh, H., 5. 166; 14, 217 Mutoh, N., IS, 543 Muxworthy, J.P., 15, 416 Muzart, J., 3, 187 Mynott, R., 15, 360 Myoung, C., 2, 174 Nabeta, K., 15, 459,460 Nadir, U.K., 10, 35, 36; 15, 567 Nagahara, K., 3, 132 Nagai, K., 15, 137 Nagai, T., 6, 94; 14, 60, 61 Nagao, Y., 1, 73; 11, 31 Nagarajan, S., 5 , 1.3 Nagaratnan, S., 13,56 Nagase, S., 6, 98 Nagata, K., 6, 99; 7, 92 Nagorski, R.W., 1, 60a; 11, 32; 13, I1 Nagoya, T., 15, 460 Nagumo, S., 11, 106 Nahas, H.M.E., 11, 62 Naito, M., 15, 443 Naito, T., 3, SO Naitou, K., 15,400 Naji, M., 2, 220 Nakabayashi, N., 15,495 Nakada, M., 2, 224 Nakadaira, Y., 15, 433 Nakagaki, R., 4, 240 Nakai, K., 15, 563, 564 Nakai, T., 3, 115; 13, 75; 15, 125, 126,209-212 Nakai, Y., 2, 143 Nakajima, T., 15, 400 Nakajima, Y., 2, 155 Nakamoto, K., 10, 80 Nakamura, E., 3, 117; 6, 50 Nakamura, H., 1, 104; 4, 207; 15, 180 Nakamura, K., 2, 23; 12, 35; 15,312 Nakamura, K.T., 3, 12 Nakamura, T., 4, 260; 10, 28 Nakamura, Y., 15, 210 Nakata, T., 2, 164 Nakatsuji, R., 6, 38 Nakawaki, Y.. 10, 20 Nakayama, L, 15, 427 Nakayama, M., 6, 36 Namazian, M., 2, 54

578 Nambi, X., 5, 44 Namkoong, E.-Y., 5, 100 Nanni, D., 3, 56, 57 Nanta, T., 3, I 15 Narasaka, K., 1, 41; 15, 34, 490 Narita, T., 13, 94 Naruta, Y., 7, 83 Nasakin, O.E., 15, 62 Naseeruddin, A. 5, 112 Nasonov, S.N., 7, 98 Nather, C., 9, 91 Nativi, C., 12, 37; 14, 146 Natsume, S., 9, 38 Nau, W., 4, 238 Nau, W.M., 3, 204 Navacchia, M.L., 3, 4 k 15, 28 I , 340 Navarrini, W., 3, 130 Navarro, C., 3, 141 Naylor, A,, 10, 11 Nayyar, N.K., 2, 88 Neagu, C., 15, 325 Neavyn, R., 3, 93 Neckers, D.C., 4, 86 Necula, A,, 15, 39 Neeb, M.J., 15, 127 Negri, F., 4, I , 2, 5 Negri, J.T., 15, 41 1 Neh, H., 13, 98 Nei, L., 7, 9 Nelander, R., 15, 594 Nelsen, S.F., 4, 163; 10, 14 Nelson, D.J., 5, 25 Nelson, D.W., 9, 49; 10, 10 Nemoto, H., 3, 154; 14, 160; 15, 398,406 Neno-Ferreira, J.C., 15, 456 Nese, C., 4, 269 Nesi, R., 14, 157 Nesterenko, V.V., 9, 90; 15, 428 Nesterov, E.E., 15, 429 Neta, P., 4, 38, 39, 41 Neugebauer, F.A., 4, 163, 164: 10, 14 Neugebauer, R., 2, 21 8 Neuinan, H., 13, 19 Neumann, B., 4, 46; 14, 23; 15, 415 Neumann, F., 14, 30 Neumann, H., 4, 145 Neumann, R., 3, 105 Neuville, L., 7, 50 Neuvonen, H., 2, 37,45 Nevecna, T., 10, 88 Neverov, A.A., 13, 13 Neville, A.G., 3, 41 Newcomb, M., 3, 20, 21, 32, 34; 4, 30 Newton, M.G., 15, SO4 Ng, K.-M., 4, 155, 186

Author Index Nguyen, C.C., 3, 185 Nguyen, J.J., 3, I85 Nguyen, K.A., 12,44 Nguyen, M.T., 6, 80; 12, 4Y; 15, 496,497 Ni, Z., 14, 26, 79 Niat, M., 4, 120; 7, 14 Nibbering, N.M.M., 11, 3; 12, 8 Nichols, D.E., 15, 503 Nichols, J.B., 15, 493 Nicholson, S., 2, SO; 12, 73 Nickisch, K., 13, 98 Nickon, A., 6, 76 Niclas, H.-J., 7, 102 Nicolaides, A,, 9, 55 Nicoletti, R., 6, 46 Nicolosi, G., 14, 80 Nicovich, J.M., 3, 96: 5, 174 Nieger, M., 15, 530 Nielsen, M.F., 15, 372 Nielsen, O.J., 3, 69 Nieto, P.N., 15, 49 Nieuwenhuizen, P.J., 14, 205 Nifantyev, E.E., 10, 113 Nijssen, W.P.M., 6, 78 Nikishin, G.I., 3, 58 Nikitin, A.V., 5, 104 Nikolaev, PV., 10, 30 Nikolaev, V., 6, 14, 17 Nilsson, Y., 15, 359 Ninomiya, I., 3, 50 Ninomiya, N., 3, 70 Nir, M., 11, 5 Nishibayashi, Y., 1, 159; 5, 200; 6. 95; 15, 246-250 Nishida, A,, 5, 109 Nishida, Y., 5, 85 Nishigaichi, Y., 15, 27.5 Nishiguchi, T., 5, 109 Nishii, Y., 8, 37 Nishimoto, M., 15, 179 Nisttimura, N., 5, 2 12; 7, 100; 11, 113 Nishimurd, T., 1, 169 Nishio, T., 15, 599 Nissan, R.A., 2, 60 Nitzuma, S., 4, 159 Niu, C., 15, 580 Niu, J.E., 7, 18 Niwa, M., 1, 95; 11, 104; 15, 488 Niwayama, S., 12, 36; 15, 313 Nixon, L.F., 15, 273 Niyazymbetov, M.E., 7, 12 Nizova, G.V., 5, 36 Noack, R., 2, 66 Noda, I., 6, 68 Noe, M.C., 5, 93; 13, 47,48 Noguchi, M., 14, 190 Nojima, M., 14, 84, 210 Nojima, T., 5, 163

Nolke, M., 3, 144; 4, 16 Nolte, R.J.M., 15, 344 Noltemeyer, M., 11, 23; 15, 367,466 Nome, F., 1, 143; 2, 131; 10, 98; 13, 74 Noms, S., 15, 290 Nomura, M., 7, 71 Nonose, S., 10, 62 Noor, H.M., 2, 5. 97 Noordman, W.H., 2, 102 Norman, S.J., 9, 88 Normant, J.-F., 15, 331, 332 Noms, P., 15, 512 Norris, R.K., 4, 119 Notari, R.E., 2, 98 Notario, R., 15, 608 Noto, R., 1, 48, 130 Nouguier, R., 3, 149 Novais, H.M., 3, 176; 4, 226 Novak, L., 15, 135 Novak, M., 9, 43, 45 Novi, M., 1, 130; 11, 129, 130 Nowak, P., 11, 35 Nowicka-Scheibe, J., 11, 124 Noyori, R., 1, 95, 96; 11, 104, 105 Nozaki, H., 6, 36 Nozoe, T., 1 , 4 2 ; 7, 37; 12. 63 Nubbemeyer, U., 15, 162 Nudelman, N.S., 2, 95 Nuss, J.M., 14, 221 Nyasse, B., 2, 21 I Nyburg, S.C., 15, 205 Nyeki, O., 2, 1 15 Nyerges, M., 14, 70 O’Brien, J.F., 2, 75 O’Connor, C.J., 2, 80 OGara, J.E., 6, 3 O’Leary, M.H., 2, 186 O’Leary, P.J., 9, 22 OReilly, N.J., 9, 49; 10, 10 O’Sullivan, B., 7, 34 O’Sullivan, S., 15, 573 Oakley, J.E., 10, I12 Occhiucci, G., 7, 3; 9, 64; 15, 40 Ocheretovyi, A.S., 11, 12 1 Ochiai, M., 6, 35; 9, 65; 15, 140 Ochoa de Echaguen, C., 4, 242 Ochterski, J.W., 4, 14, 23; 9, 5; 11, 1 Oda, K., 1 5 , 7 0 Oda, M., 11, 78 Odman, C., 15, 85 Oechsner, H.P., 15, 55 Oeser, T., 9, 92 Ogasawata, T., 11, 138 Ogawa, A., 15, 542

Author Index Ogawa, S., 4, 159; 15, 163 Ogawa, Y., 15,491 Ogino, K., 2, 127 Ogorodnikov, V.D., 2, 103 Ogoshi, S., 15, 548 Oguchi, T., 2, 143 Ogura, K., 3, 155; 7, 66 Oh, S.J., 2, 152 Ohaku, H., 15, 399 Ohashi, K., 15, 136 Ohashi, N., 10, 28 Ohata, K., 15, 48 Ohayagha, J.E., 2, 93 Ohe. K., 6 , 95: 15,247-250 Ohira, S., 6 , 36, 68 Ohishi, H., 15, 178, 296 Ohki, K., 15, 478 Ohkubo, K., 2, 130 Ohkubo, N., 15, 137 Ohlhorst, B., 11, 23 Ohnishi, K., 2, 209 Ohno, A,, 2, 23: 4, 103; 5, 216 Ohno, K., 15.70 Ohno, M., 2, 224; 15,407 Ohno, T., 15, 542 Ohosima, T., 5, 109 Ohsawa, A., 7,92 Ohwada, T., 1, 118: 8, 6, 34, 36 Ohya, Y., 4, 102 Oikawa, H., 14, 116 Oikawa, S., 15, 180 Oiso, S., 14, 25 Oivanen, M., 2, 192 Oka, H., 7, 66 Okada, K., 11,78 Okada, M., 7, 92 Okai, H., 2, 164 Okai, J., 2, 164 Okamoto, S., 15, 419,532 Okamoto, Y., 15, 604-606 Okamura, W.H., 15, 308 Okazaki, M., 3, 61; 5, 85 Okazaki, R., 6 , 56, 100 Oki. T., 3, 70, 71 Okita, H., 15, 214 Okovityi, S.I., 10, 22 Oku, A,, 6, 64 Okuro, K., 7, 71 Okuvama, T., 2, 207 Okuyama, H., 15, 459,460 Okuyama, K., 15, 609 Okuyama, T., 2, 206, 209; 9, 65 Olah, G.A., 1, 119; 2, 35; 4, 144; 8, 35; 9, 1, 29, 58, 59, 94, 95: 15, 42 Olejnik, M., 13, 23 Oliva, C., 4, 7 Olivella, S., 3, 77; 6, 9 Olivieri, A.C., 15, 612

579 Olivucci, M., 14, 89 Ollivier, J., 15, 164 Olovsson, G., 15, 299 Olsson, L., 9, 14 Olzmann, M., 3, 102 Omelka, L., 4, 51 Omura, K., 3, 68 Oniciu, D.C., 7, 84; 11, 89 Oniga, O., 1, 91: 4, 190 Oniscu, C., 2, 29 Ono, S., 2, 204 Ono, T., 3, 65 Ono, Y., 13, 18 Onodera, J.I., 15, 478 Onorato, E., 15, 470 Opeida, LA., 10, 24 Opitz, A,, 11, 90 Oppenheimer, N.J., 1, 10 Orban, M., 5, 124 Ordoiiez, M., 15, 236 Orfanopoulos, M., 5, 165: 13, 31 Organ, M.G.. 14, 99 Orlando, J.J., 3, 76, 201 Orlov, Yu.D., 6,23 Orozco, M., 15, 613,614 Ortiz, C.S., I, 133; 2, 96 Ortiz, M.J., 1, 162; 15, 300 Ortuiio, R.M., 4, 242; 14, 183 Oseroff, A.R., 5, 114 Oshea, M., 15, 290 Oshima, K., 15, 361, 362 Oshima, T., 14, 60, 61 Osio Barcina, J., 9, 67 Osmonov, T.A., 3, 106 Ostrowski, S., 7, 39; 11, 135 Otaka, A,, 15, 563, 564 Otdki, A., 15, 45 I Otera, J., 1, 158 Otera.J., 13, 75 Ott, C., 14, 122, 132 Otlaway, M.J., 14, 185, 214 Ottens Hildebrant, S., 15, 50 Otto, H.-H., 15, 559 Otto, S., 14, 11 1 Ottosson, C.-H., 6, 26; 9, 14 ou, Y., 7, 28 Ovchinnikov, I.V., 15, 501 Ovreeide, E., 8, 24 Owadd, Y., 15, 541 Owton, W.M., 1, 54 OLaki, S., 2, 2 I Ozeki, H., 15, 549, 609 Packer, J.E., 4, 66 Paddon-Row, M.N., 4, 141 Pdderes, G.D., 1, 26c Pddmaja, S., 3, 198 Padmaja, S.M., 5, 95 PddWa, A,, 13, 107; 14, 26, 79, 159; 15, 29, 223, 412 Padyukova, N.S., 2, 192

Pagani, G.A., 11, 26 Page, M., 12,48 Page, M.J., 2, 170, 171 Page, P.C.B., 11, 66 Page, S.D., 7, 9 Pagsherg, P., 5, 171 Paik, Y.-S., 15, 33 Pain, G., 1, 52; 11, 42 Painter, S.L., 4, 99 Pais, G.C.G., 5, 65 Pajunen, A., 15, 325 Pakkanen, T.A., 3, 136: 10, 90 Pakter, M.K., 2, 83 Palacios, F., 14, 148 Pdlani, A,, 5, 126 Palani, N., 15, 258 Palaniappan, A,, 5, 7 Palau, C., 4, 162 Palmer, C.F., 15, 571 Palmer, W.S., 1, 107 Palou, J., 5 , 1 15: 9, 53: 12, 70; 13, 80 Pan, D., 4, 19 Pan, K., 4, 196 Pan, Y., 2, 112; 15, 83 Pancrazi, A., 3, 39 Panda, M., 11, 1 15 Pande, P., 15. 172 Pandey, A., 1, 148; 5, 15, 43 Pandey, B., 5, 65 Pandey, U.S., 5, 122 Pandhare, N.A., 15, 134 Pandiarajan, K., 2, 219; 5, 149 Pandiaraju, S., 15, 144 Pandit, U.K., 14, I17 Pandurangan, A,, 5,8 Panek, J.S., 1, 106 Paneth, P., 2, 186 Panteleeva, E., 4, 223 Panteleeva, E.V., 5, 206: 7, 15 Pantidou, A,, 13, 31 Papagiannakopoulus, P., 3, 91 Papiernik-Zielinska, H., ;2, 159; 12.71 Paquer, D., 10, 23 Paquette, L.A., 14, 170; 15, 132, 190, 195, 315, 316, 41 1,463 Parajo, M., 5 , 118; 11, 140, 142 Paramonov, G.K., 15, 189 Parast, C.V., 3, 146 Pareschi, P., 3, 56, 57 Paris, J., 7, 30 Paris, M., 14, 199 Park, B.-S., 2, 43; 15, 4 Park, C.-H., 7, 72 Park, C.K., 2 , 100 Park, D.K., 6 , 87 Park, H., 2, 133 Park, H.-S., 11, 51 Park, I.S., 1, 170

Author Index Park, J.-H., 10, 107 Park, J.-Y., 2, 40, 41 Park. J.W., 2, 152 Park, K.K., 2, 135 Park, S., 3, 34 Park, S.H., 13, 32; 15, 569 Park, S.W., 15, 87 Park, W.K.C., 2, 201 Park, Y.S., 2, 1; 10, 70 Parker, D.C., 15,525 Parkins, A.W., 15, 205 Parkinson, J.A., 14, 150 Parnas, B., 2, 112 Parquette, J.R., 14, 68 Parra, A., 15, 470, 471 Parrain, J.-L., 7, 30 Parrindlo, M., 9, 11 Parry, D.E., 9, 61 Parsons, P.J., 15, 145, 147 Parvez, M., 15, 334 Parvulescu, V., 5, 26 Paryzek, Z., 15, 518 Paschal, J.W., 1, 109; 11, 85; 12,59

Paschke, C., 15, 466 Pasek, J., 15, 1 Pasquato, L., 10, 5 ; 13, 87 Pasquier, C.. 4, 115 Pastero, E., 2, 59 Pastorio, A,, 8, 32 Patalakha, A.E., 14, 2 Patel, H.H., 15, 69 Patel, S.T., 15, 129 Paterson, I., 1, 51, 69; 15, 149 Pati. S., 2, 78 Pati, S.C., 5, 89, 187 Patil, G.S., 4, 107 Paton, R.M., 14, 40 Patra, D., 9, 39; 15, 402, 403 Patterson, E.V., 6, 4 Patterson, W.S., 15, 277 Patti, A,, 14, 80 Patz, M., 9, 17, 34, 54 Pilzel, M., 14, 77, 81, 123 Paulini, K., 5, 145 Paulus, E.F., 14, 138 PdLIlet, F., 14, 182 PavloviC, D., 15, 441 PavloviC, V., 15, 586 Payne, M., 4, 70 Pearson, C.J., 14, 172 Pearson, W.H., 9, 24; 15, 513 Pecar, S., 15, 350 Pedersen, J.A., 4, 195 Pedersen, S., 4, 228 Pedersen, S.U., 4, 106; 10,73 Pederson, L.A., 9, 15 Pedragosa-Moreau, S., 5, 151; 15,523 Pei, W., 14, 104 PejanoviC, V.M., 12, 66 Pelletier, R., 1, 106

Pellissier, H., 1, I ; 15, 421, 422 Pelloux-Uon, N., 15, 280 Pemn, C.L., 2, 193 Peiia, M.E., 10, 56; 11, 146 Pena-Cabrera, E., 7, 64 Pendrak, I., 15, 458 Penenory, A.B., 4, I12 Peng, H.-M., 2, 175 Peng, S.-M., 2, 154; 5, 208; 15, 537 Pensabene, J.W., 11, 147 Perakyla, M., 3, 136 Percy, J.M., 1, 54; 15, 129, 218 Peregrina, J., 14, 199 Pereira, S., 15, 526 Perekalin, V.V., 2, 223 Perera, S.A., 9, 13 Pereyre, M., 3, 121 Perez, D., 7, I19 Perez, F., 5, 207; 12, 67 Perez, I.M., 2, 158 Perez, M., 12, 23 Perez, V., 8, 3; 10, 72 Perez-Moure, J.C., 5, 118; 11, 141, 142 Periasamy, M., 1, 155; 5, 201 Pericaud, F., 15, 462 Perlmutter, P., 3, 150 Perrin, C.L., I, 3a Perrin, D., 4, 78, 251 Perrio, S., 15, 171 Perrocheau, J., 14, 69; 15, 165 Persson, B.J., 3, 48; 4, 230 Persson, J., 10, 59 Persson, O., 4, 149-154; 8, 14, 16 Pervishko, T.L., 10, 95 Peter, M., 15, 265 Peter, M.G., 15, 598 Peters, E.M., 14, 167; 15, 286 Peters, J.A., 5, 194 Peters, K., 4, 236; 14, 88, 126, 167; 15,286 Peters, K.S., 10, 86 Peters, S.C., 15, 319 Petersen, A.K., 3, 22 Petersson, G.A., 4, 23; 9, 5 ; 11, 1 Petrillo, G., 1, 130; 11, 129, 130 Petrisko, M., 15, I Petrov, A.Yu.,7, 105 PetroviC, J.A., 12, 66 Petrovich, L.M., 13, 40 Petty, J.T., 10, 63 Petyak, M.E., 2, 1 18 Peyerimhoff, S.D., 4, 29 Peyman, A,, 4, 16 Peyronel, J.-F., 15, 420 Pezacki, J.P., 1, 80

Pfau, M., 1, 22, 23; 13, 76 Pfennig, D.R., 7, 57 Philippini, C., 15, 5 19 Phyland, J.R., 9, 73; 15, 319 Piattelli, M., 14, 80 Picher, M.T., 11, 19; 13, 108; 14, 186 Pickett, C.J., 15, 532 F’icq, D.,13, 24 Pielichowski, J., 13, 106 Pierini, A.B., 4, 110, 212; 7, 8; 11, 69 Pierinin, A.B., 10, 76 Piermatti, O., 1, 70; 11, 41 Piet, D.P.,14, 220 Pietila, L.-O., 15, 324 Pigge, F.C., 15, I10 Pilling, M.J., 3, 6 Pimm, A., 15,291 Pineschi, M., 10, 15, 16, 33 Pinheiro, L.M.V., 10, 89 Pini, D., 1, 97; 11, 102 Piniella, J.F., I, 168 Pinilla, E., 15, 533 Pinson, J., 3, 174 Pintar, A,, 5, 38 Pinto, I., 5, 33, 34 Pirig, Y.N., 1, 76; 11, 52 Pirok, G., 15, 135 Pirmng, M.C., 6, 52 Pisarenko, L.M., 4, 8 Pitchumani, K., 15, 24 Pitt, I.G., 3, 60 Pizzabiocca, A., 10, 8 Pizzano, A,, 15, 534 Pizzo, F., 1 , 70; 11, 41 Pla, F.P., 12, 70 Pla, P.F., 13, 80 Placucci, G., 4, 188, I89 Planchenault, D., 3, 120 Planiol, C., 15, 420 Plant, H.E., 15, 525 Plaquevent, J.-C., 13, 16 Platz, M.S., 6, 14, 17 PIC, G., 11, 70; 13, 16; 15, 365 Ple, N., 5, 218 Plenhewicz, J., 15, 98 Ploegert, Y., 14, 35 Plumet, J., 10, 26; 15, 194 Plunkett, S.J., 1, 65a Pluta, K., 15, 13 Pocar, D., 15, 89 Podryvanov, V.A., 8, 54 Poggi, G., 3, 94 Pohnert, G., 15, 191 Pointner, A., 12, 68; 15,409 Pokier, J.-M., 13, 79 Pokier, R.A., 14, 193 Poisson, V., 5, 204 Poje, M., 15, 107 Pole, N., 15, 107

581

Author Index Pokorny, I., 7,82 Polack, N.P., 4, 65 Polak, M.L., 11, 112 Pole, D.L., 6, 65 Polovinka, M.P., 9, 74; 15, 46.5 Ponomarenko, V.A., 14, 207 Ponomareva, E.A., 10, 95 Ponomareva, N.E., 10, 87 Poon, T.H.W., 5, 164; 13, 32; 15, 569 Pope, C., 7, 52; 15, 12 Popik, V., 6, 17 Popik, V.V., 2, 61 POpkOvd, v.ya., 15, 618 Popov, A.A., 11, 12 Popov, A.F., 2, 46 Popov, AS., 11, 7 Porinchu, M., 15, 192 Porta, C., 8, 32,46 Porta, O., 5, 68 Porzi, G., 1, 55, 56; 2, 116; 10, 54; 11, 45 P o d , M., 15,617 Poskonin, V.F., 4, 169 PotBEek, M., 15, 587 Pothier, P., 15, 589 Potier, P., 3, 134; 15,413, 502 Pouet, M.. 12, 13 Pouet, M.-J., 7, 101, 103; 11, 63 Pousa, A.I., 5, 118; 11, 142 Powell, D.R., 4, 163; 10, 14 Powell, H.K., 4,229 Power, M.D., 6, 81; 15, 288 Prabhakar, S., 15, 204 Prabhu, D.V., 1, 28 Pradere, J.-P., 5, 204 Prados, P., 15,49 Prakash Surija, G.K., 4, 144 Prakash, G.K.S., 2, 35; 8, 35; 15,42 Prakash, V., 5, 99 Pranata, J., 2, 75 Prasad, J., 1, 46 Prasad, K., 2, 16 Prasad, N.,1, 46 Prasad, R.M., 1, 46 Prasanna, V., 15, 192 Prassides, K., 4, 4 Pratt, L.M., 11, 20 Pratt, R.F., 2, 84 Prdieri, C., 8, 46 Prechtl, F., 11, 83 Prein, M., 5, 168; 14, 126, 167, 168, 196 Presley, A.L., 1, 107 Preston, K.F., 4, 1, 2 Pringle, K., 5, 164 Prins, R., 15, 16 Prinzbach, H., 4, 144, 146 Prinzbach, H.J., 4, 145

Pritchard, H.O., 4, 43 Pritzkow, H., 6, 102 Pritzkow, W., 4, 79; 7, 82 Procter, G., 15,416 Prodger, J.C., 15, 195 Prokopieva, T.M., 2, 46 Prokudin, V.G., 6, 37 Pross, A,, 9, 55; 10,65,66 Prtizkow, W., 3, IYO Pruski, B., 12, 14 Puerta, M.C., 15, 540 Pulley, S.R., 15, 167 Punzalan, E.R., 15, 342 Purcell, K.F., 10, 110 Puschmann, I.B., 13, 58 Pye, C.C., 14, 193 Pye, P., 15,467 Pykh, Z.G., 5, 153 Pyne, S.G., 10, 39; 14, 51, 78; 15, 238,239 Pyun, C., 7, 117 Qian, J., 11, 84 Qin, Y., 4, 35, 36 Qin, Z.-M., 2, 126 Qiu, Q., 8, 45 Qu, Y.-L., 4, 50 Quan, R.W., 6, 61 Quast, H., 15, 189 Quayle, P., 15, 536 Que, L., 5, 77 Queguiner, G., 5 2 1 8, 220; 11, 91; 15,356 Quick, J.R., 9, 73 Quiclet-Sine, B., 3, 43, 44 Quin, L.D., 2, 186 Quintanar, C., 14, 190 Quirk, R.P., 11, 67; 13, 112 Quiros, M., 2, 168 Qureshi, A,, 2, 30 Raabe, G., 15, 152 Rabasco, J.J., 15, 389 Rabideau, P.W., 11, 6 Rabinovitz, M., 11, 5 Rachdi, F.. 5, 64 Racoveanu-Schiketanz, A,, 15, 39 Radha, N., 11, 72 Radhakrishnan, K.V., 15, 358 Radom, L., 3, 112; 9, 55; 10, 65,66 Raff, L.M., 12, 43 Ragains, M., 3, 93 Raghavi, D.E., 5, 2 Ragnarsson, U., 2, 21 I Rahman, S., 15, 536 Rai, S.N., 14, 101; 15, 568 Raimondi, L., 14, 39 Raimondi, M., 8, 1 Raithby, P.R., 15, 161 Rajagopal, D., 15, 516, 579

Rajagopal, S., 5, 31 Rajamaki, M., 10, 57 Rajanna, K.C., 5, 56, 112 Rajapaksa, D., 15, 3 17 Rajappa, S., 2, 26 Rajaram, L., 6, 33 Rajzmann, M., 10,71 Rakovsky, S.K., 5, 135 Rakus, K., 4, 18 Ralhelot. I?, 3, 175 Rama, H.S., 2, 38 Raman, F., 3, 141 Raman, J.V., 15, 555 Ramana, D.V., 15, 158 Ramm, M., 7, 102 Ramos, A., 1, 162 Ramsden, C.A., 15, 506 Rancourt, J., 3, 162 Raner, G.M., 2, 175 Rang, H., 5, 180 Rankovic, Z., 14, 46 Rantanen, M., 2, 150 Rao, B.M., 2, 30 Rao, K.K., 5, 97 Rao, K.N., 5, 95 Rao, K.S., 15, 73 Rao, K.V., 5, 27 Rao, M.P., 5, 95 Rao, M.T., 5, 27 Rao, M.V.B., 14, 158 Rao, S . , 15, 553 Raos, G., 8, 1 Raoult, E., 5, 204 Raphael, R.A., 1 5 , s 19 Rappoport, Z., 1, 13; 4, 117; 10, 1-4, 80, 81; 11, 133; 12, 2, 3; 13, 90-92 Raptopoulou, C.P., 15, YO Rasmussen, K.G., 6, 54 Raspoet, G., 12, 49; 15, 497 Rastelli, G., 15, 597 Rastogi, R., 13, 45 Rasul, G., 1, 119; 2, 35; 8, 35; 9, 58, 59; 15, 42 Rathmell, R.E., 15, 226, 227 Rathore, R., 4, 123, 156 Rathore, S., 5, 12 Raubo, P., 15, 363 Rault, S., 15, 112 Ravindranathan, T., 5, 9 Ravishankar, M., 5, 7 Rawat, B., 2, 38 Rayner, C.M., 15, 562 Rayner, D.M., 3, 41 Raynolds, P.W., 14, 16 Razskazovskii, Yu.,4, 45 Razzino, P., 3, 153 Read, J.M., 12, 60 Rebbolledo, E, 1, 105; 2, 168 Recupero, F., 3, 17 1 Reddy, A.C., 4, 175-177,221 Reddy, A.K., 5, 21 1

582 Reddy, C.K., 5, 201 Reddy, Ch., 1, 155 Reddy, G.S., 15, 73 Reddy, M.S., 5, 112 Redmond, R.W., 4, 262 Redpath, J., 14, 46, 71, 75 Reed, J.E., 14, 202 Reetz, M.T., 11, 68; 13, 1 1 1; 15, 219 Refat, H.M., 7, 42 Reich, H.J., 11, 21 Reiche, T., 4, 168 Reid, G., 15, 292 Reid, I.D., 4, 3 Reinaud, O., 15, 159 Reinhardt, D., 5, 145 Reiss,S., 4, 168 Reissig, H.-U., 5, 145 Kekhk, T.I., 15, 381 Rell, S., 6, 102 Remacle, B., 13, 97 Remedi, M.V., 7, 32 Remington, R.B., 15, 59 Renaud, J., 3, 129 Renaud, P., 3, 122, 157-159 Renfrew, A.H.M., 7,75, 76 Renoux, B., 15,213 Renzi, G., 10, 8 Repas, L., 4 , 2 0 Repic, O., 2, 16 Repinskaya, I.B., 9, 97 Rescifina, A., 12, 64 Rese, M., 4, 128, 129; 14, 95, 96 Resmini, M., 14, 117 Rettura, D., 7, 75, 76 Revial, G., 1, 22, 23; 13, 76 Key, F., 5, 207 Rey, J.G., 15, 305 Reymond, J.-L., 1, 141; 5, 147 Reynolds, W.F., 1, 17 Rezende, D.B., 4, 261 Reznikov, V.A., 4, 53; 14,44 Rhodes, C.J., 4, 3 Riad, Y., 10, 93; 11, 62 Ribera, A,, 5, 207 Rihezzo, M., 3, 122 Ricci, A,, 9, 18 Rice, C.V., 4, 225 Rice, D.J., 9, 27 Rice, M.J., 1, 110; 11,80 Richard, J.P., 1, 60a; 9, 26, 27; 11, 32 Richards, C.A., 6, 7 Richardson, P.F., 15, 522 Riche, C., 14,49 Ricjardson, P.F., 5, 150 Riehl, J.-F., 12, SO Riesz, P., 2, 76; 4, 64 Rigby, J.H., 15, 110 Righetti, P.P., 14, 109 Righi, G., 5, 63

Author Index Rihs, G., 15, 559 Riley, D., 2, 112 Rinaldi, F.C., 4, 82 Rios, A,, 2, 222 Rios, A.M., 10, 56 Ripoll, J.-L., 15, 280 Rissom, B., 15, 466 Rivcros, J.M., 7, 111, 112 Rizzoli, C., 3, 56 Roach, P.L., 2, 169 Robb, M.A., 14, 89 Robba, M., 15, 112 Robbins, R.J., 9, 42 Robert, A., 10, 17 Roben, D., 10,23 Robert, J., 7, 30 Robert, M., 4, 213 Roberts, B.E., 15, 148 Roberts, B.P., 3, 99, 103, 142; 4, 24 Roberts, D.W., 2, 202; 10, 101 Roberts, E., 3, 24 Roberts, S.M., 5, 150, 151; 15, 522-524 Robertson, S.H., 3, 6 Robinson, M.S., 11, 112 Robinson, P.M., 9, 30, 53 Robinson, W.T., 8, 13, 14; 15, 37 Rock, M.H., 14, 76; 15, 218 Roddis, M., 15, 573 Rode, B.M., 15, 500 Rodios, N.A., 15, 90 Rodriguez Cardona, A.F., 1, 16

Rodriguez, J., 1 , 75; 3, 73; 12, 29, 30; 15, 305 Rodriguez, M.A., 9, 62; 15, 383 Rodriquez, C.F., 9, SO; 15, 382 Rodriguez, P., 11, 141 Rodygin, M.Yu., 13, 14 Roe, M.B., 3, 126 Roff6, I., 14, 37 Rogers, R.D., 14, 170 Roginsky, V.A., 3, 191 Romln, E., 14, 198 Romano, S., 15, 300 Romanski, J., 6, 84 Romantsevich, A.M., 10, 24 Romeo, G., 12, 64 Romeo, R., 12, 64 Rornero, A., 11, 59; 13, 89 Romo, D., 14, 19 Roome, S.J., 4, 122 Roos, G.H.P., 11,43 Ros, F., 11, 54 Rosati, O., 15, 454 Rose, H.L., 15, 506 Rose, P., 2, 65 Roseman, J.D., 3, 42

Rosenau, T., 5, 39 Rosenberg, R.E., 1, 82 Rosenbluni, J.S., 2, I77 Rosevear, J., 7, 22 Roshchin, A.I., 7, 67 Ross, D.S., 8, 22 Rossetti, M., 1, 55 Rossi, M.C., 15, 597 Rossi, P., 15, 185 Rossi, R.A., 4, 1 1 1 , 112; 10, 76; 11, 69 Rossi, R.R., 4, 110 Rossky, P.J., 10, 94 Rostovshchikova, T.N., 13, 25 Roszkiewicz, A,, 15, 98 Roszkiewicz, W., 7, 38 Roth, G.P., 7, 64; 15, 468 Roth, H.D., 3, 178; 4, 95-97; 15,259,430 Roth, M., 9 . 3 5 Roth, W., 4, 231, 247 Rothemund, P.W.K., 1, 101 Rotinov, A,, 2, 158; 12, 23, 25 Roubaud, C., 4, 114 Rougee, M., 5, 167; 14, 165 Roulet, T., 3, 121 Rousseau, G.. 8, 11 Roussi, G., 7, 48 Roussin-Bouchard, C., 5,203 Roversi, E., 15, 89 Rowbottom, C.A., 15,507 Rowlands, C.C., 4, 193 Roy, A., 15, 553 Roy, C.D., I, 134, 136; 11, 9, 10; 12, 32, 33 Roy, D., 14, 206 Roy, N.K., 5, 122 Roznavska, O., 1, 47 Ruasse, M.-F., 13, 3 Rubailo, V.L., 5, 104 Rubiales, G., 14, 148 Rubino, M.F., 5, 82, 136 Rubiralta, M., 5, 146 Rubires, R., 1, 79a; 11, 127 Rubleva, L.I., 2, 199 Ruchardt, C., 3, 144; 4, 16-18 Riick, K., 11, SO Ruder, S.M., 15, 370 Rudzinski, J.M., 11, 58; 13, 78; 14, 197 Rueda, D.R., 15,43 Ruel, J., 4, 2 Ruel, R., 15, 371 Ruhland, T., 11, 18, 77 Ruiz, C., 15, 534 Ruiz-Idpez, M.F., 14, 21, 110, 114 Runsink, J., 15, 152 Rusinov, V.L., 7. 105 Russell, D.R., 1, 62; 13, 34, 35 Russell, G.A., 4, 136

583

Author Index Russell, K., 15, 161 Rutkowske, R.D., 15, 108 Ryan, J.H., Y, 73 Ryan, K.R., 3, 60 Ryazantsev, G.B., 10, 108 Rybalova, T.V., 9, 74; 15, 465 Rychnovsky, S.D., 15, 154 Rykova, E.A., 5, 177 Rys, D.J., 13, 96 Ryu, I., 3, 3, 132 Ryu, J., 3, 51 Rzepa, H., 11, 26 Rzepa, H.S., 12, 31 Saakyan, T.A., 12, 17 Saba, A,, 6, 18 Sabapathymohan, R.T., 5, I I , 96 Sadler, I.H., 14, 150 Sadlowski, J.Z., 2, 17 Saeki, Y., 10, 80, 81, 85 Safaei-G.J., 14, 78 Safwat, A.R., 15, 102 Sagara, S., 15, 43 I Sagawa, T., 2, I30 Sagdeev, R.Z., 4, 239 Sagitullin, R.S., 7, 87 Saha-Moller, C.R., 5, 103; 15, 328,434 Sahay, A., 1, 46 Sahin, C., 4, 126; 15, 417 Sahli, A,, 6, 69 Sahu, P.K., 2, 78; 5, 89, 187 Sai Prakash, RK., 5, 56 Saigo, K., 11, 138 Saiki, T., 6, 56 Saini, A,, 15, 71 Saito, S., 1, 118; 3, 156; 4, 159; 8, 6, 34, 36; 15, 122 Sakagishi, Y., 2, 155 Sakai, M., 12, 15 Sakamoto, M., 15, 193, 274, 46 1 Sakamoto, T., 15, 3 Sakamoto, Y.,3, 54; 15, 296 Sakuragi, H., 3, 17, 78; 4, 32 Sakurai, O., 15, 202 Salas, M., 2, 7 Salaiin, J., 15, 164 Salbeck, J., 4, 224 Salcido, S.L., 15, 55 1 Salerno, L., 7, 78; 15, 72 Sallk, L., 3, 49 Salmi, T., 2, 59 Salou-Guiziou, V., 12, 74 Saltiel, J., 14, 161 Saluzzo, C., 13, 24 Salvadori, R, 1, 97; 11, 102 Salvadori, S., 15, 584 Salvatella, L., 14, 110, 114 Salzner, U., 1, 3b; 15,206 Samaryk, V.Ya., 5, 153

Sammakia, T., 14, 203 Samoilova, R., 4, 194 Samoshin, V.V., 3, 58 Samuel, C.J., 2, 10 Sancassan, F., 1, 130 Sanchex-Baeza, E, 5, 146 Sanchez, A.M., 15, 591 Sanchez, F., 5, 66 Shchez, L., 15,534 Sanchez-Montero, J.M., 2, 165 Sander, W., 6, 22, 26, 77 Sanders, H., 7, 52; 15, 12 Sanderson, M.G., 5, 170, 171 Sanderson, P.E.J., 15, 525 Sandn, S., 2, 116 Sandri, S., 1, 55, 56; 10, 54; 11,45 Sanfilippo, C., 14, 80 Sanganee, H.J., 11, 64 Sankar, P., 2,219; 5. 148, 149; 15, 25 Sankararaman, S., 13, 88 Sano, S., 1, 73; 11, 31 Santamaria, E., 15, 533 Santelli, M., 1, 1; 15, 421, 422 Santiago, A.N., 4, 11 1 Santora, V.J., 15, 197 Santos Blanco, J.G., 1, 16 Santos, J.G., 2, 6, 7 Santos, P.F., 15, 204 Sanyal, A., 5, 18 Sapik, M., 15, 587 Sapunov, V.N., 5, 75, 81 Sar, S.K., 2, 128 Sarac, AS., 5, 50 Sarada, N.C., 5, 21 1 Sarahar, S., 14, 124 Saraswathy, V.G., 13, 88 Sarker, H., 4, 61; 14, 6 Sartori, G., 8, 32, 46 Sasai, H., 15, 394 SasAi, Y., 4, 83 Sasidharan, M., 5, 9 Sastry, G.N., 4. 175,220,221 Satake, S., 14, 210 Satchell, D.P.N., 1. 6, 7a, 7b; 2, 108 Satchell, R.S., I, 6; 2, 108 Sato, E, 1,98; 3, 160; 13, 51 Sato, R., 4, 1.59 Sato, S., 15, 478 Sato, T., 1, 158; 3, 37; 15, 357, 455 Sato, Y., 8, 6; 15, 232, 244, 245 Satoh, A., 14, 160 Satoh, T., 7, 7 1 Satoh, Y., 6, 73 Satsumabayashi, S., 14, 102 Satyanarayana, J., 14, 158 Sauer, M.C., 1, 144 Sauerivein, B., 3, 66

Savage, P.E., 5, 185 SavCant, J.-M., 3, 174; 4,213 Savelli, G., 2, 132 Savelova, V.A., 2, 46, 109; 13, 14 Savin, K.A., 1, 102; 11, 107 Sawada, H., 3, I80 Sawada, T., 14, 197 Sawaki, Y., 5, 163 Sawata, S., 2, 196 Sawunyama, P., 5, 123 Sbrogib, F., 14, 169 Scaiano, J.C., 3, 15, 129; 15, 456 Scarborough, T., 2, 149 Scarton, M.G., 10, 62 Schaefer, H.F., 4, 252; 6, 7, 8, 97; 9, 86; 11, 145; 15, 59, 424 Schafer, H.J.. 7, Sl; 15,439 Schakel, M., 1, 89; 11, 14 Schank, K., 15,449 Scheffer, J.R.,15,299 Schellhaas, K., 7, 55, 56 Schepp, N.P., 4, 173; 6, 89; 9, 48 Scherer, G., 11, 120 Scherzer, K., 3, 102; 4, 253 Schiano, A.-M., 3, 43 Schiesser, C.H., 3, 45, 1381 4 0 4, 31 Schimmel, U., 13, 16 Schlaf, M., 15, 621 Schlegel, H.B., 12, 42; 15, 184 Schleyer, P. von R., 9, 13, 82, 86; 10, 63; 11, 16. 145; 15, I8 1, 304,424 Schmalz, H.-G., 7, 5 5 , 56 Schmid, T., 9, 69 Schmidlin, R., 4, 147 Schmidt, R.R., 15, 187 Schmidt, T., 15, 50 Schmitt, G., 14, 73 Schmitt, M., 14, 87 Schmittel, M., 1, 139; 4, 134, 135, 178, 179, 184; 14,24 Schmitz, E., 15, 96 Schmitz, R.F., 1, 89; 11, 14 Schnaeffer, C., 15,483 Schneider, M., 15,417 Schnute, M.E., 7, 73 Schoberl, U., 4, 199 Schofield, C.J., 2, 169 Scholz, M., 4, 148, 199, 218 Schon, I., 2, 1IS Schoneich, C., 3, 89 Schonk, R.M., 13, 60; 15,418 Schoop, A., 15, 215 Schott, N., 15,449 Schottland, E., 4, 11 7; 10, 3 Schreiner, P.R., 6, 8; 9, 86; 11, 145; 15,424

Author index Schroder, E., 15, 96 Schroeder, G., 7, 104; 11, 124 Schuber, F., 1, 10 Schuchmann, H.-P., 4, 268 Schuchmann, M.N., 4, 268, 269 Schuck, D.F., 10, I ; 12, 2; 13, 90, 92 Schulz, G., 14, 134 Schulz, K., 15, 58 Schulz, M., 5 , 67 Schussler, M., 5, 67 Schuster, A,, 11, 23 Schuster, G.B., 3, 66; 9, 63 Schwarz, H., 11, 86 Schwarz, W.H.E., 7, 18 Schwetlick, K:, 2, 66 Scorrano, G., 2, 208 Scott, L., 15, I51 Scott, L.T., 15, 39 Screttas, C.G., 4, 206 Scrivens, G., 5, 35 Seakins, PW., 3, 6 Sears, D.F., 14, 161 Sebek, P., 15, 100 Seburg, R.A., 6, 4 Secci, D., 10, 97 Secord, M.D., 7, 35 Sedaghat-Herati, R., 10, 55 Sedlak, M., 7, 33 Sedmera, P., 15, 100 Sedova, E.A., 15, 43 Seebach, D., 11, 105 Segawa, D., 2, 164 Segelstein, B.E., 7,65 Segev, S., 15, 105 Segi, M., 15, 400 Segura, C., 14, 97 Sehested, J., 3, 69 Sehested, K., 4, 215 Sehgal, A,, 15, 121 Seidel, G., 15, 360 Seitz, G., 14, 138; 15, 267 Sekar, K.G., 5, 7 Sekar, M., 5, 11, 96 Seki, M., 15, 130 Selli, E., 4, 7 Selmi, A,, 13, 83 Selva, M., 7, 63 Selvaraj, K., 5, 121 Selvarijan, S., 1, 147; 5, 10 Selwood, D.L., 15, 480 Semenenko, M.N., 15,618 Semenov, V.P., 15, 565 Semones, M.A., 14, 159; 15, 223 Sen Gupta, K.K., 5, 18 Sen, P.K., 5. 18 Senapati, S., 1, 29, 30 Sengupta, D., 12, 49 Sengupta, S., 7, 62 Senkal, F., 5 , 50 Senkan, S.M., 3, 147

Sennhenn, P., 10,6 Senogles, E., 3, 118, 119 Senskey, M.D., 7, 29 Seo, H.S., 3, 27 Seo, J.W., 1, 170 Seong, J.H., 15, 33 Sepulveda-Arques, J., 13, 108; 14, 186 Serdyuk, L., 11, 89 Seres, L., 3, 114; 4, 253 Serrano, J.A., 14, 198 Sem, A,, 3, 171 Seth, P.P., 10, 37 Sethuram, B., 5, 95 Setiadji, S., 11, 37 Sevcik, P., 5, 53, 221 Severance, D.L., 9, 86; 15, 424 Sevilla, M., 4, 45 Sevvel, R., 5 , 31 Sgarabotto, P., 3, 56 Shah, A,, 3, 166; 15, 282 Shahin, H.E., 4, 30 Shaik, S., 4, 175-177,220, 221 Shakhkel’dyan, I.V., 7, 97, 98, 107, 108 Shakirov, M.M., 8, 54 Shan, J., 5, 37 Shang, M., 7, 24, 25 Shang, 2.-F., 1, 146; 5, 83 Shao, L., 15, 121 Shapka, S., 11, 125 Shapiro, LO., 11.5 Sharifi, M., 4, 5 Sharma, A.K., 14, 101; 15, 568 Sharma, K., 1, 148; 5, 15, 43 Sharma, P.K., 5, 3, 6, 12; 14, 86 Sharma, R.P., 15, 44 Sharma, U., 15, 192 Sharma, V.K., I, 148; 5, 15, 43 Sharpless, K.B., 5, 92 Shashin, S.S., 4, 52; 5, 175177 Shatskaya, V.N., 7, 109 Shaw, J.T., 1, 107 Shaw, R.W., 10,50, 51 Shawali, A.S., 14, 56; 15, 95 Shay, B.J., 14, 137 Shcherbukhin, V.V., 9, 8, 74; 15, 380,465 Sheik, Q., 4, 97; 15, 259 Sheldon, J.C., 11,4 Sheldon, R.A., 8, 8 Shellmeyer, D.C., 15, 303 Shemchuk, L.A., 2, 214 Shen, D., 4, 43 Shephard, M.J., 4, 141 Shepherd, M.K., 4, 186 Sheradsky, T., 10, 53 Sherbum, M.S., 3, 31 Shereshovets, V.V., 3, 182, 183 Sherigara, B.S., 5, 33, 34

Sherrill, C.D., 6, 97 Shevelev, S.A., 7, 16, 17 Shevlin, P.B., 6, 5 Shi, G., 15, 128 Shi, X., 15, 216 Shi, X.W., 15, 217 Shi, Y., 1, 164 Shiau, C.-S., 15, 326 Shibaev, A.Y., 11, 12 Shibasaki, M., 15, 394 Shibata, N., 15, 447, 448 Shibuya, S. 15, 253 Shibuya, S., 15, 495 Shida, T., 4, 6 Shigero, O., 4, 140 Shigihara, A,, 14, 65 Shihaliev, K.S., 5, 179 Shiibashi, M., 2, 155 Shim, K-T., 10, 107 Shima, H., 15, 169, 170 Shimada, K., 2, 164; 15, 180, 45 1 Shimasaki, C., 2, 204 Shimizu, H., 6 , 81; 9, 68; 11, 136; 15, 288,443,450, 550 Shimizu, M., 11, 137 Shimizu, N., 12, 15 Shimizu, T., 15, 543 Shimoguchi, T., 15, 451 Shindo, K., 7, 37 Shinokuho, H., 15, 362 Shioji, K., 4, 103 Shiono, T., 14, 217 Shipman, M., 14, 59 Shirai, N., 15, 232, 244, 245 Shiraki, M., 15, 406 Shiro, M., 1, 73; 3, 154; 6, 99; 11,31

Shishkin, O.V., 15, 104 Shishlov, N.M., 3, 182 Shizuka, H., 15, 20 Shkil, G.P., 7, 87 Shmyreva, Z.V., 5, 179 Shohoji, M.C.B.L., 3, 176; 4, 219,226 Shoji, K., 15, 451 Shook, C.A., 15, 27 I Shteiman, V.Y., 8, 9, 26 Shteingarts, V.D., 4, 81, 223; 5, 206; 7, 15 Shu, L.-H., 14, 74 Shu, Y., 3, 202 Shubin, V.G., 8, 54; 15, 423 Shudo, K., 1, 118; 8, 6, 34, 36; 15, 160 Shuff, P., 10,48 Shukla, A., 5, 98 Shukla, R., 14, 163 Shul’pin, G.B., 5, 36, 69 Shuler, P., 4, 8 Shvets, V.F., 10, 25 Sibrikov, S.G., 7, 23

585

Author index Sica, F., 15, 584 Sicking, W., 14, 41 Siddons, D.C., 15, 225 Sidebottom, H., 5, 183 Sidebottom, P.J., 15. 285 Siebach, D., 1, 100 Siedem, C.S., 1, 142 Siegel, J.S., 14, 216 Siegfried, R., 9, 89; 15, 426 Siehl, H.-U., 9, 66, 83 Sierra, M.A., 15, 517 Sies, H., 5, 143 Siesel, D., 8, 38 Sieval, A.B., 14, 219 Sigalov, M.V., 15, 346 Silla, E., 1, 150; 5, 217 Sillars, N.C., 15, 147 Sillesen, A., 5, 171 Simon, J.D., 4, 105; 15, 620 Simonet, J., 4, 158 Simonov, M.A., 10, 24 Simons, K.T., 3, 185 Simpkins, N.S., 1, 140 Sinay, P., 15, 589 Sinclair, S., 1, 26c Sindkhedkar, M.D., 15, 134 Sindler-Kulyk, M., 15, 441 Singh, A.K., 1, 43 Singh, B., 2, 33; 5, 99 Singh, H., 15, 106 Singh, J.D., 15, 246, 249 Singh, K.N., 15, 347 Singh, M., 5, 99 Singh, P., 15, 106, 347 Singh, S.N., 5, 24 Singh, S.P., 2, 33 Singh, V., 15, 192 Singleton, D.A., 14, 175 Sinha, N., 15, 173 Sinha, S.C., 15, 243 Sinisterra, J.V., 2, 165 Sipamla, A.M., I, 25 Sirotkina, E.E., 5, 152 Sitpaseuth, S., 11, 39 Skaltsounis, A.L., 15, 201 Skelton, B.W., 14, 51; 15, 238 Skibida, I.P., 4, 52; 5, 175, 176 Skinner, C.J., 8, 7, 12 Skripnik, Yu.G., 1, 14, 15 Skrzypek, J., 2, 17 Slagle, I.R., 3, 189 Slassi, A,, 3, 162 Slater, M.J., 2, 171; 15, 166 Slawin, A.M.Z., 14, 171, 172 Slebioda, M., 2, 89 Slebocka-Tilk, H., 13, 11 Slief, J.-W., 13, 100 Smart, B.A., 3,45,138, 139 Smart, B.E., 4, 248 Smart, B.J., 4, 31 Smart, R.P., 14, 9 Smerz, A.K., 5, 144

Smimov, V.V., 13, 25 Smit, W.A., 13, 4 Smith, C.J., 2, 172 Smith, D., 5, 107 Smith, D.F., 3, 200; 5, 178 Smith, D.L., 11, 79 Smith, D.T., 15, 335 Smith, G., 14, 64 Smith, J.R.L., 5, 78 Smith, M.A., 5, 185 Smith, R.H., 12, 14 Smith, R.L., 4, 182, 183 Smith, S.C., 15, 225 Smith, W.B., 6, 31 Smitrovich, J.H., 1, 107 Smoliakova, J.P., 13, 4 Smonou, I., 13, 31 Smyth, T., 7, 43, 44 Snramulu, Y., 2, 78 Soberg, W., 15, 222 Sobolewski, A.L., 11, 13 Soda, S., 7, 88; 10, 43 Soh, K., 15,461 Sohma, T., 7, 1I8 Sola, M., 14, 97, 149 Solans, X., 12, 67 Solar, s., 4, 215 Soldatova, T.A., 7, 107 Sol& A,, 3, 77; 6, 9 Soliman, H., 15, 499 Solkan, V.N., 7, 16, 17 Sollogoub, M., 15, 589 Solouki, B., 4, 166 Somfai, P., 15, 228, 229, 279 Son, Y.-Y., 2, 212 Song, F., 6, 49 Song, K.H., 2, 152 Song, K.S., 12, 9 Song, S.Y., 6, 67 Song, X.-Y., 1, 146; 5, 83 Song, Y.-Y., 9, 70 Sonnenberg, J.D., 1, 107 Sonnenschein, H., 15, 96 Sonoda, N., 3, 51, 132 Sordo, J.A., 14, 21, 131, 144, 145 Sordo, T.L., 14, 21, 131, 144, 145 Sorensen, P.E., 1, 117 Sorger, K., 11, 16 Sorgi, K.L., 15, 151 Sorokin, V.D., 15, 516 Sorokina, Y.L., 15, 43 Sosnovsky, G., 3, 19; 15, 351 SOU,W.-I., 11, 2; 15, 341 Spagnolo, P., 6, 30; 14, 34; 15, 585 Sparapani, C., 7, 3; 9, 64; 15, 40 Spassov, S., 13, 29 Spate, M., 14, 105 Spath, T., 4, 147

Speck, T., 12, 62 Speers, P., 12, 70; 13, 80 Speier, J., 9, 49; 10, 10 Spek, A.L., 1, 19; 1 1 , 4 7 Sperandio, D., 15, 321 Speranza, M., 7, 3; 9, 20, 64; 10, 8; 15, 40 Spillane, W.J., 2, 216; 12, 6 Spinelli, D., 1, 130; 2, 106; 7, 77, 78; 15, 72 Spuo, T.G., 4, 204 Spitz, U.P., 9, 84 Spoyalov, A.P., 4, 53, 194 Sprules, T.J., 11, 49; 14, 189 Spyroudis, S., 15, 14 Squires, R.R., 4, 208; 11, 116 Srebnik, M., 15, 526, 527 Sridharan, V., 13, 44 Srikrishna, A,, 15, 337, 414 Srinivasan, C., 5, 31; 15, 24 Sriramulu, Y., 5, 89, 187 Srivastava, A.K., 1, 46 Srivastava, S., 5 , 86 Srivastava, S.K., 15, 248 Stack, T.D.P., 14, 99 Stadter, W., 2, 159; 12, 71 Staerk, H., 4, 89 Staffelbach, T.A., 3, 201 Stagnaro, P., 11, 129 Stahl, T., 4, 200 Staker, W.S., 6, 11 Stalewski, J., 7, 90, 91 Stllhandske, C., 14, 29; 15, 320 Stalke, D., 11, 16, 23 Stames, S.D., 2, 55 Stamm, H., 9, 23; 15, 393 Stammler, H . G . , 14, 23 Stamos, I.K., 15, 452 Stamuler, H.-G., 15, 415 Stanbury, D.M., 5, 58,210 Stanchina, D.M., 6, 58 Stanciuc, G., 4, 25 Standen, S.P., 5, 155, 156 Stanescu, M.D., 9, 54 Stankevich, LV., 7, 106 StankoviC, S.M., 12, 66 Stanoeva, E., 13, 29 Stark, M.S., 5, 184 Starling, S.M., 13, 77 Stauch, G., 2, 1.59 Staunton, J., 2, 172 Steckhan, E., 4, 94, 130 Steel, A.J., 3, 103 Steel, P.J., 9, 77; 13, 62, 63; 15, 91,436,437 Steenken, S., 4,172, 269; 9, 34 Stegmann, H.B., 4, 8 Steiner, D., 6, 82 Steiner, R.A., 14, 33 Steininger, K., 6, 24 Steinmetz, M.G., 15, 266

Author Index Stephenson, P.T., 3, 36 Sterha, V., 1,47; 7, I , 33 Sternahach, D.D., 15, 108 Stevens, C.V., 13, 58 Stevens, J.A., 7, 100; 11, 53 Stevenson, C.D., 4, 225 Stevenson, P., 14, 71 Stickley, K.R., 4, 165 Stimson, W.H., 11, 132 Stinner, C., 15, 530 Stkruchkov, Yu.T., 15, 104 Stocks, M., 15, 290 Stoelting, D.T., 9, 57, 79; 15, 384, 385 Stoesser, R., 4, 63 Stoltz, B.M., 15, 479 Stoncius, A., 1, 154; 5, 197 Stone, J.R., 2, 171 Stoppa, F., 11, 26 Storer, J.W., 15, 118 Storey, J.M.D., 3, 84 Stossel, R., 10, 32 Strasser, R., 12, 68; 15, 409 Stratakis, M., 5, 165; 11, 61 Striluch. G., 12, 71 Streefland, L., 2, 81 Streith, J., 15, 103 Streitwieser, A,, 10, 63; 11, 61 Strelenko, Y.A., 3, 58 Stronach, M.W., 2, 197; 11, 115

Struchkov, Yu.T., I, 81; 3, 58; 7,106 Strul, G., 5, 169 Studer Martinez, S., 11, 123 Stuhl, F., 5, 172 Sturino, C.F., 15, 573 Su, M.-D., 15, 36 Su, M.D 15, 269 su, P.-c., 15, 537 su, Y., 4, 205 Su,M-D 15, 297 Suiirez, A.G., 12, 18 Suirez, A.R., 12, 18 Suarez, D., 14, 21, 145 Suirez, E., 15,474 SuArez-Sobrino, A., 14, 125 Suau, R., 15, 21, 22 Suhharaju, G.V., 15, 73 Subra, R., 4, 12, 232 Subramanian, L.R., 9, 67, 69 Suhramanian, S., 11, 15 Such, P., 4, 168 Suchan. S.D., 7, 57 Suchar, G., 2, 107 Sucholeiki, I., 7, 68 Suckling, C.J., 11, 132 Sudalai, A,, 5, 9 Sudha, M.S., 15, 158 Sudo, A.. 11, 138 Sudoh, T., 13, 53 Sue, R.E., 15, 339

Sucda, T., 6, 35; 9, 65 Sueishi, Y., 1, 169; 11, 113 Sueshi, T., 7, 99 Suga, S., 1, 95; 11, 104 Suganuma, H., 5, 166 Sugihara, H., 15, 136 Sugitani, W., 10, 91 Sugiura, M., 15, 125, 126 Sugiura, T., 3, 184 Sugiyama, S., 15, 155 Suh, J., 2, 174 Suh, K.-H., 1, 68; 11, 29 Sukhai, P, 1, 117 Sukhov, L.L., 10, 108 Sulzhach, H.M., 15, 59 Surni, T.J., 4, 25 Sumiani, N., 3, 155 Sun, G.R., 15, 545 Sun, H., 6, 83 Sun, Q., 10, 99 Sun, S.S., 5, 55 Sun, X.-J., 4, 88; 10, 74 Sun, Y.-l?, 4, 84 Sun, Z., 15, 115 Sundar, S.B., 5, 2 Sung, D.-D., 2, 210; 6, 87 Sung, N.D., 2, 100 Surez, D., 14, 144 Suri, D., 5, 117 Suri, S.C., 15, 358 Surry, C., 1, 9a; 9, 40 Surya Prakash, G.K., 1, 119; 9, 29, 58, 59, 94, 95 Suss-Fink, G., 5, 69 Sustmann, R., 4, 128, 129; 14, 41, 42, 95, 96 Susuki, T., 10, 79, 81 Sutcliffe, L.H., 4, 5 Suter, H.U., 4, 29 Sutherland, D.R., 15, 285 Suzuki, A,, 3, 53 Suzuki, D., 4, 80 Suzuki, H., 4, 132, 133; 6, 100; 7, 58; 8, 19-21 Suzuki, K., 7, 118; 14, 18 Suzuki, S., 14, 201 Suzuki, T., 4, 197, 198; 14, 188; 15, 399 Suzuki, Y.,2, 155; 14, I16 Suzzi-Valli, G., 14, 89 Svechnikova, E.N., 2, 213 Svensson, J.O., 4, 149-154; 8, 15 Svetlik, 4, 51 Swanegan, L.A., 9, 43 Swarhrick, M.E., 15, 225 Sweger, R.W., 2, 137 Sychev, V.S., 7, 109 Sygula, A,, 11, 6 Sykes, B.M.. 2, 80 Symons, M.C.R., 4, 6, 203 Sypniewski, M., 15, 561

Szabo, K.J., 9, 85; 15, 438 Szantay, C., 15, 135 Szczesna, J., 13, 72, 73 Szokan, G., 5, 124 Szpakiewicz, B., 7, 38 Tabata, K., 1, 73; 11, 31 Taber, D.F., 6, 69 Tahuchi, T., 14, 84 Tachihana, Y., 1, 50b Tachikawa, H., 3, 80 Tada, M., 3, 30; 15, 543 Taddei, F., 5, 158 Tadic, Z.D., 12, 28 Taga, T., 1, 137; 15, 563 Tagaki, W., 2, 127 Taguchi, T., 3, 154 Taira, K., 2, 196 Takada, A,, 15, 602 Takagi, T., 10, 91 Takahashi, H., 14, 21 5 Takahashi, K., 1 5 , 6 I Takahashi, M., 6, 94; 15, 274, 609 Takahashi, T., 3, 54; 15, 136, 528 Takahashi, Y.. 3, 177; 14, 8; 15, 399 Takahashi,Y., 4, 102 Takahira, O., 4, 240 Takai, M., 15, 296 Takamaku, S., 4, 170, 17 1, 214 Takaoki, K., 11, 138 Takasawa, T., 15, 460 Takashima, K., 5, 70 Takata, T., 12, 21; 13, 27 Takayarna, H., 14, 188; 15, 431, 578 Takayanagi, H., 15, 155, 156 Takayanagi, T., 12, 55 Takebayashi, M., 1, 73; 11, 31 Takeda, N., 2, 153 Takeda, Y., 15. 27, 28, 461 Takehara, N., 15, 455 Takemoto, Y., 15, 538 Takeoka, J., 15, 163 Takeshita, H., 15, 352, 353 Takeuchi, K., 1, 109; 11, 85;

12,59 Takikawa, Y., 15, 180, 451 Takino, T., 9, 65 Talina, E.V., 5, 32 Talinli, N., 1, 4 Tdlec, A,, 5, 204 Talrnan, E.G., 14, 220 Talvinskii, E.V., 15, 157 Tarn, W., 14, 209 Tamamura, H., 15, 563, 564 Tamao, K., 6, 99; 15, 545 Taniaru, Y., 1, 99 Tamion, R., 15, 356 Tamura, K., 13, 86

Author Index Tan, B., 2, 119, 149 Tanabe, G., 15, 298 Tanabe, Y., 8, 37 Tinaka, A., I, 99 Tanaka, H., 3, 12, 156; 10, 62 Tanaka, M., 8, 42; 14, 27; 15, 575

Tanaka, N., 5, 85 Tanaka, T., 15, 196 Tinaka.S., 1, 99 Tananakin, A.P., 5, 206 Tang, H.R., 5, 210 Tang, S . 3 , 7, 47 Tang, T.-H., 1, 135 Tang, Z., 15, 115 Taniguchi, H., 7, 88; 10.43 Taniguchi, M., 15, 361 Tanner, D., 10, 34 Tanskanen-Lehti, K., 10, 115 TdnL?dwa,T., 15, 244, 245 Tao, F.-M., 4, 10 Tao. X . , 8 , 46 Tapia, K., 14, 105, 190 Taradella, P.A., 6, 60 Taran, N.A., 2, 109 Tarasov, V.F., 3, 8 Tarasova, O.A., 15, 346 Tarkka, R.M., 2, 188, 201 Tanant, J., 15, 467 Tarunin, B.I., 5, 32 Tarunina, V.N., 5, 32 Tashiro, M., 7, 6; 14, 197; 15, 61

Talsugi, J.. 15, 52 Tatsukawa, A,, 11, 58; 13, 78 Tatsumi, A., 4, 133; 8, 23 Tavani, C., 11, 130 Taylor, A.T., 14, 150 Taylor, D.K., 6,40; 15, 342 Taylor, D.L., 8, 53 Taylor, E.C., 15, 69 Taylor, I.R., 15, 521 Taylor, J.A., 7, 75, 76 Taylor, J.E., 5, 125 TdyklI-, PJ., 2, 24, 50; 12, 73 Taylor, R.J.K., 15, 375 Teasdale, A.J., 8, 28 Tee, O.S., 2, 139-142, 145; 10. 96

Tehrani, S.S., 7, 57 Tejero, T., 1, 35; 13, 102 Teleman, O., 15, 324, 325 Temciuc, E., 14, 29; 15, 320 Temer, F., 2, 183 Tcmkin, O.N., 13, 52 Tennant, G., 6, 29; 8, 40 Tenorio, M.J., 15, 540 Tei-asaka, T., 4, I 9 7 Terlouw, J.K., 6, 13 TeTrCt, N.K.,3, 36 Terrier, E, 7,94, 101, 103; 11, 63; 12, 13

587 Terzis, A,, 15, 90 Teso Vilar, E., 9, 67 Tessier, C.A., 7, 29 Testafem, L., 2, 74 Teton, S., 3, 199 Teuber, H.J., 15, 481 Teulade, J.-C., 11, 92 Teunissen, H.T., 14, 205 Tezcan, A.Z., 15, 185 Thaddeus, P., 4, 10 Thakkar, K., 5, 42 Thca, S., 2, 28; 12, 4 Thibblin, A., 5, 19; 10, 60, 100, 111; 12, 10, 11, 19; 15, 378 Thiebault, A,, 4, 1 16; 7, 1 1 Thielemann, W., 15, 439 Thiemann, T., 14, 197 Thijs, L., 15, 557 Thom, S., 15,467 Thomas, A., 1, 110; 11, 80 Thomas, B.E., 15, 302. 303 Thornas, C.B., 8 , 18 Thomas, R., 3, 67 Thompson, A., 10, 48 Thompson, C.M., 11. 131 Thomson, G.A., 13,36, 38 Thomson, J., 8, 7 Thomson, L., 6, 40 Thorn, R.P., 5, 174 Thornton-Pett, M., 6, 41; 14, 46, 71

Tian, A., 15, 115 Tian, A.M., 15, 117 Tian, P., 4, 157 Tidwell, T.T., 1, 12a, 12b; 10, 96; 15, 306 Tiecco, M., 2, 74 Tietze, L.F., 14, 122, 132, 134 Tikhomirov, V.A., 4, 209, 21 1 Tilley, R.I., 12, 7 Timar, T., 15, 493 Timari, G., 5, 94 Timberlake, J.W., 4, 19 Timmermanvaughan, D.J., 15, 37

Timms, A.W., 4, 203; 7, 7 Timofeev, V.V., 5, 133 Tingoli, M., 2, 74 Tirmignonc, G., 4, 7 Times, P., 2, 68; 12, 1 Titsky, G.D., 7, 79 Tius, M.A., 4, 131 Tobin, A.E., 2, 179 Tobita, S., 15, 20 Toda, F., 15, 387 Todaro, L., 15, 349 Todd, C.J., 14, 40 Todd, S.L., 2, 110 Tofani, D., 6, 60 Tohjo, T., 15, 447 Tohuacheva, I.M., 7, 23

Tojo. S . , 4, 170, 171 Tbke, L., 14, 70 Tokitoh, N., 6, 56, 100 Tokmakov, G.P., 15, 65 Tokui, M., 10, 91 Tokumara, K., 3, 17 'Ibkumaru, K., 3, 78; 4, 32 Tokunaga, Y., 2, 101; 6, 27; 15, 453

Tokuyama, H., 3, 117; 6, 50 Tokuyasu, J., 15, 357 Tolbert, L.M., 4, 88; 10, 74 Toledo, E.A., 2, 13 1 ; 10, 98 Tolstikov, G.A., 15, 157 Tomis, A., 1, 22, 23; 13, 76 Tomas, M., 14, 125 Tomaselli, G.A., 5, 72 Tomashewski;, A.A., 7, 41 Tomaszewski, M.J., 3, 3X Tomida, S . , 3, 54 Tomioka, H., 6, 12, 38, 73, 85, 92; 15, 15 Tommasini, S., 12, 64 Tomooka, K., 3, 1 15; 15,210212

Tonnard, F., 14, 69 Topolski, M., 6, 93 Toppet, S.. 14, 82 Torborg, C.J., 15, 389 Tordo, P., 4, 68, 162 Tores, G., 15, 21 Toriyama, K., 3, 61 Tormos, R., 15, 23 Torres Kusso, V.F., 15, 376 Torres, G., 15, 22 Tortelli, V., 3, 130 Toscano, J.P., 6, 14, 17 Toscano, R.M., 5, 72 Toscano, V.G., 4, 26 I Toth, C., 15, 207 Toth, G., 15, 493 Toupet, L., 15.41 3 Toyooka, Y., 5, 219 Toyota, A,, 13, 18 Traeger, J.C., 7, 4 Trahanovsky, W.S., 14, 213 Tran Huu Dau,M.E., 10, 38 Tran, H.Q., 10, 14 Tran. T.-A., 3, 139 Tranoy, I., 15, 213 Traubel, M., 6, 22 Trauner, H., 14, 204 Treacy, J., 5, 183 Treiber, A., 5, 160; 10, 32 Trenkle, H., 4, I79 Treptow, B., 13, 54 Trere, A,, 1, 21 Tretyakov, E.V., 13, 61 Triebert, J., 3, 102 Trimarco, P., 15, 89 Tripathy, G.N.R., 4. 205 Trivedi, G.K., 14, 54

Author Index Trofimov, B.A., 15, 346 Troisi, L., 1, 26 Trommer, M., 6, 26 Tronche, C., 3, 32 Trost, B.M., 13, 54; 14, 68, 99; 15, 167 Trotter, J., 15, 299 Troyansky, E.I., 3, 58 Truhlar, D.G., 10, 61 Truhler, D.C.,15, 118 Truong, T.N., 11, 118 Truttman, L., 4, 142, 143 Tsai, T.-G., 12, 45 Tsai, Y.-M., 3, 13 Tsanaktsidis, J., 3, 45; 4, 31 Tsang, W., 12, 34 Tsao, M.-L., 10, 82 Tse, J.E., 2, 2 Tse, J.S., 9, 12 Tsubouchi, A., 2, 181, 182 Tsubouchi, T., 15, 488 Tsubuki, M., 15,214 Tsuchimoto, T., 15,408 Tsuchiya, M., 3, 17, 78; 4, 32, 104 Tsuge, A., 7, 6 Tsuji, H., 15, 549 Tsuji, Y., 10, 79, 80, 81, 84, 85, 96 Tsujita, H., 15, 70 Tsukayama, M., 15, 355 Tsukinoki, T., 15, 61 Tsukiyama, K., 3, 97 Tsukunmichi, E., 2, 204 Tsunashima, S., 3, 188 Tsuno, Y., 4, 191,207; 10,7981, 84, 85, 96; 12, 15 Tsunoi, S., 3, 51 Tsuruoka, T., 14, 52; 15, 592 Tsutsumi, K., 15, 548 Tsutsumi, N., 15, 163 Tsvetkov, Y.D., 4, 194 Tu, J., 15, 374 Tubul, A,, 14, 184 Tuccio, B., 4, 68 Tucker, J.A., 13,68b Tucker, L., 14, 118 Tuleja, J., 1, 100; 11, 105 Tulub, A.V 5, 181 Tundo, A., 3, 56 Tundo, P., 7, 63 Tunina, S.G., 2, 18 Tupitsyn, I F , 11, 7, 12 Turchi, S., 14, 157 Turnbull, P., 15, 405, 588 Turner, P., 13, 11 Turro, N.J., 3, 8 Turzanski, M., 2, 17 Tveritinova, E.A., 5, 133 Tyndall, G.S., 3, 76, 201 Tyrrell, J.. 3, 195 Tzepros, N.I., 4, 20

Uccella, N., 12, 64 Uchida. T., 15, 160 Uchiyama, K., 15, 34 Uebelhardt, P., 4, 148 Ueda, I., 4, 245; 14, 57; 15, 444 Uemura, K., 6, 35 Uemura, S., 1, 159; 5, 200; 6, 95; 15, 246-2.50 Uemura, T., 15, 179 Ueno, H., 15, 28 Ueno, M., 15, 455 Ueno, S., 4, 27 Ueoka, R., 2, 164 Uera, W., 15, 388 Uffelmad, E.S., 5. 28 Ugrak, B.I., 15, 429 Uhm, T-S., 2, 210 Urn, I.-H., 2 , 4 0 , 4 1 Uma, M., 5, 23 Uneyama, K., 6, 27; 15, 35, 453 Unger, C., 4, 247 Unold, Pvon, 15, 7 Uozumi, Y., 13, 43 Upadhyay, S.K., 5.98 Urabe, H., 1, 98; 3, 160 Urano, Y., 2, 224 Urata, Y., 2, 130 Urbanczyklipkowska, Z., 15, 73 Urpi, E, 2, 63 Unini, O., 7, 3; 9, 64; 15, 40 Uscumlic. G.S., 2, 57, 58 Ushigoe, Y., 14, 210 Ushikubo, T., 15, 486 Usui, S., 2, 130 Utimoto, K., 15, 361, 362 Utsumi, H., 15, 355 Uyehard, T., 15, 455 Vadecar, J., 13, 16 Vaganova, T.A., 4, 223; 7, 15 Valderrama, J.A., 14, 105 Valerga, P., 15, 540 Valgattarri, G., 15, 89 Valgimigli, L., 3, 90 Valle, G., 14, 169 VallBe, Y., 14, 106, 136; 15, 280 Valov, PI., 5, 182 Valpuesta, M., 15, 21, 22 Valverde, S., 15, 476 van Asten, P.F.T.M., 11, 76a; 15, 313 van Baar, B.L., 14, 205 Van Bac, N., 14.49 van Bekkum, H., 1, 74; 5, 106, 194 van Dijk, J.T.M., 11, 134 Van Eldik, R., 5, 71 van Koten, G., 1, 19; 11, 46, 47

van Liemt, W.B.S., 4, 194 van Maanen, H.L., 1, 19; 11, 47 van Mannen, H.L., 11, 46 van Seggern, H., 4, 184 van der Hart, W.J., 11, 3 van der Hoeven, J., 13, 100 van der Linden, J.B., 11, 76a, 76b; 15, 373 VanBrocklin, H.F., 8, 27 VanDerveer, D., 8, 39 VanNieuwenhze, M.S., 5, 92 Vanaar, M.P.M., 15, 557 VanEik, H., 9, 7 Vanelle, P., 4, 114, 115 Vangveravong, S., 15, 503 Vanni, R., 5 , 142 Vanquickenbome, L.G., 6, 80; 12,49; 15,497 Vansweevelt, H., 6, 80 Vapirov, V.V., 2, 18 Vaquero, J.J., 1, 36 Varea, T., I, 91; 4, 190 Varea-Amo, M.C., 5 , 14 Varlamov, V.T., 3, 100 Varma, C.A.G.O., 6 , 7 8 Varvounis, G., 7, 93; 10, 102 Vasil’ev, N.V., 14, 2 Vasilevsky, S.F., 13, 61 Vass, M., 5 , 26 Vatkle, J.-M., 15, 283, 284 Vaughan, J.F.S., 15, 307 Vaultier, M., 15, 289 Vavekis, K., 4, 4 Vaz, A.D.N., 2, 175 VBzquez, S., 12, 67 Vazquez-Persaud, A.R., 3, 142; 4, 24 Vedejs, E., 11,48 Veits, Y.A., 15, 261 Velusamy, P., 15, 24 Venanzi, C.A., 2, 27 Venelle, €?,3, 175 Venkatehsha, B.M., 5, 120 Venkatesan, H., 3, 26 Venkateswaran, V., 5, 121 Venkateswarlu, S., 15, 337 Venkatraman, S., 15, 84 Ventura, M., 14, 97 Verevkin, S.P., 3, 144; 4, 18 Verkade, J.G., 10.47 Verlaque, P., 6, 79 Vernon, J.M., 15,590 Veronese, A., 2, 25 Verpeaux, J.-N., 4, 116; 7, 11 Vessibe, R., 14, 50 Vetchinov, V., 1, 112 Vetoshkin, E.V., 11, 119 Viallon, L., 15, 159 Viana, C.A.N., 10, 89 Vichi, L., 15, 446 Victory, P., 1, 168

Author Index Vidal-Fenan, A,, 1, 168 Vidyasagar, V., 15, 3 17 Viehe, H.G., 15, 168 Vieira, A.J.S.C., 3, 176; 4, 226 Vieth, H.-M., 4, 239 Viggiano, A.A., 10.62 Vigroux, A,, 1, 34; 2, 68; 10, 57; 12, 1 Vilanova, B., 2, 170 Vilarrasa, J., 2, 63 Villa, R., 5, 151; 15, 523, 524 Villanucva, J., 15, 76 Villemin, D., 15, 174, 175 Viols, H., 11, 92 Virgili, A,, 3, 149 Visser, R.J., 6, 78 Vitt, D., 2, 52 Vivona, N., 15, 93, 94 Vizgert, R.V., 2, 199: 7, 21 Vleggaar, J.J.M., 6, 78 Vleggaar, R., 15, 555 Vogel, P., 13, 9 Vogt, A., 15, 16 Vogt, R., 3, 93 Vogtle, F., 15, SO Voici, A., 2, 124 Voicu, A., 15, 392 Voitekunas, Yu.B., 1, 76; 11, 52 Volkova, V.V., 15, 56 Vollhardt, K.P.C., 14,208 Volod’kin, A.A., 13, 65 Volodarsky, L.B., 14, 44 Volodarysky, L.B., 4, 53 Volodin, A.M., 3, 14 von Schnering, H.-G., 14, 88 von Schnering, H.G., 14, 167; 15, 286 von Seggem, H., 1 4 , 2 4 von Sonntag, C., 4, 40, 268, 269 Vonwiller, S.C., 13, 77 Vorob’eva, N.P., 4, 216 Voss, J., 11, 82 VuckoviC, D.L., 15, 382 VuckoviC, D.L.J., 9, 50 Vulpius, T., 4, 181 Wada, E., 14, 104 Wada, K., 15,486 Wada, M., 9, 38 Wada, Y., 1 , 4 2 ; 12, 63 Waddington, D.J., 5, 184 Waengberg, I., 3, 69 Wagenseller, P.E., 14, 206 Waggenspack, J., 7, 42 Wagner, A.F., 4, 250 Wagner, B.D., 15,306 Wagner, P.J., 14, 9 Wagner, R., 15, 196 Wakabayashi, H., 7, 37 Wakefield, B.J., 7, 93; 10, 102

589 Walbiner, M., 3, 108 Waldhor, E., 4, 201 Waldron, N.M., 2, 90 Walek, S., 4, 21; 9, 6; 11, 110 Walker, J.A., 12, 34 Walker, M.J., 15, I 1 1 Wallington, T.J., 3, 76, 87, 95 Walters, M.A., 14, 212; 15, 199 Waltmann, R.J., 4, 185 Walton, J.C., 3, 29 Walton, T.C., 3, 104 Walz, L., 14, 88 Walzl, M., 1, 20 Wan, P., 1, 164 Wan, P.W.H., 5, 151; 15, 523 Wan, Y,, 10, 47 Wang, D., 11, 73a Wang, G.-W., 14, 74 Wang, H., 1 0 , 6 8 Wdng, H.-L., 15,463 Wang, J., 3, 17, 78; 4, 32 Wang, J.-L., 6 , 17 Wang, J.-T., 4, 143 Wang, J.-Y., 14, 120 Wang, J.J., 15, 352, 353 Wang, K.-T., 2, 136 Wang, M.-X., 15, 203 Wang, N., 7, 27 Wang, N.-J., 14, 14, 15 Wang, Q., 2, 126; 9, 95; 15, 41 3 Wang, Q.L., 8 , 4 5 Wang, S., 2, 92; 3, 96; 5, 174; la, I 14; i z , 5 2 , 5 4 , 5 7 Wang, S.-L., 2, 154 Wang, T., 10, 52 Wang, X., 15, 195 Wang, Y.,4, 163; 12, 36; 15, 313 Wang, Y.-X., 9, 47 Wang, Y.M., 1, 100; 11, 105 Wang, Z., 2, 47; 11, 79; 13, 20 Wang, Z.-M., 5, 62 Ward, P., 15,31, 32 Ward, R.S., 2, 202; 10, 101 Ward, S.C., 4, 244; 14, 10 Waring, A.J., 11, 87 Warkentin, J., 6, 65; 14, 86 Warren, S., 15, 573, 574 Warwkentin, J., 3, 38 Washabaugh, M.W., 2, 8 Washida, N., 3, 188 Washio, Y., 3, 154 Wassef, W.N., 2, 108 Wasserman, H.H., 5, 161 Wassmundt, EW., 7, 5 Wassmunett, F.W., 3, 167 Watanabe, A., 4, 83 Watanahe, K., 15, 193 Watanabe, M., 5, 130 Watanabe, S., 15, 274 Watanabe, T., 9, 38

Watanahe, Y., 2, 21 Waterman, D., 4, 9 Watt, C.I.F., 9, 30, 53 Watterson, S.H., 14, 26 Wayne, R.P., 3, 128 Wayner, D.D.M., 3, 64, 164 Weber, K., 4, 146 Webster, EX., 15, 216, 217 Wecker, U., 6, 47; 15, 572 Weedon, A.C., 4, 234,235; 14, 12; 15, 18 Wehrli, D., 13, 101 Wei, Y., 2, 166 Weickhardt, K., 15, 241 Weingarten, M.D., 13, 107; 15, 223,412 Weinreb, S.M., 15, 333-335 Weinstock, I., 5, 74 Weiser, J., 15, 466 Weiss, D., 15, 472 Weiss, M., 10, 1; 12, 2; 13, 90 Wells, A.P., 13, 58 Wells, G.N., 15, 285 Wempe, M.F., 15, 410 Wender, P.A., 14, 201, 215 Weng, H., 3, 178; 4.95-97 Weng, H.X., 15,259, 430 Wenthold, PG., 4, 208; 11, 116 Wentrup, C., 6, 75; 15, 262, 263 Wenzel, A,, 11, 77 Werber, G., 1, 48 Werkntin, M.S., 3, 164 Wermeckes, B., 5, 186 Werner, A,, 15, 608 Werner, U., 4, 89 Werstiuk, N.H., 1, 134, 136; 3, 38; 11,9, 10; 12, 32, 33; 14, 195 West, F.G., 15, 577 West, EJ., 2, 51 West, R.J., 3, 135 Westermann, J., 13, 98 Westwell, M.S., 15, 573 Whang, H.S., 3, 18 Wheeler, R.A., 4, 35, 36 Whisnant, C.C., 13, 82 White, A.H., 14, 51; 15, 238 White, A.J.P., 14, 171, 172 White, J.B., 15, 196 White, J.M., 9, 3 White, R.H., 15, 339 Whitmore, J.M.J., 7, 75, 76 Whittenburg, S.L., 14, 140 Whittington, B.I., 9, 77; 15, 436,437 Wi, Y.-D., 5, 59 Wiherg, K.B.. 4, 14, 23; 9, 5 . 75; 10,62; 11, 1, 11 Wicha, J., 15, 363 Wiegand, S., 7, 51 Wierlacher, S., 6 , 77

Author Index Wiest, 0..15, 116, 302 Wicstal. J., 15, 85 Wightman, R.H., 5, 203 Wi,jncn, J.W., 14, 33 Wild, L.M., 3, 140 Wild, R., 15, 187 Wildt, H., 4, 231 Wilhe, J., 2, 190 Wilk, K.A., 12, 12 Wilker. S., 14, 107 Wilkes, R.D., 15, 129, 218 Wilkie, J., 1, 149; 3, 104; 5, 213

Wilkinson. E.C., 5, 77 Wilkinhon, J.A., 15, 416 Willenis, J.G.H., 15. 344 Willetts, A.J., 5, 151; 15, 523, 524

Williams, A,, 2, 12, 62; 7, 75, 76

Williams, C.M., 9, 56; 15, 41 Williams, D.J., 14, 171, 172 Williams, D.L.H., 2, 222 Williams, F., 4, 142, 143 Williams, I.H., 1, 149; 5, 213 Williams, P.J., 13, 34, 35 Williams, S.J., 6, 90 Willis, A.C., 14, 13 Willoughby, C.A., 1, 27; 5, 209 Wilshire, J.F.K., 7, 22 Wilson, D.W., 15, 272 Wilson, G.D., 15, 590 Wilson, L.Y., 2, 55 Wilson, P.D., 15, 3 16 Wilson, R.M., 15, 217 Wilson, T., 12, 47 Wine, P.H., 3, 96; 5, 174 Wingen, L., 3, 93 Winkler, H.J., 6, 82 Winkler, U., 6, 102 Winn, D.T., 2, 137 Winter, J.E., 5, 159 WinLer, M., 4, 231 Wipf, P., 1, 93; 15, 84 Wirz, J., 6, 89; 9, 48 Wisedale, R., 10, 51 Withers, S.G., 1, 8 Witting, P.K., 4, I 19 Wittington, B.I., 13, 63 Witulsh, B., 14, 121, 215 Witzenbichler, W., 2, 65 Wladislaw, B., 15, 376 Wladkowski, B.D., 10, 64 Wlostowska, J., 6, 43 Wmkler, J.D., 3, 83 w o , s., 9, 33 Wocadlo, S., 15, 261 Wodzinska, M . , 5, 48 Woerpel, 1, 107 Wojnarovits, L., 3, 62; 4, 265 Wolf, D., 13, 24 Wolf. M.A., 13, 70

Wolt'e, M.M., 14,118 Wolleuweber, M., 4, 145 Wong, K.K., 3, 146 Wong. M.W.. 3, 112; 6, 75; 7, 110; 1 1 , 8; 15, 263 Wonner, A,, 9, 89; 15, 426 Wood, A.J., 1, 62 Wood, J.L., 15, 479 Wood, K., 15, 366 Worrall, J., 15, 573 Wozniak, M., 7, 38 Wright, M.A., 15, 521 Wu, H.-M., 14, 74 Wu, J., 4, 241 WU, J.Q., 3, 107-109 WU, S.-H., 14, 74 Wu, T., 2, 19 WU, Y.-D., 5, 61, 215; 13, 68b Wu, Z., 15, 594 Wubbels, G.G., 7, 52; 15, 12 Wurthwein, E.-U., 15, 309 Wyatt, J.L., 4, 6 Xi, Z., 15, 528 Xia, C., 2, 31 Xia, C.-Z., 2, 114 Xia, D., 2, 31 Xia, D.-H., 2, 114 Xia, H., 15, 576 Xianming, H., 10, 31 Xiao, H.M., 1, 38, 39 Xiao, L., 2, 183 Xidos, J.D., 14, 193 Xing, G., 3, 97; 5, 173 Xiong, Y., 15, 576 x u , c., 1, 10 Xu, D., 2, I 6 Xu, J., 3, 82 Xu, L.-H., 13, 44 Xu, R., 4, 241 Xzamaschikov, V.V., 2, 109 Yabanouchi, N., 15, 532 Yabe, A., 4, 260 Yadav, A,, 15, 172 Yadav, N.S., 15, 71 Yadav, V.K., 15, 172 Yamabe, S., 1, 42; 12, 63 Yamada, H., 3, 54 Yamada, S., 6, 92; 15, 323 Yamagishi, T., 15, 253 Yamaguchi, H., 7, 1 18 Yamaguchi, K., 3, 156 Yamaguchi, M., 8, 33 Yamaguchi, Y., 6, 7 Yamaji, K., 15, 243 Yamakado, N., IS, 451 Yamakawa, M., 1, 96; 11, 105 Yamakoshi, H., 14, 84 Yamamoto, H., 2, 20, 127; 11, 96: 14. 20. 52. 200: 15. 122. 552,599

YdllXdIllotO, K., 2, 143; 9 , 41; 14, 27; 15, 323, 575 Yamamoto, S., 5, 21 2; 7, 99; 11,113

Yamamoto, Y., 1, 104; 13, 53; 14, 177; 15, 407, 49 1 , 563, 5 64 Yarnanaka, H., 13. 86 Yamane, M., 7, 113; 12, 61; 14, 127 Yamano, E., 4. 28 Yamasaki, K., 6, 36 Yamashita. Y., I, 41; 4, 197, 198; 15, 34,490 YanMklkd, H., 1, 85; 4, 191 Yamato, M., 6, 36, 68 Ydniazaki, S., 2, 204; 14,27; 15, 575 Yamazaki. T., 8, 34 Yan, C.-C.. 3, 35 ydll, G., 15, 115 Yan, G.S., 15, 117 Yan, H., 8, 45 Yan, T.-H., 1, 71, 72; 11, 40, 44

Yanagisawa, M., 15, 125 Yanakawa, M., 15, 45 1 Yang, B., 15, 91 Yang, C., 10, I14 Yang, C.-M., 1, 80 Yang, C.C., 2, 8 Yang, J.-P, 1, 17 Yang. K., 2, 198 Yang, L., 3, 179 Yang, L.L.-N., 9, 42 Yaiig, M.G., 1, 67: 11, 28 Yang, S.S., 14, 137 Yang, T., 15, 504 Ydllg, T:H., 1, 166 Yang, X.-P., 1, 146; 5, 83 Yang, Z.-C., 5, 62 Ydllg, Z.Y., 1, 92; 4, 248 Yw. C:E, 4, 136 Yao, Q., 3, 1 I ; 15, 256 Yaounanc, J.J., 12, 74 Yarosh, A.A., 14, 207 Yarwood. T.D., 11, 87 Yashima, T., 15, 487 Yashiro, M., 2, 151 Yashunsky, D.V., 15, 413 Yaslak, S., 15, 265 Yasui. K., 1, 99 Yasui, M., 15, 433 Yasui, S., 4, 103 Yates, B.F., 15, 293, 294 Yates, P.C., 9, 22 Yato, M., 8, 6 Yatsugi. K., 10, 80, 81, 84, 85, 96

Yau, Q., 3, 10 Ye. D.. 10. 114 Yee. H., 5, 17

Author Index Yeh, S.-M., 1, 2; 11, 101 Yeo, S.K., 15, 130 Yin, C., 2, 47; 13, 20 Yli-Kauhaluomd, J.T., 14, I 18 Yliniemelii, A., 15, 324, 325 Yoh, S.-D., 2, 42, 43; 10, 107 Yokogawa, K., 15,28 Yokomatsu, T., 15, 253, 495 Yokoyama, A., 12, 55 Yoneda, R., 15, 178, 296 Yonemochi, E., 2, 143 Yonezawa, S., 8, 20 Yoo, J.U., 5, 161 YOO,K.-H., 2, 32; 15, 87 Yoon, C.M., 12, 9 Yoon, K.S., 3, 27, 33 Yoon, S., 7, 117 York, C.. 1, 119; 8, 35 Yoshiaki, M.. 15, 274 Yoshida, H., 3, 80; 4, 167 Yoshida, M., 4, 80 Yoshida, N., 15, 448 Yoshida, T., 2, 127; 7, 99; 11, 113; 15,532 Yoshida, Y., 15, 27, 41 9, 495 Yoshidome, R., 6 , I 3 Yoshihara, M., 4, 103 Yoshikawa, N., 15, 448, 538 Yoshikawa, Y., 4, 83 Yoshimatsu, M., 9, 68; 11, 136; 15, 443 Yoshimurd, T., 2, 204 You, x.-Z., 1, 31 Young, A.R.. 3, 36 Young, D.J., 15, 339 Young, M.A., 15, 535 Young, R.N., 15, 371 Youngs, W.J., 7, 29 Yousi, Z., 8, S O Yu, C.-H., 12, 45 Yu, H., 6, 69 Yu, M., 1, 17 Yu, S., 2, 22, 46; 8, 29; 15, 386 Yu, T., 3, 85 Yuan, T.-M., 1, 2; 11, 101 Yuan-Pern, L., 3, 197 Yueh, W., 4, 124, 125; 14, 1 08 Yufit, D.S.. 7, 106 Yui, S., 10, 25 Yumin, L., 2, 64 Yun, K . 3 , 11, 51 Yung, J., 9, 28 Yurkovskaya, A.V., 4, 239 Yusupova, L.. 10, 53

59 1 Zdgari, A,, 15, 584 Zaim, M.H., 15, 376 Zdjc, B., 15, 368 Zakharkin, L.I., 15, 200 Zaks, A., 5, 79 Zaman, K.M., 5, 212 Zaman, M.B., 8, 17 Zanardi, G., 3, 57 Zanda, M., 15,446 Zander, M., 9, 60 Zang, Y.-R., 1, 146; 5, 83 Zanirato.P., 14, 34 Zaragozd,F., 15, 295 Zdd, S.Z., 3, 43, 44; 15. 473 Zarkadis, A.K., 4, 20 Zavada, J.. 7, 36 Zavitas, A.A., 3, 79 Zavoianu, D., 1, 94; 11, 100; 13, 99 Zxiravkovski, Z., 11. 117; 14, 31, 32, 92, 93, 129, 130, 147, 152, 153, 155, 156, 166, 179, 187 Zdrojewski, T., 11, 55; 15, 23 1 Zecchi, G., 15, 10 Zee, S.-H., 2, 49 Zefirov, N.S., 9, 8, 74; 15, 429, 465 Zehner, R.W., 12, 43 Zemribo, R., 14, 19 Zeng, H.-W., 5, 4, 5 Zeng, X.-C., 2, 126 Zenner, J.M., 7, 74 Zerhetto, F., 4, 37 Zewail, A.H., 4, 228 Zgierski, M.Z., 4, 37 Zhan, W., 3, 28 Zhang, B., 2, 47; 13, 20 Zhang, C., 14, 58 Zhang, C.H., 15, 364 Zhang, H., 5, 162, 196; 7, 42 Zhang, H.-M., 4, 33,34 Zhang, M.-X., 3, 179 %hang, Q., 2, 47; 12, 34; 13, 20; 15.230 Zhang, S., 2, 15, 91; 11, 75, 1 1 I ; 13, I05 Zhang, W., 3, 131 ; 15, 582 Zhang, X., 5, 28; 6, 81; 15, 288 Zhang, X.-M., 2, 15; 4, 22; 11, 25, 75, 1 I 1 Zhang, Y., 1, 31 %hang, Y.-K., 4, 69, 70 Zhang, Y.X., 1, 146; 5, 83 Zhao, C.-C., 6 , 42 Zhao, C.-X., 4, SO

Zhao, D., 1, 12a, 12b; 15, 306 Zhao, G.X., 2, 125 Zhao, H.-X., 1, 146; 5, 83 Zhao, K., 10, 52 Zhao, L., 4, 73, 74; 5, 140, 141; 6, 83 Zhao, M., 15, I88 Zhao, R., 3, 98 Zhao, X.-Z., 1, 146; 5, 83 Zhao, Y., 11,24; 15, 504 Zharov, I., 12, 76; 14, 28 Zheglova, D.K., 15, 610 Zheng, B., 15, 527 Zhitnev, Yu.N., 5, 133 Zhou, H., 6, 24: 15, 1 15 Zhou, M., 2, 98 Zhou, W.-S., 5, 62 Zhou, Y.P., 2, 125 Zhou, Z., 3, 169; 11, 22 Zhu, B.Y., 2, 125 Zhu, C., 2, 82 Zhu, J., 7, 48-50; 13, 100 Zhu, L.-M., 11, 132 Zhu, Z., 1, 66; 5, 102; 14, 1 15 Zhulin, V.M., 14, 180 Zieger, H.E., 9, 33 Ziegler, F.E., 3, 22 Zielinska, A., 12, 7 1 Zielinska, G., 2, IS9 Zielinski, M., 2, 159; 12, 71 Ziglio, C.M.. 5, 70 Zimincr, H., 15, 102 Zimmerman, H.E., 15, 272 Zimmermann, G., 4, 256-258; 6, 34, 70; 15, S7, S8 Zinko, B., 15, 85 Zipse, H., 2, 156; 4, 174; 12, 41 Zlmney, B., 14, 121 Zolotukhin, M.G., 15, 43 Zona, T.A., 4, 98 Zope, U.R.. 14. 162; 15, 560 Zou, P., 2, 126 ZOU,X.-Z., 7, 26 Zou, Y., 8, 51 Zubarev, V.E., 4, 59 Zuccarelli, M., 14, SO Zucco, C., 1, 143; 13, 74 Zuffle, S., 4, 17 Zuikova, S.A., 2, 103 Zuloaga, F., 14, 191 Zumel, C.L., 1, 16 Zurbritskii, M.Yu., 13, 14 Zvilichovsky, G., 15, I05 Zwanenburg, B., 11, 76a, 76b; 13, 100; 15,344, 373, 557 Zyk, N.V., 15, 429 Zylher, J., 14. 184

Subject Index

A1 mechanism, 2 A2 mechanism, 60 A A C mechanism, ~ 41 A a i mechanism, 42 Abramov reaction, 19 Acepentalene dianions, 307 Acetals, 2 formation, 2, 13 Acetonitrile, acidity of, 305 Acetophenones, halogeno, 161 Acetylene, protonated, 260 Acetylene, trimerization of, 427 Acetylenes, perffuoroalkyl, 427 Acetylenes, perffuorooxaalkyl, 427 Acid anhydrides, 45-48 Acid halides, 48 Acidity scales, 39 Acidity, carhon acids, silyl effects, a-,321 gas-phase, 303,328, 329 kinetic, of fluoroorganics, 304 of N-H bonds, 39 Acridine carboxaldehyde, 9, 20 Acridine orange, oxidation of, 193 Acrylates addition of lithium enolates, 391 addition reactions, 383 anionic polymerization, 395 cycloaddition of, 408 hydroformylation, 373 Activation entropy, 391 Acylation, aromatic, 249. 254 Acylation, diastereoselective, 9 Acylium ions, formation, 45 Adamantanes, 505 Adamantanones, reduction, 27 Adamantyl cations, 271

Adamantyl derivatives, nucleophilic substitution, 28 1 radical reactions, 102 rearrangement, 102 Adamantyl radicals, reactivity towards carbanions, 320 Adamantylidene adamantane, 364 Addition reactions, conjugate addition, 363 diastereoselective, 1, 4, 6, 9, 11, 16, 17, 19 enantioselective, 5, 12, 15, 16, 18 intramolecular, 17 Addition to alkenes, electrophilic, 363-38 1 Addition, I ,2-dipolar, 392 Addition, 1,3-dipolar, 384 Addition, 1,4-dipolar, 367, 387,392 Addition, 1,6-dipolar, 367 Addition-elimination reactions, 26, 279, 344, 358,372,389 Agarospirol, 499 Aldehydes, addition to a,b-unsalurated, 328 addition, 7, 11, 13, 17 amino, a-, 9 base catalysed decomposition, 235 carbonylation, 29 halogenation, 30 hydration, 20, 26 oxidation, 26, 184 protonation, 29 Aldol condensation, 9-13 aza-aldol, 12 catalysis by Lewis acids, 308 diastereoselective, 9

593

diastereoselectivity, 3 10 enantioselective, 10, 3 12 intramolecular, 3 I0 mukaiyama aldol, 1 I , 12 of thioimide enolates, 312 Alkaloids formation of lycorine alkaloids, 244 tetrahydroisoquinoliies, 442 tropane alkaloids. 461 Alkaloids, rearrangement, 523 Alkanes, nitroxylation of, 273 Alkenes, bromination, 365 deuterioformylation, 373 epoxidation, 184, 186, 198 radical cations from, 157 Alkenyl metals, 489 Alkenylation, 253 Alkylation, aromatic, 252-254 by chloroalkanes, 252 using alkenes, 252 Alkylation, intramolecular, 254 Alkylation, of nitrile anions, 316 Alkynes, addition, of alkenes, 378 amination, 394 cycloaddition, 427 hydroboration, 378 hydromagnesation, 377 hydrostannylation, 377 oxidative chlorination, 377 Allene dication, 267 Allenes, 497 cycloaddition, 402 formation, 540 heterocyclic, 470 Allenic selenoates, 542 Allyl alcohols, oxidation, 181 Allyl ethers, elimination reactions, 340 Allylic alcohols, 16 aziridination, 370 epoxidation, 186

Subject Index Allylic alcohols (conr.) homo-, 17 protonation, 260 Allylic carhon, nucleophilic displacement at, 280, 28 I Allylsilanes, 1 Allyltributylstannane, 1 12 Alosetron, 487 Altemicidin, 499 Amhident electrophiles, 290 Ambident nucleophiles, 306 nitrosation of, 332 AM1 method, 24 Amidcs, hydrolysis, 50, 51 oxidation, 51 Amidines, 452 Amines, deamination of, 137 Amino acids, unnatural, 477 unsaturated, 465 Aminolysis, 37 Amphihydric compounds, 328 Angelicin, 464 Anilines bromination, 250 iodination, 250 nitration, 252 Anisole, acylation, 254 nitration, 256 Annulation reactions, 254 Annulation, 10 Annulations, [3+4], 26 [3+5], 26 Anomeric effect, 1, 2 ANRORC mechanism, 240 Anthracenes, 162 Anthracenophanes, Diels-Alder reactions, 427 Anthraquinones, 18, 159, 202, 254 Antihydrophobil effects, 13 Apigeninidin, 540 Appcl's salt, 455 Arencsulphinic acids, addition to ethenylarenes, 368 Arenium ions, 249, 252, 255, 266, 267 Aromatic substitution, radical, 108, 109 Arrhenius plots, upward curvature, 328 Arylation, of benzaldehyde, 253 Arylium ions, 445 A s ~ 2mechanism, 2 Asymmetric dihydroxylation, 189 Asymmetric epoxidation, 186, 188,203

Asymmetric induction, 4, 12, 15, 16, 313, 317, 319, 373 Ate complexes, 489 Atomic oxygen, 201, 202 Autoacceleration, 368 Autoaromatization, 98 Autoxidation, 201, 202 of illdehydes, 26 o i alkanes, I37 of alkenes, 202 of carotene, 137 of ethers, 202 of hydrocarhons, 202 Azadienes, 369 formation of, 457 Azadirachtin, 527 Azaphosphates, 533 Azapinoquinones, 467 Azapterocarpans, formation of, 407 kzdspirodienones, 445 Azepines, 2 18, 225, 450 dihydro-, 491 formation from nikenes, 224 from nitrenes, 218 heterocyclic ring annulated, 44 1 Azetidine, pyrolysis of, 352 Azetidines, 532 Azides, cycloaddition, 403 imidoyl, 523 siloxy, 523 vinyl, carbanion addition to, 332 Azidohydrins, 21 rearrangement, 525 Aziridination, 222 of allylic alcohols, 370 Aziridines, 218, 220, 535 amino-, 457 formation, 5 keto-, 478 ring-opening, 94, 26 I, 286, 287 vinyl-, 478 Aziridinium imides, 533 Aziridinium intermediates, 370 Aziridinium ions, 281 ring-opening, 287, 532 Azoalkanes, photolysis of, 164 Azocine, 425 Azocinoquinones, 467 Azodicarhoxylic ester, rearrangement, 539 Azoisopropane, thermolysis of, I68 Azoxybenzene, from nitrobenzyl sulphones, 3 18

Azulenes, nucleophilic aromatic suhstitution in, 235 radical cations, 153, 157 rearrangement, 494 B ~ c mechanism, 2 41, 42 B ~ c mechanism, 3 43 Baeyer-Villigcr reaction, I 08, 526 Balanol, 523 Baylis-Hillman reaction, 3 12 Beckmann rearrangement, 7, 523 gas-phase, 523 Belousov-Zhabotinskii reaction, 186 Benzazecine esters, 539 Benzazete, 347 Benzene derivatives, gas-phase acidities, 329 Benzene, protonated, 266 Benzenium ions, 255, 445 Benzilic acid rearrangement, 499 Benzobarrelene, oxidation of, 517 Benzocoumarins, reaction with Grignard reagents, 325 Benzocyclobutenes, thermolysis of, 419 Benzocyclobutenone, 486 Benzofuranols, 464 Benzofurans, 227 rearrangement, 394 Benzoic acid. lithiation of, 323 Benzoic anhydrides, 58 Benzoin condensation, 331 solvent effects on, 3 17 Benzonitriles, 161, 162 Benzonitrile, formation of, 216 Benzopyrenes, protonition of, 267 Benzosuberones, nitration, 252 Benzothiazoles, addition to alkenes, 379 Benzothiophenes, 416 Benzotriazoles, lithiation of, 323 Benzoxazepinones, 525 Benzoxazepins, 410 Benzoyl fluorides, aminolysis, 58 Benzvalene, 459 Benzyl cations, 261,262 Benzylation, 254 Benzylide salts, rearrangement of, 316 Benzynes, 163, 243, 244, 354, 358

595

Subject Index as intermediates in decomposition of, benzotriazines, 347 cycloaddition, 244 reaction with alcohols, 244 zirconocene complexes of, 244 Bergman reaction, 98 Betakes, cyclopropenylium, 266 thiazolium betaines, 457 Bibenzyl, nitration, 251 Bicycloalkanones, irradiation of, 138 Bicyclobutanes, 395 Bicyclo[l.l .O]butane, 351 Bicyclo[l.l.O]butanes, 363 Bicyclo[l. 1.1]pent- I-yl radicals, 105 Bicyclo[2.1 .O]pent-2-enes, 485 Bicyclo[2.1 .I]hex-2-enes, 430 Bicyclo[2.1 .I]hexyne, 430 Bicyclo[2.2.0]hexanes, 399 Bicyclo[2.2. I ]hept-2-enes, 4 8 4 , s 11 Bicyclol2.2.lIhept-5-en-2ones, 516 Bicyclo[2.2.1]hept-S-en-3ones, 533 Bicyclol2.2. I]heplan-2-ones, 527 Bicyclo[2.2.1]heptanes, 28 I , 413,526 Bicyclo[2.2.l]hepten-2-yl cations, 5 14 Bicyclol2.2.1 ]systems, 529 Bicyclo[2.2.2]octadinenols, 472 Bicyclo[2.2.2]octane-2,5diones, 304 Bicyclo[2.2.2]octanediones,24 Bicyclo[2.2.2]octanes, 41 3, 418,533 Bicyclo[2.2.2]octatrienes, 5 17 Bicyclo[3.1 .O]hexa-3, 5-dien2-ones, 214 Bicyclol3. I .O]hexanes, 347 Bicyclol3.1 .I]hept-2-yls, 516 Bicyclo[3.1 .I]heptanes, 281, 516

Bicyclo[3.2.0]hcpt-2-enes,

484,486 Bicyclo[3.2.0]heptanes, 508 Bicyclo[3.2.0]heptanones,94 Bicyclo[3.2.l]oct-3-en-2-ones, 408 Bicyclo[3.2.1 ]oct-6-en-2-ones, 5 10 Bicyclo[3.2.Iloctanes, 5 16, 533 Bicyclo[3.3.0]octanes, 406

Bicyclo[3.3.0]octanes, formation of, 404 Bicyclo[4.1 .O]hept-4-enes, 529 Bicyclo[4. I .O]heptanes, 484 Bicyclo[4.2.0]oct-2-en-7-ones, 536 Bicyclo[4.2.0]octenes, 399 Bicyclo[4.3.0]nonanes, 406, 42 1

Bicyclo[4.4.0]decen-2-ones, 510

Bicyclo[S. 1.O]oct-1-ems, 495 Bicyclo[5.1 .o]octa-2,4-dienes, 47 1 Bicyclo[5.3. I]undccenones, 472 Bicyclo[5.4.0]undecanes, 472 Bicyclo[6.3.0]undecanes, 479 Bicyclo[6.3.0]undecatrienes, 432 Bicyclo[7.3. Ilenediynes, 491

Bicyclo[8.3.O]trideca-6,10dienes, 5 18

Binaphthalenes, 25 Biradicals, 133, 162-167 Bis(cyclohexadienes), 101 Bis(trimethylsily1)aamantylidene germene, 402 Bisacylation, by phthaloyl dichlorides, 254 Bisdialine, addition of singlet oxygen, 420 Bond dissociation energies, 307 homolytic, 328 Bond dissociation enthalpies, 32 I Borates, enol borates, 527 Boron enolates, aldol-addition, 312 Borylmethylboranes, 225 Boullon-Katritzky rearrangement, 459 Brefeldin-A, 476 Brendene, 5 17 Bromination, electrophilic aromatic, 250 electrophilic, 363, 367 steroselectivity of, 363 Bromodifluoromethylimides, 227 Hromonium ion, 363 reversibly formed, 364 Bromosuccinimide, N bromination by, 251, 332, 367 BrQnsted equation for: aminolysis of esters, 37 elimination reactions, 341, 344 hydrolysis of esters, 41, 339

nitronate ion formation, 329 nucleophilic aromatic substitution reactions, 237, 239 reaction: of arenesulphonates with phenoxide ions, 79 of phenolate ions with acetic anhydride, 58 phosphonates with phenoxide ions, 73 thiolytic cleavage of 9anilinoacridine, 56 transesterification, 48 Brook rearrangement, 92, 501 retro-, 503 Bunnett and Olsen parameter,

60

Bunnett and Olson parameter, 41 Bunnett w parameter, 4 1 Butadiene, 303 Diels-Alder reactions, 423 Butadienes, Did-Alder reactions, 41 5 Butadienes, dimerization of, 414 Butadienyl anions, 304 Butadienylthionium ions, 518 Butyl cation, rerf- 260 Calixarenes, 221 Calix[4]resorcinarenes, 446 Calix[6]resorcinarenes. 447 Camphorenone, 5 I9 Cannizaro reaction, 26 Carbacephems, formation of, 416 Carbamate anions, 59 Carbamates, elimination reactions, 337 formation, 48 hydrolysis, 49, 337 Carbanions, acetylenic, 498 alkenyl, 498 alkyl, 498 allenyl, 498 allylic, 305 benzyl, 503 dianions, ambident nucleophilicity, 306 from dimesitylphenylboranes, 321 ethenyl, 303 ethynyl, 303 fluorination of, 332 from dihydroanthracenes, 304 from dioxanes, 322

596 Carbanions (cont.) from nitriles, 315 MO calculations on, 303305 nucleophilic substitution by, 294 phosphorus stabilized, 483 reaction with imines, 331 reactions of, 308 silicon stabilized, 321 silyl, a- 321 stability and structure, 303308 sulphonyl, ain Michael addition, 317 sulphur stabilized, 305 vinyl, 500 Carbapenems, 473 Carbenes, abstraction reactions, 214, 223 acetylenic, 214 addition reactions, intermolecular, 214, 217222 intramolecular, 21 5 addition to. alkenes, 215 alkylidene, 21 8, 223, 224 aminohydroxy, 214 carhomethoxyaryl, 226 carboranyl, 215 cyclohexadienylidene, 2 14 cyclohexylidene, 224 cyclopropylidene, 225 dialkoxy, 223 dialkyl, 215 diaryl, 220,226 diboryl, 225 dicarbomethoxy, 2 15 difluoro, 168, 519 dihalo, 216, 220, 227 electrochemically generated, 220 fluoro(ketenyl),213 from a-elimination, 223 from alkynes, 218 from cyclopcopanes, 2 14 from cyclopropenes, 220 from diazirines, 214, 225 from diazo compounds, 213, 214, 215, 217, 219,220,223, 226, 227 from dihalides, 217, 218 from oxadiazolines, 217 from thiones, 226 generation, 216-21 8 imidazolin-2-ylidene, 21 5 in the synthesis of tertiary alcohols, 223 insertion reactions, 214, 215, 218, 223

Subject Index keto-, 477 lifetimes, 214, 225 matrix isolation, 213, 215, 216 methylene-, 214, 219 nitroso, 217 nucleophilic, 223 phenyl(azido), 217 phenylchloro, 226 phosphino, 220, 533 phosphinophosphonio, 227 propargylic, 214 protonation, 226 reaction with alcohols, 225, 226 alkenes, 218, 219, 226 alkyl halides, 226 alkynes, 217, 224 arenes, 222 azides, 226 cyclic anhydrides, 223 cyclopentadienes, 2 19 disulphides, 21 8 electrophiles, 226, 227 enolates, 227 ethers, 216 fullerenes, 220 hydrogen chloride, 225 imines, 220 indoles, 220 ketones, 217 nitriles, 220 nucleophiles, 226, 227 styrene, 215 thioethers, 2 16 vinylethers, 220 reactivity, 213-216 rearrangements of, 213, 214,215, 216,217, 219,224, 225 siloxy, 224 singlet, 477 structure, 2 13-2 16 transition metal complexes, 213, 215, 220, 224, 528 trifluoroethoxy, 219 trifluoroethylidene, 214 vinyl, 220, 224 vinylidene-, 224 Carbenoids, 16 chromium, 224 copper, 2 IS, 220, 227 lithium, 223, 227 rhodium, 215, 220, 223, 227 vinyl, 477 Carbinolamines, 4, 8 Carbodi-hides, 54 Carbolithiation, 392 Carbonium ions, adamantyl, 271

alkoxy-, 42 antiaromatic cations, 273 aromatic, 266 aryl cations, 267-269 azido, a-,262 azo, 269 azulenyl, 263 benzhydryl, 262,263 benzyl, 261,262 bicyclobutonium ion, 27 I bridged, 271-273,516 bridgehead, 269, 270 carbomethoxy, a - , 265 carbonyl, 506 carbonyl, a-, 266, 380 cross-hyperconjugation in, 273 cyclopentenyl, 260 cyclopropylrnethyl, 507 destablilized, 265-267 dications, 20, 267, 273-296 dicyclopropylcarbinyl, 269 diffusion clock for, 263 dirnethoxyalkyl, 43 ethyl, 260 ethynyl, 269 from bicyclic and polycyclic systems, 269273 gas-phase reactions of, 260 homocubyl, 271 hydrazonium, 523 imino, a-, 265 in elimination reactions, 344 in molten salt media, 260 matrix isolation, 259 NMR spectra, 27 1 nobel lecture address on, 259 norpinyl, 272, 516 oximino, a-, 265 0x0-, 3, 25, 263 pentadienyl, 260 perfluoroalkyl, CI-, 266 prop-2-ynyl,268 reaction with nucleophiles, 260 reviews, 259 short-lived, 259 stabilities, 259 stabilization by silicon, 259, 260 stable, 262 sulphur-stabilized, 263 theoretical calculations, 259, 260,271 thio, CY-, 2 thioformamidyl, LY-, 266 tnaryl, 263 trityl, 262, 263

Subject Index vibrational frequencies of, 27 1 Carbonyl group, I3C chemical shift, 23 electrophilicity, 10 hydride affinity, 15 protonation, 20, 23 Carbonyl oxides, 217 Carbonyl oxides, cycloaddition of, 412 Carboranes, cyclic carboranes, 379 Carbovir, 505 Carboxonium ion, 20 Carboxylic acids, 13 hydroxy, Carroll rearrangement, 465 Carvenone, 506 Caryophyllene, rearrangement ot; 520 CaVdlysed reactions of carboxylic acid derivatives, association prefaced, 61 -67 enzymic, 69-7 1 in aprotic solvents, 58, 59 intermolecular, 38-57 intramolecular, 60, 61 metal ion promoted, 67 CdVdlySiS, alkali metal halides, 284 amines, in chlorinationn of phenol, 250 aminium salts, in cycloaddition reactions, 40 1 aminoalcohols, in organozinc reactions, 325 antibodies, in Dieckman cyclization, 331 antibodies, in proton transfer, 328 base, in nucleophilic aromatic substitution, 233 bifunctional in: aldol condensation, 10 boron trifluoride in, asymmetric reductions, 204 boryl catalysts, in aldol reactions, 3 12 caesium fluoride, in Claisen rearrangement, 464 chromium compounds, in decomposition of peroxides, 117 cobalt(I), in ene reaction, 495 copper in: nucleophilic aromatic substitution, 238

o-,

597 diary1 ureas, in Claisen rearrangements, 463 enantioselcctive, 1 1 enzymic in, Baeyer-Villiger oxidation, 526 Claisen rearrangement, 463 reactions of carboxylic acid derivatives, 69-7 1 enzymic, by: Diels-Alderase, 414 esterases, 70 lactate dehydrogenase, 27 lipases, 70 penicillin enzymes, 70 serine proteinases, 69, 70

urease, 70 general base, in: elimination reactions, 341 general-acid, in: reduction of aldehydes, 26 intramolecular, 39, 60, 61, 298 intramulecular, in: cycloaddition, 406 iron(II1) chloride, in hydro. chlorination, 368 iron(II1). in rearrangement of trioxanes, 486 lanthanide triflates, 10 Lewis acid, in: aldol reactions, 308 cycloaddition, 407 Diels-Alder reactions, 414,422 FriedelLCrafts reactions, 252 Michael reactions, 383 pinacol rearrangement, SO5 reactions of aziridines, 281 ring-opening of vinyloxiranes, 327 mercury(I1) acetate, in aromatic nitration, 25 1 metal ion, in: Belousov-Zhabotinskii reaction, 186 reactions of caboxylic acid derivatives, 67 micellar, in: nucleophilic aromatic substitution, 237

reactions of carboxylic acid derivatives, 6 1-67 montmorillonite, in carbocation rearrangements, 516 nickel(0) complexes, 375 nickel, in nucleophilic aromatic substitution, 23 8 nucleophilic in: anionic polymerization, 395 organoboranes, in rearrangement of epoxides, 530 organolanthanides, in hydrosilylations, 376 palladium(0) complexes, in Claisen rearrangement, 463 in bydrosilylation of styrenes, 373 in rearrangements of vinyloxiranes, 531 in sulphoxidesulphinamide rearrangement, 480 palladium(I1) salts, in Claisen rearrangement, 468 in Claisen rearrangements, 463 palladium, in nucleophilic aromatic substitution, 238 phase-transfer, in nucleophilic aliphatic substitution, 296, 297 nucleophilic aromatic substitution, 236 phosphine, in cycloaddition reactions, 405 phosphonium salts, 284 rhodium(1). in rearrangement of phenylhydrazines, 439 rhodium(II), in reactions of diazoketones, 477 in rearrangement of cyclopropenes, 493 ruthenium in, rearrangement of acyclic olefins, 372 samarium(l1) iodide, 538 silver ion, in: cycloaddition, 41 1 nucleophilic aliphatic substitution, 281 taddol, in addition to aldehydes, 325

Subject Index

598 Catalysis (cont.) tantalum oxide, in Beckmann rearrangement, 523 tetracyanoethylene, 18 tetrathiafulvalene, in electron transfer, 148 titanium trichloride, in Diels-Alder reactions, 427 titanocene dichloride, 377 transition metal complexes in, addition of alkenes to alkynes, 378 aldopentose rearrangement, 527 cycloaddition reactions, 430 deuterioformylation of hexene, 373 Diels-Alder reactions, 414 epoxidation, 374 Smiles rearrangement, 440 transition metal: in cycloaddition, 408 in disproportionation reactions, 461 zeolites, 442 in Fries rearrangement, 442 zeolites, in acylation of anisole, 254 zeolites, in alkenylation, 253 zinc chloride, in aza-Cope rearrangement, 473 Catalytic antibodies, in DielsAlder reactions, 414 Catechols, 1 17 Catenanes, 447 Cedrene, 269, 520 Ceftazidime, 55 Cephalosporins, 5.5 Chalcogenides, 155 Chalcones, amination, 382 Charge-transfer complexes, 233 Chelate control, 12 Chelation control, 9, 13, 17, 18 Chemiluminescence, 117 Chiral auxiliaries, 325, 476 in enolate alkylation, 315 in enolate alkylations, 3 19 Chlorination, electrophilic aromatic, 250 Chlorosulphite anion, 78 Chlorpromazene, oxidation of. 150

Chromenes, SO1 Chymotrypsin, 69 CIDNP, 117, 144, 166 Cieplak model, 27, 364, 382 Cinnarnates, elimination reactions, 339 Cinnamic acid, oxidation of, 190 Citric acid, decomposition of, 47 Claisen rearrangement, 462470 amino-Claisen, 466 asymmetric, 463 aza-, 468 ester enolate-, 464 iodonio-, 464 ketal-, 466 orthoester-, 466 thio-, 469 vinylogous acetylenic, 463 zwitterionic, 467 Cobaloximes, 96 Collision induced dissociation mass spectra, 214 Common-ion inhibition, 6 Conduramine E, 468 Cope rearrangement, 4 7 1 4 7 5 homo-, 433 laser-pulse mediated, 47 1 monoaza, 472 oxy-Cope, 471,472 phospha-, 475 Corannulene anions, 304 Corannulene tetraanion, 306 Coronene, 306 Corranulene, bowl-to-bowl inversion, 304 Cram’s rule, 11, 16 Cross-interaction constants, 37, 58, 79 Crown ethers, 262 in nucleophilic aliphatic substitution, 58 Cubenene, 5 19 Cuparenone, 496 Cuprates, 392 Cnrtins rearrangement, 523525 Cyanohydrins, 17 Cycloadditions, 1,3-dipolar, 403405,407409,412 2+1,402 2+2 399,399401,493 2+2+2,427,495 2+3, 403413,404,405. 410 2+4 149, 399,4 13-427, 430,494, 495, SO4 3+3+2,429 4+3 220,429

4+4,430 5+2,430 6+2 461 intramolecular, 402, 404, 408,412,413 metal catalysed, 408 Cycloalkanotetrahydrop yridines, formation of, 418 Cyclobutadienes, 224 oxidation, 202 Cyclobutane, formation, 399 Cyclobutane, 1, 2-digerma-, 359 Cyclobutanes, rearrangement of, 533 Cyclobutaquinolizidones, formation of, 40 I Cyclobutene, 1-azabenzo-, 347 Cyclobutenes, formation of, 399 ring-opening, 348, 493 Cyclobutanone, radical cation, 158 Cyclobutenones, rearrangement of, 534 Cyclohutenyl cations, SOY Cyclocondensation reactions, 369 Cyclodextrins, 41, 442 catalysis by, 10, 29, 65, 401, 414 Cycloheptadienes, formation of, 430 Cycloheptadienones, 24 Cycloheptaquinazoline, 425 Cycloheptatriene, 24 Cycloheptatrienes, formation of, 430 Cyclohexadienes, cycloaddition, 41 1 Cyclohexadienones, 16 rearrangement, 445 Cyclooctadiene, 1,3-, 222 Cyclooctatetraene, radical ions, 151 Cyclopenenyl sulphones, conjugate addition to, 393 Cyclopentadienes, addition, of phenylenediamine, 369 Diels-Alder reactions, 427 Cyclopentafluorene, 2 14 Cyclopentenones, addition, 383 Cyclopentenyl cations, 260 Cyclophanes, 23 1 Cyclopropanation, 21 8, 222 Cyclopropane, acidity of, 305 Cyclopropanes, bromination of, 271 formation, 217, 218, 219 photolysis, 225

Subject Index polyfluorinated, 167 protonation of, 271 ring-opening, 219, 380, 381 vinyl, 430 Cyclopropanones, Favorskii intermediates, 321 Cyclopropenes, bromination, 380 rearrangements, 530 ring-opening, 220 Cyclopropyl cations, 493 Cyclopropyl derivatives, reduction. 28 Cyclopropylcarbinyl cations, 269, 507 Diels-Alder reactions, 413 Cyclopropylmethyl radical, 232 Cycloreversion reactions, 493 Cyclotriphosphazene, rearrangement, 461 Darzens reaction, 5 Deaminations, oxidative, 203 Decarboxylation, 67-69, 103, 350,355 of benzoyloxyl radicals, 102 Decatrienes, 42 1 Decatrienylboranes, DielsAlder reactions of, 422 Demercaptalation, 525 Desoxyeseroline, synthesis of, 474 Desulphurization, 443 Dewar benzenes, 154 Diacylium ions, 274 Diadamanthane derivatives, 28 1 Dialkylzincs, amino alcohol complexation, 326 Didzene, electron transfer, 143 Diazepam, hydrolysis, 55 Diazepines, 445, 457, 461 Diazirines, carbenes from, 213, 225, 226 photolysis of, 225 Diazo compounds, decomposition, electronic effects, 118 Diazo coupling, 24 Diazomethane, cycloaddition reactions, 41 I Diazonium salts, 8 aryl cations from, 23 1 bonding in, 23 1 decomposition, catalysis of, 232 dediazoniation, 23 1 hydrodiazoniation, 114

599 Dications, cyclization of, 296 Dideoxynucleoside precursors, 468 Dieckman cyclization, catalysis by antibodies, 33 1 Diels-Alder reactions, 357 at high pressure, 415 hetero-, 422 intramolecular, 413,414, 420,422,423 inverse electron demand, 418,419 ionic, 4 1 3 4 2 7 , 4 2 2 molecular orbital calculations, 395, 41 3, 41 8, 420,424,425 of benzynes, 244,4 15 of buckminsterfullerene, 418 of carbocations, 260 of cyclohexa-l,3-diene, 41 6 of cyclooctadienes, 418 of cyclopentadienes, 419, 422 of cyclopropyl carbinyl cation, 413 of fulvenes, 425 of furan, 422 of heterodienes, 416 of stilbenes, 148 retro-, 348, 349, 351, 417, 484 solvent effects, 4 14 thiochalcone, 414 Dienea, electrophilic addition to, 363 radical addition, 106 Dienolates, 3 13 Differential scanning calorimetry, 66 Dihydroxazines, 261 Dimerization, 401 Dimroth rearrangement, 457 Dioxanes, rearrangement, 512 Dioxazolidines, formation of, 412 Dioxetanes, oxidation by, 198 pyrolysis, 352 Dioxetanes, nucleophilic aliphatic substitution 285 Dioximes, 536 Dioxines, 49 I Dioxiranes, 195-198 rearrangement, 5 17 Dioxolanes, 53 1 Dipole repulsions, 2 Diquinanes, 493 Diradical, 484, 533

Diradicaloid character, 47 1 Diselenides, 92 Disilacyclobutane, 225 Dispiro[2.2.2.2]deca-2,4-diene, 167

Dispiro[4.0.4.4]tetradeca-

11,13-dienes, 420 Diterpenes, 472 crenulide, 464 Dithiacyclohexane 1,3-dioxide, carbanion reactions, 322 Dithiafulvenes, 504 Dithiocarbonates, 83 Dithiocarbonates, aminolysis, 37 Dithioles, 469 Dithiolones, 100 DNA, radical reactions, 136 Dodecahedradienes, 152 Dopaminochrome, I37 EbelactoneA, 465 Effective charge, 38 Electrochemical reduction, 500 Electrocyclic reactions, 348, 490497 Electrocyclic rearrangements, 493 Electron transfer, 138-151,249 in reductive dehalogenation, 147 in Diels-Alder reactions, 413 in nucleophilic aliphatic substitution, 145, 293 photo-induced, 138-145 Electrophilic additions, 363381 Electrophilic aliphatic substitution, 332 Electrophilic aromatic substitution of acylation, 254 alkylation, 252-254 aromatic amines, 25 1 aromatic ethers, 25 1 aromatic hydrocarbons, 249, 25 1 heteroaromatics, 249, 254 nitration, 250-252 phenols, 250 Electrostatic interactions, 16, 27 Elemene, 465 Elimination reactions, 1,3-elimination, 347 1,4-elimination, 340 Cope, 351,354 cycloelimination, 348, 349 decarboxylation, 350, 352, 355

Subject Index

600 Elimination reactions (cont.) dehalogenation, 343 dehydration of alcohols, 353 dehydrohalogenation, 343, 344 Elcb mechanism, 45, 49, 337-340 E2 mechanism, 291, 341344 E2cb mechanism, 330 in synthesis, 353-356 ion-pair mechanism, 342 leaving group effects, 344 of acyltriazenes, 343 of alkyl halides, 350 of cinnamate esters, 339 of fluorenes, 34 I of Meisenheimer adducts, 242 of phenyl ethyl derivatives, 342 of sulphamate esters, 340 of sulphones, 340 of sulphonyl halides, 344 of sulphoxides, 340 of tosylates, 343 of triflamides, 359 of vinyl bromides, 35 1 of vinyl halides, 353 promotion by solid catalysts, 344 pyrolytic, 344-347 syn-elimination, 349 theoretical studies, 349-353 Enals, 17, 28 Enamide oxides, spectral evidence for, 196 Enamines, 5 1-cdrrangement,475 Enaminone, 23 Enaminones, I9 Enantioselective protonation, of enolates, 3 11 Ene diols, 3 Ene reactions, 201, 495, 531 imino-, 496 metallo-, 495 retro-, 351, 497 Enediones, polycyclic, 509 Enediynes. 223 Enol borinates, 9, 13 Enolate anions, addition to vinylsulphones, 391 Enolates, 13, 308-321 alkylation, 3 14 difluoro, 9 enan tioselective protonation, 311,314 Michael reactions, 308

molecular recognition of, 310 nitroxyl, 24 protonation, 25 recognition of, 22 zwitterionic, 26 Enolimine, 14, 23 Enolization, 21-25 in acetonitrile, 25 of acetic acid, 21 of acetylfurans, 22 of acylfluorenes, 21 of dihydroxyacetone phosphate, 22 of dioxybenzoin, 22 of glyceraldehyde phosphates, 22 of indan-1-one, 21 of methylacetate, 21 of nitroxylketones, 23 of phenacylpyrazines, 23 of phenacylpyridines, 23 Enols, oxidation of, 150 Enones, deprotonation of, 296 formation, 10 Entropy of activation for: electron transfer, 332 elimination reactions, 339 oxidation of sulphides, 189 Epichlorohydrins, 16 Epicubenol, 5 19 Episulphonium ions, 533 Epoxidation, 364, 374 of alkenes, 184 of allylic alcohols, 196 Epoxides, ring-opening, 282-285,530 Esters, additions to a,@unsaturated, 266, 380, 382,384 formation, 39,40 keto, @-, 13 oxygen exchange, of radicals, 96 rearrangement of, 506 transesterification, 40 Ethers, protonation, 263 vinyl, 26 Ethylenic acetals, bromination of, 366 Fdmesyl acetate, dihydroxylation of, 375 Favorskii rearrangement, 93, 321,499 Felkin model, 308 Felkin-Ahn model, 12, 27, 111, 382 Ferrier rearrangement, 521 Ferrocenyl selenides, 481

Ferrocenyl selenoxides, 48 1 Ferrocenyl tellurides, 481 Filiformin, 507 Fischer-Hepp rearrangement, 439 Fk-506, 489 Flavanoids, 117 Flowing afterglow technique, 328,329 Fluorenes, acidity, 21, 321 elimination reactions, 341 Fluorenyl anions, 139 Fluorinated benzenes, lithiation, 323 Fluorination, aromatic, 249 Fluoroacetylene, 2 13 Formyl dication, 20 Formylation, aromatic, 254 Friedel-Crafts reaction, 2, 20, 249, 252,253 retro-, 445 Fries rearrangement, 441 photo-, 442 Fulgides, 423,430 Fullerenes, addition to silylketenes, 106 cycloaddition, 409 irradiation, I38 Fullerenes, reaction with nickel pathalocyanine, 418 Fulleroaziridines, rearrangement of, 532 Fulvenes, cycloaddition, 425 Furanones, cycloaddition, 409 Furans, 156, 159 addition to unsaturated ketones, 384 dicarbaldehyde, 161 Furfurans, 156 Furfuryl sulphides, 470 Furoxans, amino-, S23 Fuscol, 465 Gatterman reaction, 249 Gatterman-Koch formylation, 254 Geissoschizine, 466 Germene, 359 Germylenes, 227, 228 Glycosides, hydrolysis, 3 Gorin model, I01 Grignard reagents, 16 reaction with: allylic ethers, 375 benzocoumarins, 325 cyclohexanones, 392 sterically hindered, 325 Grindelic acid, 520 Grossularines, 524

Subject Index Grunwald-Winstein equation, 49, 294-296 Guanidinium salts, 384 Hafnium trifluoromethane sulphonate, 2.54 Halogenation, 105 aromatic, 249, 250 electrophilic, 364 Hammett p-a relationship for: 2-phenylcyclohex-lenylcarboxylic acid with ROH, 46 addition: of arenesulphinic acids to ethenylarenes, 368 elimination reactions, 2 18, 338, 339, 344 hydrolysis of sulphonates, 79 nucleophilic aliphatic substitution, 297 oxidation: benzyl methyl ethers, 189 cumenes, 195 phosphine oxidation potentials 155 radical reactions, 1 18 solvolysis of: bicyclo [3.1. llheptyl bromides, 270 Hammett p - a relationship, non-linear, 54, 190 Heck reaction, 238 Hemithioacetals, 2 I Hetarenes, radical reactions, I68 Heteroscyphic acid, 519 Hexacyclo[lO.2.1 .O.O.O]pentadecadienones, 419 Hines D values, 471 Hinesol, 499 Hofmann degradation, 479 Hofmann reaction, 524 Homoconjugation, 24 Homophthalic anhydride, 369 Homopropargyl alcohols, 489 Hooker oxidation, 538 Houben-Hoesch reaction, 249 Housanes, I64 Huckel-Hubbard parameters, 476 Huisgen rearrangement, 526 Hydrazines, oxidation potentials, 155 Hydrazones, 8 Hydride, transfer, 26, 27, 28, 206,207 Marcus theory of, 206 Hydride-ion shift, l,2-, 519

60 1 1,3-, 519 Hydrindan-8-ones, 5-aza, 404 Hydroboration, 378, 379 facial selectivity in, 378 of allylic alcohols, 378 Hydroformylation, 373 Hydrogen bond proton transfer, 330 Hydrogen bond, intramolecular, 18, 22 Hydrogen bonding, in nitrenes, 216 Hydrogen bonds, intramolecular, 20 Hydrogen migrations, 1,2-, 216, 487, 498, 523 1,3-, 442, 483 1,4-, 448 1,5-, 442, 461, 486, 511 Hydrogenation, asymmetric, 205 Hy droperoxides, as oxidants, 198 butyl, fert-, 198 Hydrophenanthrenes, 253 Hydroquinones, 154, 528 Hydrosilylation, 373 Hydrostannylation, 377 Hydroxamic acids, homolysis of, 97 hydrolysis, SO Hydroxybromination, 367 Hydroxylamines, hydrolysis, 49 rearrangement, 440 Hydroxylation, of alkanes, 196 radical, 118 Hyperconjugation, 2, 15, 16, 24 Ahn-, 27 Imidazoheterocycles, reaction with methylithium 324 Imidazolidines, formation, 386 Imidazoline biradicals, 133 Imidosulphonates, 7 Imines, 4, 5 addition, 4 aziridinyl, N - , 96 formation, 4 hydrolysis, 5 reaction, with enolates, 313 reduction, 5 Iminium ions, 5-7 nitroso, N-, 6 reduction, 6 Indole-2,3-dienoate, 419 Indoles, 227,472 addition to unsaturated ketones, 384 formation, 99

Indolizidines, 479 Induction period, 368 Intermediates, direct observation of, 389 Intrinsic rate constants, 3 16 Iodination, aromatic, 250 of allenic alcohols, 367 lodofluorination, 366 Iodolactonization, 45, 367 Ion pairs, 395 in enolate alkylation, 3 I8 in nucleophilic aliphatic substitution, 295 in polymerization reactions, 370 tightly bound, 461 Ipso attack of radicals 108 Ipso-substitution, 443 Ireland-Claisen rearrangement, 465 Isatylidenes, rearrangement of, 536 lsodesmic reaction, 15 Isopagodanes, 152 Isoquinolines, rearrangement of, 499 Isositsirikine, 466 Isothiocyanates, cycloaddition, 41 1 Isotope effects, as evidence for proton tunnelling, 241 carbon, 291, 350, 358 deuterium, 42, 51, 101, 202,241 inverse, 33 1 kinetic, 183 secondary, 38,291 in elimination reactions, 341, 350,351 in proton transfers, 330 kinetic, 15, 181, 202, 350, 351, 358, 364, 372 in elimination reactions, 34 I nitrogen, 36, 71, 75 oxygen, 7 1 solvent, 20, 5 1 Isoxazoles, 2 17, 224 Isoxazolidines, elimination reactions of, 355 Isoxazolidines, formation of, 405 Isoxazolones, 224 Jahn-Teller static effect, I60 Janovsky adducts, 24 I Jaspamide, 489 Johnston-Claisen rearrangement, 465

Subject Index Kedarcidin, 494 Kekulene, 306 Ketals, 2 Ketenes, 214, 519 cycloaddition, 401,414 formation, 3, 4 hydration, 3, 4 hydrolysis, 3, 4 rearrangement of, 491 vinyl, 493 Ketenimines, 3 rearrangement, 498 Ketones, addition to a,p-unsaturated, 384 amino, p-, 4 aminovinyl, 26 azidoalkyl, 21 deprotonation, enantioselective, 3 I2 enolization, 2 1-25 halo-, 9 halogenation, 30 heterocyclic, 23 hydroxy, p-. 11 oxidation, 26 protonation, 23 seleno, a-, 28 substitution of, ir-, 25, 30 Knoevenagel condensation, 13, 382 Kyodai nitration, 25 1 Lactacystin, 467 Lactams, 467 formation, 7, 21, 523, 525, 526 iodofluorination, 366 rearrangement, 524 Lactanis, p- 4, 5 , 518 formation, 313 from acylthioamides, 84 rearrangement, 53 1 Lactones, 45, 215 addition to a,P-unsaturated, 3 84 elimination reactions, 357 rearrangement, 487 ring-opening, 37 spiro-, rearrangement, 5 10 Lanthanide triflates, 4, 10 Laser flash photolysis, 6, 419 Leaving group ability, 268 Leaving group effects in nucleophilic substitution, 290 Leffler indices, 48 Ligation sphere, 376 Linear free energy relationships, 256 in elimination reactions, 338

Lipid peroxidation, 117 Lipoic acid, 527 Lithiation, directed, 323 Lochmann-Schlosser base, 322 Luffariolide. 489 Macrocycles, formation of 14membered, 319 Macrocyclization, Michaeltype, 385 Malanonitriles, acidity of, 308 Malonates, acidity of, 308 Mannich reaction, 4, 7, 472 Marcus equation, 162, 281 Markovnikov addition, 379 Meenvein-Ponndorf-VarleyOppenauer reactions, 203 Meisenheimer complexes, 21, 24 1-243 from nitrobenzofuroxans, 242 from triazines, 242 from trinitrobenzene, 24 I , 242 in nucleophilic aromatic substitution reactions, 23s oxidation, 236 spiro-, 242 Meisenheinier rearrangement, 490 Meldmm’s acid, 224 Menschutkin reactions, 293, 295, 297 Mercaptoacetic acids, 8 I Merocyanine, 29 Metalloenzymes, 70 Methane, protonated, 260 Meyer-Schuster rearrangement, 5 1 8 Micelles, anionic, 262 cationic, in the promotion of elimination reactions, 342 in nucleophilic aliphatic substitution, 296 Michael addition, 5 , 13, 317, 383,384,386, 393,395 antibody-catalysed, 384 intramolecular, 319, 382 Michael reaction, 363 diastereocontrol in, 383 of enolates, 308-328 Migration of sulphonyl groups, 447 Migration of acetylide group, 528 Migration of acyl groups, 5 10 Migration of alkoxy groups, 484

Migration of alkyl groups, 513, 519, 530 Migration of ally1 groups, 485, 487,s 13 Migration of aryl groups, 93, 441,445,448, 501, 523 Migration of boron, 527 Migration of gerrnyl groups, 485 Migration of halogen, 92, 214, 54 1 Migration of hydroxyl group, 448 Migration of nitro groups, 8 3 , 521 Migration of oxygen, 450, 51 1 Migration of phenyl thio groups, 533 Migration of phosphorus, 485 Migration of pivaloyl group, 92 Migration of silicon, 465, 488, 501, 502 Migration of stannyl group, 485.53 1 Migration of styryl groups, 449 Migration of sulphonyl groups, 530 Migration of thioalkyl group, 531 Migration of tolylthio group, 518 Migration of tosyl group, 450 Migration of tributylltin group, 93 Migration of trimethylsilyl group, 110, 320 Mills-Nixon effect, I58 Minisci procedure, I14 Molecular recognition, 17, 22, 29 of enolates, 310 Molecular-orbital calculations, on: addition reactions, 18, 384 radical reaction, 106 anisole and thioanisole, 256 benzynes, 243 bromination of cyclopropene, 380 carbanions, 303-305 carbene reactions, 225 carbene rearrangements, 225 carbenes, 2 13-2 15 carbocationic rearrangements, 505 Claisen rearrangement, 462 Cope rearrangement, 47 1, 472

Subject Index phosphacope rearrangement, 475 cycloadditions, 399,400, 403 cyclocondensation reactions, 8 decarboxylation of carboxylic acids, 67 Diels-Alder reactions, 41 3, 415. 418, 420, 424, 425 electrocyclic reactions, 348, 490 electrophilic aromatic substitution, 249, 252254 elimination reactions, 349353 ene reaction, 495 ex poxidation of alkenes, I86 fragmentation of pyridinethiones, 469 hydride reduction of carbonyl groups, 204 hydride transfer reactions, 207 hydroboration of acetylene, 379 hydrolysis of amides, 50 hydrolysis of methanesulphonyl chloride, 78 isomerization of paracyclophanes, 449 lithiation reactions, 324 Michael addition reactions, 317 nitrenes, 215, 225 nitromethyl anions, 305 nuclcophilic addition, 387, 393 nucleophilic aliphatic substitution, 280, 28 I , 284, 289,291-293 nucleophilic aromatic substitution, 233, 237 Pictet-Spengler reaction, 450 polyfluorobenzenes, 256, 445 radical reactions, 95, 99, 102, 104, 108, 111, 118, 126, 131, 132, 163 reactions of dialkylzincs, 326 reactions of singlet oxygen, 420 rearrangement, of allylic sulphoxides, 480 ring-opening of radicals, 95

603 ring-openings of cyclobutenes, 493 sigmatropic hydrogen shifts, 483 silenes, 216 silylenes, 227, 228 Stevens rearrangement, 489 tautomerism of pyrazoles, 541 tetrahedral intermediates, 36 thiocyanates, 82 transesterification, 43 Monooxygenases, oxidation by, 198 Morse curves, 102 Muonium, 123 Munchnones, cycloaddition of, 408 Muricatacin, 528, 53 1 Naked anions, 395 Naphthalenes, oxidation, 154 radical ions, 157, 162 Naphthols, arylhalogeno, 253 Naphthoquinones, rearrangement, 537 Neighbouring-group participation by: carhomethoxy group, 195 Neighbouring-group participation in: nucleophilic aliphatic substitution, 290, 294 reactions of carboxylic acid derivatives, 60, 61 Neocarzinostatin, 494 Nitration, aromatic, 249, 250-252 by nitrogen trioxide, 25 1 with tetranitromethane, 250 by dinitrogen pentaoxide, 25 1 by nitrogen dioxide, 25 1 by nitrogen trioxide, 25 I nirosonium ion catalysed, 252 of alkylbenzenes, 251 of anilides, 25 1 of aryl esters, 25 1 of cyclic acetals, 25 1 ozone-mediated, 251 transition metal complexes, 222 Nitrenes, 8 abstraction reactions, 223, 224 acyl-, 216 addition reactions, 2 19-222 alkoxycarbonyl, 222 alkyl-, 216

aryl-, 221 azepines from, 2 I8 cycloaddition, 22 1 diphenoxy phosphoryl, 2 I6 from a-elimination, 2 I8 from azides, 215, 216, 218, 220, 221, 224, 225 from imides, 221 generation, 2 16-2 18 heats of formation, 2 I6 insertion reactions, 220, 223, 224 lifetimes of,216 phthalimido-, 21 8 reaction with alkenes, 222 reaction with ally1 silanes, 222 reaction with aromatic groups, 218, 222 reaction with dimes, 222 reaction with electrophiles, 226, 227 reaction with fullerenes, 220 reaction with nucleophiles, 226, 227 reaction with styrene, 222 reaction with toluene, 22 I reaction with water, 226 rearrangement, 21 8, 222, 224, 225 structure and reactivity, 213-216 transition metal complexes, 213 vinyl, 498 Nitrenium ions, 226, 263-266, 440 aryl, 263 lifetimes of, 265 trapping of, 265 Nitrenoids, copper, 222 Nitrile oxides, cycloaddition, 404 Nitrileimine, 323 Nitrite esters, hydrolysis, 84 Nitroalkanes, deprotoriation of, 318 Nitroalkenes, additions to, 392 Nitroarenes, radical anions, I60 radiosensitizcrs. 174 Nitronate ions, 329 Nitrones, 6 addition of trimethylsilyl cyanide, 393 cycloaddition, 404,405 radical addition, 134 Nitronium tctrafuorohorate, 506 Nitrosarnines, rearrangement, 439

Subject Index

604 Nitrosation, 332 by ethyl nitrite, 516 of carbamides, 316 Nitrosothiols, 83 Nitrostilbenes, reaction with nucleophiles, 338 Nitrouracils, S R Nreactions, ~ 146 Nitroxides and spin trapping, 133-136 Nitroxyl radicals, 166, 191 Nitroxylation, 516 Nonatrienes, 42 I Norbomadienes, 141 aza-, solvolysis of, 281 rearrangement, 5 I6 Norbornanes, 5 16 Norbornanone, 27 Norbomenes, 484 electrophilic addition to, 364 rearrangement, 516 Norbomyl cations, 272, 273, 515 Norcaradiene, formation of, 430 Norcaradienol, 24 Norpseudopelletierines,304 Norrish type I process, 29, 442 Norrish type I1 process, 21, 29 Nucleophiles, hard and soft, 287 Nucleophilic additions, 382395 Nucleophilic aliphatic substitution, allylic systems, 280, 281 ambident electrophiles, 290 anchimeric assistance of, 287,290 at elements other than carbon, 287, 288 epoxides, 282-285 gas-phase reactions, 280, 284, 291-293 intramolecular, 289 isotope effects, 291 leaving group effects, 298 linear free energy relationships, 297 miscellaneous polycyclic systems, 281 one-electron processes, 293, 294 phase-transfer catalysis of, 296, 297 salt effects, 296 solvent effects, 281, 294296 structural effects, 297 theoretical treatments, 280,

281, 284, 289, 29 1 , 292,293 vinylic systems, 279, 280, 338,387 Nucleophilic aromatic substitution, at high pressure, 234 by ANRORC mechanism, 240 by carbanions, 236, 241 by water, 235 catalysis, by base, 233 by copper, 238 by palladium, 238 by tricarbonyl chromium, 238 micellar, 237 hydrogen exchange by fluoride, 237 intramolecular, 237 of arylsuphones, 238 of dinitrobenzaldehyde, 235 of dinitrobenzenes, 234 of haloacetophenones, 237 of halobenzenes, 238 of halonitrobenzenes, 233 of halopyridines, 233 of hcterocyclic systems, 239-241 of hydrogen, in dinitrobenzenes, 236 of nitroanthracenes, 241 of nitrosoanisoles, 23.5 of phenylaryl ethers, 233 of pyridines, 240 of pyrimidines, 240 of thiophenes, 240 of triazines, 239, 240 of triazoles, 234, 236 of trinitrobenzenes, 233, 24 1 of trinitrotoluene, 241 pf nitrosophenyl ether, 235 photoinduced, 237 radical anions in, 232 radical pathway, 232 single-step mechanism, 239 solvent effects, 235 vicarious nitro group loss, 318 vicarious, 236, 241 Nucleophilic substitution, vicarious, 332 Nucleophilic vinylic substitutions, 338, 389-392 Nucleophilicity scales, 291 Nucleophilicity, 290, 297, 298, 381 Octa-l,6-dienes, 399 Octahydronaphthalenes,505

Organochromium compounds, rearrangement, 528 Organocobalt compounds, rearrangement, 528 Organogermanes, radical cations, 156 Organoiron compounds, rearrangement, 528 Organolithium compounds, 305,306, 323, 324,491 aggregate-substrate complexes, 305 nucleophilic addition, 324 racemization, 306 rearrangement of, 498 Organomolybdenum compounds, rearrangement, 528 Organopalladium compounds, rearrangement, 529 Organoplatinum compounds, rearrangement, 529 Organoruthenium compounds, rearrangement, 528 Organosilicon radical cations, 153 Organozinc compounds, 325, 496 OrganoLinc reagents, 325 Osmylation, of steriods, 374 Oudemansin, 477 Oxadiazines, 459 Oxadiazoles, 459 Oxadiazoles, in Diets-Alder reactions, 418 Oxadiazolidines, formation, 413 Oxadiazolines, 217 Oxaphosphetanes, 323 Oxathianes, 443 Oxazoles, 28 Oxazolidines, formation, 386 Oxazolines, 261 thiolysis of, 457 Oxetanes, 534 ring-opening of, 285 Oxidation by: bromate, 186 bromine, 193 bromosuccinimide N - , 190 carbon tetrachloride, 194 cerium(IV), 185, 186 chloramine-B, I90 chloro compounds, N - , 193 chromium(VI), 181, 182 cobalt(III), 188 copper(lI), 184, 186 cumene, 117 dioxetanes. 198 dioxiranes, 195-198 hydrogen peroxide, 191, 198

605

Subject Index iodosobenzene diacetate, 114 iron(III), 188, 190 lead tetra-acetate, 5 11 lead(IV), 185 manganese(II), 184 manganese(II1) 184 manganese(V), 184 manganese(VI), 184 metalloporphyrins, 188 molybdenum, 187, 188 monooxygenases, 184 nitrogen dioxide, 191 nitrous acid, 191 osmium(VII1). 189, 190 oxygen, 202 ozone, 199 peracids, 198, 490 periodic acid, 193 permanganate, 182, 183 peroxidase, 203 peroxydisulphate, 8, 191 peroxymonosulphate, I9 1, 192 quinoncs, 203 rhenium, 190, 191 ruthenium, 189 selenoxides, 192 silver(I), 184 singlet oxygen, 199 superoxide, 201 telluroxides, 192 tempo, 116 thallium(III), 184 titanium, 186 tungsten, 188 vanadium(V), 187 Oxidation of acridine orange, 193 adamantanes, 196 alcohols, 181, 191 aldehydes, 182 alkenes, 183, 188 alkylbenzenes, 114 amide ions, 202 amides, 196, 202 amines, 190, 191 amino-acids, 183 anisole, 185, 191 aromatic amines, 188, 190 ascorbic acid, I9 I benzene, 102 cycloalkanes, 185, 187 cycloalkanols, 181 cycloalkenes, 183, 202 diols, 181 ethers, 182 glycols, 190 hydrazines, 184 hydroxylamines, 184 imines, 188 ketones, 182, I89

phenols, 185, 193 prenol, 534 sulphides, 188 sulphoxides, 188, 190 Oxidation potentials, of carbanions, 328 Oxidation, anodic, 534 Oxidation, enzymic, 188, 198, 202 Oxidation, homolytic, 25 Oxidative chlorination, 377 Oximes, 7, 8 elimination reactions, 341 Oxindoles, 108,443 Oxiranes, chloromethyl, 16 Oxiranes, elimination reactions of, 349 Oxiranes, reaction with carbon disulphide, 284 Oxiranes, ring-opening of vinyl, 327 Oxiranes, ring-opening of, 282-285,530 Oxocarbenium ion, 427 Oxone, oxidation by, 191, 192 Oxonium ions, 510, 520 Oxygen-] 8 exchange studies, 36 Ozone, 199 Ozonides, 340 Ozonolysis 194, 195 of alcohols, 195 of alkenes, 195, 340 of vinyl ethers, 195 Pagodanes, 152 Papuamine, 496 Parthenin, rearrangement of, 520 Patchoulene, 520 Patemo-buchi reactions, 40 I Payne rearrangement, aza-, 532 Penicillin derivatives, 70 hydrolysis, 5 1 Pent-I-enes, 5-phenyl,430

Pentacyclo[5.4.0.0.0.O]undecan%ones, 526

Pentacyclo[5.4.0.0.0]undecanes,

517 Pentacyclo[6.5.0.0.0.O.ltrideca2, 6-diencs, 493 Peptides, tetrapeptides, 536 Peracids, 195-198 Perepoxides, 420 Perfluoroacylation, 254 Perfluoroalkylamines, 101 Perhydrohistrionicotoxin, 487 Peroxides, 117, 195-198 decomposition, 117, 198 catalysis by chromium compounds, 117

Phenacyl halides, nucleophilic displacements, 294 Phenacylpyrazines, 23 Phenanthridines, 254 Phenanthridines, rearrangement of, 448 Phenanthrolines, 160 Phenethylamines, 16, 17 Phencthylamines, horane complexes of, 28 Phenols, iodination, 250 Phenonium ion, 267, 445 Phenothiazines, oxidation of, 150, 191 Phenoxazines, 440 Phenylacetylfuran, enolization of, 329 Phenyldiazoacetic acid, hydrolysis, 47 Phenylenediamine. addition to formaldehyde, 369 Phosphaalkenes, Diels-Alder reactions, 427 Phosphates, 71-73 enzymic reactions, 75-78 hydrolysis, 75 Phosphines, oxidation of, 155 Phosphinous acids, 144 Phosphonates, 63, 71-73 aminolysis, 19 hydrolysis, 19, 73 hydroxy, a-, 504 Phosphonophosphates, 504 Phosphorus-containing acids and derivatives, 71-78 Phosphotriester, 61 Photoaddition, radical, 106 Photocyclization, of alkenylbenzaldehyde, 486 Photocycloaddition, 400, 4 I9 2+2,399 4+4,430 intramolecular, 430 Photodesilylation, 527 Photoelectron spectra, 347 Photolysis of azides, 215, 216, 224, 226 benzenediazon i u m salts, 267 diazo-compounds, 213, 214, 215, 220, 226 fluoromaleic anhydride, 2 13 hydroxypyridine-2-thiones, 172 perfluoroazooctane, 17I trisilanes, 227 Photooxidation of sulphenamides, 200 Photorearrangement of allyltins, 485 henzopyrans, 452 cyclohexa- I ,3-diencs, 445

606 Photorearrangement of: ( c o n f . ) cyclopropenes, 530 d i u o compounds, 519 furans, 452 hydroxyindoles, 448 nitronaphthalenes, 445 organosilicon compounds, 517 oxadiazoles, 459 pinacolone, 442 provitamins, 494 pyranones, 534 pyridazines, 459 quadricyclanone, 51 6 spiropentanes, 507 thiocarbamates, 485 vinyl cyclopropanes, 483 Phthalimide, aminolysis, 54 Picter-Spengler reaction, 450 Pinacol rearrangement, 263, 505, 513,517, 520 Plumbylenes, 228 PM3 method, 425 Polar-field susceptibility parameters, 27 Poly fluoro-2-alkynoic acids, 386 Polymeriz,ation, carbanion induced, 319 Polymerization, of isopropoxyethylene, 370 Polymerization, siliconmediated, 395 Polymerizations, living-type, 370 Polyquinanes, 472 Porp hyrins, i n oxidation of alkyllbenzenes, 114 metallo-, 213 oxidation by, 188 Potier-Polonovski rearrangement, 499 Prephenate, 462 F’ropargyl alcohols, 368 Propellanes, 493 formation, 412 Propellenes, 427 Prosolanapyrone, formation, 414 Prostaglandins, synthesis of precursor, 465 Protodealkoxyalkylative fragmentation, 445 Proton activating factors, 23 Proton transfer, 27, 328-330 asynchronous, 20, 26 catalysed by antibodies, 328 intramolecular, 15 linear, 20 rate-limiting, in nucleophilic aromatic

Subject Index substitution, 233 Proton tunnelling, 241, 329 Protonation, diastereoselective, 9 Protonation, enantioselective, 9, 25 Pseudomonic acid, 465 Pudovik reaction, 19 Pummerer rearrangement, 21 6, 443,518 sila-, 444 Purines, I 14 Pyranohenzoquinunes, 425 Pyranoquinolinequinone, 425 Pyranoquinones, 534 Pyranoses. rearrangement of, 538 Pyrazines, formation of, 461 pyrolysis, I68 radical anions, 159 Pyrazole-4-carboxylic acids, 405 Pyrazoles, formation, 408 in Diels-Alder reactions, 418 Pyrazolincs, formation of, 41 I Pyrazolium cations, 4 I6 Pyrenes, silyl, 161 Pyridazine, 168 Pyridazinones, 454 Pyridine N-oxides, cycloaddition, 405 Pyridines, radical reactions, 168 nitration, 25 1 Pyridines, 1,2-dihydro-,49 1 Pyridinium ions, hydrolysis of, 263 Pyridinium-3-olate, I (phthalazin-1-yl), 408 Pyridoxal, 9 Pyrimidines, 136, 168, 452 Pyrolones, cycloaddition, 409 Pyrolysis of: alkoxybenzenes. 448 alkyl halides, 347 alkynes, 224 amides, 344 amines, 102 arene sulphonates, 7 azides, 54, 218, 221, 22.5 benzocyclobutenes, 41 9 butadienes, 101 butynes, I01 carboxylic acids, 345, 353 cycloalkylidene hydrazines, 459 cyclopropenes, 220 diazepines, 461 diazo-compounds, 226

dioxctanes, 352 enaminothioesters, 356 esters 217, 353 ethylnylarenes, 170- 17 I hydrazones, 225 perfluorohepta- 1,6-diene, 171

pyrrolidinethiones, 347 pyrrolidinones, 347 silanes, 228 sulphonate esters, 346 thioaniines, 346 triazines, 346, 347 triazolines, 457 Pyrrole N-oxides, cycloaddition, 405 Pyrroles, acylation, 254 Diels-Alder reactions, 425 rearrangement, 450 Pyrrolidines, addition to unsaturated lactones, 384 formation, 22 I Pvrrolines. 222 Pyrylium salts, cycloaddition, 408 Quadricyclanes, 141, 148 Quinazolines, 458 Quinazolinones, 3-acetoxyamino-, 370 Quinodimethanes, 500 Quinolines, 1,2,3,4-tetrahydro, 416 Quinone methides, 2 I5 Quinone methides, formation of, 28 Quinones, 18 formation of, 384,443 reduction, 158 Radical anions 1 16, 157-162 in srnl reactions, I 16 reduction by, I I4 trianions, 159 Radical annulation, 99, 100 Radical cations, I5 I - 157, 1 17, 399,483, 505, 516 in electrophilic aromatic substitution, 25 1 nucleophilic capture, I 17 of diarylalkanes, 140 of diarylalkenes. 140 sigmatropic rearrangement, 142 triplex lormation, I I7 Radical ion pairs. recombination of, 140 Radical reactions, addition, 92, 105-108

Subject Index effect of Lewis acid complexes, I12 enthalpic effects, 106 intramolecular, 95-100 polar effects, 106 stereochemical induction, l,2-, 112 stereoselectivity of, 106, 112

allylation, 106 aromatic substitution, 108, 109 atom abstraction: 102-105 polar effects, 104 stereoselectivity of, 113 bromination, 105 chlorination, 104, 10.5 combination, 101, 102, 117 rate constants for, 101 cyclization: 92, 95-97, 107, 114, 116 regioselectivity of, 96 stereochemistry of, 97 stereoselectivity in, 1 1 1 stereosclcctivity, 98 tandem, 98,99 deamination, 137 delluorination, 138 fragmentation, 101, 102 homolysis, 101, 102 isomerization, 367 nucleophilic aliphatic substitution, 293, 294 oxidation: 92, 1 14- I 17, 137, 191 photolyses, 109, 171 pinacol coupling, 98 pyrolysis, 102, 110, 167 rearrangements, 92-95, 13 I , 448 reduction: 112, 114-116, 137 ring-opening, 93-95 S H reactions, ~ 98, 109 at halogens, 109 at oxygen, 109 at phosphorus, 109 at selenium, 109 at sulphur, 109 at tellurium, 109 steric effects, 112 study by ESR spectroscopy, 107 use of microwaves, 101 Radical translocation, I03 Radicals, acetaoxyallyl, 112 acetyl, I01 acyl, 96, 103, 110, 115 adamantyl, 5 17 alkoxy, 92, 97, 102 .ir-complcxcs of, 130

607 alkyl, SO, 92, 96, 101, 102, 106, 108, 109, 112, 114, 1 I7 allyl, 92 hetcro-substituted, 125 allylic strain, 92, 112 ainidyl, 97 aminoboryl, 105 aminyl, 97, 107, 110, 126, 127 ammoniumyl, 97 aryl, 96, 99, 108 azide, 105, 107 basketyl, 95 benzoyloxy, 93, 129 benzyl, 105 deuteration of, 113 butoxycarbonylrnethyl, terf-, 105

hutoxyl, trrf-, 104 butyl, trrt- 101, 106, 124, 442 captodative stabilized, I O X carbamyl, 97 carboethoxy, a-, 96 carbon-centred, 123- 126 carboxybenzyl, 129 chloroethyl, (Y-, 132 chlorofluoromethyl, 108 cubylcarbinyl, 95 cumyl, 105, 114, 128 cumyloxyl, I04 cyanoalkyl, 105, 106, 150 cyclohutylcarhinyl, 94 cyclohexadienyl, 92, 95, 108 cyclopropylcarbinyl, 93 dioxiranylmethyl, 13I dioxctanyl, 13 1 dioxolanyl, 96 diphenylphosphinoyl, 107 diphcnylpyridylmethyl, 126 electrophilic character, 106, I07 ENDOR spectra, 124, 129, 153 EPR spectra, 110, 127, 153, 154, 156 ESR spectra, 92, 123 germyl, 109 haloalkyl, 111 halogen atoms, 102 heptenyl, 96 hexenyl, 95, 111 homocubyl, 95 hydrazyl, 104 hydrogen, 101 hydroxyalkyl, 105 hydroxyl, 101, 109, 118, 188

reaction with DNA, I36 reaction with ethers, I I8

reaction with halogenated acetals, 118 reaction with halogenated alkanes, I 1 8 reaction with pyriniidines, 136 iminyl, 99 in enzymatic systems, I I I isopropyl, 100 nitrate, 107 nitrogen-centred, 126-129 nitroxides, 93, 1 11, 488 oxiranylcarbinyl, 94 oxo,95

oxy-, 486 oxygen-centred, 129-132 perchlorotriphenylmethyl, I25 peroxy, 101, 117, 118, 130 reaction with aniines, 1 I7 reaction with catechols, 117 reaction with flavanoids, 117 reaction with hydroxylamines, 117 reaction with phenols, 117 reaction with thiols, 117 phenacyl, 107 phenoxy, 1 0 1 , 102 phenyl, 104 phenylthiyl, 107 philicity, 109 phosphoranyl, 109, 483 phosphorus-containing, 107 piperidin- I - 0 ~ ~ 1 , 4 9 9 polarity, 109 polycyclic, 95 polyenyl, 12.5 silyl, 97, 103, 105, 109, I32 stannyl, 92. 108, 109 structure, stereochemistry and stability, 1 10, 11 I . 123-132 sulphonamidyl, 105 thio-, 486 thioperoxyl, I32 thiyl, 100, 101, 105 tosyl, I I 1 tributyltin, 98 tricyclohexylmethyl, 124 trifluoroacetoxy. 488 trifluoromethoxy, 104 trifluoromethyl, 101 TRIPLE spectra, 127, IS3 uredeidyl, 97 vinyl, 96, 101, 106, 114, 117, 131,486 Radiolysis, 136

608 Ramberg-Backlund reaction, 504 Rearrangement of acetoacetates, 465 acyloins, 509 alkenylanilines, 466 allenyl ethers, 463 allenyl silanes, 496 allyl ethers, 463, 464 allyl vinyl ethers, 463 allylic sulphoximines, 480 allylic trichloroacetimidates, 467 allyloxy-acetates, 477 amino acid allylic esters, 465 ammonium benzylides, 479 azatrienes, 49 I azepines, 461 azetidinobenzoquinones, 467 azides, 448 azidoazetidines, 534 aziridines, 478,486, 532 aziridinobenzoquinones, 467 azoxybenzenes, 539 benzodiazepines, 461 benzodiphospholes, 448 benzofurans, 5 1 1 benzothiopyranium methylides, 481 benzyl ethers, 477 biphenyl, 445 bisimides, 440 carbanions, 472,498, 503 carbohydrates, 521, 522 carbonium ions, 296, 505 carbothioamides, 4.59 carboxamides, 524 chlorophthalides, 445 chorismate, 462 cobaloximes, 529 crotyl e n d ethers, 463 cycloalkanones, 501 cyclobutenones, 493, 510 cyclodecenediones, 495 cyclodecynone, 510 cyclooctapyridazines,484 cycloocyenes, 496 cycloolefins, 5 16 cyclophanes, 540 cyclopropanes, 472,484 cyclopropenyl derivatives, 493 cyclopropylacylsilanes, 507 diazo keto esters, 519 diazo-compounds, 490 dienes, 47 1, 475 difluoroalkenoln, 477 diols, 507, 5 11, 533 dithiins, 504

Subject Index endoperoxides. 487 enynes, 495 ephedrine derivatives, 440 epoxides, 491,501, 507, 531 epoxy amines, 532 esters, 529 ferrocenyl selenimides, 48 I ferrocenyl telluroxides, 48 1 fervenulones, 461 furdnoid glycals, 477 furanoxyl ketones, 526 furans, 45 1 furoxans, 523 furylmeyhyl ethers, 477 glycosides, 522 heterocyclic derivatives, 450461 hydrazines, 439, 525 hydrazones, 477 hydrazonoester dienolates, 466 hydroxamic acid derivatives, 440, 467, 487 hypostrophene, 471 imidazoles, 455 imidoylketenes, 484 indenes, 498 indoles, 450 isocyanides, 528 isoquinolinium methylides, 479 ketene aminals, 467,473 ketene dithioacetals, 469 lactams, 524, 531 lithioalkyny Itriorganoborates, 489 lithioamines, 479 methylene alkanenitriles, 465 methyleneamines, 530 naphthalene monoxides, 469 natural products, 519-523 nitrides, 528 nitrosoamines, 439 norbornenes, 472 norcaradienes, 5 17 oligosilanes, 529 organometallics, 527-529 organotitanium compounds, 501 oxadiazoles, 459 oxazoles, 456 oxazolidinthiones, 456 oxime derivatives, 523 oxiranes, 536 peroxyl radicals, 131 phosphines, 483 phosphonates, 483 phthakdzine, 459 piperidines, 499

propargyl alcohols, 5 18 propargyl ethers, 464, 476 propargyl ketoximes, 498 propargylox yquinolinones, 464 propellanes, 493 propynyl ethers, 529 pseudo-esters, 501 pyrazolidinones, 475 pyrazolines, 454 pyridopyrimidines, 459 pyrimidines, 460 pyrolidines, 450 pyruvyl ethers, 463 radical cations, 507 radicals, 92-95 selenides, 470 silenes, 485 silyl ethers, 531 squarate, 493 squaric acid, 5 10 stannyldiallyl ethers, 483 sulphides, 48 1 sulphines, 321 sulphones, 442 sulphonium salts, 468 sulphonyl carboxylic esters, 505 sulphoxides, 443, 518 tellurides, 470 tetrazoles, 459 thiadiazolines, 459 thiazanes, 461 thiazetidines, 535 thiazoles, 457 thiocarbamates, 469 thioimminium salts, 469 thiols, 497 thionocarbonates, 469 thioquinanthrene, 440 thiosulphinic esters, 480 tocopherols, 445 trioxane, 1,2,4-, 114 trioxanes, 486 uracil derivatives, 460 vinyl cyclopropanes, 149 vinyl ethers, 483 vinyl sulphides, 495 vinylcyclopropanes, 142, 483 vinyletenes, 493 ylides. 477, 481 zircona cyclopentanes, 527 Rearrangement, aldopentose, 527 anionic, 498-505 aromatic, 439-461 aza-di-T-methane, 28 benzilic 440 boratropic, 528 cationic, 505-5 19

Subject Index cyclopropylcarbinyl to butenyl, 516 di-n-methane, 490 dienone-phenol, 445 dienthion-thiophenol,52 I haptotropic, 528 isomerization, 539 neopentyl, 506, 5 17 neophyl, 92 oxa-di-n-methane, 28 oxidative, 461, 522 phosphorane-phosphane, 448 pyranose-furanose, 522 ring-opening ring-closure, 530-539 selenocyanate to isoselenocyanate, 475 sulphinate-sulphone, 5 18 sulphoxide-sulphenate, 480 tautomerism, 54&542 vinylcyclopropenecyclopentene, 484 vinylketene-acylallene, 484 [I ,2]-metallate, 489 Reduction by: alkali metals, 205 borohydride, 204,205 cyanoborohydride, 204 UIBAH, 521 hydride ion, 206 metal hydrides, 203-205 molybdenum(IV), 205 NADH, 206, 207 nicotinamides, 206, 207 samarium diiodide, 205 silanes, 204 tin hydrides, 96 triacetoxyborohydride, 204 Reduction of adamantanones. 27 aldehydes, 203 aromatic amides, 205 cyclohexanone. 207 cyclopropyl ketones, 204 diketones, 204 imines, 205 iminium ions, 6 ketones, 203 nitro-compounds, 205 Schiff bases, 5 sulphones, 497 Reduction, asymmetric, 5, 204 of methyl benzoylformate, 207 of oximes, 205 diastereoselective, 27, 28 enantioselective, 27, 28 enzymic, 205, 207 regioselective, 27

609 Reimer-Tiemann reaction, 220. 256 Remote substituent effect, 363 Resolution, regiodivergent, 25 Retinal, 463 Ribofuranose, 3 Richter reaction, 380 Ring expansion, 95 Ring-opening, 530-539 of epoxides, 282-285 of radicals, 93-95 Ritter reaction, 505 Ruthenacyclopentene, formation of, 378 Sakurai allylation, 11 Salt effects, 370 in nucleophilic aliphatic substitution, 296 Samarium diiodide, 486 SANmechanism, 44 Sandmeyer reaction, 232 Santonin derivatives, ozonolysis, 195 Sarcophytol, 466 Scandium trifluoromethanesulphonate, 39 Schiff bases, 52 formation, 4 reaction with acid chlorides,

5

Schmidt reaction, 261 intramolecular, 2 1 Schmidt rearrangement, 525, 526 double, 526 photo-, 525 Sedridine, 405 Selenoaldehydes, 470 Selenoketones, 470 Selenoketones, diaryl, 4 14 Selenophthatimide, N-phenyl, 368 Selenoxides, 192, 21 6 Semibullvalenes, 47 1 radical ions, I5 1 Semicarbazones, 8 oxidation, 8 Semidine, 439 Semidiones, 161 Semiquinone anion, 154 Seselin, 464 Sesquiterpenes, 5 I 1 ceratopicanol, 464 Set mechanism, 18 Sharpless expoxidations, 53 1 Sigmatropic rearrangements, photochemical, 463 [1,21, 487 [ 1,3], 469, 483-485 [1,4], 316, 479

[1,5], 256, 455,486 [2,3], 224, 227, 3 16, 476483, 480 [3,3], 462-483 Silanes, acyl, nucleophilic addition to, 84 allyl, 1, 18, 380 allylic, 11 crotyl, 18 radical reactions, 105 rearrangement, 448, 501 Silanorbornadienes, 5 17 Silapropanols, 216 Silaziridines, 225 Silenes, 216 rearrangement, 485 Sileno-2-silylethenes,cycloaddition of, 402 Silicenium cations, 267 Silicon, nucleophilic displacement at, 287, 288 Siliconate anion, pentacovalent, 395 Siloxonium intermediates, I I Silyl enol ethers, I I , 25, 26, 387 aziridination of, 37 1 Silyl ethers, 157 transmetallation, 501 Silyl radicals, 132 Silylallylanions, 32 1 Silylcarbamates, radicals from, 141 Silylenes, 227, 228 dimerization of, 228 reaction with arenes, 228 reaction with fullerenes, 227 Silylformylation, intramolecular, 378 Singlet oxygen, 199-201 addition to alkenes, 420 reaction with imidazoles, 420 reaction with naphthalenes, 419 Smiles rearrangement, 237, 440 photo-, 440 SN reactions, mechanistic criteria, 43 sN1 reactions, 49,79, 293, 294 sN2 reaction, 1, 37,56, 58, 79, 280,285,290-293, 296,328 surface-catalysed,78, 297 sN2' reactions, 280, 328 SNAr reactions, 233-239 Solanopyrone A, 41 4

Subject Index

610 Solvent effects, in Claisen rearrangement, 463 in Diels-Alder reactions, 414 in nucleophilic aliphatic substitution, 235, 28 1, 294-296 kinetic, 104 Sommelet-Hauser rearrangement, 481 Sonolysis, 136 Sphingosine, 471 Spin-trapping, 50 inverted, 134 Spiro-compounds, 414,445, 505,508,531 chiral, 51 1 rearrangement, 445, 456, 479 spiro ketals, 5 I 1 spiro-fused bicyclicylides, 479 spiro-lactones, 495 Spirocyclobutanones, rearrangement, 526 Spiropyrans, 29 SRN1mcchanism, 109,232, 294,316,320 carbonyl group participation, 146 S R mechanism, ~ ~ 232 Stannanes, 92, 501 allyl, 12, 17 radical addition, 106 rearrangement, 531 Stannylenes, 228 Staudinger reaction, 21 6 Staurosporine, 522 Stereoelectronic control, 113, 383,392 Steric effects, 15 in alkylation reactions, 3 14 in Michael reactions, 383 in nucleophilic addition reactions, 392 Steric parameters, 38 Steroidal olefins, electrophilic addition to, 368 Steroids, addition to unsaturated, 368,374 rearrangement: 520, 521, 536 Stevens rearrangement, 3 16, 481,489 Stilbcnes, addition to, 389 Iliels-Alder reactions, 148 radical cations, 156 Stilhene halides, SRN1 re-

actions. 147 Styrenes, addition to, 387, 391 aziridination of, 371 dicyano-, p$-, 387 cpoxidation, 190 nitro-, @-, 387 Sulphamates, aminolysis, 8 1 Sulphamates, cyclic, 81 Sulphamates, hydrolysis, 8 1 Sulphamic acids, 81 Sulphenamides, 80 Sulphenates, 79, 480 Sulphides, oxidation, 188 vinyl, 495 Sulphinamides 80 Sulphines, rearrangement, 504 of aJ-unsaturated, 321 Sulphinic acids, 497 addition to 4-(2-nitroethenyl)toluene, 39 1 Sulphonamides, 18, 81, 93 N-chloro-, 105 Sulphonates, nucleophilic substitution, 78 Sulphonation, of allylsilanes, 380 of biphenyl, 256 of naphthylenes, 256 Sulphones, acidity, 321 benzyl, 3 1 8 elimination reactions of, 340 enyne, ti-lithio-, 332 388 keto, 8, rearrangement, 442 viny I .addition to, 404 Sulphonium salts, 254, 368 alkoxy, 444 keto, N-,443 Sulphonyl alkynes, reaction with cuprates, 393 Sulphonyl halides, elimination reactions, 344 nucleophilic substitution, 78 solvolysis, 260 Sulphoxides, elimination reactions, 340 keto, p-, 388 oxidation, 188, 190 reaction with magnesium amides, 263 Sulphur-containing acids and derivatives, 78-83 Sulphuranes, 80 Sulpinyl thioanhydrides, 80 Sultones, 5 1 I Superacid media, 259 Superaromaticity, 306 Superoxide,

reaction with cinnamyl bromide, 201 Supersilylating agent, 11 Surfactants, 62 Swain-Scott equation, 297 Faddo1 ligands, 325 Taft E,yvalues, 16 Taft equation for: nitrosation of nitriles, 316 oxidation of adamantanes, 195 Tautomerism, 540-542 enaminone-enolimine, 23 enzyme-catalysed, 540 bydrazone-a7,0,8 imine-enamine, 540 keto-enol, 25, 540 prototropic, 54 I ring-chain, 540 Taxane, 520 Taxanea, synthesis of, 463 Taxol, 1I , 493 synthesis of, 223 Telluroaldehydes, 470 Telluroxides, 192 Terephthalodinitrile. reduction, 205 Tetracyclo[4.3.O.O.O]nonanes, 517 Tetrahedral intermediates, anionic, 55 in reactions of carboxylic acd derivatives, 36-38, 58 zwitterionic, 55 Tetrahydrodianthracene, 366 Tetraoxazocines, formation of, 429 Tetrazole- 1 -oxides, 459 Teurilene, 53 I Thiamin, 14 Thiamine pyrophosphate, 8 I Thianaphthenes, 227 Thiazepinone, 525 Thiazines, 57, 461 reduction, 205 Thiazinium hydroxides, 41 9 Thiazolidines, formation, 386 Thiazolin-2-ylidene, bis-, 13 Thiazolium ions, 37, 81 Thiazolium salts, 13 in benzoin condensation, 331 Thiazolo[3, 4-c]oxazolium-loxides, 401 Thienium cations, 416 Thietan-3-imines, formation of, 41 1 Thiiranes, 143, 284 elimination reaction of, 349 Thiiranium ions, 285

61 1

Subject Index Thioacetals, hydrolysis of, 2 Thioamides, formation, 5 1 Thioanisole, 256 Thiocarbamates, rearrangement, 485 Thiochromanones, rearrangement, 525 Thioesters, formation of, 392 Thioethers, solvolysis of, 6 Thioflavanones, rearrangement, 525 Thioformamides, N-acyl-, 414 Thiohydroxamates, 108 Thiolcarbonates, 469 Thiophenes, 154, 159 nucleophilic aromatic substitution, 240 Thiophenium salts, 287 Thiophens, cycloaddition, 403 Thiophthalimide, N-phenyl, 368 Thioxoprolinates, 469 Tin enolates, 10 Titanocenes, 5 Toluene, nitration, 25 1 Torq~ioselectivity,348 Trdnsacylation, 65 Transamination, 9 Transcyanation, 17 Trdnsesterification, 40, 49, 70, 71 Triazenes, acyl-, 343 Triazidochlorosilane, 523 Triazines, Meisenheimer adducts from, 242 nucleophilic aromatic substitution, 239, 240 .rriazinium-S-enoIates, 408 Triazoles, 49 1 rearrangement, 457, 536 Triazoline-3,5-diones,addition to alkenes, 370 Triazolines, 468 Triazolium cations, rearrangement of, 523 Trichlorophosphaethene, Diels-Alder reactions, 427 Tricyclo[3.2. I .Oloct-6-enes, 517 Tricyclo[3.2.1.0]octanes,51 7 Tricyclo[4.1 .O.O]heptyl cation, 517 Tricyclo[5.2.1 .O]dccadienones, 392

Tricyclo[5.3.1 .OJundecanols, 517 Tricyclo[6.2.1 .OJundeca-4,9dienes, 501 Triflamides, 359 Trifluoroethene, 21 3 Trimethylsilyl cation, 11 Trinitrobenzene, formation of adducts, 315 Triphenylphosphoniocyclopentadienide, 384 Trisbicyclo[2.1.1 Jhexabenzene, 430 Trityl cations, 262, 263 Tropone oxime, 7 Tropones, cycloaddition, 425 Tropylium cations, 266 Tryptophylquinone, reduction of, 202 Tunneling effects, 330 Umpolung, 17, 25 Undecatetraene, 1,3,8,10-, 422 IJnimolecular chain transfer, I 03 Ureas, hydrolysis, 48 Ureas, N-aziridinylimino-, 491 Ureas, nitrosation, 332 Valence bond method, 249 Vernolepin, 48 1 Vicarious substitution, of hydrogen, 236, 241 Vilsmeier reaction, 256 Vinyl cations, 267-269 Vinyl ethers, 4 electrophilic addition to, 369 hydrolysis, 25, 26 polymerization of, 261 Vinyl halides, 385 Vinyl indules, cycloaddition, 149 Vinyl isoselenocyanates, 475 Vinyl pyridines, anionic polymerization, 395 Vinyl sulphides, carbolithiation of, 392 Vinyl sulphides, electrophilic addition to, 369 Vinylation, by alkynes, 253 Vinylation, or phenols, 253 Vinylic carbon, nucleophilic displacement at, 279, 280

Vinylic substitution, 385 Vulgarolide, 472 Wacker reaction, 190 Wagner-Meerwein rearrangement, 364, 516 Westphal condensation, 6 Wittig reaction, 18, 353. 464, 472 Wittig rearrangement, 1 14, 476,483 aza-, 477 Wittig-Homer reactions, 323 Wolff rearrangement, 41 2, 456 photochemical, 5 19 vinylogous, 5 19 Wootkatonc, 392 X-ray structure, cyclohexylacetate, 195 of azirines, 220 of carbenes, 2 15 of carbocations, 271 of dications, 273 of enones, 10 of silylene adducts, 228 of tetrabutylammonium salts, 395 Xanthates, 83 rearrangement, 470 Xanthobilirubic acid, 46 Ylides, 215 ammonium, 226,489 azomethine, 220 cycloaddition of, 408, 410 carbonyl, cycloaddition of, 413 chalcogen, 482 in elimination reactions, 35 I , 353 nitrogen, 219, 477 oxonium, 224,477,519 phosphorus, 353, 448, 472 selenium, 227 sulphonium, 242, 481 sulphur, 227, 477, 481 Ynamines, silylated, 269 Yukawa-Tsuno relationship for: diazonium coupling, 8 Zinc alkyl, 17, 325, 496 Zizaene, 520 Zwitterionic intermediates, 232,279