Organophosphorus Chemistry Volume 20
A Specialist Periodical Report
Organophosphorus C hemist ry Volume 20 A Review of the Recent Literature Published between July 1987 and June 1988 Senior Reporters
B. J. Wa!ker, Department of Chemistry, David Keir Building, The Queen’s University of Belfast J. B. Hobbs, University of British Columbia, Canada Reporters C. W. Allen, University of Vermont, U.S.A. D. W. Allen, Sheffield City Polytechnic 0. Dahl, University of Copenhagen, Denmark R. S. Edmundson, formerly of University of Bradford C. D. Hall, King’s College, London
4 *&$ &@
ROYAL SOCIETYOF CHEMISTRY
ISBN 0-85186-186-5 ISSN 0306-0713 Copyright @ 1989 The Royal Society of Chemistry All Rights Reserved No part of this book may be reproduced or transmitted in any form or by any m e a n s - g r a p h i c , electronic, including photocopying, recording, taping, or information storage and retrieval systems-without written permission from The Royal Society of Chemistry
Published by The Royal Society of Chemistry Thomas Graham House, Cambridge CB4 4WF Printed in Great Britain by Whitstable Litho Printers Ltd., Whitstable, Kent
Introduction Organophosphorus chemistry continues to provide unexpected examples of reactivity to surprise the experimenter and tease the mind, and the reaction of triethylphosphite and malononitrile to afford bis(cyano)methyl diethylphosphonate and ethane provides such an instance. Mechanistic studies appear to exclude the involvement of nucleophilic catalysis in the reactions of phosphoramidites with alcohols catalyzed by amine hydrochlorides. Dinucleotide phosphorodithioates, in which the phosphorus atom forming the inter-nucleotidic link bears two sulphur atoms and is achiral, have been reported for the first time, and exemplify the continuing interest in nucleotide and oligonucleotide analogues containing modified phosphate groups, especially oligonucleotides which are of potential use for the control of gene expression. Phosphorothioates have proved to be particularly useful in a number of areas: they can protect oligonucleotide sequences from digestion by nucleases, they are exploited in a site-directed mutagenesis procedure which affords particularly high mutant yields, they appear to offer advantages in genetic control using anti-sense oligonucleotides in comparison to oligonucleoside methylphosphonates or phosphotriesters, and they have now been utilized in a gel sequencing procedure for nucleic acids appiicable to both DNA and RNA. Much attention has also been applied to the synthesis of oligonucleotides containing anucleoside residues and/or otherwise derivatized in such a way as to effect the site-specific modification or cleavage of nucleic acids. Much effort has also been directed to the synthesis of the physiologically active polyphosphates of myo-inositol. There is increasingly convincing evidence for the generation of the highly reactive metathiophosphate, as indicated by studies of the chirality of thiophosphate products formed, and elegant mechanistic studies using chiral phosphates labelled with oxygen-17 and oxygen-18 continue to be described. Lawesson's reagent is finding increasing use for sulphurizations and in the synthesis of ring systems. Interest in pX-bonded phosphorus compounds continues at a high level with a substantial increase in the number of papers published compared to last year. The further decline in the number of publications dealing with hypervalent systems reflects the level of understanding of this type of chemistry that has been acheived. Among many notable contributions, however, a number deserve special mention since they represent new
vi
Organophosphorus Chemistry
departures in the area or report particularly elegant experiments. Kolodyazhnyi et a/ have prepared a series of 1-fluorooxaphosphetans from -P-fluoroylids and Vedejs has offered more evidence on the mechanism of the Wittig reaction involving phosphetans as intermediates. A number of phosphoranes with exocyclic anionic groups have been described by Garrigues and Munoz which lead to good models for the intermediate postulated in the hydrolysis of enol-pyruvate phosphate esters. Finally, Denney has provided evidence for hexa-co-ordinate structures as intermediates in ligand reorganisation of phosphoranes containing ether linkages within their exocyclic groups. Phosphorus-based olefination continues to be used as the method of choice for the synthesis of alkenes from the simplest to the most complicated. Phosphorus ylide-anions are reported to have many of the advantages of both ylides and phosphonyl- and phosphonyl-stabilised carbanions and appear to offer an alternative to these reagents in olefination reactions. Interest in the mechanism of the Wittig reaction continues and perhaps the most significant result in this area is that the formation of trans-oxaphosphetanes can be kinetically-favoured while &,oxaphosphetanes can be thermodynamically-favoured in some cases; previously the opposite had always been assumed to be the case. In phosphazene chemistry, there has been strong interest in the phosphazene unit acting as an N-bonding ligand towards transition metals both in linear and cyclic systems. The phosphazene is a strong donor and promotes metal-nitrogen multiple bonding. The fact that peralkylated polyaminophosphazenes are exceptionally strong, non-nucleophilic bases, suggests another applicatiorl of phosphazenes to synthetic organic chemistry. After the initial report last year, a large number of 2-D, and other sophisticated, NMR techniques have been applied to the study of cyclophosphazenes, particularly the numerous, complex structures derived from the reactions of polyamines with (NPC12 E 2)3. Synthesis and physiochemical characterization studies of poly(ph0sphazenes) continue unabated with interest in phosphazene based membranes increasing. Owing to the pressure of other committments one of our regular contributors has been unable to provide the usual Chapter on “Physical Methods” in this Volume. We hope that this area will be covered as usual in the next Volume in this series.
J B Hobbs and B J Walker
Contents CHAPTER
1
Phosphines and Phosphonium Salts B y D.W. A l l e n
1
Phosphines
1
1.1 Preparation
1
1.1.1
1.1.2 1.1.3 1.1.4 1.1.5
2
1 3 8 8 11
1.2 Reactions
13
1.2.1 1.2.2 1.2.3 1.2.4
13 13 14 16
Nucleophilic Attack at Carbon Nucleophilic Attack at Halogen Nucleophilic Attack at Other Atoms Miscellaneous Reactions
Halogenophosphines
19
2.1 Preparations 2.2 Reactions
19 19
Phosphonium Salts
23
3.1 Preparation 3.2 Reactions
23 26
4
p -Bonded Phosphorus Compounds
30
5
Phosphirenes, Phospholes, and Phosphorins
39
References
42
3
CHAPTER
From Halogenophosphines and Organometallic Reagents From Metallated Phosphines By Addition of P-H to Unsaturated Compounds By Reduction Miscellaneous Methods
2
Pentaco-ordinated and Hexaco-ordinated Compounds By C.D. Hall
1
Introduction
52
2
Structure, Bonding, and Ligand Reorganisation
52
3
Acyclic Phosphoranes
56
4
Ring Containing Phosphoranes
56
4.1 Monocyclic Phosphoranes 4.2 Bicyclic and Tetracyclic Phosphoranes
56 62
References
70
...
Organophosphorus Chemistry
Vlll
CHAPTER
CHAPTER
3 1
Introduction
72
2
Preparation of Acyclic Phosphine Oxides
72
3
Preparation of Cyclic Phosphine Oxides
72
4
Structure and Physical Aspects
74
5
Reactions at Phosphorus
78
6
Reactions at the Side-chain
78
7
Phosphine Oxide Complexes
a5
References
85
4
Tervalent Phosphorus Acids By 0. Dahl
1
Introduction
87
2
Nucleophilic Reactions
87
2.1 Attack on Saturated Carbon 2.2 Attack on Unsaturated Carbon 2.3 Attack on Nitrogen, Chalcogen, or Halogen
87 90 95
Electrophilic Reactions
95
3
4
CHAPTER
Phosphine Oxide and Related Compounds B y B.J. W a l k e r
3.1 Preparation 3.2 Mechanistic Studies 3 . 3 Use €or Nucleotide, Sugar Phosphate, or Phosphoprotein Synthesis 3.4 Miscellaneous
106 109
Reactions involving Two-co-ordinating Phosphorus
109
References
114
5
Quinquevalent Phosphorus Acids By R.S. Edrnundson
1
Phosphoric Acids and their Derivatives
95 102
119
1.1 Synthesis 119 1.2 Reactions 128 1.3 Synthetic Uses of Phosphoric Acid Derivatives 137 2
Phosphonic and Phosphinic Acids and their Derivatives
138
2.1 Synthesis 2.2 Reactions 2.3 Synthetic Uses
138 152 165
References
165
1x
CHAPTER
6
Nucleotides and Nucleic Acids By J . B . Hobbs
1
Introduction
172
2
Mononucleotides
172
2.1 Chemical Synthesis 2.2 Cyclic Nucleotides
172 185
3
Nucleoside Polyphosphates
188
4
Oligo- and Poly-nucleotides
200
4.1 Chemical Synthesis 4.2 Enzymatic Synthesis
200 219
Other Studies
224
5.1 5.2 5.3 5.4 5.5
224 227 230 242 246
5
6
CHAPTER
Affinity Separation Affinity Labelling Sequencing and Cleavage Studies Post-Synthetic Modification Metal Complexes
Analytical Techniques and Physical Methods
248
References
253
7
Ylides and Related Compounds B y B . J. Walker
1
Introduction
267
2
Methylenephosphoranes
267
2.1 Preparation and Structure 2.2 Reactions
267 270
2.2.1 2.2.2 2.2.3 2.2.4
Aldehydes Ketones Ylides Co-ordinated to Metals Miscellaneous Reactions
270 276 276 279
3
Reactions of Phosphonate Anions
283
4
Selected Applications in Synthesis
290
4.1 Alkaloids 4.2 Carotenoids and Related Compounds 4.3 Leukotrienes and Related Compounds 4.4 Macrolides and Related Compounds 4.5 Pheromones 4.6 Prostaglandins 4.7 Miscellaneous Reactions
290 294 294 294 298 298 302
References
311
Organophosphorus Chemistry
X
CHAPTER
8
Phosphazenes B y C.W. Allen
1
Introduction
315
2
Acyclic Phosphazenes
315
3
Cyclophosphazenes
323
4
Cyclophospha(thia)zenes
332
5
Miscellaneous Phosphazene Containing Ring Systems 333
6
Poly( phosphazenes )
334
7
Molecular Structure of Phosphazenes
341
References
344
AUTHOR INDEX
353
Abbreviations bisazoisobutyronitrile Chemically Induced Dynamic Nuclear Polarization Complete Neglect of Differential Overlap cyclopentadienyl diethyl azodicarboxylate 1,5-diazabicycloi4.3.0 Inon-5-ene 1 5-diazabicyclo[5.4.0 hndec-5-ene
AIBN
CIDNP CNDO
CP
DAD
DBN DBU IXC DIOP
I
dicyclohexylcarbodi-hide [ ( 2 I 2-dimethyl-l,3-dioxolan-4, 5-diyl )bis- (methylene)1
DMF DMSO DKtY
MTA E.H.T. ENU
FID g .1.c -m..s. HMPT h.p.1 .c. i.r. L.F.E.R.
.
MIND0 MMk
MI MS-Cl
blS-nt MS-tet NBS
n.q.r. p.e. PPA SCF TBDMS TDAP
T%AA Tf 23 THF
Thf ThP TIPS t.1.c. TPS-CI
TPS-nt TPS-tet TsOK U.V.
bis(dipheny1phosphine) dimethylformamide dimethyl sulphoxide 4,4'-dimethoxytrityl ethylenediaminetetra-acetic acid Extended Huckel Treatment Wethy 1-Wnitrosourea Free Induction Decay gas-liquid chrmtography-mass spectrometry hexamethylphosphortriamide high-performance liquid chromatography infrared Linear Free-Energy Relationship Wdified Intermediate Neglect of Differential Overlap 4-mnanethoxytrityl mlecular Orbital mesitylenesulphonyl chloride mesitylenesulphonyl-3-nitro-l,2,4-triazole mesitylenesulphonyltetrazole Sbrmsuccinimide nuclear quadrupole resonance photoelectron plyphosphoric acid Self-consistent Field t-butyldimethylsilyl tris(diethy1amino)phosphine trifluoroacetic acid trifluormthanesulphonic anhydride tetrahydrofuran 2-tetrahyd1ofuranyl 2-tetrahydropyranyl tetraisopropyldisiloxanyl thin-layer chrmtography tri-isopropylbenzenesulphonyl chloride tri-isopropylbenzenesulpt.lonyl-3-nitro-l,2,4-triazole tri-isoproplybenzenesulphonyltetrazole toluene-p-sulphonic acid ultraviolet
* Abbreviations used in Chapter 6 are detailed in Biochem. J.,1970,120,449 and 1978,171,l
1
Phosphines and Phosphonium Salts BY D. W. ALLEN
1 Phosphines 1.1 PreDaration 1.1.1 From HalogenoDhosphines and OrPanometallic Reagents. Grignard reagents derived form chloromethyl ethers have been used in the synthesis of the alkoxymethylphosphines ( l p 3 A series of phosphine ligands bearing a silicon-containing back-bone, u, (2), has been prepared by the reactions of chlorodiphenylphosphine with Grignard reagents derived from a- haloalkylsilanes! Sequential alkylation of aryldichlorophosphines has been achieved using bulky Grignard reagents, giving rise to chiral phosphines, (3), in good yield? Grignard procedures have also been employed in the synthesis of chiral phosphines-, (4), derived from the a- pinene system! the substituted thienylphosphines (5): and the ''C-labelled phosphine (6)? The reaction of methylmagnesium halides with phosphite esters in ether affords a route to high purity trirnethylphosphine. The generation of organolithium reagents by the metallation of readily available substrates using butyllithium or lithium di-isopropylamide continues to be a popular strategy for the synthesis of unusual phosphines. Metallation of acetonitrile affords cyanomethyllithium, which on treatment with chlorodiorganophosphines gives the cyanomethylphosphines (7)." Treatment of bis(cyclopentadieny1)chromium with butyllithium, in the presence of TMEDA, results in the formation of the 1,l'-dilithio derivative which, with tetramethyldiphosphine, results in the new bidentate ligand (@.I1 Two more reports have appeared of the synthesis of 10-phenylphenoxaphosphine (9) based on the direct di-metallation of diphenyl ether.12913 Full details have now appeared of the synthesis of tris- and tetrakis- (dipheny1phosphino)allenes (lo), based on the reaction of chlorodiphenylphosphine with the product of metallation of diphenylpropynylphosphinein the presence of b~tyllithium.'~In a similar vein, metallation of 1,l-dimethylallene using lithium di-isopropylamide is the key step in the synthesis of the monophosphinoallene (11). Subsequent metallation of (11) at carbon adjacent to phosphorus, using butyllithium, affords a
-
2
R~, P(CH~OR*i3-" (1 1
R' = atkyI or Ph;
Ph2P
R2 = a l k y l ; n =o-2
CH2
( 5 ) R = H, Me,Bu', or Me3Si
(4)
RZPCH2CN
(7)
R = alkyl or Ar
(9)
Me Ph2P
Me
(10) R = H or PPh,
R
R
Q+
PPh2 P P b
(13) R = Me or NEt2
Me
(11)
(12)
1: Phosphines and Phosphonium Salts
3
route to the geminal bis(phosphino)allene (l2).'* Organolithium reagents derived from the appropriate 6,6' -disubstituted 2,2' dibromobiphenyl have been employed in the synthesis of the chiral diphosphines (13),which have been resolved the use of chiral palladium complexes.16 The reaction of Qlithiophenyldimethylphosphinewith triphenylphosphite has given the tetradentate phosphine ligand A simple route to tris(trimethylsily1)phosphine is afforded by the reaction of lV(dich1orophosphino)piperidine with lithium and chlorotrimethylsilane.18 Organolithium reagents, Grignard reagents, and, an unusual alternative, the trimethylsilyl derivatives of heterocyclic systems, have been used to convert bis(dich1orophosphino)-methane and -ethane into a variety of new, chelating, diphosphine ligands, w, The reaction of the sodium enolate of ethyl acetate with isopropyldichlorophosphine provides a route to the phosphinocarboxylate ester (16), and hence, by hydrolysis, the corresponding phosphinodicarboxylic acid. Such compounds, involving bulky electron-donating substituents a t phosphorus, cannot be prepared &t the use of the Reformatsky reagent derived from ethyl bromoacetate, previously employed by these workers in the synthesis of related systems?' Phosphorus-carbon as well as phosphorus-oxygen linkages are formed in the reactions of cyclometallated pal(17),with halogenophosphines, giving novel ladium phosphinoenolates, ligand systems, u,(18).21
-
=,
1.1.2 Preparation of Phosphines from Metallated Phosphines.- Further examples of stable crystalline complexes of lithiophosphide reagents with TMEDA or THF have been reported, 22923enabling &ray structural studies to be carried out. Two groups have reported the reactions of the dilithiodiphosphide (19)with dichlorometallo-organic reagents to give heterocyclic systems (20)?3924A 31P n.m.r. s t u d g 5 of the lithium-cleavage of cypbis(dipheny1phosphino)alkanes, Ph2P(CH2)nPPh2, (n = 1-S), has shown that in all cases except bis(diphenylphosphino)methane, the dilithiodiphosphide reagents (21) are the principal products. However, in the case of bis(dipheny1phosphino)methane, the products are lithium diphenylphosphide and lithiomethyldiphenylphosphine. Cleavage of a diphenylphosphino group from bis(dipheny1phosphino)ethane was also observed a s a side reaction, in varying amounts up to 30% conversion. Also of interest is the observation that attempted removal of the cleavage product, phenyllithium, using t-butyl chloride, leads to the formation of But-P linkages in the case of bis(diphenylphosphin0)-ethane and
-
Organoph osp h orus Chemistry
2
(15) Ph
I
P-Li P-
I Li
(17)
(19 1
Ph2 (181
Ph a P : M PR 2
aR
PhPLi(CH2), PLiPh
Ph zP
Ph
(20) R = alkyl or 715-Cp;
(21)
(22)
M =Sn,Ti,Zr or Hf
PhR' P,
XMe
P Phz2p
PhR'P
(23) R' = H, alkyl or b e n z y l ; R2 = H , benzyl or COR
H
(24)
(25)
OH
R A P P h , I
Ph,
I
P (26)
Ph
CHZ
CHz
PA r2
PA rz
I
I
( 2 7 ) Ar = rn-CF3C6Hb
5
I : Phosphines and Phosphoniurn Salts
propane, unless the reactions are conducted below -10 *C. Lithium-induced cleavage of phenyl groups from the diphosphine (22)provides a route to a new series of chiral diphosphine ligands (23)F6 The unsaturated diphosphine (24) has been isolated in low yield (m 10%) from the reaction of lithium diphenylphosphide with 1,l-dichloro-1- propene. Addition of primary and secondary phosphines to the double bond of (24)provides a route to chiral triphosphine ligands, u, (25)?7 Lithiophosphide-induced ring-opening of epoxides and displacement of tosylate groups are involved in a three-step conversion of achiral allylic dcohols into the chiral diphosphines (26).28 Displacement of benzylic halogen is the key step in the synthesis of the "trans-spanning" bidentate phosphine (27)F9 Halogen-displacement from reactive alkyl halides by lithiophosphide reagents has also been utilised for the preparation of a range ( 2 8 ) : ' (29):' and of new phosphines possessing additional functionality, (30)?2 The photostimulated displacement of bridgehead halogen by phosphide reagents, giving systems of type (31), appears to involve the S R N ~ me~hanism.3~ Various polyphosphorus anions, which have considerable potential for the synthesis of new phosphines, have been obtained by the ring-opening of pentaphenylcyclopentaphosphine with organo-lithium and organosodium reagent^?^ The reactions of lithiophosphide reagents with halogenoboranes have been used for the synthesis of a range of boron-phosphorus heterocyclic c o m p o ~ n d s , w, 3 ~ ~(32), ~ a planar system in which all boron-phosphorus bonds are equal in length and shorter than other single bonds between these elements, implying the existence of a delocalised boronphosphorus 7r-system. There is, however, no evidence of a n aromatic "ring-current" in n.m.r. studies. 37 Sodium- and potassium-organophosphide reagents have also found extensive application in the past year. The reactions of sodium methyl(pheny1)phosphide with various alkyl halides in liquid ammonia have yielded a series of chiral phosphines?8 However, in the case of related reactions with t-butyl halides, the outcome depends on the nature of the halogen. Whereas t-butyl bromide gives the expected tertiary phosphine, t-butyl chloride suffers elimination, resulting in the protonation of the phosphide reagent?9 A partial alkylation of phenylphosphine, to give (33),has been achieved by the reaction of monosodium phenylphosphide with dichloro- or dibromo-methane, and also by the reaction of the methylene dihalides with phenylphosphine and potassium hydroxide in aqueous dimethylsulphoxide or aqueous dimethylformamide. 40 The chiral secondary phosphine (34),from which a series of chiral phos-
=,
6
Organophosphorus Chemistry
R PK H 2 CH *oR213-
(28) R' = Ph OT C6Hll R2 = Me or Pri; n = 0,l or 2
Ph2PCH2SMe ;
Ph2PCH$ONHMe
(29)
( 30)
H
P ,Ph
Ph2P*R (31)
R = Hal or PPh,
CH2-P
/
H
'Ph
CY
(33)
(32)
H
( 34)
\
h
(35) R2P = 5-dibenzophospholyl or
R
(37)
R
(38)
(39) R = H,Et ,Me,Si or But
X(SiMe3)C=PMe2
I
(42) X = Me3Si or Me2P R' ( 4 3 ) R' = PhCH,; R 2 =H
I : Phosphines arid Phosphoriium Salts
7
pholanes is accessible yia the PH functionality, has been prepared by the reaction of a ditosylate ester, derived from tartaric acid, with sodium dihydrogenphosphide!’ Similar reactions of sodium diorganophosphides with tosylates and mesylates have been employed in the synthesis of the chiral diphosphines (35)42 and (36)43. Issleib’s group has described several applications of diphos(37), for the synthesis of heterocyclic u phide reagents, u, (38).45 These studies have also revealed the unexpected formation of the tetracyclic system (39) in such cyclisation reactions of g-phenylene diphosphine The aminoalkylphosphine (40) has been prepared by the react ion of 0 -chloroet hyl (benzy1)amine with potassium diphenylp hosp hide!7 A stereoselective reduction of mdichlorocyclopropanes occurs on treatment with potassium diphenylphosphide in liquid ammonia in the dark, yielding rnonochlorocyclopropanes!8 A stereospecific synthesis of chiral, coordinated, alkylation of a coordinated secontertiary phosphines has been achieved dary phosphine in the presence of potassium t-b~toxide.4~ Arylation of diphenylphosphine, to form triphenylphosphine, occurs on treatment with chlorobenzene in the presence of potassium hydroxide in aqueous dimethylsulphoxide. 50 Baudler’s group has continued to exploit the reactivity of metallophosphide reagents in the synthesis of polyphosphines of ever-increasing complexity.5 1-54 Among these is the polyphosphinostibine (41),54 a yellow solid which decomposes above -30 ‘C, or on exposure to light. There has also been considerable interest in the synthesis of heavily silylated p o l y p h o s p h i n e ~ particularly ~~-~~ 63 by Fritz and co-workers, and this area has been reviewed. Several groups have reported the synthesis of organophosphido derivatives of other main group metals, u, gallium, and and of transition metals, e.g., copper, silver and gold.66 Carbon dioxide undergoes insertion into the molybdenum- phosphorus bond of molybdenum diorganophosphides to form phosphinocarboxylate l i g a n d ~ .The ~ ~ coordination chemistry of phosphinomethanide ligands continues to be exploited by Karsch and co-workers,68” who have reported stable complexes of these systems with both main group68-70 and transition metals?’ Whereas the simple dimethylphosphinomethanide anion is oxidised by nickel@) chloride to form 1,2bis(dimethylphosphino)ethane, related phosphinomethanide anions bearing additional anion- stabilising substituents a t the carbanionic carbon undergo metal- promoted coupling with the formation of phosphorus-phosphorus linkages, to give a novel type of bisylide (42)?’
8
Organophosphorus Chemistry
1.13 PreDaration of Phosphines bv Addition of P-H to Unsaturated Compounds.- This route has found a number of applications in the synthesis of cyclic phosphines. Cyclocondensation of benzylphosphine with vinyl isocyanide in the presence of potassium t-butoxide has given the 13-azaphospholine (43)?3 Addition of phenylphosphine to the unsaturated ketone (44) yields the bicyclic phosphorinanone (45)?4 Photolysis of phenylphosphine with divinylsulphide has given the 1,4- thiophosphorinane (46), but in only 5.7% ~ i e l d . 7A ~ metal template effect has been exploited in the preparation of new crown-phosphine ligands. Thus, diethylamino(diviny1)phosphine undergoes addition to the P-H functional nickel@) complex (47) to give the complex (48), from which it has not been possible to displace the metal ion, even on treatment with cyanide ion?6 The unsaturated secondary phosphine (49) undergoes intramolecular addition of P-H to the double bonds to give a mixture of the isomeric bicyclic systems (50) and (51)?7 A variety of acyclic phosphines has also been prepared by this route, many of which have interesting additional functional groups. Addition of a primary phosphine to an imine is involved in the synthesis of (52)?8 Additions to vinylstannanes and vinylsilanes have given the phosphines (53)79 and (54). 80
Subsequent elaboration of the latter with cyclopentadienyl sodium, followed by treatment with butyllithium and iron(II) chloride has given the ferrocene system (55).8' Base-catalysed addition of phenylphosphine to 1,l-bis(dipheny1phosphino)ethene has given the new pentadentate ligand (56).8' Further examples of addition of secondary phosphines to isothiocyanates have been reported, leading to the chiral systems (57).82 New chelating diphosphines have been assembled in the coordination sphere of a transition metal by the Michael type addition of coordinated P-H systems to@-unsaturated carbonyl compounds. Additions to both C = C and C = 0 bonds have been 0bserved.8~ 1.1.4 Preparation of Phosphines by Reduction.- Trichlorosilane continues to find use as a reagent for the reduction of phosphine oxides, the past year having seen it used in the synthesis of several new chelating diphosphines, (58),s4 (59)85and (60). Subsequent dehalogenation of the latter, using zinc, has given the bis(phosphin0)butadiene (61).86 A route for the regeneration of triphenylphosphine from its oxide has been developed which involves conversion of the oxide to the corresponding sulphide, treatment with dimethyl sulphate to form the thiomethylphosphonium salt, electrolytic reduction of which
1: Phosphines and Phosphonium Salts
9
(46
1'
NEt2
I
L
J
Ph
Me3SnCHRCHzPPhz
ClMe2SiCH;! CH2PP hz
(53) R =Me,Ph,Me3Si o r E t
(54)
QSi
Me2CH CH,P Phz
ph2p)-?y
I
i
(&Me2 (55)
(Ph2P)ZCH CH,CH, PPh2
CHR' R2
CH(PPh2)z
(56)
1
(57) R =Me or Ph; R2= Et or Pr'
0rgan oph osph oriis Chern istry
10 y
2
(60) X = halogen
PhzP QP.1
R2
-
xPPh2 (61
--+ PR’ R2
(62) R’= Ph, o -to[, p - Me2NC,H,
(63)
or Pr‘
PhZPCH2 H
“-.iq.“YO
CH2PPh2
-
CH2=C
/R
\
Me \
CH =CH
PH2
\ PH2
CH20(CH2CH2C),Me
or
(64) n = -16
42
( 6 5 ) R = H or Me
(66)
‘5
MeHP(CH2), PHMe
I1
S
(67)/I = 3 0r4
(69) R = HorMe
R’ 2PCtl(OR2 l2
(70) R! R: R 3 = alkyl
(71 1
0 ( 7 2 ) R = P h or But
1: Phosphines and Phosphoniurn Salts
11
provides the phosphine?’ The Birch reduction has been applied to a range of phenylphosphines (62), which on treatment with sodium in THF and liquid ammonia form the reduced systems (63), together with varying amounts of the phosphide anion resulting from phenyl cleavage.88
1.1.5 Miscellaneous Methods of Preparing Phosphines.- Interest in the synthesis of water-soluble phosphines continues, routes to the water-soluble chiral diphosphines (64) having been described, 89 and the area as a whole reviewed?’ Two further reports have appeared of the formation of the vinylphosphines (65) and (66) by flash-vacuum-thermolysis of Diels-Alder adducts of these phosphines with anthracene, cyclopentadiene, and 13- diphenylisobenzofuran, which are accessible by indirect routes?1992 Attempts to prepare a silyl ester of Me2PSH by treatment with dimethylaminotrimethylsilane unexpectedly resulted in the formation of the monosulphide of tetramethyldiphosphine, thereby establishing a new method of forming the phosphorus- phosphorus bond. Application of this approach to the disulphides of bis(secondary phosphines) (67) has given the monosulphides of cyclic _P,,P-diphosphines (68)?3 The tetracyclic system (69) is formed in the reaction of thioanisoles with phosphorus trichloride and aluminium ~ h l o r i d e ? The ~ protected formylphosphines (70) are converted into the alkyoxycarbonylphosphines(71) on treatment with chloroform ate^?^ A series of cyclic acylphosphines, u,(72), has been prepared by the reactions of di-acid chlorides or the corresponding acid anhydrides with bis(trimethylsily1)phosphines. These compounds exhibit the usual reactivity at phosphorus on treatment with hydrogen peroxide, sulphur, iodine or transition metal acceptors, but undergo ring cleavage on treatment with chlorine or methanol?6 A patent for the synthesis of diphenylphosphine by the thermal disproportionation of diphenylphosphine oxide has ap~ e a r e d . ~New ’ macrocyclic diaminophosphines (73)are accessible by the reactions of precursor acyclic a,o-bis(2-aminophenyl)polyetherswith bi~(dirnethy1amino)phenylphosphine~~ The macrocyclic diphosphines (74) have been isolated from the mixture of oligomers which results from the reaction of bis(2- mercaptoethy1)phosphines with di-t-butyldimethoxystannane. 99 Elaboration of other functional groups present in ferrocenyl diphosphines has led to a new series of chiral diphosphine ligands (75).lo0
12
Organophosphorus Chemistry R
%I
NH
s
S
sn '2
Y;"
HN
IV
\ P/ Ph
( 7 3 ) n = 1 or 2
Ph3kH2CH2CO R X' (77)
(75) R=Bu or Pri
Bu'2PCHR'OR'
K'4
ButzP-
( 8 0 ) R' = H,CI or Ph; RZ = Me or Et
C-R'
0 0
C
H
(82) R' = Et Pr'; RZ = H, Pr or Pr'
(81)
R -P
2C H Z PPh,
I
p 'OR
ph2pB 0
(86)
/
(87)
1: Phosphiries and Phosphoniuni Salts
13
1.2 Reactions of Phosphines L2.1 Nucleophilic Attack at Carbon.- Nucleophilic attack at C-3 of the heterocyclic system occurs in the reactions of 3-aryl-5- methyl-1,2,4oxadiazoles with triphenylphosphine a t ca 200 'C, with the eventual formation of cyanoarene, acetonitrile and triphenylphosphine oxide. lo' Studies of the react ion between tributylphosphine and bis(et hoxythiocarbonyl) suIphide reveal an increase in the conductivity of the system followed by a gradual decline, indicating the initial formation of the ionic system (76), followed by slow decomposition of the anion to form carbon disulphide. This then forms the expected adduct with the phosphine.lo2 The importance of steric and conformational effects has been demonstrated in a study of the reactivity of cyclic epoxides towards tripheny1pho~phine.l~~ Michael-additions of triphenylphosphine toq3-unsaturated carbonyl compounds to form 3-oxoalkylphosphonium salts (77) are promoted in the presence of 2,6-lutidinium salts as the proton source.lW The reaction of tributylphosphine with diphenylacetylene at 190 O C results in the formation of the zwitterion (78), protonation of which gives the related vinylphosphonium salt.lo5 In a similar vein, the corresponding reaction with propargyl alcohols results in reduction of the triple bond to the corresponding substituted vinyl alcohol, with formation of tributylphosphine oxide.' O6 1.2.2 Nucleophilic Attack at Halogen.- N.m.r. studies have revealed that the course of the reaction between tris-(t- buty1)phosphine and iodine in dichloromethane is more complex than might appear a t first sight. Distinct signals for the products are not observed, and the n.m.r. parameters change continuously during the addition of the reagents, and also beyond the 1:l equivalence point. These observations have been explained in terms of the rapid establishment of equilibria between dihalophosphorane and halophosphonium salt, and also between halophosphonium cation and phosphine. Also reported is an X-ray study of di-iodotris-(t-butyl)phosphorane,which has the rather unusual linear structure (79).'07 Nucleophilic attack on halogen is believed to be the initial step in the ring-opening of a-bromocyclopropyl ketones on treatment with triphenylphosphine in refluing methanol."* A 1,2(P-, C)chlorotropic rearrangement occurs in the reaction of the alkoxymethylphosphines (80) with carbon tetrachloride, which results in the achloroalblphosphines (8l).'O9 In contrast, alkylbis(dia1kylamino)phosphines are converted to the ylides (82) in this solvent. 110
14
Organophosphorus Chemistry
Applications in synthesis of phosphine-positive halogen reagents continue to appear. Combination of the phosphine (83) with carbon tetrachloride provides an efficient and mild reagent system for conversion of alcohols to chloroalkanes, with the advantage that the phosphine oxide biproduct is easily removed by acid- extraction.'" Allylic and homoallylic rearrangements of steroidal alcohols during halogenation with triphenylphosphine- carbon tetrachloride are indicative of a substantial ionic character in the halogenation reaction.'12 Hydroxymethylpyridines have been converted into the related cyanomethyl derivatives on treatment with triphenylphosphine- carbon tetrachloride in the presence of potassium cyanide and 18- crown-6 in a~etonitri1e.l'~Further examples of the use of hexachloroethane as the halogenating solvent have appeared. In combination with a polymer-bound and with triphenylphosphosphine, it has been used to prepare polyamides, phine in the presence of triethylamine, it provides a source of dichlorotriphenylphosphorane for the generation of nitrilim-ines from N-acylated hydrazines, the nitrilimines then being trapped in-situ with dip01ariphiles.l'~ Combination of triphenylphosphine with ethyl trichloroacetate has been used for the chlorination of primary and secondary alcohols.'16 Direct chlorination of triphenylphosphine, and also polymerbound phosphines, in dichloromethane provides a system which converts dialkyl phosphonate esters into the chloroesters (84).'"
1.23 Nucleophilic Attack at Other Atoms.- A study of the Mitsunobu reaction conducted in a poorly nucleophilic solvent (trifluoroacetic acid) has revealed the existence of a dual mechanism. Depending on the order of addition of the reactants, the reaction proceeds either (a) exclusively by slow conversion of the protonated betaine to an alkoxyphosphonium s a l t e r (b) by rapid conversion of a dialkoxyphosphorane to the same alkoxyphosphonium salt, with recycling of the liberated half- equivalent of alcohol by pathway (a) (Scheme 1). Addition of sodium benzoate resulted in a dramatic increase in the rate of the reaction, giving trifluoroacetyl esters in high yield, and providing the basis for an unusually mild procedure for the inversion of certain secondary alcohols.'l8 A series of bis(phospha- X5-azenes), w, (85), has been prepared by the reactions of the bis(dipheny1phosphino)alkane with various amides in the presence of diethyl az~dicarboxylate.'~~ Combination of triphenylphosphine with diisopropyl azodicarboxylate has been used to form large ring cyclic phosphoranes from long chain a,w-diols,12'. Triphenylphosphine-azodicarboxy-
15
I : Phosphines and Phosphonium Salts
+
Ph3P
Ph3;-
EtO;!CN=NCOZ
Et
N-NCO;!Et
I
C02Et $H
+
Ph3P-N
I
(*H
/OR Ph3P
-NHCQEt
'OR
CO;!Et
+
Ph3POR X -
RX
+
k'ow Ph,PO
Scheme 1
(91)
(92)
16
Orgun op h osp h orus Chernistry
late reagents have also been used for the direct conversion of a-hydroxy esters to protected a-_N-hydroxyamino acids.121 A comparison of the reactivity of triphenylphosphine-benzoylperoxide and triphenylphosphine-diethylazodicarboxylate-benzoic acid reagents systems for the chemoselective benzoylation of 1,2-diols has shown that both appear to behave in a very similar manner. Monobenzoylations of 1,2-propanediol with these reagents afford a predominance of the more sterically crowded C2-benzoate, with complete inversion of configuration.122 Nucleophilic attack at nitrogen is also involved in further examples of the reaction of phosphines with bridgehead a ~ i d e s , and '~~ also with tetrasulphur tetranitride. 124
Tetrakis-(t-buty1)diphosphine is oxidised by dioxygen to the diphosphine dioxide, whereas the monoxide can be obtained from the reaction with cumene h y d r ~ p e r o x i d e .The ~ ~ ~order of reactivity of a series of triarylphosphines, bearing polynuclear hydrocarbon substituents, u,(86) and (87), towards hydroperoxides reflects the increasing steric crowding a t phosphorus as the size of the substituent increases.126 Phosphines are converted into the corresponding sulphides on treatment with Lawesson's reagent in refluxing benzene.I2' The tributylphosphine-2,2 ' -bis(benzothiazolyl)disulphide combination has been used in a procedure for the conversion of secondary alcohols to the corresponding parent hydrocarbon.128 Nucleophilic attack a t phosphorus appears to be involved in the reaction of tripropylphosphine with dithiophosphorochloridites which, a t low temperatures, give the phosphino-phosphonium salt (88). On raising the temperature, this then decomposes to give the salt (89), which in turn eventually gives rise to tripropylphosphine sulphide. 129 1.2.4 Miscellaneous Reactions of Phosphines.- A study of the autoxidation and basicity towards perchloric acid in nitromethane solution of the bisphosphinoalkanes (90), (which are reported to have antitumour properties), has revealed the expected features, i.e. diethylphosphino centres are both more easily oxidised and more basic than the diphenylphosphino centres.13' Phosphine basicities have also been studied by enthalpies of protonation in 1,2dichloroethane as determined by titration The efficiency of a series of methoxyphenylphosphines a s extractants for gallium(III) from acid solution is dependent on their basicity, the highly basic phosphine (91) being the most effective.132 This phosphine also catalyses the Michael addition of some nitroalkanes to a$-unsaturated esters and nit rile^.'^^ The reactions of the sterically crowded primary phosphine (92) with various reagents capable
I : Phosphines und Phosphonium Salts
17
of acting as hydrogen acceptors have been rep01-ted.I~~Anodic oxidation of tertiary phosphines generates cation radicals which then are subject to attack by nucleophilic components of the s01vent.l~~ The water-soluble triarylphosphine (93) has been shown to undergo rapid oxidation even in the absence of oxygen when present in aqueous solutions containing rhodium(III) compounds, the latter suffering reduction to r h ~ d i u m ( I ) . ' ~Tertiary ~ phosphines are reported to form highly coloured charge-transfer complexes with p o l y n i t r ~ a r e n e s .Treatment ~~~ of the heterocyclic phosphine (94) with potassium amide in liquid ammonia does not lead to cleavage of the exocyclic phenyl group, but results in proton removal to generate the phosphaanthracenide anion (95) in which the negative charge is delocalised the porbitals of the ring carbons. No significant n.m.r. ring-current effects due to the anion have been observed.138 Exchange reactions of tetraethyldiphosphine with secondary arsines lead initially to phosphino-arsines, u.,(96), which then undergo self-exchange to form the tetra-alkyldiarsine and the original d i p h ~ s p h i n e . ' ~ ~ Further examples of cyclocondensation reactions of bis(hydroxymethy1)phenylphosphine have appeared. With various acetals and ketals, the heterocyclic system (97) is formed.14' In related work, condensation of phenylphosphine, an aldehyde and an alkoxydiphenylborane yields the nvitterionic heterocycle (98), which, on treatment with a second aldehyde, is transformed into the heterocyclic phosphine (99).14' Phosphorus-boron-oxygen heterocycles have also been formed in the reactions of the C- functionalised phosphine (100) with aromatic a 1 d e h ~ d e s . lThe ~ ~ four-membered ring polyphosphino-zirconium system (101) undergoes ring-expansion on treatment with ethyl diazoacetate to form the six-membered ring system (102).143 The diselenadiphosphetane (103) is formed in the reaction of phenylphosphine with a complexed transition metal d i ~ e 1 e n i d e . lCyclopentadienyldiphenylphos~~ phine, when present in &square planar palladium complexes of the type (R3P)2PdC12, undergoes intramolecular Diels-Alder dimerisation by endo-addition to form complexes of two new isomeric diphosphine ligands (104) and (105).145 Full details have now appeared of the cyclometallation reactions of trimesitylphosphine in its complexes with palladium and p 1 a t i n ~ m . l ~ ~ Cleavage of the both P-C and C-H bonds in bis(dimethy1phosphino)methane has been observed in the decomposition of various triruthenium cluster complexes in refluxing toluene. 147
Organophosphorus Chem istry
18 Me2As-PEt
Ph P
(96)
Ph
(97) R’= H or Me; R2= Me,Ph or 2-fury\
(95)
Ph R \+r0,-/Ph
Ph
R’tplR2 NH
HOCH,/ ‘ L d B \ p h (100)
OBPh,
R ’ = Me,Et,Ph, R 2 = Me or Et
co ZE
Ph
N\ P - P P\h
/p\
Cp2Zr PPh \N-p/ph
z P /pphi Ph
cp2
/
N
\\
(101
CH COZEt
(103) Cp’= SMeCp
(102)
PPh2
I
PhZP
P
(104)
h
2
P
PPh,
(105)
t ( 107)
q
(108)
R’ R2PCL
(106) R’ =Me, Et,Pri or Ph; R~=B or J M~,CHCH,
I : Phosphines and Phosphonium Salts
19
2. HaloeenoDhosphines 2.1 Preparation,- Controlled alkylation of alkyl- and aryl- dichlorophosphines with bulky Grignard reagents has been used for the synthesis of the monochlorophosphines (106).148 Similarly, the reaction of di-(tbuty1)cyclopentadienyllithiumwith phosphorus trichloride has given the dichlorophosphine (107), which, from n.m.r. studies, does not appear to be a fluxional system. In contrast, the reaction of the above cyclopentadienyllithium reagents with chlorodi(isopropy1)phosphine results in the formation of five phosphorus-containing isomeric products, to which it has not been possible to assign precise structures.149 A modified route to 1- chlorophosphorinane (108) involves cleavage of the related diethylaminophosphine using chlor~diphenylphosphine.~~~ The chlorophosphines (109) are formed in the reactions of primary or secohdary phosphines with hexachloroethane or phosphorus pentachloride in the absence of a base.lS1 Routes to 1- adamantyldichlorophosphine (110)152and 1- adamantylmethyldichlorophosphine (111)153have been developed which involve the reduction of higher oxidation state halogenophosphorus compounds with triphenylphosphine, and aluminium, respectively. Reduction of intermediate chlorophosphonium compounds using tetraalkylammonium iodides is a key step in the synthesis of (l12).154The chloroisophosphindoline (113) has been prepared by reduction of the corresponding phosphinyl chloride using t r i c h l o r o ~ i l a n e , 'and ~ ~ the bis(dich1orophosphine) (114) has been prepared by desulphurisation of the corresponding bis(thiophosphony1) halide with dichlorophenylphosphine.156 Treatment of the acetylenic alcohol (115) with phosphorus trichloride in the presence of pyridine results in the formation of the substituted vinyldichlorophosphine ( ~ 6 ) ? The ~ reaction of the imino systems (117) with phosphorus trichloride leads to the heterocyclic chlorophosphines (118).158 Further examples have appeared of the synthesis of phenyl chlorophosphines by high temperature exchange reactions of triphenylphosphine with phosphorus trich10ride.l'~ 2.2 Reactions of Ha1ogenophosphines.- Phenyltetrachlorophosphoraneand phenylphosphonic dichloride have been isolated from the chlorination of dichloro(pheny1)phosphine under various conditions.160 The reactions of antimony trifluoride with alkyldichlorophosphines have been investigated as a route to the corresponding alkyldifluorophosphines. Thus, treatment of (119, X = C1) with antimony trifluoride yields the related difluorophosphine (119,
Organophosphorus Chemistry
20
Et 02 CC
/Me
B ~t
C C-,
=
\
\
OH
PhNHN=C
(116)
i
/R
X2PCH2 x 2
‘OEt (117)R = Me, E t , Pri, PhCHZ, Ph orAr
F
1
F.’
(118)
‘P-N’
’
(119)
0
0
Ph
‘
Si Me3
N-P‘
(121)
F’I
Ph
‘BU‘
PCI 2
( 115 1
F
(120)
0
Me\ N O=P-
I
A,,”. I
Ph (123)
PPh
BUt \ N-B=N-BU‘
M e3Si
/
8 But &-+NBU‘ ‘P/
R
(124)
(125 1
R CF2 PCIZ
L C I RCFZP,
0
II
~ 1P ,C
H OR^ ~
’CH2 C I (126)
(127) R = F or CF3
(128)
I : Phosphines wid Phosphonium Salts
21
X = F), the phosphonyl chloride centre also undergoing exchange.161 In contrast, attempted fluorine exchange of iso-butyl- and 2-chloro-iso-butyldichlorophosphines results in a mixture of products, involving the monofluoroand difluorophosphines, together with related tetrafluorophosphoranes. 162 Whereas most fluorophosphines give rise to the expected Staudinger products in their reactions with phenyl azide, the corresponding reaction of difluoro(pheny1)phosphineresults in the formation of the four- membered ring system Treatment of the silylurea (121) with dichloro(pheny1)phosphine gives rise to the bis(ch1orophosphine) (122), which, on subsequent reaction with the bis(trimethylsily1) ester of oxalic acid, undergoes conversion to the heterocyclic system (123).164 The reactions of sterically crowded aminoiminoboranes, m, (124), with dichloro(organo)phosphines, provides a route to new three- and four-membered heterocyclic systems involving boron, A route to the alkoxymethylphosnitrogen and phosphorus, w, phine oxides (126) is provided by the reactions of dialkoxymethanes with the ionic adducts of chlorodiorganophosphines with hydrogen chloride and aluminium chloride.166 Heating the fluoroalkyldichlorophosphines(127) with formaldehyde in a sealed tube gives rise to the chloromethyl(fluoroalky1)phosphinyl chlorides (128).167 Di-(t-buty1)iodophosphine is oxidised to the related phosphinyl iodide on treatment with ethylene- or propylene-oxide.168 Nucleophilic displacement reactions of halogenophosphines with oxygen, nitrogen and sulphur nucleophiles continue to attract interest. The preparation of chiral aminophosphine and phosphinite ligands from amino-acid or amino-alcohol precursors has been and further examples of chiral systems, m,(129), reported.17o9171 The reactions of lithium alkoxides derived from Cinchona alkaloids with chlorodiphenylphosphine have given a series of chiral phosphinite l i g a n d ~ . ' ~Cyclocondensation ~ of bis(dich1orophosphino)methane with bulky primary amines has yielded the cyciic system ( I ~ O ) ! ~With ~ sodium alkyltrithiocarbonates, alkyldichlorophosphines form the related thiophosphorus systems (131).'74 The reaction of equimolar amounts of dichlorophosphines with methanethiol in the presence of base yields the half-acid chloride (132), which can be utilised in McCormack cyclistions with dienes to give 3- phospholene ~ u 1 p h i d e s . l The ~ ~ cyclopropylphosphine sulphide (133) is formed in the reaction of a precursor bromocyclopropane with chlorodiethylphosphine, followed by treatment with
Organophosphorus Chemistry
22
A .N (Me)PPh
RNHP\N/PNHR R
(130) R = Pri,BuS,or BU'
(1291
RP
/
(131) R =Et or Pr'
CI
'SMe
Et2P
II
(132)
S (133)
(134)
H (136) R = H,CI or Br
(135)
(137)
+
+
PPh3 I'
CH2 PR3 + 0+H2pR33Br-
SR
H
CHZPR,
(138)
CH2
II
+
Br CH 2CH 2C C H2PP h3 Br-
Br-
(141 1
(142)
+
BU,PCH2CH=CRMe CI ( 144)
1 : Phosphines and Phosphoniurn Salts
23
hydrogen ~ u 1 p h i d e . l The ~ ~ reaction of dichloro(pheny1)phosphine with lithium selenide gives a reactive intermediate of unknown structure which undergoes further reaction with carbon disulphide or acetone to give the new heterocyclic systems (134) and (135), re~pective1y.l~~
3. Phosphonium Salts 3.1 Preparation.- Quaternization of triphenylphosphine with a range of 2bromomethylarylisothiocyanates has given the salts (136), which are converted into the indolylphosphonium betaines (137) on treatment with triethylamine.
Subsequent alkylation at sulphur with iodoalkanes then provides the related phosphonium salts (13S).'78 Conventional quaternization procedures have also been used for the preparation of the 1,2,4- triazolylmethylphosphonium salts (139) 179 and lipophilic triphosphonium salts, u,(140), which have found use for the solvent extraction of triply charged anions.18* A detailed study of the dependence of the kinetics of quaternization of triphenylphosphine with benzyl chloride on the nature of the solvent, concentration of reactants, and effects of temperature ,has provided optimum conditions for the reaction.181 Ring- opening of 1,2-bis(bromomethyl)cyclopropane occurs on 182 reaction with triphenylphosphine, giving the unsaturated salt (141). Cyciopropyl ketones also undergo ring-opening on treatment with triphenylphosphine in the presence of hydrogen bromide in chloroform under sealedtube conditions to give the oxoalkylphosphonium salts (142). Subsequent protection of the carbonyl group affords the salts (143), of value in Wittig procedures for carbonyl (n + 4) h o m ~ l o g a t i o n . ' ~The ~ p ?- unsaturated phosphonium salts (144) have been prepared by the reaction of related quaternary ammonium salts with t r i b u t y l p h o ~ p h i n e .In ~ ~a~similar approach, a series of alkylalkynylphosphonium salts (145) has been isolated from the reactions in sunlight of related iodonium salts with triphenylphosphine. 185 A simple route to pyridyl- and pyrazinyl- phosphonium salts, w, (146), is afforded by the reactions of triphenylphosphine with 1y- trifluoromethanesulphony1 quaternary salts of the parent heteroarenes, substitution occurring a t positions 2- or 4- of the ring systems.186 The benzimidazole (147, X = Br) provides another example of the coordination kinetic template effect in its nickel(II)-catalysed reactions with tertiary phosphines in ethanol which proceed with regiospecific replacement of the bromine of the 242-
24
Organophosphorus Chemistry
I
[):Ph3
6°r
X'
(
R = H orMe
(150)
149)
+
Ph3P
(140 1
+
Ph3PCHPhN=CClPh
R & f i 0D
"O'
CI(1 5 2 )
(151) PhCOCH,S
SePh M p p h 3 x -
0
4
Ar ( 153)
+
PhpCHXR Y -
.(155) n = 2 - 5
[ Ph,P--N--PPh,]+X-
(156) X = CL, Br o r I
+
[ R3P-
+
CHF-PR3 (159)
J 2X'
(157)
Ph, P' Me2N
1: Phosphines and Phosphonium Salts
25
bromophenyl) substituent to give the related phosphonium salts (147; X = R3P' Br-).187 A radiochemical procedure has been developed which gives the pentatritiated arylphosphonium salts (148) via the reaction of tertiary phosphines with the pentatritiophenyl cation. 188 Further examples have appeared of the formation of hydroxymethylphosphonium salts from the reactions of phosphines with carbonyl compounds under acidic conditions.1893190The reaction of triphenylphosphine under acidic conditions with acraldehyde, followed by treatment with triisopropyl o_rthoformate, results in the salt (149) which functions as a useful three carbon homologating agent in the Wittig reaction, providing a route to (3,Y-unsaturated acetals that are very easy to hydrolyse without migration or isomerisation of the double bond.191 A further report of the synthesis of aalkoxyphosphonium salts from the reactions of vinyl ethers with phosphines under acidic conditions has appeared.192 The 0 - acylvinylphosphonium salts (150) are formed in the reactions of tertiary phosphines with the appropriate 2-furoylacetylene in the presence of a n acid, and undergo the expected range of reactions. Thus, u,with cyclopentadiene, the Diels-Alder adduct (151) is formed.193 The iminoalkylphosphonium salt (152) is formed on treatment of the related N-(a-chlorobenzy1)benzimidoyl chloride with triphenylphos~ h i n e .A ' ~series ~ of allylphosphonium salts has been obtained by the trapping of electrochemically generated triphenylphosphonium radical cations with allylic silanes. 195 The reactivity of ylides towards electrophilic reagents has been utilised in the preparation of a number of unusual phosphonium salts. The oxazolylphosphonium salts (153)are formed on alkylation of the related sulphur stabilised ylides with phenacyl bromide.196 Treatment of a series of cycloalkylmethylidene ylides with phenylselenenyl bromide results in the a selenomethylphosphonium salts (154). On oxidation these are converted into the cycloalkylidenemethylphosphoniumsalts (155), which may have some potential in synthesis.197 Halogen abstraction occurs on treatment of haloperfluoroalkanes with reactive ylides, resulting in the formation of CY haloalkylphosphonium salts (156).198 An improved, economical, small scale preparation of p - nitridobis(tripheny1phosphonium) halides (157) has been r e ~ 0 r t e d . lThe ~ ~ related nitrite salt (157, X = ONO) is reported to react with dichloromethane a t room temperature to give a potent nitrosating reagent?00 The fluorinated phosphoranium salts (158) have been prepared by the reaction of phosphines with
26
Organophosphorus Chemisrry
fluorotrihalomethanes in a non-ether solvent. On protonation, the related diphosphonium salts (159) are formed?'l Interest has continued in the chemistry of phosphonium salts bearing unusual anions. Full details of the chemistry of tetraarylphosphonium fluorides have now appeared?02 Three forms of tetraphenylphosphonium nitrite have been recognised. The reaction of tetraphenylphosphonium bromide with potassium nitrite in DMSO a t temperatures below 120 O C results in an ionic nitrite, m.p. 224 225 OC, which, on heating a t 270 O C forms the volatile nitritotetraphenylphosphorane,before depositing crystals of tetraphenylphosphonium nitrate. Related metathesis in DMSO a t 130 O C provides a third form of the compound of m.p. 296 - 297 'C, believed to be a n ion-pair in which a strong phosphorus- oxygen interaction is pre~ent.2'~The reaction of long chain alkylphosphonium azides with potassium bisulphate in dilute sulphuric acid has given a series of lipophilic salts?04 Combination of tetraphenylphosphonium iodide with antimony triiodide in acetonitrile has given two salts involving complex antimony-containing p~lyanions?'~A series of phosphonium hexachlorozirconates has also been prepared?06 Phosphonium halides have been shown to take up one mole of an anhydrous hydrogen halide to form the related phosphonium hydrogen dihalide &P+ [HXYI-?" 3.2 Reactions of PhosDhonium Salts.- The presence of 0- dimethylamino substituents has a marked influence on the rate and course of alkaline hydrolysis of triaryl(benzy1)phosphonium salts. Thus, w, the salt (160) undergoes hydrolysis, with predominant loss of the o-dimethylaminophenyl group, a t a rate of approximately one thousand times that of the corresponding pdimethylaminophenylphosphonium salt, which, in contrast, occurs with predominant loss of the benzyl substituent. It has been suggested that a reasonably strong N2p P(Iv) "hypervalent" through-space interaction exists in the s-dimethylaminophenylphosphoniumcations, which hinders approach of hydroxide ion opposite the benzyl group, and hence the preferred mode of attack is opposite the hindering group?'* The course of alkaline hydrolysis of the unsaturated salts (161) and (162) has been studied under various conditions of alkalinity and solvent homogeneity. Both salts behave like vinylphosphonium salts bearing a n electron-withdrawing carbon-substituent and undergo hydrolysis in the presence of a n equimolar amount of alkali under heterogenous conditions via nucleophilic attack a t phosphorus, followed by anionotropic phenyl migration to give the salt (163). In the presence of a large excess of alkali under homogeneous conditions, the course of the reac-
-
-
27
1 : Phosphines and Phosphonium Salts
+
Ph$CH=
CH-CHzCHPPh3
+ Ph3PCH2 C-
26r-
(1 611
A
CCHz PPh3
21
(162)
+
-
f
Ph3PCHZCH=
Br-
Ph3PCH =C=CHPh
0
Br(1 63)
(165)
PR, BF4(164) R = Ph or Bu
PhCHZC-
I
+
CH,PPh
Br-
C Hz COPh
+
X'
+
RSNa
RSX
+
RSNa
R3P=CH2
+
RSSR
R3PCH,X
+
R3PCH2SR RS-+
-
(167) R = S03H,Br,NO2 W A C
(166)
t
Ph3PCH2X X-
(168)
+ RSX + NaX
R3P=CH2 RSSR
+
NaX
+
R3PCHZSR
+
R3PCHzSR X -
RS-
+
R3P=CH2
+
RSX
Scheme 2
+
ArCONHCH,PPh, (169)
Cl'
+ CIC(AreNCH2PPh3 (170)
CI-
' N Ar
N %N N/Cy6Ph3 C104'
28
Organophosphorus Chem istry
tion is more complex and a mixture of products is f0rmed.2'~ The cycloheptatrienylphosphonium salts (164) behave abnormally on alkaline hydrolysis in that the main product is the tertiary phosphine arising from nucleophilic attack at the ring carbon bound to phosphorus rather than a t phosphorus. Similar displacement of tertiary phosphine occurs on treatment with other nucleophiles, u,cyanide, iodide, and thiocyanate ions, and also with triethylamine?" The effects of addition of aliphatic and aromatic amines to binary aqueous solvent mixtures on the kinetics of alkaline hydrolysis of benzyltriphenylphosphonium chloride have been investigated, and reveal a dependence on the concentration of the amine. 21 1 A convenient and quantitative source of gaseous hydrogen bromide is provided by the thermolysis in refluxing xylene of triphenylphosphine hydrobromide, which can be prepared conveniently by chloroform extraction of a solution of triphenylphosphine in aqueous hydrobromic acid (48%)?12 Addition of methyl ketones to unsaturated salts, w, (165) has been studied, and shown to give rise to salts of type (166)?13 A series of substituted naphthyl phosphonium salts (167) has been prepared by electrophilic substitution of the parent 1- naphthylphosphonium salts?14 A study of the photochemical decomposition of the e-cyanobenzylphosphonium salt (168) has shown that the products are derived from "out of solvent cage" coupling processes, whereas both "out of cage" and "in cage" products are formed on photolysis of the related arsonium salt?15 The reaction between a-haloalkylphosphonium salts and various sulphur nucleophiles, u,sodium N,N-dimethyldithiocarbamate, in non-protic solvents, leads to the substitution products, Ph3P+ CH2SR X-. However, evidence has been presented that such reactions are not S N proces~ ses, but involve a three step nucleophilic chain process (Scheme 2). When similar reactions involving sulphur nucleophiles are conducted in methanol, the intermediate ylide is protonated, with formation of the methylphosphonium salt?16 Treatment of the acetamidophosphonium salts (169) with phosphorus pentachloride results in the formation of the salts (170) which undergo cyclisation with azide ion to form the heteroarylmethylphosphonium salts (171)?17 On heating, the salts (172) are converted into the betaines (173)?18 The stable alkoxyphosphonium salts (174) (obtained by the reaction of trisdimethylaminophosphine and an alcohol in carbon tetrachloride) have
1: Phosphines and Phosphonium S a h
EtO/
P-C-
0
+
CH2 P B y Cl’
II
29
RO-
II
+
p-c=cweu3
I I
+
(Me, N& POR PFs-
0’ M e
CHZ
(173 1
(172) R = Et or I-adamantyl
(176) Ar = 2,4,6-f3ut3C&
(175)
(174)
(177)
\v
RzNN(R)P,
R-P-P-R
\ /
sc
RzNN(R)P=PP(CI)NRNR,
(178) R = (Me3SiI2CH
(179) R = Me3Si
,NNR2
P
( 180)
R = Me3Si
Ar P=PAr R2 N N(R) P
- P -P
NNR2
(181 ) R = Me3Si
F3CP=C
/F “R,
(184)
RP=CF2 CF3 (185) R = Me or Et
(186) R = Me or Et
Organophosphorus Chemistry
30
been shown to react with phenols and thiophenols, under basic conditions, to give the related alkylaryl-ethers and -thioethers?19 Long chain alkylphosphonium salts have been used as phase-transfer catalysts in the synthesis of thioethers from sodium thiolates and alkyl halides?20 Q , -Bonded Phosphorus Compounds
Activity in this area continues unabated. Solid state n.m.r. studies indicate that the P = P system is very similar to C = C and Si = SiF2' A theoretical study has concluded that ,-bonds to phosphorus are stronger than those to silicon, which is consistent with the reduced tendency of pT -bonded phosphorus compounds to undergo addition reactions?22 Routes to the new diphosphenes (175) and (176) have been developed, thus enabling a study to be made of the electronic effects of such substituents a t phosphorus on the reactivity of d i p h o ~ p h e n e s . 2Two ~ ~ new high yield routes have been devised for the synthesis of the least crowded yet reasonably stable diphosphene (177), in a pure state. This compound slowly dimerises at room temperature, with a half- life of one week a t 20 'C. It forms the usual adducts with dienes, and on reaction with selenium, the three-membered ring system (178) is formed.224 Ultra-violet irradiation of diphosphenes bearing pentamethylcyclopentadienyl substituents results in an initial dimerisation, followed by cleavage of the cyclopentadienyl substituent, and recombination of the remainder to give bicyclic a-bonded phosphorus compounds.225 Attempts to convert the diphosphene (179) into the azatriphosphabicyclobutane (180) resulted instead in the formation of the tricyclic N2P6 system (181)?26 The reaction of white phosphorus with a mixture of 2,4,6-tri-t-butylphenyllithium and l-bromo-2,4,6-tri-tbutylbenzene results in the formation of the bicyclic system (182), in addition to the diphosphene (183, Ar = 2,4,6- B U ' ~ C ~ H ~ ) ? ~ ~ The coordination chemistry of diphosphene ligands has continued to attract interest, and a number of new approaches to such complexes have been reported.228-234 Further examples of diphosphenes and related phospha-arsenes involving a complexed transition metal substituent a t phosphorus have been and Weber's group has also been active in exploring the reactivity of the P = P bond in such compounds towards addition of other reagents. 237-241 Initial reports of the synthesis of transition metal complexes of p,-bonded polyphosphorus ligands from white phosphorus have also ap~ e a r e d . 2 ~ ~ ~ ~ ~ ~
1: Phosphines u n d Phosphoniurn Salts
31
Once again, the greatest activity has been in the area of P = C compounds, and several reviews have been p ~ b l i s h e d ? ~Methylidenephosphine, ~-~~~ CH2 = PH, has been prepared under high dilution conditions by the gas-phase or liquidphase elimination of hydrogen chloride from chloromethylphosphine, and unambiguously characterised by chemical trapping and spectroscopic a n a l y ~ i s . 2The ~ ~ simple phospha-alkenes, MeP = CH2 and PhP = CH2, have been generated under very mild conditions in virtually quantitative yield by the thermally-induced cleavage of the phosphorus-containing bridge from appropriately substituted 2-phosphabicyclo[2,2,2]octa-5,7-dienes.Again, the phospha-alkenes are readily trapped in [2 +41 cycloaddition reactions with conjugated d i e n e ~ ?Pyrolysis ~~ of trimethylsilylmethyl (chloro)cyanophosphine yields the cyanophospha-alkene, CH2 = PCN, which has been characterised by microwave s p e c t r o ~ c o p y ? ~Gas-phase ~ infrared studies of the unstable phospha-alkenes, CF2 = PH, CF2 = PCF3, and CH2 = PCI, have also been rep0rted.2~' Various addition reactions of CF2 = PCF3,=., with trimethylgermane and trimethylstannane, have given new phosphines which undergo subsequent elimination of fluorotrimethyl-germane or -stannane to form the new phospha-alkene, F3CP = CHF, characterised a s its adduct with a conjugated diene?51 A mixture of isomeric cycloadducts of F3CP = CF2 with isoprene has been ~ h a r a c t e r i s e d : ~and ~ their coordination chemistry e ~ p l o r e d . 2This ~~ phospha-alkene also reacts with a variety of secondary alkylamines to give the new phospha-alkenes (184)which are stable a t room temperature, probably as a result of the involvement in conjugation of the nitrogen lone pair. These systems are also accessible by the reaction of secondary amines with bis(trifl~oromethyl)phosphine?~~ Thermolysis of bis(perfluoroethy1)trimethylstannylphosphine has now been shown to produce the Z-isomer of F5C2P = C(F)CF3, as revealed by a n X-ray study of a metal complex derived from its adduct with ~yclopentadiene.2~~ Thermolysis of the stannylphosphines (185)has given the new phospha-alkenes (186),which undergo polymerisation even a t very low temperatures. Cycloadducts of (186)have been obtained from the reactions of the percursor phosphines (185)with dienes a t 120 0C?56 Routes to other halo phospha-alkenes, w, (187), hawe been developed:57 and full details of the synthesis, characterisation and photochemical interconversion of the E- and g-isomers of (188)have now ap~ e a r e d . 2A~range ~ of established procedures has been used for the synthesis of a series of phospha-alkenes, w, (189)which bear less sterically crowded dialkylamino substituents a t phosphorus.259 Nucleophilic displacement of the
c-
32
Organoph osph orus Chemistry
(187) X = F o r I
( 188 1
ArPH (190) R = 2,4,6-8Ut&H,, Pr2'N, or But(Me3Si )N
( 1911 Ar
Ar P
HPAr
ArP
= 2,4,6-But,C6Hz
"
C1P-c
/ Ph 'SiMe,
(194) Ar = 2,4,6-But3CGH2
( 193)
PHAr ( 19 2)
PB ut
( 1955)
/pr' 'OB(NR25),
(196) R = Me, Et or Bu
Ar,
P==C
/
o r Pr'; or Me3Si
Me3
RP-CHSi
But P=C
R' = Et R2 = H
(109)
H
lAr
\p /Ar
\
CI
Ar
P'
H
ArP=C=PAr
I : Phosphines and Phosphonium Salts
33
bis(trimethylsily1)aminosubstituent in more crowded versions of (189) using organolithium or amidolithium reagents has given another series of phosphaalkenes (19O)F6O A 1,3-prototropic shift is involved in the thermal- or acid-induced rearrangement of the oxalyldiphosphine (191), which is violet in colour, into the yellow phospha-alkene (192), isolated in quantitative yield?61 The reaction of the dichloromethylene system (193) with dipotassiumdi(tbuty1)diphosphide has given the first phosphinidenediphosphirane (194), together with other products?62 A variety of new systems has been isolated from the lJ-dipolar cycloaddition reactions of the P-chlorophospha-alkene (195)?63 The phospha-alkenes (196) are reported to rearrange on heating to Remarkable difthe organoboron-functionalisedvinylphosphines ferences have been noted in the reactivity of the 5-and _Z-isomers of the phospha-alkene (198) towards heat and dioxygen, respectively, in terms of their ease of conversion into the phospha-alkyne, ButC Z P. It has also been demonstrated that these isomers do not undergo either thermal o r photochemical i n t e r c o n v e r ~ i o n . ~ Treatment ~~ of the &lJ-diphospha-ally1 chloride (199) with potassium t-butoxide a t low temperatures results in the formation of the &isomer (200), via a n allylic rearrangement. Heating (200) causes it to rearrange to the corresponding E-isomer?66 The reactions of the 13-diphospha-allene (201) have been the focus of some interest. On heating in toluene, it is converted into the 1,2,3,4-tetrahydro-l-phosphanaphthalene system (202) via addition of a C-H bond of a n 9-t-butyl group Related to the P = C bond, resulting in carbon-carbon bond f0rmation.2~~ rearrangements occur in the presence of transition metal carbonyl complexes?68 Both nucleophilic attack, 269,s., with methyllithium, and with sulphur, occur a t phosphorus, leading to electrophilic attack,270, u,, (203) and (204) respectively, the formation of the latter also involving cyclisation of a n 94- butyl group. The existence of tautomerism between 3H-phosphaallenes (205) and alkynyl-lH-phosphines (206) has been dem0nstrated.2~~ The l,3-diphospha-ally1 system (207) is formed in the reactions of iminomethylidenephosphines, ArP = C = NR,with trimethylsilylphosphines in nonpolar solvents. In polar solvents, other, more complex, products are obtained, -, (208),272 and compounds similar to these have also been obtained in the reactions of phosphaketenes, A r P = C = 0, with s i l y l p h ~ s p h i n e s ? Various ~~ 1phospha-1,2-butadienese.g. (209),and l-phospha-1,2,3-butatrienes, (210), have been isolated from the reactions of 2,4,6-tri-(t- buty1)phenylmonochlorophosphines with l-lithio-3-trimethylsiloxy- l - p r ~ p y n e s ? Treat~~
34
Orgcinopho s ph orus Cher nisrry
(202) Ar = 2,4,6- But,C,H2
(204)
(
203)
(205) R = Me, But or Ph Ar
Ar
N R ~
\p
‘P=/ ‘NR:
(206)
=(,,*
Ar /P_QPh
(207) A r = 2,4,6-t3ut3C6H2; R’ = Pr”, Me,Si or Ph R 2 = H,Me, E;,Bu‘, Me3Si o r Ph
( 200)
NR2
Si Me3
M e3Si N Si Me3 ( 210)
(212)
(211)
(213)
(214) Ar = 2,4,6-Bu\GH2; R’ = H or Me; RZ = H or Ph;
35
I : Phosphines und Phosphoniurn Salts
ment of the 1-phosphadiene (211) with trimethylsilylazide results in the formation of the phosphacyclobutene (212), whereas in the reaction of (211) with sulphur, the three-membered ring system (213) is the initial product. However, treatment of the latter with triphenylphosphine causes it to rearrange to form another example of the phosphacyclobutene ~ y s t e m . 2Related ~~ phosphabutenes have been shown to act as masked 1-phosphabutadienes, giving the expected [4 21 cycloadducts on heating to 100 O C with appropriate dien0philes.2~~ Heating the phosphines (214) in hydrocarbon solvents at temperatures > 100 OC causes them to undergo valence isomerisation with the ( 2 1 5 ) F ~ The ~ first examples of formation of 1-phosphahexadienes, u, diphospha-13-butadienes,ArP = CR-CR = PAr, have been prepared, making use of the bulky group effect. However, attempts to carry out pericyclic reactions with maleic anhydride and related dienophiles have proved unsuccessful?" The stable 1- phosphabutadiene (216) has been prepared by dehydrochlorination of a precursor substituted allyl(chloro)dialkylaminophosphine, and aspects of its coordination chemistry ~ t u d i e d . 2The ~ ~ coordination chemistry of stable 12-and 1,4-diphosphabutadienes has also been explored?" Reactions of acyl halides with silylphosphines continue to be utilised as routes to new P = C systems, among which are the phosphadienes (217)2'1 and (218)?2 The 2,3-diphosphabicycl0[2,1,0]pentane system (219) arises as a result of intramolecular [2 21 "dimerisation" of the 1,5- diphosphapentadiene formed as a transient intermediate in the reaction of dimethylmalonyl chloride and lithiumbis(trimethyl~ilyl)phosphide?'~ Several reports have appeared of the coordination chemistry of p h ~ s p h a - a l l y and l ~ ~ diphos~ pha-ally12'5-287 ligand systems. A considerable volume of work has also appeared on compounds involving p,bonds from phosphorus to other elements, notably boron, nitrogen, and sulphur. An x-ray study of the previously described stable germaphosphene (220) reveals a significantly shortened phosphorus-germanium bond and the planarity expected for a true Ge = P system?88 A number of reactions which lead to the isolation of 2,4-diphospha-lJ-diboretanes are believed to involve the dimerisation of intermediate phosphaborenes, R-P = B- R?89-291 The area of P = N systems has been r e ~ i e w e d . 2 ~ Reports ~ have continued to appear on the synthesis of new and studies of the reactivity of the P = N bond, with particular regard to addition reactions, and of the reactivity of the phosphorus atom. 295-301 A number of P = S systems have been characterised either by spectroscop~02~303 or by trapping experiments?047305
+
+
Organophosphorus Chemistry
36
,OTMS
Ar'3ph ' P=C
'0"'
=C HR
R, NP= CRCH
R'
(215) R = Me
(216) R = Me3Si
,OTMS
But
(p=c
( 217 1
/Ph
R
P4
//P-Me Ar-!
'FP-Me Ar
P +C-*r
I
R
(223) Ar = 2 , 4 , 6 - B u i CsHz
( 2 2 4 ) R = But
R'
-tYP =C
(225)
R = But
Bu'
(226)
R'
'hi'
/\
RZC=P
(227) M = Si or Ge; R' = But or CH(SiMe3)2
R 2 = But or I-adamantyl
I : Phosphines and Phosphonium Salts
37
The chemistry of phospha-alkynes, especially that of ButCEP, continues to attract much attention. The first examples of nucleophilic addition to the triple bond of the phospha-alkyne (221) have been reported. Depending on the stoichiometry and subsequent trapping of intermediates, the reaction with methyllithium leads to either the phospha-alkene (222) or the lJ-diphosphabutadienes (223). The direction of addition clearly indicates a reversal of polarity in the C P bond compared with that in comparable nitriles, although steric factors may also have a bearing on patterns of reactivity?06 There have been many reports of the cycloaddition reactions which the phospha- alkyne B u b P undergoes with dipolar and diene-like reagents, including mesoionic compounds,307 (which yield a variety of heterophosphole systems), anthracenes308 (providing a route to 2- phosphabarrelenes (224)), 13d i e n e ~ ~ ~(involving ~ ~ ' ' previously unknown homo-Diels Alder reactions leading to unusual structures, (225)310),azides?" nitrilium betaines?I2 and d i a ~ o a l k a n e all s ~ of ~ ~the latter group yielding a further range of heterophospholes. A related reaction with a sterically crowded diazoalkane has provided the first example of a 2H- phosphirene (226)?14 The reactions of bulky phospha-alkynes with crowded silylenes, RzSi:, and germylenes, R2Ge:, have given the first examples of the phospha-silirene and-germirene systems (227)?1533 Pyrolysis of the phospha-alkyne, ButCZP, under high vacuum, results in the formation of HCEP, which has been subsequently trapped with 1,3-dipolar reagents, again to give heteropho~pholes?~~ There has also been considerable interest in the cyclo-oligomerisation reactions of phospha-alkynes in the presence of transition metal complexes, which lead to the synthesis of comdiphosphabicyclobutanesplexes of l,3-diphosphacyclobutadienes:18 (228),319 1,3,5- triphosphabenzenes,320 and a valence isomer thereof?21 The reaction of Bu'CGP with a cyclopentadienylmanganese carbonyl complex has led to the isolation of a manganese complex of the bis(phosphaviny1)ether (229)?22 Other features of the coordination chemistry of phospha-alkynes have also been reported?23Y324 Interest has also continued in the area of terminal phosphinidene complexes, which involve a pT -interaction between phosphorus and a metal, and this topic has been r e ~ i e w e d . 3The ~ ~ first stable compounds of this type (230), have been characterised, and shown to have very low field 31P chemical shifts, 666 -,799 ppm?26 A number of studies of the reactivity of unin the range stable terminal phosphinidene complexes have been reported, and some unusual products i ~ o l a t e d : ~ ' - ~w, ~ ~ the metallaphosphirene complex (231).332
=,
+
38
Organophosphorus Chemistry \
Cpfl =PAr
t (22 8)
M = Mo or W;
(230)
(229)
A r = 2,4,6-But3 C&
P
7wcc0)5 R-P
HX
/i
(TM512 C
Pr',N
YT
XP
MS)2
\C(T
M9
2
Ph#Ph
\P
CI
R\p//"Ar PhAPh
AlClG
PhAPh
(236) R = Bu'; Ar = 2,4,6-But,C6H2
123L)
R P R& Me
( 2 3 7 ) R = alkyl or Ph
(239)
W(CO),
R = Et, Ph or CO2Et;
2 = Ph or C02Et
"WR
H
Me02C
/ \o
R
( 240)
( 2 4 1 ) R', R 2 = H o r M e
CqMe
I: Phosphiries urid Pho.yphoniurn Salts
39
Terminal phosphinidene complexes have also been shown to cause the ringoxiranes, thiiranes, and opening of three-membered ring heterocycles, aziridines, with the subsequent formation of heterocyclic phosphorus comof dinuclear phosphinidene complexes has also been p o u n d ~ ?A~ series ~ 334 characterised. Further progress has been made in the characterisation of phosphenium ions of the types (R2N)2P+ and [R2NPCI] Evidence for a P = N interaction in such systems has been presented:35 but the main emphasis has been studies of their r e a ~ t i v i t y ? ~ ~Also - ~ ~noteworthy ' is increasing activity in the study of the u3-X5-systems (232), and a useful review has a ~ p e a r e d . 3The ~ ~ reactions of bis(dich1orophosphines) with lithium bis(trimethylsi1yl)chloromethanide at 100 'C have given a series of D ~ Xzbisphosphoranes, u.,(233)."42 Treat5 ment of the chloro- X -system (234, X = CI) with isopropylmagnesium chloride has given the related hydridosystem (234, X = H), the first example of a metalfree three coordinate P(V) h ~ d r i d e . 3The ~ ~ same workers have also prepared the first X5-metallobis(methylenephosphorane) (234, X = (C5H5)(CO)2Fe)?44 Ethylmetaphosphate (232, R = EtO, X = Y = 0), generated by thermolysis of appropriate phosphole oxide dimers in toluene solution, can be trapped in the presence of silica gel, with which it reacts a t the surface via Si-OH groups, thereby providing a means of surface functionalisation of the gel?45
=,
+.
5. Phosphirenes. Phospholes and Phosphorins
Mathey has contributed three useful review articles covering (a) a comparison of the chemistry of phosphirenes and ~ i l i r e n e s ?(b) ~ ~the organic chemistry of 1H-, 2H-, and 3H-phospholes 347 and (c) aromatic phosphorus heterocycles as 348 T -1igands in transition metal chemistry. An _X-raystudy of the phosphirenium salt (235) (prepared by the reaction of a chloro(di-isopropy1amino)phospheniumion with diphenylacetylene) clearly suggests the existence of cyclic delocalisation in the cation, the average phosphorus-carbon bond length indicating a bond order of 1.5:~~ The phosphirene (236)has been obtained by the addition of diphenylacetylene to a stable iminoph~sphene."~' Treatment of the trivalent phosphirenes (237) with a dichlorophosphine, followed by tributylphosphine, results in a n insertion
40
Organophosphorus Chemistry
into the phosphorus- carbon bond with the formation of the dihydrophosphete system (238)?51 Insertion processes have also been observed in the palladiumcatalysed reactions of phosphirene-tungsten carbonyl complexes with terminal alkynes, which result in the formation of the phosphole complexes (239)?52 The parent phosphole heterocycle (240) and the related phospholyl anion, have been characterised by 'H and 13C n.m.r. spectroscopy for the first time?53 A one-pot procedure for the synthesis of l-phenyl-2,3,4,5-tetramethylphosphole has been developed which involves the reaction of 2-butyne and phenyldichlorophosphine in the presence of aluminium chloride, the resulting intermediate chlorophospholium salt being dechlorinated using tributylphos~ h i n e . 3The ~ ~ reaction of lithium phospholides with trimethyltin chloride yields 1-trimethylstannylphospholes, which have been shown to react with titanium tetrachloride to give the a-phospholyl complex (t41),which is not accessible from the reaction of the lithium phospholide with titanium t e t r a ~ h l o r i d e . 3The ~ ~ cyclic ylides formed in the reactions of trialkylphosphites or dialkyl phosphonites with two moles of dimethyl acetylenedicarboxylate undergo protonation and dealkylation in the presence of hydrobromic acid to form the phospholene-oxides (242), which readily eliminate an alcohol on heating to give the phosphole oxides (243)?56 An improved route has been developed for the synthesis of 5-phenyldibenzophospholeon a large scale through the reaction of lithium diethylamide with tetraphenylphosphonium br0rnide.3~~ A photochemical route to a series of stable 2H-phospholes (244) has been d e ~ c r i b e d . 3The ~ ~ reaction of the phosphole dimer (245) with phenyl azide results in the expected bis(pheny1imino) derivative, which on hydrolysis yields the related phosphine oxides with retention of configuration at the bridging phosphorus, but inversion of configuration a t the 2-phospholene phosp h 0 r u s . 3 ~Metal ~ carbonyl complexes of phospholes having the 2-positions free undergo addition reactions with thiophene or ferrocene in the presence of aluminium chloride to form the 2-arylphospholene complexes (246)?60 Interest has continued in the synthesis of polyphosphaferrocenes, and a number of new systems have been described, u, (247). 3619362 In related work, a metal complex involving both triphospholyl and a 1,2,44riphosphabutadiene ligand systems has been d e ~ c r i b e d . 3Two ~ ~ reports of the synthesis of pentaphosphametallocenes derived from the pentaphosphacyclopentadienideanion, Pg-, have also appeared?649365 The chemistry of azaphosphole systems also continues to attract attention. Phosphines bearing azaphosphole substituents, w, (248), have been prepared by the reactions of diazomethylphosphines with
$
1: Phosphines and Phosphonium Sults
Me02C
C02Me
M eO2 CO C O 2 Me R/
\\o
TMSO
(243) R = alkyl, aryl or
(244)
RO
41
R
R = Me, Ph, Mesyl or 2,4, 6-(MeO),CgH2
+
Ph\ Me O
A
& ' Me
Me
Ph ( 245)
Me A
dr'.
r
'W(CO),
(246) Ar = 2 - thienyl or ferro cenyl
(247)
X
PhQ
R =
(249)
(248)
Me or Ph
(250)
P
h
X = CN, C02Me
or CHzCN
MePM PP
RO
(251)
(254)
R = Me,
Vinyl or Ph
(253)
42
Orgntiopho.rpliorirs Chemistry
the phospha-alkyne, B ~ ~ C r p The . 3 ~azaphosphole ~ dimers (249)are formed 367 in the reactions of tris(dimethy1amino)phosphine with diamidrazones. Dimeric azaphosphole systems have also been isolated, albeit in low yield, A diphosphene bearing from the photolysis of 1,2,3-dia~aphospholes?~~ azaphosphole units as the substituents a t the P = P bond has been isolated in the form of a metal complex. 369 A range of new X 3-phosphorin systems (250) has been prepared under mild c0nditions.3~~ The bis(dipheny1phosphino)phosphorin (251) is formed in the reaction of 1,2,5-triphenylphospholewith bis(diphenylpho~phino)acetylene?~~ The reactions of (251) with sulphur have also been investigated, the first stable 3 phosphorin-1-sulphide being among the products.372 The phosphaphenanthrene (252)has been obtained from the reaction of a coordinated carbene with the phospha-alkyne, B u ' C E P ? ~ ~Mark1 and coworkers have continued to explore the reactivity of X3- phosphorin systems, with particular regard to their cycloaddition reaction^?^^-^^^ The first 1,2- X3-azaphosphorin (253)has been prepared, and shown to be very sensitive to moisture, undergoDimroth and coworkers have continued to ing addition to the P = N study the chemistry of AS-phosphorins and have reported the synthesis of a range of 1,l-dialkenyl- and 1,l-dialkynyl-substituted ~ y s t e m s . 3The ~ ~ first 1,2X5- benzazaphosphorins (254)have been prepared by the Staudinger reaction of p-azidoesters with alkyldiphenylphosphines,followed by base-induced cyclisation of the intermediate p h o s p h a ~ e n e s . 3The ~ ~ triphosphorin (255), involving both X3- and X5-phosphorus atoms, has also been characterised?80
.
-
References 1.
2.
3. 4.
5. 6.
7.
8.
9. 10.
11.
12.
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1: Phosphines and Phosphonium Salts
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a
m,
a,
Organophosphorus Chemistry
44
59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92.
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&,
s,
a
2
111.
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m,
I: Phosphiries 102. 103. 104. 10.5. 106.
107. 108. 109. 110. 111. 112. 113 114. 11.5. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142.
and Phosphonium Salts
45
M.S.Giovanetti, J.G.Santos, and F.Ibanez, J.Chem. SOC..Perkin Trans, 2, 1987, 1899. L.I.Kas’yan, N.V.Stepanova, M.F.Galafeeva, I.E.Boldesku1, V.V.Trachevskii, and N.S.Zefirov, Zh. Orp. Khim,, 1987, 122 (Chem. Abstr,, 1987,107. 197 950). H.Ohmori, T.Takanami, H.Shimada, and M.Masui, Chem. Pharm. Bull., 1987,35,2558. M.Zh.Ovakimyan, SKBarsegyan, G.Ts.Gasparyan, and M.G.Indzhikyan, Arm. Khim. Zh., 1986,39.463 (Chem. Abstr., 1987,107,236 833). G.Ts.Gasparyan, G.G.Minasyan, hl .Zh.Ovakimyan, G.A.Panosyan, and M.G. Indzhikyan, Arm. Khim. Zh., 1986, 445 (Chem. Abstr., 1987,107.236 831). W.-W. du Mont, M.Batcher, S.Poh1, and W.Saak, Aneew. Chem.. Int. Ed. EnFl., 1987, 26, 912. O.G.Kulinkovich, I.G.Tishchenko, and S.V.Sviridov, Zh. Ore. Khim., 1987,2,982 (Chem. Abstr., 1988,148, 131 18.5). O.I.Kolodyazhnyi, Zh. Obshch-Khim, 1 9 8 6 , s 2422 (Chem. Abstr., 1987,107, 176 119). 2423 (Chem. Abstr., 1987,107, O.I.Kolodyazhnyi, Zh. Obshch. Khim,, 1986, 176 1201. S.D.Totb, and J.T.Doi, h m 1987,2,4999. J.R.Hanson, P . B . H i t c B.Reese h c p and A.Truneh, J.Chem. SOC..Perkin Trans. 1, 1988. 1469. H . W h o f f , and H.L.Rub, Chem.-Z 1986,110.336. N.Ogata, KSanui, M . W a t a n d . S a k a i , Polyn. J., 1987, 1351. H.Wamhoff, and M.Zahran, Svnthesis, 1987,876. E.D.Matveeva, A.L.Kurts, A.S.-Erin, and Yu.G.Bunde1, Vestn. Mosk. IJniv.. Ser. 2: Khim, 1986,27.603 (Chem. Abstr., 1988,108.37 163). L.Ylagan, R.Benjamin, AGupta, and R.Enge1, Svnth. Commun., 1988,l8,285. J.Varasi, KA.M.Walker, and M.L.Maddox, J.OrP. Chem., 1987 52,4235. s,Bittner, M.Pomerantz, Y.Assaf, P.Krief, S X , and M.K.Witczak, J.Ore. Chem., 1988, 22, 1. M.von Itzstein and I.D.Jenkins, J,Chem. SOC..Perkin Trans. 1, 1987,2057. T.Kolasa, and M.J.Miller, J.Ore. Chem., 1987,52, 4978. 2300. A.M.Pautard, and S.A.Evans, &Ow. Chem,, 1988, Kag&u Kaishi, 1987, 1280 (Chem, S.Eguchi, H.Takeuchi and N.Watanabe, -Don Abstr, 1988, Ins,149 952 . C.J.Thomas, and M.N.Sudheendra Rao, J.Chem, SOC..Dalton Trans., 1988, 1445. M.Baudler, and H.Heumuller, Z.Naturforsch.. B:AnorP Chem.. Or?. Chem,, 1987, 1075. 731. K.Akasaka, T.Suzuki, H.Ohrui, and H.Meguro, Anal. Lett, 1987, N.G.Zabirov, R.A.Cherkasov, 1.S.Khalikov and A.N.Pudovik, Zh. Obshch. Khim., 1986, 2673 (Chem. Abstr., 1987,107,236 846). Y.Watanabe, T.Araki, Y.Araki, Y.Ueno, and T.Endo, Tetrahedron Lett., 1986,22,5385. V.kAl’fonsov, G.U.Zamaletdinova, K.M.Enikeev, A.V.Il’yasov, E.S.Batyeva, and 198 467). kN.Pudovik, Zh. Obshch. Khim, 1986,56. 1697 (Chem. Abstr., 1987, 197. S.J.Berners-Price, R.E.Norman, and P.J.Sadler, J.Inorg. Biochem., 1987, R.C.Bush and R.J.Angelici, Inore. Chem., 1988,22,681. Y .Yamashoji, T.Matsushita, M.Wada, and T.Shono, Chem. Lett., 1988,43. M.Wada, A.Tsuboi, K.Nishimura, and T.Erabi, Nippon KaPaku Kaishi, 1987, 1284, (Chem. Abstr,, 1988, UB, 149 866). J.Navech, H.Germa, and S.Mathieu, PhosDhorus Sulfur, 1988, S , 247. kS.Romakhin, E.V.Nikitin, O.V.Parakin,-YuAIgnat’ev, B.S.Mironov, and Yu.M. Kargin, Zh Obshch. Khim., 1986,%, 2597 ( h m. Abstr., 1988 108 56 227). C.Larpent,k.Dabard, and H.Patin, Inore. C;eG., 1987,& 292i.M.GkBeg, and M.S.Siddiqui, Pak. J.ScL Ind. Res., 1986,29,315 (Chem. Abstr., 1987, 58 321. H.S.Kasmai, J.F.Femia, L.L.Healy, M.R.Lauria, and M.E.Lansdown, J.Ore. Chem., 1987, 52,5461. V.K.Gupta, L.K.Krannich, and C.L.Watkins, Inow. Chim. Acta, 1987,134, 197. B.A.Arbuzov, OAErastov, and A.S.Ionkin, Izv. Akad. Nauk SSSR. Ser. Khim., 1986, 2506. (Chem. Abstr., 1987,107.96 797). B.A.Arbuzov, G.N.Nikonov, A.S.Balueva, and O.A.Erastov, Izv. Akad. Nauk SSSR, Ser. Khim.. 1986.2502 (Chem, Abstr.. 1987. 107,96 796). BAArbuzov, G.N.Nikonov, A.S.Balueva, and O.A.Erastov, Izv. Akad. Nauk SSSR, Ser. Khim.. 1986.2510 (Chem. Abstr.. 1987.107. 134 379).
a
~
~~~
a,
s,
m,
a
46
143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164, 165. 166. 167. 168. 169. 170. 171. 172. 173. 174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184.
Organophosphorus Chemistry
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m,
s,
a,
1: Phosphines and Phosphoniunl Salts
185. 186. 187. 188.
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47
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a,
2
Pentaco-ordi nated and Hexaco-ordi nated Compounds BY C. D. HALL 1. Introduction. - The amount of information published in the area of hypervalent phosphorus chemistry has declined further during the year and once again the emphasis has been on monocyclic and bicyclic phosphoranes. The maturity of the field of phosphorus chemistry is further reflected by the proposal of a new systematic classification of free and coordinated phosphorus compounds, to complement and extend the systems proposed by Wolf and Martin. This new system uses the number of free electrons (NFE), the number of valence shell electrons (N), the number of ligands ( L ) and the number of electron doublets (D) donated and/or accepted by the phosphorus atom when it acts as a Lewis base (negative D ) or Lewis acid (positive D) to generate a NFE(NPL)D code number. Thus pentaco-ordinate phosphorus and hexaco-ordinate phosphorus become O(10 P 5) and O ( 1 2 P 6) respectively. An excellent review on the synthesis, physical properties, structure and reactivity of acyclic alkoxy- and aryloxyphosphoranes has appeared4 covering the literature to early 1984. Another extensive survey (to 1986) discusses the reactions of organophosphorus compounds with quinones, many of which, especially with 2-quinones, lead to monocyclic and bicyclic pentaco-ordinate phosphorus compounds. 2 . Structure, Bonding and Ligand Reorganisation. - Rearrangement of the 1,3,2-diazaphospholidine (1) in acetonitrile gives, via (2)-(4), a structurally stable dioxadiphosphetidine (5) - the first to be characterised by X-ray analysis. The coordination geometry at phosphorus is essentially tbp with one axial and one equatorial bridging P-0 bond at each phosphorus. The 0-P-0 bond angle is 82.6(2)O and the axial P-N (quaternary) bond (at 193.4 pm) is unusually long but comparable to the P-N distance of 198.68 reported7 for the phosphatrane, [HP(OCH2CH2)3N]+BFq-. The observation of two diastereomeric forms of (7a) or (7b) from three diastereomeric forms of (6) - two meso and one g pair, was ascribed to rapid pseudorotation within (7ab) involving
2: Pentuco-ordinated and Hexaco-ordinated Compounds
53
Ph-
( 7 a . b ) ( a ) 2 = Me
(61
(8)
@ , _ JPi' h B
( b l Z = CF3
54
Organophosphorus Chemistry
diequatorial disposition of the dioxaphospholene ring, thus violating the strain rule. An alternative explanation however, involves the intermediacy of hexaco-ordinate structures represented schematically by the interchange of the two meso forms ( 8 ) and (11) & y (9) and (10). This hypothesis was tested by the preparation of a phosphonite (12) containing two chiral centres which on condensation with biacetyl gave a mixture of three diastereomeric phosphoranes (13) as evidenced by three 31P n.m.r. signals at -34.49, -34.52 and -34.56 ~ p m . ~ A variable temperature IH n.m.r. study of (14a) gives a free energy of activation of 13.9 kcal mol-I for conformational inversion of the 8-membered ring which compares well with a barrier of 13.9 kcal mol-I for (15)" and lends support to the suggestion by Denneyl' that steric factors are operative in the slowing of pseudorotation in phosphoranes such as (16). A high resolution n.m.r. study of several 4- and 5-coordinated phosphorus compounds (17a-d and 18a-d) has revealed the nature of the conformational effect which describes the influence of the phosphorus coordination on the molecular conformation.l2 It was established that conformational transmission was purely electrostatic in origin due to a larger charge density in the axis of the tbp structure. The pseudorotational equilibrium around phosphorus was described by accurate determination of J P O M ~coupling constants and the findings were corroborated by quantum mechanical calculations. A variable temperature 35Cl n.m.r. study of solid ( 1 9 ) revealed "fading" of the spectral lines due to C12, C12' and C13 at 270K and of the line due to C14 at 380K. This, together with the temperature-dependent behaviour of the T1 for spin-lattice relaxation of C12, C12', C13 and C14, allowed the calculation of two energy for the intramolbarriers (9.9 ? 0.2 and 16.3 ? 0.3kcal.mol-l) The two barriers are ecular exchange of the chlorine atoms." alleged to be associated with the existence of "two independent exchange motions proceeding at different rates". These were ascribed to a trigonal twist motion (lower barrier) and the more restricted Berry pseudorotation which includes rearrangement of all four chlorine atoms attached to phosphorus. Finally in this section, a 31P n.m.r. and K-ray study has led to the proposal of a structural alternative €or halophosphoranes in the form of (20) which is yellow in solution and in the solid state, probably due to iodine-iodine interactions.l4
2: Pen[aco-ordinated und Hexaco-ordinated Compounds CH3
,
I
Me
OC H2CHCH2CH 3
Ph-P,
55
OCH2CHCH2CH3
0,
I
CH3
C HZCHCH2 CH3
I
CH3
(12I
(131
R'
But
OCH,CF3
I
'
P
I
-0C HzC F3
OCHZCF3
B"t 'Me B"' But
(151
( 1 4 a. b) (a) (b)
R'= But; R2= R3= R'= R2= R 3 = Me
/
(16 1
Me
C/
Me
(17 a - d 1
(18 a - d 1
( a ) X = OMe ( b ) X = NMe2
+ -
(But I 3 P - I
( c ) X = CH2Me (d) X
2 PhPCt. (21)
=
-I
(20 I
SMe
-t EtOCH=CH,
I
4
Iadductl-
(22) PH3
0 II
PhPCH=CHCl
I
Cl
(231
+
0 II
PhPCH=CHOEt I Cl (2L)
i-PhPCIZ
(25I
56
Organophosphorus Chemistry
3. Acyclic Phosphoranes. - The reaction of phenyltetrachlorophosphorane (21) with ethyl vinyl ether (22) gives an adduct which on treatment with phosphine gives a mixture of three products (23)-(25).15 In a similar vein, the reaction of (26) with (22) gives a complex which on treatment with SO2 yields a mixture of (27) and (281, separable by fractional distillation.16 In view of the affinity of fluoride ion for L i ' , a somewhat surprising result was obtained for the reaction of (29) with tris(perfluoroalky1)-difluorophosphoranes (30). A perfluoroalkyl group was displaced in preference to fluorine to give (31) and steric hindrance by the bulky perfluoroalkyl groups appears to play an important part in these reactions.l7 A novel and convenient synthesis of a series of dialkyl phosphorochloridites (34a-e) has been reported based on the reaction of trialkylphosphites (32a-e) with triphenyldichlorophosphorane ( 33 1 . The phosphine oxide by-product is readily separated from (34a-e) which are isolated by distillation in yields from 38 to 76%. A re-examination of the Mitsunobu reaction by 31P n.m.r. and using a poorly nucleophilic acid (CF3C02H) to retard reactions of the intermediate, has revealed a dual mechanism which may be represented by Scheme 1." The betaine ( 3 5 ) is formed initially (S3IP = +43) but when acid is present during the formation of (35) or is added subsequently, protonation occurs immediately to give (36, b31P = + 5 1 ) . On addition of alcohol, this salt undergoes slow conversion to (38, b3IP = +59) which then decomposes to products. In the absence of acid however, half of the betaine (35) reacts with two molar equivalents of alcohol to form the phosphorane (37, b31P = -50). Addition of CF3C02H at this point protonates the remaining (35) and converts (37) instantaneously to (38) leaving the liberated half mole of alcohol to recycle through (36).
4.Rinq Containing Phosphoranes 4.1 Monocyclic Phosphoranes. - An interesting paper by Kolodyazhanyi reveals that P-fluoroylides (39) react with benzaldehyde or 2,2,2-trifluoroacetophenone to form P-fluorooxa-phosphetans (40) and (41) respectively.20 The hydrolysis of (40, R = But, R' = Pr) gave a mixture of diastereomeric phosphine oxides (42ab) in the same ratio as the diastereomeric mixture of the starting phosphoranes, showing that the reaction was stereospcific. On heating,
2: Pentaco-ordinated and Hexaco-ordinated Compounds
2PhOPC14
+
(221-
*
so2
I
[adduct
(
- SOC12,HCI 1
57
I
(27 1
= Ph or p-MeC6H4 ;
(RO1,P
II 4- PhOPCl
CI
(26)
Ar
0
0 II
PhOPCH=CHOEt
+
(32a-e)
Ph3PCI2
R,=
o r C,F,
CF ,,
___I)
(33)
(281
+
(R012PCl
Ph3P0
(3La-el
-k EtO,CN=NCO,Et
Ph,P
1
+
-
Ph3PN-NCOZEt I
I
C02Et
(35)
-
+
Ph3PN-NNC02Et
I
PhgP(OR1,
X
CO,Et
-
H X , fast
I
+
Ph,POR
X
-
(381
Scheme 1
I
slow
Ph,PO
(37)
+
RX
Orgun oph osph orits Chemistry F
I
R~ P =CHR'
(39) 0-CHPh I I R ~ P - C HR'
0-C-Ph I I R ~ P -CHR'
I
I
i
F (LA) R =
( L O ) R = But; R ' = Pr" or H
R = Et2N; R ' = Pr'
0-CHPh I I 6": P-CH-Pr
I
H20 (-HF)
F
BU';
R ' = Pr"
R = Et2N; R ' = Me or Ph
O H H II I I Bu: P-C-C-OH
I
0 H Ph II I I Bu\P-C-C-OOH
+
I
Pr Ph
(C2a)
(LO)
I
I
o
prn
Pr H (C2b)
?-c
//O BuLy-CHPr F
(46)
NPh
0-c 4
i i
Bu: P-CHPr
I
F (L5)
R
PhN,
+
R,PF3-n-T
PhN=PR,F3-,
= Ph or
n=l
Et2N
C
F*.'I
P .,R I
N
/
P
IflR
2: Pentaco-ordinated and Hexaco-ordinated Compounds
59
the oxaphosphetans lost HF to form ( 4 4 ) probably (431, h. heterolytic C-0 bond cleavage. The paper also describes the reactions of the fluoroylides with phenyl isocyanate and carbon dioxide which lead to the formation of pentaco-ordinate structures (45) and (46) respectively. The latter gradually decomposes to the phosphaketene (47) whose thia-analogue is obtained immediately from the reaction of ( 3 9 ) with carbon disulphide. In three recent papers, Vedejs et g . describe some elegant experiments providing evidence against the reversibility of the Wittig reaction with stabilised ylides2' and non-stabilised yli es22 and hence reach the conclusion that the variation in Wittig reaction stereochemistry in the alkene product is dominated by kinetic control in nearly all cases.23 The reaction of phenyl azide ( 4 8 ) with trico-ordinate phosphorus-fluorine compounds (e.g.4 9 ) generally proceed in accord with the Staudinger reaction to form phosphine imines ( 5 0 ) which in = 1) dimerise to the diazadiphossome cases ( R = Ph or EtzN, ; phetans ( 5 1 ) with 31P n.m.r. signals in the region of -17 p.p.m., consistent with the pentaco-ordinate structure.2 4 The 1,3,2-dioxaphospholane ( 5 2 ) reacts with the 1,3-dithietene (53) to form the ylide(55) which rearranges on standing at ambient to the 1,3, 2 - A 5 , 0 5 - f luorophosphorane (561, separable from the byproduct (54) by vacuum distillation. 25 The phosphorane ( 5 9 1 , prepared from (57) and ( 5 8 ) was also surprisingly stable and was isolated in 63% yield (b3IP = -49.3).26 The synthesis of a range of monocyclic and bicyclic compounds from the condensation of trico-ordinate phosphorus compounds (e.g_. 60 ) with anthraquinone ( 61 ) has also been reported,27 together with their 'H, I 3 C and 31P n.m.r. data. The 31P shifts for these compounds range from -34.7 ( f o r 62) through +16.8 (for 63) to +33.6 p.p.m. (for 6 4 ) but solvent effects and the retention of P-C coupling throughout the range indicate that all of these compounds are true phosphoranes. In an extensive study of the chemistry of tris(t-buty1)phenylphosphine (651, the reaction with methyltrifluoromethanesulphonate ( 6 6 ) gave two isolable monocyclic phosphoranes, ( 6 7 ) and (681, by the route outlined in Scheme 2.28 In the same paper, the reaction of (65) with diethylazodicarboxylate (69) ultimately leads (70) and (71) to the spirophosphorane (72). Finally in this section, during a study of 1-halogenophosphorinanes ( 7 3 ) , the fluoro compound was shown to disproportionate to a
Organoph osph orus Chemistry
60
PhP(0Et
+
og 0
(62)
(611
(60 1
Me I
p
M e,-b;;" S
Me
O
/
(63 1
(64)
2 . Pentaco-ordinated und Hexaco-ordinated Compounds
%
I
@J
61
HMe
r
L
7
(681
-
Scheme 2 2 (65)
+ 2Et02CN= (691
NC02Et
&N CO,E t 2 Ar P* NC02Et (70)
CO2E t
I
e---
Ar\
Et0,CN4
P,P P
/
‘N’
I
C02Et (72 1
(711
Ar
*NC02Et
62
Organophosphorus Chemistry
mixture of (74) and (75) whereas the chloro-, bromo- and iodophosphorinanes were all isolable ,29 thus emphasising yet again, the stabilising effect of fluorine on pentaco-ordinate phosphorus. 4.2 Bicyclic and Tetracyclic Phosphoranes. - The crystal and molecular structure of the pentaoxy-spirophosphorane ( 7 6 ) reveals the smaller influence on the stereochemistry at phosphorus of the six-membered ring in comparison with five-membered rings. The structure is a slightly distorted tbp (13% towards s )and the large difference between the two axial P-0 bond lengths (161.6 and 171.0 pm) and between the three equatorial P-0 bond lengths (157.7 - 163.6 pm) is ascribed to the influence of the CF3 groups on the electronegativity of the oxygen atoms.30 Cyclic phosphites (77a-c) react with bromal (78a) or chloral (78b) to give a series of spirophosphoranes of types (79) or (801, some of which were isolated and analysed.31 In each case bromal reacted faster than chloral and when (81) was used as the cyclic phosphite, the Perkow product (82) was obtained by ring opening. Oxidative addition of hexafluoroacetone (84) to the 1-chlorophosphorinane ( 83 1 gives the X I o -dioxaphospholane ( 85 ) which is hydrolysed by aqueous acid to (861 and forms a salt (87) with ring rearrangement on treatment with antimony pentachloride.32 Starting with (88) however, one obtains (90) (89); ligand permutational processes are not observed for bicyclic phosphoranes of this type. The oxidative addition of 2-chloranil to diphosphanes (91ab) has also been reported and affords phosphoranes of type (92ab) with A4P - h 5 P bonds.33 Three interesting papers on hydrido and hydroxyspirophosphoranes have appeared from Garrigues and Munoz. In the firstr3* a series of novel phosphoranes containing exocyclic anionic groups (94-97) are described, prepared by the reaction of the corresponding hydridophosphoranes (93ab) in the presence of triethylamine, with sulphur, selenium, Lawesson's reagent, and tosyl azide respectively. The compounds were isolated and characterised by analysis, IH, 13C and 31P n.m.r. and i.r. spectroscopy. With chlorotrimethylsilane however, the affinity of silicon for oxygen produced the phosphite (98). Further to this work, the reaction of phenylpyruvic acid (99) with PCl3, 2-chloro-1,3,2-dioxaphospholane ( 1 0 0 ) or the cyclic chlorophosphate (101) produced two hydridophosphoranes (102) and (103) and a hydroxyspirophosphorane (104).35 The latter is a good
2: Pentaco-ordinated and Hexaco-ordinated Compounds
3
/P~
-
w
~
p
63
-
+
F
p
F - Q I~ 7
x
F
(73) X = F
(75)
0
(a1
(a) X = Br (b) X = C I
H2C MeCH -
(b)
( =
(c)
(=
I
a;-
MeCH-
OCH2CF2CHF2
-
(800-C)
OCH2C H2CHZCl
C > P -
OCH2CF2C F3 (811
CI,C = C H O
I - P-OCH2CF2CHF2 I1
Q
(82)
64
Organophosphorus Chemistry
0 II
(CF3 l2CO
(851
( C F3 1,C HO
(881
(89)
(901
6 "P, - 1 8 . 7
c'"z'7
Me-P-
P- Me
o' '0 II Cl CL
Cl (92a. b )
65
2: Pentaco-ordinated and Hexaco-ordinated Compounds
R (94)
(95)
or Et3N, Se
Lawesson's r e agent
+ R
R
(93a,b ) (a) R = Me ( b ) R = Ph
(931
Et3N
R
x = s X = Sc
66
Orgarioy h osph orus Clietnistry
ti
Hog-ph J
2 Cl-P,
(100 1
HO
H
(1021
0
+Et3N
H
(1031
H
(1041
(1051
(1061
H NEt3
H
I
N-P-N
H
I
N-P-i'
AA'.JJ (1081
H
H\+
I
(1091
+ H
2: Pentaco-ordinated and Hexaco-ordinated Compounds
67
model for the intermediate postulated in the hydrolysis of enolpyruvate phosphoric esters. A new adduct (105) has also been isolated from the reaction of BH3.SMe2 with the conjugate base of (93). In solution it exists as an equilibrium between the spirophosphorane and a tetraco-ordinated phosphorus compound (106) containing a novel phosphorus-boron bond. 36 Further work has appeared on the protonation and alkylation of the cyclenphosphorane ( 1071 . 37 The phosphorane structure maintains its integrity whether monoprotonated (to 1081, diprotonated (to 109) or alkylated (to 110). The crystal structure of (109) revealed a geometry which was close to tbp with the equatorial P-N bonds at 164.6 and 162.9 pm being very much shorter than the apical P-N bonds at 186.7 and 186.4 pm, which suggests that a bond distance of E. 187 pm can be considered typical for an apical bond between bipyramidal P and tetrahedral N. A comparative study of the reactivity of ( 1 0 7 ) and (111) towards trifluoromethyl phenyl ketone (112) - an activated carbonyl compound, affords evidence for two quite distinct mechanisms.38 With (107) the reaction proceeds slowly to give ( 1 1 4 ) by attack at carbonyl carbon, probably ( 1 1 3 ) , the conjugate base of (107). Evidence for this is provided by the fact that (115) reacts rapidly with (112) to give the same product. On the other hand the cyclamphosphorane (111) reacts with (112) to give (117) by exclusive attack on carbonyl oxygen, presumably via the phosphoramidite tautomer (116). The reactions of the phosphetidinone (118) with tertiary phosphines (119ab) or butyltriethylammonium iodide ( 1 1 9 ~ )lead to a spirophosphorane ( 120) with concomitant formation of PCl3. 39 In a continuation of their series of papers on fluorodiazadihave described the reaction of (121) phosphetidines, Utvary et with a series of substituted hydrazines (122a-c) to form quantitative yields of compounds of type (123).40 These betaines are the first examples of diazadiphosphetidines with one A - 5 and one A - 6 P atom. They were characterised by analysis, mass spectrometry, and 1H/31P n.m. r . with the pentaco-ordinate phosphorus appearing g. -69 p.p.m. and the hexaco-ordinate phosphorus at z. -150 p.p.m. Silylated hydrazines ( 3 . 1 2 4 1 also react with (121) to form monoor disubstituted diazadiphosphetidines (125) or (126)41 which were again isolated and characterised as described above. Finally, in the presence of Et3N.PF5 (127) the betaine (123a) has been shown to lose HF and hence form (128). The reactcon of (123a) with DABCO (129) however, proceeds to form a salt (130) with two hexaco-
a.
Organophosphorus Chemistry
68
(107 1
OH
I
-
H+
Ph CC F3
(1121 slow
I
N-P-N
/
(113 1
&&JJ (114)
(1121, fast
(115 1
-
21 ____, (11
L
fast
(116)
Me
Me
I
I
N N
I
I
Me (118 1
(117) R
Me
(119a- c 1
(a1 Z
= Bu3P
( b ) Z = Ph3P ( c ) 2 = BuEtgNl
Me
I
t
Me
(120 1
= CH(CF3)Ph
69
2: Pentaco-ordinated and Hexaco-ordinated Compounds
Me
Me
-
(122 a c 1
(121)
(123 a - c 1
M@
I
N
F
/ - - \1
F3P,
,P,-NHNMe2 N F
I
Me (1251
(1211
Me
I
M
F\ N ,, /F N N H7 P \ P /-, N H N Me2 F N F
I
Me (1261
(127 1
Me (1281
Organophosphorus Chemistry
70
ordinate phosphorus atoms.42 References 40 and 42 are the only papers in this year's review to include a substantial amount of material on hexaco-ordinate phosphorus and hence a separate section on this topic has been omitted. References 1
2 3 4
5 6
7 8 9 10
11 12
13 14 15
16
17 18 19 20
21
22 23 24 25 26 27 28 29 30
31 32 33 34 35. 36
37 38
J.-M.Dupart, Phosphorus Sulfur, 1987, 2 , 15. R.Wolf, Pure Appl. Chem., 1980, 52, 1141. C.W.Perkins, J.C.Martin, A.J.Arduengo, W-Lau, A.Alegria, and J.K. Kochi, JAm. Chem. SOC., 1980, 102, 7753. L.N. Markovskii, N.P.Kolesnik, and Yu.G.Shermolovich, Russ. Chem. Revs., 1987, 56 (9), 894. A.A.Kutyrev and V.V.Moskva, Russ. Chem. Revs. 1987, 56 (ll), 1028. J.Powel1, K.S.Ng, and J.F. Sawyer, J. Chem. SOC. Chem. Commun., 1987, 1131. J.C.Clardy, D-S-Milbrath,J.P.Springer, and J.G.Verkade, J. Am. Chem. SOC., 1976, 93, 623. L.H.Koole, J.W.M. van der Hofstad, and H.M. Buck, J. Org. Chem., 1985, 50, 4381. D.B.Denney, D.Z.Denney, and M.N.Raab, Phosphorus Sulfur, 1988, 131, 1 7 5 . S.D.Pastor and D.Z.Denney, Phosphorus Sulfur, 1987, 2 , 105. W.M.Abdou, D.B.Denney, D.Z.Denney, and S.D.Pastor, Phosphorus Sulfur, 1985, 22, 99. M.H.P.van Genderen, L.H.Koole, B.C.C.M.Olde Scheper, L.J.M.van de Ven, and H.M.Buck, Phosphorus Sulfur, 1987, 2,' 7 3 . E.S.Kozlov, I.A.Kyuntsel', V.A.Mokeeva, and G.B. Soifer, J. Gen. Chem. USSR, (Engl. transl. ) , 198'7, 57, 846. W.-W.du Mont, M.Batcher, S.Poh1, and W.Saak, Angew. Chem., Int. Ed. Engl., 1987, 26, 912. S.V.Fridland and L.I.Lapteva, J. Gen. Chem. USSR, (Engl. transl.) 1987, 57, 203. S.V.Fridland and L.I.Lapteva, J. Gen. Chem. USSR, (Engl. transl.) 1987, 57, 1480. M.V.Pavlenko, G.I.Matyushecheva, V.Ya.Semenii, and L.M.Yagupol'skii, J. Gen. 99. Chem. USSR, (Engl. transl.), 1987, P. Majewski, Phosphorus Sulfur, 1987, 2,37. M.Varasi, K.A.M. Walker, and M.L.Maddox, J. Org. Chem., 1987, 52, 4235. 0.1. Kolodyazhnyi, J . Gen. Chem. USSR, (Engl. transl.) 198'1, 57, 724. E-Vedejs, T.Fleck, and S-Hara, J. Org. Chem., 1987, 52, 4639. E.Vedejs, C.F.Marth. and R.Ruggeri, J. Am. Chem. SOC., 1988, 110, 3940. E.Vedejs and C.F.Marth, J. Am. Chem. SOC., 1988, 110, 3948. R.J.Singer, W.Storzer, and R.Schmutzler, 2 . Anorg. Allg. Chem., 1987, 555, 154. J.Heine and G.-V.Roschenthaler, Chem. Ber., 1987, 120, 1445. A.A.Prishchenko, M.V.Livantsov, S.A.Moshnikov, and I.F.Lutsenko, J. Gen. Chem. USSR, (Engl. transl.), 1987, 57, 1484. N.Lowther, P.D.Beer and C.D.Hal1, Phosphorus Sulfur, 1988, j s , 133. J.Navech, H.Germa, and S.Mathieu, Phosphorus Sulfur, 1988, 2 , 247. H-Hacklin and G.-V.Roschenthaler, Phosphorus Sulfur, 1988, 36, 165. D.Schomburg, H-Hacklin, and G.-V.Rijschenthaler, Phosphorus SulEur, 1988, 3 , 241. I.V.Konovalova, E-N-Ofitserov,T.N.Sinyashina, V.F.Mironov, and A.N.Pudorik, J. Gen. Chem. USSR, (Engl. transl.), 1987, 51, 1078. H. Hacklin G.-V.Roschenthaler, u n o r g . Allg. Chem., 1988, 561, 49. R-Schmutzler, 0-Stelzer, and N.Weferling, Chem. Ber., 1988, 121, 391. L.Lamand6 and A.Munoz, Phosphorus Sulfur, 1987, 2,1. A.Munoz and L.Lamand6, Phosphorus Sulfur, 1988, 35, 195. S.Garrigues, L.LamandP, and A-Munoz, Phosphorus Sulfur, 1988, 3,309. F.Bouvier, J.-M.Dupart, and J.G.Riess, Inorg. Chem., 1988, 27, 427. F-Bouvier, P-Vierling, and J.-M.Dupart, Inorg. Chem., 1988,1099.
z,
2: Penraco-orciinared arid Hexaco-ordinated Cornpoutids 39
40 41
42
71
V.K.Dmitriev, B.V.Timoktin, A.V.Kalabina, T.I.Kazantseva, and V.I.Donskikh, J. Gen. Chem. USSR, (Engl. transl.), 1987, 2 , 2143. K.Galle and K.Utvary. Monatshefte fur Chemie, 1988, 119, 53. K.Galle and K.Utvary, Monatshefte fur Chemie, 1988, 119, 165. K.Galle and K.Utvary, Monatshefte fur Chemie, 1988, 119, 173.
3
Phosphines Oxides and Related Compounds BY B. J. WALKER 1
Introduction
Complex phosphine oxides are increasingly being used as alternatives to phosphonates in the synthesis of macromolecules.2 8 ' 3 2 2
Preparation of Acyclic Phosphine Oxides
a-Methoxyallylphosphine oxides (2) are conveniently prepared by the reaction of chlorodiphenylphosphine with the allylic acetal (1) (Scheme 1).
Although this reaction is only successful with acetals
(1) carrying certain substituents, (2) are readily converted into
methoxydienes by base-induced reaction with carbonyl compounds even A new, albeit restricted route to phosphine oxides is
below 0 O C . I
available from carbon-centred radical addition to the vinylphosphine oxide (4). which is available from ( g ) - l , Z - b i s ( t r i - n - b u t y l s t a n n y l ) ethene ( 3 ) (Scheme Z ) . ' Photoinduced oxidation of phosphine sulphides and selenides t o phosphine oxides has been extensively studied.
Oxidative
desulphurisation of phosphine sulphides has been achieved in moderate to good yield by radical species photogenerated from acylphosphine oxides and acylphosphonates.
Phosphine sulphides and
selenides can be converted into the corresponding oxides by photooxidation in the presence of dialkylsulphides o r diazo compounds4 o r by reaction with manganese( 1 1 1 ) mesotetraphenylporphyrin chloride in the presence of tetrabutylammonium periodate and imidazole. The mechanism o f the photoinduced oxidative desulphurisation and deselenation of pentavalent phosphorus using pyridine
I t is suggested that the
oxide has been
reaction occurs by direct oxygen transfer from the fl oxide ratner than formation of intermediate oxaziridine.
t.mL!!
3 - .pr_el!r_a_ f CYc_lic 1, h O?Lh. in (3 . 0 xi dE s. General routes to phosphetanes are restricted to multimcthyl derivatives.
~
I t is now reported that l e s s substituted 1-phcriyl
phosphetane oxides (5) can b e prepared by the reaction of cyclopropanes with the electrophilic dichlorophcnylp ho s p h i n e / a 1urn i. n i um t r i. c h 1o r id e r cage n t f o 11 owed by hyd r o 1 ys i s . "
;,&
3: Phosphine Oxides and Related Compounds
Ph2 0 Ph,PCI
+
i_
Me0 OMe R2
Me0
R3
Reagents :
i,
Heat
;
R'
~2
Y
R
Me0
73
R'
ii. L O A , R 3 R 4 C O
Scheme 1
I1
(3)
(6)X = C02Me
0
(7) X = C02Me
(8) X =C02Me
74
Continuing investigations o f the reactions of dimethyl acetylene dicarboxylate with terval ent phosphorus compounds have Heactions with dialkyl revealed new chemistry and intermediates
.'
phosphonites provide (6). which on treatment with hydrogen bromide o f f e r a route to 2.5-dihydrophosphole oxides ( 7 ) and, under more vigorous conditions, the phosphole oxides
( 8 ) .
l'he hydro1y:ii:; o r
methanolysis of bis(pheny1i.mino) derivatives of phosphole dimc?rs provide new routes to the corresponding diphosphine dioxides and d ~ e especially useful since the reaction proceeds with retent.ion o f configuration dt one phosphorus and inversion at the other t o qivc? previously unknown dioxide stcreomers ( 9 ) . 9 1,6-Dihydrophosphorin 1-oxides ( 1 1 ) have been synthesised f r o m the corresponding ketones (10) by reduction and dehydcation (Scheme 3).1°
D i e l ' s Alder reactions o f
( 1 1 ) with alkenes and alkynes
provided Z - p h o s p h a b i c y c l o [ 2 . 2 . 2 ] -( 1 % ) and octa-5 ; f - dic?ne-( 1 3 ) ring systems, respectively. Under very mild conditions oxides ( 1 2 ) a n d (13) could be reduced to the corresponding phosphines without fragmentation.
Reaction of t-he X 3 - phosphi nine (14) wi.th e x c e s s
sulphur leads to Lhe formation of the monosulphide (1.5) a s the major product and the trisulphide ( 1 ' / ) a s a minor product."
Under mi.ld
conditions i t is possible to isolate an intermedidte which the authors convincingly identi€y as a phosphinine 1-sulphide wit.h structure (16a) o r (16b); (16) is slowly converted into ( 1 ' 1 ) in prolonged reactions.
l'he reaction o f dichlorocarbene wi.th
dihydro- 1EI- phosphole oxides under phase transfer conditions has been investigated. 1.2'13 2.3-Dihydro-4 -methyl- 1-phenyl- 1H. phosphole oxide ( 1 8 ) did not react (presumably due to the electronic effect o f the adjacent PO function), however the 2.5-dihydro analogues (19) gave the simple adducts (20). This latter reaction offers a route to tetrahydrophosphorin- (21) and dihydrophosphorin- (22) 1-oxides v i a
silver nitrate-induced ring expansion of the adducts (20) (Scheme 4) . I 3
The addition of dichlorocarbene to the 2,5-dihydro-3.4-
dimethyl derivative (23) gave a much more complex reaction (Scheme The phosphacycloheptatricne (24) was one o f several products isolated and evidence is presented for its formation v r the mechanism shown. 5) .12
4
Structure and Physical A s p e e
A n a b initio.M.0. study comparing the structure o f the simplest phosphine oxide (25) with related ylides and anions h a s been reported. l4
3: Phosphine Oxides and Related Compounds Ph,
75
Ph
,NPh P’
‘p”/o
J
0 +J-R
(13)
Reagents : i , N a B H 4 , C e C L 3 , MeOH
;
W
ii , K H S 0 4 , C s H s C l ; iii ,
x iv, X C s C X ;
v , HSiCL3 , 0 . C
Scheme 3
x
;
Organophosphorus Chemistry
76
excess S
+
___c
Ph
Ph
II
JJPPh2
Ph
PPh2 II S
S
(14) (16a) R’
3
(15)
= Ph2P, R 2 = Ph,P
f
(16b) R’ = PhZP, R Z = Ph2P
CI
Me NaOH, H20 CHCl3,TEBAC
Ph’
0 ‘
(18)
R’ “0 (19)
R’
*O (20)
77
3: Phosphine Oxides and Related C h p o u n d s
Cl
CI
CI
+
I
T
(21)
(20)
O4 ‘R Reagents : i , AgNO3, H20
;
ii NaHS04 , Toluene ~
Scheme
ct
OG ‘R
4
CI
Cl
c‘
II
c-
Meph/ %Me “0 (24) Reagents: i , NaOH, HzO.CHCI3. TEBAC; i i , NaOH
Scheme 5
Organophosphorus Chemistry
78
A low temperature e.s.r. study of 5-ray-irradiated single crystals of trialkylphosphine sulphides and selenides has been reported and reveals the formation of the corresponding radical anion in each case.15 Parallel ab initio quantum mechanical studies do not reproduce the experimental coupling and spin density values. E . s . ~ . studies of the U.V. irradiation of 2.4.6-trimethylbenzoyl-
diphenylphosphine oxide (26) in oxygen-free benzene indicate that carbonyl-phosphorus bond breaking takes place to give the diphenylphosphinoyl radical (27). l6 This radical rapidly adds to unreacted ( 2 6 ) to give (28). The structure o f the oxide of 9 phosphaanthracene and its anion have been investigated by 'H. l 3 C and 3 1 P n.m.r. ~ p e c t r o s c o p y . ~ ~ ' The results suggest a butterfly-type conformation (29) f o r the oxide. The substantial downfield shift in the 3 1 P n.m.r. spectrum of the anion (30) when compared with that of the neutral oxide (29) is in agreement with a large contribution from the canonical form (30b). Triphenylphosphine oxide is known to form crystalline complexes with a variety of organic molecules capable of H-bonding. It is now reported that many of t,hese complexes are easily crystallised as large crystals, much greater in size and quality than those obtained from the pure organic molecule.'* Crystalline complexation with optically active 2 , 2 ' - d i h y d r o x y - l , l ' - b i n a p h t h y lhas been used to provide efficient resolution o f chiral phosphine oxides (e.g. 31) An 5- ray study of the diastereomeric complexes and phosphinates." formed between the resolving agent and methyl methylphenylphosphinate identified some of the interactions involved in complexation. Hydrogen-bond basicities (@-values) have been determined f o r a large number of compounds containing the PO bond, including several phosphine oxides. 2 o ______.__5 Reactions at phosphorus Triphenylphosphine may be regenerated f r o m its oxide by conversion to the m e t h y l t h i o t r i p h e n y l p h o s p h o n i u m salt ( 3 % ) followed by electrolysis (Scheme 6). 2 1
-6
Reactions at the Side-Chain .... methylphosphine oxides (e.g. 33) have been prepaced by the reaction of (ch1oromethyl)dimethylphosphine oxide with the sodium salt o f the corresponding ~~
A variety of heterocyclicsubstituted
3: Ph osphitie Oxides cititl Relriterl
(25)
8
hv
(26)
-
0
II ArCOPPhz
+
79
i p m t i (Is
R ArCOPPh2
H3P(O)
PhzP.
C‘ot j
0 I1
+
Arc* II
Ph2P.
0
(27)
0 II Ar CPPh2 I 0
I
Phz P=O
(28) Me
Me
\ /
Ph,P(O)
-
\
\
- /\
’ 0 ‘Ph
i,ii
0
(31) R = H , M e
+
Ph3P-S-Me
MeSOc
(32) Reagents : i , P4S,o; ii, Mc2S04 ; iii , c-, MeOH
Scheme 6
111
Ph
Ph3P
80
-
0
II M e 2P C H2 C I
RN NaNvJ
+
-
0
NR;
i,ii
ph21/\JNR:
(37)
HO
Organophosphorus Chemistry
0
k II Me2PCH2-N
N
4
iii,iv
R2CH=CHCH2NRi
0 II
0
R2CH=CHCH2NHCOPh Reagents : i , B u L i ; ii, R 2 C H O ; iii, Separate diostereomcrs; v, 2 x B u L i
Scheme 7
R'
Reagents : i , B u L i
;
ii, R'R'CO
;
R2
iii , K O t B u ,
Scheme 8
i v , NaH. DMF
;
3: Phosphine Oxides and Related Compounds
81
heterocycle. 22 The phosphine oxides readily undergo the Horner reaction with aldehydes and ketones to give the expected alkenes as mixtures of isomers in moderate to good yields. Over the last ten years Warren and his group have developed routes to the 2-hydroxyalkylphosphine oxide intermediates in the Horner reaction (and hence to alkenes) which allow substantial stereochemical control. In the latest reportz3 these methods are applied to the synthesis of a variety of pheromones and related compounds, e.g. (34). (35) and (36). Warren has also reported a stereospecific synthesis of
N-ally1 amines and amides by Horner reactions of, respectively, 8-diphenylphosphinyl alkyl amines (37) and the corresponding amides (38). followed by separation of the diastereomeric intermediates and final base treatment (Scheme 7).24 In the case of the amides (38) the dianions are used since the first deprotonation occurs at nitrogen, however the carbanionic centre o f the dianion reacts with carbonyl compounds to give the expected alkene. The reaction of c y c l o p r o p y l i d e n e d i p h e n y l p h o s p h i n e oxide anion with aldehydes and ketones provides a new synthesis of alkylidenecyclopropanes (Scheme The 8 hydroxylakylphosphine oxide may be decomposed to alkene by conversion to its potassium salt or by direct heating at 22OoC (the latter procedure has advantages for volatile olefins). The problems associated with the possible sites o f attack on allylic phosphine oxide anions have been largely solved f o r 1-methyoxyallylic examples by initial reaction with titanium(1V) isopropoxide to give (39) followed by a-attack of the carbonyl compound.26 The isomer (40) (which leads to (E)-alkene after base treatment) predominates in the mixture of stable diastereomeric 2-hydroxylakylphosphine oxides formed (Scheme 9). Surprisingly, similar reactions of (39) with acyl chlorides gave exclusively the y-adducts (41). A highly (2)-stereoselective Horner reaction of (43) provides the second olefination step in a new one-pot synthesis of 1.6-dienes from 1 . 1 - d i p h e n y l p h o s p h o r i n a n i u m bromide (42) . 2 7 Olefination using the complex phosphine oxide (44) has been used as the final step in a new convergent synthesis of 1.25-dihydroxy24(R)-fluorochole-calciferol (45) .28 A variety of optically active phosphine oxides (46) have been prepared by alkylation of the corresponding optically active vinylphosphine oxide in the presence of a zinc-copper couple under ultrasonic conditions.29 The reaction takes place without any observable epimerisation at phosphorus and without polymerisation. Direct addition o f secondary phosphine oxides and primary o r
Orgun oph ospli oriis CCi emistry
82
-
::
P h 2 P y J R' 4
Me0
I
Li+
R'
0 Ph2e,&R2
Li
Me0
Ti(OiPrI3
(39)
1
ii
Reagents: i , T i ( O i P r ) &
i i , R3CHO
Scheme 9
F OQPPh,
(44)R = SiMe2'Bu
+
83
3: Phosphine Oxides and Related Compounds
Z n ( Cu)
RX Sonication, r . 1 .
Ph
0 It
Me"-P
4
Ph
v
(47)
i - iii
Reagents : i , P h 2 P ( 0 ) C H Z L i , DME , ii, ( S )
- PhCH(MelNC0, resolve
iii, NaOEt , EtOH
Scheme 10
;
Organophosphorus Chemistry
84
Ph,P(O)H
+
Et3B
[R
Ph2P-O-BEt2
.__c
*’
P - Te - Te - PR3J
(57)
R13P [-(OC)2Co-PR2-S2
I
R’3 P
(59)
-
(58)
(54)
secondary amines to the optically active vinylphosphine oxide (47) provides a route to a variety of ‘-chiral
1.2-diphosphinoylethanes
(48)30 and 2 - aminoethylphosphine oxides (49), 3 1 respectively. the latter case methods based o n 31P n.m.r. and o n chemical
In
correlations indicated that there was no racemisation at phosphorus during the reaction. The reaction of diphcnylmethylphosphine oxide carbanion with the epoxide (50) (Scheme 1.0) has been used in a synthesis of the complex phosphine oxide (51) with the ultimate aim of synthesis of the avermectin natural pr0duct.s.3 2
a -Phosphonyl thioacylamides
(52) have been prepared by the reacLion of the corresponding
phosphine oxide car bariion with me thy1 is0 thiocyana te. 33 a - D i a z o 8 - ketoalkylphosphine oxides undergo rhodium( 1 1 ) catalysed intramolecular carbenoid cyclisations to give substituted d i p h e n y l p h o s p h o n o - 2 - c y c l o p e n t a n o n e s ( 5 3 ) which can be converted t o a-methylene cyclopentanones by the IIorncr reaction. 3 4
The reactions of diphenylphosphine oxide with organoboranes have been investigated.35
The ini.tial products are the tervalent
adducts (e.g. 54). although these are easily converted i n t o the thermodynamically stable rearrangement products (e.g. 55). Zwitterionic addition products are obtained from further reactions with borane.
Phosphine tel.lurides a r e oxidiced by €erricenium salts
to give the dications (56) containing the tritellurium link rather than the expected dications ( 5 - 1 ) . 3 6 The structure of (56, H r t B u ) was determined by X - r a y crystal analysis. 7 _ Ph-gsphine -
.
Oxide Complexes
Examples of reports of phosphine oxides and related compounds coordinated to transition metals include the synthesis and chemistry of
thiophosphinito complexes of cobalt ( 5 8 ) . 3 7
readily f o r m oligomers (59) bonded &v
Co
The compounds
and s u l p h u r .
REFERENCES 1. E.F. Birse, M . Maleki, J.A. Miller, and A.W. Murray, J . Chem. Res., S y n o p . , 1988, 85. 2. G . E . Keck, J.H. Byers, and A.M. Tafesh, J . O r g . Chem., 1988, 5 3 , 1127. 3. J . E . Baxter, R . S . Davidson, M . D . Walker, and H.J.H. Hageman, J . Chern. @. , Synop., 1988, 164. 4. R.K. Bhardwaj and R.S. Davidson, Tetrahedron, 1987, 43, 4473. 5. R.S. Davidson, M . D . Walker and R.K. Bhardwaj, Tetrahedron Lett., 1987, 28, 2981. 6. R.K. Bhardwaj and R.S. Davidson, J.Chem. Res., Synop., 1987, 406. 7. S . A . Weissmann and S.G. Baxter, Tetrahedron Lett., 1988, 29, 1219. 8. J.C. Caesar, D . V . Griffiths, and J.C. Tebby, J . Chem. SOC., Perkin Trans.l., 1988, 175. 9. L.D. Quin, G. Keglevich, and K.C. Caster, Phosphorus Sulfur, 1987, 3 l , 133.
86 10.
11.
12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.
Organophosphorus Chemistry L.D. Quin, A.N. Hughes, J.C. Kisalus, and B. Pete, J. Org. Chem., 1988, 53, 1722. F G . Holah, A.N. Hughes and K.L. Knudsen, J. Chem. SOC., Chem. Commun.. 1988, 493. G . Keglevich, I. Petnehazy, P. Miklos, A. Almasy, G. Toth, L. Toke, and L.D. Quin, J . O r g . Ck~gm.,1987, 52, 3983. G. Keglevich, G. Toth, I. Petnehazy, P. Miklos, and L . Toke, J. O r g . -Chem., 1987, 52, 5721. A. Streitwieser, J r . , A. Rajca, R.S. McDowell, and R. Glaser, J . Am. Chem. SOC., 1987, 109, 4184. R.A.J. Janssen, J.A.J.M. Kingma, and H.M. Buck, J. Am. Chem. SOC., 1988, 110, 3018. M. Kamachi, K. Kuwata, T. Sumiyoshi, and W. Schnabel, J. Chem. SOC., =kin Trans.2, 1988, 961. H.S. Kasmai, J.F. F'emia, L.L. Healy, M.R. Lauria, and M.E. Lansdown, IT_L O r g . Chem., 1987, 5 2 , 5461. M.C. Etter and P.W. Baures, J. Am. Chem. So?., 1988, X O , 639. F. Toda, K. Mori, Z. Stein, and 1. Goldberg, 11_, O r e , . Chem., 1988, 53, 308 R.W. Taft, W.J. Shuely, R.M. Doherty, and M.J. Kamlet, J. O r g . C a . . 1988, 53, 1737. J.-L. Lecat and M. Devaud, Tetrahedron Lett., 1987, 28, 5821. L. Maier and G. Risk, Phosphorus Sulfur, 1987, 2 , 65. A.D. Buss, N. Greeves, R. Mason, and S . Warren, J. Chem. S-oc., Perkin Trans.l., 1987, 2569. D. Cavalla, W.B. Cruse, and S. Warren, J. Chem. S O C . , Perkin Trans.l., 1987, 1883. F.G. Meijs and P.C.H. Eichinger, Tetrahedron Lett., 1987, 28, 5559. E.F. Birse, A. McKenzie, and A.W. Murray, J . Chem. S O C . , Perkin-Trans.!, 1388, 1039. I. Yamamoto, T. Fujimoto, K. Ohta, and K. Matsuzaki, J. Chgnl-Soc., Perkin Trans.1, 1987, 1537. S.-J. Shiuey, J.J. Partridge, and M.R. Uskovic, J. O r e . Chem., 1988, 2 , 1040. K.M. Pietrusiewicz and M. Zablocka, Tetrahedron&st-t., 1988, 29, 937. K.M. Pietrusiewicz and M. Zablocka, Tetrahedron Lett., 1988, 29, 1987. K.M. Pietrusiewicz and M. Zablocka, Tetrahedron Lett., 1988, 29, 1991. A.G.M. Barrett and T.A. Miller, Tetrahedron Lett., 1988, 29, 1873 U. Kunze and V. Kruppa, Phosphorus Sulfur, 1987, 31, 33. B. Corbel, D. Hernot, J.-P. Haelters, and G. Sturtz, Etr-+hedion Let&., 1987, 28, 6605. R. Koster, Y.-H. Tsay, and L. Synoradzki, h-r., 1987, lZ0, 1117. N. Kuhn, H. Schumann, and R. Boese, J. Chem. S o c . , Chem. Corn., 1987, 1257. E. Lindner, K.E. Frick, R. Fawzi, W. Hiller, and M. Stangle, Chem-.--Kgr.. 1988. 121, 1075.
4
Tervalent Phosphorus Acids BY 0.DAHL
1 Introduction
Reviews of relevance for this chapter are one on the preparation of chiral ligands from amino acids for use in catalytic asymmetric synthesis, and one on the chemistry of aminoiminophosphines ( R1R2N-P=NR3 ) 2
.
2 Nucleophilic Reactions
2.1 Attack on Saturated Carbon.- Arbuzov reactions of the easily obtainable phosphonite (1) with various benzyl halides gave predominantly one diastereomer (2); this was used in an asymmetric synthesis of phosphine oxides (3) . g-( 1-C hlorobenzyl )benzimidoyl chloride ( 4 ) with tervalent phosphorus esters, e.g. ( 5 1, reacts selectively at the saturated carbon center to give ( 6 ) . 4 & - ( 2 Chloroethyl) or ~-(3-chloropropyl)-2-pyrrolidones (7) gave phosphites (8) with some cyclic phosphites but the normal Arbuzov products ( 9 ) with phosphonites or phosphorodiamidites. Arbuzov reactions performed on acylphosphonites (10) or (dialkoxymethy1)phosphonites (11) sometimes gave products resulting from P-C bond cleavage instead Gf the normal phosphonates, as shown €or two examples: the anomalous reaction is promoted when alkyl chlorides are used instead of iodides. 1-Aryl-1-(alkyl(12) can be made in an analogous way to the alkoxy analogues from dithioacetals as shown.7 A large number of N-substituted aminomethanephosphonates or phosphinates, e.g. (131, have been prepared from hydroxymethylated amides and triethyl phosphite or diethyl methylphosphonite; the free acids could be obtained without concomitant amide hydrolysis by enzymathio)methanephosphonates
Organophosphorus Chemistry
88
CI
CL
I
I
PhCH-NZCPh
+
-
Ph2 POEt
(4)
(5)
CL
Ph I 1 Ph2 P(0)CH-N=CPh
(6)
X ,Y = E ~ ~ N , B u ~ XN =E ; t,Ph,Y=OEt
( EtO), P-COBu'
(10)
ClCOOMe
90 - 100 *C
(€to), P-CH(OEt12
( EtO),P-COOMe
ClCOOMc 35
*C
c ICOoMe
fl
EtOP(COOMe)2
(Et0)ZP-COOMe
4: Tervalent Phosphorus Acids
(EtO),P-OSiMe,
89
+
(RS)2CH
-ox 0
fl
SR
( E t 0)2 P-CH'
e
x
rN WN7OH
HO
0
R = CH,, OEt
a:;P-X
+
CH2(NEt2),
CH;! NEt 2
1
(16)
X = O R , NEt2, Et
90
Orgatiopiio.iphon r s CIi em isiry
tic hydrolysis, using phosphodiesterase I or alkaline phosphatase. Benz-1,3,2-oxazaphospholens (14) with bis(diethy1amino)methane gave P-substituted dimers (15); these upon distillation gave monomeric N-substituted products (16), although (15, X=Et) could be distilled unchanged.' A remarkable reaction, exemplified by the formation of the phosphonate (17) and ethane ( ! ) from triethyl phosphite and malononitrile, has been discovered.lo Methylphosphonites were more reactive and gave diphosphinates, e.g. (18), under forcing conditions. The mechanism proposed, Scheme 1," does not explain much: a 1,2-elimination of RH from a phosphorane (19) is a possibility. 2 . 2 Attack on unsaturated Carbon.- Excess trimethyl phosphite and dimethyl acetylenedicarboxylate has been shown to give the bisylide ( 2 0 ) ,I1 and not the bisphosphonate (21) as claimed earlier. A new route to 1-alkoxyphosphonates, e - g . (22), has been described. E-Styrylphosphonates (23) are formed under mild conditions and in high yields from phenylacetylene via a manganese complex as shown.l3 j3-Nitrostyrenes (24) with diethyl trimethylsilyl phosphite and titanium tetrachloride gave the adduct (25), which with zinc gave 1-aryl-1-cyanomethylphosphonates (26).l4 2-
Alkenals, protected as the t-butyl imines (27), react exothermically with triethyl phosphite in the presence of formic acid to give 2-formylalkylphosphonates (281 ; l 5 without formic acid the reactions are very slow. The kinetics of the reaction of trialkyl phosphites with a-halogenoacetophenones in alcoholic solvents have been examined. The data gave evidence for a common first intermediate (29), formed in the rate-determining step, which leads to the main products, vinyl phosphates (30), a-hydroxyphosphonates (31) , and acetophenones (32). Bis( trimethylsily1oxy)phosphine (33) is a very reactive alternative to hypophosphorous acid for addition to imines, to give 1-aminoalkylphosphonous acids ( 34 ) after hydrolysis.l7 An improved method to prepare a-aminobenzylphosphonic (or phosphinic) acids consists in using diphenyl phosphorochloridite (35) (or phenyldichlorophosphine) with aromatic aldehydes and a nitrogen donor as shown.18 The reaction conditions are milder and the yields higher than the analogous reactions using triphenyl phosphite. Nitrones (36) react with trialkyl phosphites in the presence of alkyl iodides to give 1-(alkoxyamino)alkylphosphonates ( 37 1. Benzaldehyde and the 1,3,2dioxaphospholan ( 3 8 ) in methylene chloride gave on precipitation with hexane a solid 1:l adduct, probably the dimer (39);20 in so-
4: Tervalent Phosphorus Acids
2 Me P (0Bu’ l2
t
91
CHz(COOEt)z
210 ‘C
0 II
(MeP-I2 C(COOEt)2
I OBu
+
2 C4 Hlo
(18)
Scheme 1
2 (Me0)3P
+
MeOOCC=CCOOMe
K
0 Me Me 0 It
( Me O), P-C
I
I
MeOOC
I -C-
I
II P (OMe
COOMe
( 21 1
Organophosphorus Chemistry
92
0 PhC=CH
+
+
(MeO),P
HCI r.t.
CpMn(C0)3
Cp(C0)z Mn=C =CHPh
Ph
(EtO),P-OSiMe,
+
ArCH=CH-N02
(24)
Tic14
ArCH-CH=N
I
P(OXOEt)2 (25)
R' R2C=CR3CH=NBut
+
(Et013P
Ar CH
/
OSiMe,
+/
CN
\
-
0-Tic1
93
4: Tervalent Phosphorus Acids
CHzX (RO),P
t
0I
+
I
C-0
I
Ar
+
(RO), P -0 I C =CH2 XI Ar
0
II
OH
I
t-
( RO),P-C-CH2X
(RO),PX
I
0
t
(32)
(31)
(33)
t
RCH=NCHPh2
I
Ar
Ar
(Me3Si0)2PH
&-CH3
__c
r.t .
RCHNHCHPh2
I
P(OSiMe3I2
RCHNHCHPh2
I
HP(0)OH
(341
Organophosphorus Chemistry
94
(PhO),PCI
+
ArCHO
(35)
+
(Et0)2P(S)NH2
1
ZnCL 2
NH2 I ArCH-
P03H2
3
( Ph0 12 P ( 0 ) C HNHP( S ) ( 0E t )2
1
Ar
J
(36)
P-Me
(38)
+
PhCHO
(37)
( 3 9)
95
4: Tervulerit Phosphorus Acids
lution there are indications for an equilibrium between (39) and the oxaphosphirane (40), an elusive intermediate often postulated. Acylphosphonites (41) , which are difficult to prepare, are formed rapidly from (42) and acyl chlorides in ether;21 only the most hindered phosphonite (41, R=But) is stable towards dimerization, 2.3 Attack on Nitrogen, Chalcogen, or Halogen.- Tervalent phosphorus compounds are known to give phosphoranes with 2 eq. of hexafluoroacetone, e. g . ( 43 ) A 1:1 adduct, the phosphite ( 44) , has now been identified at low temperatures,22 which is strong evidence for the reactions going via nucleophilic attack on oxygen as shown. Trialkyl phosphites gave phosphoramidates (46) with benzothiazol-2-yl-sulphenamides (45) ; the lack of stereoselectivity for chiral phosphites points to a phosphorane mechanism with initial attack on sulphur.23 The thiaphosphatidyl choline ( 47 ) has been prepared using the triethylsilyl phosphite ( 48 ) ;24 with alkyl phosphites ring-opened products were formed along with
.
(491.
3 Electrophilic Reactions
3.1 Preparation.- Tri-t-butyl phosphite (50) has been known for many years to be an undistillable compound which decomposed to di-t-butyl phosphite (51) upon heating to 50°C.25 This has now been shown to be due to the presence of acid impurities, or phosphorochloridites, in the crude product; by using an excess of both t-butyl alcohol and triethylamine, (50) could be prepared from phosphorus trichloride and purified by distillation. 26 It did however decompose at 115OC to give phosphorous acid (52); diethyl t-butyl phosphite (53) was also prepared and shown to be stable to elimination of isobutene up to 170°C.26 A series of dialkyl phosphorochloridites (54) has been prepared from trialkyl phosphites and dichlorotriphenylphosphorane and obtained fairly pure (96-99%) after a simple d i ~ t i l l a t i o n .The ~ ~ synthesis of 1chlorophosphorinane (55) from (56) has been improved by using dichlorophenylphosphine instead of gaseous hydrogen chloride.28 Di-ti-biityl FJ,N-diethylphosphoramidite ( 57 ) has been prepared as shown;29 it is recommended for phosphorylation of alcohols as a stable, distillable reagent, which is nevertheless highly reac-
96
Organophosphorus Chemistry
(EtO),P-COR
+
EtOP(O)[CH(OEt)2]2
(41) R = Me, Pri,But
(R0)zPCI
+
(CF3)zCO
-
,+ (R0)2P,
CL o--C(CF~ 1 2
R = Me,Et;R2 = CH2CHZ,(CH2),,CMe2CMez CI
97
4: Tervalent Phosphorus Acids
( EtO);! P-OBU'
(53)
(RO),P
+
Ph3PClz
(R0)ZPCl
+
Ph3PO
(54)R = M e . E t , P r . P r ' . B u
C
P-NEtZ
(56)
PhPClz
C P - C l
(55)
RCl
Orgutioph osphoriis Clieniisrry
98
Et2NPCL2
+
ROPO, H 2
2
Bu'OH
E t 3N
1 , MCPBA 2 , HCL
E t 2 N P (OBU' )2
(57) tetrazole
1
ROH
ROP(OBU')~
OR
I
(60)
R L Bpk~ R 2 = M e , Pri
,
99
4 : Tervalent Phosphorus Acids
tive when activated by tetrazole. The first example of a 1,3,2,4-dioxadiphosphetane, (58), has been prepared by heating the trioxatriphosphorinane ( 5 9 ) under vacuum;30 The X-ray crystal structure of (58) shows that the ring is nonplanar with the substituents cis. Some chiral phosphonamidites (60) have been prepared optically active (up to 55% ee) as shown, using an optically active tertiary amine as a catalyst.31 The thermally unstable 2-phenylethynylphosphonite (61) has been prepared as shown from the likewise unstable, although distillable, dichloro compound (62).32 The E-alkylphosphoramidite ( 63) is stable below 35OC but rearrangesto ( 64) upon attempted distil1 a t i 0 n . ~8-Iminoketones ~ ( 6 5 ) could in principle be phosphitylated at oxygen, nitrogen, or carbon; however only N-substituted products (66) were found from reactions of phosphorochloridites with ( 65 ) .34 The aryl phosphorodichloridite ( 67 ) and a-diketones, e . g . (68), when stirred with magnesium, gave fair yields of 1,3,2--dioxaphospholens, e . g . (69), probably via trapping of the aryloxyphosphinidene ( 70 ) .35 The yield of cage phosphites derived from mutarotating sugars, e . g . (711, could be improved by adding the phosphorus triimidazolide in portions, thus allowing time for the mutarotation to occur.36 The optically active bis-phosphites and bis-phosphorofluoridites (72) have been prepared €or use as l i g a n d ~ .For ~ ~ the same purpose, a series of bis-phosphinites (73) has been prepared by modified, known methods;38 (73, R=Me) was found to be thermally unstable. A number of bicyclic phosphites (74) containing the 1,3,2-dioxaphosphorinane system have been prepared for a study of their preferred conformations.39 Synthesis of myo-inositol phosphates continue to challenge phosphorus chemists, and three groups have made the optically active 1,4,5-tri- and 1,3,4,5-tetraphosphates (75) along with some other analogues, using the tervalent phosphorus reagents ( 76 ) ,40 ( 77 ) ,41 or ( 78 ) 42 The methyl thiophosphonochloridites (79) have been prepared from dichlorophosphines ( 80) and methanethiol: 43 they slowly decompose at room temperature to the symmetrical products (80) and (81). Another group has prepared (79, R=Me) by heating (80) and ( 81 ) together at 90OC;4 4 apparently an equilibrium may be established between (79) and (80)+(81). The compounds (79) have been used forcheleotropiccycloadditions to give 3-phospholene sulphi44 des, e.g. (82),43 or for preparation of a thiophosphonite (83). Some trialkyl thiophosphites ( 8 4 ) have been made from the enolphosphite (85) and a t h i 0 1 ; ~two ~ of them could be distilled, but
.
0rganoph osphorus Chemistry
100
(65)
( 6 6 ) R'=Me,Et,OEt R2=Et, Pr
-q-opcl,*o-p:xph +
o=cI NPh o=c, Ph
Mg
THF
Ph
OH H,03P0 H z O - j P dOP03H2
MeOPC1,
(PhCH20)2P-NR2
HO ( 7 5 ) R =H,P03H2
(77) R=Et (78) R=Pri
101
4 : Tervalent Phosphorus Acids
RPCIz
+
MeSH
-
CI
&3N
RPC
- 7 8 to 20 ' C
SMe
(79) R =Me. Et , Ph
\
Me
x -
MeP,
/
c'
Pr'OH
SMe
B
OP~
MeP, SMe
(83)
(82)
+
RSH
( 8 4 ) R = Bu, P hCH2, CH2COOEt
D S h N S - P R 2
(87) R = E t . P h , O E t
Me2P 'H
+
( 8 6 ) R = CH2C00Et
fl
Me2P- S-SiMe3
(88)
Me3SiNMe2
\r
S
II Me2P- PMe2
+
(Me3Si 12 S
102
Organophosphorus Chemistry
(84, R=CH2COOEt) rearranged to (86) upon attempted distillation.
similar rearrangement occurred for (87, R=Et, Ph) upon boiling in benzene, whereas (87, R=OEt) could be distilled unchanged.46
A
Attempts to prepare trimethylsilyl dimethylthiophosphinite (88) from dimethylphosphine sulphide gave the diphosphine monosulphide (89).47 Ethane-1,a-dithiol with tris( dimethy1amino)phosphine gave the bis-trithiophosphite (90) instead of the expected phosphorane (911.~~ An unusual fused benzo-1,2,3-thiadiphosphole (92) was formed by reaction of thioanisole with phosphorus trichloride and aluminium trichloride.49 In contrast to phosphorus trichloride, which gives a benzo-1,3,2-oxazaphosphorinane with salicylamide, tris( diethy1amino)phosphine gave ( 93 ) 50 An improved method to prepare the chlorodibenz-1,2-oxaphosphorin (94) and derivatives has been published. 51 Two o-substituted aryldiaminophosphines ( 95) have been prepared and used to obtain the dihalophosphines ( 9 6 ) and (97).52 The urea derivative (98) has a very short P . . P non-
.
bonding distance and reacts with oxalic acid bis(trimethylsily1)ester to give the cyclic compound (99).5 3 3.2 Mechanistic Studies.- The r-eactionsof phosphoramidites with alcohols are catalysed by amine hydrohalides , including hydrofluorides. The mechanism of catalysis by amine hydrohalides has been postulated previously to be exchange with halide, i . e . nucleophilic catalysis, and not just acid catalysis. This has now
been shown not to be the case, at least €or hydrofluorides, since the postulated intermediate (100) of the reaction of (101) with alcohols was much less reactive than (101).54 In the same study it was shown that amine hydrofluorides, -chlorides, and -bromides had similar catalytic activities, which also points against a nucleophilic catalysis mechanism. In another study, MNDO calculations with complete geometry optimization on N-protonated (102) and P-protonated (103) model intermediates for an acid-satalysed substitution reaction gave the result, that ( 102) had both the lowest energy and the largest positive charge on the phosphorus atom! 5 5 The enormous rate difference between acid catalysed hydrolysis of trimethyl phosphite and trimethyl phosphate (ca. 10l2 to 1) has been discussed in terms of initial protonation on P in trimethyl phosphite.56
4: Tervalerir Pliosphoriis Acids
103
[s\P-s-
s - P:’3s
S’
( 9 2 ) R = H,Me
+
Q -
i) PC13
(94)
x = 0,s
104
-
Organophosphorus Chemistry
i ) BuLi or Mg
ii) CLP(NEt,),
( 9 5 ) X = OMe,NMe;r
Me,Si
SiMe,
NP,
Ph
0
Me \NKN/Me \
Ph
,P-
I
P=o
I
Ph
F C I Ph
105
4: Tervalent Phosphorus Acids
'
H
p-h/-H
X
X
'H
X
= H . F , CL
(103)
RX-( C Hz)" - 0, NCCH2CH20
/P-NPri2
( 1 0 4 ) X = N H , R =MMT,DMT, p i x y l , n = 6 X = S , R = t r ityl , n = 3,6
QTC' 0
0
PhCHZO, /
P-NEt2
NCCH~CHZO
(107 1
106 3.3 Use for Nucleotide, Sugar Phosphate, or Phosphoprotein Synthesis.- A series of dialkyl phosphoramidites (104) containing a protected amino or mercapto group (for further reactions with e . g . fluorescent groups) has been prepared and used to 5‘-phosphorylate protected oligonucleotides on a solid support.57 Simi-
lar H-phosphonate reagents were also prepared from the van B o o m reagent (105).57 The reagents (105), ( 106), and (107) have been used
to prepare
1,4-diphosphorylated lipid monosaccharide ana-
logues;58 the phosphoramidite (107) was superior to (106) for preparation of the monoalkyl phosphates, since the second cyanoethyl group from use of (106) could not be removed without hydrolysis of the lipid ester group. Phosphorylated serine and threonine have been made using (108):59 the phosphosylated amino acids could be coupled to other amino acids to give phosphorylated dipeptides.59 The protected 3’-deoxyribonucleoside phosphorodiamidites (109) are stable enough to be purified by column ch7ornatography: they have been used to prepare oligonucleoside H-phosphonates and, after oxidation, oligonucleotides.6 o The approach, exemplified by syntheses using the dimer (110), is versatile for the preparation of phosphate-modified analogues. Protected 3’-deoxyribonucleoside phosphoramidites (111) or phosphites (112) have been prepared as shown and used to obtain nucleoside phosphorochloridates
(
.
113 ) 61
The phosphorodiamidite (114) has been used to prepare nucleoside phosphoramidites which were employed for standard solid phase synthesis of oligonucleotides: 6 2 like 2-chlorophenyl, the hexafluoroisopropyl group can be removed after the synthesis by an oximate treatment. Bis( diisopropy1amino)methylphosphine ( 115), 6 3 or the similar aminochlorophosphine ( 116), 64 has been used to prepare nucleoside methylphosphonamidites (117) and the derived oligonucleotide analogues, methylphosphonates. The 31P n.m. r. chemical shift of (115)65 is stated since an erroneous value is given both in the above-mentioned paper63 and in another work concerned with methylphosphonothioates.6 6 Bis ( diethylamino )methylphosphine ( 118 ) gave (119) which was used to prepare a nucleoside methylphosphonothioate.67 The first example of an achiral, phosphate-modified nucleotide, a dinucleoside phosphorodithioate ( 120), has been prepared from the dinucleoside phosphoramidite (121) as shown. 68 The intermediate H-phosphonothioate could, instead of being oxidized with sulphur, be oxidized with iodine and water, alcohols, or
-
4 : Tervalent Phosphorus Acids
+
n
(OVN)?PCI
B
OH
"""v 107
DMTov ""'"v DMTov Y
t et razole
OR
Z z o t e
OR
+ OH
X2P-OSiMe3
O,
P-OSiMe 3
X' R = But MezSi
(111) X = P r ' 2 N
(112) X = CF3CH2O
O\$O
x
/ \
(113)
CI
Organophosphorus Chemistry
108
DMTov O\
/
P-NR2
Me
(117) R = P r i (119) R = Et
DMTov DMTo NP-’vT i 1 H2S, tctrazolc
0,
‘“v
O\ 4 s
ii) S 8
P
pr i 2 N
-s’
OAc
OAc
(120)
C
N-PCI2
P(SiMe3)2 (122) 71 O/o
+
4Me3SiCl
+c
N-SiMe3
+
6Li
+
6LiCl
4 : Tervalent Phosphorus Acids
109
amines to give phosphorothioate diesters, triesters, or phosphorothioamidates, respectively. Miscellaneous.- Earlier methods to prepare tris(trimethy1sily1)phosphine (122) involve the use of rather dangerous reagents or long reaction times: the new, safe method shown gave (122) in good yields.69 Tervalent phosphorus acid derivatives used this year as ligands in asymmetric catalysis reactions are (123),70 (124),71 ( 125)72 and some hexapyranoside bis-phosphinites, e.g. (126).73 A review on ligands prepared from amino acids has been published. 3.4
4 Reactions involving Two-co-ordinate Phosphorus
Thiophosphenyl bromide and fluoride (127) have been prepared and characterised by mass and matrix infrared spectroscopy.74 Phosphenous acid or its methyl ester (128) is probably formed in the acid catalysed fragmentation of the acylphosphonates (129).7 5 The previously unknown 1,2-h3-azaphosphinine ( 130) has been prepared by flash vacuum thermolysis of ( 131 1 . 76 It readily adds water, methanethiol or isopropylamine to give (132) or (133). A full paper on the preparation of 1,2,3,4-triazaphospholes (134) and flash vacuum thermolysis of (134, R=aryl) to benzazaphospholes has appeared.77 Tris( dimethy1amino)phosphine reacts with oxalbisamidrazones (135) to give bis-1,2,4,3-triazaphospholes 78 (136). Phosphinimines (137) participate readily in cycloaddition reactions with butadienes, however the product is a h5-phospholene (138) and not a Diels-Alder product (139).79 This is in accordance with quantum chemical calculations which have shown that the HOMO is the P lonepair, and not the P=N IT orbital. With diphenylacetylene (137, R1=But) reacted similarly to give (140).79a A review on the chemistry of aminoiminophosphines (141) has appeared. Reactions of some N-phosphino aminoiminophosphines (142) with methanol, alkyl halides, and sulphur have been studied.8o The phosphenium ion (143) with cycloheptatriene gave the 8 phosphabicyclo( 3.2.1 )octa-2,6-diene ( 144) after hydrolysis.81 The same phosphenium ion, or a mixture of dichlorophenylphosphine and aluminium trichloride, with cyclopropanes gave phosphetanes (145)
Organophosphorus Chemistry
110
R I P~~P-OCHZ$HNHCH~CH~~-PP~~
R -P,
,';3. 0
(124) R = aryl, aryloxy,Me2N
PhzP-O OMe
S=P-x
(127) X=F.Br
0 II
OMe I R'-C - P=O I OR
(129) R 2 = H,Me
A
R'COOMe
+
[$O-P=O]
(128)
"20/
(132)
(133) X = SMe,NHPr'
4: Tervalerit Phosphorus Acids
2
A
RNH-N
P=N
R'
'
/
-
H*NHN-N"R
+
P(NMe2I3
111
NH2
R2
(137) R ' = Bu',Ph,
9+
g
R' \
I
R2
Ph
R' R 2 N
P=N'
'
(141 1
Ph (140)
(139) R3 R' R 2 N
, P=N' (142)
PBut2
Organophosphorus Chemistry
112
(143)
+
"R 27 4R4
R3
or PhPCI, + AICI,
J CI
0
R2 R4
R2 R 4 ( 1 4 5 ) X = NPr'2,Ph R1-R4=H,Me,Ph
(148) X
(146) R =
= Bu'O,BU'S
But2P,(MejSi)2N,
(Me3Si)3Si.
, R'
P=P
/ N(SiMe,),
(149) R'=
R2Li
P=P'
__c
R'
9
R2= Bu',(Me3Si),C, mesit y l
'
R2
B+
113
4 : Tervulent Phosphorus Acids
RP=PR
(150) R = ( Me3SiI2CH-
RPH2
-
,
SiMe3
RP
A 0 ‘C
RPF2 --D
F
I
SiMe3
I
RP-PR
‘Li
(Me3Si ),CH
CH( SiMe,I2 P-P
\ /
Se
(151)
6
CF,
P=P’
CF3
(152) R =
R
&9 ,
ci,
/
P=P
v (1 53)
Organophosphorus Clt em istry
114
82 in an unusual insertion reaction. The amino group of the aminodiphosphene (146) may be substituted with hydrogen chloride at low temperatures to give the very reactive chlorodiphosphene ( 147 ) :83 further reactions with various organolithium compounds gave the heteroatom-substituted diphosphenes (148). The amino group of ( 149) could be substituted with alkyl or aryllithium reagents directly.8 4 The known diphosphene (150) has been prepared by two new routes as shown.85 It dimerizes slowly at room temperature, and readily gives Diels-Alder adducts with dienes; with elemental selenium it gives the selenadiphosphirane (151). Two new, stable diphosphenes ( 152 ) have been prepared via germylphosphines.86 Another new diphosphene (153) was prepared by two known routes.87
References
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va, F. Sh. Shagvaleev, and V. V. Kiselev, 1987, J. Gen. Chem. USSR, 57, 2071. I. F. Lutsenko, A. A. Prishchenko, and M. V. Livantsov, 1988, Phosphorus Sulfur, 35, 329; M. V. Livantsov, A. A . Prishchenko, and I. F. Lutsenko, 1987, J. Gen. Chem. U S S R , 57, 928; A. A . Prishchenko, M. V. Livantsov, and I. F. Lutsenko, 1987, J. Gen. Chem. USSR, 57, 1260.
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D. Y. Kim, T. H. Kim, and D. Y. OH, 1987, Phosphorus Sulfur, 34, 179. I. A. Natchev, 1987, Synthesis, 1079. S. A. Terent'eva, M. A. Pudovik, and A. N. Pudovik, 1987, J.
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4: Tervalent Phosphorus Acids
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24. B. Mlotkowska and A . Markowska, 1988, Liebigs Ann. Chem., 191. 25. V. Mark and J. R. van Wazer, 1964, J. Org. Chem., 29, 1006. 26. T. Kh. Gazizov, Yu. V. Chugunov, and A . N. Pudovik, 1987, J. Gen. Chem. USSR, 57, 414. 27. P. Majewski, 1987, Phosphorus Sulfur, 33, 37. 28. H. Hacklin and G.-V. Roschenthaler, 1988, Phosphorus Sulfur, 36, 165. 29. J. W. Perich and R. B. Johns, 1988, Synthesis, 142. 30. D. W. Chasar, J. P. Fackler, Jr., R. A . Komoroski, W. J. Kroenke, and A . M. Mazany, 1987, J. Am. Chem. S O C . , 109, 5690. 31. L . N. Markovski, V. D. Romanenko, A . V. Ruban, and A . B. Drapailo, 1988, Phosphorus Sulfur, 36, 267. 32. G. Yu. Mikhailov, I. G. Trostyanskaya, M. A . Kazankova, and I. F. Kutsenko, 1987, J. Gen. Chem. USSR, 57, 2349. 3 3 . A . A . Krolevets and A . G. Popov, 1987, J. Gen. Chem. USSR, 57, 417. 34. F. S. Mukhametov, R. M, Eliseenkova, and E. E. Korshin, 1987, J. Gen. Chem. USSR, 57, 1812. 35. D. W. Chasar, 1987, Phosphorus Sulfur, 34, 149.
116
Organophosphorus Chemistry
36. E. E. Nifant'ev, M. P. Koroteev, A. A. Zharkov, and A . I. Lutsenko, 1987, J. Gen. Chem. USSR, 57, 1236. 37. A. F. Cunningham, Jr. and E. P. Kundig, 1988, J. Org. Chem., 53, 1823. 38. L. Manojlovic-Muir, I. R. Jobe, B. J. Maya, and R. J. Puddlephatt, 1987, J. Chem. SOC., Dalton Trans., 2117. 39. R. J. M. Hermans and H. M. Buck, 1987, Phosphorus Sulfur, 31,
255. 40. J. L. Meek, F. Davidson, and F. W. Hobbs, Jr., 1988, J. Am. Chem. S O C . , 110, 2317. 41. C. E. Dreef, R. J. Tuinman, C. J. J. Elie, G. A. van der Marel, and J. H. van Boom, 1988, R e d . Trav. Chim. Pays-Bas, 107, 395. 42. K.-L. Yu and B. Fraser-Reid, 1988, Tetrahedron Lett., 29, 979. 43. J. Apitz, J. Grobe, and D. L. Van, 1988, 2. Naturforsch., 43b, 257. 4 4 * L. J. Szafraniec, L. L. Szafraniec, and H. S. Aaron, 1987, Phosphorus Sulfur, 31, 177. 45. L. N. Ustanova, A . R. Burilov, R. U. Belyanov, T. Kh. Gazizov, M. A. Pudovik, and A. N. Pudovik, 1987, J. Gen. Chem. USSR, 5 7 , 1278. 46. M. N. Danchenko and A. D. Sinitsa, 1987, J. Gen. Chem. USSR, 57, 1716. 47* R. Schmutzler, 0. Stelzer, and N. Weferling, 1988, Chem. Ber., 121, 391. 48. F. M. Akhmetkhanova, M. V. Proskurnina, S . S. Zlot-skii, and D. L. Rakhmankulov, 1987, J. Gen. Chem. USSR, 5 7 , 204. 49. G. Baccolini, E. Mezzina, P. E. Todesco, and E. Foresti, 1988, J. Chem. S O C . , Chem. Commun., 304. 50. A . K. Kuliev, V. V. Moskva, and D. A. Akhmedzade, 1987, J. Gen. Chem. USSR, 57, 200. 51. S. D. Pastor, J. D. Spivack, and L. P. Steinhuebel, 1987, Phosphorus Sulfur, 31, 71. 52. L. Heuer, M. Sell, and R. Schmutzler, 1987, Polyhedron, 6, 1295. 53. G. Bettermann, R. Schmutzler, S . Pohl, and U. Thewalt, 1987, Polyhedron, 6, 1823. 54. E. E. Nifant'ev, M. L. Gratchev, E. V. Borisov, and A. R. Bekker, 1987, Phosphorus Sulfur, 34, 105. 55. A . A. Korkin and E. N. Tsvetkov, 1987, J. Gen. Chem. USSR, 57, 1929.
4: Tervalent Phosphorus Acids
117
56. F. H. Westheimer, S. Huang, and F. Covitz, 1988, J. Am. Chem. S O C . , 110, 181. 57. N. D. Sinha and R. M. Cook, 1988, Nucleic Acids Res., 16, 2659. 58. P. Westerduin, G. H. Veeneman, and J. H. van Boom, 1987, Recl. Trav. Chim. Pays-Bas, 106, 601. 59. H. B. A. de Bont, G. H. Veeneman, J. H. van Boom, and R. M. J. Liskamp, 1987, Recl. Trav. Chim. Pays-Bas, 106, 641. 60. B. Uznanski, A . Wilk, and W. J. Stec, 1987, Tetrahedron Lett., 28, 3401. 61. W. Dabkowski, F. Cramer, and J. Michalski, 1987, Tetrahedron Lett., 28, 3559. 62. H. Takaku, T. Watanabe, and S. Hamamoto, 1988, Tetrahedron Lett., 29, 81. 63. A. Viari, J. P. Ballini, P. Vigny, C. Blonski, P. Dousset, and D. Shire, 1987, Tetrahedron Lett., 28, 3349. 64. S. Agrawal and J. Goodchild, 1987, Tetrahedron Lett., 28, 3539. 65. Ref. 2 in W. K.-D. Brill and M. H. Caruthers, 1988, Tetrahedron Lett., 29, 1227. K.-D. Brill and M. H. Caruthers, 1987, Tetrahedron Lett., 28, 3205. 67. W. Niewiarowski, Z. J. Lesnikowski, A . Wilk, P. Guga, A . Okruszek, B. Uznanski, and W. J. Stec, 1987, Acta Biochim. Polonica, 34, 217. 68. J. Nielsen, W. K.-D. Brill, and M. H. Caruthers, 1988, Tetrahedron Lett., 29, 2911. 69. E. Niecke and H. Westermann, 1988, Synthesis, 330. 70. A . Bendayan, H. Masotti, G. Peiffer, C. Siv, and R. Faure, 1987, J. Organometal. Chem., 326, 289. 71. P. Cros, G. Buono, G. Peiffer, D. Denis, A . Mortreux, and F. Petit, 1987, New J. Chem., 11, 573. 72. Y. Vannoorenberghe and G. Buono, 1988, Tetrahedron Lett., 29, 3235. 73. R. Selke, 1987, J. Prakt. Chem., 329, 717. 74. M. Binnewies and H. Borrmann, 1987, Z. Anorg. Allgem. Chem, 552, 147; H. Schnockel and S. Schunck, 1987, Ibid., 155 and 163. 75. E. Breuer, R. Karaman, H. Leader, and A . Goldblum, 1987, Phosphorus Sulfur, 33, 61. 76. C. Bourdieu and A . Foucaud, 1987, Tetrahedron Lett., 28, 4673.
66.
w.
Organophosphorus Chemistry
118
77.
w.
Rosch, T. Facklam, and M. Regitz, 1987, Tetrahedron, 43,
3247. 78. T. N'Gando M'Pondo, C. Malavaud, L. Lopez, and J. Barrans, 1987, Tetrahedron Lett., 28, 6049. 79. a. E. Niecke and M. Lysek, 1988, Tetrahedron Lett., 29, 605; b. V. D. Rornanenko, A. B. Drapailo, A. V. Ruban, and L. N. Markovskii, 1987, J. Gen. Chem. USSR, 57, 1253. 80. L. N. Markovskii, V. D. Romanenko, E. 0 . Klebanskii, M. I. Povolotskii, A. N. Chernega, M. Yu. Antipin, and Yu. T. Struchkov, 1987, J. Gen. Chem. USSR, 57, 909. 81. S. A. Weissman and S. G. Baxter, 1988, Phosphorus Sulfur, 35, 353 * 82. S. A . Weissman and S. G. Baxter, 1988, Tetrahedron Lett., 29, 1219. 83. L. N. Markovskii, V. D. Romanenko, M. I. Povolotskii, A . V. Ruban, and E. 0 . Klebanskii, 1986, J. Gen. Chem. USSR, 56, 1904. 84. V. D. Romanenko, E. 0 . Klebanski, and L. N. Markovskii, 1986, J. Gen. Chem. USSR, 56, 1905. 85. H. Ranaivonjatovo, J. Escudie, C. Couret, and J. Satge, 1987, Phosphorus Sulfur, 31, 81. 86. J. Escudie, C. Couret, H. Ranaivonjatovo, M. Lazraq, and J. Satge, 1987, Phosphorus Sulfur, 31, 27. 87. P. Jutz and U. Meyer, 1987, J. Organometal. Chem., 326, C6.
5
Quinquevalent Phosphorus Acids BY R. S. EDMUNDSON The recently published proceedings of a symposium on biological aspects of phosphorus chemistry contains papers of interest in connection with the present Chapter;' however, because of considerations of space, individual papers have not been reviewed here. 1.PhosDhori.c Acids and their Derivatives.
1.1 Synthesis of Phosphoric Acids and their Derivatives.-Kecent work2 nas confirmed earlier findings concerning the reactions between PC15 and a,6-unsaturated ketones. The decomposition of the intermediate obtained when the ketone is added to the chloride in a solvent (PieCOC1 at -20°, or better, Me2SiC12 at 2 0 " ) with S O 2 , affords moderate yields of a phosphorodichloridate. When the order of mixing is reversed, the product consists of a phosphonic dichloride (Scheme 1). Phosphorofluoridates are obtainable by the cleavage of trimethylsilyl phosphites with sulphuryl chloride fluoride; phosphinic iluorides may be obtained in a similar manner using an appropriate tervalent ester.3 A l s o of interest in the same connection, and applicable to nucleoside derivatives, is the cleavage of P-N bonds in N-phosphorylated azoles by benzoyl fluoride.4 Several 3-substituted-2,4-dioxa-3-phosphabicyclo[4.3.0]nonane 3-oxides and 3-sulphides (I; X=O or S ; Y=OMe, OPh, C1, or NMe2) epimeric at phosphorus, have been prepared in cis5 and trans6 (ring junctions) iorms as model compounds for spectroscopic studies. A route to 1,2-diol bis(dihydrogen phosphates) has been explored in which the diol ( a s its di-sodium derivative) is phosphorylated with a di-t-butyl phosphorohalidate and the t-butyl groups are removed by subsequent trifluoroacetolysis.7 Elsewhere in the general area of 2-phosphorylation, the year has seen much activity in the synthesis of inositol polyphosphoric
Organophosphorus Chemistry
120
MeCOC H E C H ,
Reagents:
i,
3PCL5.
ii, M e C O C l
or M e 2 S i C I Z ; iii, S O 2 ;
iv,
2PCI5;
v, A c 2 0
Scheme 1
(yJ-y X
R 5o
OR’ OR6
0
R e a g e n t s : i, HzO, P h I ( O A c I 2 ,
o r M e C N ; ii, R’CH2COR2;
Scheme 2
iii, H i C = C H C H R Z C H R I C O O H
5: Quinquevulent Phosphorus Acids
121
acids, in particular that of myo-inositol-1,4,5-tris(dihydrogen phosphate), a substance involved in signal transmission in mammalian cells. All the syntheses utilized initial phosphitylation of an appropriately protected (isopropylidene; cyclohexylidene; or benzyl ) inositol by PC13, or bis (2-cyanoethyl) phosphorochloridite, or substituted 2-cyanoethyl phosphoramidite (R2N)(NCCH2CH20)PX where R=Et or i-Pr, and X=C1 or OCH CH CN;1°-12 dibenzyl diisopropylphosphoramidite has also been employed.13 After the conversion of R2N into NCCH2CH20 with 2-cyanoethanol and tetrazole, the triester is oxidized, generally using either MCPBA or t-BuOOH. The removal of the inositol ?-protecting groups by conventional means is followed by that of the 2-cyanoethyl groups using a weak base e.g. aqueous ammonia. Such procedures have allowed the synthesis of the racemic lY4-bis(dihydrogen phosphate) (2a), l o the racemic9’13 and optically active14 forms of the 1,3,4-tris(dihydrogen phosphate) (2b), the 1,4,5-tris(dihydrogen phosphate) (2c) also in ra~emicll”~ and optically active12 forms, the 2,4,5-tris(dihydrogen phosphate 1 (Zd), and various tetrakis (dihydrogen Similar sequences lead to the corresponding phosphate 1 s . l3 dihydrogen phosphorothioates .l o The direct phosphoryloxylation of ketones has been achieved by the use of phenyliodoso diacetate in combination with a dihydrogen phosphate (Scheme 2 ) . The same reagents convert 4-pentenoic acids into 0-phosphorylated hydroxytetrahydrofuranones.17 The interaction of 1,l-dichloronitrosoalkanes and dialkyl phosphonates18 or the ester chlorides (RO)nPC13-n (n=3,2, or 1),19 all at low to ambient temperature, has afforded new alkylchloroformimino phosphates of the general type K1R2P(0)ON=CC1R, where R1 and R 2 are C1 or alkoxy. Dialkyl fluoroformimino phosphates (R0)2P(0)ON=CHF,havebeen prepared analogously from trialkyl phosphites and chlorofluoronitrosomethane. 20 In another area of biochemical interest, the 0-phosphorylethanolamine derivatives ( 3 ) have been prepared by the acid-catalyzed hydrolysis ot 3-substituted-2-alkoxy-l,3,2oxazaphospholidine 2-oxides , 21 and the related phosphorylhomocholines ( 6 ) have been made from the cyclic esters ( 5 ) where Y=O, and either or both of X and 2 is sulphur.22 Also of interest here is the isomerization of the esters (4) into ( 5 ) brought
122
Orgatlophosphorus Chetnisrry 4.
RO-P-OCH,CH,NH,R'
Rc H2 Y P F T >
/-Yo
Il'z
0'-'
X
x = s,
(L)
Y = Z
R C H X Pp
Il'z
=o
1
Me3N
RCH,X-
Y
Y
4.
P-ZCH2CH2CH2NMe3
4-h -
0
(5) Y = O , X = Z = S ; Y = 0,X = 0, Z = S or X = S , Z = 0
0
c c l3CH,
It
O C - P (OR),
5
II
0
; /
11.
A r C-
II
II
iv
M e 3 S i 0 P (OR),
______) ttI
P(OR),
0 Reagents'
1,
Zn;
ti, Me3SiCI,
111,
BuNH,,
Scheme
0
( R ' O 1 2 II PSCI
DBU,
lv, ' 1 8 S 8
3
0
+
(R201,POSiMe3
.-.3--,
( R ' 01,
O S i Me3
II P -s-
1
y
1
OR^ i2C I -
- M e 3 Si CI
0
II
(R'O) 2P-
5
0
- PII(0r2)
(71
5: Quinquevalent Phosphorus Acids
123
about by phosphonium salts. Nucleoside phosphorochioates have been prepared using the two proceaures indicaied in Scheme 3 . 2 3 S-sp-Unsacurated phosphoroihioates have been obtained by the interaction of 1-bromoalkynes and the copper(1) salts of dialkyl phosphorochioic acids; the reaction is thought to proceed 2 paramagnetic and unstable copper( I1 1 complexes.2 4 7 2 5 A useful route to unsymmetrical monothiopyrophosphates ( 7 ) is provided chrough the interaction of phosphorylsulphenyl chlorides and dialkyl trimethylsilyl phosphices in CH2C12 at - 4 0 " . 2 6 The kinecics of the homogeneous methanolysis of P4Sl0 in CS 2 have been studied in some detail; the sole detected product was CQ-dimethyl phosphorodithioate obtained through a multi-step sequence.2 7 The reaction of P q S l 0 with diols affords cyclic phosphorodithioic acids,,but these and related sulphur-containing five and six-membered ring compounds have been obtained also (as their anions) from the appropriate difunctionalized alkane (or arcne) and che pyridinium betaine ( 8 ) .2 8 0,3-Piethyl hydrogen phosphorodithioace adds regio-and stereo-spe,ifically t o the 1,3-butadienes ( 9 1 . 2 9 Additions of such acids to the ketenimides (10)occur at room temperacure, neat, or in a low boiling solvent to give the thiophosphorylated enamines (12) probably by rapid prototropy in the initial addition compound ( 1 1 ) ; the phosphorotropic rearrangement of (11) to ( 1 3 ) seems not to occur.30 The d i a l k o x y p h o s p h i n o t h i o y l t h i o a c e t i c acid derivacives ( 2 4 ) react with formamide acetals and related comp31 ounds to give Lhe thiophosphorylated (El-thioenamines. The cleavage of Sn-S bonds in the tin compounds ( 1 5 ) by N-bromosuccinimide yields cryscallizable t h i o p h o s p h o r a n e s u l p h e n y l bromiaes ( 1 6 ; X=Br), but the corresponding iodides were not isolable.3 2 0,O-Dialkyl t h i o p h o s p h o r a n e s u l p h e n y l chlorides ( 1 7 ) cannot be prepared by the direct chlorination of dithioxodisulphides under conditions similar to those under which direct bromination does afford dialkyl t h i o p h o s p h o r a n e s u l p h e n y l bromides. However, the chiosulphenyl chlorides have been prepared from the corresponding bromides as indicated in Scheme 4 : so prepared, they have stability sufficient for storage at room zemperature for several days. 3 3 The cleavage of the disulphide bond in the dioxo and
Organophosphorus Chemistry
124
A = CH,CH,,
CH,CH,CH,
, or
1, 2-C6H,
X , Y = 0 , s o r NH B = Et,N
or
pyr
H M c SP II
HHC
(Et0)2PS2H
OE t ) 2
A r CH=CR-CH=CH, R
Ar
(9)
0
0
II Arc
il
‘C=C=
NH
/
( RO),PS2 H
Arc \H
*
NH
//
/t- c\ SP(OR
NC
NC
IIII
1,
S (101
(111
0
It
S
Arc,
/
II
CH-CNHP(OR),
II
NC
S (13 1
(12)
S
II
S
It
(ROI,PSCH,X (14) X = CN, COOAlk,
sHH
‘Ro)2P- X
NMc,
S
X
N Me
125
5: Quinquevalent Phosphorus Acids
dithioxo disulphides (18; X=O or S ) by silyl cyanides yields oxophosphoranesulphenyl cyanides (phosphoryl thiocyanates) (19; X=O) or t h i o x o p h o s p h o r a n e s u l p h e n y l cyanides (thiophosphoryl thiocyanates) (19;X=S); the corresponding reactions in the phosphonic and phosphinic acid series also occur. When, for X=S, the reaction mixtures are held over for 4 to 10 days, the silyl esters (20;X=S) disappear with resulting formation of the annydrosulphide (21). The important feature of this sequence is the indication ( by 31P nmr spectroscopy) of the direct formation of compounds possessing the P(X)SCN moiety, here demonstrated for the first time, since subsequent distillation of the reaction mixtures yields the isothiocyanates.34 A rather unusual way of forming a phosphorus-nitrogen bond consists in the treatment of a trialkyl phosphate with bis(diethylamido)manganese(II) at O o , the product being the dialkyl diethylphosphoramidate; using diethyl phosphonate, one or both of the ethoxy groups can be replaced.35 Aldimines can participate in the Todd-Atherton reaction36 as can a-aminocarboxylic acids, when the resulting phosphoramidates (RIO)2P(0)NHCHR2COOH have been converted into the N-phosphorylated peptides (RIO)2P(0)NHCHR2CONHCHR3COOR4.37 The phase-transfer catalyzed cyclization of dialkyl N-(2-bromoalkyl)phosphorarnidates is an effective synthesis of N-phosphorylated aziridines 3 8 Dialkyl phosphoramidates have been prepared from trialkyl phosphites and inorganic azides in the presence of inorganic chlorides, followed by acidification.39 Further details of the study of the reactions between toluidines and the halides PXC13 have appeared and a mechanism has been proposed for the reaction between the latter and 4-dimethylaminotoluene to afford inter alia the compounds (22) in unsatisfactory yields. Better yields of (22) might be expected with the use of ( 2 3 : R 1=H, R 2=Me) but could not be achieved in practice; new cyclic compounds were obtained using ( 2 3 ; R 1=R2=HI.40
.
New optically active diaszereoisomeric bicyclic phosphoric diamides (24;X=C1) and t riamides ( 24;X=NR1R2 , epimeric at phosphorus, have been prepared from (S)-glutamic acid, and their geometries assigned on the basis of H ' and 31P nmr data.41 When diethyl (thio)phosphoryl isothiocyanidate is allowed to react with cyanoacetic or malonic esters in an ethereal solvent at -10 to O o , the products, after further
[
126
Organophosphorus Chemistry
3-s-
(CHZC0l2NX
( A rO),P
Sn Ph,
X = B r or I
S
II
*
( A rO) ,PSX
115 1 S
S
S
II
II
- F‘(OR1,
(RO),P-S-S
( R O1 ,PSB r
liv
S
S
II
II
( RO),PCl
II
I
ki
J i’
S
( 1 61
H
d
(RO1,PSCI
(RO), PSOMe
(17) Reagents :
I,
Br,,
C H 2 C 1 2 , at
2.6 -Me2C5H3N,
-80°C to -1O’C, v.
SOCl2,
‘11,
C1,,
lv, M e O H ,
3
Scheme
4
X
X
X
11,
M e SiCI
S
II
R;
1181 (a) R’
R2’
(19)
i
(X:S
$
X
S
S
II
R\ RZ/pNcs
R’,
II
Q
Me N
PXCl3 X=OorS
II
R’
Mex3:: R2’
P-
x-
(211
Me2N
Bu,
I201
d is t I llat con
= R 2 = t - BuCH20
(b1 R’ = t-Bu, R2 = P h ( c l R ’ = 1-Bu, R 2 = Me0
P-XSi
\
N/p\cI
Me
\ /
(22)
Me
Me
HX
Me
P(
R2
-ip9: - w
-
5: Quinquevalent Phosphorus Acids
HOOC
N H2
NHR H
Z
X
127 C Q R
0
H
SR2
>L;: zHsR2 II II L
7
(Z
C N , COOR')
R'OOC
x =o,s
N H P ( OEt 12
(Z = COOR')
NPIOEtl,
R'OOC
X
X
I25a 1
( NC 1,
C=C
/
(25bl
S- E t , N H
'N
H P(OEt
I1
X (26)
R'
S
H \
'k
H
NH*
R'
~
COOH
II
P-
C H,O
Ar 0"'A Me0
H
B
D R
0
-ArOH
'OMe
129)
R =
L-O,NC,H,
or
2,6-CI,
-4-MeC6H2
p
-HCI
CL
128
Organophosphorus Chemistry
S-alkylation, have proved to be thermally unstable, and to consist of 2-3:2-1 mixtures of the tautomers ( 2 5 , a and b). By contrast, malononitrile affords adducts which cannot be alkylated even under more forcing conditions,and the salts (26) can be isolated.42 All of the chiral isomers of the 1,3,2-oxazaphospholidine 2-sulphides ( 2 9 ) have been identified spectroscopically as the result of the reactions between the optically active amino alcohols (27) and the optically active alkyl aryl phosphorochloridothioates (28). Enantiomers of salithion (2-methoxy-4H1,3,2-benzodioxaphosphorin 2-sulphide) have likewise been obtained.4 3 1.2 Reactions of Phosphoric Acids and their Derivatives.-Two reports have described the participation of 2-[(dialkoxyphosphinyl) oxyj-lY3-butadienes in Diels-Alder reactions. For the diethyl ester, the best Lewis acid catalyst appears to be SnC14 working in CH2C12 at 0°.44 Other authors have described such reactions of the dialkyl esters as 'poor' and, in the reactions of (30) with representative dienophiles such as maleic anhydride and cyclohexenone have suggested that the bis(2,6-dimethoxyphenyl) ester is highly useful in reactions catalyzed by traces of A1C13.45 The reactions between Q-dialkyl (or alkylene) hydrogen phosphorodithioates and Ge, Sn, or Pb organohalides, and the properties of the products, have been reviewed.4 6 The oxidation of phosphorothioic esters and of phosphorodithioic esters by MCPBA have been investigated. In aprotic solvents, the conversions (Et0I2P(S)OPh into (Et0)2P(0)OPh; (Et0)2P(0)SPh into (Et0)2P(0)S02Ph; and (Et0)2P(S)SPh into (Et0)2P(0)SSOPh occur. In the presence of ROH, however, the principal product in each case is (Et0)2P(0)OR, the reaction proceeding more readily for lower primary alkyl groups R than for secondary or tertiary R groups. 31P Nmr data, obtained during the course of the reactions, have been advanced in support of oxathiaphosph(v)iridines as intermediates.4 7 The [ 180]-induced j l P chemical shift changes suggest that for solutions in D20, the anion of alkylammonium salts of diethyl phosphorothioic acid is best represented as (Et0)2P(0)S-, whereas for solutions in organic solvents, the structure lies between this and (Et0)2P(S)O-.48 When the imidoyl chlorides ( 31 ;R2=z-alkyl,9-alkyl,
129
5: Quinquevalent Phosphorus Acids
1311
(32)
x
v
I1 ii ( R’ 0 IzPN P h C R 2
(R’OI~PSOH
R*C N
1
R2C-S-PP(OR’),
II
II
NH
0 (3L)
]
-
1331 05
II
II
(R’0I2PNHCR2
(351
130
Organoph osph orits Ch eniistrjl
react with dialkyl phosphorothioate salts, the N-dialkyl,SP(S)R2 initially-formed esters (32: Y S , X - 0 or S ) are not isolable since a rapid, irreversible, 5 to phosphorotropic rearrangement occurs to give the phosphoramidothioates (33;X=O,Y-S) 1 isolable as o i l s . The compound (32; R =iPr, R2=Ph, X-Y-0) rearranges to the corresponding cornpound (33) but, at temperatures higher than 1 2 0 ° the latter yields tetraisopropyl pyrophosphate, suggesting that, in this case, (33) is equilibrating with ( 3 2 1 , a structural type known to act as a phosphorylating agent, in this case towards more of the acid anion (iPrO)2P(0)0-.49 Reactions between dialkyl hydrogen phosphorothioates and aryl cyanides occur slowly at ordinary temperatures (being slower than the comparable reactions of the dithioates) to give the very unstable and non-isolable esters (34), trom which the t h i o a c y l p h o s p h o r a m i d a t e s ( 3 5 ) may be isolated. (34) is phosphorylated in the presence of more tree phosphorothioic acid to give the monothiopyrophosphate ( 3 6 1 , isolable together with the concomitantly produced thioarylamide (37). Similar reactions occur with thiocynnates but the resultant dithiocarbamates (35; K'=Z-alkyl or 5-aryl) cannot be isolated because of their ready decomposition into the phosphoryl isocyanate and thiol. 50 The S,S,S-trisphosphorylated compound (39) (the 'SSS' - compound), prepared by an Arbuzov-like reaction, undergoes stepwise S to phosphorotropic rearrangement through an intramolecular mechanism (by crossover experiments) in contrast to the corresponding triazine (see Organophosphorus Chemistry, Vol. 1 9 ) . The products have the SSN, S N N , and finally N" structures. 51 The to 0 rearrangement ot N-phosphorylated P-esters requires the participation o t amino, serine and threonine hydroxyl, and carboxyl groups in an intramolecular process. 52 The rapid cis-trans equilibration observed when cis4 - a l k y l t h i o c y c l o p h o s p h a m i d e s ( 4 0 ) are treated with base occurs possibly the intermediate ( 4 1 ) ;the latter, termed ' i m i n o c y c l o p h o s p h a m i d e ' , is recognised as an intermediate in the metabolism of cyclophosphamide itself. 53 Two reports cover investigations into the acylation of the phosphoramidates (Et0I2P(O)NHR, where R=Mel, Ph, or PhCH2. When such secondary phosphoramidates are treated with acyl chlorides or acid anhydrides, the products consist of mixtures of the N-acylated phosphoramidate and the carboxamide obtained by P-N bond fission. These compound types are formed i n proportions
13 I
5: Quinquevalent Phosphorus Acids
B :’ (LO)
-
M = NIC,H,CI)2
0
II
(EtO),PN R’R2
+
R3COX
o
COR~
II I (EtO),P-+N-R’
X-
I
RZ (42)
0
II
(EtOIZPNR’COR3
R
+
y
y
#
H
R2X
R3C 0 NR’ R Z
0
I1
+
{”‘OH
PhCONHPh
2O
0
I
Ph
-{Tp\d
0
II
NPh
II
C ‘Ph
0- C‘ ‘Ph
Ph
0
I1
(PhOl ( E t o ) P ( S 1R
132
Organophosphorus Chemistry
which depend on steric and electronic features associated with both the acylating agent and the phosphoramidate N-substituent. The kinetics of the reactions are best interpreted in terms of a bimolecular nucleophilic attack of the phosphoramidate nitrogen atom at the acyl carbonyl group to give the cation (42) which can then breakdown in two possible ways. The wide range of reactivities can be illustrated by the acylations with acid anhydrides. Thus, no reactions occur for acetic and benzoic anhydrides without the addition of a catalyst; trifluoroacetic anhydride at room temperature yields only the N-acylated phosphoramidate, and trichloroacetic anhydride affords a 1:l mixture of N-acylated phosphoramidate and carboxamide. In pyridine at 3 5 O , a secondary phosphoramidate with benzoyl chloride yields the 2-benzoyl derivative without carboxamide formation.54 From an examination of the acylation of the [180]labelled phosphoranilide (43) (and its epirner at phosphorus) with benzoyl chloride - pyridine, it appears that the pyridine catalyzes the transformation of the N-benzoyl derivative (44) into the thermodynamically more stable (451, hydrolysis of which furnishes benzanilide. No 0-benzoyl compounds were detected. 55 It has long been generally accepted that 2-substituted1,3,2-oxazaphospholidine 2-oxides and 2-sulphides (46; X=O or S ) are configurationally stable, and that exocyclic reactions generally proceed at the phosphorus centre with retention of configuration. On this basis, such compounds have been employed in the synthesis of isotopically chiral phosphates and thiophosphates. Now comes the disturbing news that, in the presence of nucleophilic catalysts, and in particular, pyridine, the chlorides (46; X=O or S , Y = C 1 ) are epimerized. There are important implications in the optical purities of these compounds and in the determination of enantiomeric excesses in chiral amines and alcohols made with their use.56 The role of metal ions in the hydrolysis of phosphate esters has been discussed;57 it has been found that Mgf+ and Gaff ions catalyze the reactions of 4-nitrophenyl phosphate dianion with substituted pyridines.58 The acid-catalyzed hydrolyses of diethyl 1-hexynyl phosphate ,59 bis (4-chloro-2,6dimethylphenyl) hydrogen phosphate ,6 o and of 1-phenylethyl dihydrogen phosphate,61 have been studied. The base-catalyzed hydrolyses of 2-cyanoethyl phosphate62 and of the series of
5: Quinquevalent Phosphorus Acids
133
di(4-nitrophenyl) phosphate esters (47: n=l or 2, X=CH or N) have been examined. In the last case63 the introduction of the heterocyclic nitrogen increases the rate of reaction, although the enhancement is not 1arge.The alkaline hydrolysis of the chiral compounds (48; R=OMe or SPr) occurs with loss of PhO- and inversion of configuration, in addition to l o s s of MeO- or PrS(and retention of PhO) with retention of configuration. For (48;R=iPrO, NH2 or NHEt), hydrolysis occurs with inversion of configuration during l o s s of PhO- although when R=4-02NC6H40, it is this last group which is lost.A4 The hydrolysis of 4-nitrophenyl diphenyl phosphate in microemulsions has been studied,65 and the solvolysis of diethyl (2-cyano-1-phenyl-1-propenyl) phosphate compared with the behaviour of chlorofenvinphos and tetrachlorvinphos .6 6 The rates of displacement of aryloxy anions from aryl diethyl phosphates by imidazole at 25" have been measured.6 7 The configurational analysis of g-substituted [ l60,180]thiophosphates by 31P nmr spectroscopy is rendered possible following 2-alkylation using myrtenyl bromide and subsequent 2-alkylation using, for example, diphenyldiazomethane (see also ref. 1 7 6 ) . 6 8 Although it is widely accepted that pentacoordinate phosphorus species play an important role in nucleophilic displacement reactions at phosphorus in five-membered cyclic esters and other derivatives of phosphoric acid, the role of such species with regard to derivatives possessing six-membered rings is far from being clearly understood, and conclusive evidence for their participation is distinctly lacking. The study of the acid-catalyzed hydrolysis of trans-5-t-butyl-2-methylthio1,3,2-dioxaphosphorinane 2-oxide (49) in an ?-isotopically labelled medium is therefore particularly relevant. 31P Nmr spectroscopy reveals that the hydrolysis proceeds with predominant retention of configuration (Scheme 5 ) . Towards the end of the reaction, substantial epimerization at phosphorus is also to be noticed. The formation of the +-isomer, substantially isotopically enriched at the phosphoryl oxygen, has been rationalized in terms of a pentacoordinate intermediate. A similar explanation is advanced to account for the mode of hydrolysis of O,O,S-trimethyl phosphorothioate under similar conditions.6 9 The possible involvement of 1,3,2,4-dioxadiphosphetanes ~
134
0
II
Organophosphorus Chemistry S Me
OH
I
+H20
SMep & ; l
0
OH
1L9)
I--0
OH
Scheme 5
0
II ( a ) R',P-o-PR~, 0
0
II
II
( b ) R'?P-O-
0
0
0
II
(C
II
Ii
I R~~P-O- P R ~ ~ 0
0
PR',
( 5 0 ) 0 = "0, R ' = PhO, R 2 = EtO
0
(51I
0 R'
11
hv
+ H
0 152)
O
135
5: Quinquevalent Phosphorus Acids
in the reactions between phosphoryl chlorides and phosphoric acid anions leading to pyrophosphoric acid esters has been reassessed (see Organophosphorus Chemistry, V o l . 18, page 138). This was done through a detailed study of the "0-induced changes in the "P chemical shifts of the labelled product pyrophosphates (50) obtained from R12P(0)C1 and R22P(180)0-, or alternatively, from RZ2P(0)C1 and R12P(180)O-. The spectrum of the product obtained from ( EtO)2 P ( 0 )C1 and ( PhO 1 2P(180)0-was consistent with it being a mixture of the isomers ( 5 0 ; a,b, and d). Likewise , the product from ( PhO 1 2P ( 0) C 1 and ( EtO 1 P ( l 8 O ) 0contained (50; b and c) but no (5O;dI.The absence of component c in the first case, and d in the second, was consistent with the lack of any need to predict dioxadiphosphetane intermediates to account for the previously observed results. 70 Tricoordinate quinquevalent species in both aqueous and non-aqueous systems appear to be receiving ever-increasing attention. Two reports describe the apparent generation of such species from 2,3-oxaphosphabicyclo[2.2.2]oct-5-ene derivatives. 'Thus, the pyrolysis of (51) at 100-llOo yields a product which, when chromatographed on silica gel, binds strongly to the support; the strong binding of phosphorus through oxygen to silicon is consistent with the generation of a particularly reactive phosphorus-containing species.71 More conventionally interpretable is the photolysis of ( 52; R1=OEt or NMe 2 ) to give a species which can be trapped by R 2OH to give (53L7* The nature of the intermediate length polyphosphate mixture produced by the hydrolysis ok the pyridinium betaine ( 5 4 ) suggests the intermediate formation of metaphosphate. 73 The quest for metaphosphate formation during the solvolysis of 'normal' phosphate ( or related) esters h a s continued, the evidence for such formation being based on the complete, or near complete, racemic narure of the materials obtained by the trapping of the intermediate. Complete racemization has now been shown to occur during the solvolysis of the bi s ( tetra butylammonium 1 salt of ( 1 - [ 160, 7O , 8O I -4ni trophenyl phosphate in t-butanol at 30".7 4 When the solvent system is changed to t-butanol in acetonitrile, the phosphoryl 75 transfer is much less stereoselective. Last year's Report included mention of a brief preliminary note on experiments designed to test for the
RP
136
Organophosphorus Chemistry
/i]
S-
A r -O-f'<'-
II
0
[ArO-
0-
+
[/i] S-
_ArO
EtOP,
0
0
(551
2-
II 0
0-
(56)
S-
Ar-0-P'
Ar-6-P'
I
1P.H
H
0
It'.-
S-
EtOH
1156) + ArOHl 4 EtOP,
II
O
0
157)
0
R ' r O - F " O PIIr ' ) 2
+
0
II -PI
OKNR 0
Q
(61)
0
II
(Et0)2POCHRCN
O" 0
160) R = - 0 3 ~ 1
R = N
I
/
(62)
sOH
5: Quinquevalent Phosphorus Acids
137
formation of a thiornetaphosphate ion, and in which the ethanolysis of isotopically chiral 4-nitrophenyl thiophosphate dianion proceeded with predominant racemization. Two turther reports have now appeared. The first concerns the hydrolysis by [180]H20 of (Rp)-deoxyadenosine 5’-[~ - ~ ~ O ] - f i - t h i o d i p h o s p h a at t e pH 7.2 - the compound then existing as the trianion; the reaction proceeds to organic monophosphate and inorganic thiophosphate with complete inversion of configuration at phosphorus. On the other hand, at pH 4.5, when the species present is the dianion, the hydrolysis occurs with 50% racemization and 50% inversion. It was concluded that ‘free’ rnetathiophosphate could exist with a finite lifetime.76 Other work has shown that the ethanolysis of (Rp)-4-nitrophenyl [ 180] thiophosphate monoanion proceeds with extensive racemization, but the reaction of the dianion occurs with complete racemization; solvolysis in aqueous ethanol proceeds with only 70% racemization. These results were considered to be conclusive evidence for the formation of the (probably solvated) monomeric metathiophosphate monoanion (56) from the dianion (55; Ar=4-nitrophenyl) in ethanol, and a relatively long-lived intermediate from the monoanion (57;Ar=4-nitrophenyl)in ethanol or aqueous ethanol.77
1.3 Synthetic uses of Phosphoric Acid Derivatives.Newly reported synthetic uses of phosphate esters in organic chemistry include the conversion of o - d i a l k y l a m i n o a l k y l p h o s p h o r a m i d a t e s into w-dialkylaminoalkyl(alkyl)carbodiimides by reaction with isocyanates in the two-phase, K2C03-xylene, system. 78 The coupling of ketones with diisopropyl 2-alkenyl phosphates in the presence of Sm(I1) iodide in THF occurs to give tertiary alcoho1s;depending on the organo groups the total yield of products (10-93%) contains the a and y compounds, (58) and (59) 79 respectively, in ratios varying from 3 : l to 1 : 3 . The aryl bis(2-oxo-3-benzoxazolinyl)phosphinate (60) and the tris(2-oxo-3-benzoxazolinyl)phosphine oxide (61) are new condensing agents for the preparation of B-lactams from B-aminocarboxylic acids ( see also Organophosphorus Chemistry, Vol. 18, page 178).80 Condensations between diethyl phosphorocyanidate and the aldehydes RCHO where R=Ar, CH3CH=CH, or PhCH=CH, in the presence of LiCN, yields the cyanophosphates ( 6 2 ) which, after deprotonation with BuLi in THF-Me2NCH2CH2NMe2 at -78O, may be
138
Organoph osp h oriis CheriiiJ rry
alkylated or acylated. Benzoins have been prepared by further reactions involving (62; R=aryl) and ArCHO followed by alkaline hydrolysis. Reactions between the carbanion of (62) and H 2C=CR1R 2 yield cyclopropanes.81 2.Phosphonic and Phosphinic Acids and their Derivatives. The chemistry of phosphorylated allenes has been reviewed.82
2.1 Synthesis of Phosphonic and Phosphinic Acids and their Derivatives.-Thiirane provides the source of the tniophosphoryl sulphur in its reactions with the complexes from alkenes and PC1 5 to give phosphonothioic dichloriaes; the mixcures of saturated and unsaturaced products so obcained from 1-alkenes may be treated with triethylamine to give only che unsaturated dichlorides RZK2C=CHP(S)C12.83 Decomposition of the adauct from PC15 and divinyl ether with S O 2 yields the cyclic phosphinic chloride (63; X C1) together with [Z-(l-chloroethoxy)vinyl;phosphonic dichloride; che treatment of the ether-PC1 adduct with AsF3 yields the phosphinic fluoride (63;X-F)!45 An inceresting variation in the use of PC15 to give cyclic chlorides is exemplified by the formacion of che complex (64) which, with S O 2 , gives the chloride (65;X=O), and with H 2S affords the corresponding (65;X=S).85 The treatmenc of N-alkyldiacecamides with PC1 and decornposicion 5 of the resulting complexes with SO2 can be made to give the phosphinic chloride (66;X=C1lg6 whilst the use of the enamides (67) with tne same reagents is a l s o a useful route to phosphorylated 1,4-dihydro-1,4-azaphosphorines, in this case (66;X=H).8 7 D i c h l o r o t r i p h e n y l p h o s p h o r a n e has been used to convert dialky 1 a1ky 1phos phona t e s into a1ky 1 a1ky 1phosphonoc hlor ida tes ;8 8 in the preparation of alkylphosphonic dichlorides from alkylphosphonic acid bis(trimechylsily1) esters and oxalyl chloride in DMF, the only byproduccs are volatile and easily removable.8 9 Dialkyl- and diarylphosphinic chlorides are obtainable from secondary phospnine oxides and sulphides by reaction with PC1 5. 9 0
A wide range of methylenediphosphorus di- and tetrahalides, many of them new compounds,and including mixed halides, has been prepared for spectroscopic study.9 1 The anoaic oxidacion of tetraalkyl pyrophosphites in the presence of arenes or 1-alkenes affords dialkyl arylphosphonaies or alkylphosphonates .9 2 Alkylphosphonic diesters have been
5: Quinquevalent Phosphorus Acids
139
(65)
(641
?' R N (C O M e ) ,
(R'=H,
=Cc
1
&
-
RN-C=C.PCI~PCI~
h,
.
0
I
1
PCL 5
4
(X
=
RN(
H)
COMe
CH=CHR'
(67)
0
II
It
.
( P r 'O),PC F X P f 0 P r ' I 2
(68)
( ~ 3 0 ) ~ ~0 =P I0R 3)2
CI
I
R'C--NCH,R~ (69)
R' C= I
N c H, R~
(70 I
1-
'
o =P(OR~I, R'CHN
=C H R Z
171)
Organophosphorus Chemistry
140
prepared by the alkylation of dialkyl phosphonates using alkyl halides in ihe presence of crown e i h e r ~ .Potassium ~~ carbonate may be employed as condensing agent for reactions involving 6,y-unsaturaced halides when the halides RCcCCH2X yield the expected product except when R=H, when mixtures of allene94 and 1-propynylphosphonic diesters result. Benzologues of heterocyclic systems can be C-phosphorylaced at a halogen-carrying aryl carbon using dialkyl phosphonates in the presence of Pd(Ph3P)4-Et3N.95 The same catalyst system allows the synthesis of dialkyl arylphosphonates from dialkyl 96 phosphonates and perfluoroalkyl arylsulphonates in 68-89% yield and (R)-isopropyl meLhylphosphinate is likewise arylated (by ArBr) to give (S)-isopropyl arylmethylphosphinates with no change in configuration at phosphorus.y7 Ni (111 halides catalyze the reactions between trialkyl phosphites and the bromoarene moieties in dibromodibenzo-18-crown-6 compounds at 170-180° to give the bisphosphonic tetraalkyl esters;98 in the presence of BSA, the reactions between dialkyl phosphonates and allylic acetates yield allylphosphonic dialkyl esters.99 The successive treatment of aryl bromides with t-butyllithium in THF at - 7 8 O , Cu(I) iodide at O o , and dieihyl (chloromethy1)phosphonate affords diethyl (arylmethy1)phosphonates. 100 Because of its higher boiling point, tribromofluoromethane is superior to trichlorofluoromethane in Arbuzov reactions with tzriisopropyl phosphite. The resulting phosphonate, (iPr0)2P(0)CFBr2, reacts with sodium diisopropyl phosphonate to give the tetraisopropyl ester of f l u o r o m e t h y l e n e b i s p h o s p h o n i c acid (68; X=H) by way of its derivative (68;X=Br). These reactions form the basis of a simplified synthesis of f l u o r o methylenebisphosphonic acid. The Arbuzov reaction between trialkyl phosphites and the imidoyl chlorides (69) yields the (imidoylmethy1)phosphonates (70) which, at room temperature, undergo irreversible and rapid prototropic conversion into the phosphonates (7l);kinetic and thermodynamic factors are both important in determining the final product composition. Titanium reagents have proved valuable in the synthesis of (1-a1kene)phosphonic diesters. The condensation between aldehydes and phosphonoacecic esters (72) may be catalyzed in products. 103 such a way as to provide either ( E l or
(z)
5: Quinquevalent Phosphorus Acids
141
TIC14
0
II
(RO),PCH,COOR
+
R'CHO
0
II
1721
R#PIOR12
H
0
COOR
0
II
PhSe 'R i i i , ButOK; i v , H C=CHCH Br; v, M e S 0 2 S M e ; 2 2 P h S e S e P h ; v i i , MCPBA or N o I 0 4 , h e a t ; v i i i , H 0 2 2
Reagents: i, B u L i ; ii, H C = C C H 2 B r ; v i , P h S e C l or
Scheme
0
CI,
II
6
R
R heat
0
142
Organophosphorus Chemistry
hethods for the synthesis of (l-substituted-1,3-butadienyl)phosphonic diethyl esters I73 1 have been described (Scheme 6 ) . I o 4 When heated, the (1,3-butaaienyl)phosphonic dichlorides ( 7 4 ; X=Cl, R=H, ClCH2, aryl, t-butyl; X=SPIe, R=aryl or MeOCH2) undergo cyclization to the (2-cyclobu~en-1-yl)phosphonic dichlorides ( 7 5 1 , one of very few routes to compounas based on 105 a cyclobutene ring with attached phosphorus. Malonic chloride esters undergo the expected Arbuzov reactions with trialkyl phosphites to give the (1,3-dioxoalkyl)phosphonic triesters (76; n=l) although these are in equilibrium with their (g)-enol forms.106'107 The unusual reactions between trialky? phosphites and perfluoroalkanoic acid chlorides have already been noted in earlier Reports, and they have now been explored further. The nature of the product depends on the temperature of interaction. Ac temperatures between -20" and ambient, and without solvent, (~)-[l-(dialkoxyphosphinyl)oxy-F-l-alkene]phosphonates(77) are obtained in high yields. However, at -78" and in an ethereal solvent, the exclusive product is a dialkyl [1-(dialkoxyphosphiny1)oxy-1;-F-alkyljphosphonate (78). Under no circumstances are p e r f l u o r o a c y l p h o s p h o n a t e s obtained. The treatment of (77) with butyllithium-Cu(1) iodide in T H F - t e t r a m e t h y l e t h a n e d i a m i n e results in the loss or' the phosphate ~ n o i e t y . ' " ~ ' ~ ~ ~ (1-Fluoro-2-oxoalkyl)phosphonic acid escers ( 7 9 ) are obtained through alkylation of the appropriate acid chlorides .'lo (l,l-Difluoro-2-oxoaIkyl)phosphosphonic diescers ( 8 0 ) have also been obtained by the reactions between tne appropriate acyl halides and phosphorylorganometall ic reagent s l l l whi 1 st the corresponding 1,l-dichloro compounds have been prepared by the direct chlorination (C12, 0 " ) of (2-oxoalkyl )phosphonic dieqterc Japanese authors have reported a novel synthesis of (2-oxc 4 hydroxyalky1)phosphonic diesters (81) from dia1koxyphosphiny;aceconitrile oxide. 113 The treatment, with singlet oxygen, of a methanolic solution of dimechyl (2-nitroethy1)phosphonate (82) also containing methoxide and an appropriate sensitizer, ultimately affords dimethyl [ (1-formy1)alkyl Iphosphonaces ( 8 3 ) .l14 These, (841,have been converted into the formerly unknown trans-(2,3-epoxy-4oxoalkyllphosphonic esters (86) using two methods. The first method employs the Wittig reaction through the escers ( 8 5 1 , arid is
5: Quinquevalent Phosphorus Acids
143
0
II
(R'o),P-
C=CH.COOR*
I
OH
0 R, C Fz C 0 C I
I
II
RfXop(
Z(RO)jP
P(ORI2
F
-2O'C
II
0
Z ( R O I 3 P -78 'C
R,CF,CH
(77)
1
BuLi, C u l . -76 'C
0
,OP
II
RfXH
(0R l2
P(OR12
F
'P( OR),
II
II
0
0
0
II
(R'OI~PCHFCOOH
SOClZ
0
II
(R'OI,P C H F C O C I
R*M
-
0
II
(R'OI~PCHFCOR~
(79)
M = L i or MgX
0
II
(EtOJzPCFZZn6r
+
RCOCI
R = O E t , COOEt, NEtZ
0 (Et
II
0 )z P C FzC 0 R (80)
Organophosphorus Chemistry
144
0
II
'h
(Meo)zR
0
II
(Et 01, P C R ' R C HO
+
P h,P
=C H CO R3
145
5: Quinquevalent Phosphorus Acids
useful when R 1=R 2=H or Me, and R3=alkyl, but when R 3=aryl, the 'dimer' (87) may also be produced. When R 1=alkyl or aryl, and R2=H, the initial olefination compound ( 8 5 ) may also be accompanied by the isomer ( 8 8 ) . The second procedure involves the Sn(I1) triflate-Et3N catalyzed reactions of the esters ( 8 4 ) with Sn(I1) enolates of a-bromoketones and subsequent cyclization of the bromohydrins (89) A new synthesis of diethyl (2-formylalkyl)phosphonates (YO) is based upon the interaction of trialkyl phosphites and keteneimines only in the presence of formic acid.l16 The marked stereoselectivity in the reaction between diethyl phosphonate and the protected xylose ( 9 1 ) to give the phosphonates (92) has been interpreted in terms of the direction of approach of the phosphoryl reagent to the carbohydrate aldehyde group. 117 2,3-Dihydro-3-K2-2-R1-1,4,2-benzodioxaphosphorin 2-oxides (93) have been prepared from catechol and (1-chloroalky1)phosphonic dichlorides118 and also by the cyclization of diethyl [(2-hydroxyphenoxy)methyllphosphosphonate induced by potassium t-butoxide. The 1 2,4-oxadiphospholanes (941 are the ultimate products when methylenebisphosphonic trialkyl esters react with the ketones R2R3C0 in the presence of C s F , and with subsequent loss of R'OH. I2O (w-Aminoalky1)phosphonic and (o-aminoalky1)phosphinic acids can be converted into their monoethyl esters through an initial reaction with triethyl orthoformate. Deformylation from nitrogen and monodeethylation (of the phosphonic diethyl ester) is readily achieved by successive treatment with MeOH-HC1, and sodium carbonate.1 2 1 ( a - Am ino- x- pyr ia iny 1me thy 1 ) pho sphoni c d i e s t er s and analogous quinoxaiine compounds 123 nave been obtained from aldimines and aialkyl hydrogen phosphonates. The treatment of phosphonoacetic triester carbanions with t-butanol-EtON0, or tosyl azide, or even chloramine(this only on a small scale), yields 1- (diethoxyphosphFny1)glycine esters What is stated to be an improved synthesis of [a-aminobenzyljphosphonic and analogous phosphinic acids ( 9 5 ) scarts from an aromatic aldehyde and appropriate tervalent phosphorus chl oriae . N- Alky 1aminomethy l-E-e t hy 1and N-alkylaminomethyl-1-t-buiylphosphinic acids have been N-alkylformamides, formaldehyde, and RPC12 prepared using -
'
146
0
II
(871
R'
R3 (EtO)g P
CHO
* -
H COOH
-HC02Et
O = P (OEt),
x ;$ ;.; (91)
0
( 9 2 1 ( a ) A = H, 6 = O H , 3 ( b ) A = OH, 6 = H, 9 7
O/.
5: Quinquevalent Phosphorus Acids
147
The reaction between glycine and ethyl alkyl(ch1oromethyllphosphinate in the presence of base yields the phosphinic acid ( 9 6 ) as the sodium salt .127'128 When R is CF3 or C 2 F 5 , the reaction proceeds with l o s s of RfH and leads efficiently to the phosphonic acid (96;R=OH).lZ8 Other similar products (97) have been obtained from the hexahydro-s-triazines derived from amino acid esters, (CH2N.A.CO0R3l3 where A is CH2, CH CH2, etc., by reaction with the phosphonous monoesters R'P(0) (OR )H.1 2 9 A synthesis of 3-phosphonoalanine (98) has used hydroxyimino
3
phosphonates (Scheme 7 ) .130 Scheme 8 outlines the synthesis of a simple phosphapeptide, capable of acting as an inhibitor of 131 D-alanine-g-alanine ligase. Full details of a study of the synthesis of phosphinochricin by the Michael addition of the chiral glycine Schiff base ( 9 9 ) to methyl e t h e n y l m e t h y l p h o s p h i n a t e in the presence of ~-buioxide,have appeared (see also Organophosphorus Chemistry, Vol. 16, p. 186). Although the course of the reaction i s evidenily unaffected by the n.it:irc of solvent, the stereospecificity of the reaction is remarkab:y d pcbndent on reaction temperature. Thus zhe ( S ) - - ( - ) Schiff base j i e ~ d s( S ) - ( + )product when the reaction is carried out at -78", but as the reaction temperature is raised to O o , an increase in the formation of ( E l - ( - ) phosphinothricin (evidently the thermodynamic product) occurs until the isolation of the latter in pure form is possible. The form of phosphinothricin does n o t possess the herbicidal aczivity of the ( 2 ) form.132 T h e synthesis of racemic y-hydroxyphosphinothricin ( 1 0 0 ) is depicted in Scheme 9. The compound is a new, powerful inhibitor of glutamine synthetase. Several derivatives of the compound are also described. 133 Several [(a-amino--w-carboxy)alkyl]phosphonic and phosphinic acids, HOOC ( CH2 I nCH ( NH2 1 P (0) ( OR2 1 R1, have been obcainea by the reduction of the oxime of the a'ppropriate (1-oxoalky1)phosphonic ( or phosphinic 1 acid ester. 107 Syntheses of phosphonohistiaine ( [(l-amino-2-imidazol4-y1)ethyljphosphonic acid 1 and phosphonoisohiszidine ( (l-amino-2-imidazol-2-yl~e~hyl]phosphonicacid ) have been described. I n these long and elaborate syntheses, che linkage between phosphorus and a-amino nitrogen through the a-carbon was achieved immediately by the addition of diethyl phosphonate to aiethyl a c e t a m i d o m e t h y l e n e m a l o n a t e , with the many remaining steps
148
Organophosphorus Chemistry
6
X
t
Y
II
Et 0, ,PNHz
+
3\
R’
P-Cl
RZ’ i, R 2 = R3 :PhO i i , R2 E P h , R3 s Ct
X = O o r S
HO
X
0 I,
/
HBr, A c O H
ii, epoxypropane
Y
Y
( 9 5 ) i, R Z = O H ii, R Z : P h
\y0
HOOCCH2NHCH R’
R’
‘OH
R’O’
(961
0 (EtO),
II P-
‘CHzNHACOOR3
(97) R1 = a l k y l or Ph;
0
II C-C-X II NOCOR’
0
\pH
’
0
0
II II (EtOI,PCH,C-C-X II
NOCOR’
R 2 = Et o r P h
0
‘I
0
II II ( E t 0 ) 2 P C H , C H C-X I
I
NH2
iii
0
II
(HO),P C H2CHCOOH X
I
= amino, alkoxy
NH2
R ’ = Me, P h , EtO, o r M e 2 N
(981
Scheme 7
5: Quinquevalent Phosphorus .4cids
0
II
i, ii
YP(OPhlz NHC b z
yL<e;
149
0
NHCbz Ill, I V
O 0-
v
I!/
y'-;Acoo-
0 OMe
1 I/
ypL i*COOMe
NHCbz
NHCbZ
R e a g e n t s : i, MeOH, KF, 18-crown-6; ii, NaOH, dioxane; iii, S 0 C l 2 , CHC13; i v , A l a - O M e ;
Scheme
V,
NaOH
8
(991
0
NHCbz
CbzNH
OSiMe3
0
N H 2 OH
1100) R e a g e n t s : i , M e P ( O ) H ( O E t ) , B S A , CH2C12; ii, Me3SiBr, CH2Ci2; iii, H 2 , P d l C , M e O H , H O -
Scheme 9
OII
/
(ROI~PCH~Y
0
II
(1011
Y = CN, COOEt, or Et,NCO
150
Organophosphorus Chemistry
being concerned with the construction of the imidazole ring. 134 In a study of new enzyme inhibitors, the condensation between the sodium salt of tetraethyl methylenediphosphonate and N-protected racemic alaninal, with subsequent deprotection, has furnished (E)-(3-amino-l-butenyl )phosphonic acid ( l O 1 ; R 1 = H ). I 3 ' The synthesis of esters of the acid (lO1;R1=alkyl) from (1-acetyloxy-2-alkeny1)phosphonic diesters and dialkylamines through 'umpolung' in the presence of Pd(Ph P ) -Et3N yields product mixtures in which the 'E-fOrmS predominate. 1 3 5 Phosphorylated enamines e.g. (102) and (1031, have been prepared by the condensation of acetal5 a n d dialkyl (cyanomethy1)phosphonate. The replacement of CN by COOEt or Et2NC0 raises the requirement f o r external heat application for a successful reaction. 136 The presence of BF3 is necessary in order that tetraalkyl pyrophosphites and formic esters (R1CO0C.H) react together to give a l k o x y m e t h y l e n e b i s p h o s p h o n i c acids, KIOCH[ P ( 0 ) (OHI2j2;other carboxylic esters with P406-BF3 yield a - h y d r o x y a l k y l b i s p h o s p h o n i c acids. 137 The synthesis of dialkyl [(l-phenylthio)alkyl]phosphonates by the direct replacement of the OH group in (a-hydroxyalkyllphosphonic aiesters by PhS can be achieved at room temperature by the use of a combination of the reagents PhSH, Ph3P, and diethyl a ~ o d i c a r b o x y l a t e .Dialkyl ~~~ [bis(alkylthio)methyl]phosphonates are obtainable from dialkyl trimethylsilyl phosphite and HC(SRl3 in the presence of SnC14.139 The novel conversion of the esters (104)into ( 1 0 5 ) by the use of F3C.S03SiMe3-HMDS in ether has been described. 14' Tervalent phosphorus reagents have been employea to prepare esters of [(alkylthio)alkyl]phosphonicand phosphjnic acids, as well as other derivatives of the general structure R1R2C(SR3)P(0)XY ( X , Y = C1 or alkylthi~)'~' while Arbuzov reactions between phosphonite dialkyl esters or bis(trimethylsily1) esters and chloroformic esters ClCOOR yield the phosphinic esters (106;R1=alkyl or Ph, R 2 =Et or Me3Si, R3=alkyl 1 .142 A conventional
'
Arbuzov reaction assisted in the synthesis of phosphonobaclofen ( 4-amino-3-( 4-chlorophenyl)-2-phosphonobutanoic acid 1 . 143 Examples of the dihydro-1,2,4-aiazaphosphorine system (107) have been prepared by the addition of phosphonothioite esters to nitrilimines The action of heat on a mixture o t P4Sl0 and l-bromo-
151
5: Quiny u evuleii I Ph osp h oriis Acids 0
0
II
(EtOl,PC(SR’)=
11
R’P<
CH R 2
OR2
COOR~
R2 N
EtO,
+
,PCPh=CHCI EtS
a--
R’t=NNR2
Ph
I p X R 1 OH ‘SEt
(107)
(1081
(109) But
\p’
// ‘s’
S
S
‘p/
S ‘But
(110)
Me,SiO+
Me heat
Me
Me (112)
0
II
R’R*PON=C
0
II
‘R3
0
II
(R ~1 O 2pHc
~R10)2p+4R2 H H H
Hc I R 2
SeR3
0
R3Se
H
152
Organophosphorus Chemistry
naphthalene results in the tormation of the novel dithiaThe tin compounds (109) are obtained diphosphetane ( 1 0 8 ) from ciie reactions between organotin halides and either diphenyldithiophosphinic acid or its ammonium salt, or between the free acid and organotin oxide or hyaroxide.'46 Bis(trimethylsily1) phosphonotrithioates react with DMSO to give the 3,6-dithioxo-1,2,4,5,3,6-tetrathiadiphosphorinanes (110); these are capable of existence in either cis or trans forms (R=Me).Whilst fairly stable in the crystalline state, the dimethyl compound in solution loses sulphur to give 3,5-dimethyl-3,5-dithioxo-l,2,4,3,5-trithiadiphospholane. Under similar conditions, the 3,6-di-t-butyl compound (llO;R=t-Bu) yields (1111 A reaction between diethyl trimethylsilyl phosphite and 2,5-diacetyl-4-methylphenyl trimethylsilyl ether yields che compound (112) as a mixture of diastereoisomers; the action of heat on this product results in the loss of one of each of the phosphoryl and silyl moieties to give the benzoxaphosphole (113).I4' Unaer milder conditions than those required in the phosphate series, 1,l -dichloro-1-nitrosoalkanes react with diphenylphosphinous acid to give the chloroformimino with alkyl methylphosphdiphenylphosphinates ( 114;R1=R2=Ph) 1 2 inites to give (114;R =Me, R =alkoxy), a l s o obtainable from dialkyl m e t h y l p h o ~ p h o n i t e s ;and ~ ~ ~( 114;R1=Me, R 2 = C 1 1 from methylphosphonous dichloride . 51
'
2.2 Reactions of Phosphonic and Phosphinic Acids and their Derivatives.-Tetraalkyl e t h e n y l i d e n e b i s p h o s p h o n a t e s react easily with N, P , and S-containing nucleophiles (HX) to give the products XCH2CH[P(0)(OR)2]2, readily convertible to the free acids through reaction with bromotrimethylsilane 152 ap.2
additions of thiols also occur on to the free acid in the same regiospecific manner.'53 Theory predicts that, in the fully ionized form, the polarity of the carbon-carbon double bona should be reversed. 154 The addition of acetylsulphenyl chloride to ethenylphosphonic diesters yields esters of 2-Thiiranephosphonic acid. 155 Diels-Alder reactions between cyclopentadiene and (2-phenyletheny1)phosphonic acid (giving both encio and exo-[3-phenylbicyclo[2.2.ljhept-5-en-2-yl~phosphonic
153
5: Quinquevalent Phosphorus Acids
acid 1 , 156 with 5-phosphorylated ketenes ( giving phosphonocyclobutand with imines to give C-phosphonolactams,157 have 2-enes all been described. 2-(Dialkoxyphosphinyl)alkanals (115;X=H)are chlorinated (C12 at 0 " ) at the a-CH bond to give (115;X=C1), and further reaction, when R 2=H, gives the dichloro compounds which react normally as aldehydes with diethyl phosphonate or ethanol.158 The addition of the selenenyl chlorides R3SeC1 (R3=Me or Ph) to 1,2-alkadienylphosphonic diesters (116) has been examined in some detail. Each of the potential products (117-120) is capable of existence in (El and (5)forms. The 1,2-oxaphospholes (120) are obtained only when R2=alkyl. When R2=H, the principal products are the 2,3-adducts (117) together with the compounds (119) resulting from a 1,3-sigmatropic rearrangement of (117), the 1,2-adducts (118) not being formed initially. When R2 is alkyl, both the 1,2-adducts (up to 1lX) and their rearranged products (119) are obtained in only low yield. By and large, products are obtained in higher yields than are their (E) isomers. 1 5 9 The chemistry of (a-aminoalky1)phosphonic acids and relatea phosphinic acids, and their derivatives, has been reviewed.160y16' ( + I - ( 1-Amino-1-methylpropyl )phosphonic acid has been shown to have the (S)configuration.162 The carbanions ( 1 2 1 ) undergo cycloaddition to a,~-unsaturatedcarboxylic esters to yiela the C-phosphorylated pyrrolidines (122) following deprotonation, a reaction which, overall, is regioselective and stereospecific, and which is probably a concerted one. Subsequently, the phosphoryl moiety is readily lost to give (123) and, at the end of the reaction, the proportions of (122) and 1123) depend on steric effects and experimental conditions.163 The oximes of dialkyl [(aminocarbonyl)oxojphosphonates (124) undergo methylation to give a mixture of the and ( E l forms of the phosphorylated nitrone (125) in addition to the products (126) and ( 1 2 7 ) ? 6 4 The first example of the dephosphorylation of an (a-aminoalky1)phosphonic acid by pyridoxal has been reported. In the presence of a metal ion, (a-amino-2-hydroxybenzyllphosphonic acid ana pyridoxal react at E. pH 9 and looo with P-C bond cleavage. The intermediate complex (128) represents the most likely initial reacting species and indicates a
(z)
(z)
154
Organophosphorus Cheniisrry
0
SeR3
0 11
N
C-
( E t O),P-
I
R5
R3
R’
1211
0
-
0
II
II
CHZNZ
(RO), P-C-CNH2
II
NOH
I1241
RHCOOEt
~
R6
.1
11221
0
[
0
0
II
11
123) 0
it
II
+
(EtOl,P-CC-CNH,
(Ro)zpYcNII I-i Me
NOMe
I1251
(1261 0
.1
0
II
II
(EtO1,PCH,CCNHz
d; Ho-tJo-
II
NOMe
Yo
+
Poi-
(1271
+
Me
&H
OH
+
O *‘H
Me
(128)
5: Quinquevalent Phosphorus Acids
155
requirement of the phosphonic acid, i s that it has a chelating group in the 13 position to the amino group.1 6 5 Further examples of the isomerization of phenyl esters of arylphosphonic acids to 2-hydroxyaryl(aryl)phosphinic acids, and of triaryl phosphates to tris(2-hydroxypheny1)phosphine oxides, under the influence of lithium diisopropylamide, have been recorded ( see Organophosphorus Chemistry, Vol. 18, p.157).166 Some arylphosphinic acid esters have been resolved efkiciently by the crystallization of their complexes with 2 , 2 ' dihydroxy-1,l'-binaphthyl. The two diastereoisomers of the latter with methyl methylphenylphosphinate have been studied by X-ray diffraction techniques.167 Esters of unsaturated phosphonic acids have been hydroxylated using Os04 or t-RuOOH. The distillation of certain esters can result in a cyclization a feature dependent on the relative positions or the ester and hydroxyl groups; thus ( 1 2 9 3 yields ultimately the 1,2-oxaphosphole (130).168 The thermolysis of the phosphonoformic acid esters (131) can take one or more oE three possible pathways; of- these, pach ( b ) appears to be the principle mode of degradation, although pathway (c) does also occur when K1=Me and R2=PhCH2.169 Measurements of the kinetics o i the coupling reaction between d i m e t h o x y p h o s p h i n y l a c e t a l d e h y d e and aryldiazonium salts, giving compounds (1321, have been carried out. 170 The course of the reaction between a C-phosphorylated nitroalcohol and SOC12-pyridine reagent depends not only on the experimental conditions but a l s o on the degree of substitution at the phosphorylated carbon atom (Scheme 10). Thus, for ( 133;R2=H), both dialkyl (1-chloro-2-nitroalkyl Iphosphonate and dialkyl (2-nitroetheny1)phosphonate may be formed. However, for tertiary compounds (133;R2=alkyl), only the (nitroalkenyllphosphonates are obtained. The main course of the reaction between trimethyl phosphonoacetate carbanion and the cyclopentadiene (134) at room temperature is illustrated. The principal product is (135) which affords ( 1 3 6 ) on acidolysis; (137) is additionally formed together with its geometric isomer. The isomers of (137) may be converted into ( 1 3 6 ) upon treatment with Et 3N or m e t h 0 ~ i d e . l ~ ~ The acid hydrolysis of methylphosphonofluoridic acid is
Organophosphorus Chemistry
156
0
It
(R~OI,PR~
0
II
I R’O1,P
0
It
- COOR’
(R’OI2POR2
+ CO
L o
(1311
I,
R’0.P
0
II
+ co,
OR2
‘R’
+ co,
0
(MeO),PCH,CHO
+
Ar
II
A,
___)
(McO),P-C’
CHO NHA~
\N.
(1321
/ (R’O
0
II
0
OH
,,”,‘ II \
P-C-CH,NO, It I (
OAc
0
I
II
(R’O)~P-C-CH,NO,
(R’O),P-C
I
R2
CI
I
I
- C H,NO,
R2
II
I R’ 01,P-
c =c H NO
1
,
R2 R e a g e n t s : i , S 0 C l 2 , p y r ; ii, h e a t ; iii, A c 2 0 , H‘;
S c h e m e 10
iv, N a 2 C O J ,
PhH
xvx
157
5: Quinquevalent Phosphorus Acids Ph Ph
+
@CHX
&t
x
0
0
@
(134 1
xqx NaO
0
II
0
II
= (MeO),P
Hqc:x x9c: &J
Ph Ph
R-P-
COOMe
Ph Ph
Ph Ph
+
H+
4
X
X
CH
I X
Nao
Q
"0
OPh
I
(
II
P h S 1 P C, H,O M e
R'
II
1 4 - M e 0 C,H,P(OPh 1 12S2
(141)
[ArI-S-CR
L
c'
0 II
.T--
ArP-0-CR S II
I
CI
1
S
S
-L
0
R-P\S/i
0
S
X
'11
S
\p4 R2S' 'x
158
Organophosphorus Chemistry
second order. The acid-catalyzed deuterolysis proceeds at 1.5 times the rate of hydrolysis, and a two-step reaction mechanism has consFquent ly been proposed. 1 7 3 Detailed studies on the hydrolysis of aryl esters of diphenylphosphinic acid and diphenylphosphinothioic acid have beep reported. By contrast to 4-nitrophenyl diphenylphosphi nate, which reacts with nucleophiles with phosphorus-oxygen bond cleavage to give 4-nitrophenol and diphenylphosphinoylated nucleophile, 2,4-dinitrophenyl diphenylphosphinate reacts, almost exclusively, with N-H nucleophiles through carbon-oxygen bond cleavage giving diphenylphosphinicacid and 2,4-dinitrophenylated nucleophile. The compounds (138; R=alkyl or aryl, Y=MeO, or Me N) show chemoselectivity towards the OH group with 2 phosphorus-oxygen bond fission. 1 7 5 . 180-Labelling provides a useful tool for the investigation of reaction mechanism e.g. of the hydrolysis of phosphinate esiers, R1R2P(0)OR3, where R1 and R2 are non-identi-cal, and one of the oxygen atoms is l80, providing that 180/160 exchange does not occur during the course of the hydrolysis or in the final hydrolysis product. The chirality of the resulting labelled acid, R1R2P(180)OH or R1R2P(0)180H, can be ascertained by the measurement of the l 8 0 induced 31P nmr chemical shifts, pariicularly after appropriate esterification of the free acid e.g. with a chiral azide. Unfortunately, one of the drawbacks to che procedure is indeed the occurrence of oxygen exchange in the freed acid anion, or through a pyrophosphate intermediate. although this process can be reduced by immediate conversion of the acid into, for example, its tetrabutylammonium salL. Conversion of the acid anion into a diastereoisomeric ester by reaction with a chiral alkyl halide ( e.g. menthyl or neomenthyl) may also run into practical difficulties associated either with oxygen exchange or general Lack of reactivity. The reaction of the hydrolysis product acid e ~ singly . labelled methylphenylphosphinic acid, with a chiral alcohol in the presence' of t r i p h e n y l p h o s p h i n e - d i e t h y l azodicarboxylate (Mitsunobu reaction) also tends to yield some doubly labelled ester. The best procedure for obtaining a singly labelled ester of value from the 31P - I 8 O nmr viewpoint, appears t o be t h a t of reaction of the potassium salt with myrtenyl bromide in the presence of 18-crown-6 in DMSO. The technique was applied to an examination of the
5 : Qit inqir evalen t Phosphorus A cids
159
alkaline hydrolysis of MePhP( 180)OMe which was shown to occur wiih greater than 98% inversion at phosphorus.176 The decomposition of ( E ) - j a - ( h y d r o x y i m i n o ) b e n z y l l phosphonic acid in acid solution yields benzonitrile and phosphoric acid in a pH-dependent manner consistent with a aissociative mechanism involving the liberation of monomeric rnecaphosphate as the first step.1 7 7 Attention has been turned to a study of displacement reactions at phosphorus in cyclic phosphonic acid esters, in particular, the phenyl ester (139) ('axial' phosphonate) and its phosphorus epimer; at equilibrium, the relative proportions of axial and equatorial esters is z. 1:9. For each compound, methanolysis (MeONa-MeOH) proceeds with 100% inversion of configuration at phosphorus and ring retention, a result explained by assuming the involvement of pentacoordinate intermediates in which the six-membered ring is placed in a diequatorial position. A slight increase in reaction rate for the equatorial ester by a factor of 5-8 times, is evidently consistent with a kinetic stereoelectronic effect. 178 Considerable further interesc has been shown in the applications of dithiadiphosphetidine disulphides (1401, both in organophosphorus chemistry and in more conventional organic synzhesis. Once again, this year, i t is the 2,4-bis(4-methoxyphenyl) compound (Lawesson's reagent) which has received most attention (see also Section 2 : 3 ) ; i t converts triphenylphosphine and triethyl phosphice each into its thiophospnoryl derivative. 1 7 9 The same reagent yields (141)from thiophenol, whereas with phenol, the product is (142).180 The reactions between Lawesson's reagent ( as well as other 2,4-dialkyl analogues) and a reactive alkyl (e.g.allyl, benzyl, propyl) halide in the presence of lithium halide and 15-crown-5 in hot toluene afford the phosphonodithioic halides (143);18' acyl chlorides behave as thioacylating agents possibly acting through the intermediacy of the species (144;R=Cie or Ph).182 The reaction between Lawesson's reagent and sodium alkoxides has been advocated as the basis for a new synthetic approach to thioinezin (2-ethyl 2-benzyl phenylphosphonothioate 1 . 183 Yet a third important use f o r Lawesson's reagent and related compounds is in the synthesis of novel phosphorus-containing ring compounds, as exemplified by (145-1481 . 184-186
Organoph osph orus Chemistry
160
R e f 184
Ref 184
0
OH (146)
R e f 185 ArN
Ar
0
(140)
Ref 186
PhCO
0
0
I1
11
RO,
/
-0
0
II
+
Ph2PNHNMc2CH2Ar
0 Br-
HO____)
II
Ph2P-
-
+
+
P C HC , t i *N H
N-NMe2CH2Ar
5: Quinquevalent Phosphorus Acids
161
The chemistry of the diimino compounds ( 1 4 9 ) , structurally analogous to metaphosphoric acid, has been reviewed . I a 7 The 1,2-azaphosphetidines (150) react normally with valency-expansion reagents, and on hydrolysis yield the (2-aminoethy1)phosphonic monoesters (151) also produced, in company with dialkyl (2-aminoethy1)phosphonate by the alcoholysis of (150).188 Basification of the initial product (152) from diphenylphosphinic 2,2-dimethylhydrazide with 4-nitrobenzyl bromide, yields, it is thought, a unique hydrazinium inner salt (153). The same type of product is obtainable from diphenyl N,N'-dimethyl phosphorohydrazidace but not from the analogous d i e t h r e s t e r . 189 The strained phosphaimidazolidones (154;R=Me, Et,or P h ) hydrolyse under alkaline conditions in MeCN at 35" at about 10' tlmes as fasc as do the N-phosphorylated imidazolidones (155; R=Me or Ph) under the same conditions. The compounds (154) hydrolyse to give (1561, but (155) also cleave at the P-N bond. The results were rationalised on the basis of pentacoordinated incermediaces.190 An interesting example of asymmetric induction has been found in the Claisen rearrangement of the perhydro-1,3,2oxazaphosphorines (157;R1=H o r Me) to the isomeric compounds (158). The rearrangement of the compounds (157;K2=R3= H I occurs at 100" to give (158) with relative asymmetric induction ratios of ca.6:4 (R1=Me) or 7: 3 ( R1= H I . Rearrangement in the presence of KDMSO occurs at 20" co give products in the ratio 1:l. However, increasing added LiCl changes the ratio eventually ( 6 equivalents) to G. 9 : l . Added LiCl has no effec? on the thermal rearrangement of cis (157;R1=R2=R 3=H) to che corresponding (158). The absolute sense of asymmetric induction was decermined by oxidative degradation of (158;R1=R2=K3=H) L O ( 1 5 9 1 , Cis-(ZS)-(158) yielding ($)-(159) . I 9 ' The effect of chiralicy at phosphorus and that of substituents ac ring carbon atoms have been examined also in the further reactions of the 1,3,2-oxazaphospholidine 2-oxides (1601, in particular, their additions co cyclic enones. The (25,45,55) and (2:,4?,5E)-3-methyl compounas undergo good enantioselective aaditions to 5,6, and 7-membered cyclic enones. However, chiral effects are even more marked for the E-isopropyl compounds; for +_hissyscem, the (2!,4E,5!) isomer gave poor diastereofacial selection whereas che corresponding (2s) - compound gave 1,4-adducts
0
0 HN
U
N-P-R
I
II
,OR MeNHCONMeC HZP,o-
OPh
OR
(1541 R'
0
?-R3
0 II
o
R3
f 157)
MeOOcrCOOMe
*
Me
11591 Ph
R ( 16 0 )
(164) R'CON HCMeR2CONMe
(166)
4
(1671
5: Quinquevalent Phosphorus Acids
163
/ R’= H
0
>’kR3
R’
R2
VN R4
RL
0 OAc
R2&R3
YN R4
0 II (Et0)2P
HO
Reagents
I,
v
YN
R4CSNH2,
v, BuNH2,
BuNH
VI,
11,
C S F , DMF,
NoHC03,
H20;
H20,
1 1 l . 0 ~M0e ~ N (~C H ) 0 ; I V , h e a t , 2 4 2 V I I , AcZO, pyr
MeOH, h e a t ,
Scheme
11
164
NOH
Reagents.
I,
Ph2PCL;
ii,
I
LiBHBuS3
;
iii,
H30+
Scheme 12
Organ oph osp h orus Chemistry
5: Quinyuevalerit Phosphorus Acids
165
with 88-98% E. 192 2.3.Synthetic uses of Phosphonic and Phosphinic Acids and their Derivatives.-Synthetic applications of Lawesson's reagent include and each of the ketones the conversion of (161) into (162) ( 163) and ( 164) into the 1,2-dichiolene-3 (165).186 The analogous 2,4-bis(4-methylphenylthio)-l,3,2~4-dithiadiphosphe~ane 2,4-disulphide converts (166) into (1671 Amongst other newly recorded applications of phosphonic and phosphinic acid compounds in organic synthesis are the use of diethyl (3-bromo-1-propeny1)phosphonate as an acetone equivalent for the annulation of five-membered rings and diethyl ( 3-iodopropynyl )p h ~ s p h o n a t e lfor ~ ~ the same purpose. Dialkyl (2,3-epoxy-4-oxoalkyl~phosphonates (168) are reagents for the synthesis of 1,3-thiazoles (Scheme 11 1 . 197 The reaction between a substituted cyclohexanone oxime and chlorodiphenylphosphine forms the first stage in a sequence leading to the axial diphenylphosphinic amide, and thus, by acid hydrolysis, to the axial cyclohexylarnine (Scheme 12 1 Finally, N-diphenylphosphinoyloxyarylamines ( 1-aryl0-diphenylphosphinyl oxirnes) react wich secondary amines to give unsymmetrical hydrazines through electrophilic amination, together with azobenzene, possibly via phenylnitrene intermediates References 1 . Proceedings of the IInd International Symposium on Phosphorus; Bioactive Molecules Vol. 3: Biophosphates and their Analogues (Eds. K.S.Bruzik and W.J.Stec), Elsevier, 1987(Conf. Lodz, Poland, 1986). 2. Krolevets, A.A., J. Gen. Chem. USSR (Engl. Transl.), 1986, 2, 1796. 3. Dabkowski, W. and Michalski, J., J.Chem. SOC.,Chem. Commun., 1987, 755. 4. Dabkowski, W., Cramer, F., and Michalski, J., Tetrahedron Lett., 1987, 28, 3561. 5. Hermans, R.J.M. and Buck, H.M., J. Org. Chem., 1988, 53, 2077. 6. Hermans, R . J . M . and Buck, H.M. J . Org. Chem., 1987, 52, 5150. 7. Dhawan.B. and Redmore, D., Synth. Commun., 1988, 18,327. 8. Watanabe, Y., Ogabawara, T., Shiotani, N., and Ozaki, S., Tetrahedron Lett. 1987, 28, 2607. 9. Dreef, C.E., Van der Marel, G.A., and Van Boom, J.H., Recl. Trav.Chim. Pays%, 1987, 106, 161. 771. 10 Hamblin, M.R., Flora, J.S., and Potter, B.V.L., Biochern. J., 1987, 3, 11. Cooke, A.M., Potter, B.V.L., and Gigg, R . , Tetrahedron Lett., 1987, 8, 2305. 12. Reese, C.B. and Ward., J.G., Tetrahedron Lett., 1987, 28, 2309. 13. Yu, K.-L. and Fraser-Reid, B., Tetrahedron Lett., 1988, 29, 979. 14. Ozaki, S., Kohno, K., Nakahira, H., Bunya, M., and Watanabe, Y., Chem. Lett. 1988, 77. 15. Meek, J.L., Davidson, F., and Hobbs, F.W., J. Arner. Chem. SOC., 1988, 110, 2317. 16. Cooke, A.M., Gigg, R., and Potter, B.V.L., J. Chem. SOC., Chem. Commun., 1987, 1525.
Organophosphorus Chemistry
166
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122. Boduszek, B. and Wieczorek , J.S., J. Prakt. Chern., 1986, 328, 627. 123. Niclas, H - J . , Sukall, S., and Richter, H-J., 2 . Chem., 1985, 25, 368. 124. Shiraki, C., Saito, H., Takahashi, K., Urakawa, C., and Hirata, T., Synthesis, 1988, 399. 125. Yuan,C. and Qi, Y., Synthesis, 1988, 472. 126. Tyka, R . , Hzgele, G., and Peters, J., Synth. Commun., 1988, 2 , 425. 127. Golovanov, A.V., Maslennikov, I.G., Medvedev, A.E., and Lavrent’ev, A.N., J. Gen. Chem. USSR, 1987, 57, 1080. 128. Golovanov, A.V., Naslennikov, I.G., Shubina, T.V., Kirichenko, L.N., and Lavrent’ev, A.N., J. Gen. Chem. USSR, 1987, 57, 722. 129. Issleib, K. and Mggelin, W., Synth. React. Inorg. Met-Org. Chem., 1986, 16, 645. 130. Mikityuk, A.D., Strepikheev, Yu A., Kashemirov, B.A., and Khokhlov, P.S., J. Gen. Chem. USSR, 1987, 57, 260. 131 Vo-Quang, Y., Gravey, A.M., Simonneau, R., Vo-Quang, L., Lacoste, A.M., and Goffic, F. Le., Tetrahedron Lett., 1987, g ,616‘7. 132. Minowa, N., Hirayarna, M., and Fukatsu, S., Bull. Chern. Soc. Jpn., _1987, 60, 1761. 133. Walker, D.M., McDonald, J.F., and Logusch, E.W., J. Chem. SOC. Chem. Cornmun., 1987, 1710. 134. Merrett, J.H., Spurden, W.C., Thomas, W.A., Tong, B.P., and Whitcombe, I.W.A., J . Chem. SOC. Perkiri Trans.1, 1988, 61. 135. Zhu, J. and Lu, X., J. Chem. SOC. Chem. Commun., 1987, 1318. 136. Kozlov, V.A., Churusova, S.G., Ivanchenko, V . I . , Negrebetskii, V.V., Grapov, A.F., and Mel’nikov, N.N., J. Gen. Chem. USSR, 1986, 56, 1775. 137. Alfer’ev, I.S., Bobkov, S. Yu, and Kotlyar.evskii, I.L., Bull. Acad. Sci. USSR, Div. Chem. Sci., 1987, 571, 577. 138, Gajda, T., Synthesis, 1988, 327. 139. Kim, D.Y., and Oh, D.Y., Bull. Korean Chem. SOC., 1986, 486; Chem. Abstr., 1987, 107, 198490. 140. Oh, D.Y., Kim, T.H., and Seoul, D.H., Bull. Korean Chern. Soc., 1987, S, 213; Chern. Abstr., 1988, %, 167578. / 141. Al’fonsov, V.A., Nizamov, I.S., Batyeva, E.S., and Pudovik, A.N., Doklady Chem., 1987, %, 9. 142. Issleib, K. and Stiebitz, B., Synth. React. Inorg. Met-Org.Chem., 1986, 16, 1253. 143. Chiefari, J., Galanopoulos, S., Janowski, W.K., Kerr, D.I.B., and Prager, R.H., Aust. J. Chem., 1987, 40, 1511. 144. Namestnikov, V.I., Tamm., L.A., Trishin, Yu. G., and Chistoklet,civ, V.N., J. Gen. Chem. USSR, 1987, 57, 1263. 145. Slawin, A.M.Z., Williams, D.J., Wood, P.T., arid Woollins, J.D., J. Chern. Soc. Chern. Commun., 1987, 1741. 146. Silvestru, C., Ilies, F., Haiduc, I., Gielen. M., and Zuckermann, J.J., J. Organomet. Chern., 1987, 330, 315. 147. Hahn, J. and yataniel, T., 2 . Nat., 1987, 842, 1263. 148. Nifant’ev, E.E., Kukhareva, T.S., Popkova, T.N., and Bekker, A.R., J . Gen. Chem. USSR, 1987, 57, 1792. 149. Sokolov, V.B., Epishina, T.A., Ivanov, A.N., Kharitonov, A.V., B r e l ’ , V.K., and Martynov, I.V., J. Gen. Chern. USSR, 1987, 57, 1478. 150. Sokolov, V.B., Ivanov, A.N., Epishina, T.A., and Martynov, I.V., J . Gen. Chem. USSR, 1987, 57, 845. 151. Sokolov, V.B., Ivanov, A.N., Epishina, T.A., and Martynov, I.V., J. Gen. Chem. USSR, 1987, 57, 1479. 152. Hutchinson, D.W. and Thornton, D.M., J. Organomet. Chem., 1988, 346, 341. 153. Alfer’ov, I.S., Mikhalin, N.V., Kotlyarevskii, I.L., and Vainer, L.M., Bull. Acad. Sci. USSR, Div. Chem. S c i . , 1987, 786. 154. Zverev, V.V., Bernikov, E.A., Levin, Ya A., Gazizova, L., and Bazhanova, Z.G., J . Gen. Chern. USSR, 1987, 57, 454.
z,
155. S h i l o v a , E.V., B y s t r o v a , V.M., Karimova, N.M., K i l ' d i s h e v a , O.V., arid K n u n y a n t s , I . L . , I z v . Akad. Nauk SSSR, S e r . Khim.Nauk., 1 9 8 6 , 73;'; Chem. A b s t r . 1 9 8 7 , log, 50297. 1 5 6 . K r o l e v e t s , A . A . , Popov, A.G., a n d A n t i p e v a , V.V., J . Gen. Chcm.ilSSR. 1 9 8 7 , 57, 1 1 2 6 . 157. M o t o y o s h i y a , J . a n d H i r a t a , K . , Chem. L e t t . 1 9 8 8 , 211. 1 5 8 . I s m a i l o v , V.M., Moskva, V . V . , Guseiriov, F . T . , Zykova, T . V . , a t i d S a d y k o v , I . S . , J . Gen. C h m . USSR, 1 9 8 6 , 56, 1 7 6 8 , 159. Mondeshka, D .M., T a n c h e v a , C .N., a n d Angi-I U V , C . M . , t ' h o s p h o r u s S u l f u r , 89. 1987, 160. Dhawan, B. a n d Redmor-c, D., k'hosphorus S u l f u r , 1 9 8 7 , 119. 1 6 1 . K u k h a r ' , V.P. a n d S u l o d e n l i o , V.A., Russ. Chcm. Rev. ( E n g l . T r a n s l . ) , 198;, 56, 8 5 9 . 1 6 2 . C h e k l o v , A.N., B e l o v , Yu F'. , Martyriov, T.V., a n d Aksinc,riko, A. Y u , B u l l . Acad. S c i . USSR, D i v . Chem. S c i . , 1 9 8 6 , 258'7. 1 6 3 . D e h n e l , A . , Kanabus-Kaminska, J . M . , aiid L a v i e l l e , G . , Can. .I. Chrm., 1 9 8 8 , 66, 310. 1 6 4 . K h o k h l o v , P . S . , M i k ~ t y u k ,A.D., : - ' : 1 ,lv, U . A . , Chc,rvin, I.:. , a n d K o s t y a r i o v s k i i , R.G., J . Geri. c 1 6 5 . C a l v o , K.C., J . O r g . Chem., 1 9 8 , ' 1 6 6 . P e t r v v , K . A . , Agnfunov, S . V . , a l r d 1987, 83. 167. Toda. F . , Mori, K., S l c i r i , Z., a n d Gr)IdScr~g, I . , < J . Org. Chern., 1 9 8 8 , 53, 3 0 8 . 1 6 8 . I'ondaveii-Rapti ,den, A . , arid S t u r z , G . , i ' h o s p h o r u s Sill f u r , 1 9 8 7 , @, 3 2 9 . 1 6 9 . E r i g c l , R . , P h o s p h o r u s S u l f u r , , 1 9 8 7 , 19. 169. 1 7 0 . S o k o l o v , M.1'. , Mavi.iti, G.V., G a z i z o v , I.G., Ivariova, V.N., P a v l o v , V . A . , arid L i o r b e r , D.G., J . GL,n. C h m . USSR, 1 9 8 7 , 7 , 1118. 1 7 1 . B a r a n o v , G . M . arid P c r k a l i r i , V . V . , J . G C I I . Chrm. USSR, 1 9 8 7 . 57, 6 9 9 . 17%. Fuzhc,nkova, A . V . , G a l y a i i t d i n o v , N.I., and Vagapova, N.N., J . Gvn. Chem. USSR, 1 9 8 7 , 57, l ? X . 1 7 3 . B e c h t o l d , W.E. arid D a h l , A . R . , E'hosphor.us S u l f u r , 1 9 8 7 , 193. 1'74. E l i s e c v n , G . D . , B a r a r i s k i i , V . A . , a n d Sukhoruk.uva, N . A . , J . Gcri. Chem.USSR, 198'7, 5'7, 52. 1 7 5 . H v r n e r , L. a n d R v c k e r , M., P h o s p h o r u s S u l f u r , 1 9 8 7 , 99. 1'76. Kay, P.B. a n d T i - i p p e t t , S . , J . Chem. S o c . P e r k i n T r a n s . 1, 1 9 8 7 , 1813. 177. B r e u e r , E . , Karamari, R . , G i b s o n , D . , L e a d e r , H . , arid Goldblum, A . , J . Chern. S o c . Chem. Commun., 1 9 8 8 , 504. 1 7 8 . Chang, J-W.A., a n d G o r - c n s t e i n , D . G . , T e t r a h e d r o n , 1 9 8 7 , 43, 5187. 1 7 9 . Z a b i r o v , N.G., C h e r k a s u v , R , 4 . , K h a l i k o v , I.S., a n d P u d o v i k , A.N., J . Gen. Chem. USSR, 1 9 8 6 , 56, 2 3 6 5 . 180. E l - B a r b a r y , . 4 . A . , C l a u s e n , K . , a n d Lawesson, S.O., _Egypt. J. P h a r m . S c i 236854. 1 9 8 4 ( P u b ] . 1986), 22, 2 0 3 ; Chem. A b s t r . , 1 9 8 7 , 181. C h a v d a r i a n , C . G . , _ P h o s p_ h u r u s_ S u l f_ u r , 1~ 9 8 7 , 31, 7 7 . 182. Y o u s i f , N.M. a n d Salama, M.A., P h o s p h o r u s S u l f u r , 1987, 51. 183. S h a b a n a , R . , P h o s p h o r u s S u l f u r , 1 9 8 7 , 29, 2 9 3 . 1 8 4 . Y o u s i f , N.M., S h a b a n a , R . , a n d Lawesson, S . O . , B u l l . S o c . Chim. F r . , 1986, 283. 185. S h a b a n a , R . , Mahran, M . R . , a n d H a f e z , T . S . , P h o s p h o r u s S u l f u r , 1 9 8 7 , 186. P a s h k e v i c h , K . I . , R a t n e r , V.G., a n d L a t y p o v , R.R., B u l l . Acad. Sci.USSR, D l v . Chem. S c i . , 1 9 8 7 , 8 4 8 . 1 8 7 . Ruban, A . V . , D r a p a i l o , A . B . , Romanenko, V.D., a n d M a r k o v s k l l , L . N . , J. Gen. Chem. USSR, 1 9 8 6 , 5 6 , 2 4 7 2 . 188. G u b n i t s k a y a , E . S . , P e r e s y p G n a , L . P . , a n d Parkhomenho, V . S . , J. Gen. Chem.USSR, 1 9 8 6 , 56, 1 7 7 9 . 1 8 9 . C a t e s , L . A . a n d L i , V . S . , P h o s p h o r u s Sulfur, 1 9 8 7 , 29, 2 4 9 . 190. K l u g e r , R., T h a t c h e r , G . R . J . , a n d S t a l l i n g s , W . C . , Can. J . Chem., 1 9 8 7 , 65, 1838. -
2,
2,
z,
2,
2,
107,
2,
s,1.
171
5: Quinquevaletir Phosphorus Acids
1 9 1 . Denmark, S.E. and M a r l i n , J . E . , J . O r g . Chern., 1 9 8 7 , 52, 5 7 2 . 1 9 2 . Hua, D . H . , K i n g , R.C.Y, McKie, J . A . , and Myer, L . , J . Amer. Chem.Soc., 1 9 8 7 , 2 ,5026. 193. Wudl, F . , S r d a n o v , G . , R o s e n a u , B . , Wellman, D . , W i l l i a m s , K . , a n d Cox, S . D . , J. A m e r . Chem. S o c . , 1 9 8 8 , 110, 1316. 1 9 4 . Wipf, P . , J e n n y , C . , and H e i m g a r t n e r , H . , Helv. Chirn. Acta, 1987, 70, 1001. 195. P o s s , A . J . a n d Smyth, M.S., S y n t h . Commun., 1 9 8 7 , 1735. 196. Poss, A . J . a n d B e l t e r , R.K., J. O r g . Chem., 1987, 52, 4810. 197. O h l e r , E . , Kang, H-S., a n d Z b i r a l , E . , Chem. B e r . , 1 9 8 8 , 533. 1 9 8 . H u t c h i n s , R . O . and R u t l e d g e , M.C., T e t r a h e d r o n L e t t . , 1 9 8 7 , 28, 5619. 1 9 9 . Boche, G., Meier, C . , and K l s e m i S , W . , T e t r a h e d r o n L e t t . , 1 9 8 8 , 9, 1777.
17,
121,
Nucleotides and Nucleic Acids BY J. B. HOBBS 1. Introduction The amount of innovative phosphorus chemistry in this area is being maintained, while the use of established phosphorus chemistry in biochemistry and molecular biology seems to be growing exponentially, and new areas to excite interest emerge constantly. In transduction in frog taste receptor cells, for instance, CAMPappears to decrease potassium ion conductance &y protein phosphorylation rather than v & direct gating of ion channels as in vision and o1faction.l Further revelations concerning 'RNA enzymes' were made at the 52"d Cold Spring Harbour Symposium on Quantitative Biology, together with fascinating speculations that 3'tRNA-like sequences at the 3'-ends of RNA viral nucleic acids (themselves suggested to be possible 'living fossils', throwbacks to a pre-DNA 'RNA world') may have been signals for replication by RNA replicases and played a role in the evolution of protein synthesis from an 'all-RNA ribosome' due to attachment of an amino acid to the terminus by a mutant-replicase.2 Several leading figures in 'prebiotic chemistry' have argued against the ancestral genetic system having been based on RNA on several grounds, notably that of the required selection for p-Dribonucleotide units from the enantiomers available being unlikely in view of the strong inhibition of abiotic template-directed polymerization by the other enanti~mers.~ The initial evolution of genetic material based on an acyclic, possibly prochiral, 'carbohydrate' subunit in the nucleosides-such as glycerol-has been suggested. Once again, several symposium reports merit recommendation for their interesting ~ o n t e n t . ~ Several reviews on the chemical synthesis of oligonucleotides by leading practitioners have appeared,s and reviews on unusual structures in DNA6 and RNA7 deserve attention. A novel structure in guanine-rich sequences at G - a - G base pairs and christened 'Gchromosome ends, thought to involve DNA', may be part of a mechanism to prevent chromosomes undergoing endshortening during successive rounds of replication.8 A well-reviewed volume on pyridine nucleotide coenzymes has a ~ p e a r e das ,~ also has a third volume of chemical procedures in nucleic acid chemistry.10 2. Mononucleotides
2.1 Chemical Synthesis. Treatment of adenosine with thiophosphoryl chloride in triethyl phosphate results in exclusive phosphorylation at the 5'-hydroxy group, the regiospecificity of reaction being higher than when using phosphoryl chloride. Hydrolysis of the intermediate adenosine 5'-thiophosphorodichloridateformed in
6: Nucleotides and Nucleic Acids
173
"801 water, followed by oxidation using bromine in the same solvent, affords adenosine 5'-[1803] phosphate in fair yield." An alternative procedure in which using DCC ['8O3I phosphorous acid was coupled to adenosine-2',3'-di-Q-acetate resulted in unsatisfactory loss of the isotopic label. Of three procedures investigated for the preparation of 9-(P-D-ribofuranosyl) uric acid 5'-monophosphate, phosphorylation of the 6,B-di-Q-benzyl-protected nucleoside with phosphoryl chloride in trimethyl phosphate gave the best yield, following deblocking.12 In a procedure for the enzymatic 5'-phosphorylation of purine nucleosides, the nucleoside was incubated with A T , PEP, pyruvate kinase, adenosine kinase, and pl,~5-bis(S'-adenosyl)pentaphosphate (to inhibit contaminating adenylate kinase)? The nucleotides formed, in moderate yield, included 5'-monophosphates of inosine, 8-bromoadenosine, 6-methylpurine riboside, 6-methylthiopurine riboside, purine riboside and 2-aminoadenosine. Homocytidine has been converted to its 6'monophosphate (1) using wheat shoot phosphotransferase, and thence by standard methods to its 5'-diphosphate.14 While (1)was neither substrate nor inhibitor of 5'nucleotidase from snake venom, the diphosphate was a potent inhibitor of this enzyme, although not a substrate for polynucleotide phosphorylase from Micrococcus luteus. Wheat shoot phosphotransferase was also used to using 4-nitrophenyl p h 0 ~ p h a t e . l ~ phosphorylate 5-fluoro-4-thio-2-deoxyuridine The 5'-monophosphate formed was about ten times less efficient at inactivating thymidylate synthetase from three tumour cell lines than 5-fluoro-dUMPJpossibly reflecting the difference in pKa values of the N(3)-H dissociation, which seems to be required intact for efficient binding to the enzyme. 3'-Q-Acetyl-S-fluor0-2'deoxyuridine has been phosphorylated with phosphoryl chloride in trimethyl phosphate and the product condensed with cortisol, corticosterone or prednisolone to give the lipophilic steroid conjugates (2-4).16 5-Fluoro-dUMP has been encapsulated in human red blood cells by a haemolysis/resealing procedure, after which the cellular pyrimidine 5'-nucleotidase hydrolysed the phosphate to release the nucleoside e ~ t r a c e l l u l a r l y This . ~ ~ offers the intriguing prospect of using nucleotide-loaded erythrocytes as time-programmed drug delivery systems. Inevitably, interest has focussed on the cellular phosphorylation of drugs active against HIV. 2,3'-Dideoxynucleosides are phosphorylated in human cell lines by deoxycytidine kinase rather slower than 2'-deoxynucleosides, and apparently via a different catalytic interaction, judged by inhibition studies.18. 2-Chloro-2'-3'dideoxyadenosine was phosphorylated by the same enzyme, was resistant to adenosine deaminase, and showed activity against HIV in culture cells, albeit less than that of 2',3'-dideoxycytidine.19 5-Ethyl-2'-deoxyuridine was specifically phosphorylated in a cell line infected with Herpes Simplex Virus 1 (HSV-I), and incorporated predominantly into the viral DNA of the infected cells with concomitant inhibition of viral yield.20 Bredinin 5'-oleyl and 5'-cetyl phosphates (5,6) have been prepared as potential
Organophosphorus Chemistry
174
0 HO-
II
P-OC
I
HO HO
I 1 1
OH
0 0
II I
0- P-
0
H0
HO
0 ( 2 ) R = R ' = O H ; s i n g l e bond at C I l ) - C I Z ) ( 3 ) R = R' = OH; d o u b l e bond at C ( ? ) - C ( 2 ) ( 4 ) R = O H ; R ' = H ; s i n g l e bond at CI11 - C I 2 )
xy
H,NOC
0 II
Ro:i-oY? HO
OH
(5) R = o l e y l (6) R = c e t y l
(7)
R'ovoH P I
(8) R' = H; R 2 = NHCOCH,;
NHCOCH20H; OH or R'
= COCH,;
R 2 =NHCOCH,
6: Nucleorides and Nucleic Acids
175
prodrugs of bredinin 5'-monophosphate by treating (7) successively with 4chlorophenylphosphorobis (lH-1,2,4-triazolide) and excess of the appropriate alcohol, removal of the acid-labile protecting groups with TFA, ring-closure with triethyl orthoformate,and removal of the aryl protection with oximate.21 More direct routes from 2'-3'-QQ,-isopropylidenebredininwere prevented by interference from the base moiety. Both (5) and (6) showed strong antitimour activity in mice. An efficient synthesis of cytidine 5'-monophosphosialic acids (8) has been reported using a sequence of four immobilized enzymes.22 Nucleoside monophosphokinase, pyruvate kinase and PEP were used to convert CMP to CTP, after which CMP-sialic acid synthetase and pyrophosphatase were hsed to form the sialic acid conjugates. Phospholipase D from a species of Streptornyces has been used to transfer the phosphatidyl residue of 3-m-phosphatidylcholine to the 5'position of a number of nucleoside acceptors to give 5'-(3-=-phosphatidyl) nucleosides (9).23 A two-phase system was employed, and several of the products displayed greater antileukaemic activity in mice than the parent nuclmsides. Studies on the biosynthesis of 2-deoxycoformycin show that C-1 of D-ribose is the source of the C-7 carbon in the heterocyclic b a e , and thus that ring expansion of an adenine ring occurs, and the species (lo), formed &5-phosphoribosylation at N-1 of the adenine ring of ATP or dATP using PRPP, followed by an Amadori-type rearrangement, has been suggested as an intermediate.24 Since (10) is an intermediate in the biosynthesis of L-histidine, 2'-deoxycoformycin may share a part-common pathway of biosynthesis with the amino acid. An extensive review, albeit in Japanese, on the phosphorylation of nucleosides in the synthesis of oligonucleotides by phosphotriester and phosphi te triester methods has been published.25 In one-pot procedure for preparing 2'deoxyribonucleoside 3'-phosphoramidite derivatives (111, bis(diisopropy1amino)chlorophosphine is treated with the protecting alcohol (k. of R in (11)) in the presence of base in ether, the volatile components removed, and in the presence of the residue treated with 5'-Q-dimethoxytrityl-2'-deoxythymidine diisopropylammonium tetrazolide.26 The preparation is quick and high yields are reported. Protected 5'-amino-2',5'-dideoxyribonucleoside3'-Q-phosphoramidites of type (12)have been prepared by phosphorylation of the corresponding nucleosides with 2-cyanoethoxy-~~-diisopropylaminochlorophosphine,~7 and the analogous protected 5'-mercapto compounds (13) have been prepared similarly.28 Both (12) and (13)were used in the terminal stage of automated solid-phase oligodeoxyribonucleotide synthesis to place a primary amino group and a sulphydryl group, respectively, at the 5'-terminus of an oligomer. After removal of the protecting trifluoroacetyl group with ammonia, a 5'-amino-2-deoxycytidylateterminated 10-mer was coupled to a water-soluble tetrairidium cluster to give a metallated self-complementary 10-mer containing a restriction site,27 while 5'mercapto-2'-deoxyguanylate-terminatedoligomers were derivatised with 5-
176
Organophosphorus Chemistry CH,OCOICH,),,CH, CH,(CH21,,C00
;I
+H
C H, 0
-P-O-( I
NUc
- 5’)
HO ( 9 ) N u c = U r d ; 5 - f l u o r o - U r d : Cyd; 5 f I u or o - C y d ; 5 - f I uor o - u r u C y d ; Ado; dAdo; 3 ’ - d A d o ; Bredinin; Ncplanocin A
-
-
I
HO
HO
Id ) Ri b-S’-_P (11) R = 2-pyridylethyl; m e t h y l ; 2-cyanoethyl; 2,2,2 - trichloroethyl; 1,l -dimethyl -2,2,2 - t r i c hlorocthyl; 2 - ( 4 - nitro)phenylethyl
(101
.
0
I
Pr’2N - P -OCH,CH,CN
(121 R = CF,CONH (131 R = Ph,CS *B = T h y ; CytBz; G u a B U ’ ; A d e P i v
0 COCH M e .,
0
0 MeO-
I
P-NPr
‘2
(14)
6: Nucleotides und Nucleic Acids
177
iodoacetamidofluorescein and an organomercurial.28 The phosphoramidite (14)has been prepared using methoxy-N,N-diisopropylamino chlorophosphine in a conventional phosphitylation as a means of introducing 5,6-dihydro-5-aza-2'deoxycytidine or 5-aza-2-deoxycytidine into oligonucleotides.29 Two decamers were prepared by automated synthesis using (14), as also was the dinucleoside phosphate formed by coupling (14) with 3'-Q-acetyl-2'-deoxythymidine.Oxidation of the latter using bis(trimethylsily1)trifluoroacetamide and oxygenated acetonitrile afforded the 5-azacytidine-containingdinucleotide d(n5CpT) in modest yield. The phosphoramidite (15) has been prepared by conventional phosphitylation of the corresponding nucleoside and used to incorporate the spin probe into a selfcomplementary 12-mer.30 The presence of the probe did not significantly disturb the stability of the duplex, while e.p.r. evidence indicated that the motion of the spin probe correlated with that of the tumbling of the whole oligomer, suggesting its suitability as a reporter group for examining motion in other DNA structures. 2-Chlorophenylphosphorodichloridatehas been treated with an equimolar amount of 5-nitrobenzotriazole, presumably forming (161, which was not isolated or characterized but used directly in successive reactions with appropriately protected ribonucleosides in the presence of pyridine or 2,6-lutidine to afford protected diribonucleoside p h o ~ p h a t e s . ~The ' ribonucleoside component with a free 3'hydroxy group was phosphorylated first, as usual. The method was extended to prepare the anticodon triplet of tRNALYsfrom yeast. Of several routes to deoxyribonucleoside 3'-hydrogenphosphonates which have been explored, the method offering the highest yield of (17) from N3-benzoyl-5'-Q-dimethoxytrityl-2'deoxythymidine without formation of 3'-3'-linked product involved condensation with phosphinic acid using mesitylenedisulphonylchloride in ~ y r i d i n e .Addition ~~ of lH-1,2,4-triazole to the reaction gave improved yield and fewer by-products. The heteroaromatic lactam systems of uridine, guanosine and 2'-deoxythymidine, fully protected on the sugar rings by acetylation, react with 4chlorophenylphosphorodichloridate in pyridine to give the 0 4 - or (for guanosine) Q6-phosphorylated species, the phosphate group subsequently being displaced by pyridine to form the corresponding fluorescent pyridinium salts.33 In a new variant of dinucleotide synthesis via the phosphite route, 5'-0-tbutyldimethylsilyl-2'-deoxynucleosidesare treated with bis(2,2,2-trifluoroethyl)trimethylsilylphosphite or bis(N,N-diisopropy1amino)trimethylsilylphosphite to give (18), which is treated with sulphuryl chloride to generate the phosphorochloridate (19) which in turn reacts with a 3'-Q-benzoyl-2'deoxynucleoside to give the protected dinucleoside phosphate (ZO).34 Irradiation of the protected d(TpT) species (21) using acetophenone as triplet sensitizer, followed by chromatographic separation of the products affords the cisthymine dimer as the major product. This was derivatized in conventional manner to give (22)as a building block for sequence-specific introduction of the
=
a-
178
Organophosphorus Chemistry
CI
DMTrO
0
I
~~‘~J-P-OCH~CH~CN
NO*
(151
DMTr 0
(16)
PhYBZ *B
0
o=P-
1 I
H
X
OH 117)
(18) X = CF,CH,O or Pr,\N; Y = OTMS; Z missing 119) X = CF,CH20 or PrI2N; Y = CI; Z = O
“B 1201 X = CF,CH,O
z =o
or Pri2N; y = oJ-;Bz;
”0 = Thy; A d e B Z
DMTr 0
‘0
0
0 4 ‘OMe 121 1
(221
I
0 Me
6: Nucleotides and Nucleic Acids s y ~ thymine l
179
dimer into oligodeoxyribonucleotides.3~After (22) had been used to prepare d(TpT[c,s)pTpT) by standard solid-phase methodology, photolysis of the oligonucleotide gave d[(Tp)sT] as the major reversion photoproduct. A similar protected trans-svn thymine dimer synthon has been prepared by virtually the same On irradiation the route and incorporated into d(CpCpTpApT[t,~]pTpApTpGpC).~~ major product was the photoreversion species, while a minor product coeluted with the same sequence containing the cis-sE dimer. Irradiation of UpU using acetone as photosensitizer, followed by work-up using reverse phase-h.p.l.c., afforded the cisdimer as the major photoproduct, with the trans-syn dimer as the major bypr0duct.3~ Analysis by multinuclear NMR spectroscopy showed markedly different furanose and exocyclic bond conformer distributions between the two dimers. Similar irradiation of ~ [ ( T P ) ~(n T I= 1-3) followed by separation as above has afforded the corresponding oligonucleotides with cis-= thymine dimers formed between all possible pairs of adjacent t h ~ m i n e s . 3Spectroscopic ~ analysis shows that while the photodimer conformation is essentially invariant with position, the structure of the oligonucleotide on the 5'-side of the dimer is more perturbed than that on the 3'-side. Dinucleoside monophosphates containing arabino- and xylonucleosides, (araU)p(dA), dAp&-U), d w T ) p d A and dApd(xy1o-T) have been prepared, and the introduction of the modified sugar in the 5'-residue shown by CD to perturb the structure far more than the presence of the same modification in the 3'-residue.39 All four compounds were bound by snake venom phosphodiesterase with similar facility to d(TpA) but were hydrolysed more slowly. It has been reported that diribonucleoside phosphates, treated with a large excess of I-aminonaphthalene-5-sulphonic acid and l-ethyl-3-(3dimethylaminopropy1)carbodiimide at pH 5.8, give rise to derivatives of type (23) in which the fluorescent naphthalene derivative is attached to the dinucleotide via a secondary amine link.40 The characterisation of the products requires further substantiation, but if verified the procedure would appear to afford a very simple method for fluorescent labelling via a stable 5'-aminonucleoside derivative. Upon treatment with benzoyl fluoride in dichloromethane, protected nucleoside 2-,3'-or 5'- (2-chlorophenyl)phosphoro lH-l,2,4-triazolides (or imidazolides) afford the corresponding phosphorofluoridates (24) in nearquantitative yield, together with the benzoylazolide as b y - p r o d ~ c t .The ~ ~ procedure was extended to prepare protected d(TpT) which was similarly fluorophosphorylated at the 3'-hydroxy group. N4-Benzoyl-5'-Q-dimethoxytrityl-2'-deoxycytidine has been coupled to 542cyanoethy1)phosphorothioateusing DCC, and the product (25) condensed with 3'-0acetyl-2'-deoxythymidine using mesitylenesulphonyl (MS)-5-(pyridin-2-yl)tetrazole or MS-nt.42 Deprotection of the products (the cyanoethyl group was removed using t-butylamine-pyridine (lO:l, v/v) without desulphurization) and analysis of the mixture of diastereoisomers of d(Cp(s)T) formed by h.p.1.c. showed that coupling
=
Organophosphorus Chemistry
180
so, I 0
II
RO-P-F
I
-0 (23) B, = Ura; B, = Adc or Gua 6, = Ade; 8, = Ura or Cyt
(24) R = N6, 3'-Bz2dAdo; 3', 5' - Ac U r d
kH! F 9
CytBZ
I
S c ti,
DMTrO
c H,C
5'-O-Pixyl-dThd;
0-P-0
OBDT
COR
N
1261 B =Thy or AdeDMTr; R = Ph or L-CIC6H,; BDT = 1, 3 - B e n z o d i t h i o l - 2 - y I
(25)
T hY
hY
F
-ti
DMTrOJ;-r-o,
-0Ac
DMTrO
NPr',
H
0-P-0
OAc
X
(28) X (29) X (30) X (31) X (321 X
(27)
0
=H = SH
= CH3(CH,),NH = 9-anthracenylmethoxy =OH
0
II
It
Me
HO (34) B = Ura; A d e
OH
6: Nucleotides and Nucleic Acids
181
using MSnt gave 62%s p and 38%l3p product distribution, while the MSpyridinyltetrazole gave up to 79% s p and 21% Bp. The selectivity for formation of the Sp product is thus less than that previously reported for dinucleoside aryl phosphate triesters, but high preference for coupling at the pro-S oxygen atom of (25) is still shown. Since diastereoselectivity is still seen when MSnt is used as coupling agent, it cannot be due solely to the influence of coordination by the pyridine nitrogen atom, as previously suggested. The full paper on the stereospecific and stereoselective generation of dideoxyribonucleoside phosphorothioates via acylphosphonate intermediates, previously reported briefly, has now a ~ p e a r e d . ~A3 curious observation was reported: when the acylphosphonate (26) was treated with DBU and n-butylamine to remove the aroyl group, then oxidized with sulphur and deprotected, only the Ep-isomer of the resulting dinucleosidyl phosphorothioate was formed. Using other combinations of 3'- and 5'- protecting groups and bases, diastereoisomeric mixtures were obtained. No fully convincing explanation for this phenomenon could be advanced: presumably a rather specific steric constraint is involved. Dinucleoside phosphorodithioates have been prepared by treating a conventionally prepared protected dinucleoside phosphoramidite (27) with hydrogen sulphide in acetonitrile in the presence of tetrazole to give thiophosphonate (281, which was further oxidized with sulphur in the presence of 2,6lutidine to give (29).44 Deprotection by standard methods followed to give the dinucleoside phosphorodithioate, which was stable to snake venom phosphodiesterase, in conditions in which d(TpT) was fully hydrolysed. The internucleotide link in (29) could be alkylated using 2,4-dichlorobenzyl chloride, after which deacetylation and phosphitylation using 2-cyanoethylbis(KNdiisopropy1amino)phosphiteafforded a synthon for introducing the phosphorodithioate link into oligodeoxyribonucleotides. Further, oxidation of (28) with iodine and n-butylamine, 9-anthracenylmethanol, or aqueous pyridine afforded (30-321, respectively. In a new procedure for preparing phosphonate analogues of 5'-nucleotides, Dglucose has been converted in several stages, one involving an Arbuzov reaction, to the sugar derivative (33), which was acetolysed and coupled to appropriately protected, silylated bases using the silyl-Hilbert-Johnsonpr0cedure.~5. After deblocking, the phosphonates (34) were obtained in good yield. The isomeric chloromethylphosphonyl derivatives of 9-(2,3-dihydroxypropyl)adenine (35) and (36) have been prepared by several methods, the best being direct treatment of the 'nucleoside' with chloromethylphosphonodichloridatein triethyl phosphate, with aqueous work-up.46 Alkaline treatment of (35) then affords (371,and (36) gives (381, in quantitative yield, intramolecular cyclisation followed by hydrolysis. The stereoisomer (38) was reported last year as a powerful anti-viral with a broad spectrum of activity.47 The phosphonylmethyl ethers (37) and (38) were also
Organ oph osph orus Chemistry
182
Ad e
CH,OR~
OH OH
I
135) R’ = P-CCH,CI;
R2=H
II
(391
0
OH
I
( 3 6 ) R’ = H ; R Z = P-CH2Cl
I1
0
0
II I
137) R ’ = H; R 2 = CH,P-OH
OH
0
II 1
(38) R’ = CH, P-OH
; R2 = H
OH
0
II
K O ) R’ = CHzP-OMe;
I
OH
RZ = H
I L L ) R ’ = OTOS; R2= R3 = E t ( L 5 ) R ’ = CI; R 2 = R 3 = E t 1 4 6 ) R’ : B r ; R Z = R 3 = E t (47)R’ = A d e ; R 2 = R 3 = E t ( L 8 ) R1 = A d e ; R 2 = R 3 = H (49) R ’ = A d e ; R 2 = R 3 = Me
6: Nucleotides and Nucleic Acids
183
prepared in the enantiomeric and racemic series, and their structures confirmed by synthesis via independent routes. Cyclisation of (38) using DCC affords (39) (the intermediate formed on alkaline hydrolysis of (3611,and methanolysis of (39) affords (401.48 Using a high concentration of reactants, (38) could be converted to its phosphonomorpholidate using DCC and morpholine, and treatment with pyrophosphate then gave the triphosphate analogue (41). The same method was used to prepare the pyrophosphate analogue (42) from (371, and a variant route using diphenylphosphorochloridate was used to prepare (43) from (38). Diethyl-2hydroxyethoxymethanephosphonate was tosylated to afford (44) or halogenated with triphenylphosphine and tetrachloromethane or tetrabromomethane to afford (45) or (46)respectively, all of which reacted with the sodium salt of adenine to afford (471.49 Removal of the ethyl groups with TMS-bromide gave (48) which was converted to its morpholidate and phosphorylated or pyrophosphorylated using the standard method. An alternative method, treating tosyloxymethylphosphonic acid dimethyl ester with 9-(2-hydroxyethyl)adenine and sodium hydride, was used to prepare (49). Alkaline hydrolysis of (47) or (49) permitted removal of a single ethyl(or methyl) group. A substantial number of 2'-5'-linked and 3'-5'-linked analogues of diribonucleoside monophosphates containing phosphonylmethyl internucleotidic bonds (50) and (51) have been prepared, using (52) as starting material for (50), and (53) as starting material for (511, and employing essentially phosphotriester synthetic pro~edures.5~ All the analogues (50) and (51) were resistant to cleavage by ribonucleases A and T2 and snake venom phosphodiesterase, but while (50) were also stable to alkali, (51) were degraded to form the 2 - or 3'-@phosphonomethyl ribonucleosides as appropriate, with release of the 3'-terminal ribonucleosides. Treatment of methylphosphonodichloridate successively with 5'-Qmonomethoxytrityl-2'-deoxythymidineand 4-nitrophenol, in pyridine, affords the methanephosphonate (54) as a separable mixture of stereoisomers.51 When 3'-Qacetyl-2'-deoxythymidine was treated successively with t-butylmagnesium chloride and (Rp) or E p ) (541,the corresponding diastereoisomers of the protected (Rp) and fip) 2-deoxythymidylyl (3'-5') 2'-deoxythymidylyl methanephosphonates (55) were formed. Assignment of stereochemistry in (54) was made using a cyclisation procedure. The formation of (55) from the stereoisomers of (54) proceeds essentially with inversion at phosphorus, but some racemisation was observed, possibly due to racemisation in (54) due to ligand exchange by 4-nitrophenolate formed in the course of reaction. Treatment of methylphosphonothioic dichloride successively with 5'-Q-trityl-2-deoxythymidine (or its @-anisoyl derivative) and 3hydroxypropanenitrile or n-octanol afforded nucleoside QQdialkylmethylphosphonothioates (561.52 The diastereoisomers of (56) were separable chromatographically for the cyanoethyl esters (3-anisoylthymine as base) and the octyl esters (thymine as base). If the chlorothiophosphonate intermediate (57) was
Organophosphorus Chemistry
184
HowB' cH20wB2 *
0
0
0
H , CH, O=P-OH
I I
H , O=T-OH
I
HO
(501 8, = Ura; B, B , = Ade; B, B, = C y t ; B, B1= Gua; 82
0
OQB2 HO
OH
= A d e , Ura, C y t = A d e , Ura
OH
(51) B, = Ura; B, = A d e , Ura B, = Ade; B,= A d e , Ura El= C y t ; B,= Gua E l = Gua; Bz= C y t
= Gua = Cyt
Ho-7-cH20w Bzow 0
II
*
Me0
0
OBt
BzO
0
Y j H Z
O=P-OH
I
OMe (521
(531
B
Me
Me
( 5 6 ) B = T h y or T h y A " R = OCH,CH,CN or O(CH21,CH3 (571 B = T h y ; R = C I
(58) B
:T h y
; R
dThd
- 5'
6: Nucleotides and Nucleic Acids
185
treated with 2'-deoxythymidine, thiophosphorylation occurred regioselectively at the 5'-position, giving (58) as a separable mixture of diastereoisomers. A series of 2'deoxynucleoside 3'-Q-&alkyl) and 6-aryl) methylphosphonothioates (59) has been prepared by treating the 5'- and baseprotected nucleosides with methylphosphonicbis(oxybenzotriazo1ide) and the product with the appropriate alkyl or aryl thiol species.53 This procedure was for superior to a similar one employing methylphosphonobis(imidazo1ide). The mixtures of diastereoisomers could be resolved chromatographically, and the 5-benzyl and chlorobenzyl species subsequently dealkylated using thiophenol, giving the chiral phosphonothioates (60). 5-Phosphonouridine has been prepared by treating sugar-protected 5bromouridine successively with n-butyllithium and diethylphosphorochloridate and then deblocking by standard procedures, and 8-phosphonoadenosine has been prepared by a similar route from protected 6-chloropurine riboside.54 6Phosphonouridine was prepared similarly, except that sugar-protected uridine was treated initially with lithium diisopropylamide. The phosphononucleosides were essentially inactive as cytostatic and antiviral agents in vitro. The self-association of 2'-AMP, 3'-AMP and 5'-AMP has been studied as a function of pH, using 'H n.m.r.55 The position of the phosphate group had little influence on the self-association of the dianionic, monoanionic or neutral species in water, the stacking being maximised when half the adenine bases were protonated. 5'-Nucleotide salts which form weakly-associated disordered base stacks appear to form hydrophobic complexes with 2,2-dimethyl-2-silapentane-5-sulphonate in water, with consequent upfield shift of the trimethylsilyl resonances.56. In a study of the hydrolysis of (~)-7~,-8a-dihydroxy-9a,lOct-epoxy7,8,9,10tetrahydrobenzo[alpyreneby solutions of the 2'-, 3'-,and 5'-monophosphates of adenosine, guanosine and cytosine in aqueous dioxan at different pH values, it was concluded that general acid catalysis by the nucleotide occurred, together with a secondary catalytic interaction to enhance the effectiveness, probably stacking between the nucleotide base and the aryl rings.57 The adsorption of AMP and CMP to soluble mineral salts has been studied as a function of ionic strength, pH, and the surface area of the solid salt, and found to depend on the charge on the nucleotides, adsorption probably being governed by electrostatic forces.58 The reaction of DLserine and adenosine 5'-phosphorimidazolidate in the presence of adenosine 5'O(methy1phosphate) and imidazole afforded 2'(3')-Q-seryl-adenosine-S'-(Qmethylphosphate) containing 90% enantiomeric excess of D-serine.59. This curious finding, together with similar results, may be significant for understanding the origin of the biological association between L-amino acids and nucleotides containing D-ribose. 2.2. Cyclic Nucleotides. The cobalt (111) complex [Co(trien)(OH2)(OH)lC12 is
reportedly highly efficient at catalysing the hydrolysis of CAMPto adenosine in
0rganop h osph orus Chem isrry
186 JC
B
Thy
I
Me
Me 160)
(61)
16 2)
Y
Y
:I
OR
( 6 3 ) X = PhNH ; Y = 0 16L) X = 0 ; Y = P h N H
S L-NO C H O - - - P - O Y ~ ~ ~ ~ '
II
2 6 4
HoYoG
d
PhNH
HO
166)
OH
Me
(70)
B=
0
Ura; 5-fluoro
-
Ura
6: Nucleotides and Nucleic Acids
187
neutral water.@ In the mechanism proposed, displacement of water by cAMP affords the intermediate (61), and intramolecular attack of the metal hydroxide on the cyclophosphate displaces the 3'-oxygen function to give (62). Further attack by water then releases the nucleosidyl moiety, affording the (trien) cobalt (111) phosphate. 8-Bromo-cGMP has been treated successively with thiourea to afford 8mercapto-cGMP, and then with lithium methoxide and iodoacetic acid to give 842carboxymethy1thio)-cGMP(631, which was highly selective for binding to site 1, rather than site 2, of cGMP-dependent protein kinase.61 Treatment of adenosine with thiophosphorylchloride in triethyl or trimethyl phosphate at room temperature, followed by cyclisation of the resulting thiophosphorodichloridate at high dilution using potassium hydroxide in aqueous acetonitrile at 80°C affords a mixture of (Rp) and 6p)-adenosine 3',5'-cyclic phosphorothioates in roughly equal proportions in about 50% yield.62. The diastereoisomers could be separated using reversed phase flash chromatography. This convenient and direct method was also applied to prepare the cyclic phosphorothioates of a number of other nucleosides, the IXp isomer generally being formed predominantly. A much more elaborate method of preparing these compounds in which base- and 2'-protected ribonucleosides were treated with 0 4 2 chlorophenyl)-O.O-bis[6-trifluoromethyl)-l-~~otriazolyllphosphorothioate and the intermediates cyclised in the presence of N-methylimidazole has also been described.63 The absolute configuration of (Rp)-uridine 3',5'-cyclic phosphorothioate has been defined by X-ray diffraction analysis, the bond lengths of the non-esterified P-0 and P-S bonds suggesting that the negative charge is distributed between the groups.64 The full paper describing Stec's route to ribonucleoside cyclic 3',5'phosphoramidates and related systems using the Appel reaction has now appeared.65 For instance, treatment of a base- and 2'-protected nucleoside 3',5'-cyclic phosphate with triphenylphosphine-carbontetrachloride and aniline affords the cyclic phosphoranilidates (63) and (64).These are separable, and can be converted into the corresponding phosphorothioates with retention of configuration using sodium hydride and carbon disulphide, or the corresponding "801 cyclic phosphates, with retention, using sodium hydride and [180]benzaldehyde. Treatment of the sugar-protected cyclic thiophosphoranilidate (65), formed by cyclisation of (66)using potassium t-butoxide, with sodium hydride and carbon disulphide gives adenosine 3',5'-cyclic phosphorodithioate (67) after deprotection. This species has been found to antagonize the activation by cAMP of CAMP-dependent protein kinase, like (Rp)CAMPS(68) but unlike Gp)-cAMPS (69) which is an agonist.66 An equatorial exocyclic oxygen thus seems to be required for dissociation of the holoenzyme. Adenosine 3',5'-cyclic phosphoramidate and "-dimethylphosphoramidate have been prepared by treating cAMP with a sulphonyl chloride, followed by aminolysis
Organoph osph orus Chernistry
188
of the anhydride formed.67 The sp-diastereoisomers were formed preferentially. The cyclic phosphoramidates (70) have been prepared by treatment of the mono(dimethoxytrity1)ated acyclonucleosides with 2-chloro-N-methyl-l,3,2oxazaphospholane, followed by oxidation with MCPBA and detritylation with zinc bromide in nitromethane.68 The compounds showed little or no antiviral or antitumour activity. The diastereoisomers of 2’-deoxythymidine 3’,5’-cyclic phosphate phenyl ester have been prepared and subjected to IH n.m.r. and X-ray crystallographic analysis.69 The nucleoside was treated with tris(dimethy1amino)phosphine to give the cyclic phosphoramidite, which was then treated with phenol and carbon dioxide, and oxidized with dinitrogen tetroxide, to afford stereospecifically the cis ( S ) diastereoisomer, with the cyclophosphate ring in chair conformation and the phenoxy group axial. The trans (R)diastereoisomer was prepared by using 4nitrophenol in place of phenol in the procedure described, subsequently inverting at phosphorus by displacement of nitrophenate using sodium phenate. In the trans isomer the chair and twist forms of the ring were in equilibrium. Among studies involving CAMPanalogues, 8-bromo- and 844chloropheny1thio)-CAMPhave been found capable of replacing nerve growth factor in promoting long-term survival and neurite outgrowths in cultures of rat sympathetic and sensory neurones, probably activation of CAMP-dependent kinases,70 while 8-chloro-, N6-benzyl-, and ~6-phenyl-8-(4-chlorophenylthio)-cAMP were the most effective analogues in suppressing growth in fifteen human cancer cell lines.71
3. Nucleoside Polvphosphates.
A multinuclear n.m.r. study of the binding of sodium ions and protons to ATP at pH 6.7 and 37°C has demonstrated exchange-broadening in the 31P n.m.r. spectra, probably due to two-step conversion between two pools of ATP differentiable by NMRone, the ATP- species with or without sodium ion bound, and the other the H(ATP)3- species with or without sodium ion bound. Physiological levels of sodium and potassium ions probably result in exchange broadening in in vivo 311’ n.m.r. spectra by the same mechanism.72 A IH n.m.r. study of non-dissociable proton shifts in ATP in D20 at 27°C in the range of pD from 1.5 - 8.4 indicates that indefinite non-cooperative stacking predominates at pD ~ 4 . 5and , dimeric stacking predominates at pD >4.5.73 Stacking in dimers of H2(ATP)2- is thought to be favoured by intermolecular ion pairs and H-bonding. The adenines are stacked head-to-tail, with the HO-group attached to Py on each ATP molecule H-bonding to N7 of its own adenine ring while the dissociated oxyanion on Py simultaneously forms an ion pair with the protonated N1 of the other adenine ring. The effect of altering water activity by addition of DMSO or ethylene glycol on
6: Nucleotides arid Nucleic Acids
189
the rates of hydrolysis of ATP in 1M HCl or IM NaOH have been examined at different temperatures74 At 3OoC,the decrease in activation energy and entropy of activation consequent on replacing 90% of water by an organic solvent results in a 46 fold increase in the rate of hydrolysis of ATP. Such effects may be important in the catalytic sites of Amases associated with cell membranes. The 31P n.m.r. signals of ATP and ADP alter in the presence of the acridine-bearing macrocycle (711, with a 1:l complex being formed with ATJ? and downfield shifts of the Pp and Pr ~ignals.~5 The macrocycle (72)lacking the intercalator bound ATP only half as strongly. While (71) catalysed the hydrolysis of ATP at pH 7 less strongly than did (721, it showed higher selectivity for hydrolysis of AT" (about 8 times as fast as ADP) than (72). In aqueous DMSO, (72) reacts with acetyl phosphate to form what is thought to be (731, a species capable of phosphoryl transfer to AMP, ADP and other phosphorylated acceptors.76 The intermediate (73) was in fact isolable, and afforded 51% ATP on incubation with ADP in 30% aqueous DMSO at pH 7 and 40". Some pyrophosphate and tripolyphosphate are also formed, due to hydrolysis of (73) affording orthophosphate which then acts as acceptor. The macrocycle (72) thus behaves as a pseudo-enzyme, catalyzing phosphoryl transfer (which was not observed in its absence) via a double displacement mechanism. Treatment of the cobalt (III) complex N4 Co(ATP)- (where N4 is a tetracoordinating tetraamino ligand) with NqCo(H20)(OH)2+results in increased hydrolysis to form phosphate, rather than pyrophosphate, but addition of cupric or calcium ions to N4Co(AW)- promotes hydrolysis to release pyrophosphate a1so.v Possibly metal ion exchange, followed by a mechanism similar to that described previously60 account for the first observation, while different patterns of metal ion coordination by copper and calcium to the triphosphate chain promote pyrophosphate release. A study of the pH-dependence of CAMP-dependent protein kinase indicates inter a h that MgATP2-binds preferentially in its fully ionised form and requires an enzyme residue, probably lysine, to be protonated.78 The mechanism illustrated (74) has been proposed, with the magnesium ion shifting to ligate the oxygens of Pa and Pp in the ADP formed. The stereochemical course of phosphoryl transfer catalysed by CAMP-dependent protein kinase has been investigated, using [y@p)-160,170, I*OlATP as substrate and a serine-containing heptapeptide as accept0r.~9 The phosphoryl group was subsequently transferred from the phosphoserine residue to (S)butane-l,3-diol using alkaline phosphatase (E. coli), and stereochemical analysis revealed that the original phosphoryl transfer by protein kinase had occurred with inversion at phosphorus, via a single displacement mechanism. Positional isotope exchange (PIX) in ATP by cleavage of the Pp-0-P, bond has been analysed using [ ~ l p * ~ P-1702, O, Py180,y18031ATP (75). This was prepared by treating adenosine 5'-phosphoromorpholidate with [170410rthophosphate to make [P-17041ADPrwhich was used as substrate together with more [170410rthophosphate in the Glynn-Chappell procedure to prepare [ap-170, P-1702, Py'80, y18031ATP,
190
Organoph osph orus Chemistry
CNH
H N 3
HO
HNH)
C N H
HO
(72) R = H (731 R = PO:-
0
II
-@-P-O-Pp0 II
I
II
8 - P p0- 0 0 -
I
I
-0
-0
Ho&
8II
(Ado - 5 ' )
-0
0
II I
OH
0
11
-
-0
0-
0
0
I
OH
-0
0
0
II II II O-P-O-P-N-P-O-(Ado-5') I
I
0-
(77) 0
0- P - 0 - P - 0 - II
-0:i-oHO
~-P-O-P-O-(Urd-5')
1
0
I
-0
H
1
-0
(781 H
coo(82)
/I
= 2
(83) n = 3
I
-0
6: Nucleotides and Nucleic Acids
191
which in turn was used with AMP and adenylate kinase to increase the quantity of [p-1704]ADP, a neat trick. On conversion to the phosphoromorpholidate and treatment with [1*04lorthophosphate, this afforded (75). Analysis of ATP species before and after exchange reactions was performed by transferring the pyrophosphoryl unit to C-1 of D-ribose-5-phosphate using phosphoribosylpyrophosphate synthetase to give (76) after which alkaline treatment resulted in ring closure with displacement of the original Py together with its attached oxygen atoms as orthophosphate. Isolation, ethylation, and mass spectrometric analysis of this orthophosphate permitted simultaneous analysis of PIX (replacement of I 8 0 in the bridge by I7O giving odd m / e values) and washout of by 1 6 0 giving even m / e values). the y-nonbridge 1 8 0 atoms (replacement of This ingenious procedure was used for (74) in the presence of myosin, when rapid washout of the y-nonbridge oxygens without PIX was observed. Previous observations of apparent PIX by myosin were ascribed to the activity of contaminating adenylate kinase: the presence of Pl1P5-bis(5'adenosy1)pentaphosphate to inhibit adenylate kinase eliminated the apparent exchange. When UMP is incubated with ADP, [1804]carbamoyl phosphate, carbamate kinase and nucleoside monophosphate kinase, [ f3-1803]UDPis formed. If nucleoside diphosphate kinase is also present, [p-1802, Py-l80, y-l*031UTP is formed. Incubation of [ p-1803IUDP with sucrose and sucrose synthase then affords [p18OglUDP-glucose(77). When (77) was incubated with galactose-1-phosphate uridylyltransferase in the presence of unlabelled glucose-1-phosphate, the uridylylenzyme intermediate was formed, and its partitioning back towards free enzyme could be measured by PIX at the bridge position in (77), while its partitioning forward toward free enzyme could be measured by the rate of formation of [ p-16031UDP-glucose.~1The energetics of the reaction catalysed by UDP-glucose pyrophosphorylase have been analysed by investigating the inhibition of PIX reactions by added substrates.g2 The PIX in [b1802, py-180, y-1803]UTPwas measured for the forward reaction as a function of the concentration of glucose-1-phosphate present, while in the reverse reaction PIX within [ P-l8Oj]UDP-glucose was measured as a function of pyrophosphate concentration. Adenylate kinase is not solely specific for adenine nucleotides, but can catalyse the equilibration of CMP, CTP and CDP, while pyruvate kinase can phosphorylate CDP to CTP. These properties have allowed the construction of a membrane-enclosed enzyme reactor in which adenylate kinase and pyruvate kinase were used to convert a mixture of CMP and PEP to CTP in good yield, on a gram scale.83 8-hidoadenosine 5 ' - [ ~ 3 ~triphosphate Pl has been prepared by replacing ADP by 8-azido-ADP in the Glynn-Chappell procedure for the synthesis of [y32PlATP.84 The preparation is performed in subdued light, to limit photolysis. The incorporation of "3CI formic acid as C-8 of the guanine ring, followed by phosphoribosylation of the base using phosphoribosylpyrophosphateand
192
Organophosphorus Chemistry
hypoxanthine-guanine phosphoribosyltransferaseand subsequent phosphorylation of the resulting [8-13ClGMP using guanylate kinase and ATP has been used to prepare [8-13C]GDP.s Adenosine 5'-[a,P-imido]triphosphate(78) has been prepared by treating 5'-0tosyladenosine with the tris(tetra-N-butylammonium)salt of imidodiphosphate to give adenosine 5'-imidodiphosphate, which was phosphorylated to (78) using creatine phosphate and creatine kinase.86 Both the di- and triphosphate analogues were good substrates for creatine kinase, and (78) was an effective substrate for T7 RNA polymerase, possibly due to a proton donor or metal ion coordination assisting cleavage of the Pa-N bond. Adenosine 5'-[py-imidoltriphosphateis a substrate for RNA polymerase I1 from wheat germ, affording kinetic plots which show negative cooperativity.87 Commercial preparations of adenosine 5'-[pyimidoltriphosphate appear to be contaminated in some cases by ADP, which must be eliminated carefully before using the analogue for inhibition studies, since adventitious kinases may otherwise lead to the formation of ATP, affording spurious results.88 5'-~-~-[(L-Homocystein-~-yl)methyl] adenosine 5'-[pyimidoltriphosphate (79) has been prepared by coupling the 5'-OH group of the protected nucleoside with benzyl phosphate using DCC, hydrogenolysis to the 5'phosphate, conversion to the phosphorimidazolidate, treatment with imidodiphosphate, and deprotection. It is a powerful inhibitor of methionine adenosyltransferases from both normal rat tissue and from rat hepatoma.89 So,too, were two similarly prepared and closely related analogues (80) and @I),which differed in the position of insertion of an extra methylene group, compared with (79).90 All three analogues were competitive inhibitors with respect to Lmethionine and Mg.ATP2-, suggesting dual substrate site binding modes. Coupling alanine ethyl ester to ADP and ATF' using DCC in DMF affords the phosphoramidates (82) and (83); the corresponding serine analogues were too labile to isolate. While both compounds were cleaved at the phosphoanhydride bonds in alkaline medium, (82) was hydrolysed at both the phosphoanhydride and phosphoamide bonds, and (83) only at the phosphoamide bond, in acidic medium.91 Treatment of adenosine .5'-phosphoric di-n-butylphosphinothioic anhydride with a-D-glucopyranosylphosphonatehas been used to prepare the ADP-glucose analogue (84);the UDP-galactose (85) and GDP-mannose (86) analogues were prepared similarly.92 Only (85) was found to inhibit glycoprotein p-Dgalactosyltransferase, but (84) and (86)showed mild activity against human leukaemia cell lines. Coupling 2,3,4,6-tetra-Q-acetyl-a-D-glucopyranosyl methylenediphosphonate to 2,3'-Qacetyladenosine using MS-nt, followed by deblocking, gave the methylenediphosphonate analogues (87) of ADP-glucose, and again the corresponding analogues of UDP-galactose and GDP-mannose [(88) and (89)l were obtained similarly.93 While (88)was also a competitive inhibitor of glycoprotein galactosyltransferase, none of these compounds showed antiturnour
6: Nucleotides and Nucleic Acids
0 R4
I
HO
I
HO
(84) R 1 = R 3 = (85) R1 = R4 = (86) R ’ = R 4 = (87) A S ( 8 4 1 ,
H; R 2 = R 4 = OH; X is m i s s i n g ; Y = 0 ; Nuc = A d o OH; R 2 = R 3 = H ; X is missing; Y = 0; Nuc = U r d H; R 2 = R 3 OH X is m i s s i n g ; Y = 0; Nuc = U r d b u t X = 0; Y = C H , (88) A S (851, b u t X = 0 ; Y = CH, (891 A S (86), b u t X = 0 ; Y = C H 2
0
8-
0
II II HO-P-O-P-CH20-(N~~-5’) I I HO
x--;
S=P-0-P-”Me2
(93)
P-O-P-O-
Y
II
I
S (Nuc--5‘1
0-
PhC H,O-
II
P-
I
0-
s
l
o
l
(98)
4
II
P- 0
I
0-
(96)
(91) X = “ O ; Y d 7 0 ; N u c = A d o (92) X = 1 7 0 ; Y ~ ’ ~ N0 uc ;= Ado (9Ll A s 191), N U C d A d o (95) A S {92), N U C = d A d o
I
\
0 n/-P-o-(4
0
0-
o
N Me2
Ado, C y d , U r d , Guo
0
\
I
I
0-
HO
1901 Nuc S
NMe2
+I
I
s
I
o
l
.
l
(99)
ado-5’)
194
Organophosphorus Chemistq
activity. The ribonucleoside 5-Q-phosphorylphosphonylmethylethers (90) are not substrates for polynucleotide phosphorylase from E . c d i , but act as efficient competitive inhibitors of the polymerisation of normal nucleoside 5'd i p h ~ s p h a t e s .No ~ ~ incorporation into the polymer chain or at the 3'-terminus could be demonstrated, but the presence of the analogues appeared to cause longer homopolymers than usual to be formed from nucleoside 5'-diphosphates. The reaction of (Rp) or @p>-[p-1701ADPPS[(91) and (9211 with diphenylphosphorochloridate for 15 minutes in HMPA followed by aqueous workup produces an epimeric mixture of (Hp) and (Sp)-~*-5'-adenosyl-P3-phenyl-2-thio[2-1701triphosphates.95 Analysis of the phenyl [P-thio] triphosphate released by treatment with periodate and alkaline hydrolysis, using mass spectrometry, shows that, irrespective of the starting material used, the labelling pattern is similar in both epimeric products with oxygen-17 now distributed between bridging and nonbridging positions. Epimerisation at phosphorus must occur during the initial coupling reaction for this distribution of oxygen-I7 to be observed, in principle either by reversible formation of [l7Olthiometaphosphate, or via the reversible transfer of the thiophosphoryl group to solvent HMPA. The latter explanation was preferred on the basis of reaction rates, with formation of the zwitterionic Q[170]thiophosphoryl-HMPA (93) being postulated. The stereochemistry at phosphorus is randomised by swapping the thiophosphoryl moiety of (93) between HMPA molecules. (Rp) and (Sp)-[P-170]dADPpS have been prepared and their hydrolyses studied at p H 4.5 (dianionic forms predominate) and pH 7.2 (trianionic forms predominate) at 50°C in [180]water.96 The chiral thiophosphate released was isolated and its chirality determined.97 While hydrolysis at pH 7.2 occurred stereospecifically with inversion at phosphorus, some 27% racemisation was observed in the thiophosphate released at pH 4.5. It is thought that thiometaphosphate is formed at pH 4.5, some of which remains associated with AMP in an ion pair and is attacked by water giving inversion, and some of which dissociates from AMP to be hydrolysed in bulk solution giving racemisation. A model experiment showed that no positional isotope exchange of oxygen-I8 between the @-bridge and a-nonbridge positions occurred in adenosine 5'4aP180,p-1802]f3-thiodiphosphatein similar conditions, suggesting that formation of the AMP, thiometaphosphate ion pair is probably irreversible. Adenosine 5 ' - [ ( 3 ) a thio,y-benzylltriphosphate (96) has been prepared by treating benzyl phosphate with diphenylphosphorochloridate and (SpIADPaS, and on treatment with cyanogen bromide in [180]water affords adenosine 5'-[l~O,y-benzyl]triphosphate in which 31P n.m.r. reveals 50% of the 180-label to be at Pa, 44% at Pu and none at Pp.98 Evidently the presence of the benzyl group does not suppress the participation of the yphosphate group in forming a cyclotriphosphate intermediate (97). Hydrolysis of the product in [170]water with snake venom phosphodiesterase and stereochemical analysis of the chiral AMP released shows that the mode of displacement of sulphur
6: Nucleorides und Nudeic Acids
105
in (96) by oxygen occurs predominantly if not exclusively with retention of configuration at phosphorus, supporting the proposal that (97) is formed as intermediate (inverted at phosphorus) and subsequently hydrolysed by attack of [180]water at Pa (reinversion) or P, In a new synthesis of "adenosine 5'-[(&p)-y170,1801y-thiotriphosphate",phosphorus trichloride is hydrolysed in [170] water, and the [*703]phosphorous acid obtained persilylated, the "7031 tris (Th4S) phosphite obtained treated with bis(4-nitrobenzyl)disulphide, and the silyl groups removed by hydrolysis to give 5-(4-nitrobenzyl) [170~]phosphorothioate.99 This is treated successively with diphenylphosphorochloridate and [1803]AMP,to give adenosine 5'-[a-1802,a~-1s0,~-170~l~-thiodiphosphate, which is phosphorylated using PEP and pyruvate kinase, and then treated with hexokinase and D-glucose to remove selectively the (l7p) isomer of the ATPPS species (the preferred substrate for the enzyme) leaving adenosine 5'4( ~ p ) - c ~ ~ ~ O ~ , c ~ ~ - ~ ~ O P-thiotriphosphate ,~-~~O,py-'~0] (98). Upon incubation with methionine and methionyl-tRNA synthetase, the thiophosphoryl moiety of (98) is removed and restored to form the more stable (99) the target compound with additional 1 8 0 labelling at Pa and 1 7 0 labelling at the Py
bridge. When (99) was used as a substrate for glutamine synthetase,99 treatment of the y-glutamylthiophosphate formed with hydroxama te released chiral thiophosphate which on stereochemical analysisg7 was shown to be the Gp) isomer, showing that thiophosphoryl transfer to glutamate proceeds via. an 'in-line' mechanism. When (99) was treated with glycerokinase from E . coli in the presence of D-glyceraldehyde, the same isomer of chiral thiophosphate was released, indicating that the hydrolytic reaction had proceeded with inversion of configuration at phosphorus.lO0 It is thought that the hydrate of D-glyceraldehyde acts as substrate for the enzyme in mimicry of L-glyceraldehyde, the normal substrate, with thiophosphoryl transfer to a hydroxy group of the hydrated aldehyde being followed by breakdown to release thiophosphate. This accounts nicely for the observation that L-glyceraldehyde is phosphorylated by the enzyme in the presence of ATP, while D-glyceraldehyde promotes the hydrolysis of ATP. In an extensive review, the self-association, protonation and metalcoordination properties of l,Nf'-etheno-AMP and -ATP have been compared with those of the parent nucleotides.101 ltN6-Etheno-AMP furnishes a convenient assay for 5'-nucleotidase activity, the 1,N6-ethenoadenosine released being monitored by fluorescence spectrometry.'o* 1,Nb-Etheno-ADP has been hydrolysed with sodium hydroxide to give 5-amino-4-(2-imidazolyl)-l-(5-pyrophospho-~-D-
ribofuranosyl)imidazole, which after ring-closure with carbon disulphide, alkylation with 3-bromopropylamine and removal of the etheno group with NBS affords 2-[(3aminopropy1)thiolADP (loo), an effective agonist of platelet aggregation.lO3 Several analogues of N7-methyl-GMP containing modified phosphate groups [(101)-(103)]have been prepared as analogues of the mRNA 5'-'cap' structure and thus potential inhibitors of translation in eukaryotes.lW For (101) and (103),2',3'-
Organophosphorus Chemistry
196 y
Me
2
0
Rib -_P_P HO
(1001
H2°6 2'
OH
(101) R = H (102) R = N H z (103) R = M e
pu
H206 HO
(10.4)
NH2
( 1 05)
HO
CONH2
HO COOH
(1061
0
S
II P-0I
(Ado-5'1-0-
II P-X I
0-
0
S
I
I
II -P-O-
0-
0-
II P-0
0-
(108) X = 0 (109) X = C H z
N % N > W C H zOH O - OH i'-OH
H Z N AN
N
0
II
OH
1110)
-(Ado
-5')
6: Nucleotides and Nucleic Acids
197
QQ-isopropylideneguanosine was coupled to phosphorous acid and methylphosphonic acid respectively using carbodiimides, the guanosine rings being methylated following acidic deblocking. The phosphoramidate (102) was obtained by coupling GMP with ammonia using DCC, followed by ring methylation. The acycloguanosine analogue of (103) was also prepared, together with &methyl- and 8amino-N7-methyl-GMP. The H-phosphonate and methylphosphonates (but not the phosphoramidate) displayed lessened activity as inhibitors compared to "-methylGMP, suggesting that the protein binding site may require an H-bond receptor site on the phosphate group, while 8-amino-N7-methyl-GMP, with predominantly anti conformation, was a stronger inhibitor than 8,N7-dimethyl-GMP, with wconformation. 'Cap' analogues have been used to show that the presence of a cap structure in mRNA precursors with two introns selectively promotes the efficient splicing out of the upstream (proximal) intron.105 CTP Synthetase from Ehrlich ascites tumour cells catalyses the formation of N4-hydroxy-CTP and N4-methoxy-CTP from Vm and hydroxylamine and methoxyamine, respectively, in the presence of ATP and magnesium ions.lM The range of acceptable substrates suggests that nucleophilicity and basicity of the attacking amine are critical determinants in the reaction. A number of 5-substituted analogues of U-UTP have been prepared by conventional phosphor ylation of the corresponding nucleosides and tested for their ability to inhibit DNA polymerase from salmon testes, and five bearing styryl or substituted styryl groups were found to display strong, selective inhibitory acti~ity.10~ In a review on 'Radicals in Biological Catalysis', Stubbe has laid pardonable emphasis on her distinguished work with the ribonucleotide reductases.lo8 Examination of the products of inactivation of ribonucleoside diphosphate reductase from E. coIi using 2-azido-2'-deoxy-UDP variously labelled in the pyrophosphate group (32P), at the 3'- and 5'-hydrogens (3H) and in the azido group ('5N) has led to the proposal that abstraction of a hydrogen radical from 3'-C-H occurs initially to give (1041, the azide group acting as a radical trap and decomposing with loss of nitrogen gas to give a stabilized radical which gains a hydrogen atom to form (105) (or a tautomer thereof).lOg Sequential loss of uracil and pyrophosphate from (105) follow logically and generate a Michael acceptor which alkylates the enzyme stoicheiometrically to inactivate it. In further investigation of the process of inactivation of ribonucleoside triphosphate reductase from Lacfobacillus leichrnanii by 2'-chloro-2'-deoxy-UTP using the 5I-tritiated nucleotide, the chromophore which is formed during the process has been identified tentatively as a p-aminoenone structure, formed by reaction of the enzyme with a methylenefuranone Michael acceptor generated by breakdown of the nucleotide.110 Chemically, reductive chlorination of phosphate- and sugarprotected dinucleotides containing 2'-chloro-2'-deoxyuridine to the corresponding 2'-deoxyuridine species has been accomplished using tri-n-butyltin hydride in the
198
Organ oph osph orus Chemistry
presence of A I B N . ~ ~ ~ 2'-Amino-2'-deoxy-GDP has been prepared by phosphorylating the parent nucleoside with phosphoryl chloride in aqueous triethylphosphate, treating the 2'amino-2'-deoxy-GMP obtained with guanylate kinase, pyruvate kinase, PEP and a catalytic quantity of ATP, and finally hydrolysing the 2-amino-2'-deoxy-GTP product with myosin subfragment 1 to give the diphosphate.ll* After condensation with fluoresceamine in acetone, the fluorescent product (106) proved to bind tightly to elongation factor Tu from E . coli, permitting time-resolved fluorescence studies to be performed, and appears likely to have general utility in probing guanosine nucleotide-dependent systems. The a-and p-anomers of nicotinamidearabinoside adenine dinucleotide have been prepared by phosphorylation of the mixture of epimers (107) of nicotinamidearabinoside with phosphoryl chloride as above, acetylation of the 5'monophosphate obtained to protect the sugar residue, and condensation with AMP using diphenylphosphorochloridate.l~3 The a- and P-anomers of --NAD+ obtained had slightly different standard redox potentials and absorption maxima, but both were coenzymes for alcohol dehydrogenases from yeast and horse liver. Carbanicotinamide adenine dinucleotide, in which the D-ribose ring attached to nicotinamide is replaced by the corresponding carbocycle, has been prepared by an essentially similar route except that di(n-buty1)phosphinothioyl bromide was used to activate AMP in the coupling r e a ~ t i 0 n . IIt~ ~ is also a substrate for the above dehydrogenases, while the L-analogue (which was also prepared) is not. CarbaNAD+ is resistant to cleavage by NAD+ glycohydrolase. r1-5'-Uridine-P2-glucos-6-yl pyrophosphate, prepared by treating uridine 5'-phosphoromorpholidate with glucose-6-phosphate, inactivates UDP-D-galactose-4-epimerase irreversibly by reducing enzyme-bound NAD+ to NADH.lI5 The dependence of this process on pH has been used to derive a pKa value of about 6.1 for a group on the enzyme required for the catalytic process. CDP-Abequose has been prepared by activating CMP with diphenylphosphorochloridate followed by treatment with a-abequosyl phosphate, and the reactivity of various N-N_-carbonylbis(azoles) in the synthesis of NDPsugars has been examined.116 The substrate behaviour and inhibitory properties of a variety of modified nucleoside 5'-triphosphates with respect to human, bacterial and viral DNA polymerases and viral reverse transcriptases have been investigated in a number of studies. 2',3'-Dideoxy-2',3'-didehydro-'ITP acts as a chain termination substrate for DNA synthesis catalysed by E . coli DNA polymerase I KF, rat liver DNA polymerase p, and viral reverse transcriptases, but does not affect DNA synthesis catalysed by DNA polymerase a.1173'-Azido- and 3'-amino-(E)-5-bromovinyl-2'-deoxyuridine5'-triphosphate displayed largely similar behaviour.118 2',3'-Dideoxythymidine-Striphosphate, its 2'-3'-didehydro derivative (as above), and 3'-fluoro- and 3'-azidod'ITp are all powerful inhibitors of HIV reverse transcriptase, and relatively poor
6: Nudeorides and Nucleic Acids
199
inhibitors of cellular DNA polymerase a and (to a lesser degree) DNA polymerase p.lI9 The insertion and extension of acyclic, dideoxy and m-nucleotides in DNA chains by herpesviral and cellular DNA polymerases has been investigated.120 &nucleotides were inserted by human DNA polymerases with greater frequency than the other analogues, but acted as simple chain terminators, while viral DNA polymerases inserted mnucleotides less easily than the acyclic analogue 1,3dihydroxyprop-2-oxymethylguanine(DHPG) monophosphate but could extend the chain past single e-nucleotide insertions. The viral polymerases stalled after adding DHPG monophosphate and one additional nucleotide. Acyclic nucleotides were poorly incorporated by the human DNA polymerases a and p. El, E n-Dinucleosidyl-5' polyphosphates continue to attract much attention.
P1,P4-Bis(adenosine-5')-tetraphosphate (A(5')ppppA) and its triphosphate analogue are stored in human platelets and on platelet activation are released into the blood where they are long-lived signal molecules regulating platelet aggregation.l2l Both may be synthesized using leucyl-tRNA from Bacillus stearofherrnophilus together with leucine and ATP, the leucyl-AMP formed being attacked by ATP to give A(5')ppppA, while attack by adventitious ADP gives rise to A ( 5 ' ) ~ p p A . lThis ~~ latter reaction may be suppressed by addition of acetate kinase, acetyl phosphate and adenylate kinase to convert any ADP present to ATP, and if pyrophosphatase is also added to prevent the back-reaction of leucyl-AMP formation, A(5')ppppA can be prepared in high yield. A new possible in vivo route to this compound may have been defined with the disclosure that diadenosine 5',5"'-p1,c4-tetraphosphate or,@phosphorylase from yeast forms A(5')ppppA from ADP and ATP, i.e. by reversal of the phosphorolysis reaction which it catalyzes.123 In fact the enzyme can bind ATP or GTP at the triphosphate site and ADP, CDP, UDP, GDP or dADP at the diphosphate site, and thus produce a range of N(5')ppppN' species. It is thought that a new set of bis(5'-nucleosidyl)tetraphosphates of this type (N and N' = C, G or U) identified in Saccharomyces cerevisine and E . coli may have been formed in this way.124 Moreover the yeast enzyme can utilize adenosine 5'-phosphosulphate as substrate, the sulphate group being displaced irreversibly by ATP to form A(5')ppppA, or, if alternative substrates adenosine 5'-tetraphosphate, adenosine 5'(ap-methy1ene)triphosphateor adenosine 5'-(py-methylene)triphosphateare bound in place of ATP, A(5')pppppA, A(5')ppp[CH2lpA or A(5')pp[CH2lppA respectively.125 The latter two compounds, and also A(5')pp[CHBr]ppA are all substrates for A(5')ppppA hydrolase and phosphodiesterase I from lupin, but not for the bacterial hydrolase, and only A(5')ppp[CH2lpAis degraded by yeast A(5')ppppA phosphorylase, although all three analogues (and, more weakly, A(5'>p[CH2lpp[CHzlpA)are competitive inhibitors of all these enzymes.' 26 Methylenediphosphonate is a powerful growth inhibitor for the slime mould Dictyosteliurn discoidewm, and 31P n.m.r. investigations indicate that adenosine 5'(py-methyleneltriphosphate and A(5')pp[CHzlppA accumulate in vivo at the
Organophosphorus Chemistry
200
expense of cellular nucleoside triphosphates when D. discoidam is exposed to the inhibitor.127 Treatment of adenosine 5'-phosphorothioate with diphenylphosphorochloridate and pyrophosphate affords A(5')p(s)pp(s)pA (108) as a mixture of stereoisomers, and replacement of pyrophosphate in this reaction by methylenediphosphonate gives the corresponding species (1091, separable with difficulty by reversed-phase h.p.1.c. to give the @p,Sp), @p,Rp) and @p,Sp> stereoisomers.128 Stereochemical assignments were made by using the known selective cleavage of (Bp) isomers of adenosine 5'-thiophosphoryl species by snake venom phosphodiesterase. All three stereoisomers of (1091, and to a lesser extent the mixture of unseparated stereoisomers of (108) were highly resistant to hydrolysis by the A(5')ppppA hydrolase from Artemia, compared with the parent compound. In the hydrolysis of (1081,however, some ADPaS was formed, suggesting that the enzyme does not catalyse hydrolysis exclusively at the Pa-O-Pp bridge. D-Neopterin 3'-monophosphate (I 10) has been prepared by condensing 4hydroxy-2,5,6-triaminopyrimidinedihydrochloride with D-ribose-5-monophosphate phenylhydrazone, and was subsequently protected at the hydroxy groups, converted to its triphosphate using carbonylbis (imidazole), deblocked and reduced to afford enzymically active D-7,8-dihydroneopterin-3'-triphosphate.129A range of 'openchain' nucleotide analogues have been investigated for their affinity for human purine nucleoside phosphorylase, the mono- and tri-phosphates of DHPG being particularly effective with lower affinities than those reported for the corresponding acyclovir analogues.*30 4. Olieo- and Polvnucleotides
4.1 Chemical Svnthesis. A book on the synthesis and application of DNA and RNAJ31 a review of the chemical synthesis of naturally-occurring DNA and FWA sequences with normal and unusual linkage~,'3~ and a review on the solid-phase synthesis of oligonucleotides by the phosphoramidite method,l33 have all appeared. Methoxydichlorophosphine, often required as an intermediate in the preparation of nucleosidyl phosphoramidites used in oligonucleotide synthesis, has been prepared conveniently by using the exchange reaction between trimethyl phosphite and phosphorus trichloride. An improved recipe for an iodine/ water reagent with better storage properties for use in the oxidation stage of oligonucleotide synthesis &a the 'phosphite' procedure has been described.135 In an investigation of the formation of a fluorescent species from deoxyguanosine residues in a conventional solid phase oligonucleotide synthetic procedure using (2-cyanoethyl)-N,Ndiisopropylphosphoramidite monomers, it was deduced that the guanine ring became phosphitylated at 0 6 , with subsequent reaction with 4dimethylaminopyridine (DMAP) used in the 'capping' stage leading to the formation of fluorescent (111) units.136 Upon exposure to ammonia at 550,
6: Nucleotides and Niicleic Acids
20 1
0
0 dRib (1111
(112)
*B
0
II
0-c--But
0 '
-c-
B "t
II
0
(11L)*B
(1131
GuaBu'; Thy; c y t B z
AdeBz;
R'O, P-
NPri2
R 20'
(115) X
= N-O
(117) R' = R 2 = CH,CH,CN (118) R' =CH2CH2CN; R 2 = L-CIC6H,CH2
u
(116) X = O E t ; OPr
I
T r OC H2CH
RS-P-0
I
I
SPh
PhNH
2- C I C6H40
(119) R = P h or L-MeOC6H4
@-
CONH ICH,),
NHCOICH,),
(120)
0
scH,cH,o
0
II - P-OR
1
0(121) R =CH2CH2CN (122) R = 4 - h y d r o x y a c r i d i n e
202
Organophosphorus Chemistry
dimethylaminopyridine was displaced to give 2,6-diaminopurine deoxyriboside, an observation which may explain the occasional formation of 2,6-diaminopurine residues in synthetic oligonucleotides. The use of N-methylimidazole in place of DMAP caused suppression of this side-reaction. In an investigation of the desirability of protecting the amide functions of thymine and guanine rings in solid phase oligodeoxyribonucleotidesynthesis using phosphoramidites as above, it was found that there was no experimentally detectable difference in the quality of the oligonucleotides obtained using amide-protected and non-protected monomers so long as the coupling time was kept low - about 30 seconds.137 Using longer coupling times, protection of guanine at 0 6 offered sufficient advantage to justify the extra synthetic effort. In large-scale oligodeoxyribonucleotide synthesis on controlled-pore glass (CPG) using protected 2'-deoxynucleoside-3'-~-phosphonates as addition monomers and pivaloyl chloride as coupling agent, coupling yields of about 93% could be obtained with as little as two equivalent of the deoxynucleoside H-phosphonate, but a capping step was found desirable since self-capping was inefficient.l38 A capping step with 2-cyanoethyl-H-phosphonateand pivaloyl chloride was therefore used, with the result that, after deprotection, the failure sequences bore 5'-phosphate groups, facilitating separation. Others have preferred I-adamantanecarbonyl chloride to pivaloyl chloride on the grounds of its greater stability, and have used this reagent with isopropyl-H-phosphonate in a capping procedure.139 Investigation by 31P n.m.r. of the mechanism of hydrogen phosphonate diester formation using pivaloyl chloride as coupling agent indicates that H-phosphonoacyl mixed anhydrides of type (112) are formed initially in the presence of pyridine.140 A small amount of the symmetrical bis(nuc1eosidyl)H-pyrophosphonate may also form. These species react rapidly with hydroxy groups to form H-phosphonate diesters, but if allowed to react with excess pivaloyl chloride or to stand in pyridine, the bis(pivaloy1)nucleosidyl phosphite (113) is formed and the desired diesters are not then obtained. Preactivation of the u-phosphonate with pivaloyl chloride has been observed to depress coupling yields, presumably for this reason. Deoxyribonucleoside 3'-phosphordiamidites of type (1 14) have been prepared by treating the appropriately protected nucleoside with chlorodimorpholinophosphine in the presence of ethyldiis~propylamine.~~~ On treatment with a 3'-Q-methoxyacetyl-2'-deoxynucleoside and tetrazole, the dinucleosidyl phosphoromorpholidite (115) was formed, which was readily converted to the dinucleosidyl-H-phosphonatein aqueous tetrazole, or to the phosphite (116) using the appropriate alcohol. Conventional oxidation then afforded the corresponding P(V) species in each case. Alternatively, (114)could be coupled to the 5'-hydroxy group of a nucleoside immobilized on CPG, as part of a solid phase cycle, with a single oxidation step using aqueous iodine (for phosphates) or sulphur in ethyldiisopropylamine (for thiophosphates) being performed at the
6: Nucleoddes and Nucleic Acids
203
conclusion of the chain elongation steps. Nona(deoxythymidylate1 containing exclusively phosphorothioate links was prepared in this way. The use of TPS-cl and 4-dimethylaminopyridine-I-oxideas condensing agent in a rapid automated solid phase synthesis on silica gel has been described.'** The use of the 4-decyloxytrityl group in place of the dimethoxytrityl group in oligonucleotide synthesis has been found to aid reversed-phase h.p.1.c. purification of oligonucleotides of up to 140 residues in length.143 The phosphoramidites (117) and (118), prepared by conventional means, have been used for the 5'-phosphitylation of detritylated protected oligonucleotides attached to solid supports, after which oxidation and deblocking (the chlorobenzyl, group was removed with thiophenol) afforded the 5'-phosphorylated o l i g o n ~ c l e o t i d e s .Alternatively, ~~~ 5'-terminal phosphate groups have been introduced by coupling 5-phenylphosphoranilidothioateor 5phenylphosphoranisidothioate to a protected nucleoside 3'- 55-diphenylphosphorodithioate species using mesitylene-1,3-disulphonylchlorideto give (119), which was then extended in the 3'-direction using methods previously described in these Reports.145 3'-Q-Benzoyl-2'-deoxythymidine 5'-(2-chlorophenyl)phosphate has been coupled to lipophilic secondary amines using TPScl and Nmethylimidazole to afford species such as (l2O).146 An oligonucleotide bearing a similarly constructed lipophilic 5'-phosphoramidate moiety was synthesized on a polystyrene support, partially unblocked, and readily isolated using a reversed-phase column before acidic cleavage of the phosphoramidate. In a different approach to the solid-phase synthesis of oligonucleotides bearing 5'-phosphate groups, 2cyanoethylphosphate was coupled to a functionalised polyacrylamido acryloylsarcosine methyl ester using DCC to give (1211, which was then coupled to 4hydroxyacridine using MS-nt and the cyanoethyl group then eliminated to give (122).147 This was subsequently used as the template for the assembly of an oligodeoxyribonucleotidein the 5'3' direction by standard phosphotriester methods, the product being released from the solid phase by oxidation to the sulphone using NCS, followed by p-elimination. Methods for the preparation of oligonucleotides bearing a 3'-terminal phosphate group using phosphotriester synthesis have been examined, the synthesis of oligodeoxyribonucleotidesbearing a 3'-terminal uridine residue which was subsequently removed by periodate oxidation and p-elimination being an effective procedure.148 5'-Q-Dimethoxytri tyl-
~-acyl-2'-deoxynucleoside-3'-(2-cyanoethyl)(~-methyl)phosphorothioates have been prepared as monomer units for the synthesis of oligonucleotides in solution by the phosphotriester method, apparently without the need for chromatographic separation of intermediates.149 The use of polyethyleneglycol (PEG) as a soluble polymeric support for liquid-phase oligodeoxyribonucleotidesynthesis by the phosphotriester method has been proposed.150 The 3'-terminus is immobilized as in (1231, detritylated, and a standard phosphotriester protocol used, the PEG-bound
Organ o ph osph orus Chemistry
204
kH B
DM Tr 0
00 C.C H2CH2COO@ OCsH4CI - 2
(123)
( 1 2 4 ) R = H , B = Thy o r Gua; R-OBz, B = U r a
0
CF3CONH (C H2),0
-PI
- PII I
Of01igo- 5')
HSCH,CH,CONH CH,C H20
N Pr i p
OCH,CH,CN
0-
(1251
I1261
0
II 1
ln-O-
Ar3C-X-(CH2
P-0-
2-C I C,H40
H
1130) X = NH; Ar3C = MMTr, DMTr or P i x y l ; n = 6 (131) X = S; Ar,C Tr; n = 3 or 6 *B
osi S-
OC6HiCI-2 (1321
S(CH,),OH
MMTrO&O-~-OR'
* (133) B = AdeB:
N R2 R 3
CytB: Ura; S i = Bu'Me2Si; R 1 = Me or CH2CH,CN; R2, R3 = I C H 2 C H 2 ) 2 0 or P r ' o r * B =GuaBz; Si = Prl,Si; R', RZ, R3 a s above ,
1134) A n = A n i s o y l
6: Nucleotides and Nucleic Acids
205
oligonucleotide being precipitated with ether after each coupling cycle. Much effort is being expended on the synthesis and application of oligodeoxyribonucleotide probes of DNA sequence, and a review of analytical strategies for their use is timely.151 Several methods for the synthesis of DNA fragments linked to a solid support have been d e ~ c r i b e d . 1 5Nucleotidyl ~~ units (124) are converted to their 4- or 6-(1H-1,2,4-triazole) derivatives using 2chlorophenylphosphorodichloridateand triazole, and then immobilized by treatment with aminoalkylated silica, or polyacrylmorpholide or (best) CPG. The immobilized monomer is then used as the initiation site for conventional oligonucleotide synthesis.152 Unfortunately, any failure sequences which arise are also immobilized indiscriminately. Alternatively protected heptanucleotides containing 5-methyl-4-triazolylpyrimidin-2-one-l-(~-D-2'-deoxyribofuranoside) in the sequence may be treated with 1,6-diaminohexane, deblocked, and added to Sepharose 4B bearing a hexanoate spacer activated as its N-hydroxysuccinimide ester. Oligodeoxyribonucleotides bearing 5'-primary amino groups have been prepared by using (125) in the terminal stage of a solid-phase synthesis using pho~phoramidites.15~ After oxidation and deblocking, the primary amino group was treated with succinic anhydride to introduce a 5'-carboxylate terminus, or dithiobis(succinimidy1propionate) followed by DTE to introduce a thiol terminus (126) in order to permit immobilization on solid supports containing 4chloromercuribenzoate or activated thiol groups. Direct chemical synthesis in the 3'-direction on polystyrene resin by the phosphotriester method to form, eventually, immobilized unprotected oligomers has also been described.154 Lipophilic protecting groups have been coupled to 3'-Q-protected-2'-deoxythymidine-5'-(2chlorophenyl) phosphate by standard methods, giving (127)and (128).155 Acidic detritylation of (127)was rapid compared with phosphoramidate hydrolysis, but the latter process speeded up as n_ increased. Compounds (128) were used to prepare oligonucleotides with an aliphatic amino group attached to the S'-phosphate, as also was (129) (with 3'-Qlaevulinoyl protection), prepared via Appel reaction of the 5'phosphoranilidate to introduce the sulphur atom, followed by alkylation. 6Aminohexan-1-01, 3-mercaptopropan-1-01, and 6-mercaptohexan-1-01, protected at their respective nitrogen and sulphur atoms, have been treated with 2-chloro-5,6benzo-1,3,2-phosphorin-4-one and the products hydrolysed without isolation, affording the H-phosphonates (130) and (13Q.156 These were coupled to the 5'hydroxyl termini of synthetic protected oligodeoxyribonucleotides on solid supports using pivaloyl chloride or adamantoyl chloride as coupling agents to afford, after deblocking, oligonucleotides bearing derivatizable amino or thiol groups at the 5'terminus. The same protected amino- and mercaptoalcohols were also used to prepare phosphoramidite species analogues to (125)and used for the same purpose. Oligodeoxyribonucleotides with thiol groups attached to the 3'-termini have been prepared, for instance, by treating 5'-Q-dimethoxytrityl-2-deoxythymidine
206
Organophosphorus Chemistry
successively with 2-chlorophenyl phosphoro-bis(1-benzotriazolide)and 3,3'dithiopropanol to afford (132), which was coupled via a succinate linker to aminopropyl-CPG and used as the 3'-terminus in synthesis of the 01igomer.l~~ Deprotection followed by cleavage of the disulphide with D l T afforded the 3'thiolated oligonucleotide for further derivatization. The automated chemical synthesis of long oligoribonucleotides on CPG using 2'-Q-silylated-3'-Q-phosphoramidites (133) has been described.l58 The diisopropylphosphoramidites reacted faster, due to their readier activation by tetrazole, and the cyanoethyl group was easier to remove than the methyl group, though offering no significant advantage in the quality of the final sequence. The silyl protection was reported to be adequately stable in the conditions used in the synthetic cycles. The presence of 4dimethylaminopyridine has been found to enhance the coupling efficiency observed using phosphoramidites in the presence of tetrazoles, consistent with the proposed attack by tetrazole on a protonated phosphoramidite as the mechanism involved, and the use of mixtures of DMAP with 544-nitrophenyl) tetrazole has been reported as particularly effective, giving better than 96% coupling yields after three minutes reaction time.159 Other groups have also described protocols for solid phase oligoribonucleotide synthesis using protected nucleoside 3'-(2-cyanoethyl)N,~-diisopropylphosphoramidites,but used protection of the sugar 5'-hydroxy pixy11at161or (4-metho~y)phenylxanthen-9-y1~6~ group, and tetrahydropyranyl161 or 1-[(2-chloro-4-methyl)phenyl1-4methoxypiperidin-4-ylla protection of the 2-hydroxy group. The bases were protected variously but protection of the imide functions of uracil and guanine was performed in each case. The internucleotidic 2',3',5'-phosphotriester (134)has been prepared as a model for the putative intermediate formed in oligoribonucleotide synthesis if accidental loss of a protecting group from the 2'-hydroxy function is followed by transesterification with loss of the phosphate-protecting group.162 Upon deblocking (134)with ammonia, the internucleotidic bonds were cleaved fully, suggesting that any 2'-5'-internucleotidic linkages formed do not survive treatment with ammonia under normal deprotection conditions, and thus that such isomerized linkages are unlikely to be found in oligoribonucleotide products. Another description of oligoribonucleotide synthesis on a polymer support employed cellulose acetate functionalised with a 4-(2-hydroxyethylsulphonyl) dihydrocinnamoyl spacer, and block coupling of protected oligoribonucleotides by conventional phosphotriester methods.'63 A fragment of mRNA has been prepared using phosphotriester chemistry and a novel combination of protecting groups: 3rnethoxy-l$-dicarbomethoxypentane-3-ylfor the 2-hydroxy function, 944octadecylphenyl)xanthen-9-y1for the 5'-hydroxy function, and the 6-methyl-3pyridyl group to protect the 04-and @-functions of uridine and guanosine.Ia In a comparison of oligoribonucleotide syntheses V J the phosphotriester and phosphoramidite methods on aminopropyl silica, the latter method was favoured
h: Nncleorides and Nuclric Acids
207
on the grounds of speed and efficiency.165 Solid phase oligoribonucleotide synthesis on long chain alkylamine-CPG using a-phosphonate chemistry, pivaloyl chloride as activating agent, and the 2-nitrobenzyl group to protect the 2'-hydroxy function has also been described.166 As usual, a number of novel protecting groups for use in oligonucleotide synthesis have been described. The 1,1,1,3,3,3-hexafluoro-2-propylgroup has been introduced for the protection of internucleotidic phosphate during oligodeoxyribonucleotide synthesis using the phosphoramidite approach.167 It is readily removed using oximate. Nucleoside 3'-phosphoramidites of type (135) have been prepared for oligodeoxyribonucleotidesynthesis.168 Since the amino functions on the bases are all protected by 2,2,2-trichloro-1,1-dimethyloxycarbonyl groups also,. it is envisaged that at the completion of oligonucleotide assembly, the bases and phosphates can be unblocked by a single treatment with copper (I) phthalocyanine. The full paper on oligonucleotide synthesis via deoxynucleoside 3'4-5diphenylphosphorodithioates, in which the phenylthio group protects the internucleotide link, has now appeared.169 The fluorescent l,l-bis(4-methoxyphenyl)-l'-pyrenylmethylgroup has been used to protect the 5'-hydroxy function of 2'-deoxythymidine in constructing the phosphoramidite (136) and the phosphonamidite (137).170 These were then used, respectively, in the final coupling stages of oligonucleotide syntheses performed using cyanoethyl phosphoramidites or methylphosphonamidites, so that only the completed sequences bore the fluorescent group. Upon cleavage from the support, the lipophilic group facilitated separation by reversed phase h.p.1.c. from the nonfluorescent failure sequences, and was then removed readily using acetic acid. ~~-Bis(2-oxo-3-oxazolidinyl)-phosphorodiamidic chloride was a convenient reagent for the regioselective acylation of baseprotected 2'-deoxynucleosides by carboxylic acids at the 5'-position, prior to their further derivatization for use in oligonucleotide ~ y n t h e s i s . 1 The ~ ~ (buty1thio)carbonylgroup, introduced using (buty1thio)carbonyl chloride and ethyldiisopropylamine, has been used to protect both the N2-amino group and the 0 6 of the amide function of guanine and N3 of the imide function of uracil during oligoribonucleotide synthesis by a phosphotriester procedure, in which (5-chloro-8-quinolyl)-(2,6dichloropheny1)phosphorochloridate was used to prepare the monomer nucleotide uni ts.172*l73 The (buty1thio)carbonyl group was removed using methanolic ammonia. In a new method for preparing 'capped' oligoribonucleotides, 2'.3'--methoxymethylidene-N2-trimethoxytritylguanosine has been phosphorylated using s,S-diphenylphosphorodithioateand isodurenebis(sulphony1 chloride), after which reductive removal of one phenylthio group using hypophosphite followed by methylation at N7 afforded (138). Treatment of (138) with silver ions in the presence of orthophosphate gave the diphosphate (139), which was coupled to
208
Organophosphorus Chernis try OMe
"B
BH
D M T r O a 0 - P-
I
0-
NMe2
P -NPr
I
l2
R
OC MezCCI,
/
/
(136) R = O M e (137) R = Me
(1351
NHTMTr
0
0
HXOMe (138)R=PhS; n = 1 (139)R=OH; n = 2 DMTrO
0
A 1
O
N-P-
u
1LO)
DMTrO(CH,),,O
- P-
I
OCH,CH,C N
( 1 L 2 ) n = 2 or 3
OCH2CH,CN
209
6: Nucleotides and Nucleic Acids
pGpUpApUpUpA (protected at the internal 2'-hydroxy functions with the tetrahydropyranyl group and activated at the 5'-terminal phosphate using carbonylbis(imidazo1e)) to give m7G(5')pppGUAUUA, after deb10cking.I~~The synthesis of the branched oligonucleotides encountered at the ring junction in 'lariat RNA', in which an adenosine residue forms 2'-5'- and 3'-5'-phosphodiester links simultaneously, has gain drawn attention, and the syntheses, combining Tp5'G
phosphoramidite and phosphotriester methods, of Ayp5#cand two analogues with 2p5'C
different purine bases in place of guanine,l75 and N1pAypyN* (N1 = U or A, N2
=U
or C)I76 present nice examples of the art of synthesis of oligonucleotides of unusual structure. IH and 31P n.m.r. studies on these and similar compounds indicate that adenine (2'-5') nucleobase stacking is the principal feature determining secondary structure in the branched triribonucleotides, but that the branched tetraribonucleotides form a distorted A-RNA helical conformation without 2p5'G
appreciable 2' + 5' stacking. In yet another synthesis, to form CpUpGpAg*p5sc,the adenosine 2-bis(thiophenyl)phosphate-3'-bis(anilido)phosphate(140) was formed initially, and the capacity for selective removal of the phenylthio and anilido groups used in constructing the desired internucleotidic links.178 Among other oligoribonucleotides less remarkable for their primary structures but interesting on account of the properties of their secondary structures, several self-cleaving RNA duplexes have been constructed using synthetic 21-mers,*79and evidence has been presented that a 19-mer of deliberately designed sequence forms a stable 'pseudoknot' (a hairpin loop with some of the stem sequence folding back to basepair with some of the loop residues to form an additional stem and loop structure), a novel structural element which may occur naturally.180 In oligodeoxyribonucleotide synthesis, gene syntheses of interest include those for somatomedin Cl81, human tumour necrosis factorl82, and the interleukin2 receptor.183 A gene for cow colostrum trypsin inhibitor has been assembled by anchoring a 29-mer to CNBr-activated Sephacry1,then hybridizing triads or tetrads of separately annealed oligonucleotides successively to the immobilized sequence until the gene duplex was completed, hybridising further with a restriction sequence at one end of a linearised plasmid, and ligating the entire set of hybridized sequences en bloc using T4 polynucleotide kinase and DNA ligase.184 The entire construct was then released from the solid phase using a restriction enzyme, circularized, and used for transformation. A number of deoxyguanylate-rich fragments of the terminal sequence of macronuclear DNA from hypotrichous ciliates, up to d[(G4T&G41 in size, have been prepared by the solution phosphotriester method, with additional enzymatic ligation steps for the largest fragments.185 S-Q-Dimethoxytrityl-2'deoxycytidine-3'-(2-chlorophenyl) phosphate has been coupled to polyacrylamide
210
Organophosphorus Chernislry
functionalised to bear carboxy groups using DCC, in order to immobilise the nucleotide via the @amino group of the base.186 The immobilized nucleotide was then used to form immobilized oligodeoxycytidylates by conventional phosphotriester methods, and the groups protecting the 5'-hydroxy and 3'phosphate termini then removed and the oligomers cyclised using MS-nt. The cyclic oligodeoxyribonucleotides, cd(Cp)E] (g=2-7) were released from the support with ammonia, and found to be resistant to digestion by exonuclease I, but degraded fully by micrococcal and Sl endonucleases to give the expected products. A conventional phosphoramidite of structure identical to (115) but containing [6-'3C] thymine as the base has been prepared and incorporated in a DNA hairpin loop sequence d(CGCG?TGTZTCGCG),in order to use NMR relaxation measurements to indicate possible internal motion in the l00p.187 2'-Deoxyuridine, labelled with carbon-13 in the 1'- and 3'-positions, has been used in preparing d(GCGUGCG) and d(CCGUGCC).188When annealed to its complementary oligodeoxyribonucleotide,the latter sequence afforded NMR ('H and l3C) data consistent with the presence of two slowly interconverting oligonucleotide conformations, while the former sequence did not. The d(GCGUGCG1 was incubated with uracil-DNA glycosylase to remove the uracil base, and mixed with complementary heptamers so that each of the four possible bases was situated opposite the abasic site.189 NMR data indicated that the abasic site was populated by roughly equal amounts of both anomers of the hemiacetal, with no significant contribution from the aldehyde or its hydrate. Duplexes with cytosine or guanine opposite the abasic site did not appear to form. Oligonucleotides up to 18-mers of lac operator sequence containing nitrogen -15 at N4 of cytosine and N6 of adenine have also been prepared in order to measure 15N n.m.r. data.l90 Hybrids containing a deoxyribonucleotide oligomer linked to a ribonucleotide oligomer have been prepared by a conventional combination of the methods of synthesis usually employed for each type of oligomer.191 As usual, oligonucleotides containing modified base or sugar residues have been synthesized. Thus, m-cytidine has been incorporated into oligodeoxyribonucleotides,l~~ and so have 5,6-dihydr0thyminel9~ (which was extremely labile to alkali), N4-methoxycytosine and N4-methoxy-5methylcytosine,l93 N4-methylcytosine and 5-methyl~ytosine,19~ putrescinylthymine,l95 5-bromouraci1193~1965-cyanouracil and 5-ethyluracil.196 In most cases the effect on duplex stability or enzyme susceptibility of the introduction of the base analogue was studied. Oligonucleotides containing abasic sites have also been synthesized either (as above)l89 by preparing a uracil-containing sequence which was treated with uracil DNA-glycosylase (the resultant oligomers being cleaved very readily by base at the abasic sites)197 or by incorporating a derivatized tetrahydrofuran (141) or alkane (142) in the course of solid-phase synthesis.198 Some DNA polymerases were blocked initially when using strands containing abasic sites
6: Nucleotides and Nucleic Acids
21 1
derived from (141)and (142) as templates, but subsequently read through the abasic sites with dAMP being inserted most commonly opposite the gap. Two complementary nona(2'-Q-methyl)ribonucleotideshave been prepared using conventional solid-phase phosphotriester chemistry, and hybridisation studies indicated that compounds of this type may offer advantages over oligoribonucleotide probes in RNA hybridization.199 Variously derivatised 5'-Qdimethoxytrityl-2'-deoxyuridine-3'-(N,~-diisopropyl) methylphosphoramidites (143)?m (144),(145I2o1and (146)*02 have been prepared by conventional methods and used in oligonucleotide synthesis. Deblocking of oligonucleotides formed using (143)with ammonia released the 5-(3-aminopropyl) function which could be treated with ~-hydroxysuccinimidyl-5-azido-2-nitrobenzoate to introduce a photoaffinity label which was subsequently used to label T4 DNA polymerase and avian myeloblastosis virus (AMV) reverse transcriptase.200 Oligonucleotides formed using (144) and (145) were deblocked and conjugated with fluorescein isothiocyanate to introduce multiple fluorescent labels. More efficient hybridization was achieved using the oligonucleotides prepared using (145).201 Oligonucleotides prepared using (146)were deblocked with ammonia and treated with &T-biotinyl-6-aminocaproic acid N-hydroxysuccinimide ester. Oligonucleotides with biotin labels at or near the ends of hybridization sequences were more efficient hybridization probes than those with internal biotin labels.202 Oligonucleotides have been prepared similarly using the derivatised 2'-deoxycytidine species (147), deblocked, and the amino group coupled to fluorescent dyes, chemiluminescent species or enzymes (horseradish peroxidase or alkaline phosphatase) as 'reporter groups' for hybridization probes.203 The enzyme-coupled probes afforded sensitivity in hybridization assays comparable to that attained using phosphorus-32. Oligonucleotide syntheses involving atypical nucleosides have included residues and 2'-5' internucleotidic octamers containing 3'-chloro-3'-deoxyuridine links,2M and oligodeoxyribonucleotides containing 5-fluoro-2'-deoxyuridine residues which may base-pair efficiently with either adenine or guanine bases on a complementary strand and thus afford a simplification in the synthesis of hybridization probes for screening gene libraries.205 2'-Deoxyinosine may be used similarly to base-pair to cytosine or adenine residues, and oligonucleotides containing 2'-deoxyinosine have been prepared to study this hybridization.206 Oligonucleotides containing l-(2-deoxy-~-D-ribofuranosyl)-2-oxo-4-imidazoline-4carboxamide (148) residues have also been prepared as possible alternatives to the mixed probe m e t h ~ d . ~The O ~ base of (148)shows promise as a substituent for thymine or cytosine residues at positions where the sequence is ambiguous, but appears a poor replacement for purine bases. 5-Carbamoyl-2'-deoxyuridine, investigated for the same purpose, caused considerable destabilization of the duplex, 2-Aminopurine deoxyriboside has been introduced into oligonucleotides using its protected 3'-(2-cyanoethyl)~.N-diisopropylphosphoramidite, and complementary
Organ oph osp h orus Chemistry
212
0
0
1
MeO-P-NPr'Z 0
(144) (lh5) (146)
R = C=C-CH2NHBoc R = C=C-CH2NHCO(CH2)5NHBOC R = CH=CHCH,NHCOCF3
N9
';J H (CH2)2NHCO (CH 2)5NHCOC F3
o&coNH* N DMTro$
1
0
dRib
I
RO-P-NPrI2 ( 1 L 7 ) R = M e or CH,CH,CN
I
OMe
(CH,I,NHCO(CH,),CO
6: Nucleotides and Nucleic Acids
213
oligonucleotides containing 2-aminopurine opposite a cytosine base were found significantly destabilized in comparison with otherwise identical sequences in which 2-aminopurine was opposite thymine.208 A self-complementary hexanucleotide containing two 6,2'-Qcyclocytidine residues and two 8,2'-Qcycloguanosine residues has been prepared by phosphotriester methods, and spectroscopic data suggests that it adopts a left-handed double helical structure with a 'high-anti' glycosidic conformation.209 S-Q-Dimethoxytrityl-2'-deoxy-l-~6ethenoadenosine-3'-(2-chlorophenyl)phosphatehas been prepared and used to construct a hexamer containing a single 1,Nb-ethenoadenine base, which was ligated into the bacteriophage M13 genome to place the modified base specifically at the A site of an amber codon.210 The rate of restriction cleavage at the site by Nhe I was markedly diminished by the modification. The incorporation of 2'-deoxytubercidin and 7-deaza-2'-deoxyguanosineinto oligonucleotides their 3'-0phosphoramidites has been reviewed.2l A 13-mer containing 4-amino-l-(2'-deoxyP-D-ribofuranosyl)-2(1H)pyridinonehas been prepared.212 Oligodeoxyribonucleotides containing a 3'-peptide moiety have been prepared by assembling an oligopeptide on aminopropyl-CPG, acylating it to introduce a spacer terminating in a deblockable primary hydroxy group, and coupling this to a conventionally protected deoxynucleoside 3'-phosphoramidite to give (1491.213 This was then used as the support for solid phase synthesis of a 30-mer which, following deblocking and removal from CPG, proved fully resistant to snake venom phosphodiesterase and partially resistant to spleen phosphodiesterase and nuclease PI. Since the oligopeptide moiety was (Ala-tys)gAla, this suggests that a positively charged 3'-terminal peptide may confer resistance to hydrolysis upon the adjacent oligonucleotide sequence. 2'(3')-@Aminoacyl oligoribonucleotides of trimer to pentamer length have been prepared using the benzotriazolyl phosphotriester approach as models of the 3'-terminal sequence of aminoacyl-tRNA species, and found to be active as acceptor substrates in the peptidyltransferase reaction in a model system.214 Several compounds containing phosphoramidate and phosphodiester bonds, uridylyl(5'-+N)puromycin, dTp-Ser(pdC)-OMe and dTpDLAla-DLVal-Ser(pdC)-OMe have been prepared by DCC-mediated couplings as simple models of DNA fragments linked to peptides.215 The 2'-5'-linked oligoribonucleotide pppA(2')pA(2')pA(2')pA has been oxidised with periodate at the 3'-terminal ribose, condensed with P-alanyltyrosine methyl ester, and the resulting conjugate reduced with sodium cyanoborohydride to introduce a stable palanyltyrosine 'tai1'.216 The presence of this moiety increased the stability of the 5'triphosphate group to phosphatases, and the stability of the internucleotidic bonds to 2'-5'-phosphodiesterase,and the conjugate inhibited protein synthesis in mouse L, cells more efficiently than unmodified '2-5A.
2 14
Organophosphorus Chemistry
Oligodeoxyribonucleotides formed from a-nucleosides are currently exciting a great deal of interest. They may be prepared using regular solid-phase phosphoramidite217 or phosphotriester techniques,218-220and have been linked to intercalating agents by various p r o c e d ~ r e s . ~ ~ 9These - ~ ~ 5have included condensation of 6-chloro-2-methoxy-9-(5-hydroxypentylamino)acridine with protected a-oligodeoxyribonucleotidesat termini bearing 3‘- and 5’-phosphate groups219~220~224~25 and alkylation of oligo([al-2’-deoxy-thymidylate) species bearing thiophosphate groups at their 5’- or 3’-termini using 3-azido-6-(3bromopropy1amino)acridine or 3-amino-6-(3-bromopropylamino)acridine.~~~~~~~ The alkylation procedure has also been used to introduce 4-azidophenacyl, acridinylpentyl, and 5-amino-(l,1O-phenanthrolinyl)groups at thiophosphate termini attached to oligo([~l-2’-deoxythymidylate)226, and the 4-azidophenacyl group similarly in a-o~tadeoxythymidylates.2~~ The oligo-[a]-deoxynucleotidesform stable right-handed double helices with parallel strands with complementary oligo-[p]deoxynucleotide~.~~8.219,228 The nucleotide units have anti conformation with 3’exo sugar puckering and participate in Watson-Crick base pairing. Also, aoligodeoxyribonucleotides bound more strongly to ribose-containing complementary oligonucleotides than to the analogous 2-deoxyribose-containing s p e c i e ~ . ~ ~Oligo(a-thymidylates) 0~~~9 were more resistant to endonucleases and exonucleases than the P-analogues, with terminal acridine groups giving added protection against exonuclease atta~k.220#~30 Hybridization of an RNA sequence with the complementary a-oligodeoxyribonucleotideprotected the RNA strand from digestion by RNase H.229 Photoactivable species linked to a-and poctadeoxythymidylates have been used to effect sequence-targeted photocrosslinking to duplex DNA containing a (dA)s ~ e q u e n c e . ~ ~ ~ ~ 2 Examination 2 3 , 2 ~ ~ of the pattern of chain breakage upon treatment with piperidine suggests that a triple helix is formed initially, with the photolabelling a-octamer in parallel orientation with the (dA)s sequence. Oligodeoxyribonucleotides covalently linked to intercalating agents and complementary to viral RNA, can be used to effect selective inhibition of the cytopathic effect of type A influenza viruses in cell culture,224 while a similar species complementary to rabbit globin mRNA blocked its translation in Xenopits oocytes more efficiently than the unsubstituted analogue, presumably indicating the extra stabilization of the mRNA-DNA hybrid due to stacking by the intercalator.225 The automated synthesis of oligodeoxyribonucleoside methylphosphonates has been improved by using nucleoside methylphosphonamidites (150) as starting m a t e r i a l ~ . ~These 3 ~ were formed by successive treatment of methyldichlorophosphine with diisopropylamine and the correspondingly protected nucleoside, and were employed in automated synthesis using the same conditions as employed for phosphoramidites. Deblocking of the assembled oligonucleoside methylphosphonate with ethanolic ethylenediamine caused a small amount of degradation of the internucleosidic phosphonate groups. Studies
21s
6: Nircleotides a r i d Nucleic Acids
Me (151)
(150)
Me
(152) m varies; n = 2 or 4 ; x = 0 or 1
0'
dRib
- 5'-_P_P_P
d R i b- 5 '-p _PI'
(155)
0
0 ' d R i b -5'-_PfR 1156)
Me Me
216
Urganoph osph orus Chemistry
with model compounds indicated that the presence of two consecutive methylphosphonate links at the ends of oligonucleotides confers protection to degradation by exonucleases. Duplexes of [GGAATKC] modified to contain either l3p or sp-methylphosphonate links variously between the GG and AA, AA and TT, or TT and CC residues, have been prepared using methyl (N.&Jdiisopropy1amino)chlorophosphine and their thermal stabilities and conformations studied.232 Duplexes containing sp-methylphosphonate links showed lower thermal stability than those with corresponding Ep links, the perturbation being greater for methylphosphonate links at the centre of the duplex. The data obtained were rationalised on the basis of electronic and steric effects. Similar studies involving also phosphorothioate and phosphotriester internucleotidic links have been described and surveyed.223 The hexamer d[(Tp)5lmethylated at the phosphate groups to form the internucleotidic methylphosphotriesters, appears to form a stable, parallel, right-handed duplex in aqueous solution.234 It thus appears that T-T base pairs can form if interstrand electrostatic repulsion is suppressed. Similarly, the Ep and s p isomers of (151) appear, from IH n.m.r. data, to form stable, symmetric, right-handed mini-duplexes with parallel sugar phosphate strands. Phosphorothioate analogues of oligodeoxyribonucleotideshave been found to inhibit replication and cytopathic effects of HIV, with homooligomers (1Cmer and 28-mer) of dCMPS being particularly effective, indeed more so than thiophosphorylated anti-sense sequences of the same length.235 The oligomers were thought to inhibit the synthesis of proviral HIV DNA. Physicochemical studies on a number of phosphorothioate-containingoligodeoxyribonucleotides indicated that while the presence of sulphur in the internucleotidic link generally stabilized it to attack by nucleases, poly (rA) hybridized to thiophosphorylated (dT)40 showed higher susceptibility to hydrolysis by RNase H than poly(rA) hybridized to (dT)40.236 The presence of thiophosphate links produced greater depression of thermal stability in A-T basepairs in DNA than in G-C base pairs, relative to nonthiophosphorylated controls. In a comparative study of the abilities of antisense oligonucleotide analogues containing alkylphosphotriester, methylphosphonate, or phosphorothioate linkages to inhibit expression of plasmid-directed chloramphenicol acetyltransferase gene activity in a cell line, the suppression of gene activity by a phosphorothioate-containing15-mer was twice as strong as that for the analogous oligo-(methylphosphonate) 15-mer, which in turn was more effective than 15-mers containing phosphodiester links alternating with methylphosphonate links, ethylphosphotriester links, or isopropylphosphotriester links.237. The photocrosslinking of oligodeoxyribonucleoside methylphosphonates linked at the 5'-terminus to 4-(aminoalkyl)-4,5',8-trimethylpsoralen(152) to synthetic 35-mer oligodeoxyribonucleotides containing the complementary sequence has been studied.*3* The rate and extent of cross-linking depended on the length of the aminoalkyl linker, the concentration of the oligomer, and the fidelity
6: Nucleotides and Nucleic Acids
217
of complementary basepairing between the methylphosphonate and target sequences. Oligodeoxyribonucleotide 15-mers containing 12 phosphoramidate links have been prepared by constructing a polymer-bound 13-mer containing twelve Hphosphonate linkages, oxidizing it using carbon tetrachloride and methylamine, dimethylamine, morpholine, or 2-methoxyethylamine to form the phosphoramidates and then performing two more rounds of coupling oxidizing with aqueous iodine to generate the 15-mer with two phosphodiester links at the 5'end.239 When hybridized to the complementary all-phosphodiester-linked oligomer, the analogues containing phosphoramidates derived from secondary amines formed the least stable duplexes (which may not have been fully hybridized) and those derived from primary amines formed less stable duplexes than the corresponding oligo(methy1phosphonate) sequences. In contrast to phosphodiestercontaining oligomers, the analogues showed little increase in stability of duplex formation with increasing ionic strength. A synthesis of the 2'-5'-linked 'core trimer' A2'pA2'pA by the phosphotriester approach using quinolinesulphonyl chloride and 3-nitrotriazole as condensing agent, and the 4-nitrophenylethyl group to protect phosphate, gave higher yields than using TPS-tet and 2-chlorophenyl for the same respective purposes.240 2'-5'-Linked oligoadenylates, mainly phosphorylated forms of A2'pA, have been shown to be present in E . coli under normal growth conditions, in concentrations which increase when bacterial growth is inhibited by viruses or c h l ~ r a r n p h e n i c o l .Analogues ~~~ of 2'-5A' (pppA2'pA2'pA) containing 3'deoxyadenosine in place of adenosine in the first (k. 5'-) or second or third residues respectively have been prepared by phosphotriester methods and tested for their ability to bind to and activate ribonuclease L.242 The 3'-OH group of the second residue was found to be required for efficient binding to RNase L, and essential for its activation, while replacement of the 3'-OH of the first and third residues by hydrogen had relatively little influence on these processes. The individual diastereoisomers of core trimer containing a thiophosphate link, i.9. A2'pA2'p(S)A, have been prepared by a modified phosphotriester method utilizing 2chlorophenylbis(6-trifluoromethyl-l-benzotriazolyl~phosphorothioate to introduce the thiophosphate link, separating the diastereoisomers of fully-protected A2'p(S)A by chromatography, and completing the synthesis using the same (but non-thiated) reagent.243 5'-Phosphate groups were subsequently introduced using 6trifluoromethyl-l-benzotriazolylphosphoromorpholidate. (sp)-ATPaS has been used as a substrate for 2-5 A synthetase from rabbit reticulocytes, affording 2'-5'phosphorothioate dimer and trimer analogues of 2-5A containing &p)internucleotidic links and (5p)-stereochemistry at Pa of the thiotriphosphate moiety.244 The dimer was able to bind to and activate RNase L (pppA2pA cannot), albeit more weakly than 2-5A, while the trimer showed similar activity to 2-5A.
Analogues of 2-5A bearing thiophosphate residues in the triphosphate chain have been prepared using (IXp)-ATPPS,&p)-ATPPS and ATPfi as substrates for the synthetase.245 While 2-5A thiophosphorylated at Pyor Pp (Sp) showed comparable activity to 2-5A in binding to and activating RNase L, the analogue with (Rp) stereochemistry at Pp showed markedly less activity in both these functions. In addition, (Ep)-ATPPS was a much poorer substrate for the synthetase than the other triphosphates. In a study of the activation of RNase L using the four diastereoisomeric phosphorothioate core trimer analogues and their 5'monophosphates, all four analogues (and their 5'-monophosphates) bound to RNase L, but the ratios of activation were g p R p : ~ p R p : E p ~ p : ~=p65:20:15:0.246 ~p The s p s p trimers were in fact powerful antagonists of activation, showing that activation of the RNase L is critically dependent on the stereochemistry at phosphorus, while binding is not. In another study in which both A T V and adenosine 5'-(~y-difluoromethylene)triphosphate were used as substrates for the synthetase, the resultant modified tetramer analogues of 2-5A were isolated and oxidized at the 3'-terminus with periodate, a step which affords a point for conjugation to poly (L-lysine) and also (on reduction of the oxidized terminus by cyanoborohydride) permits conferment of resistance to 3'-exonucleolytic degradation.247 The difluoro compound antagonized the activation of RNase L by the thiophosphate analogue when both were microinjected into HeLa cells. The polylysine-conjugated thiophosphate analogue showed increased stability in v i m compared with its non-thiated control. The authors felt that the narrow spectrum of antiviral activity of 2-5A will severely restrict its possible use in chemotherapy, but the disclosure248 that a viral reverse transcriptase is inhibited by 2'-5'-linked oligoadenylates seems likely to maintain interest in these compounds. Short oligocytidylates [C(pC)n;n = 4-71 are efficient templates for the oligomerization of guanosine 5'-phosphor(2-methyl)imidazolidate,giving distributions of products similar to those obtained on comparable oligodeoxycytidylates but with differences in the isomer rati0s.~~9 The reactions are less regiospecific than those observed using poly (C) templates. 3'-Amine3'-deoxyguanosine-5'-phosphorimidazolidateis oligomerised on a d[C(pC)q] template more rapidly and regiospecifically than related nucleotide derivatives by virtue of the greater nucleophilicity of the amino group, behaviour which may be useful in examining models of plausible prebiotic polymerization.250 The relative efficiencies of formation of phosphodiester, phosphoramidate, and pyrophosphate internucleotidic links between the terminus (OH, NHz or phosphate, respectively) of one oligodeoxyribonucleotide and the phosphorimidazolidate terminus of a second oligodeoxyribonucleotide,the two oligomers being hybridized to a complementary DNA template so that the termini to be joined lie adjacent, have been studied.251 Phosphoramidate and pyrophosphate links were formed with high efficiency, which fell appreciably if ribo-oligomers were ligated instead, or if a gap
6: Nucleotides and Nucleic Acids
219
was present between the termini to be ligated. Cyanogen bromide has been found to be an effective coupling agent for chemical ligations of this type within DNA duplexes, joining 3'-phosphate to 5'-OH with high efficiency, 3'-OH to 5'-phosphate with markedly lower efficiency, but also 3'-amino groups and 3'-phosphate groups to 5'-phosphates to give phosphoramide and pyrophosphate links, respectively, in good yields.252 A large excess of cyanogen bromide is used at 0" for 1-2 minutes, and by-product formation is reportedly minimal. The reagent may afford a useful alternative to water-soluble carbodiimides for certain coupling processes. As an alternative means of joining oligonucleotides on a complementary template, the S(Cnitropheny1)-,5'-(2-pyridyl)-,and 5'-(l-benzotriazolyl)- esters of d(pTCTAG) have been prepared, and using the benzotriazolyl derivative, ligation to the 3'-terminus of a 13-mer with expulsion of the leaving group was effected in N-methylimidazole b ~ f f e r . ~ 5The 3 activated esters were also used to prepare 5'-aminoacyl oligodeoxyribonucleotides. The relative efficiencies and abilities of l-ethyl-3dimethylaminopropylcarbodiimide(EDC) and DNA ligase in catalysing assembly of 35 base pair duplexes from synthetic oligonucleotides which formed adjacent complementary duplexes on template strands have been examined.254 Chemical ligation required that the duplex segments joined should be stable, while DNA ligase could join oligomers even under conditions of DNA duplex instability, but required a minimum duplex size of 9 - 15 basepairs. 4.2 Enzvmatic svnthesis. With the refinement of the Polymerase Chain Reaction (PCR), a formidable new procedure has been established.255 Suppose one wishes to copy (amplify) a gene sequence, replicating both strands simultaneously: DNA primers are synthesised chemically which are complementary to the 3'-ends, one on each template strand, which define the length of the sequence to be copied. The solution is heated and then cooled, permitting the primers to anneal to their DNA complementary sequences on the gene. The highly thermostable polymerase (from Thermus aauaticus) is then added, together with the necessary cofactors, and copy synthesis is allowed to proceed at 70°C (!). The solution is then reheated and re-cooled in the presence of the same primers as before, and on reannealing, the extension products of the primers used in the previous round(s) serve as templates for primer extension in the new round: each successive cycle of heat denaturation, annealing with primers, and polymerisation essentially doubles the amount of DNA synthesized in the previous cycle (Scheme I). The use of Taa DNA polymerase (the original method used DNA polymerase I from E . coli which was not thermostable and required to be replenished in each round of amplification) gives increased specificity, yield, and length of products (up to 2000 base pairs) which can be amplified. With 20 - 30 rounds of amplification, single-copy gene sequences can be amplified by factors of 106 - 109. Morever, the efficiency of PCR amplification is not substantially affected by the presence of sequences at the 5'-ends of the primers which are mismatched with the original template DNA, and thus modified
Organo p h osp h orus Chemistry
220
I
(I) Heat
(11) P r l m e r s (hm)
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 lLl~llo-
+
Cycle
1
I i I I I I 1 I I I I I I I I I l I I I l l l l l l l l ~
I
(1111
Polymerase
1 1 1 1 I I I I I I 1 I l l I I l l I Illlllllllll,-
+
0
I I I l I I I I I I I l 1 I I I I I I I I I I I I I I I ~
I I I i I 0
I
( I ) Heat
I 1 I I I II I I1 I 1 I 1 I
+
( 1 1 )P r i m e r s
IIIIII1lIllo-
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ,
+
Cycle 2
l l l l l l l l l l l l l l l l l l l l l l l ~ l l l l o ~
+
0
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 l l l l l l l l ~
I
(111) P o l y m e r a s e
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 I I I I I I I I I I I ~
+
0
l l l l l l l l l l l l l l l l l l l l l l l l l l l l o
0
l l l I l l I l l l l l l l l l l l l l l l l l l l I~~
0
l l l l l l l l l l l l l l l l l l l l l l l l l l l l ~
+
+
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Cycles 3 t o n
e t c . etc
Scheme
1
6: Nuckotides and Nucleic Acids
22 1
sequences involving nucleotide substitutions, deletions, insertions, regulatory elements or restriction site linkers may be introduced via the oligonucleotide primers. Not surprisingly, the method has been automated. A commercial instrument built in collaboration with Cetus Inc., the originators of the technique, is available,256 but directions for building low-cost laboratory amplifiers have also been published.257 The uses of the technique are legion, particularly in diagnostics: to give only a few examples, DNA sequences have been amplified to detect HIV-1 sequences,z8 cystic fibrosis?59 ras gene mutations?m and polymorphic sequences for forensic andysis.261 The amount of hindrance to 'copy synthesis' on a single-stranded DNA template presented by a tract of duplex structure, either in the form of a stable 'hairpin loop' or due to an extraneous oligonucleotide of complementary sequence, has been evaluated for DNA polymerase a,T4 DNA polymerase, Klenow fragment ( E . coli DNA polymerase I large subfragment), and reverse transcriptase from avian myeloblastosis virus.262 While the first two polymerases were arrested at the 5'-end of the double-stranded hindrance, and the rate of copy synthesis by Klenow fragment was diminished, the reverse transcriptase was virtually unaffected. For certain purposes, it might therefore present a useful alternative to DNA polymerases. It has certainly been of value in a procedure permitting the specific synthesis of cDNA complementary to propiomelanocortin mRNA by reverse transcription in situ in fixed tissue sections.263 In an enzymatic method for continuous monitoring of DNA polymerase activity, the pyrophosphate released upon nucleotide incorporation into DNA is used to displace sulphate from adenosine 5'-phosphosulphate to give ATP, a process catalyzed by ATP-sulphurylase, and the ATP is monitored in a luminometer using luciferin and luciferase.264 As usual, a number of modified nucleotides have been incorporated enzymatically into DNA. The carbocyclic analogue of (E)-5-(2-bromovinyl)-2'-dUTP (153)is a poor substrate for Klenow fragment, but can act as a cosubstrate with dTTP and dATP in polymerisation on a poly[d(A-T)] template.265 Even with only 3.6% incorporation of the analogue, the ability of the resulting copolymer to act as a template for DNA and RNA polymerases was markedly diminished, compared with poly[d(A-T)]. Poly (2-amino-&methyl-2'-deoxyadenylate)has been prepared using 2amino-8-methyl-dATP as a substrate for terminal deoxynucleotidyl transferase.266 The presence of the 8-methyl group caused little destabilization of the double helices formed with poly (pyrimidine nucleotides) compared with the duplexes formed by poly(2-amino-2-deoxyadenylate). In the -series, by contrast, the 8-methyl group causes considerable destabilization, probably due to steric hindrance with the 2'CHOH moiety. Terminal deoxynucleotidyl transferase has been used to add 'tails' from 1-4 nucleotides in length to the 3'-termini of synthetic oligodeoxyribonucleotides.~~~ The substrates used were 8-(6-aminohexylamino)
222
Orgnn op h osph orus Chemistry
AT", N6-[(6-aminohexyl)carbamoylmethyll-ATP, 5-(3-aminoallyl)dUTP, and 5amino(l2)dUTP (in which a primary amino group is separated from the uracil ring by a twelve-atom spacer). All the tailed oligonucleotides were then labelled using biotin _N-hydroxysuccinimide ester or fluorescein isothiocyanate for comparison of their detection efficiencies with a biotin-1I-dUTP-tailed probe, and proved to have similar sensitivities with a biotic detection system. The spin-labelled nucleotides (154) and (155) have been incorporated at specific sites in a 26-mer duplex by preparing the 17-mer 5'd(CCCCACCCGCGAAlTCG)which is self-complementary at the last 8 residues by automated solid phase synthesis, permitting it to self-anneal, and incubating the duplex with Klenow fragment, dGT", dCTP and (154)or (15512@. The spin label was inserted specifically opposite the unpaired adenine base, in each case. The presence of the spin label did not appear to alter the stability of the 26-mer duplex from that with thymine in the complementary sites, and the e.s.r. line shapes reflected the local dynamics of the nucleic acid constituents. Both (154) and (1551, and also (156) have been introduced into poly[d(A-T)] in partial replacement of the thymidylate residues, using Klenow fragment, the kinetics of spin label incorporation being dependent on both tether length and geometry.269 The proportion of spin label incorporated varied from 1-9%. Spin-labels with tethers sufficiently short to permit the nitroxide ring to reside in the minor groove were good reporter groups for monitoring hybridization. Oligodeoxyribonucleotides containing 2-amino-dATP have been prepared both using Klenow fragment and also by solid-phase meth0ds.2~0Dodecamers containing 2-amino-2'-deoxyadenylate which were complementary at the 3'-termini could be oligomerised using T4 DNA ligase to give oligomers more than 1000 base at the 5'-terminus pairs long. Also, oligomers with 2-amino-2'-deoxyadenosine were efficiently labelled using T4 polynucleotide kinase, and hybridization probes containing 2-aminoadenine in place of adenine showed increased selectivity and strength of hybridization to complementary sequences. DNA polymerases have also been used to site a single residue of @-methyl-, @-ethyl-, @-isopropyl-, or 0 2 methyl-2'-deoxythymidylate at position 16 of a 21-mer, so that the Q-alkylthymine was opposite the adenine residue of a bacteriophage amber c o d ~ n . ~Transfection ~' and replication of these duplexes in an E . coli strain deficient in the repair alkyl transferase which dealkylates @-alkylthymine residues gave mutant progeny phage and permitted the reversion frequencies to be calculated. Sequence analysis of the mutant phages derived from Q4-methyl- or -ethyluracil-containing DNA showed that guanine had been incorporated opposite the alkylthymine residues resulting in transition mutations. In other studies involving mispairing induced by elongation of oligodeoxyribonucleotide primers on templates in the presence of only three dNTPs, the occurrence of mispairing was found to be greatly influenced by nucleotide sequence.272 Transitional base substitutions were most common, but
h: Nuclt.orities n r i d Nucleic Acids
;123
transversions resulting from A.A mispairing were also found. A study of the relative rates of formation of 5-bromouracil.guanine and T.G mispairs as a function of pH gave results consistent with a model in which the anionic form of 5bromouracil on the template strand mispairs with g ~ a n i n e . ~ ~ 3 A method of oligoribonucleotide synthesis using synthetic DNA templates containing the T7 promoter, together with T7 RNA polymerase, permits the synthesis of milligram amounts of oligomers from 12 to 35 residues l 0 n g . 2 ~The ~ template DNA requires to be base-paired in the -17 to +1 promoter sequence for efficient transcription, but may otherwise be single-stranded. The method appears to offer a useful alternative to the chemical synthesis of oligoribonucleotides of moderate length. Essentially the same method has been used to prepare cRNA probes of 40 to 77 bases long, which were very successful as hybridization pr0bes.~~5 The efficient synthesis of RNA transcripts from oligodeoxyribonucleotides of 12 to 65 residues length without the need for primer or promoter has been described, using SP6 RNA polymerase.276 While the products are not entirely homogeneous, a proportion of full-length transcripts of at least 85% is reported. Oligoribonucleotide blocks from one to five units in length have been obtained by placing a homopolyribonucleotide together with an RNase specific for its cleavage s.poly(A) and RNase U2 - in a dialysis bag, and separating the oligomers which were dialysed out of the bag (which was impermeable to the enzyme).277 The characteristics of the elongation of an RNA primer by the catalytic RNA 'ribozyme' from the intervening sequence of Tetrahymena therrnophiln have been d e ~ c r i b e d . ~The ~ B ribozyme, some 388 residues long, transfers the 3'-residue of GpN (N=A,C or U) to the 3'-terminus of a (pC)5 acceptor to give (pC)spN, a process which may be repeated to give, at maximum, dodecamers. The acceptor is more readily extended by cytidylate or uridylate residues than adenylate residues, indicating that the addition is template-influenced. It is not yet clear whether the repeated addition involves a mechanism in which the pentacytidylate and its elongated derivatives dissociate from and rebind to the guide sequence after shifting along it by one residue ('distributive') or one in which they remain attached throughout the elongation processes ('processive'). In an assay for NDP-kinase, the formation of [3H]ATP from [3HlADP by the enzyme is made the rate-limiting step in the synthesis of RNA by RNA polymerase in the presence of the other (non-radioactive) nucleoside triphosphates and a DNA t e m ~ l a t e . ~Measurement ~9 of the radioactive RNA formed by standard methods then permits assay of the NDP-kinase activity. In the presence of a complementary polydeoxyribonucleotide, oligodeoxyribonucleotides containing a single apurinic or apyrimidinic site, or a single mispaired base, at the 5'- or 3'-end, could still undergo ligation to oligodeoxyribonucleotides with appropriate termini (5'-phosphate or 3'-OH) lying adjacent, albeit at slower reaction rates than those with non-modified ends.280 The
224
Organophosphorus Chemistry
rate of attack of the 3'-OH group on the adenylated 5'-terminus (A(5')pp N- .... seemed to be diminished. Non-base sites or mispairs at the 5'- or 3'-termini of duplexes prevented blunt-end ligation, however, although the presence of a single unpaired nucleotide at either the 5'- or 3'-end of the complementary duplex did not. The DNA ligase from Drosophila rnelanogaster embryos has been characterized and exhibits some of these properties, and much behaviour similar to that of homologous prokaryotic DNA ligases.281 In a study of the reactivity of intermediates formed in the reaction catalyzed by T4 RNA ligase, A(S)pp(dT)pand A(5')ppGpGpGp have been prepared by established phosphotriester methods and ligated to UpUpC.282 The results were compared with those obtained incubating UpUpC with A m , the enzyme, and p(dT)p or pGpGpGp respectively, and showed that use of the pre-adenylylated donor resulted in efficient reaction, while little or no activity was observed otherwise. Self-aggregation of pGpGpGp may have accounted for its poor donor activity. 5. Other Studies 5.1 Affinity Seuaration. An affinity column of immobilized dTTP has been prepared by attaching a 4-azaheptane-l17-diamine arm to CNBr-Sepharose 4B, succinylation, and then coupling the 4-aminophenyl ester of dlTP to the spacer arm thus generated.283 The column was used to purify deoxycytidine kinase from human leukaemic spleen. Adenylophosphopropionate (157), prepared from 6chloropurineriboside 5'-phosphate and DL-2-amino-3-phosphopropionicacid, is an inhibitor of adenylosuccinate lyase from rat skeletal muscle, and has been used to purify this enzyme by use of a column formed by oxidation of (157) with periodate, condensation with the primary amino group of Affi-Gel 102, and reductive amination with sodium cyanoborohydride.284 Elution of the retained enzyme was effected with adenylosuccinate. Biotin-11-dUTP (in which biotin is attached to C-5 of the uracil ring of dUTP via an 11-carbon linker) can be incorporated into a DNA fragment containing the lac operator site using Klenow fragment. Incubation of the resultant biotinylated DNA with an E . coli extract, followed by passage over streptavidin-agarose, permits proteins binding to the DNA fragment sequence to be isolated.285 A comparison of different methods for covalent attachment of oligonucleotides to solid supports derivatized with alkylamine or carboxylic functions has been made.286 5'-Phosphorylated oligonucleotides (17-29 mers) were coupled to 1.c. alkylamine-CPG using DCC and N-methylimidazole at pH 6, and 5'aminohexylphosphoramidate and 5'-cystaminylphosphoramidatederivatives of the same oligomers were either coupled to carboxyl-bearing supports with DCC or to NHS-activated carboxyl supports. Aminated 1%cross-linked polystyrenedivinylbenzene resin proved a poor support, with low coupling efficiency. Coupling efficbncies were assayed by acid hydrolysis of the phosphoramidate bonds
6: Nucleotides and Nucleic Acids
225
H H,
I
,C-CH2PO;N I
($N jOOH
O
H
0 I
I
C=O
R i b-5’-_P
(157)
R
(158) R = PhCO (159) R = PhCHOH H B i ot i n -N ICH, l6 NHCO CH, YH
0’
(160)
(161)
0 N
3
II
0 COCH,S -P - 0
I
- ( A p U - 5’)
0-
R
’
’
(162)
\
I
0
II
0
II I
0-P-0-P-O-P-O-~NU~
d
0-
I
0-
0-
(163) N U C = A d o ; R ’ = C H O ; R 2 = H (164) NUC = G U O ; R ’ = CHO; R Z = H 1165) N U C = G U O ; R ’ = H ; R 2 = C H O
- 5’)
and were generally good (5040%). The efficiency of coupling to the NHSactivated carboxyl of Sephacryl was lower, but the proportion of end-attached oligonucleotide (as opposed to linkage via the aminated bases) was high. The hybridization properties of nucleic acids immobilized on Sephacryl dextran supports have also been examined, and prehybridization of the support-bound oligonucleotides in the presence of dextran sulphate found to improve substantially the efficiencies of hybridization to target sequences.287 The detection efficiency using support-bound oligonucleotides was substantially higher than when using a nitrocellulose-based filter system. In another study, the use of DNA bound at pH 4 - 5 and high ionic strength to cyanuric chloride-activated paper has been compared for use in Southern blotting (hybridization) with a commercially available nylon membrane.288 The DNA-CCA paper permitted simpler hybridization conditions to be used, and offered more sensitive detection as well as the possibility of re-use. In a new method for attaching double-stranded DNA fragments to a solid support using DNA ligase, a palindromic oligomer forming a hairpin loop, containing an 'activated thymine' residue in the loop and also bearing a cohesive end, has been synthesized, treated with hexane-1 h-diamine to permit linkage to activated Sepharose, and, following linkage, ligated to a double-stranded oligonucleotide containing the desired sequence and with a complementary cohesive end.289 A less versatile but more direct means of affinity chromatography using immobilized DNA involves solid phase synthesis of the oligodeoxyribonucleotide required on a Teflon fibre support, deblocking, and hybridization to the complementary strand, to afford an affinity column for a sequence-specific binding protein.290 Brominated poly[d(G-C)l has been attached to an agarose column matrix via the biotin-avidin binding interaction, the immobilized 'Z'-DNA structure permitting isolation of an activity catalyzing ATPdependent homologous pairing and strand exchange of duplex linear DNA and single stranded circular DNA.291 An eicosamer containing a specific binding sequence for mammalian transcription factor IIIc, which is self-complementary with 'sticky ends' has been allowed to self-hybridise, oligomerised using T4 DNA ligase, and the resulting polymer coupled to Sepharo~e-CL2B.~9~ This affinity adsorbent permitted separation of the DNA-binding component of the transcription factor from the non-DNA-binding component. In a study of models for primordial tRNAmRNA interaction in the absence of protein, hairpin DNA sequences containing oligo(dA) loops of 3 to 6 residues were synthesised and tested for their ability to bind to oligo(dT) cellulose.2y3 Hairpins containing five or six dA residues in the loop were able to form stable duplexes, and digestion of the complex formed between the hairpin with the (dA)5 loop and oligo(dT) using mung bean nuclease revealed that three base pairs were formed, as in the codon-anticodon interaction. Hairpins containing oligo(dT1 loops could not bind to oligo(dA)-cellulose, however. Oligo(dT)-cellulose binds the enzyme tyrosine hydroxylase (which is activated by
6: Nucleolides and Nicdeic Acids
227
low concentrations of RNA) very tightly; this material, and also DNA-cellulose and poly(A)-Sepharose, may be used as affinity columns to purify the enzyme.294. The interaction of tRNA species containing thiated modified bases, and also of nucleic acids containing phosphorothioate groups, with [(N-acryloylamino) phenyllmercuric chloride incorporated into polyacrylamide gels has been ~tudied.29~ The retardation of the thiated molecules was dictated by the nature of the modification and its accessibility for binding: single- or double-stranded DNA or RNA containing a phosphorothioate group at the 5'-terminus (as 5'phosphorothioate or -[y-thio]triphosphate) or at the 3'-terminus (phosphorothioate:) were strongly retained by the mercurated column, but phosphorothioate internucleotidic links gave no detectable interaction. It is suggested 'that while binding to the thiotriphosphate probably involves bidentate interaction, binding to the monophosphorothioate may occur via coordinated water, a process which occurs too weakly for the thiophosphate diester to be retained. 5.2 Affinitv Labelling. As usual, only novel or unusual nucleotide affinity labels are reported in this Section, and labels which have been used so commonly as to be regarded as routine reagents are omitted. The recently-described 5-azido-UTP has been employed for the photoaffinity labelling of RNA polymerase from E . coli resulting in the labelling of the p, p' and cs subunits in the presence or absence of DNA, a different pattern from that observed using 8-azido-ATP as the affinity 2'-Deoxy-3'-Q-(4-benzoylbenzoyl)(158) and 3'(2')-Q-(4-benzoylbenzoyl)1,Nb-ethenoadenosine 5'-diphosphates, fluorescent photoaffinity labelling analogues of ADP, have been prepared from l,@-etheno-dADP and -ADP, respectively, by standard methods, and their interaction with myosin subfragment 1 i n v e ~ t i g a t e d . ~The 9 ~ corresponding compounds with 4-carboxybenzhydrol in place (159) - were also prepared similarly. Evidence based of 4-benzoylbenzoic acid on comparison of photophysical data for photoincorporated (158) with those for (159) trapped at the active site of myosin subfragment 1 suggested that the carbonyl group of the benzophenone moiety is converted to the covalently attached tertiary alcohol. The ATPase site of myosin has been located by three-dimensional electron microscopy with the aid of a multi-functional nucleotide analogue (160), prepared by conventional methods.298 After (160) was hydrolysed to the corresponding ADP analogue by incubation with myosin subfragment 1, the ADP analogue was trapped in the ATPase site using vanadate, and covalently immobilised by UV illumination. The location of the ATPase site could then be determined by site-specific labelling with avidin and comparison of 3-D image constructs obtained from electron micrographs with those of controls. A photoaffinity spin-labelled derivative of ATP (161) has been prepared, again using standard chemical procedures, and found to exhibit an e.s.r. spectrum indicative of strong immobilization when complexed to mitochondria1 F1-ATPase.299 Upon irradiation it becomes covalently incorporated,
s.
though apparently at non-catalytic tight binding sites. 5'-[[(4-
228
Organophosphorus Chemistry
Azidophenacyl)thiolphospholadenylyl (3'4') uridine (162) has been prepared by alkylation of 5'-thiophosphoadenylyl(3'-5')uridinewith 4-azidophenacyl bromide.300 Upon incubation with RNA polymerase ( E . coli), a DNA template, and nucleoside triphosphate substrates, it serves as a primer for RNA synthesis, and irradiation then effects covalent cross-linking to the enzyme. The DNA and enzyme subunits with nascent RNA transcripts attached were separated by PAGE, electroeluted, and the P-S bond cleaved with phenylmercuric acetate to release the attached oligoribonucleotides from the subunits. Measurement of the lengths of the nascent RNA molecules by PAGE then allowed correlation to be made between the length of the growing transcript and the labelled component. The syntheses of a number of nucleoside S'-mono-,di-, and triphosphates with reactive groups attached to the (terminal) phosphate moieties have been de~cribed.30~ The reactive groups were variously alkylating (N-2-chloroethyl), condensing (formylphenyl), or phosphorylating (imidazolide) derivatives. One such species, adenosine 5'-(y4-formylphenyl) triphosphate (163), has been used as a primer in reactions catalysed by RNA polymerases A, B and C of y e a ~ t . 3The ~ ~ label reacted with the enzymes, the condensation being rendered irreversible by borohydride reduction. Following formation of a phosphodiester bond with [a32PlUTPin the presence of template, the radioactivity was found to be associated solely with the second largest subunit of each polymerase, indicating their functional homology. Comparable studies on the active site of T7 RNA polymerase have utilised (163) and guanosine analogues (164,165) and other related labels (166,167).M3The most efficient label was found to be (166, n=21, and the least efficient was (165) with an ortho-formyl group. In another study of the functional topography of RNA polymerase from E. coli (d. ref. 300 above) oligonucleotides of general formula [p(dN)], p(dG)pC (n= 0.5) have been treated with 2,2'-dipyridyldisulphide and triphenylphosphine in the presence of imidazole, N-methylimidazole, or DMAP to generate the corresponding oligonucleotide 5'-phosphoramidates as phosphorylating affinity reagents.3a The oligodeoxyribonucleotide sequence was chosen to be complementary to parts of promoter A2 from phage T7. Reaction of the RNA polymerase.promoter A2 complex with the affinity reagent followed by [a-32P]UTP afforded enzyme labelled via the 5'-phosphate of [p(dN)],p(dG)pC[32P]pUwith the P-subunit being maximally labelled for = 1, and the o-subunit for n = 5. 2-[(4-Bromo-2,3-dioxobutyl) thio-I (168) and 2-[(3-bromo-2oxopropyl)thioladenosine 2',5'-bisphosphate (169) have been prepared and used as affinity labels of NADP+-specificisocitrate dehydrogenase.305 NADP+ was cleaved with NAD+-ase from NeurosDora to afford 2'-phospho-ADP-ribose, which was oxidised to its @-oxide with MCPBA and treated with alkali resulting in elimination of the ribose moiety and also in ring cleavage to give (170). Ring closure with carbon disulphide followed by alkylation with 1,4-dibromobutanedione
6: Nucleotides and Nucleic Acids
229
0';" \
OHC
N-CH2CH20 -)O-[{
( Nuc
0-
- 5' 1
n
( 1 6 6 ) Nuc = Guo; n = 1 or 2 (167) NUC = A d o ; n = 2
1 170)
1168) R = COCH,Br (169) R = CHzBr
R2
0
OH
I II
C H 2 N - C ( C H 2 12
H (171) For For For For
H
Ura ( a s shown) R' = Me; R 2 = H R1 = R2 = Me Cyd Ade R ' = H * R2=Me R' = R' = H Gua
\0
I
(RNA -3' )
0
~
~
-Pd-
I
N
Me A Me
IM 0 '
(172)
(173)
Me e
f
230
Orgatiop h osph orus Chemistry
or 1,3-dibromopropanone gave (168) and (169) respectively. Pyridoxal 5'-diphospho5'-adenosine (ADP-pyridoxal) and its tri- and tetraphospho analogues are all effective affinity labels of the ATP-binding site of adenylate kinase from rabbit muscle, with the same lysine residue being labelled by each reagent.3m. ADPpyridoxal has also been used to label the a-subunit of F1-ATPase from E . coli, again by condensing with a lysine residue.307 The Schiff bases formed initially when using these affinity labels must be reduced with borohydride or a similar reagent to render the labelling irreversible. The same applies to the use of periodate-oxidised tRNAphe as an affinity label for phenylalanyl-tKNA synthetase from E . cob, in which three different peptides labelled at lysine residues were isolated.308 5.3 Sequencing and Cleavage Studies - The automated synthesis and sequence analysis of biological macromolecules, including DNA, have been reviewed.309 A new method of sequence determination equally applicable to both DNA and RNA, based on phosphorothioate chemistry, has been described.3'0 Endlabelled strands of the nucleic acid to be sequenced are generated by copy synthesis using a mixture containing three normal (d)NTP species and one (d)NTPaS phosphorothioate species, the process being performed four times with a different (d)NTPaS species being used each time. Consequently each of the four samples generated contains a different base of which the derived nucleotide carries a 5'phosphorothioate link. Alkylation of the phosphorothioate links with 2iodoethanol results mainly in sulphur extrusion but also in some strand cleavage at the phosphorothioate link, and gel chromatographic separation then generates a sequence ladder. Since the cleavage process can generate 3'-OH or 5'-OH termini, doublets may be resolved for the smaller DNA fragments, but ignoring the band of weaker intensity gives reliable and unequivocal sequencing. The method offers convenient advantages: the (d)NTPaS species are good substrates for the polymerases most commonly used, and enzyme inhibition by the dideoxynucleoside-5'triphosphatesis avoided. Band intensity variations seen when sequencing RNA may be due to secondary structure, and may prove to be a method for gaining information on secondary structure, while the method itself may be adaptable for 'footprinting'. In a new system for rapid DNA-sequencing using fluorescent chainterminating dideoxynucleotides, different succinylfluorescein derivatives (171; the substituent attached to give the T analogue is illustrated) are attached at C-5 of 2,3'dideoxy-CTP and -UTP, and at C-7 of 7-deaza-2',3'-dideoxy;GTPand -ATP, respectively.311 The DNA fragments generated are resolved by gel electrophoresis in a single sequencing lane and are identified by a fluorescence detection system matched to the emission characteristics of the set of dyes. The fluorescent nucleotides are not substrates for Klenow fragment but are acceptable substrates for reverse transcriptase from avian myeloblastosis virus (AMV). In another account of DNA sequence analysis using fluorescent-labelled oligodeoxyribonucleotides, the
6: Nucleotides and Nucleic Acids
23 1
oligonucleotide to be sequenced, tagged at the 5'-terminus with a thiol group, was alkylated with 5-iodoacetamidofluorescein, and applied to paper for a solid-phase sequencing protocol employing normal base-specific reagents.312 Application of the cleavage products to a sequencing gel and on-line sequence determination allowed a 21-mer to be sequenced in about 30 minutes, and moreover u p to ten fragments to be sequenced simultaneously. In another cunning stratagem to permit many DNA sequences to be determined simultaneously, each different sample of DNA to be sequenced is ligated initially to an oligonucleotide 'tag', which will serve later as its identification labe1.313 The tagged molecules are pooled, amplified in vectors, and submitted to Maxam-Gilbert chemical fragmentation. The fragmented DNA is separated on ion gradient sequencing gels, electroblotted on to nylon, and there immobilized by cross-linking. The bands generated from each individual sample of DNA are revealed by hybridisation with a radioactive oligonucleotide probe complementary to the 'tag' sequence. After autoradiography the hybrid probe is removed and replaced by another complementary to a different tag sequence, thus revealing the sequence information for a second DNA sample, and so on. In a method of DNA sequencing employing colorimetric detection, a synthetic oligodeoxyribonucleotidewith biotin linked to its 5'-terminus is used as the primer in a dideoxysequencing protocol.314 The strand extension products are separated on a short electrophoresis gel, from which they are electroblotted on to an immobilizing matrix to which, after drying, they are cross-linked by irradiation. The band positions are revealed by treatment with streptavidin, washing, and application of biotin-alkaline phosphatase conjugate, with development using a nitro blue tetrazolium - 5-bromo-4-chloro-3-indolyl phosphate mixture. The biotinavidin system has also been employed to immobilize DNA in a solid-phase sequencing protocol: biotinylated DNA (generated by end-filling a restricted DNA fragment using Klenow fragment and biotinylated dUTP, together with other dNTPs, and treatment with a second restriction enzyme to eliminate one biotinylated terminus) is immobilized by passage over avidin-agarose, heated or treated with alkali to remove one strand of the duplex, and used as a template with a general sequencing primer in the dideoxynucleotide sequencing procedure.3'5 A comparison of the reactivity of oligodeoxyribonucleotidescontaining 2'deoxytubercidin (2'-deoxy-7-deazaadenosine) with others containing 2'deoxyadenosine under the conditions conventionally used for base-specific cleavage in solid-phase chemical DNA sequencing has been made.3l6 Generally the 7deazaadenine is rather less reactive than adenine but exhibits a spectrum of reactivity which permits its identification. For instance, it reacts weakly with osmium tetroxide. At pH 4.3, permanganate reacts preferentially with thymine, 5methylcytosine, and (weakly) with purines, but not appreciably with cytosine, an observation which permits 5-methylcytosine to be differentiated from cytosine in chemical ~equencing.3'~ At pH 2.0, adenine reacts with potassium
232
Organophosph orus Chernistry
tetrachloropalladate in a reaction which results in selective depurination at adenine and strand cleavage on work-up with piperidine.318 Reaction is slower if adenine is methylated at N6, probably due to steric hindrance to formation of an intermediate such as (172). The reaction thus joins others useful in effecting adenine-specific cleavage. In a comparative study of the hydrazinolysis of pyrimidine 2'deoxynucleosides and nucleotides in the presence and absence of sodium chloride, it was concluded the effect of adding salt was to promote the ionisation of the ionisable heterocycles - those containing a uracil or thymine ring - thus decreasing the population of the non-ionised forms.319 Since hydrazinolysis involves reaction largely or exclusively with the non-ionised forms, it is decreased for ionisable pyrimidines by the presence of salt. This rationalises the Maxam-Gilbert sequencing protocol utilizing hydrazine for pyrimidine-specific cleavage. Systematic examination of the conditions used for the one-lane sequence analysis of DNA following solvolysis in hot aqueous piperidine have permitted an optimum procedure to be defined.320 For the dideoxynucleotide chain termination method of DNA sequencing, the use of T7 DNA polymerase which has been exposed to free radicals to eliminate its 3'-exonuclease function ("sequenase") offers substantial advantage over the previously-used Klenow fragment of E . coli DNA polymerase I: it has higher processivity (little tendency to dissociate from the DNA chain which it is replicating, to give artefactual bands) and accepts nucleotide analogues as substrates rapidly and effi~iently.3~'In consequence the sequencing gels show little background variation due to premature termination, pause sites, or secondary structure, and the use of ITP instead of GTP can eliminate band compression. The use of sequenase in fluorescence-detected automated dideoxy sequencing has also been described and found a d ~ a n t a g e o u s . 3Others ~~ have described the double-stranded DNA sequencing procedure, reported some years ago, as the method of choice for DNA sequencing, particularly in combination with the use of sequenase.323 By using sequencing primers located internally to the amplification primers in the PCR, genomic DNA sequence information can be obtained directly from enzymatically amplified DNA using the dideoxynucleotide chain termination method.324 A protocol for rapid chemical RNA sequencing, essentially a streamlined variant of the procedure devised by Peattie and reported many years, has been de~cribed.3~5 A solid-phase procedure involving the immobilization of 3'terminally labelled RNA on DEAE-cellulose sheets prior to application of Peattie's base-specific chemical cleavage conditions has also been detailed.326 A collation of the susceptibility to cleavage reactions, both enzymatic and chemical, of the modified nucleosides most common encountered in tRNA species, together with their ability to give rise to atypical spacings on sequencing gels or in mobility shift analysis, permits the preliminary identification of modified nucleosides occurring in tRNA.327 In a very different, if limited, method of base-pair sequencing of the 3'-
6: Nucleorides and Nucleic A c i h
233
terminal stem of yeast ribosomal 5 S RNA, the 3'-terminus was oxidised with periodate, condensed with 4-amino-2,2,6,6-tetramethylpipridin-l-oxyl, and the product reduced with borohydride to give terminal structure (173).328 Comparison of the 1H n.m.r. spectra of the modified and unmodified 5 S RNA permitted the terminal and penultimate base pair protons to be identified due to the distancedependent line broadening caused by the paramagnetic nitroxide, and this, together with data resulting from primary and secondary n.O.e.'s, permitted most of the sequence and base-pairs of the terminal helix to be identified. In a theoretical consideration of possible mechanisms for the catalyzed formation of 5'-phosphates from RNA and the origin of nucleases, it has been argued that in the case of disjunct (or 'distant nucleophile') mechanisms (that is, those in which no adjacent nucleophile is present at C-2') minimal spatial and electronic reorganization will occur at the phosphorus atom if the incoming nucleophile attacks opposite the 3'-P-0 bond (174) with 'in-line' displacement of the C3'-OH and inversion of configuration at pho~phorus.3~9 The most likely alternative, involving attack opposite the 5'-P-O bond, would require pseudorotation in the trigonal bipyramidal intermediate prior to expulsion of the C3'-0H, and require spatial reorganization of the furanose ring atoms and their appendages, a process which would be energetically demanding, particularly in the polymer. In a recently reported study of the hydrolysis of poly(U) in imidazole buffer, a sequential base-acid mechanism of catalysis was proposed, although the alternative sequential acid-base mechanism could not be excluded on the basis of kinetic data. Stereoelectronic considerations, supported by data on the hydrolyses of methyl and ethyl ethylene phosphates, have now been cited as affording support for the baseacid mechanism.330 In base-catalysed hydrolysis the intermediate (175) formed by the initial base-catalyzed step affords the product of endocyclic cleavage (176) since the lone pairs on the equatorial oxygen atoms of (175) are antiperiplanar to the axial leaving group, to assist its expulsion. In acid-catalyzed hydrolysis of (175), protonation on the exocyclic oxygen atom is favoured, with loss of the exocyclic group and formation of the cyclophosphate (177). The base (to form (175)) - acid (to form (177))mechanism, as proposed, thus accounts satisfactorily for the products observed, while the reverse mechanism does not. Site-directed mutagenesis studies on ribonuclease Ti, in which histidine-40, histidine-92, and glutamate-58 were replaced separately by alanine, have shown that the two histidine residues are vital for catalytic activity of the enzyme, while the glutamate, previously thought to be essential, is not.33' The mechanism proposed for the catalytic activity of RNase Ti strongly resembles Breslow's classical mechanism for RNase A, despite the dissimilarities in sequence and tertiary structure. A 19-mer RNA fragment which conforms to the 'hammerhead' model for catalytic self-cleavage of oligoribonucleotides~~* has been constructed by
234
Organ oph osp h orus Chemistry
R OH
____)
I
OR
II
0 (177)
I1761
5'-pppG 3'-C
U C G A
C G C C
G C-3'
I 1 1 1 1 1
I I I I I
G
A
G C G G
C
A
C U C G Gppp-5'
G U A G U
1178) ( C l e a v a g e p o i n t a r r o w e d )
k o
I o=p-oI 0
\0 I
owHo
o=p-oI
+
H
Scheme
H
2
0
II I
HO-P-0-
0-
6: Niicleotidrs and Nucleic Acids
235
transcription from a synthetic DNA template, and found to effect specific hydrolytic cleavage at the predicted site (arrowed) 0x1 a part-complementary 24-mer substrate strand (1781333 (see also ref. 179). The rate of hydrolysis is zero at pH 5 but increases with pH, differs from the normal kinetics of alkaline cleavage of RNA, and is absolutely dependent on the presence of divalent cations. The products from the 24mer strand are the 5'-18-mer, terminating in cptidine 2,3'-monophosphate and the 3'-6-mer. Since the 19-mer can turn over many 24-mer strands (it gives a reasonable Eddie-Hofstee plot) and is specific (within constraints) for the structure which it cleaves, it can be regarded as a mini-ribozyme. Considerable interest and ingenuity are being displayed in the construction of agents to effect site-specific cleavage or modification of nucleic acids. b n e of the most direct approaches consists in constructing a hybrid enzyme containing a nuclease activity attached to an 01igonucleotide.33~ For instance, a disulphide exchange reaction between cysteine-116 of a mutant staphylococcal nuclease and an oligodeoxyribonucleotidyl3'-(2-pyridyl)disulphide moiety has been used to attach a 14-mer to the enzyme in high yield.335 The hybrid was able to form a duplex with the complementary sequence on a 59-mer RNA substrate strand, and upon activation of the nuclease with Ca2+ ions, cleavage occurred specifically over a 3-5 nucleotide tract directly adjacent to the hybridization site. Cleavage by the nonhybrid or non-mutated enzyme was much slower and relatively non-specific. Similar results have been obtained using virtually the same system but with singlestranded DNA as the target.336 Class 11s restriction enzymes recognize a specific sequence on double stranded DNA but cut the DNA not within this sequence but at a precise distance from it along the adjacent sequence. This property permits DNA to be cleaved at any predetermined site: an oligodeoxyribonucleotide adaptor is constricted comprising a hairpin domain which contains the recognition site of the class 11s nuclease (FokI) together with a single-stranded domain complementary to the single-stranded DNA target sequence to be cleaved, and of such length that the cleavage site of the enzyme is situated at the chosen position when the adaptor is hybridized to the target sequence.337 In studies on more conventional restriction endonucleases the effects of functional group changes in the Eco RI recognition site have been examined,338 the effects of methylation at N4- or C5- of the cytosine bases in the sequence d(..CCCGGG) upon cleavage by a number of restriction endonucleases specific for this sequence have been investigated (methylation at N4 caused strong suppression of cleavage),339 and the relaxation of the sequence specificity of pvU I1 in the presence of organic solvents (DMSO, ethanol, glycerol) has been rep0rted.3~0 Examination of the susceptibility of different mRNA species to degradation by reticulocyte nucleases and by 2-5 A-stimulated 'RNase L' shows that the mRNA species are rapidly degraded when the 3I-non-coding regions of the molecules contain large quantities of ( U P ) ~ Atracts, while mRNA species which are relatively
0 d(CpG-3')-O-P-O
0
II
II
dICpG-3') -0-P-0
A-
OI HO-OH 0
I
D
O
H
0
-
0 =P -0 Id( T3A3GCG) 5'1
I
01182)
(181)
0 d1CpG - 3')-
I1
0-P-0
I
0 dfCpG-3')-0-P-
II I
0
k
T
7
O
R-
N=O
O
H
'O HO
11831
(1841
+
1186) Scheme 3
\
H
6: Nrdeotides and Niicleic Acids
237
poor in these tracts are largely ~table.34~ Their presence or absence may thus determine, and indeed be used by the cell to determine, the destruction or retention of discrete mRNA species. Hybrid arrest of trmslation of mRNA by 15-30 mer complementary oligodeoxyribonucleotides injected into Xenouus oocytes has been shown to be due to the selective destruction of the hybridized mRNA by a ribonuclease H-like activity.M* The sequence d(TGTGTATp)has been joined chemically to GCCAU, pGCCAU, and d(pGCCAT) to form ligation products, two of them chimaeric, and two of them containing a single pyrophosphate internucleotidic link. Upon hybridization to the complementary AAUGGCAUACAC, the product d(TGTGTATpp[r(GCCAU)]),whichwas thus chimaeric as well as containing a pyrophosphate link, directed cleavage at a unique site by ribonuclease H, the other constructs directing lesser degrees of cleavage specificity.343 A new ribonuclease isolated from cobra venom appears to be specific towards cytidylic acid residues in single-stranded RNA, and may thus prove useful in the sequencing and structural determination of RNA.34 Endonuclease I from bacteriophage T7 displays site-specific cleavage at the branch points between duplex regions of DNA, such as those found in the cruciform 'Holliday junctions' and related s t r ~ c t u r e s . 3 ~ ~ When using mismatch-containing oligodeoxyribonucleotides for the purpose of site-directed mutagenesis, it is highly inconvenient if the mismatched oligonucleotide is degraded by an exonuclease activity of the polymerising enzyme employed in the procedure. Using 18-mers synthesised with a mismatch at position 10 and with phosphorothioate groups incorporated variously at the first four internucleotidic links form the 5'-end, it has been shown via a mutational assay that the introduction of phosphorothioate, particularly at the second and third links, slows greatly the degradation of the oligonucleotides by the 5'-exonuclease activity of E. coIi DNA polymerase 1.346 The mutation rate observed for an 18-mer with a mismatch at position 5 and similarly protected by phosphorothioate links was by contrast much poorer, however. The phosphor0 thioate-based oligonucleotidedirected mutagenesis method described in a previous Report has been extended by the use of 5'-3' exonucleases from bacteriophages T7 and h to digest the nonphosphorothioate-containing non-mutagenized nicked strand of double stranded circular DNA prior to its replacement by copy synthesis to afford doublestranded DNA properly basepaired at the mutagenized site.347 The nick in the nonphosphorothioate-containing strand is produced using a restriction enzyme: it has now been shown that many restriction endonucleases, which previously linearised DNA containing phosphorothioate in one strand by cleaving in both strands, can be limited by the presence of the intercalator ethidium bromide to introducing a nick in the non-phosphorothioate-containingstrand alone.348 In a different study, the presence of phosphorothioate links at cleavage sites recognized by RNase I11 appeared to slow, but not to prevent, cleavage by this en~yme.3~9 When the heptamer d(GCGUGCG), in which the 2'-deoxyuridine residue was
238
Organophosphorus Chemistry
labelled at the 1'- and 3'-positions with carbon-13, was treated with uracil glycosylase to create an abasic site, and then with UV endonuclease V, the n.m.r. spectrum of the cleavage products demonstrated the decay of the signals from the 1'- and 3'carbons of the abasic site and the appearance of aldehydic (l'-)and vinylic (3'-) signals, showing that the enzyme catalyzes chain cleavage by p-elimination (Scheme 21, rather than hydrolysis.350 Cleavage thus occurs vfa C - 0 scission, ix. by lyase rather than hydrolase activity. This establishes the mechanism previously suggested to occur for this enzyme, and also for E . coli endonuclease 111.351 A similar mechanism of action appears to operate for y-endonuclease from Micrococcus
luteus, which possesses an N-glycosylase activity to release thymine glycols from damaged DNA and an endonuclease activity thought to involve P-elimination.352 The structure of the adduct formed on reaction of 3-aminocarbazole with the apurinic site oligonucleotide model d[Tp(AP)pTl (AP=abasic site) has been shown to be (1791,which is believed to arise by firstly catalysing p-elimination to form an enal 3'-terminus as in Scheme 2, followed by Michael addition involving the amino group and ring closure with aerial oxidation.353 9-[(IO-(Aden-9-y1)-4,8diazadecyl)aminol-6- chloro-2-methoxyacridine (180) also effects DNA scission at apurinic sites (but not at reduced apurinic sites) to leave termini with 3'-deoxyribose (or similar) and 5'- phosphate termini, and is thought to effect P-elimination.354 Heptadeoxythymidylate linked at the 3'-terminus via a spacer arm to iron methylpyrroporphyrin XXI, or else to an intercalating acridine with the iron porphyrin linked to the 5'-terminus via another spacer arm, has been shown to bind and damage a 27-mer containing a target octadeoxyadenylate tract.355 The damage, which in dark reactions included base oxidation, cross-linking and chain scission, was much more localized when induced by reductants than by oxidants. Three oligonucleotides of almost identical sequence with alkylating (N-2-chloroethyl) moieties linked either to the 3'- or the 5'-termini and (in one case) with an intercalating phenazinium ring also attached via a 5'-phosphoramidate link have been tested for their ability to react irreversibly with complementary sequences in hybrid M13mp7 bacteriophage single-stranded DNA, to destroy the bacteriophage's infectivity.356 The oligonucleotide with an alkylating 5'-moiety, and the one with the 5'-phenazinium ring and alkylating 3'-moiety proved effective, but the one with an alkylating 3'-moiety alone did not. Homopyrimidine oligodeoxyribonucleotides containing a 5'-terminal 2'-deoxythymidine residue with EDTA.iron attached to the 5-position have been shown to cause sequence-specific double-strand breakage in a DNA target.357 Analysis of the location and asymmetry of the cleavage pattern generated indicated that the oligomer binds in the major groove parallel to the homopurine strand of the Watson-Crick double helix, to form a triple helix, prior to cleavage. A synthetic peptide, a trimer of tetra-N-methylpyrrolecarboxamide units linked by p-alanine and with EDTA attached to the amino terminus, has been
6: iVircleotiries uttd Nuclt.ic Acids
239
prepared and shown, via its capacity for cleaving DNA in the presence of ferrous ions, to bind in the minor groove to 16 base pairs of DNA: a full turn-and-a-half of 'B'-form DNA.358 A different type of DNA-cleaving peptide has been prepared by linking EDTA to the amino terminus of a synthetic 52-residue peptide modelled on the sequence-specific DNA binding domain of Hin recombinase.359 In the presence of ferrous ions and a reducing agent the DNA is cleaved specifically at the Hin recombination sites. In an analogous study, the tryptophan gene repressor protein of E . colt has been converted into a site-specific nuclease by covalent attachment of a 1,lO-phenanthroline-coppercomplex.360 In the presence of thiols and co-repressor L-tryptophan, the synthetic nuclease cleaved DNA specifically at the repressorbinding sites. Bis(netrospin)-3,6,9,12,15-pentaoxaheptadecanediamidewith EDTA.iron attached to one end of the molecule exhibits strong specific DNA cleavage patterns in the presence of strontium and (particularly) barium dications, but not in the presence of other common monovalent and divalent metal cations.361 It is thought that complexation of the activating ions by the pentaoxaheptadecane moiety and flanking carbonyl groups, to form a pseudocrown-ether complex, draws the molecule into a crescent shape complementary to the minor groove of DNA, and, with the netropsin moieties binding to their preferred (A,T)4 sequences, metalloregulated sequence-specific cleavage follows. Mechanisms of the bleomycin-induced degradation of DNA have been r e ~ i e w e d . 3In ~ ~a study of the action of bleomycin-Fe(II)-02 on the hybrids poly(dA).poly(dT), poly(rA).poly(dT) and poly)(dA).poly(rU), essentially complete specificity for degradation of the deoxyribonucleotide strand(s) was seen in each case, the products from the degraded residues being the bases and base pr0penals.36~ A far higher ratio of adenine:adenine propenal was formed from poly(dA).poly(rU) than from poly(dA).poly(dT),possibly due to the former hybrid having a more open minor groove than B-form DNA, and bleomycin-induced cleavage occurring via initial partitioning between abstraction of hydrogen from the C-1' and C-4' sites. While the base propenals are thought to derive from the C4'-hydroperoxy derivative of the DNA deoxyribose moiety, the free base could arise via a C4'hydroxy derivative, and evidence has been presented that the alkali-labile product formed on loss of cytosine-3 from d(CGCTITAAAGCG) is a C4'-hydroxy apyrimidinic acid (1811.364 In alkali, p-elimination of the 5'-phosphate followed by condensation gives a 2,4-dihydroxycyclopentenone(182) as the 3'-terminal appendage. The presence of an alkylamine causes the loss of d(CpGp1, possibly via P-elimination from a Michael addition product, while treatment with hydrazine gives a pyridazine derivative (183). The identity of these derivatives of the alkalilabile lesion was established by comparison with authentic synthetic samples prepared from (184) (which was obtained via a phosphotriester synthesis). The alteration of bleomycin cleavage specificity consequent upon platination of a DNA oligomer of defined sequence has been investigated.365 Using
240
Organophosphorus Chemistry
oligodeoxyribonucleotides which form linear duplexes or double hairpins containing, in either case, a single-strand nick in a duplex tract, phosphorylated to model the structure at a bleomycin cleavage site, it has been shown that the presence of negative charge at the nick enhances the ability of bleomycin to cleave the intact strand opposite the nick, to complete double-stranded cleavage.366 This explains why the frequency of double-stranded scission by bleomycin exceeds that expected from the random accumulation of single-stranded nicks. In anaerobic conditions and with the nitroaromatic radiation-sensitizer misonidazole substituting for oxygen, DNA strand breakage by the chromophore of neocarzinostatin leads to the formation of formyl phosphate from the C-5' of 2'deoxythymidine residues.367 Formyl transfer to suitable acceptors in quantity comparable to the amount of thymine released could be demonstrated. Abstraction of a hydrogen atom from C-5' followed by reaction with the nitro group is thought to afford (185) which fragments as indicated (Scheme 3) to give (186). A similar mechanism involving oxygen may account for 10-15%of the strand breaks of this type seen in the aerobic reaction. Neocarzinostatin appears to generate a different type of alkali-labile abasic site at 2'-deoxycytidylate residues of d(AGC) sequences in oligodeoxyribonucleotides, and quantitation of abstraction of hydrogen from specifically tritiated substrates suggests that attack at C-1' is occurring initially.368 The characteristics of strand cleavage at DNA bulges (unpaired nucleotides on one strand of a DNA double helix) by intercalating drugs such as neocarzinostatin and bleomycin have been compared.369 Calicheamicin y11 is an antitumour antibiotic with a remarkable diyne-ene structure and the ability to cause site-specific double stranded cleavage in DNA.370 It is thought that activation by a thiol cofactor generates a 1,4-dehydrobenzene diradical species which abstracts a CS-hydrogen from the deoxyribose ring to initiate oxidative strand scission, the proposed course of reaction resembling that thought to obtain in cleavage at 2'-deoxythymidylate residues by neocarzinostatin. Examination of the cleavage of DNA in vitro by hydrogen peroxide and ferrous ions (the constituents of a Fenton reaction system) and the effects of added radical scavengers has led to the proposal that a ferry1 (F$+-OH') radical, rather than the hydroxyl radical, is the species primarily responsible for damage to DNA, and that this is also the case in vivo.371 The hydroxyl radical, generated by the complex of EDTA and ferrous ions in the presence of oxygen, is of considerable value for 'footprinting', however.372 It has also been used to investigate DNA bending: bent DNA generates a sinusoidal cleavage pattern with the minima phased with the 3'-ends of the adenine tracts, and it has been shown that [d(GAAAATTITC)J, which gives the anomalous migration on gel electrophoresis associated with bent DNA, affords such a cleavage pattern, while [d(GTTTTAAAAC)I,, which runs normally on gels, does not.373 It is thought that the minor groove of the A4T4 sequence opens and closes in width with a periodicity responsible for both the cleavage pattern and the bending, while the
6: Nucleofides and Nucleic Acids
24 1
T4A4 sequence has a minor groove of essentially uniform width. Complementary 10-mers, containing a central tract of five consecutive A.T pairs or with one or more of these pairs replaced by analogues to form different base pairs have been synthesized, ligated to form multimers, and their gel mobility measured as an index of bex1ding.3~~,3~5 The presence of a methyl group on the pyrimidine base is not essential for the formation of H-DNA (the designation given to the polymorphic structure adopted by A-T tracts) but the presence of a 2-amino group on the purine base tends to suppress its formation. A model incorporating an appreciable roll component at the 5'-end of the adenine tract, opening the minor groove at the 3'end relative to the 5'-end374 is consistent with the footprinting re~ults.3~3 It has also been proposed that the A.T base pairs fold towards the minor, groove due to the absence of the 2-amino group, causing a negative tilt angle to the (normally flat and parallel) base pairs in DNA relative to the helical axis, with the cumulative negative tilt angle resulting from tracts of consecutive A.T pairs in the same periodicity as helical B-DNA causing bending.375 The presence of thymine photodimers situated in phase with the helix screw axis has also been shown to cause bending in DNA.376 Repair of the photodimers by DNA photolyase abolished the anomalous migration. The structure and mechanism of the self-splicing intervening sequence (1VS)RNA for Tetrahyrnena thermophila continues to attract much attention. A threedimensional model of the rRNA precursor has been c o n ~ t r u c t e d , 3and ~~ examination of the catalytic activity of a number of forms of the IVS progressively shortened from the 3'-end has shown that truncated molecules which retain all the conserved sequence elements within the catalytic core and possess guanosine or an oligopyrimidine tract at the 3'-OH terminus can cyclise under physiological ~onditions.3~8 If the 3'-terminal guanosine residue of the IVS is removed via oxidation with periodate followed by p-elimination, the IVS cannot undergo selfcyclisation, but can utilize free guanosine (or an oligonucleotide terminating in guanosine) to perform nucleophilic attack at the normal cyclisation site.379 The reaction thus becomes intermolecular, rather than intramolecular. The phosphodiester bond at the cyclisation site is somehow activated towards attack by the 3'-OH group of a guanosine residue, or by hydroxide ion: it is also susceptible to pH-dependent hydrolysis. The catalytically active "M1 RNA" component of ribonuclease P, which processes tRNA precursors, has been investigated for its ability to cleave tRNA precursors lacking specific domains of the normal tRNA ~equence.38Ot~~~ While a 3'-terminal-CCA sequence was found essential for specific cleavage, the smallest precursor to undergo effective cleavage retained only the acceptor stem, and the T stem and loop.380 The occurrence of an extra 5'-guanosine residue on the amino acid acceptor stem of tRNAHis from B. subtilis or E. coli following processing by RNase P is a consequence of the precursor structure at the amino acid stem: the cleavage site can be altered by a single base change.381 The protein component of
RNase P appears to modulate the atypical cleavage in mutant precursors by M1 RNA. Mutants of MI RNA with base changes in the UGAAU sequence complementary to the GTvCR sequence found in all E . coli tRNAs did not show significant changes in cleavage activity, suggesting that base pairing interactions between these sequences are not essential for cleavage of the tRNA precurs0rs.38~ 5.4 Post-Synthetic Modification - Two general methods for ligating oligonucleotides to nucleic acids, or to proteins, via disulphide bonds have been described.383 To join two oligonucleotides, the 5'-phosphate of each unprotected oligonucleotide is condensed with cystamine using a water-soluble carbodiimide to give (187), the adducts are mixed, the disulphide bonds reduced with DTT, the DTT removed by dialysis and the disulphide bonds permitted to reform by aerial oxidation. Homodimers are of course formed as well as heterodimers. To conjugate oligonucleotides with thiol-containing proteins, (187) is treated successively with DTT and 2,2'-dipyridyldisulphide to give (188), which is then reacted with excess of the peptide or protein. A peptide lacking thiol groups may be treated with iminothiolane in order to introduce them. The efficacy of the method is well proven and it seems likely to find widespread use, for instance in preparing enzyme-linked oligonucleotide probes. Synthetic oligonucleotides complementary to unique sequences in the heat-stable enterotoxin gene of E . coli, with a 30-atom spacer arm and a 3'-terminal thiol group have been coupled to bromoacetylated alkaline phosphatase to afford probes for enterotoxigenic E . coli in clinical specimens.384 Other nucleic acid hybridization probes permitting non-radioactive assay methods have been prepared by treating active (s. N-hydroxysuccinimide) esters of biotin with alkanediamines, and cross-linking the resultant conjugates to nucleic acids using glutaraldehyde or diepoxyoctane, or v& iodoacetylation of the conjugate followed by alkylation of DNA.385 Treatment of DNA with NBS at pH 9.6 affords some S-brorno-2'-deoxyguanylateresidues besides other brominated residues, and subsequent treatment with "-(2,4-dini trophenyl)hexane-1,6-diamine gives 8-(6-~-(2,4-dinitrophenyl)aminohexyl)amino-2'-deoxyguanylate re~idues.3~~ The hapten (2,4-dinitrophenyl) can thus be attached to a DNA probe, permitting very sensitive detection of target sequences by use of a high-affinity anti-DNP antibody. Limited (a. 30%)bromination of the bases in poly[r(G-C)] has been shown spectroscopically to induce formation of a mixture of A and Z-conformations, the latter being stabilized at high ionic strength, while more extensive (B. 45%) bromination gives a Z-conformation at lower ionic strength.387 Antibodies to ZDNA were able to recognize the Z-RNA (is. brominated poly[r(G-C)I ) in an interaction apparently involving the phosphodiester backbone. Treatment of poly[d(G-C)] with formaldehyde and n-butylamine is believed to result in Nz(buty1amino)methyl substitution of the guanine bases, and low levels of substitution suppress the normally observed transition from the B- to the Zconformation seen in high salt.388 The introduction of the amine,which is
243
6: Nucleotides and Nucleic Acids
0 H2NCH,CH,S-SCH,CH2N-
H
11 I
P-O-
(oligonucleot ide-5')
01187)
0 S-S-CH,CH,N
H
11
-P-0-
I
(oligonucleotide-5'1
0(188) OH
H
R = H or Me
+H
//"
q S--N
HH
01
NH2
Gua-1
Scheme
+
L
( 19 0 )
(192) R = H ( 1 9 3 ) R = SO2NHCHzCH,N (CH,CH,NH,),
Gua-2\
244
Organophosy h orus Chemistry
positively charged at neutral pH, into the minor groove is thought to stabilize the Bform by electrostatic interaction. A reexamination of the reaction of bromoacetaldehyde with nucleotide residues at B-2 junctions in DNA and with the single-stranded loops of DNA cruciforms has shown that the residues at B-Z junctions do react with bromoacetaldehyde, but less readily than those at the cruciforms.389 The usefulness of the reagent for detecting unusual secondary structure remains valid. Chlorotetrolic esters react with adenine and cytosine bases in poly(A) and poly(C), the reaction discriminating between bases in single-stranded (reactive) and double-stranded (unreactive) tracts and thus possibly of similar use to bromoacetaldehyde in eliciting conformational information.390 Moreover, the reactive chloromethyl group introduced at the derivatized bases can be used to bind the modified polymers to other molecules. Treatment of d(TpT) with N-chloroethyl-N-nitrosoureaafforded both hydroxymethyl and chloroethyl phosphotriesters of d(TpT) among the pr0ducts.39~ Substitution at N3 occurred when 2'-deoxythymidine was treated similarly. When and poly(dT) was treated with "4C] ~-2-chloroethyl-~'-cyclohexyl-~-nitrosourea, the product annealed to poly (dA), the lesions resulting from chloroethyl phosphotriester formation were selectively repaired by an E . coli extract which transferred the chloroethyl group to bacterial protein. The hydroxyethyl phosphotriesters were chemically too unstable to be assessed as substrates for repair. There is a consensus between leading workers in the field that the modes of repair of alkyl phosphotriester and Qalkylpyrimidine lesions in nucleic acids in mammalian cells differ from those characterized in E . coIi.312 A regioselective mechanism has been proposed to account for the site- and sequence-specific alkylation at Q6 of the second guanine base in d(GGN) sequences which is related to the mutagenic and oncogenic properties of MNU and ENU.393 Evidence has been marshalled against the likelihood of alkylation by a carbocation, and it is instead proposed that addition of the imidourea tautomer occurs at 0 6 of guanine-1, to form an intermediate (189) in which the alkyl group is oriented correctly for alkylation of 0 6 (or N7) of guanine-2 (Scheme 4). Following alkylation the unstable by-product (190) decomposes to afford firstly the @-carbarnate and subsequently unchanged guanine-1. The observed sequence preference of uracil and quinacrine mustards in alkylating guanine at N7 in 5'-d(YGC)-3' sequences (Y=pyrimidine) has been ascribed to hydrogen-bonding by the mustard at N4 of the cytosine base serving to position the aziridinium moiety adjacent to N7 of the guanine.394 Reaction rates involving other mustards were attributable to effects of nearest-neighbour base pairs on the molecular electrostatic potential near the reaction site. The bioactivation of the carcinogen ethylene dibromide involves initial conjugation with glutathione, and data consistent with the formation of an episulphonium intermediate prior to attack at N7 of guanine residues has been 0btained.3~5 Two Wmer oligodeoxyribonucleotides containing a single thymine residue
6: Nucleotides und Nucleic Acids
245
close to the 5'-end have been treated with osmium tetroxide to introduce a single thymine glycol residue in each, annealed to a 14-mer primer complementary to the first 14 bases from the 3'-terminus, and the effect of the thymine glycol lesion upon copy synthesis studied.396 Synthesis by Klenow fragment, by T4 DNA polymerase, and by polymerase a2 was arrested quantitatively at the site of the lesion, while AMV reverse transcriptase was less inhibited. While dAMP was generally inserted opposite the lesion, it was also perceived as a misinsertion by enzymes with 3'exonuclease proofreading functions, contributing to the apparent inhibitory effect of the lesion on DNA synthesis. Upon treatment with dimethyl sulphate, adenine bases in non-duplex regions of mRNA are methylated and arrest reverse transcription, while those in duplex regions are not methylated and do not.397 Analysis of the pattern of transcription arrest may be used to obtain information on mRNA secondary structure in ribonucleoprotein particles. End-labelled (dT)lo has been annealed to poly(dA) and irradiated at 290 nm to generate 'photoligated' oligomers of 20, 30 and 40 nucleotides in length, which were B. Under fluorescent light, used as substrates for the gene product of E . coli efficient photoreversal of the dimerisation was seen, demonstrating that DNA cyclobutane pyrimidine dimers with a cleaved internal phosphodiester bond can undergo enzymic photocleavage.398 The characteristics of the photoreactions of three different psoralen derivatives with a complementary 14-base pair tract containing a single d(TpA) site (the favoured site for reaction) have been studied, and differences in sequence specificity for the formation of monoadducts and crosslinks, and in strand selectivity, could be demonstrated.399 A supercoiled M13 DNA molecule containing a site-specifically placed psoralen monoadduct has been constructed via chemical and enzymatic synthesis and ligation, and the psoralen found to pose a severe block to T4 DNA polymerase holoenzyme when attached to thymine either via the furan side or v& the pyrone side.400 A thiol-containing psoralen derivative has been photoadducted to plasmid DNA (containing a singlestranded tract as a hybridization site) and the thiol used to attach(v& a maleimidepoly (L-1ysine)bridge)diethylenetriamine pentaacetic acid as a chelating site for fluorescent europium ions.401 The resulting conjugate, detected by time-resolved fluorometry, gave good sensitivity of detection in dot-blot hybridization assays. The intercalation and binding of carcinogenic hydrocarbon metabolites to nucleic acids has been reviewed.402 Octadeoxythymidylate linked to the intercalator 9-aminoelliptiane (191) is easily made by treating d[(Tp)sA] with acid to effect depurination, followed by condensation with 9-aminoellipticine and reduction with cyanoborohydride, the depurinated deoxyribose thus affording a 3,4dihydroxypentamethylene linker which may subsequently be cleaved with periodate, if desired, to release the intercalator.403 The intercalator enhanced the stability of binding of (191) to poly(A). Details of the synthesis of alkylating derivatives of oligodeoxyribonucleotides with a 5'-terminal intercalating _N-(2-
246
Organophosphorus Chemistry
oxyethy1)phenazinium attachment (see also ref. 356) have been g i ~ e n . ~ M The intercalator was attached via alkanediamine linkers, one end of which formed a 5'phosphoramidate link to the oligonucleotide, and substantially enhanced the stability of the complex formed by an attached heptamer with a part-complementary 12-mer. The presence of the intercalator at the 5'-end of the heptamer increased the efficiency and rate of alkylation by a 3'-terminal 4-(N-2-chloroethyl-Nmethylamino) benzylidene moiety of the part-complemen tary 12-mer, but did not affect the specificity of the alkylati~n.~oS When single-stranded DNA containing a (dG)l8 sequence was alkylated by oligodeoxyribocytidylate[(dC)n; n= 9 or 151 bearing a chemically similar 5'-alkylating terminus, gel analysis of the cleaved products showed that alkylation occurred at the 3'-side of the (dG)l8 target sequence consistent with initial antiparallel duplex formation, but when double-stranded DNA containing a (dG)fs.(dC)18tract was used as the target, alkylation occurred at the 5'-side of the (dG)ls sequence, suggesting that a triple-stranded complex (dG)ls.(dC)ls.(dCH+)12had been formed initially.406 The reactivity with the target DNA was highest at pH 4.5, consistent with this finding. The enzymatic construction of mutants of tRNA continues to yield fascinating results. The introduction of a G.U base pair as the third base pair in the acceptor stem of tRNACYS and tRNAPhe species from E . coli permits these molecules to become charged with alanine, showing that a single base pair can direct an amino acid to a specific tRNA m o l e ~ u l e . ~Conversely, 0 ~ ~ ~ ~ substitution in the G.U base pair in the corresponding position of tRNA*la abolished the ability to become charged with alanine.407 Changes in the anticodon loop sequence, adjacent to the guanine residue replaced by glycosylated queuine in the maturation of certain yeast tRNA species, have been found to affect the glycosylation process, rather than the replacement of guanine by queuine, when the tRNA species are microinjected into Xenopus Iaevis oocytes.409 An unusual tRNA species identified in E . coli with an anticodon complementary to the UGA 'stop' codon is charged with serine by seryltRNA ligase, the serine being subsequently converted to selenocysteine.410 The tRNA thus behaves as a natural UGA suppressor. 5.5 Metal Comdexes - Treatment of hexaaquochromium (111) with ADPPS, ATPPS and ATPyS, respectively, affords the exchange-inert chromium complexes a$bidentate Cr(H20)4 ADPPS, Py-bidentate Cr(H20)4ATPPS,and py-bidentate Cr(H20)4ATPyS.411The stereoisomers were separated by reverse-phase h.p.l.c., and subjected to stereochemical analysis, the configurations at Pa in the Cr(H20)4 ADPPS isomers and Pp in the Cr(H20)4 ATI'pS isomers being established by bromination in water to afford isomers respectively of Cr(H2014ADPand Cr (H20)4 ATP which were compared with standards of known configuration, and the configuration at Pa in Cr(H20)4ATP@ being identified by treatment with nucleotide pyrophosphatase and comparison of the product with standards of tetraaquochromium (111) monothiopyrophosphate prepared independently. The compounds afford a set of
6: Nircleorides orid Nucleic Acids
247
new chiral active site probes for enzymes. In a spectrophotometric study of the binding of cupric ions to ATP, close correlation was found between the rate of dephosphorylation of ATP in the presence of Cu(I1) and the binding of the metal ion to the adenine base, supporting the hypothesis that metal ion-base interactions are prerequisite for metal ion-promoted d e p h o s p h o r y l a t i ~ n .Incubation ~~~ of cupric isonicotinohydrazide with DNA seems to result in binding of the cupric ion to phosphate oxygen of the backbone, as evidenced by 31P n.m.r., and subsequent cleavage of the DNA, a reaction which is not elicited by cupric ions or isonicotinohydrazide applied inde~endently.~l3 More evidence for the interaction of cupric ions, and also lead (11) ions, with the phosphate groups of DNA comes from a laser Raman spectroscopic study.414 While the lead ions were found to interact only weakly with the base pairs, the cupric ions were found to bind strongly to guanine and cytosine, disrupting the double helix. N.m.r. spectroscopic evidence indicates that the antitumour agent bis(cyclopentadienyl)molybdenum(II) chloride reacts with disodium AMP to form a complex in which molybdenum is chelated directly by N7 of adenine and a phosphate oxygen function?'5 and FAB-m.s. data suggest that diaquodiaminoplatinum(I1) triflate with equimolar GMP forms a complex in which chelation by phosphate and N7 of the base are similarly seen.416 The structural aspects of platinum antitumour drug interactions with DNA have been reviewed.417 A duplex E . coli bacteriophage M13 genome,in which a single c&dichlorodiaminoplatinum(II) (&-DDP) adduct was incorporated crosslinking two adjacent guanine bases at a Stu I restriction site on the minus strand, has been constructed and the cross-link found to inhibit completely cleavage by the restriction enzyme.418 Removal of the cross-link using cyanide restored the susceptibility to cleavage. The presence of such a cross link in the plus strand of a single-stranded genome of the bacteriophage was lethal, but did not affect survival of a double-stranded bacteriophage. In a study of cis-DDP-induced mutations in E . culi, most mutations were found to be single base-pair substitutions occurring at d(ApG) and d(GpG) sites, ik. at the potential sites of &-DDP adduct formation, with the former more mutagenic and tending to lead to transversion mutations.419 cisDDP reacts with [d(C-G)], (n=4or 5) and also with p~ly[d(G-C)]to form both interstrand and intrastrand cross-links, with the latter predominant when poly[d(GC)] reacts with low concentrations of the drug.420 The links are formed between two guanine bases. The trans-isomer of the drug was found to be more efficient at forming interstrand cross-links in uitru. On treatment of [d(ApGpGpCpCpT)]z with trans-DDP, a predominant monofunctional single stranded adduct is obtained, in which the platinum atom is coordinated to N7 of adenine1 and guanine-3, the intervening guanine being destacked from its n e i g h b o ~ r s . ~ Some z ~ polymeric species, probably the result of interstrand cross-linking, are also seen. Trans-DDP reacts with DNA to form initially monofunctional adducts at guanine bases,which
a-
248
Organophosphorus Chernistry
may rearrange slowly to form bifunctional adducts, a faster process in singlestranded DNA than in duplex DNA, but which react rapidly with sulphur reagents such as thiourea and glutathione to limit further damage.422 Trans-DDP has also found use as a reversible RNA-protein cross-linking reagent, the reversal of crosslinking being achieved using thiourea.*23 A ruthenium (11) complex, containing two 4,7-diphenyl-l,lO-phenanthroline (192) ligands and one similar ligand (193) bearing in addition two trien moieties for chelating metal ions, has been found to bind to closed circular double-stranded DNA to afford nicked and linearised DNA following activation with cupric ions.424 The reaction is enhanced by adding hydrogen peroxide. At low copper: ruthenium ratios more single stranded cleavage is seen, presumably because only one trien site is occupied by copper, but with increasing copper concentration, double-stranded cleavage becomes dominant. The complex can be activated as a cleavage reagent by redox active (copper (111, cobalt (11)) ions, and also some ions which are non-redoxactive (zinc (II), cadmium (II), lead (II)).425 The latter group appear to catalyse phosphodiester bond hydrolysis to give both 3'- and 5'-phosphate termini, of which some 40% can be religated with T4 DNA ligase. In contrast, the cleavage sites generated using the (far more active) redox-active metal ions are seldom able to be ligated. It is thought that the non-redox-active metal ions chelated by the trien group become coordinated also to the phosphodiester link to promote hydrolysis. ATris(3,4,7,&tetramethyl-l,l0-phenanthroline)ruthenium (11) binds cooperatively and specifically to DNA in the A conformation to cause photocleavage, probably via the agency of singlet oxygen, and preferentially at guanine residues, on irradiation with visible light.426 The excited state of tris (1,4,5,8-tetraazaphenanthrene)ruthenium (11), which unlike the excited states of tris(1,lO-phenanthro1ine)ruthenium(11) and tris (2,2'-bipyridy1)ruthenium (11) is strongly quenched upon binding to poly[d(G-C)l and calf thymus DNA, is much more effective at causing cleavage of the DNA backbone.427 The complex appears to intercalate initially, and cleavage, thought probably to involve singlet oxygen, occurs predominantly at guanine residues. In a DNA segment containing a 200 base pair tract capable of bending, the proportion of highly bent molecules could be increased up to thirty-fold by incubation with metal (zinc, cobalt, barium or manganese) cations, demonstrating that sequence-directed bending is an inducible phenomenon.428 Terbium (111) ions quench the fluorescence of ethidium bromide bound to double stranded RNA very much more strongly than that'of ethidium bromide bound to single stranded RNA or DNA or double stranded DNA429 This difference can be used to detect double stranded RNA among other nucleic acids in separating gels. 6 . Analytical Techniaues and Phvsical Methods The uses of h.p.1.c. in separating DNA restriction fragments430 and for the resolution of RNA431 have been reviewed. DNA restriction fragments of up to 500-
6: Nucleotides and Nucleic Acids
249
600 base pairs in length are also separated efficiently by f.p.1.c. ion exchange chromatography on Mono Q and Mono P columns, in high recovery yields.432 5'-QDimethoxytritylated oligodeoxyribonucleotidescontaining strong secondary structure may be denatured in strongly alkaline (0.5 M NaOH) conditions and purified by reverse-phase h.p.1.c. on PRP-1 columns without alkaline damage to the heterocyclic b a ~ e s . ~ 3Reverse 3 phase ion-pair chromatography of large oligodeoxyribonucleotides using tetra-n-butylammonium phosphate as ion pairing reagent and a linear gradient of acetonitrile concentration has been found to afford effective separation.434
The quantitation of 5-methylcytosine in DNA has been achieved by hydrolysis in 48% hydrofluoric acid at 80°C to remove the bases, and separation and quantitation of the bases by h.p.l.c.435 This procedure avoids the deamination of cytosine and 5-methylcytosine which occurs on removal of bases with mineral acids. The separation of modified bases formed in DNA adducts (s. 04-ethyl-2'deoxythymidine) has been achieved by h.p.1.c. on a silica column derivatized to carry ligands which mimic the hydrogen-bonding functions of nucleic acid bases.436 A book on 3l P n.m.r. spectroscopy in stereochemical analysis which includes much material on nucleic acids has appearedj37 and a review on stereoelectronic effects in biomolecules also includes much discussion of the 31P n.m.r. shift as a probe of DNA str~cture.~38 Studies of the interaction of ADP and ATP with cadmium (11) and mercury (11) ions using 31P n.m.r. indicate that cadmium is apparently coordinated by base and phosphate groups, while mercury is coordinated to phosphate and the N1-side of the base in ADP and ATP at pH 3.439 In the absence of the metal ions, the nucleotides adopted predominantly the conformation at low pH. Multinuclear n.m.r. evidence indicates that deuterated &-bis(methy1amino)diaquoplatinum (11) forms monomeric macrochelates with purine nucleoside 5'-triphosphates in which the platinum atom is coordinated to N7 and an oxygen atom of the y-phosphate group.440 A 3IP n.m.r. titration of ATP with adenylate kinase, together with other evidence, suggests that, in the absence of magnesium ions, ATP binds only to the Mg.ATP binding site of the enzyme, and not to the AMP binding site.441 In studies of ATP resonances during ischaemia in perfused rat liver, the ATP levels appeared to decrease much faster than the total ATP as measured in tissue extracts.442 It is thought that, for reasons which are largely conjectural, ATP (and ADP) sequestered in the mitochondrion are 'n.m.r. invisible', and that the observed n.m.r. signal reflects only cytosolic ATP. A 3IP cross-polarization magic angle spinning n.m.r. study of 2'-CMP bound to ribonuclease A in the crystalline state has been performed .443 A new method which permits the measurement of previously unresolvable 3 J ~ ~ couplings, o p to obtain extra structural information about the DNA backbone,
consists in using semiselective pulses in the course of the normal pulse sequence which effectively suppress all other multiplet splittings.u4 Regiospecific labelling with oxygen-17 to eliminate selectively the resonance of an attached phosphorus nucleus from the 31P n.m.r. spectrum is a valuable method for assigning chemical shifts, as exemplified in the n.m.r. analysis of a symmetrical 14-base pair DNA fragment.445 31Pn.m.r. has also been used to show backbone perturbation in a selfcomplementary oligodeoxyribonucleotideduplex containing two 1.A base pair mi~matches4~6, and in a duplex self-complementary except for an extra adenosine 'bulge' in each strandu7, and in a duplex self-complementary except for an adenine base opposite an abasic site.4483IP N.m.r. and other spectroscopic studies of a 16-mer duplex designed to contain a B-Z junction indicate that in high salt concentrations part of the duplex is indeed in the B conformation and part Z, with the junction ~ 9binding of actinomycin D to selfitself spanning 4 to 6 base p a i r ~ . ~The complementary oligodeoxyribonucleotides containing multiple adjacent d(GC) sites has been characterized using 31P n.m.r.450 and the sequence-dependence of conformational changes induced by the presence of 5-methylcytosine on oligoribonucleotides has been dernon~trated.~5~ The effect of ethylation of the phosphate backbone on the stability and conformation of the DNA double helix has been investigated by monitoring the 31P (and imido proton) resonances of the selfassociating duplex d(CCAAGp(Et)AlTGGl (both and 5 stereoisomers), an identical but non-ethylated sequence, and the complexes of these sequences with a fully complementary sequence.452 The presence of the ethyl group did not perturb base pairing, but did perturb the backbone, the isomer more so than the & with the perturbation being transmitted along the helix. A book on the dynamics of proteins and nucleic acids453includes much coverage of their investigation by spectroscopic methods. The dynamics of the RNA in alfalfa mosaic virus have been investigated using 31P n.m.r. spectroscopy, the data suggesting that the RNA is held rigidly inside the virion at low temperature but exhibits internal mobility at higher Solid-state 3IP n.m.r. studies of the isotropic to cholesteric transition in the liquid crystalline phase of 146 base pair fragments of DNA have been performed, and a phase diagram obtained for the transition .455 Raman spectroscopy has attracted increasing attention as a means of characterising nucleotide and nucleic acid structure. The interaction of magnesium ions with ATP at pH 3.0 and 7.5 has been investigated by i.r. and Raman spectroscopy, using ATP molecules variously substituted with l 8 0 at the a,p and y phosphates and in the bridge positions, both in the presence and absence of magne~ium.~56 The isotopic substitution permitted certain absorption bands to be assigned to specific groups. It appears that at pH 3.0, with the y-phosphate protonated, [Mg.ATP]-exists as a mixture of aP, and ay bidentate complexes,
6: Nucleotides and Nucleic Acids
25 1
while at pH 7.5 a mixture of Py and aPy (tridentate) complexes is obtained. Raman spectroscopy of 2-5 A and model compounds showed marked differences between 2'5'- and 3'-5'-linked oligoadenylates in the region of the spectrum arising mainly from phosphate vibrational modes, and suggested that the phosphodiester backbone may be more restrained in the biologically active 5'-triphosphorylated 2-5 A than in the core trimer.457 The pH-dependence of the Raman spectrum of &bromo-5'-AMP has been Raman, n P n.m.r., and other spectroscopic studies of poly(GC)permit two distinct forms of 2-RNA to be distinguished, one (ZR) observed in high sodium chloride or perchlorate solutions with a characteristic CD spectrum, the other (ZD) in high magnesium chloride solution with a CD spectrum similar to that of p0ly[d(G-C)1.~59The Raman spectra reveal that the forms differ in backbone geometry. In high salt concentration, the addition of small amounts of nickel (11) ions to poly[d(A-C)].poly[d(G-T)]causes a change from B to 2 conformation, as shown by changes in the phosphodiester backbone absorption lines (and 0thers).~60 The interaction of the nickel ion with N7 of the purines is critical in promoting the transition. Similar observations have been made for poly[d(A-T)1.461 Changes in phosphodiester backbone geometry for poly(rA).poly(dT) with physical state have been observed by Raman spectroscopy, the duplex exhibiting a conventional Ahelical structure in fibres at low relative humidity but A- and B-forms, deriving from 3'-endo-riboadenosine and 2'-endo-deoxythymidine residues, in s0lution.~6~ In the B-helical dodecamer d(CGCAAATlTGCG), the backbone torsion angles in the CGC and GCG sequences appear by Raman spectroscopy to differ significantly between the structures in the crystal and in solution, with a greater heterogeneity of sugar puckers and backbone torsion angles in the crysta1.463 Raman spectroscopy has also been used to investigate the heterogeneity in phosphodiester group geometry found in the encapsidated single-stranded circular DNA genomes of the filamentous bacteriophages!& and the changes in phosphodiester conformation occurring upon complex formation between poly(rA) or poly(dA) and DNA binding protein gp 32 of bacteriophage T4.465 Band assignments in the FT-i.r. spectra of oligo- and polynucleotides have been made by comparison with the Raman and i.r. spectra of their constituent monomers.466 Electrically neutral, protected dinucleoside monophosphates of the type used in oligonucleotide synthesis have been analyzed by FAB-m.s. in the negative ion mode, and afforded simple spectra which included sequence-specific ions resulting from C-0-P bond cleavage.467 Using a similar technique with small oligonucleotides (ribotrinucleotides and trimers to hexamers in the deoxyriboseries), metastable decompositions involving loss of base and elimination of neutral CONH were observed in all cases, but the base loss afforded information on the bases present rather than their sequence.468 The chemistry consequent on collisional activation altered with chain length, and the sequence ions observable
252
Orgariophosp h orus Chemistry
for short chains due to progressive fragmentation from the 3'-terminus became masked due to different competing fragmentation processes becoming favoured with increasing chain length. In a study of Californium-252 plasma desorption m.s. of homo- and heterooligomeric nucleoside methylphosphonates, however, use of the negative ion mode with heteroligomers revealed that 3'-C-0 bond rupture occurred to leave a negative charge on the methyl phosphonate, and it was possible to sequence short fragments in the correct The association of polyintercalators, containing between two and six acridine rings, with DNA during polyacrylamide or agarose gel electrophoresis is sufficiently efficient to retard its migration, due to the combined effects of charge neutralization and helix extension.470 The effects observed are sequencedependent and may serve to separate DNA fragments which would otherwise comigrate. The anomalous low mobility of large open circles of DNA on gel electrophoresis in high electric fields has been examined and interpreted using a model in which large open circular forms are trapped by engaging the free end of an agarose gel fibre.471 Hoop-La! Examination of a salt- or alcohol-induced conformational isomerisation in the poly[d(2-amino A-T)] duplex by CD spectroscopy suggests that the alcoholinduced conformation is the same as the non-Z zig-zag double helix previously observed in poly [d(A-TI],and is stable.472 Bolaamphipiles containing positively charged quaternary amines and electroneutral mannose residues have been used to coat negatively charged nucleic acids in an electroneutral coating, and may be of use in effecting tran~fection.~~3 A tFWA molecule coated with amphiphiles of this type was taken up by macrophages, while the uncoated tRNA was not. The electrostatic potentials associated with 16SRNA474 and with tRNA475 as determined by ionic conditions, the state of the RNA, and association with proteins, have been measured by observing the pKa shifts of attached fluorescein derivatives.
6: Nucleotides and Nucleic Acids
1. 2.
3. 4.
5. 6. 7. 8. 9. 10.
11. 12. 13. 14.
15. 16. 17. 18.
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6: Nucleotides and Nucleic Acids
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Ylides and Related Compounds BY B. J. WALKER
1 Introduction Perhaps the most striking feature of the year is the extent to which phosphorus-based olefination continues to be used as the method of choice for the synthesis of alkenes from the simplest to the most complex. That the formation of trans-oxaphosphetanes is thermodyndmically-favoured, while that o f cis-oxaphosphetones is kinetically-favoured is the latest aspect of the mechanism of the Wittig reaction to be refeuted. 2 Met hy 1enephos p hor dries
2.1 P r w a-r a _ t- i_ o_n _ and _ ~ Structure.- A new
ab-Lnltb
M.0
study of the
simplest ylide ( 1 ) compares the parameters produced with those calculated for the corresponding phosphine oxide (2 and related anions (3). (4) and ( 5 ) . ' forms ( 6 ) . (4)
The results suggest that the dipolar
(7) and ( 8 ) dre major contributors to the structures ( 3 ) ,
and (5). respectively.
AG
values for the rotation barriers of
mcthoxycarbonyl groups have been determined for ylides (9). (10). (-L1)
dnd (12) by low temperature
'€1
n.m.r.'
The electrochemically-generated radical anion of the quinoncmethidc (13) and re]-ated dianions have been successfully used
as bases in the Wittig rcaction.3
A further report of Wittiy
reactions carried out under heterogeneous conditions involves generation of the ylides (both reactive and semi-stabilised) by reaction of an organic phase containing the appropriate phosphonium salt and aldehyde with hydrated solid alkaline hydroxide (see also Section 3 )
.4
A variety of semi-ylidic phosphonium salts (9. 16) have been
obtained from alkylation of t r i - ( 1 4 ) and tetra- (15) phosphinoallenes under appropriate conditions. Attempts to remove two protons from the cyclopropyl bisphosphoniuin salt (17) led to the carbodiphosphorane ( 1 8 ) rather than the expected double ylide.6 The renewed interest in arsenic ylides continues. The synthesis and reactions of a variety of new arsenic ylides (e.g.
19) and mixed
arsenic phosphorus ylides ( ~ g - 20) , have been reported.-'
Attempts
268
Organ oph osph orus Chemistry
H, PO
H3PCH2
+
-O-PH,-O-
H,PO,-
-
OPH,CH
+
,-
+
-
O-PH,-CH,
H,P (CH,);
CH,-PH,-CH,
-
0
OH
( 9 ) R = H, X = N (10) R z C02MeJ X = N ( 1 1 ) R = C02MeJ X = CH
BuQ 'Ph :
(12)
Ph2P
(14)
MePh P *;>C-C=C-&McPh, McPh,P
PPh,
PPh, Ph,P
'/
I(1 6)
269
7: Ylides and Related Compounds
+ 2 Et3P=CH2Me
2x-
+
A
-PPh2Me (17)
(18)
McPhzAs = CH-AsPh2
McPh,P=
CH-AsPh,
(20)
(19)
McPh,P=C=AsPhzMc (21)
+
Ph,PCH2X
X-
+
RSNa
R S X + RSNa Ph,P=CCH, Ph3kHzSR
SR
+
+
RSSR
+
Ph3P=CH2
-
+
RSSR
+
+
Ph,PCH,SR
XScheme
1
+
NaX
NaX
Ph3;)CHZSR
Ph36CH2X X -
RSX
RS-
+
Ph,P = C H 2
+
RSX
270
Organophosphorus Chemistry
to prepare the carbodiarsonane ( 2 2 ) were unsuccessful, although the phosphorus-arsenic analogue ( 2 1 ) was obtained. Surprisingly, reactive ylides appear to be the intermediates in reactions o f ( a - h a l o a l k y 1 ) p h o s p h o n i u m salts with simple sulphur nucleophiles.8 The initial step in the reaction is thought to be attack of sulphur nucleophile on halogen to give the methylene ylide (23) followed by a step-wise chain mechanism (Scheme 1). D i a z o m e t h y l e n e p h o s p h o r a n e s (25) have been prepared for the first time by reaction o f the diazomethylphosphine ( 2 4 ) with carbon tetrachloride or tetrabromide.’ The ylides ( 2 5 ) undergo a variety o f reactions (Scheme 2) and offer potential as synthetic reagents. The benz-azaphosphinones (27) have been synthesised by base-induced intramolecular cyclocondensation of phosphine imides (26). The fluorinated phosphoranium salts ( 2 8 ) . which contain an ylide function, have been prepared in excellent yields by the reaction of phosphines with fluorotrihalomethanes in a three to one The reactions of (28) have been thoroughly investigated. ratio.” The unusual phosphorus ylide (30). containing a P - P bond has been obtained after prolonged reaction times by treatment o € the ... phosphine carbanion (29) with bismuth trichloride.” Reactions of Methylgnephosphoranes Aldehydes.- The kinetic preference for cig-oxaphosphetane, and hence a - a l k e n e , formation and the thermodynamic preference for trans-oxaphosphetane, and hence ttns-alkene, formation are the latest aspects of the wittig reaction to be refuted. The Wittig reaction o f the stabilised ylide ( 3 1 ) with c y c l o h e x a n e c a r b o x a l d e h y d e gave a 95:5 (E):(Z)-alkene ratio. However, in a series o f elegdnt experiments, Vedejs has shown conclusively that this i s due t o -kinetic-control .-e.i( the trans-oxaphosphetane is formed fastest) and not due to the generally accepted oxaphosphetane equilibration reversal to ylide and aldehyde.13 While at low temperatures the base-catalysed decomposition of the diastereomerically pure tiydcoxy phosphonium salt (32) is stereospecific to yive alkene, at room temperature substantial amounts o f (E) alkene are formed. However, 2.2
2.2.1
(z)
even this loss of stereospecificity is not due to reversal to ylide and aldehyde, but rather to competitive formation of the ylide (33) and the betaine ( 3 4 ) as shown i n Scheme 3 . The ylide (33) can then react by proton transfer to give a mixture of diastereomecic betaines and hence ( g ) - and (Z)-alkenes. Vedejs has also shown that (E)-alkenes can be prepared highly stereospecifically by the
27 1
7: YIides and Related Compounds
x
IN*N
(Pri,N),P=C
/
x (Pr'zN)zP-
CH
II
\C,NPh
I
0
--b (Pr'2N)2P=C = N,
lPr',N),PX
+
N2 (2L1
125)
X
I
N2
(Pri N) P--c&
I
0-CHPh
0
II
1Pr N l2 P C Z C P h
Scheme 2
(27)
(26)
CHZCl
3R3P
+
CFC13
+R3PCFPR3
(28 1
Cl-
Carbon
272
Organophosphorus Chemistry
(301
(29)
C 0,Et I
(311
MeoMe LI
Reagent.
i,
Me
Scheme
3
7: Ylides and Related Compounds
273
reaction of the d i b e n z o p h o s p h o l e - d e r i v e d ylides (35) and ( 3 6 ) with aliphatic aldehydes under salt-free conditions .14 Although the ylides react rapidly to give the oxaphosphetane intermediates decomposition to phosphine oxide and alkene requires relatively 3 0 minutes at 110OC). vigorous conditions (3.
31P n.m.r. studies
of reactions at low temperatures and the stereochemistry of alkenes obtained by the decomposition of isomerically pure oxaphosphetanes indicate that the (1)-selectivity observed in these reactions is due to a kinetic p r e f e r e n s for formation of trans-oxaphosphetane (37) rather than thermodynamic control.
The reactions of alkylidene
ylides with acylsilanes (38) have been investigated.15
Since the
preference for cis-stereochemistry in Wittig reactions of reactive ylides with aldehydes is enhanced by increasing bulk of the aldehyde and acylsilanes are known to act as sterically-modified aldehydes, these reactions promised to increase the flexibility of stereo-control.
This appears to be the case since the reactions are
reported to be highly (TI-stereoselective, although the yields are reduced by competitive formative of acylsilane enolate and in the case of salt-free ylides this is the only observed reaction and no alkene is formed.
This last result suggests that non-lithium salt
catalysed pathways to alkcne do not operate in this system and so the reactions could provide a new probe in studies o f the Wittig reaction mechanism.
The authors draw conclusions concerning the
3 9 ) involved and structure o f the oxaphosphetane intermediates (3.
use these to explain their own results and those reported by others. Although the coordination chemistry of ylide-anions (40) has been extensively investigated by Schmidbaur, the use of (40) as synthetic reagents has been almost totally ignored.
Cristau now
reports that (40) are more reactive than the corresponding ylides, but react in a similar way, undergoing alkylation and the Wittig reaction with aldehydes.16 However, they differ €rom ylides in that Wittig reactions can be more easily achieved with esters and amides, although not with enolisable ketones. The reaction o f one and two equivalents of benzaldehyde with the ylide anions derived from the salts (41) gives excellent ylides of stilbene with high (g)-stereoselectivity (Scheme 4) .17
Generally reactions with a
second equivalent of benzaldehyde show greater (E)-selectivity than are also do those with one equivalent. Ylide-anions ( e ~ 42) . formally the intermediates in reactions of X5 phosphinines with base and aldehydes. l8
Orgutiophosphorirs Chernistrj,
274
(35) R = Me (36) R = C,H,
+
RCOSiMe,
(37)
Ph,P =CHR’.
LiX
-
Si Me, R‘
138)
R
+ ,CHR
Ph P
( L O ) R = H, Et, Ph, CH=CMe2, COPh
(39)
-
R1R2i(CH,Ph), Br-
+,CHPh R’R’P,
-!-+ R 1 R 2P-,
C H,Ph ( L 1 ) R’
1,
eHPh CHPh
L i+
2PhCH=CHPh
R’ = Ph, R2 T CH,Ph R ’ = R2 = CHZPh
Reagents:
0
-%A
= RZ = Ph
R1,Rz =
Li+
‘CHR
f&-fJ BuLi, T H F ; ii, Z X P h C H O
Scheme 4
275
7: Ylides and Related Compounds
-b
Ph
Ph
LDA
Ph Me’
PM h& e’ P h ‘Me
Ph
‘CH,LI
+
Ph3P=CHX
NHAc CHO
R
+ +
A
Bu,P
I
11,
Ill
n = 1 , 2 or 3 Reagents
I,
P d ( P P h 3 ) & , THF,
MeOH,
11,
BULB;
111,
RCHO
Scheme 5
OX R’R2R3
Me Ar3P=CHiHXR’R*R3 ( L 6 ) X = Si ( L 7 ) X = Sn
I
+
PhCH,CH,CHO
A
PhCH,CH,CH
XH
H
Me
276
Orgun op h osp h orus Chernistry The use of formylmethylene ylide in Wittig reactions can lead
to the formation of diene aldehyde competing with en01 formation.” In these cases a step-wise procedure using an ester-stabilised ylide followed by reduction to aldehyde is preferred. Thiazolyl-(43) and benzothiazolylL(44) m e t h y l e n e t r i p h e n y l p h o r a n e s provide alternatives to formylmethylene ylides and have been used to synthesise the extended-chain amino sugars (45) .”
A
new highly @-stereo-
selective route to dienes involves a one-pot procedure to generate The salt and ylide and carry out the wittig reaction (Scheme 5).’l use of triphenyl rather than tributylphosphine in the reaction sequence leads to much reduced stereoselectivity. 1.3-Dienes are readily prepared stereoselectively from glyoxal monoacetal by phosphorus-based olef ination. 2 2 Highly stereoselective (g)-propenylation of aldehydes can be achieved using B-silyl-(46) or B-stannylL(47) phosphonium ylides .23 In the case of a-chiral aldehydes high diastereoselectivity is observed. ______2.2.2 Ketones.-
The known advantage of using high-pressures in
Wittig reactions of stabilised ylidesZ4 also applies to reaction of n - b u t y l i d e n e t r i p h e n y l p h o s p h o r a n e with sterically-hindered cyclohexanes . 2 5 The low reactivity o f stabilised ylides towards ketones has hindered the use of the Wittig reaction in the synthesis o f tri- and tetrasubstituted alkenes. It is now reported that a-hydroxy ketones react much more readily with ester stabilised ylides than do the parent ketones .26 Wittig reactions involving c y c l o p r o p y l i d e n e t r i p h e n y l p h o s p h o r a n e often give low yields. These yields are now reported to be greatly enhanced by the addition of the phase-transfer agent (48) to such reactions in THF.27 The cyclic salt (49) has been used in a one-pot reaction to synthesise 1,6-dienes &y two olef inat ions (Scheme 6). Dialkyl ( 2 , 3 - e p o x y - - 4 - o x o a l k y l ) p h o s p h o n a t e s (52) have been prepared for the first time by Wittig olefination o f the 1 - f o r m y l a l k y l p h o s p h o n a t e s (50) followed by epoxidation (Scheme 7).” Unfortunately in both steps, depending on the substituents, side-reactions occur to give (51) and (53). respectively. 2.2.3 Ylides Coordinated to Metals.- The reactions of the isovalent g o l d complex (54) with phosphorus ylides have been i n ~ e s t i g a t e d . ~ ’
Among the products obtained is the trinuclear complex (55) containing a double paddlewheel structure. Polyauriomethane compounds (e.g. - 57) are available for the first time by desilylation
277
7: Ylides and Related Compound5
Reagents.
I,
BuLI, R1R2C0,
BuLl,
11,
111,
PhCHO, I V , NaH, DMF, 5 0 ° C
Scheme 6
(511
(50)
0
0 R3
+ I E t O),P
R3
0 (53)
(52)
R e a g e n t s : i, Ph3P=CHCOR3,
11,
H202, N a 2 C 0 3 , MeOH, 1 0 ° C
Scheme 7
Organophosphorus Chemistry
2 78
CI-AU
I
-Au-Cl
CH
Me3P=C,
I
CH,
/H
+
SiMe,
-
PMe,
+
L[CIAuPPh31
3CsF
+
Cl-
+
2Me3SiF
+
3CsCI
+
[(Me3PCH2AuPPh3)C11
PPh, (57)
0 C p,U=CH
(58)
PMe,
(59)
II
(60)R = CH2SiMe3
279
7: Hides urid Reluted Compounds
of the ylide ( 5 6 ) . ” Other examples of ylide-gold complexes include (58).3 2 ‘ 9 7 h u Mcssbauer spectroscopy has been used to investigate the structure of a variety of polynuclear, mixed-valent ylide complcxcs of gold. 3 3 Novel ylide organometallics include the uranium derivative ( 5 9 ) . an X ray structure of which suggests significant uraniumcarbon multiple bond character, 3 4 and the rhenium derivative (60) where stabilisation of the ylide depends entirely on the metallic s u b s t i tuent. 3 5 2.2.4
Miscellaneous Reactions.-
The formation of alkenes from
reactions of phosphonium ylides with carbonyl compounds other than aldehydes and ketones has been reviewed.36 The reaction of phosphonium ylides with the t butyloxalyl iminoether (61) followed by reaction with hydroiodic acid provides a stereoselective synthesis o t protected a dehydro a-amino acids ( 6 2 ) (Scheme A similar reaction of o-halogenated atkylidene ylides with the oxamate ( 6 3 ) in the presence of excess base provides a convenient 38 route to heterocycl ic a-dehydro a-amino esters (64). Surprisingly good yields ( 4 0 . 6 0 % ) of fluorodienes are obtained by the one-pot sequence shown in Scheme 9 . 3 9 Temperature control i s important during the reaction involving methylenetriphenylphosphorane if the alternative mode of phosphine oxide elimination is to be avoided. The cycloaddition reactions of oxovinylidenetri phenylphosphorane (65) and g -p h e n y l i m i n o v i n y l i d e n e t r i p h e n y l phosphorane (66) with vinyl isocyanates and isothiocyanates have been investigated.40 The react‘ions are largely predictable in that they lead to C4-123 cycloaddition products (9. 67). A simple two-step synthesis of E-acylated 3-hydroxypyrroles is available from 41 the reaction of symmetric imides with phosphoranes (Scheme 10). lntramolecular olefination o f the y-acylphosphonium ylides (70) provides a route t o tetronic, thiotetronic and tetramic y - l a ~ t o n e s . ~ ’The ylides (70) are available from the y - lactones ( 6 8 ) either directly by reaction with triphenylphosphoranthe bromoacetyl derivative (69) (Scheme 11) ylideneketene or &y Flash vacuum pyrolysis of Zmethoxy-(71) and 2-methylthio-(72) b e n z o y l a l k y l i d e n e t r i p h e n y l p h o s p h o r a n e s provide synthesis of
benzofurans and benzothiophenes, respectively, in poor to good 43 yield. The reactions of reactive, ~ e m i - s t a b i l i s e dand ~~ ~ t a b i l i s e d ~ ~
Organophosphorus Ch enzistry
280
o=c
R’
,CO,Bu‘
/ OMe
\N=C
,CO,
But
A >c=c
R’
&
OMe
R2
‘N=C
\CHMe2
/
R2
‘CHMe,
’
(611 Reagents
I ,
/C02Bu‘
‘C-C
\NHCOCHM~~
(62) Ph P-CR’R’, 3
11,
H I , H20
Scheme 8
-+
,CO,Et
o=c
+ N ‘
______, 2 x ease
Ph3PCH,YBr
HC0,Me
I
Br-
C02Me
(63)
(64)
Me
Reagents
I,
(R,C0)20,
11,
P h P=CH2, 3
III,
PhLl,
Scheme 9
IV,
RCHO
7: Ylides and Related Compounds
28 1
- .0PP
PPh,
X
II
C +
II II
C
R
(65) Y = 0 ( 6 6 1 Y = NPh
RCO, NH
RCO/
(67)
+
Scheme 10
oT0g2
HX
BrY$:2
i , X
R'
\
Y
I
Y
J
Scheme 11
R'
-
2x2
FVP
XMe
R
(71) X = 0 (72) X = S
+
Ph,P=CHR
Sex
[Se=CHRI
+ Ph3PSe Me
I
+
Ph3PSe
Reagents
+ RCH=CHR
90°c, toluene;
1,
R
11,
x"' Me
S c h e m e 12
0
OC Me2COCl
I
+
Ph,P=CHCN
X
gqt
CHMez
X
CN
X
I
CN
Reagents:
1,
Et3N; Ii, 2 6 O - 2 7 O 0 C , 1 - 2 m m H g
Scheme 13
CN
7: Mides and Related Compounds
283
ylides with elemental Selenium are analogous to those with oxygen and give the appropriate alkene and phosphine selenide. The intermediate selenoaldehydes and selenoketones could not be isolated, but were trapped by dienes (Scheme 12). The fact that the formation o f alkene from the original ylide could also be achieved by catalytic quantities of selenium o r even triphenylphosphine ~ e l e n i d esuggests ~~ that unlike the Wittig reaction the final elimination step is reversible. Triphenylphosphonium ylides are oxidised to triphenylphosphine oxide and ketone or aldehyde by oxo(sa1en)chromium (v) complexes.46 Vacuum thermolysis of the stabilised phosphoranes (73). prepared as shown in Scheme 1 3 . gives 2tI-1-benzopyransor benzofurans or a mixture of both.47 I t is reported that, in aprotic solvents at least, a l k o x y c a r b o n y l m e t h y l e n e t r i p h e n y l p h o s p h o r a n e s react with alkyl propynoates and dialkyl acetylene dicarboxylates to give adducts (74) and ( 7 5 ) . respectively, by a [2+2]-type mechanism rather than by Michael addition and proton transfer as previously reported.48 The [ 2 i 2 ] - type mechanism is well established f o r stabilised phosphoranes which do not possess an a hydrogen atom. a - M a l o g e n o a l k y l p h o s p h o n i u m salts ( 7 6 ) have been prepared in good yields by reaction of the appropriate alkylidene ylides with perhalogenof luoroalkanes,49 presumably v& nucleophilic attack on ha logen. ._ 3.
Reactions _of _ _P h o 9 h o n a t e Anions -
Bases yenerated in s i t u . by electtochemical methods h a v e been used i n phosphorus-based oletin synthesis. I t is now reported that simple electrolysis of t h e appropriate phosphonate in the presence of carbonyl compound using platinum or glassy carbon electrodes
leads t o olefination.50 A thorough investigation of the use of activated barium oxide as the basic catalyst f o r phosphonate--based o l e f in synthesis under sonochemical conditions has been reported.51 The main advantage of using ultrasound appears to be the lower reac t ion t empcra tu re r equ i r ed5l' 5 2 and it is suggested that the base functions through initial SKT from its strong basic sites to the phosphonate. Attempts to u s e the irninoalkylphosphonates ( 7 ' 7 ) in olefination reactions l e a d in certain cases to rearrangement of the intermediate catbanion to t h e phosphoramidate anion (78) and hence to the 2-azadienes ( ~ 1 9 .)c'3 No such rearrangement is reported in the preparation u f cyclo nitronc spin traps (81) by [3+2] cycloaddition
Organophosphorus Chemistry
284
+
Ph,P=CHCO,R’
YCSCCO,RZ
Y = H, CO,R*
(7L) Y H ( 7 5 ) Y = C02RZ
+
Ph,P=CHR.LiBr
+
XCR,
Ph3P-CHXR
Br-
(76)
0
0
II
(RO), P C H,N=
NaH
C H Ar
______)
THF
II -
(RO),PCH N=CHAr
(77)
Ar’ C H =N-CH=CH
Ar
(79)
Ar’ CH 0
0
II -
(EtO),PCHN=CR’RZ
+
R3R4C=CHC02Et
0
II -
( R O ) , PN-
CH=
-
CHAr
(78)
R3
C02Et
R4%R: (81)
(80)
0
+
II
(EtO),PCH(CN)NMe2
Ho8, BuLt 3
,,-,C(CN)NMe,
&OR I
OR
R 0.-
(82)
(83)
7: Ylides and Reluted Compounds
285
of the phosphonate anions (80) to activated alkenes. 54 A Wadsworth-Emmons reaction of the phosphonate (82) has been used to convert y-lactols into a-cyanoenamines (83) and hence to S-lactones and c-hydroxy carboxylic acids. 55 Corey's modification hds been used to synthesise a variety of (E)-arylprop-1-enes (Scheme 1 4 1 . ~ a-Deuterated ~ alkenes (85) can be prepared in high yield with >90% deuteration by a one-step procedure involving reaction of the appropriate phosphonate (84) with aldehyde and 6 M potassium carbonate in deuterium oxide.57 The reaction i s successful presumably because the rate o f deuteration of phosphonate and olefination is much faster than deuteration of aldehyde; a two-step procedure involving prior deuteration of phosphonate gave slightly higher yields. Reactions of the ketone ( 8 6 ) with tetraethylmethylenebisphosphonate carbanion and tetraethylfluoromethylenebisphosphonate carbanion provide the a-vinylphosphonates (87) and (88). ~ e s p e c t i v e l y . ~In~ the latter case the reaction showed little selectivity and this was a disadvantage since the ultimate goal was a stereoselective route to the phosphonate analogues 89) of 2-phosphono-D-glyceric acid. Moderate yields o f aldehydes (91) have been obtained by one-carbon homologation of
(u.
ketones and aldehydes using the carbanion of 1.3-benzodithiol-2phosphonate (90) (Scheme 15). 59 3 - P h e n y l s el e n o a l k - 1 - e n y l i d e n e carbenes 92) have been generated by olefination o f a-phenylseleno carbonyl compounds with diethyl diazomethylphosphonate carbanion and trapped to give the corresponding cyclopropanes (Scheme 1 6 ) 6 0
(x.
Various heterocyclic-substituted alkylphosphonates have been used in olef ination. 2-Hydroxy-2- ( 5 - t h i a z o y 1 ) a l k y l p h o s p h o n a t e s ( 9 3 ) undergo two types o f fluoride-induced elimination to give the normal alkene product (94) or, through the l o s s of (1-formylalkylb phosphonate, the thiazole (95). depending on the thiazole substitution (Scheme 17) . 6 2 The phosphonates (97), obtained from cycloadditions of the ( d i e t h o x y p h o s p h o r y 1 ) a c e t o n i t r i l e oxide (96) to alkenes. undergo base-induced olefination, alkylation and oxidation to give a variety of 3,5-disubstituted 2-isoxazolines (Scheme 18) 63 Intramolecular olefination of 5-oxoalkylphosphonates continues to be used to synthesise bicyclo[3.0.3]octaenone systems (e.g. and the parent ring system (100). 6 5 In the latter case the required phosphonate is generated from diethyl 3 - i o d o p r o p y n e p h o s p h o n a t e (99). which is a useful, new alkylating f3-keto phosphonate equivalent
Orgarlophosphorus Chemistry
286
0
0 Et P II (NMe2)z
I ,
WezN12!$Ar
11
Scheme 11
0
II
(EtO),PCH,X L L
+
6M K z C 0 3
RCHO
020
+
RCH=CDX
(851
(84)X = CN, C0,Et or COMe
(87) X = H (88)X = F
F
287
7: Ylides anti Related Cornpourids
Scheme 15
[a.YP
0
+
(EtOI,PCH=N, II
0%) SePh
S c h e m e 16
-
288
Organophosph orus Chemistry
I
R *”3R 2
s /N
Y
R4
( 9 L ) R 4 = Ph or 3 - p y r i d y l
(93)
R4
( 9 5 ) R 4 = N H P h or N H M e Reagent :
CsF,
I,
HZO, D M F
S c h e m e 17 0
II
+
(EtOlzPCH2CEN-0
N-0
-
(EtO$!&
R
(96)
(97)
1
ii
N-0
R
’
R
Z
C
A
R
*
0 (EtO),P
LI
N-0
Reagents
I,
OR , 11,
Bu”L1,
iil, R ’ C O R 2 ,
IV,
Scheme 18
R’X,
v, O 2
7: Ylides und Reluted Cornpourids
289
(99)
Scheme 1 9
(101)
290 (Scheme 1 9 ) .
Base- cataly:;ed
c y c l i s a t i o n of
the y- acyloxy B kcto
p h o s p h o n a t e (101) g i v e s t h e 2(3FI)- f u r a n o n e ( 1 0 2 ) r a t h e r t h a n t h e 3(2tI) furanone (103) expected from
r3
conventional intramolecular
A m e c h a n i s t i c s t u d y exclude:;
olefination.66
s e v e r a l possible routes
t o ( 1 0 3 ) . b u t d o e s n o t p r o v i d e a d e f i n i t i v e mechanism. The isomer r a t i o of e x o c y c l i c d l k e n e s produced f r o m c ~ r r t a i n c y c l i c k e t o n e s s h o u l d b e i n f l u e n c e d by t h e phosphorus carbanions. s y n t h e s e s of
the
IISC
of
o p t i c a l l y a c ' t ivc?
T h i s p r i n c i p l e h a s b e e n a p p l i e d t o sc1ec-t i v c
( c ) isomers -
(1.04) a n d ( 1 0 5 ) a n d t h e
(E-)
( 1 0 6 ) atid
(Z ) -(10-1) i s o m e r s o f 3 o x a c a r b a c y c l i n p r e c u r s o r s u s i n g . f u r P X ~ ~ I I t h e c h i r a l p h o s p h o n a t e s (LOU) a n d ( 1 0 9 ) . 6 " Heactions o f t h e a n i o n s
I ~ ) ~ ~
of t h e c h i r a l 2 - a l l y 1 1 . 3 . 2 - o x a z d p h o s p h o l i d i n c 2 o x i d a s ( c . g . 1 1 . 0 ) w i t h a , B -u n s a t u r a t e d c y c l i c e n o n e s g i v e a d d i i c t s ( [ ? . ( 4 .
from M i c h a e l a d d i t i o n a l m o s t e x c l u s i v e l y a t t h e
111)
p h o s p h o n a t e a n i o n ) w i t h m o d e r a t e t o e x c e l l e n t 1c:vcls of induction.
'*
O z o n o l y s i s of
Llie
ar;ymmet r ic:
t h e s e a d d u c t s p r o v i d e s a n e x c e l lerit
s y n t h e s i s o t c h i r a l a l d c h y d e s w i t h enanlr i o m t ? r i c c?xcr!s:;es from 2 8 % t o 95% (Scheme
(dcrivc!d
y - p o r j i t i o n of
'The a l k y l d t i o n of
2U).
ranyirig
chir:al c y c l i c
a - d m ~ n o m e t ~ i y l p h o s p h o r i a t c( ~e s. g . 1 . 1 2 ) h a s b e e n i n v e s t i g d t e d as a
p o t e n t - i a l r o u t e t o c h i r a l a -a m i n o a l k y l p h o s p h o n i c a c i d s ( 1 1 3 ) . 6 9 b e s t t h e mcl.hod g i . v e s o n l y m o d e r a t e e n a n t i o s e l e c t i v i t y .
At
Optically
a c t i v e 1 ( d i m c t h y l p h o s p h o r y l e t t ~ y l )p - t o l y l s u l p h o x i d e ( I L L ) ) h a s h r r n p r e p a r e d by t w o r o u t e s . " ' of
(i )
-
F 2 i r s t l y by m e t h y l a t i o n o f t h e ( ~ a r l ~ a i i i o n
( 5 ) -1-d i m e t h y l p h o s p h o r y l r n e t h y l
s e c o n d l y by t h e r c ? a c t i o n o €
(- )-
p- t o l y l s u l p h o x i d e ( 1 1 4 ) dnd
( s ) m. e n t h y l
dimethylphosphorylethyl carbanion.
p- t o l u e n e s u l p h o n a t e w i t h
l n b o t h cases t h e r e w d s
s u b s t a n t i . a l a s y m m e t r i c i n d u c t i o n a n d t h e s t r u c t u r e of d e t e r m i n e d by
5-~
d ay n a l y s i s .
( 1 1 5 ) was
Diethylphosphorylmethane
(116) a n d t h e c o r r e s p o n d i n g e s t e r
sulphonate
(11'7) u n d e r g o o l e f i n a t i o n
r e a c t i o n s w i t h a l d e h y d e s and k e t o n e s t o g i v e a , @ - u n s a t u r a t e d s u l p h o n a t c s i n e x c e l l e n t and m o d e r a t e y i e l d s , r e s p e c t i v e l y (Scheme 21). -I1
V a r i o u s d e r i v a t i v e s ( 1 1 9 ) of d i f l u o r o p h o s p h o n o a c e t i c a c i d h a v e b e e n p r e p a r e d b y t h e C u ( 1 ) - c a t a l y s e d r e a c t i o n s of [ ( d i e t h o x y -
phosphonyl)difluoromethyl]zinc 4-
bromide (118) w i t h a c i d c h l o r i d e s .
72
Selected Applications i n Synthesis
~ 4 ._ 1 _ A l_k _ al_ o i_ d s_. -
A high yield
i n t r a m o l e c u l a r w i t t i g r e a c t i o n of t h e
y l i d e (120) t o g i v e t h e b i c y c l i c s y s t e m (121) i s a k e y s t e p i n a s y n t h e s i s of a l k a l o i d s i n t h e r e t r o n e c i n e s e r i e s . 7 3
The y l i d e (122)
h a s been used t o i n t r o d u c e t h e s i d e - c h a i n and a p p r o p r i a t e f u n c t i o n
7: Ylides and Related Compounds
29 1
””#” \
\
I
H
C02R’
aR
I
6R3
6 R3
Et
(106) R2 =
( 1 O L ) R ’ = CO,R ( 1 0 5 ) R ’ = CH,OH
II
( M e 0 1,PC H,
(107)
I
OH
Id0
(Me01 PCH,C-O(-)2
t r o n s -2-p h e n y l c y c l o h e x yl
Me
J Reagents
I,
BuLI,
THF,
11,
,
111,
03, CH2Cl2
S c h e m e 20
Organophosphorus Chemistry
292
(1121
0
0
II - II
(MeO), P C H S
A
----:
1-TO I
0
II
(Me0l2P
(11L1
0
II -
s --__.
\
4-Tol’
( M e 0 ) 2 P CHMe
(115)
’
0
0
II
II
(EtO),PCH,
+ (EtO),PCH,SO;
1,
R’RZCH=CHSOgEt
11,
MejiSOT,
111,
II
Ill
(EtO),PCH,SO;Li+
I, B u ” L I ,
To I
0 - Ment h y l
0
Reagents
-
”
Bun4N+
0
II
(EtO),PCH,SO,Et
Bun4AHSOC, LIOH,
IV,
F S 0 3 E t ; v, R’R’CO
S c h e m e 21 0
0
II
(EtO),PCF, Z n B r (1181
+
RCOCl
CuBr
II
( E t O ) , P C F,COR (1191
293
7: Ylides and Related Cornpourids
(120)
(121)
OH
h3P
OR
0
ph3p+
R2
(126)
pow) &
R ’ = R2
0
(127)
R’ =
,
HO
(128)
R’=
OH
R 2 =
OH
porn) 8
HO
1
OH
R2 =
(-c=c
2 94
Organophosphorus Chemistry
f o r cyclisation in a total synthesis o f
(+)-anhydrocannabisativine
( 1 2 3 1 . ~Complex ~ phosphonates continue to be widely used in large molecule synthesis, e.g. in syntheses of the alkaloids lythrancepine I 1 and I I I . 7 5
4.2 Carotenoids and Kelated Compounds.-
The Wittig reaction
continues to be used extensively in the synthesis o f carotenoids a n d their analogues.
Examples include the use of the ylide (124) to
form the polyene B-diketones (125) and (126). the synthesis of trikentriorhodin (127), 7 6 the synthesis of a
c i s - isomer
of
mytiloxanthin (lZ8)77 and the synthesis o f a series of polyenes and carotenoids
(e.g. 129
proper tie^.^'
and 130) with potential non-linear optical
Wittig reactions of the aldehydes (131) and (132)
have been used to synthesise a number of conjugated polyenes carrying terminal 9 anthryl and 1-naphthyl groups in order to study their optical properties.
79
Both Wittig and phosphonate based methods have been used in the total synthesis of (5)-citreoviridin (133), a potent mycotoxin." The tetra-(z)-isomer (136) of lycopene has been synthesised by the use o f successive Wittig reactions of the phosphocane (134) with the triene aldehyde (135) as k e y steps.'l Well-tried phosphonate-based methods have been used to synthesise 5-methoxy retinal (137) and 5 ethylretinal (138) ," various isomers of the spin labelled retinals (139)R3 and 84
7 . 9 . 1 1 - t r i - d - and all cis-retinals.
4.3 Leukotrienes and Rxl-ated Compoundr~.- The Wittig reaction continues to be used extensively i.n the synthesis of 1eukot.riencs and related molecules. Recent examples include synt.heses of T,I'B and its a n a l o w e s (140).
85
5- (2)hydroxy- 1 . 4 . 1 5 I . T A ~ ( 1 4 1 ) ( d n
intermediate in the biosynthesis o t 1i.poxins), R 6 I . l ' A 4 (142),'"
4
methyl rst.er
12- (R)-k11.:?'K,88 dehydroacachiclonic acid dcrivat i v e s ( 1 4 3 ) , R 9
and novel antagonists of L l ' U 4 . ' ' One development wocth noting i s the use of the arsenic y1.ide (144) in t h e synthesis o t 1 9 - h y d r o x y L T E q . 91
lntramolecular o l c f ination 4.4 Macrolides and Related _Co-m&gilnds. of complex phosphonates continues to be a widely used cyclisation step in macrocycle synthesis. A key step in a synthesis of the natural cernbranoli.de (+)-anisomrlic acid ( 1 4 - 1 ) is f o r m a t i o n o f the
7: Ylides (i t i (i Related Cornp 011 tids
29.5
(1291 X = C H O
(131)
R = CHO
(132) R =
(ycHo 0
OMe
Me - - *
Me
(1361
(1371 R = M e 0 (138) R = Et
Orgatlop hosp h orus Chemistry
(1391
HO v
X\
( 1 L O ) X = CH,,
A\
O
2
H
Y = CH3; X = CH,, Y = CH,OH; X = S , Y = CF,
X = S , Y =CH,;
OH
CO, H
C
297
7: Ylides and Related Compounds
( 1 4 5 ) X = H, OMe; Y = H,;
R ' = Me
( 1 4 6 1 X = H, O M e ; Y = H 2 ; R ' = M e (1.47) X = O ; Y = C H , ; R ' = H
Meo IEtO),P=O
OHC
OMe
CHO
OMe
I
Orgci t I opli osplr o r us c‘h em IJ try
2 98
carbocyclic skeleton (146) from the phosphonate (145) . 9 2
The
reaction conditions t o r the formation of (146) were optirnised A r i d
iri
all cases the reaction. u n l i k e intermoleciilar reactions of s i i r i i l d r phosphonates, was highly
(L)stereoselect ive.
‘1’hi.sw a s a
disadvantage in a n attempted synthesis of the s e s t e ~ t e r p e n e (&)-methyl
ceri-fecate f corn the phosphonate (148) since the unwdrit
(Z)-isomer was dgain the major p r o d u c t . 9 3
Macchantin
( I d
A arid
riccardin H , cytotoxic bis(biphenyls) obtained f coin Livc?rwort:;, have' been synthesised by cyctj.sdtion of phosphonatcs ( -__.. r ! . g . 149) . q 4 ‘I’he highly complex phosphonate required for t.he synthesis of 19-dehydroamphoteromi lide U (152) (Scheme 2 2 ) has been for-rricd by
esterification of the phosphonate (150) with the (151) . 9 5
(3
hydroxyaldchyde
(K,H_)-( )-Gcahamiinycin A. has bccn synthesised
the?
Ii:;inq
reaction o f the alcohol ( 1 5 3 ) with keLenyl.idenct[I iphenylphosphor3ric to pcovidc the intermediate (L54) for the cyclisation s t e p (Schernc 23).
96
Olefinat ions involvi.rig complex phosphonates have a l s o b c ( ? n iisc.d to generate acyclic f cayinents o f niacrocycles. 9‘/.98 l’he
( E , g , K ) -tricne
(Ir>’a /n ) ,intermediat-e
in a pldnnerl synthesis o t the
macrocycles k i janol i d e and Uetronol.ide, has b e e n prepared as
d
s i n g 1 . e isomer b y oletination of the aldehyde (156) with the
phosphonatc
( L55).
412Pher0m~one5.-
’’’
Wittiy reactions continue to be widely c’mploycd in
the synthesis of pheromones.
The highly
(2)
stereoselective
olefination of the acylsilane (158) with u n a d e c - 1 0 - e n y l i d e n eylide (159) provides a route to (160). the sex-attractant o f the sweet potato leaf f o l . d e r moth, i n >99% isomeric purity.” D - X y l o s e has been convert.ed into the salt margin caterpillar moth pheromone (161) and its 38.6g-isomer using a Wittig reaction with 3 z - h e x e n - 1 y l i d e n e t r i p h e n y l p h o s p h o r a n e a s a key step.loO The previously reported stereoselective formyl-oiefination of aldehydes using the
formylmethylenearsonium salt (162) has been used in a highly stereoselective synthesis of various insect sex pheromones (e.g. 163,164) containing the (El), (z)-diene function.“‘ 4.6 Prostaglandins.- The Wittig reaction and. to a lesser extent,
~~
phosphonate-based olefination continue to be the methods o f choice in the synthesis of prostaglandins and their analogues. include prostaglandin endoperoxide analogues,
Examples
heteroaromatic
prostacyclin analogues,lo3 anacardic acids and ginkoic acids. l o 4
7: Ylides and Related Compounds OR
(150) R = S i B u ' M e z
+
Ro CHO
RO
RO
0
Reagents.
1,
DCC, D M A P ,
11,
KZC03, 1 8 - c r o w n - 6 ,
Scheme 2 2
b e n z e n e , 80.C
Organ op h osphorus Chemistry
300 OH
P h, P = C H COO I
Reagents
I,
Ph P=C=C=O,
3
HCI,
11,
H20,
111,
pH
=
8.4
Scheme 23 OMe
0 hOEt1,
RO
(155)
Me
C HO (156)
Me
30 1
7: Ylides and Related Compounds
C O S i Me,
Ph,P=CH(CH,),CH=CH,
( 1 581
(1591
+
P h,As CH,CHO W
C
1
1
H
Z
Br-
3
(162)
(163) R ’ = CBH,,, (161) R ’
R Z = (CHZ),0COCH3
= ICH,),CHO
, R
’=
C,Hg
Me
ICH, 13CH3
0
HQ,CC H,Q
Organophosphorus Chemistry
302
(-)-preclavulone-A(165) ( a metabolite of arachidonic acid),lo5 and the prostanoid intermediate (166). Various approaches to the synthesis of both enantiomers o f the 15 deoxy analogue (167) of the potcnt antiulcer agent U 68,215 have been investigated.lo7 The best route reported involved a one pot reaction of the y-keto ester (168) with phosphonate in the presence of three equivalents o f base tollowed by addition of acetic acid and heating to generate the required tricyclic skeleton (169) directly in good yield (Scheme 24). lhe success of this reaction depends on the relative kinetic and thermodyndmic acidities o f protons at various sites. Various problems associated with syntheses of aryloxy analogues (170) of arachidonic acid have been overcome by suitable choice of solvent and ccaction ternperature,lo8 however, the low stereoselectivity of the reactions reduced their usefulness. 4 __ . 7 .Miscellaneous - .. - - __ _____ - - .Reactions.__ - ______ - -
The naturally occurring trienes (172) and (1.73) have been synthesised from (E)-3-oxiranylprop-2-enal (171) by a method, based on stereospecific (I,)-olefination, which clearly has many other applications (Scheme 25) .lo9 The rather unstable dienylphosphoni~~m salt ( 1 7 4 ) has been used under "salt free" conditions to synthesise the triene (175) with high
(5)- s e 1 ec t i v i ty .
lo
New routes to optically active tetrahydrofurans and tetrahydropyrans are available from the reaction of the phosphonate-sulphone carbarlion (176) with unprotected aldohexoses (Scheme 26).111
Both a- and 6-anomers of ethyl (2.3.4.6- tetra-
0 - b e n z y l - D - g l u c o p y r a n o s y 1 ) a c e t a t e ( 1 7 7 ) have been obtained in good yields by reaction of tetra-2-benzylglucose with triethyl phosphonoacetate anion.'" A similar reaction did not take place with the corresponding phosphorane. The enantiomerically pure diene (178) is obtained as one geometrical isomer from the reaction o f 2 . 3 . 5 - t r i - Q - b e n z y l - D - a r a b i n o s e with diethyl cyanomethylphosphonate
in the presence of more than two molar equivalents o f base.l13 Similar reactions with other phosphonates give the expected cyclic product (179). Both enantiomers of the dihydroxycyclopentenone (180).have been synthesised from D-ribonolactone and D-mannose, respectively, using the anion of dimethyl methylphosphonate in the cyclopentenone ring-forming step (Scheme 27) A wittig reaction of the ylide ( 1 8 1 ) and the aldehyde ( 1 8 2 ) has been used to construct the protected structural skeleton in an enantiospecific
q-&;’. 303
7: Ylides and Related Compounds
0
II
0 II C0,Me
-2~
+ (EtO),PCH,R
OMe
OMe
OMe R =
( C H 2 l 4 G
//
(168)
q0
0
O E (% fJp A .
0 Me
OLi
OMe
1169)
Scheme 24
(172) R = Et ( 1 7 3 ) R = n -C,H,, Reagents:
I,
salt-free;
11,
H2NC(SiNH2;
III,
S c h e m e 25
Ph3P
+
MeOLi
Organophosphorus Chemistry
3 04 C H,S i Me
%;Me
C H ,S i Me
I
Ph2
1-
OH
OAc
OAc
Scheme 2 6
OR (177)
R = PhCHZ
6zO'
OBz BZ=
OBz
PhCH,
Eke-($* BZ
d (1791
BzO
OBZ
'CN (178 I
305
7: Ylicles und Reluted Compounds
Yo*o I
S
I
0 Reagent.
I,
It
CH3P(OMe$,
Bu"LI.
THF,
2 5 h , - 7 8 to 2 0 ° C
Scheme 2 7
(-7-PPh3
+
-p
x
I
I
OEt
OEt
O X 0
N?) 0
CH,X
23 0
H2C0
HOMe
,
H
CONHMe
OT BS
X
306
Organophosphorus Chemistry
total synthesis of the naturally occurring a,@--unsaturated
6 - lactone anamarine.’l5 The isoxazole phosphonate (183) and phosphonium salt (184) have been studied a s potential reagents for the synthesis o f tetramic Although (183) and (184) were efficient acid derivatives.‘l6 olefination reagents attempts to use them in a new approach t.o tetramic acids were not successful. The complex tetramic acid-derived phosphonate (185) has been synthesised with a view to 117 its use in the synthesis of che antibiotic streptolydigin, however olefination reactions with model aldehydes gave poor yields. Olefination with complex phosphonates has been successfully used to synthesise the 5 ~ , 8 K , 9 3 , 1 1 ~ - d e p h o s p h o r y l a t ederivative d (186) of the antibiotic CI-920.118 1-Fluoro-2-oxoalkylphosphonates (187) have been synthesised and used to prepare a variety o f fluoroalkenes including the 2 -f luocoethcnyl pyrethroid precursor (188) .’I9 A highly stcrcos(?lccI:ive route to methyl t_g_ans--1K, 3.-K -hemicaronic aldehyde ( l 9 1 ) , and hence chrysanthemic acid derivatives, is available from _O isopropylidene tartrate ( 1 8 9 ) (Scheme 2 8 ) . l Z o The dimethyl %K,3g stcreocherni!;try of the cyclopropanation step is highly dependent on
the ~Lereochemistryof the a l k e n e g r o u p s in (190) and the s o i i r c e o f
i s dependence has been i nvcs t. iya tcd . Whiti.ng has continued his work on t-he synthesis of long-chain dlkancs o f high purity. After a thorough assessment o f possible routes he concludcs that a method (shown in Scheme 29) bdrjed on the I ti
W i t t i r j ccaction i s the most efCicient.’”
T h i s method provided,
dcprotaction, dcbrornination and hydroyenal.ion a number of a l k a n e s with specific chain lengths. llowcvc-?r, mainly due to
df I(?c
i ~ i ~ p i i r i t iformed c~ in I.he early reaction steps, C l o 4
was the longest
chain Obtained from early attenipts. Much longer chains, u p to C 3 9 0 , cdn be ohI.aincd u s i n g the sdme basic scheme, but modifying the r-c’dct i on conditions, work up and purification procedures. l Z 2
Chains
w i t h 150 or mot(? carbon acorns show chain folding in the crystalline
behavioiir associdted with linear polyethylene. but previously unknown f o r p u r e paraffins. Similar methods have been applied to
stdie,
the synthesis of 123
side r h ~ i n s .
long-chain p a r a f t i n s with specifically sited alkyl Wittig reactions o f ylidcs (192) and (.L93) have
been u s e d in syntheses of: various unusual long-chain ketones (e.g. 1 9 4 ) of
alyal. The ylide (195) h a s been used to introduce the (E)-enamide
fragment in syntheses o t several new isobutylamides (196) . I Z 5
The
307
7: Ylides untl Related C:ompounrls
C H,O H I
(1861
0
E t CO
II
(R’OI~PCHFCOR’
‘C=CH
F
CO’Et
/
(187)
(1881
C02Me
I
I
C0,Me
C0,Me
(1891
(1901
1“
oHc’ C02Me
I
Me
Me
(191 1 COzMe Reagents
1,
DIBAH,
11,
e x c e s s (EtO)zP(0)CHNaCOzMe, DME
L I I , T H F , l v , HCIO4, HZO, T H F ;
v.
Scheme 2 8
;
N a I O & , pH
III,
e x c e s s Ph3P=
= 7-2
c tiZ,
308
Orgunoph osphorus Chemistry
Reogents'
I,
Ph3P,
11,
Deprotection;
111,
Wittlg;
IV,
Repeat
Scheme 29
n
PhgP = C H ( C H2) C H ( 0M e 1
P h,P=CH(C
(19 2 1 C,H,,CH=CH(CH,),C
Hz),2-
0, /o
c,
Me
(193) H =CH (CH,),CH
= CH (CH2),CH = C H (CH2I5COC H,
(19t)
HNCOCH ( O H ) ( CH2Il3CH3 I
7: Ylidtis and Related Compounds
HO---
Et
(1991
(1981 ICH2l6COOH
'6
3
(2021
(201) Reagents
1,
Ph
3
P=CHCONMep,
toluene,
A,
18h,
11,
L I A I H ~ ,T H F
Scheme 3 0
RTo--
OSiMe3
R F C 0 2 R R
R
CO,R
+
Reagents. I, F';
ti,
P h S ) (
PPh3 BF~-
(203)
Scheme 3 1
R RJ$R
CO,R
3 10
~
>
3
1,
II
0
C0,Et
0 CO,R
\
CO,R (2051
Reagents'
I,
03, CF3COOH,
11,
Me2S, N o H C 0 3
Scheme 3 2 X
(206)
(207) X=CHO, CH=CHPh,(CH=CH)2Ph
R
R (208)
311
7: Ylides und Related Compounds ilJittig reaction h a s been used extensively in the synthesis o f cerebroside B16
(197)
and its stereoisomers'26
the self-defence substances
(198).
(199)
and
and in s y n t h e s e s of (200)
i n rice and
timothy plants. 127 A n improved route to the 3 - s u b s t i t u t e d 7-methoxybenzofuran (202)
is available from the reaction of ( N . N - d i m e t h y l c a r b a m o y 1 ) -
m e t h y l e n e t r i p h e n y l p h o s p h o r a n e w i t h the k e t o n e ( 2 0 1 ) T h e previously reported
(Scheme 30). l z 8
route (Scheme 31) to annulated cyclopentanes
using a - ( p h e n y 1 t h i o ) v i n y l p h o s p h o n i u m s a l t (203) has been applied to the total synthesis of pental.enolactone FJ methyl ester
(204) .Iz9
T h e n o w w e l l estahlished intramolecular Wittig route continues to be applied to bicyclic @ - l a c t a m s y n t h e s i s , for e x a m p l e that of the carbapen 1 em (205) (Scheme 32) .l3O T h e high ( Z ) - stereoselectivity observed in the olefination of the k e t o n e
(206)
w i t h dimethyl
1-methoxycarbonylethylphosphonate carbanion is attributed to electronic interaction o t the o x i r a n e w i t h the e s 1 . e ~q r o u p . 1 3 1
Both
phosphorus y l i d e - and phosphonate- based oletination methods have been used in the synthesis of fluorescent cholesterol analogue probes ( 2 0 7 ) from pregnenolone.13'
Y l i d e - based methods continue to
be used in the synthesis of dnnulenes, for cxdmple, the methano- bridged tetradehydro annulenes
( 2 0 8 ) . '133
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Organophosphorus Chemistry
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2941.
74. 75. 76.
H.H. Wassermann and B . C . Pearce, Tetrahedron, 1 9 8 8 , $3,3 3 6 5 . D.J. Hart, W-P. Hong, and L-Y. Hsu, J2 Ore,. Chem., 1 9 8 7 , 2 , 4 6 6 5 . A.K. Chopra, G.P. Moss, and B.C.L. Weedon, J. Chem. S o c . , Perkin Trans.1,
Jl.
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A.K. Chopra, A. Khare, G.P. Moss, and B.C.L. Weedon, J. Chem. Soc., Perkin Trans.1, 1 9 8 8 , 1 3 8 3 . M. Blarichard-Desce, I. Ledoux, J M. Lehn, J . Malthete, and J. Zyss, Chem. S o c . , Chem. Conunun., 1 9 8 8 , 7 3 7 . b’. Effenberger, H. Schlosser, P. Bauerle, S. Maier, H. P o d , and H.C. W o l f , Angew. Chem., Int. Ed. EnRl., 1 9 8 8 , 21, 2 8 1 . D.R. Williams and F.H. White, J . Ore. Chem., 1 9 8 7 , 22, 5 0 6 7 . G . Pattenden and D.C. Kobson, Tetrahedron Lett., 1 9 8 7 , 28, 5751. E . Kolling, D. Oesterhelt, H. Hopf, and N. Kraus, Angew. Chem., Ink. Ed.
83. 84. 85.
Renk, Y.S. Or, and R.K. Crouch, J. Am. Chem. S o c . , 1 9 8 7 , 1 3 , 6 1 6 3 . A. Trehan and R.S.H. Liu, Tetrahedron Lett., 1 9 8 8 , 29, 4 1 9 . Y. Guindon, D. Delorrne, C.K. Lau, and H. Zamboni, J. Org. Chem., 1 9 8 8 ,
86.
Y. Leblanc, B.J. Fit~simmons,J. Rokach, N. Ueda, and S . Yamamoto, Tetrahedron Lett., 1 9 8 7 , 28, 3 4 4 9 . S . R . Baker, D.W. Clissold, and A. McKillop, Tetrahedron Lett., 1 9 8 8 , 29.
1988, 1371.
78. 79.
87.
E_n_e., 1987,
26,
580.
G.K.
23,
267.
991.
88. 89. 90. 91.
I.M. Taffer and R.E. Zipkin, Tetrahedron Lett., 1 9 8 7 , 28, 6 5 4 3 . E.J. Corey and R. Nagata, Tetrahedron Lett., 1 9 8 7 , 28. 5 3 9 1 . J. Morris and D.G. Wishka, Tetrahedron Lett., 1 9 8 8 , 29, 1 4 3 . Y. Le Merrer, A. Bonnet, and J.C. Depezay, Tetrahedron Lett., 1 9 8 8 , 29,
92. 93.
J.A. Marshall and B . S . Dehoff, Tetrahedron, 1 9 8 7 , 43, 4 8 4 9 . M. Kodama, Y. Shiobara, H. Sumitomo, K. Fukuzumi, H. Minami, and Y. Miyamoto, J . O r e . Chem., 1 9 8 8 , 53, 1 4 3 7 . M. Kodama, Y. Shiobara, H. Sumitomo, K. Matsumura, M. Tsukamoto, and C. Harada. J. Org. Chem., 1 9 8 8 , 53, 72. R.M. Kennedy, A. Abiko, T. Takemasa, H. Okumoto, and S. Masamune, Tetrahedron Lett., 1 9 8 8 , 29, 4 5 1 . H-J. Bestmann and R. Schobert, Tetrahedron Lett., 1 9 8 7 , 28, 6 5 8 7 . K. Takeda, T. Kobayashi, K. Saito, and E . Yoshii, J. Org. Chem., 1 9 8 8 ,
2647.
94. 95. 96. 97.
53,
1092.
3 14 98. 99. 100. 101. 102. 103. 104.
105. 106. 107. 108.
109.
110. 111. 112. 113. 114. 11 5 .
116.
Urgatiophos~~horiis Chemistry I . P a t e r s o n , D . D . P . L a f f a u , a n d D . J . Rawson, T e t r a h e d r o n L e t t . , 1 9 8 8 , 29, 1461. J . A . S o d e r q u i s t a n d C.L. A n d e r s o n , T e t r a h e d r o n L e t t . , 1 9 8 8 , 29, 2 7 7 7 . J . R . Pougny a n d P . R o l l i n , T e t r a h e d r o n 1 9 8 7 , 28, 2977. Y-2. Huang, L . S h i , J . Yang, a n d 2 . C a i , J . O r g . Chem., 1 9 8 7 , 3558. R . C . L a r o c k , M . H . H s u , a n d K . N a r a y a n , T e t r a h e d r o n , 1 9 8 7 , 33, 2 8 9 1 . S . Cook, D . H e n d e r s o n , K . A . R i c h a r d s o n , R . J . K . T a y l o r , J . S a u n d e r s , a n d P . G . S t r a n g e , J . Chern. S O C . , P e r k i n T r a n s . 1 , 1 9 8 7 , 1 8 2 5 . Y . Yarnagiwa, K . O h a s h i , Y . Sakarnoto, S . H i r a k a w a , a n d T . Karnikawa, T e t r a h e d r o n , 1 9 8 7 , 43, 3 3 8 7 . E . J . C o r e y a n d Y . B . X i a n g , T e t r a h e d r o n L e t t . , 1 9 8 8 , 12, 9 9 5 . W.F. B e r k o w i t z a n d A . F . A r a f a t , J . O r g . Chern., 1 9 8 8 , 53, 1 1 0 0 . C - H . L i n , P . A . A r i s t o f f , P . D . J o h n s o n , J . P . H c G r a t h , J . M . Tirnko, a n d A . R o b e r t , J . O r g . Chern., 1 9 8 7 , 52, 5 5 9 4 . D . K . B u c k l e , A . E . F e n w i c k , D.J. O u t r e d , and C . J . M . H o c k w e l l , H e s . , Synop., 1981, 394. M . Goldbac.h, E . J a k e l , and M . P . S c h n e i d c . r , ,J.. _C_h_m._rnSoc ~, Ckern. Cornrnun., 1987, 1434. E. V e d e j s and S . Ahmad, T e t r a h e d r o n _ _ r L e t t . , 1 9 8 8 , 22, 2 2 9 1 . A.H. D a v i d s o n , L . R . H u g h e s , S . S . Q u r e s h i , a n d B . W r i g h t , TetraheArori L e t k . , 1 9 8 8 , 7.2, 6 9 3 . U . MonLi, P. G r a n i a l i c a , G. S p e r a n z a , arid P. M a n i t t o , TkJyahedron Lett., -1987, ? 8 , 5 0 4 7 . A . B . H c i t z , A . 1 ) . J o r d a n , J r . , and B . E . M a r y a r i o l f , J . Org. Chem., 1 4 8 7 , 52' 4 8 0 0 . 1987, 1I.H. Borc.ht-~r-ir-ig,S . A . Scholtz, and H . T . B o r c h a r d t , J 2 _ , ~ g - - C & ~ m . , 52_, 5 4 5 7 . S . Va 1 vc?r.de , A. Ilr.r~riatidc.z, B . t i f ~ r r a d o r i , K . M. Kabana 1 , arid M . NAi-tin l,oiilas, ?etrahc?t.ori, 1 9 8 1 , 43, 3/19'), k'. D c Shong, J . A . C i p o l l i r i a , arid N.K. I,owniastr,r, J . O r L . ( : ~ i c ! n . . , 1 9 8 8 , 5 5 ,
m.,
Jz,
J.s-h~&-
1 i>G.
S c h 1 c s : ; i i i g r : r a n d U.D. G r a v e s , T g t r . a h _ e _ d r o n - L g t t . , 1 0 8 1 , ?8., 4 3 8 5 . 1 1 8 . C : . J u s t a n d B O'Coririor, T g J r a h e d r o r ~ - I . e t t . ., 1 9 8 8 , ? q , 1 5 3 . 1 1 9 . t ' h . C O U t r O t af-ld C. ( ; r i S l J t l , '1'etrahedrOn I , ? t t . , 1988, 2 9 , 7 6 -120. A . K r - i e f , IJ. Diimorit, arid 1'. P a s a u , TgJr.alyd-rori- & ! L t . , 1988 K r i e f and w. h i r n o r i t , 'r at! e d L'O n--1-c:1.5. . , 1 8 8 , 9 , 108 9 . . J . Siriimoiids, M . C . W h i t i r i e , J l_-Chcml-Sq-g,_, 1 3 1 . b:. L g n c r , 0 . 1 . t ' a y r i t e r 1'rr.kiri l ' r . a r i s . 1 , 1 9 8 7 , 2 4 4 7 . 1 7 7 . 1 , H i d d , O . W . l i o l d u p , arid M . C . W h i t i r i g , J,- $hem. ~ ~ . c ,j'c!.kir-Tczinsi..l, , I O H I , 2455. 1 2 { , k,. A . Adcgclkf., I I . k:phr'a i m Ha 1-1, L ) . . l . Kr.1 ly, arid M.C. W h i t i n g , J . - C h e n i , kiri Tr-an:;. 1 , 198 I , 3 4 6 5 . kn arid J . H . M a x w e l 1 , T e t z r a h g 4 r o n -!.ett. , 1 9 8 8 , 2 9 , 2 3 9 9 . - 1 7 5 . H . J . U l a d r . , J . F : . H o b i r i s o n , K . J . I'c:ek, arid J . H . Wf'ston, T c t r a h g d r o n L e t t . , 1987, 3851. 1 2 6 M . Ndkagawd, S . K o d a t o , K . N a k a y m a , arid 1. H i n o , "etI'ahf~di:on_I,ett.. , 1 9 8 1 , 2 8 , 6781. I / I . A , V . K. Hao, b:. H . K e d d y , A . V . l ' u r . a n d a r t ~ , and Ch.V. N . S . V a r a p r a s a d , Tetrahcdi:on, 11981, 4 3 , 4 3 8 5 . I / R . M . F : . J i i n g arid S . Abrc.cht, J . O r g . .Chyin., 1 9 8 8 , ! 1 3 , 4 2 3 . 1 1 9 . J , P , M a r i n o , C . S i l v f . i r a , J . C o m a n s e t o , arid N. P ~ ~ t r n g r - i a n iJ, l 3 r & _ < h e j . , l c l 8 7 , ' 2 , 4139. ! 30 K . S h a r m a , K . J . S t o o d l c y , arid A . Whit-ing, J . _ _ C ~ I ! ? ~ . ~Sox-. , P f . r k . i n T r a n s . l - , I'lH7, 2301. l i t . I ' . ! d c ~ y e r ~ s l r i t i 1 I, t . Marsctial 1 W f ~ y c ~ r s t a h lJ, . Pennjrigc)r arid I,. W a l t h e r . 'L'cJr.ahe:jror!, 1987, 43., !1%8/. 137. J . Ilrc.w, M . I . c ~ t f ~1 1i e r , 1'. Morand, arid A.G. S z a b o , J . O r e , . Chern. , 1 9 8 7 , 17.i. K.11.
;Is,
52,
4011 1 .
1 3 3 . J . O j i r n a , S . Y u j i t a , M . M a s u m o t o , P:. E j i r i , T . K a t o , S . K u r o d a , Y . Nuzawa, S . I { i r o o k a , Y . Y i ~ n t ~ y n m a and , H. T a t f m i t s u , J . Chern. S o c . , Perki.n Trans. 1. 1988, 385.
Ph0s p hazenes BY C. W. ALLEN 1.
Introduction T h i s chapter covers t h e literature of phospha(v)azenes.
The combination of basic science and numerous applications
In
continues t o insure an active interest in t h i s area.
contrast t o t h e wide availability of general review's noted last year, reviews this year are highly focused and will b e quoted in t h e appropriate sections below.
Acyclic Phosphazenes Numerous publications have been devoted to acyclic phosphazenes (phosphazo derivatives, phosphine imines, phosphoranimines) with a particular emphasis on transition 2.
metal derivatives being noted. Reviews covering the preparation and reactions of F l - s i l y l p h o s p h o r a n i m i n e s ’
,
reversible and irreversible migrations i.e. group transfer from oxygen to nitrogen and between oxygen atoms, in acyclic phosphazenes*, synthetic transformations of phospha(I1T)azenes into phospha(v)azenes3 and the synthesis, structure and reactions, particularly reactions leading to coordinated metal species, of diiminophosphoranes and imino (methylene)phosphoranes* have appeared.
Ah
rrirfio
calculations of the phosphinic nitrene (H,P(O)=El)oxoiminophosphorane (HP(O)=NH) system suggest that the Curtistype rearrangement takes place
via
a non-nitrene mechanism in
its singlet ground state. If the starting materials are excited to the triplet state, the triplet nitrene is expected to form and the Curtis rearrangement would not be o b ~ e r v e d . ~ The redox chemistry of a series of N-aryltriphenylphosphazenes, ArN=PPh,, has been examined by cyclic voltametry and the data compared to the corresponding gsulfonyl and x-acyl derivatives. Substituent effects are observed in the oxidation but not the reduction processes. The oxidation mechanism was investigated by a combination of NMR, HPLC and electrochemical methods and was found to proceed by dimerization of the parent 1-arylphosphazenes. 6 The
316
Organophosphorus Chemistry
phosphazides la,b (R’=Ph) undergo single electron oxidation and reduction to unstable ions which have been detected by ESR spectroscopy. Decomposition occurs via diazoalkene radical anions and carbenes.’ Molecular reorientation of Cl,P=NCCl,CF, in the solid state has been probed using variable temperature NQR spectroscopy. The Staudinger reaction continues to be the most popular method of synthesis of acyclic phosphazenes. The structure of the stable phosphazide intermediate, lc (R’=NMe,) , derived from 13-azidopropanol shows that delocalization does not occur between the phosphorus-nitrogen and nitrogen-nitrogen double bonds.g It is claimed that, in contrast to some recent reports, the reaction of a wide range of phosphorus (111)fluorides, X,Y,F3+,,+,~P (X=Et, CMe, , Ph, Me,N, Et,N, OEt; Y=Me,N, Et,N), with phenylazide gives rise to the monophosphazene in all cases except for PhPF, where the dimer is formed. All products were characterized by NMR (‘HI ”F, 31P) spectroscopy.lo N-phosphorylated l12-azaphosphatidines (2) react with RN, (R=Ph, ArSO,) to give the expected exocyclic phosphazo substituents.” Molecules containing the P(V)-N=P(V) grouping are available from the reactions of phosphorus(v)azides with Ph,P. Species prepared from the N, and (C,H402),PN,12 and catechol derivatives, (C,H,O,) P (0) bis (tJ,tJ’-dimethyl(urea) azido-ph~sphorane’~ have been reported. The reactions of 1- and 2-adamantylazide with phosphines and phosphites give the 2-adamantylphosphazenes. Reactions of these materials with CO, and CS, give isocyanates and isothiocyanates respectively while the reaction of RN=PR’, (R=adamantyl and R’=phenyl) with PhNCX (X=O,S) gives RN=C=NPh.’, The Staudinger reaction of triphenylphosphine with azidoethylene gives g-vinyl-iminotriphenylphosphorane which undergoes thermal reactions with a , /?-unsaturatedketones to give pyridine derivatives in modest yields.” The advantages of using Et,P over Bu,P or Ph,P in the Staudinger reaction and subsequent conversions to amides and phthalimides have been noted.16 The reaction of Ph(R)PH (R=Me, Et) with Me,SiN, gives Ph(R) P(NHSiMe,) =NSiMe, while the analogous reaction of Ph (R)PCMe, gives Ph (R)P ( CMe,) =NSiMe,. l7 The iodophosphines, (R,N) PhPI (R=Et, Pr :R,N=morpholino) , combine with N,SO,Ph and N,Ph to give the expected phosphazenes. The g-phenylphosphazo
8: Phosphazenes
317
0
R’,P
=N-
(b) ER = ( c ) ER =
II ’ U
N=ER
(RO),PN-POR
Ph,C N(CH,),OH
H
I
I
Et
Ph, P =NSO,N
%s
sH2>,
s 1
Ph,P=N Ph,P=N
0 (6) n = 2 or3
(7)
R R
I co
R
31s
Orgarr o y h osp h orus Chemistry
derivative undergoes a slow, unusual, acyclic dimerization to give [ Ph (R2N)P( I)N (Ph)PPh (NR,) =NPh] 'I-. Addition reactions of phosph(II1)azenes represent another route to phosph(v)azenes. While the reaction of adamantyl iodide (AdI) with (Me,Si),NP=NSiMe, yields (Me,Si),NP( I)Ad=NSiMe,, 1 , 3 addition reactions occur when (Me,Si),NP==NP(CMe,) is treated with RX (adamantyl iodide or isopropyl bromide) providing (Me,Si)2N(R)P-N=P (CMe,) 2X.'9 The reaction of RP=NR' (R=mesityl, R'=tri-t-butylphenyl) with BrN(SiMe,), gives the bis (imino)phosphorane, RP(=NR1)=NSiMe,.20 The n+l cycloaddition reactions of Me,CP=NAr(Ar=tri-tbutylphenyl) with 2,3-dimethylbutadiene and diphenylacetylene lead respectively to five (3) and three ( 4 : R,=Ar,R,=Ph) membered phosphorus heterocycles. Alternatively 2+1 cycloadditions of Me,CP=NR, (R,=SiMe,, 1-adamantyl, 2,4,6Me,C,H,) also give 4 . 2 2 Phosphines can be converted to phosphazenes in a particularly interesting redox condensation reaction involving amides in the presence of diethylazodicarboxylate. Thus phthalamjde and Ebenzenedisulforamide are converted to the upon reaction with triphenylphosphine. The diphosphines, Ph,P(CH,),PPh, (n=1,2) can be converted to the mono and diphosphazenes derived from NH, and H,NCN. 23 The reaction of a p-MeC,H,SO,NH, , Ph,P (0) dichloroamine, CF,S02NC1,, with arylfluoroalkyl-phosphines leads to the phosphazenes ( C3F,) ArP=NSO,CF,, (Ar=C,H,, ml 1bis(tripheny1phosphazo)derivatives
C,H,F). A set of substituent constants, u , , u R I uM and up, for the phosphazene function were obtained from the "F NMR spectra .*, Aminophosphorus (111) derivatives also continue to be employed as phosphazene precursors. The reaction of the hydrazonyl chloride , p-NO,C,H,CCl=NNHPh with 2arylamidophosphites give RC,H,N=P (OEt),C (C,H,NO,-p) - =NNHPh (R=H,Me, NO,) for which intramolecular hydrogen bonding between the hydrazine hydrogen and phosphazene nitrogen atoms has been proposed.25 Treatment of R,PNHR1 (R=Et, Me,CH; R1=MMe3, M=C, S i , Ge) with butyl 1.ithium followed by R;AsCl (R2=Me, Me,C) gives R,P(=NR') AsR,~.,~ Treatment of the bis catechol p-Me, pspirophosphorane, (C,H,O,) ,PC1 , with (EtO),PNHC,H,R (R=H,NO,, m-C13) gave the spirophosphoranes with an exocyclic
8: Ph osph az en es
phosphorus-phosphorus bond , ( C,H,02) ,PP ( EtO),=NC,H,R. 23 An improved synthesis of the popular p-nitro-bis (triphosphonium) cation, PPN', from Ph,PBr, and hydroxylamine hydrochloride has been reported. The Kirsanov reaction of DL-threonine with PC1, in dioxane gives MeCHClCH(COCl)=NPCl, while in benzene a phosphate rather than the phosphinimine is formed.29 Treatment of (R,N),P+X-(R=Me,Et,Pr) with hydrazine followed by sodium in liquid ammonia provides (R,N),P=NNH,. Reactions of these materials with organohalides results in alkylation of the phosphazene nitrogen atom.30 Reactions of acyclic phosphazenes, including those discussed above, continue to attract attention. The most interesting report involves oligomeric peralkylated polyaminophosphazenes, ( (Me2N),P=N],(Me,N) ,.,P=NCMe, (n=0-3), which can be prepared from the reactions of (Me,N),P=NH, Me,NH and Cl,P=NCMe,. The related derivative (Me,N),P=NP(NMe,) ,=NMe was prepared by the reaction of Me,P=NH with C1P(NMe2),+C10; followed by a demethylation step. The polyaminophosphazenes are exceptionally strong bases, the later derivative has a pK, is the of 32.66 in acetonitrile and (Me,N),P=N-P(NMe,),=NCMe, strongest known neutral nitrogen base. The low nucleophilicity of these bases allows for their effective use in deprotonation and elimination reactions.31 Treatment of (Me,N),P=NSiMe, with xenon difluoride gives quantitative conversion to (Me,N),P=NF which upon reaction with Me,SiN, C1, with produces [ (Me2N),PNH,] N,. 32 The reaction of Cl,P=NP (0) N,O, gives a derivative which has been described as being in N=PCl,ONO and which yields between [ N (POC1,) ,]-"o+ and C1,P (0) waxes and oils upon polycondensation followed by derivatization with fluoroalcohols.33 An improved synthesis of N,N-octamethylimidodiphosphotetramide, [(Me,N),P(O)],NH from Cl,P=NP(O)Cl, has been reported. Deprotonation leads to the delocalized phosphazene anion which is a weaker nucleophile than the anion derived from phthalimide.34 Quaternization of the bromophosphazene, (Et,N), PBr=NEt with aziridine in ether gives (Et,N),P(NC,H,) NHEt' which upon treatment with sodium in liquid ammonia yields (Et,N) ,P (NC,H,) =NEt. The corresponding
-
quaternization in benzene results in aziridine ring opening to give 5 . Treatment of the analogous chlorophosphazene with two
319
320
Organophosphorus Chemistry
equivalents of aziridine followed by sodium in liquid ammonia gives (Et,N) ,P (NHEt)=NCH,CH,NC,H,. The reaction of (Me,N),PCl=NPh with KNC,H, gives (Me,N) ,P (NC,H,=NPh)which upon treatment with aziridine produces (Me,N) *P(=NPh)NHCH,NC,H,. 35 Direct 2-alkylation of [ (NMe,),P=N],P(O)H with alkyl halides gives [(NMe,),P=N],P(OR)H+ which upon treatment with sodium in liquid ammonia provides the phosphite, EtOP[N=P(NMe),],.36 Transsilation of (Et,N),PCl,,=NSiMe, with trichlorosilane gives The reactions of Ph,P=NSO,Cl with (Et,N) nPC1,,=NSiHC1, (nrl-3) 2-imino-lI3-dithianesand dithiolane hydrochlorides gives the sulfamoyl iminodithianes 6 A significant increase in the number of reports of interactions of transition metal compounds with acyclic phosphazenes has been noted over the past year. The reaction of [Cl,PNPCl,]Cl with MoC1, gives the simple salt, [Cl,PNPCl,]MoCl,, which upon hydrolysis by trace amounts of water gives the oxomolybdenum salt, MoC1,- rather than attack at the phospha~ene.~' By way of contrast, the tungsten nitride, WNCl,, reacts with [Cl,PNPCl,]Cl to initially form the simple salt [ Cl,PNPCl,] WNC1, which rearranges to Cl,WNPCl,NPCl, , a tungsten complex with a phosphazene chain as a ligand. The ,'P NMR spectrum of this material indicates significant tungsten-nitrogen double bond character.40 The tendency towards metal-nitrogen multiple bond character in metallophosphazenes has been noted in several other systems. The reaction of Cp,AnCl (Cp=n5-C,H,; An=U, Th) with LiNPPh, provides Cp,AnN=PPh, where, in the case of Uranium, a short metal-nitrogen bond is observed. Relativistically parameterized extended Huckel calculation on the model compound Cp,UNPH, show that the large negative charge on the nitrogen atom in the NPH, fragment promotes uranium-nitrogen multiple bond character.,' The reaction of the pyridine adduct of MoC1, (N3S2) with triphenylphosphine yields MoC1, (NPPh,) .py which exhibits a short and nearly linear molybdenum-nitrogen bond. This report also provides a useful summary of structural data on Ph,PN metal complexes. 4 2 Short molybdenumnitrogen bonds are also observed in [MoCl,(NPPh,)], which is obtained from the reaction of Mo,Cl,, with Ph,PNSiMe,. The dimer may be converted into the anionic monomer by reaction
.,'
8: Ph osphazenes
with Ph4PC1.43 The reaction of CH,WCl, with Ph,PNSiMe, gives The cyclic voltamagram of this derivative shows NeWCl,N=PPh,. two, reversible, one-electron reductions while the previous reported F,WN=PPh, and F,W (N=PPh,) show a reversible oneelectron reduction. The parent phosphazene, Ph,P=NSiMe,, was not reduced under similar conditions. These data were interpreted in terms of the stabilizing effect of the NPPh, ligand, due to its strong electron donor ability, on high tungsten oxidation states.44 Other g-bonded phosphazene metal complexes include [Ph,PHSiMe,-CuCl,], which is derived from the reaction of Ph,PNSiMe, with copper (11) chloride.45 While the reaction of Ph,PNPh with copper (I) chloride gives the 1:l adduct P ~ , P N P ~ - C U Cthe ~ ~ corresponding ~, reaction with gold (I) chloride proceeds with disproportionation to give metallic 47 The Staudinger reaction of 2 ,3gold and [ Ph,PNHPh] +Au12-. diazomalic acid E-methylimide with triphenylphosphine gives the diphosphazene, 7 ,47 which forms a 1:1 adduct copper (I) chloride adduct. The mode of coordination in this complex is through one of the phosphazene nitrogen atoms.46 A novel reaction occurs between Mo(NO),(dttd) (dttdH2=2,3:8,9-dibenzo1,4,7,10-tetrathiadecane) and phosphines, PR,, to give Mo(NO)NPR,(dttd). Fast reactions are observed with alkylphosphines (R=Me,C,H,,) and slow reactions with arylphosphines. NMR ( 13C, 14Nl 95M0) data indicate that the NPR, ligands are strong donors.48 The reaction of MoOY, (acda) (Y=F,Cl,Br;acda=aminocyclopent-l-ene-l-dithio-carboxylate)
with Ph,P=NC,H,X ( X = H ,C1 ,NO,) gives the imido complexes Mo(=NC6H4X)Y,(acda),. 49 Thermolysis of the sily1imi.de bridged complex (CO),Re-NR-P (NR)C1 (NR2) (R=SiMe,) yields the complex cubane like structures 8 and 9 . The reaction of the cyclophosphazene with a terminal phosphazene, R2N(RN)(RN)P-NRP (NR)NR, (R=SiMe,) , with Re (CO)5X or Re (CO),X2 leads to the phosphonium cyclophosphazene with a terminal phosphazene , 10.50 The reaction of (CO),Re-NR'-P(NR') C1 (NR2) ( R'=SiMe,, CMe,) with RR'N P=NR' gives the complex structures 11 and 12.5' The reactions of (Ph,PCH,CH,PPh,) Ni ( v2-R,NP=NR) (R=SiMe,) with Me,SiN, and diazo-t-butyl ester gives the side on coordinated ( v 2 ) phospha (v)zene 13 (R=SiMe,;R'=SiMe,;CHCO,CMe,) . Analogous reactions occur if the bipyridyl ligand is used in place of
32 1
Organ oph osp h orus Chemis try
322
I
CH,
‘si
/NR Me, ”’
R
Ph,
R
R
R
R
(17)
L
3 23 the diphosphine. The bipyridyl complex 14 reacts with azides ( V ~ Q elimination of R,NP=NR) to give complexes such as 13 while reactions with diazo t-butyl ester gives 15. 52 The interaction of R,NP(=NR), (R=SiMe,) with diphenyl zinc gives the complex 16 which forms 1:l adducts with Ph,P=O and pyridine and also reacts with a second equivalent of R,NP(=NR), to yield 1 7 . ~ ~ Coordination of the phosphazene nitrogen atom in PhN=PPh,CH=C(NH,)C,H,Me with rhodium and iridium cyclooctadiene complexes has been observed.54 A few additional miscellaneous applications of acyclic phosphazenes including the use of (phosphorimido)arylpyrazoles as herbicides and plant growth regulators55 as well as the use of salts such as [ (PhO),P(O) 1,N-K' to improve the fire resistance of aromatic p o l y ~ a r b o n a t e shave ~ ~ been reported. Other examples of linear phosphazenes as substituents on inorganic ring systems may be found in sections 3 , 4 and 5. Cvclophosphazenes A monograph, IIInorganic and Organometallic Polymerst157, contains reviews on the current status of phosphazene and polymers obtained from organofunctional cycloph~sphazenes~~ as well as specific investigations which will be quoted below. An extremely valuable, comprehensive review of NMR ('H, 13C, "F, ,'PI 14'15N)data on cyclophosphazenes and correlations of these data has become available.60 Focused reviews of various aspects of cyclophosphazene chemistry including organsiloxane derivatives6', cyclolinear polymers from functional oligomers and cyclophosphazenes62and rearrangement reactions (cis-trans, geminal non-geminal, tautomerism, etc) have appeared. Electrochemically determined oxidation potentials for fifteen ferrocenes with trimeric and tetrameric phosphazenes as substituents show the strong electron withdrawing effect of the phosphazene. This effect is of sufficient magnitude as to induce the largest positive (potential) shift yet reported for a substituted ferrocene.63 The electron withdrawing ability of the phosphazene unit in N3P,C1,NRR1 , N4P4C1,NRR1 and trans-2 ,6N4P4Cl6(NRR1), (R=Me;R1=Ph) has been estimated from UV spectral data .64 While specific crystal structures are reported in 3.
Organ oph osph orus Chemistry
324
section 7, it is appropriate to refer to efforts directed towards correlation of structural (X-ray) and NMR data at this point. The value of ,-JpoCcin spiro lI3-propanedioxy cyclotriphosphazenes is related to the electron withdrawing/releasing properties of the remaining phosphorus substituents e.g. with increasing electron donation from the distant exocyclic groups, the spiro phosphorus-oxygen bond lengthens and the value of 'JpoCc decrease^.^^ In selected aminophosphazenes, the value of 4JpN,.c (through the exocyclic nitrogen center) can be correlated with pyramidal character and associated increase in the exocyclic phosphorus-nitrogen distance.65 On the other hand, upon comparing 2,2-N3P,C1,NH(MMe,), (M=C,Si) one finds a large difference in "P NMR chemical shift at the substituted phosphorus atom but essentially equivalent bond lengths and statistically indistinguishable bond angles.67 The 13C and 31PNMR spectra of all isomers of N3P3C16-n(OPh)nhave been analyzed in situ. The ,'P shifts and coupling constants along with the ips0 13C shifts can be correlated with the degree of substitution (n). The values for ,JpOcand 3J,0cc are greater at zP(OPh), centers.68 NMR, IR and mass spectrometry data show that oligophosphazenes (chloro, ethoxy, amino and anilo) are mixtures of trimers, tetramers and oligomers with large numbers of phosphorusnitrogen units in the chain.69 More sophisticated NMR techniques have been brought to bear on structural problems arising in compounds derived from the reactions of polyamines with (NPC1,) The structure of N3P,C1,NH (CH,) ,N (Me)N,P,Cl, was established by a combination of high field (,'P and 'H) and two-dimensional ( J resolved 'H and ,'P COSEY) technique^.^' The high field (202.45 MHz) 31PNMR spectra of ( [NH(CH2)mNH]N3P3C13)2"H(CH2)nNH] (18) (m=2, n=7-9) show nearly first-order ABC spin systems which are uneffected by the variation in n, with two conformations being observed for each c~mpound.~'In the same series (18; m=3 ,4 ;n=6-9), the high field 31PNMR spectra again show of doubling of resonances ascribed to two conformations arising from folding due to hydrogen-bonding of one phosphazene ring to the N-H center of the other.72 Two-dimensional 31P NMR (J resolved, COSEY) for 18 (m=3, n=6) shows which coupling patterns are assoicated with
,.
325
8: Phosphazenes
individual resonance centers . 7 3 A new pulse sequence application involving selective excitation pulse transfer allows for resolving of the two AMX subspectra arising from the two conformations of 18 (m=3, n=6) .74 Another modification of the standard recipe for the preparation of cyclic chlorophosphazenes has been disclosed.75 Aminolysis reactions continue to be the most extensively examined nucleophilic substitution process of the cyclophosphazenes. The 2 ,4-trans-N3P3C1,(NRR') (R,R'=piperdino; Et,;H,Me;H,Et;H, i-pr) isomers have been detected by GC along with 'H NMR and IR s p e c t r o s ~ o p y . ~ ~ The preparation of hexa(1-pyrroly1)cyclotriphosphazene can be improved by the use of phase transfer catalysts.77 The reaction of (NPCl,), with 9-aminophenaleimine provides the spirocyclic derivative 19 .78 The reactions of 2 ,6N,P,Cl,(NHET), with amines lead to the fully substituted, 2,6N4P4(NRR') 6 ( NHEt) , and bicycl ic , N,P, (NRR' ) (NHET)NEt (NRR'=pyrrolidino , piperdino, morpholino, diethylamino and cyclopropylamino) derivatives. Cyclopropylamine reacts with (NPC1,) to give N,P, (NHC,H,) and N,P, (NHC3H5) 6NC3H5rthe latter being the first bicyclic phosphazene derived an a-branched alkylamine. The reaction mechanism has been discussed in terms of basicities of the solvent and the amine and the NMR (31P,'H) parameters have been related to the structures involved. The reactions of polyamines with chlorocyclophosphazenes continue to provide interesting and structurally complex derivatives. In addition to those studies devoted to NMR investigations quoted above, new synthetic studies have also appeared. The reactions of the aziridinocyclotriphosphazene, N,P, (NC,H,) ,C1 , with NH, (CH,) "NH, (n=4,5,8,12)give the diamino bridges (bino) species N3P3(NC,H,) ,NH (CH,) ,NHN,P, (NC,H,) ,, which exhibit such poor water solubility that biological activities could not be measured." The reactions of NH, (CH,) ,O (CH,) NH, ( LH,) with (NPC1,) leads sequentially to the 2,4-bridged (ansa) derivative, 2 , 4 N3P3C1,L, and then to the ansa/spiro species 2 ,4 ,6,6-N3P,C1,L, ( 2 0 ) 8 " 8 2 which was originally assigned a diansa structure." Further reactions of 2,4-N3P3C1,L confirm that aminolysis occurs only at the =PC1, center i.e. addition of azirine gives
,
,
,
,
Orgatioph osphorus Chemistry
HN, N//‘\N
YH
I
(21)
n = 6
I
or 8
N ,H
327
8: Ph osp hazeries
,,
of NH, (CH,) ,NH, gives the ansa/bino 2 ,4 ,6,6-N,P3C12L(NC,H4) N,P,Cl,LNH (CH,) ,NHN,P,Cl,L and with NH, (CH,) ,NH, to give the ansa/spiro N,P,Cl,L[NH (CH,) ,NH] which is analogous to 2 0 Crown and cryptan like phosphazene derivatives result from the reactions of (NPCl,), with NH,(CH,),,,NH,. At each degree of substitution only a =PC1, center is attached leading first to N,P,Cl,NH (CH,) ,,,NHN3P,C1, then to the doubly bridged species 2 ,4N,P,Cl, [ NH (CH,) 6,8NH] ,-2 ,4-N,P,Cl, and finally to the unique triply bridged species 2 1 for which three conformational isomers were The ~ primary amino groups in detected by ,'P NMR s p e c t r o s ~ o p y . ~ spermidine and spermine can be protected by reaction with phthalic anhydride. Since the secondary amino group is the only remaining reactive site, the mono substituted 22, and spiro, 23, derivatives are obtained in reactions with (NPC1,),.84 In spite of a partial response in phase I clinical trials,85 a phase I1 trial of the biologically active aziridinocyclophosphazene, trans-2 ,4-N3P3(NC2H4),(NHMe),, on non-small cell lung cancer showed cumulative bone marrow toxicity.86 Since all clinical trials on azirodinophosphazenes show this toxicity, it is doubtful that these compounds will have any therapeutic applications. The geminal to non-geminal rearrangement previously with alkoxides reported in the reactions of 2 , 2-N,P4C1,(NH,) has been examined in more detail. The range of disubstituted (R=Me, Et, n-Pr, isomers ( gem, cis, trans) for N,P,(OR),(NH,), n-Bu) can be observed with the trans isomer being the predominant non-geminal form. The monoamido species,
,
N,P,(OMe),NH,,
has also been prepared.87
Kinetic studies on the
formation of [N,P,C150NC6H,Me] '(21- from (NPC1,) and 4-methylpyridine-F-J-oxide show the existence of two pathways, a bimolecular route vra a five-coordinate phosphorus intermediate and another catalyzed by a second molecule of the N-oxide.88 The reaction of sodium 2-[ 4-[ (4-n-butylphenyl)azo]phenoxy]ethoxide with (NPC1,) gives [ NP ( OCH2CH,0C,H,N=NC,H4n-C4H,) ,I3 which exhibits a reversible thermotropic phase The analogous preparation of (NP[ ( OCH,CH,O) ,C,H4N=NC,H40Me]2) also has been reported. Phosphazenes with extended side
,
,
."
,
chains , [ NP (OR),] (R=(CH,),C,H, ,x=1-3 ;CH,C,H,) , were prepared as models for the corresponding polymers.g' A continuous process
Organophosphorus Chem istry
328
,
,
for the conversion of (NPC1,) to [ NP (OAr),] (Ar=C,H, ,C,Cl,) has been patented. 92 Numerous mixed substituent derivatives containing alkoxy and aryloxy functions have been reported. The cis and trans isomers of 2 ,2’,4 ,4’,6,6’-N,P, (OMe) (OPh) have been prepared and individually found to undergo a thermally induced phosphazene-phosphazene rearrangement. 93 Other mixed cyclotriphosphazene derivatives include the 4’-vinyl-4biphenylphenolates, N,P,X,OC,R,C,H,CH=CH, (X=OCH,CF,) 94 , mixed OCH,CF,/OCH,CH=CH, ,95 allylphenoxy/phenoxy/ethylphenoxy= and potentially biologically active derivatives obtained from the sequential reaction of (NPCl,), with hydroquinone and a~iridine.~’The reaction of (NPC1,) with bis (hydroxymethyl) o-carborane leads to the series of spirocyclic derivatives 2 4 (n=l-3) .98’99 A few reactions of the chlorocyclotetraphosphazene, (NPCl,),, have been studied. In the series of labile trifluoroethoxy derivative, N,P4,X, .(OCH,CF,), (X=C1, NMe) , although only 2,6 and 2,4 disubstituted isomers were detected, substantial amounts of =P(OCH,CH,), groups were noted in the tris and tetrakis stages of chlorine replacement. looMixed substituent tetramers containing the 2-hydroxyethylmethacrylate as well as the trifluoroethoxy, octafluoropentoxy, phenoxy and unreacted chlorine have been reported . l o ’ Reactions at the exocyclic positions continue to represent new routes for further structural elaboration of cyclophosphazene derivatives. The reactions of N,P, (OPh),OC,H,NH, with aldehydes, HC (0) C,H,X, provide Schiff (X=OMe, OH , CN) , while bases of the type N3P3(OPh),OC,H,N=CHC,H,X reactions with the acid chlorides, ClC(O)C,H,X, leads to the amides , N,P, (OPh),OC,H,NHC (0) C,H,X (X=OMe, CN) . Other Schiff base derivatives are obtained from the reactions of N,P, (OPh),OC,H,C (0) H with HN,C,H,X which give N,P, (OPh)50C,H,CH=NC,H,X (X=OMe, OH) . Reduction of the same aldehyde to the alcohol followed by reactions with the acid chlorides , C1C ( 0 )C,H,X gives the esters, N,P, ( OPh),OC,H,CH,O (CO)C,H,X (X=OMe, CN) .” The reactions of the aziridino azide, 2,2-N,P,(NC2H4),(N3), (obtained by a metathesis of the chloride and sodium azide) with phosphines gives N,P, (NC,H,) ,N3 (NPR,) (R=Ph, NMe,) . The mixed derivative
,
,
,
-
329
8: Phosphazenes
(2C1
(251
(261
(28)
(29)
Ph
(301
(31 1
Orgun nph osphoriis Chemistr!?
330
N,P, (NC,H,) (NPPh,) [ NP (NMe,) ,] can also be prepared.lo2 The diaminophalene derivative 19 (X=OCH,CF,) is amphoteric and consequently can be protonated or deprotonated.
A 31P NMR investigation of the effect mainfested at the distant, i.e. =P(OCH,CF,),, phosphorus atoms by each of these reactions indicates that substituent lone pairs in the diamine unit do not have an orientation which is effective for long range conjugation with the phosphazene ring. Polymers containing cyclophosphazenes as substituents are available L ’ i o exocyclic group reactions.59 The 4’-vinyl-4-biphenylphenol derivatives. N,P,X,OC,H,C,H,CH=CH, (X=C1, F, OCH,CF,) , all undergo radical initiated vinyl addition polymerization to yield flame
retardant polymers which retain 60-70% char yield at 7 0 0 800 C.94 The p-aminophenoxy derivatives, N,P, ( OPh) (OC,H,NH,) and N,P,(OC,H,NH,), have been used as curing agents for expoxy resins. The cured resins have high char yield and laminates prepared from these resins have meclianical properties which are superior to those from commonly used epoxy resins.103
,
,
Epoxidation of mixed trifluoroethoxy-allyloxy cyclotriphosphazenes followed by curing leads to resins.95 Oligomerization of the siloxane units in N,P, (OCH,CF,) (Me)CH,?i (Me) (SiMe,),6 occurs upon treatment with sulfuric acid.’04 Hydrosilation of allylphenoxycyclophosphazenes with siloxanes containing silicon-hydrogen bonds gives rubbery foams.’’
A considerable decrease in the reactions of cyclophosphazenes with organometallics or transition metal organometallics has been noted over the past year. The synthesis of N,P,Cl,CI-I,CMe, from the Grignard reagent and of 2,2’-N3P,Cl4(Me)CH,CMe, from the copper phosphine catalyzed addition of the same Grignard followed by reaction with methyl iodide has been rep~rted.’’~The reaction of aluminum alkyls (Me3A1 Et2A1C1 on Et,Al) with N,P3C1,,(NMe,) , (n=1-3) leads only to alkylation of the chlorine atoms geminal to a dimethylamino group. The dimethylamino groups may be removed by reaction HCl to give alkylphosphazenes. By way of contrast] all chlorine atoms in the tetramers, N4P4C1,,(NMe2),(n=2, 4 ) are I
replaced by alkyl groups in reaction with aluminum a l k y l ~ . ” ~ The sequential reactions of LiBEt,H and FeCp (CO),I with
33 1
8: Phosphazenes
N,P,Cl,, (OCH,CF,) , (n=4, 5) (derived from a three step sequence of dimethylaminolysis, reaction with trifluoroethoxide and
,
then HC1) give N,P, (OCH,CH,) ,FeCp (CO) and N,P, (OCH,CF,) (C1)The interaction of chloroplatinic acid with FeCp(C0),.lo, (NPX,), (X=Cl, NHEt) has been investigated using ‘H and ,‘P NMR techniques while (NPCl,), doesn‘t undergo reaction, A study 2 [ NP (NHEt),] ,.H,PtCl, can be detected and isolated. lo7 of the effect of various phosphazenes on the activity of H2PtC1,*6H,O as a hydrosilation catalyst show no effect for and inhihitory effects for (NPX,), (NPC1,) and N3P,(NMe,),C1, (X=NHEt, NHBu) and N,P,(NRMe), NH(CH,),MediO(Me,SiO)3b.107 The
,
reactions of Mo(CO), with (NPb),,, (L=NC,H,,; NHC,Hll) yield (NPb),.Mo (CO) and (NPb),-Mo(CO) IR spectra of the later suggest, in that case, bidentate coordination involving both the endo- and exocyclic donor sites. Mixed ligand complexes of both the trimers and tetramers can be prepared by analogous reacitons with (2-phen)Mo (CO)4 . lo’ The applications potential of cyclophosphazenes continues to be manifested in numerous patents. The foremost interest
,
continues to be in the area of fire retardancy. Specific systems which have attracted attention include the use of [NP(OR) (OR’)1, [ R , R ’ = halosubstituted C1-Clo,C,-C,,; nz3] as flame retardant finishes for cloth from hydrophobic fibers’” and [NP(NH2),In (nl 3) as an additive for cellulose fibers and knitsl10-l’3 and a coadditive for cotton.’14 Increased granule strength is observed if (NPX,),,, (X=Cl, NH,) is added to urea in the melt.ll5 Evaluation of the soil urease inhibition activity of non-geminal phenoxyamidocyclotriphosphazenes, N,P, (NH,)6.n (OPh) (n=1-3), shows a decrease in the immediate inhibition with an increase in n while sustained inhibition increased with n.l16 The use of [NP(OR)2]3,4 (R=C,H,, C11-30r alkyl or aryl) as components of lubricating grease”’, 2,6C (CH,) =CH,] as a denture base re1 ining N,P, (OCH,CF,) [ OCH,CH,OC (0) material,118[NP(oc,H,-E-R),I,,, (R=H, Me, Et, c1, Br) as a component of polymeric potting compositions for serniconduct~rs”~ and of (NPCl,), (nz3) in heating sensitive recording materials’20 has been noted. Siloxanes prepared in the presence of (NPCl,), are stabilized against viscosity changes which result from reactions with catalyst residues .12’
,
,
332
Organop h osp h orus Chemistry
study of the pyrolysis of a cellulose, (NPCl,), mixture, shows that flamability is reduced by an increase in water and decrease release of other volatiles from cellulose.12,
A
CvcloDhospha(thia1zenes A s in the case of last year's review, the volume of work on cyclophospha(thia)zenes has decreased. This is, in part, due to the fact that , in spite of earlier promise, the aziridino derivative NP(NC,H,) ,NSO(NC,H,) (SOAz) did not perform well in clinical trials as an anticancer agent. A review of molecular orbital studies, and conclusions drawn therein, on sulfur-nitrogen rings including H,PS,N, and (H2P),SN3+ has been ~ub1ished.l~~ New synthetic routes to divalent (sulfur) phospha(thia)zenes have been explored. The reaction of R,P(NHSiMe,)=NSiMe, (R=Ph) with S,N, yields Ph,PS,N,(25) . If (NSCl), is allowed to react with R,P[N(SiMe,),]=NSiMe, the bicyclic species 26 (R=Me, Ph) is obtained which upon heating in toluene is converted to 25. The alkyl species 25 (R=Me, Ft) are obtained in impure form and upon sublimation decompose to 1,5-(R2P),N,S,(27). Alternatively, 27 (R=Ph, Me) can be prepared by the reaction of R,P [ N (SiMe,) ,] =NSiMe, with SCl,. 124 The Lewis and Bronsted base behavior of 25 (R=Ph) have been explored resulting in the isolation of 25H+-X-(X=BF4,CF,SO,), 25*BC13, 25Me+CF3S0,7 and (25)" SnC1, (n=1,2). The reaction of 2 5 with HBF, was followed by 31P NMR and UV-VIS spectroscopy. In the methylation reaction, X-ray and NMR studies show that methylation occurs at the nitrogen atom cy to the phosphorus center. Ab initio Hartree-Fock-Slater S C F MO calculations on a model system for 25 (R=H) shows that protonation of the anitrogen atom is favored by electrostatic interaction energy and leads to stabilization of the HOMO.'25 The novel transition metal carbonyl derivative, 28, is obtained, in low yield, when Cr(CO),-(PrNPCl,) is allowed to react with (Me2N),S+NSO-.126 The reaction of 5-phenyl-1,3 ,2 ,4 ,6dithiathiazine (29) with triphenylphosphine initially forms 1triphenyl-phosphinimino-5-phenyl-l,3,2,4,6-d~th~atr~azene (30) which undergoes ring expansion to the kinetically favored exo4.
3-imino-5-phenyl-1,3,5,2,4,6,8-trithia-tetrath~azene
(31)
followed by isomerization to the thermodynamically favored
333
8: Phosphurenes
endo isomer
(32). The corresponding reactions with other phosphines show the following rate order (relative to Ph3P) 3PI (2-tolyl),P>Me,P and the importance of a 1 , 3 PH,MeP> ( C6Hll) shift mechanism in these reactions has been emphasi~ed."~ Details of the previously report of the synthesis exocyclic phosphazo units on a triazene ring have appeared. The reaction of (morpho1ino)diphenylphosphine with S,N, gives rise to Ph, (Morph)P=NS3N, and 1,5-[ Ph, (Morph)P=N],S,N,. The first direct observation of a ring contraction of an eight-membered ring (the later species) to a six-membered ring (the former species) has been noted and followed by UV-VIS spectroscopy.'21 Reports on four coordinate (sulfur) phospha(thia)zenes come exclusively from the Groningen group. In a comparison of phospha(tria)zene structures, the difference between phosphorus-nitrogen and sulfur-nitrogen distances in SNP fragments has been related to the relative electronegativities of the respective exocyclic substituents. The reactions of the lithium enolate of acetaldehyde, LiOCH=CH,, with (NPCl,), NSOPh lead to (NSOPh)N,P,Cl,, (OCH=CH,) , (n=l-4). For n = l , a single isomer is observed and for n=2 a non-geminal isomer with trace amounts of the geminal derivative is observed. The aziridolysis reaction of the vinyloxy derivatives provides (NSOPh)N,P, (NC,H,) ,OCH=CH, and the mono and bis derivatives of the disubstituted (n=2) derivative.130 The first organometallic phospha(thia)zene, the ferrocene bridged derivative, (NSOPh),NP (F)C,H,FeC,H, (F)PN (NSOPh) , has been reported (33).13'
,
Miscellaneous PhosDhazene Containinq Rinq Systems. Phosphatriazines (azaphosphorins, triazaphosphinimes), which are formally related to symmetrical triazines by replacement of a =CR unit with a =PR, unit, have received renewed attention. The reaction of NH,CONHA,, with PC1, represents a convenient route to the tetrachloro derivative, 3 4 (X=Y=Z=Cl)132 which undergoes regioselective substitution Reactions with Me,NSiMe, occur at the =CC1 center rea~ti0ns.l~~ while the attack of LiOCH,CF, occurs at the =PC12 site.133 Numerous reactions of 3 4 (X=Y=F; Z=CF,) and selected reactions of the related dichloro derivative have been thoroughly 5.
Orgunophosphorus Chemistry
334
examined.134’135 While the reactions of amines or silylamines lead to the monoamino fluoro derivatives 3 4 (X=F; Y=NHCMe,, N(R)SiMe,), the use of two equivalents of (Me,Si),NMe gives 3 5 (R=Me; E=NSiMe,; X=N (Me)SiMe,) .134 The corresponding reactions with selected alcohols and silanols gives the hydroxy derivative 3 4 (X=F,Y=OH,Z=CF,). Direct substitution leading to the mono and disubstituted species, 3 4 (X=F,Y=ER(E=O,Si), Z=CF, or X=Y=ER), can be achieved using sodium alcoholates or thi~lates’,~.A phosphazene-phosphazane rearrangement occurs when
34
(X=F,Y=EtO, Z=CF,) is heated and
35
(X=F, E=O, R=Et) is
obtained. 134 The reaction with alcoholates is more complex than initially indicated in that the use sterically crowded alcoholates lead to the formation of the oxyanions of 3 4 (X=F; Y=OM; M=Li,Na,K; Z=CF3).135 Selected reactions of these oxyanions have also been investigated. Interestingly, the reactions of NaOSiMe,CMe, leads to the mono and disubstituted OSiMe,CMe, derivatives. Metallation of 3 4 (X=F; Y=NHR; Z=CF,) followed by reaction with ClSiMe, gives the secondary amine deri~ative.’~ A ~different monophosphazene heterocycle 3 6 , is obtained by the reaction of the cyclic phosphonium ion, 5 , with sodium in liquid ammonia.35 Interest in cyclometallaphazenes has increased over that past year. The reaction of numerous transition metal halides with the linear phosphazene, (N,NPPh,NPPh,NH,) C1 , gives rise to a broad range of cyclometallaphosphazenes 37 (M=Mo, Xn=Cl,’36; M=Nb, Xn=C1,’36; M=V, Xn=Cl,’37; M=W, Xn=Br3, F,’37; M=Re, XnC14’37) thus demonstrating that the phosphazene skeleton exhibits the ability to stabilize transition metals in high oxidation states . 1 3 7 A cyclodimetallaphosphazene, 3 8 , has been prepared via the reaction of VOC1, with Me,SiN=PPh,N (SiMe,) 13’ A more
,.
complex, bicyclic, dimetallaphosphazene, 3 9 , can be obtained from the reaction of WC1, with (H,NPPh,NPPh,NH,) C1 . 1 3 ’
Polv(phosphazenes) This section is devoted to polymers containing open-chain phosphazenes. Cyclolinear and cyclomatrix phosphazene polymers are covered in section 3 . Reviews include topics such as the current status of phosphazene chemistry5’; organosiloxane derivatives6’; synthesis (including mechanism) , structure and properties of phosphazene p~lymers‘~~’’~’; 6.
335
8: Ph o s p huzrries
iF3 R
Z
””I
( E t 2 N )P
N ‘
I
Et
(37)
(361
(38)
(39)
I C‘ 2 p\
N,
336 poly(alkyl/aryl)phosphazenes
Organ ophosph orus Chemistry
obtained from N-
silyphosphoranimines"142 ; polybis (pyrrolyl)pho~phazenes'~~;
preparation methods, commerical processes, characterization and applications of poly(phosphazenes) with specific reference to high temperature and chemical resistant coatings and adhesivesi44and physiochemical properties and applications of fluoroalkoxy and aryloxyph~sphazenes'~~. The synthesis of poly(phosphazenes) from cyclophosphazenes is a continual source of interest. Further investigations of the kinetics and mechanism of the BC1, catalyzed cationic ring opening polymerization of (NPCl,), have been reported.i467i47 New catalysts for cyclophosphazene ring opening polymerization such as transition metal complexesi48, CaSO,. 2H,0i4', as well as substituted cyclophosphazenes, PPh, and benzoyl peroxidei4' have been examined. Phosphorus thionitride, (NPS),, has been reported to be a product of the reaction of P4S,, with NH4C1. Poly (phosphazenes) with organosilane side chains have been prepared by thermal ring opening polymerization of N,P,Cl,CH,SiMe,, 2 , 2'-N,P,C1,(CH2SiMe,) The carbon analog N,P,Cl,CH,CMe, and 2 ,2-N3P,C1, (CH,) CH,SiMe,. polymerized but 2 ,2'-N,P3C1,(CH,) CH,CMe, did not although both derivatives underwent copolymerization with the corresponding organosilane derivative. In all cases, the phosphoruschlorine bonds can be derivatized with the trifluoroethoxide ion although in some case P-CH, functions were also obtained vin carbon-silicon side group cleavage.lo4 Transformations of poly(phosphazenes) to new derivatives continues to represent a major attractive feature of these systems. The largest number of synthetic processes involve reactions of poly(dichlorophosphazene), (NPCl,),, with oxyanions. A study of substituent effects in the alcholysis of (NPCl,), show that introduction of a fluoroalkoxy group favors formation of geminal, =P(OR),, units while aryloxy groups favor non-geminal , =P (OAr)C1 , unit.15' The alkoxy substitution route has been used to prepare two new liquid crystalline poly(ph0sphazenes). An azophenoxy derivative with a methylene oxide spacer, (NP[ (OCH,CH,O) ,C,H,N=N-C,H,OMe] 2 ) has a mesophase detected between 118"-127" on heating and between 126"-94" on the cooling cyclerg0while the mixed substituent
8: Phosphazenes
derivative [ NP ( OCH,CH,0C,H4N=NC6H4-nC4Hg) l.j (OCH,CF,) 0.7] , exhibits liquid crystalline behavior between 123"-175" The reaction of (NPCl,), with bis(hydroxymethy1)-Q-carborane leads to poly(phosphazenes) with spirocyclic units such as those found in the cyclic analogs 2 4 . The underivatized phosphoruschlorine units can be removed by reaction with LiOCH,CF,CF,H. Complete substitution, accompanied by some carborane decomposition,can be attained if the dilithio salt of the hydroxymethyl carborane is employed.997152 Poly(ph0sphazenes) with linear oligo(oxyethy1ene) branches, some of which are cross-linking and some with free hydroxy units, have been prepared by the reaction of (NPCl,), with a mixture of NaOCH,CF,CF,H and Na (OCH,CH,) ,ONa (n=3-5 ,7). These "pseudocrown ether" structures are good solid supports for catalysts.lS3 A true crown ether derivative derived from (NPCl,), and 15-crown-5-ether will solubilize lithium and sodium perchlorates. Ionic conductivity measurements on these systems have been conducted.lS4 Mixed substituent phosphazenes with alkyloxy, fluoroalkoxy, aryloxy and alkenylphenoxy groups have been ~atented"~ as have purification methods for poly etheroxy-substituted phosphazenes which are of value as solid electrolytes.1563157 Alkylation of phosphorus-chlorine sites in [ (NP(Cl)NMe,),, (NP(NMe,),),.,], can be effected using trimethylaluminum, however significant amounts of chain cleavage are observed during the reaction."' An interesting patent reports the reaction of (NPCl,), with cyclopentadienyl sodium followed by fluoroalkoxide or aryloxide ions. Heating of the polymers causes cross-linking at the cyclopentadienyl groups."* The reactions of [ NP (OCH,CF,) C1 1 [ NP (OCH,CF,) ,] with LiBEt3H followed by FeCp(CO),I or directly with NaFeCp(CO), allows for the preparation of poly(phosphazenes) with iron cyclopentadienyl side chains, [ NP (OCH,CF,) FeCp (CO)2] [ NP (OCH,CF,) ,] ".lo6 Ferrocenyl units may be conveniently attached to the phosphorus-nitrogen backbone by treatment of [NP(Me)Ph], with n-butyl lithium followed by ferrocenecarboxaldehyde or acetylferrocene thus providing The [NP(Me)Ph],[NP(Ph) CH,CR(OH)C,H4FeCp]y (R=H, Me) .lS9 reactions of p-aminophenoxy and 1-formylphenoxy poly(ph0sphazenes) with amines and acid halides allow for the
337
production of numerous mixed substituent polymers with aryl ester and aryl Schi ff I s base side groups , [ NP (OC,H,Me) (OC,H,R) 3 , (R=CH=NC6H,X;CH20COC6H4X; X=OMe, CN, OH) . Details of the specific reactions are identical to those reported for the The use of the cyclic model compounds in section 3.’’ aminophenoxy substituent to bind catecholamines to the phosphazene chain I ’ I U diazonium coupling reactions has been discussed.’6o The release of prolactin from cells was eliminated in the presence of poly(dopamineazophenoxyphosphazene).’60 while the dopamine bonded polymers remain intact when performing their biological function,160 a biodegradable phosphazene, poly(imidazo1e methylphenoxy) phosphazene) has been prepared as evaluated as a drug delivery systems.16’ Photo and radiation induced reactions of poly(ph0sphazenes) have also attracted careful study. Irradiation of [ NP (OC6H4C(0) Ph)2], can induce either chainscission or cross-linking depending on solvent and dissolved oxygen. The photo reactions originated from the first excited state of the benzophenone chromophore which leads to the ketyl. The ketyl radical reacts with residual phosphoruschlorine groups to form phosphorus macroradicals.162 Crosslinking and chain-scission also occured when [NP(OC6H4-~-R),], (P=H, Me, CMe, and cumyl) where exposed to ionizing radiation.16’ Physiochemical investigations of the properties of poly(ph0sphazenes) continue to be a main focal point of interest in this area. Some of these studies have been noted above. A calculation of the conformational energies of (NPCl,), from non-bonded and dipole moment interactions indicates that the PNP unit has considerable conformational freedom while the NPN unit is relatively rigid. These conclusions provide a rationalization for the low Tg and high end to end distance for the macromolecule.’64 A study of dielectric relaxation times molecular weight for [NP(OPh)2]n shows the existence of a dipole moment parallel to the chain which was interpreted in terms of alternating single-double phosphorus-nitrogen bonds.165 An extensive study of the (X=1-9) shows a variation of Tg in the series [NP(O(CH,),CH,),], minimum (-105”)at X=5.’l Thermal analysis (Tg and Tdecomp.)of 115
339
the mixed substituent polymers [NP(OPh),(OR),,], (R=C,H,-p--Me; OCH,CF,) have been reported.’,’ DSC studies of the phase transition behavior in aryloxy and alkoxy poly(phosphazenes) show a single Tg and two first-order phase transitions separated by a large mesophase region. Crystallinity changes above the mesophase transition but Tg is independent of levels of crystallinity. The natures of the phase transitions are not mutually exclusive and depend on process conditions. Three crystalline modifications of [NP(OPh,)], were studied by electron microscopy. Electron diffraction patterns observed as a function of phase transition allow for a detailed study of morphological changes in this system.167’168 Twinning of crystalline forms, which is common in phosphazenes having a T(l) mesophase transition, was observed films of [NP(OPh),], cast from THF. Phase transitions, including Tg, T(1) and T,, (which corresponds to motions of dipolar groups in the crystalline phase) , have been detected for [ NP ( OC6H,-~-F)2 ] n . Quantitative studies of the T,, transition were rep~rted.’~’ Dielectric relaxation studies of (NPX,) (X=Cl, OPh, OCH,CF,) show one peak for X=C1 while two peaks in the dielectric loss curve are noted for X=OPh and OCH,CF,. The second transition was related to side group rotations. The dielectric constant showed a stepwise increase in the mesophase regions for X=OPh A stress-strain and thermoelastic study of and OCH,CF,. 17’ cross-linked (NPCl,), shows low degrees of cross-linking and that at low temperature the system undergoes strain induced Melt spun fibers of [ NP (OCH,CF,) 2 ] crystallization. 1721173
consist of a thin shell about highly oriented long fibers with a diameter of 1 0 - 5 0 p . 174 Alternatively, spherical particles with a diameter of 1pm can be obtained by adding a poor solvent to solutions of the polymer in a good s01vent.l~~ The preparation of moldings has been examined as a function of the relationship of drawing temperatue to other types of bulk characterization data such as tensile strength, elongation etc. for [ NP (OCH,CF,) ,] n177 and commerical f luoroalkoxy polymers178 have been studied in tropical conditions (climate and sea water)’77 or with respect to the effect of carbon black or silica fillers.17* Degradation in tropical conditions was traced to reaction at residual phosphorus-chlorine sites’77
0rgan o ph osp h or us Chemistry
340
while favorable properties of the commerical systems recommend them for oil field service under artic condition^."^ The first reports of the applications of the magic angle spinning (MAS) solid state NMR techniques in phosphazene chemistry appeared this year. No extra lines were observed in the 31P MAS spectrum of cross-linked (NPC1,),17' thus suggesting a low number of cross-links (in agreement with thermoelastic . However hydrolyzed sites in heated samples of cross-linked (NPCl,), and residual phosphorus-chlorine bonds in Large main-chain [NPOR),In (R=Me, Et) have been detected."' motion above Tg is seen in the I3C MAS of The "F MAS and two dimensional NOE alkoxyphosphazenes.I7' spectra of [NP(OCH,(CF,),CF,),],, allow for assignment of chemical shifts for individual "F centers.la' Poly(ph0sphazene) solid electrolytes are still attracting interest. The ionic conductivity of lithium polyfluoroalkane sulfonate complexes of [NP(O[C2H40]xCH3)2], (x=1,2,7,12,17)and the same polymer cross-linked with polyethyleneglycol varies with side-chain length and cross-linking with considerable improvement being noted upon cross-1inking. Mixtures of poly[bis(methoxyethoxide)phosphazene] and polyethylene oxide complexed with lithium salts make excellent thin film electrodes for Li/TiS, rechargeable batteries. The other major recent application attracting quantitative study is the use of poly(ph0sphazenes) as membranes. Gas permeability studies of poly(organophosphazenes) show that the membranes with high oxygen permeability exhibit low selectivity and that the normal linear relation between Tg and permeability was not observed in these systems. The highest O,/N, selectivity was found in [NP(OC6H,-~-C1),],,.'83s184 Preparation of poly(phosphazene) membranes as well as preliminary results on the separation properties of [NP(OCH2CF3),], membranes for dilute ROH-aqueous solutions (R=Me, Et, i-Pr, Ph) have been Quantitative studies of permeation and reported."' pervaporation of water and several organic solvents through this membrane show a permeation flux order of MeOH>EtOH>C,H6>H20>C6H12. Effects of phase transitions in the membranes were noted. The separation characteristics of the membrane range from slightly to significantly better than I
341
8: Phosphazenes
simple distillation.lE5 Separation of aqueous ions ( Cr3+, Co2+,Mn2+) by diffusion across a [ NP (OPh)2] membrane has been examined. The divalent ions exhibited a high diffusion coefficient. Diffusion activation energies were also reported.lE7 In addition to the studies cited above, numerous references to applications of poly(phosphazenes) have appeared. Poly(phosphazenes) with cure sites, usually a vinyl group, on the side chain have been prepared.'89-190 Phosphazene polymers are useful components of high thermal decomposition temperature, fire resistant composites.lS1 Other fire resistant applications include amidophosphazenes for cellulose192and aryloxyphosphazenes for wire and cable coatings.lg3 Membranes for separation of liquids (see above also)lS4 and as inert matracies for 0, transport which enable ~ ~ ~ - ~ ~ selective 0, enrichment via electrochemical ~ e l l s utilize poly(phosphazenes). Long chain fluoroalkoxy phosphazene cyclic oligomers make useful lubricants for vacuum pumpslS7 and for use in processing thermoplastic-resin parts.19* Semiconductor coatings stable to high temperature and humidity also employ fluoroalkoxy phosphazene polymers.lg9 Strong surface and interfacial reactions between YBa,Cu,O, superconductors and poly (phosphazenes) occur.2oo Biological applications also continue to appear. Biomedical uses such as body implant devices ,210 soft-denture liners202 and opthalmological materials203 have been patented. Hydrolysis of phosphazenes to release antifouling agents has also been noted.204 7. Molecular Structure of Phosphazenes. The following structures have been determined by 2-ray diffraction. All distances are in piecometers and angles in degrees. Compound Comments Reference lc (R'=NMe,)
( C6H402)
P ( 0 )N=PPh3
P-NMe2163.8 (1)-165.1 (1): P=N 161.5 (1);N-N=N Single, double bonds
9
PN 156.8(20, 1 5 8 . 7 ( 2 ) fPNP 131.7(2)
12
Orgatiopli osph orus Chernisrry
342 Compound
Comments
(Me,Si),N(adamantane)PN=P (CMe,) ,I
P=N 153.9(3): PN 174.2(3)
MesP (=NSiMe,) =NC,H,(CMe3)3
Reference
P=N 154.9(3) , 153.3(4): LNPN 135.2(1)
[PhnP(S)I2N-K(18-crown-6)+PN 159.9(1): L P N P 132.8(2); long PS
19
30 205
(Cl,PNPCl,) +MoCi,‘
PN 154(2) ; L PNP 139
39
Cl,WNPCl,NPCl,
PN 152, 157
40
Cp,UNPPh3
PN 161(2) , L UNP 172(1)
41
PN 165.3 ( 9 ) L MoNP 176.6 ( 6)
42
PN 165.6(4) L MoNP 168.4(3) ; c1 bridged dimer; trans terminal NPPh,
43
[ MoC1, ( NPPh,)
Py ] CH,Cl,
[ Me3SiNPPh, CuCl,]
,
PhNPPh,. CuCl 7.CuCl
PN 159.8(3); L PNCu 114.2(1) 45 LPNSi 127.0(2); C1 bridged dimer, Cu-N bonded PN 160.1(4), N coordinated PN (coordinated) 162.0 (1) PN(free) 158.7(1): LCNP 128.1(1), 123.1(1)
46 46
PN 155.3(2) , 157.1(2):
47
Ph,PPNPh
PN 160.2(3); LPNC 130.4(3)
47
M o (NO)NPPh, (dttd)
PN 160.6(6) ; L M o N P 129.7(4): (see text for dttd ligand)
48
7
L PNC 136.0(2) , 133.0(2)
P=N 156.8(9) , 161.1(9) , 162.2(9); PN 165.3(8) , 167.9(5) , 171.1(8)
9
10
P=N 148.7(3) PN 162.6(3) - 174.1(3)
11
P=N 145.8(14) PN 165-172.8
12
P=N 154.2(7) PN 162.9 (8)-184.3 (8)
13
(R=SiMe,)
, 143(2)
50
50
51 51
P=N(coord.) 160.7(2) : 52 P=N(free) 155.0(2); PN 167.6(2)
8: Ph osph u2ene.y ComDound
343
Co m e nts
PN(e=) PN(e*o)
16
Reference 168.3(2); 160.7(2),
53
160.5(2)
PN 1 5 6 . 9 ( 2 ) , 1 5 9 . 8 ( 2 ) PO 1 5 8 . 6 ( 2 ) ;
65
L NPN 1 1 9 . 0 ( 1 ) (at PO,) L OPO 1 0 2 . 4 (1); planar
trans-N,P,[O(cH,) (NC,H, 12c12
,o] -
PN 1 5 8 . 0 ( 2 ) , 1 5 6 . 8 ( 3 ) ; PO 1 5 7 . 1 ( 2 ) ; L NPN 1 1 1 7 . 1 ( 1 ) (at PO,) L OPO 1 0 3 . 4 ( 2 ) ; planar
65
N,P,Cl, [ MeN (CH,) ,NMe ]
preliminary report
66
N4P4(NHEt),NEt
preliminary report
66
N4P4( NMe,) (NHEt)NEt
redetermination
66
PNendo1 6 1 . 7 ( 5 ) , 1 5 5 . 1 ( 5 ) ,
67
2,
2-N3P,C14 (NHSiMe,)
159.1(5);
PNeXo(AV) 1 6 0 . 9 ( 5 ) ; long Si-N
-
PNendo1 5 8 3 ( 6 ) ; PN,,, 1 6 7 . 1 ( 8 ) ; 77 L NPN 1 1 7 . 7 ( 4 ) : L PNP 1 2 1 . 1 ( 4 ) planar 19*CHC13(X=C1)
PNendo1 5 4 . 8 ( 4 ) - 1 6 1 . 7 ( 4 ) PN,,, 1 6 2 . 0 ( 4 ) , 1 6 1 . 1 ( 4 ) ;
78
166.0(4), 165.7(5)
PNendo 1 5 6 - 3 ( 5 ) , 1 6 0 . 0 ( 5 ) , 158.4(4) PN,,, 1 6 2 . 0 ( 5 )
87
extensive H-bonding cis-N,P,(NH,),(OMe),
PNendo1 5 8 . 0 (2) , 1 6 0 . 2 ( 2 ) ,
-
158 9 ( 2 )
87
PN,,, 1 6 2 . 7 ( 3 ) LPNP 1 1 4 . 0 ( 2 ) at P(NH,), LPNP 1 1 7 . 0 ( 1 ) at P(OMe),
-
PNendo1 5 8 2 ( 2 ) , 1 5 8 . 1 ( 2 ) ,
161.2 ( 2 ) PN,,, 1 6 2 . 6 ( 3 ) L PNP 1 1 6 . 4 (at L P N P 1 1 6 . 9 (at 40
87
P(NH,) (OMe)) P(OMe)),
PN 1 4 7 . 9 ( 1 ) : envelope conf. organic and inorg. rings perpendicular P,N, rings parallel
206
344
0rgarioph osp honts Chemistry
Compound
Comments
2 ,2’-N,P3C1, ( P r ’ ) CH ( O H ) C,H,FeC,H,
N3P3 (°CH2CF3)
-
5FeCp (co)2
Reference
PN 1 6 2 . 0 ( 3 ) , 1 5 5 . 9 ( 3 ) , 1 5 8 . 5 ( 2 ) ; L CPC 1 1 5 . 7 ( 1 ) ; LClPCl 1 1 9 . 0 (1): envelope conformation; l i n k e d via OH--H a n d CH--0 H-bonds PN 1 6 3 , 157 (Av) ;
( 2 5 ) ,SnCl4-2CC1,
106
L NPN 1 1 3 . 1 ( a t POFe) ; LNPN 1 1 8 . 3 ,
25Me+CF3S0,
2 07
120.9
PN 1 6 6 . 8 ( 6 ) ,
164.9(5) ;
125
PN 1 6 4 . 8 ( 3 ) ,
164.9(3)
1 25
L NPN 1 0 8 . 7 ( 3 ) ; N M e n i t r o g e n o u t of r i n g p l a n e
L NPN 169-3 ( 2 ) N-Sn N i t r o g e n o u t of r i n g p l a n e PN,.,do 167-171 ; PN,,, 1 6 6 ; f PNS 1 5 0 - 1 5 3 ; nearly planar
28
(NSOPh),NP ( H ) OPr’
PN 1 5 9 . 4 ( 2 )
,
159.8(3);
t r a n s phenyl groups: SO---H H-bond;
126
129
boat
conformation
33
(NSOPh),NPCl[ CH ( SiMe,)
PN 1 5 8 . 0 ( 2 ) (Av) Mutually cA-Ph groups are t r a n s a c r o s s C,H4FeC,H,
131
PN 1 5 9 . 0 ( 8 )
208
(Av);
t r a n s phenyl; envelope
conformation
PN 1 6 6 . 7 ( 8 ) , 1 6 3 . 3 ( 6 ) , 1 5 8 . 1 ( 7 ) (M=Mo, Xn=C1,) 1 5 8 . 5 ( 6 ) : L PNP 1 2 7 . 5 ( 4 ) : LNPN 1 1 2 . 4 ( 3 ) , 1 1 3 . 2 ( 4 ) ; MO NCCH, a d d u c t
3 7 CH3CN
PN 1 6 1 . 8 ( 5 ) ,
38
162.1(5) ;
L NPN 1 1 6 . 9 ( 3 ) : p l a n a r P-N
39
156.9 ( 6 ) -164.6 ( 6 )
136
138 139
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352
Orgarlophosphorus Chemistry
191. M. Takashima, M. Sakai, Y. Mori and H. Matsumoto, Jpn. Kokai, Tokkyo Koho JP 62/43436 (Chem. Abst., 1988, 108, 57408s). 192. T. Goto, T. Asano and K. Ishihara, Jpn. Kokai Tokkyo Koho JP 62/276077 (Chem. Abst. , 1988, 108, 152113a). 193. W.B. Mueller, Saqamore Army Mater. Res. Conf. Proc., 32nd (Elastomers Rubber Technol.), 1987, 421 (Chem. Abst., 1987, 107, 41451~). 194. F. Suzuki and T. Masuko, Jpn. Kokai Tokkyo Koho JP 62/49903 (Chem. Abst., 1987, 107, 97882~). 195. F. Jeanne, E. Schmidt and S. Lombard, Fr. Demande FR 2583067 (Chem. Abst., 1987, 107, 66555~). 196. F. Jeanne, E. Schmidt and S. Lombard, Fr. Demande FR 2583066 LChem. Abst., 1987, 107, 66556~). 197. T. Morimoto, T. Nakanaga and Y. Tada, Jpn. Kokai Tokkyo Koho JP 62/4296 (Chem. Abst., 1987, _107, 99590e). 198. T. Nakanaga, Y. Tada, S . Yamada, M. Hirohama and T. Akata, Jpn. Kokai Tokkyo Koho JP 62/265394 (Chem. Abst., 1988, 108, 115566e). 199. A. Nishikawa and T. Yokoyama, Jpn. Kokai Tokkyo Koho JP 62/109346 (Chem. Abst., 1988, 108, 23482~). 200. T.P. McAndrew, K.G. Frase and R.R. Shaw, AIP Conf. Proc., 165 (Thin Film PRocess. Charact. Hish-Temp. SuDercond.), 1988, 451 (Chem. Abst., 1988, 108,2147572). 201. H.R. Penton, M.E. Kucsma and F . A . Pettigrew, Eur. Pat. Appl. EP 205349 (Chem. Abst., 1987, 107, 12971h). 202. L. Gettleman and P.H. Gebert, U.S. US 4661065 (Chem. Abst. , 1987, 107, 46369h). 203. T. Kojima and N. Kajiwara, Jpn. Kokai Tokkyo Koho JP 62/6217 (Chem. Abst., 1987, 107, 64922n). 204. K. Nanishi and H. Nakayama, Brit. UK Pat. Appl. G B 2183240 (Chem. Abst., 1988, 108, 57930f). 205. R. Cea-Olivares and H. Noth, 2 . Naturforsch. B, 1987, m, 1507. 206. A. Meetsma, J.C. van de Grampel, K. Brandt and Z. Jedlinski, Acta Crvstalloqr., Sect. C: Crvst. Struct. Commun., 1988, W , 1122. 207. A. Meetsma, P.L Buwalda and J.C. van de Grampel, Acta Crystalloqr., Sect. C: Cryst. Struct. Commun., 1988, E, 58. 208. A. Meetsma, J.K. Herrema and J.C. van de Grampel, Acta Crystalloqr., Sect. C: Crvst. Struct. Commun., 1988, w, 181.
Author Index
I n t h i s i n d e x t h e number g i v e n i n p a r e n t h e s i s i s t h e C h a p t e r number of t h e c i t a t i o n and t h i s i s f o l l o w e d b y t h e r e f e r e n c e number o r numbers o f t h e r e l e v a n t c i t a t i o n s w i t h i n t h a t Chapter
Aaron, H.S, ( 4 ) 44 Abdou, W.M. ( 2 ) 11 Abiko, A. ( 7 ) 9 5 Abraham, K.M. ( 8 ) 182 Abu-Orabi, S.T. (1) 149 Achiwa, K . ( 1 ) 4 3 Adachi, K . ( 8 ) 1 6 5 Adamiak, R.W. ( 6 ) 33 Adamov, A . V . ( 1 ) 1 6 2 Adams, R.J., j u n . ( 8 ) 7 5 , 156 Adcock, W. (1) 33 Adegoke, E.A. ( 7 ) 1 2 3 A f a n s ' e v , M.M. ( 5 ) 4 9 A f f a n d i , S. (1) 357 Afkham-Ebrahimi, A. ( 6 ) 102 A f z a l , D. ( 7 ) 3 4 Agafonov, S.V. ( 1 ) 1 5 9 ; (5) 166 Agrawal, S. ( 4 ) 6 4 ; ( 6 ) 231 Ahmad, S. ( 7 ) 110 Aitken, R.A. ( 7 ) 4 3 Akasaka, K . (1) 1 2 6 A k a t a , T. ( 8 ) 1 9 8 Akhmedzade, D . A . ( 4 ) 50 Akhmetkhanova, F.M. ( 4 ) 48 Akimova, L . I . (1) 9 5 Akpan, C.A. ( 1 ) 268 Akpapoglou, S. (1) 364 Aksinenko, A.Yu. (5) 162 Akutagawa, S. (1) 8 4 A l a m g i r , M . (8) 182 Albanov, A . I . (1) 75 A l b r e c h t , S. ( 5 ) 3 9 ; ( 7 ) 128 A l d e r f e r , J . L . ( 6 ) 3 7 , 38 Al-Dulaymmi, M.F.M. (1) 19 A l e g r i a , A. ( 2 ) 3
A l e i n i k o v , N.N. ( 8 ) 32 A l e k s e e v , N.V. ( 8 ) 107 A l e x s a n d r o v a , L.A. ( 6 ) 118 A l f e r ' e v , I . S . (5) 1 3 7 , 153 A l ' f o n s o v , V.A. ( 1 ) 1 2 9 ; (5) 141 Al-Hakeem, M. ( 6 ) 429 Al-Hakim, A.L. ( 6 ) 385 A l k u b a i s i , A.H. ( 8 ) 65 A l l c o c k , H . R . (8) 5 7 , 58, 61, 63, 90, 91, 104-106, 1 6 0 , 1 6 1 , 181 A l l e n , A . D . (5) 5 9 A l l e n , C.A. ( 8 ) 185, 187 A l l e n , C.W. ( 8 ) 5 9 , 67 A l l e n , D.W. ( 1 ) 1 8 7 A l l s p a c h , T. (1) 283 A l l y , S . ( 6 ) 71 Almasy, A. ( 3 ) 1 2 Al-Resayes, S . I . (1) 324 A l - S h a l i , S. (8) 91 Alster, D. ( 6 ) 242 Altman, S . ( 6 ) 3 8 0 , 382 A l t m e y e r , 0. (1) 226 Alyea, E.C. (1) 4 , 1 4 6 , 357 Ambrose, B . J . B . ( 6 ) 320 A m i c i , A . ( 6 ) 257 Amor, A . B . H . ( 1 ) 158 Amouroux, R . ( 7 ) 22 Amrani, Y. (1) 8 9 An, S.H. ( 6 ) 1 6 Anand, N.N. ( 6 ) 1 9 3 A n d e r s , E. (1) 186 A n d e r s o n , C.L. ( 7 ) 15, 9 9 Anderson, D.M. (1) 2 2 , 23 A n d e r s o n , G.K. ( 1 ) 31 Ando, T. ( 5 ) 108, 109 A n d r u s , A. ( 6 ) 139 A n g e l i c i , R . J . (1) 131
Angelov, C.M. (5) 159 Angermund, K . (1) 321 Annan, T.A. (1) 6 6 Annen, U . (1) 3 0 8 , 3 1 0 , 373 A n s o r g e , W. ( 6 ) 3 1 2 , 322 A n t i p e v a , V.V. ( 5 ) 1 5 6 A n t i p i n , M.Yu. ( 1 ) 1 7 3 , 293, 298; ( 4 ) 8 0 ; ( 8 ) 1 2 , 1 9 , 2 0 , 53 A n t i p o v , E.M. ( 8 ) 174 A n t i p o v a , V . V . ( 5 ) 83 Antonova, A.B. ( 4 ) 13 Antony, A . ( 6 ) 413 A n z a i , M. ( 8 ) 1 0 1 , 118 Aoki, T. ( 6 ) 6 8 A p i t z , J . (1) 1 7 5 ; ( 4 ) 4 3 .4ppel, R . (1) 2 4 4 , 257, 261, 272, 273, 277, 2 7 8 , 280, 282, 285-287, 342 A p p e l h a n s , A.D. ( 8 ) 185 A p p e l l a , E. ( 6 ) 447 A p p e l t , A . (1) 69 A r a b s h a h i , A. ( 6 ) 115 A r a k i , S. (5) 79 A r a k i , T. (1) 128 A r a k i , Y. (1) 1 2 8 A r a r f a t , A.F. ( 7 ) 1 0 6 Arbuzov, B.A. ( 1 ) 140-142, 368 A r c a n g i o l i , B. ( 6 ) 289 Arduengo, A . J . ( 2 ) 3 A r i f , A . M . (1) 3 0 6 , 3 3 0 , 334 A r i s L o f f , P.A. (7) 107 A r k h i p o v , V.P. ( 5 ) 8 4 Armstrong, M.M. ( 5 ) 6 3 Arnold, J.R.P. ( 6 ) 97 A r n o l d , L. ( 6 ) 184 A r r l i n g t o n , D.E. ( 8 ) 38 Asano, T. ( 8 ) 192
354 A s e e v a , R.M. ( 8 ) 6 9 A s h i r b e k o v a , D.T. ( 6 ) 252 A s h l e y , G.W. ( 6 ) 110 A s h t o n , W.T. ( 6 ) 130 Assaf, Y . ( 1 ) 1 1 9 ; ( 8 ) 23 A s s e l i n e , U. ( 6 ) 2 1 9 , 220 A t a b e k o v , J . G . ( 6 ) 343 A t a b e k o v , K . J . ( 6 ) 343 Atarnas', L . I . ( 5 ) 9 8 A t o r , M.A. ( 6 ) 109 A t r a z h e v , A.M. ( 6 ) 118 A t r u c h k o v , Yu.T. ( 8 ) 19 A t t a l i , S. ( 1 ) 234 A t t a r , A. (1) 8 Atwood, J . L . (1) 6 4 Auch, K . ( 1 ) 305 Aug6, C. ( 6 ) 22 A u s t i n , P.E. ( 8 ) 1 6 0 , 181 A v e n e t , P. ( 6 ) 1 A v r o r i n , V . V . (1) 188 A y e r s , M . E . ( 6 ) 320 A z a f r a n i e c , L . L . ( 4 ) 44 B a b b i t t , P.C. ( 6 ) 8 6 B a b i n , F. ( 6 ) 4 5 1 B a h k i n , Yu.A. ( 5 ) 92 Baccar, B. ( 1 ) 158 B a c c o l i n i , G . (1) 9 4 ; ( 4 ) 49 B a c e i r e d o , A. ( 7 ) 9 B a e r , M . F . ( 6 ) 382 B a t c h e r , M. ( 1 ) 1 0 7 ; ( 2 ) 14 B a h a d i r , M. (1) 8 B a i l e y , J . M . ( 6 ) 305 D a i l l y , V. ( 6 ) 280 B a k e r , D.C. ( 6 ) 24 B a k e r , S.R. ( 7 ) 87 B a l a s h o v a , A.M. ( 5 ) 25 B a l g o b i n , N . ( 6 ) 1 6 8 , 177 B a l l , H.L. ( 5 ) 21 B a l l , W . A . ( 7 ) 67 B a l l e s , R . ( 1 ) 322 Ballini, J.P. ( 4 ) 63; ( 6 ) 469 B a l u e v a , A.S. (1) 1 4 1 , 142 B a l z a r i n i , .J. ( 6 ) 54 Barngoye, O.A. ( 8 ) 76 Barngoye, T.T. ( 8 ) 7 6 B a n n w a r t h , W . ( 6 ) 144 B a n v i l l e , D . L . ( 6 ) 450 B a r a n i a k , J. ( 5 ) 4 8 , 5 5 ; ( 6 ) 6 5 , 66 B a r a n o v , G.M. ( 5 ) 171 B a r a n o v a , L.V. ( 6 ) 149 B a r a n s k i i , V.A. ( 5 ) 174 B a r b a t o , S . ( 6 ) 186 B a r c h a s , J . D . ( 6 ) 263 B a r l u e n g a , J. ( 1 ) 3 7 9 ; ( 7 ) 2 , 1 0 , 4 8 ; ( 8 ) 54
B a r r a n s , J . (1) 3 6 7 ; ( 4 ) 20, 78 B a r r e t t , A.G.M. ( 3 ) 32 B a r r o n , A.R. ( 1 ) 9 6 , 265, 3 0 6 , 3 2 0 , 3 2 5 , 3 4 3 , 344 B a r r y , M . A . ( 6 ) 422 B a r s e g y a n , S.K. (1) 105 B a r t l e t t , P.A. ( 7 ) 6 9 Bartlett, R.A. ( 1 ) 228, 229 B a r t o n , J . K . ( 6 ) 424-426 Bartsch, R. ( 1 ) 340, 361, 363 R a - S a i f , S.A. ( 5 ) 67 B a s i l e , L . A . ( 6 ) 4 2 4 , 425 B a s u , A . K . ( 6 ) 210 Ratra, J . K . ( 6 ) 88 B a t y e v a , E.S. ( 1 ) 1 2 9 ; ( 5 ) 141 B a u d l e r , M. ( 1 ) 51-54, 1 2 5 , 2 6 2 , 364 B a u e r , B. ( 1 ) 174 B a u e r , Ch. ( 8 ) 144 B a u e r l e , P. ( 7 ) 7 9 Baum, G . (1) 11 Baumann, U. ( 6 ) 293 R a u r n e i s t e r , K. ( 6 ) 311 B a u r e s , P.W. ( 3 ) 18 Bax, A . ( 6 ) 444 Baxter, J.E. ( 3 ) 3 B a x t e r , S.G. ( 1 ) 3 3 6 , 339, 349; ( 3 ) 7 ; ( 4 ) 81, 8 2 B a y a r d , B. ( 6 ) 247 B a z h a n o v a , Z.G. ( 5 ) 154 B a z u r e a u , J . P . ( 7 ) 3 7 , 38 B e a b e a l a s h v i l l i , R.S. ( 6 ) 1 1 7 , 262 B e a c h l e y , O.T. (1) 6 4 R e a r d s l e y , G.P. ( 6 ) 396 Beattie, K.L. ( 6 ) 2 7 2 , 273 B e a u v a l l e t , C. ( 6 ) 308 B e c h e r , R . (1) 53 B e c h t o l d , W.E. ( 5 ) 173 Beck, J . ( 8 ) 4 6 , 47 B e c k , S . ( 6 ) 314 B e c k e r , G . (1) 3 2 2 , 380 B e c k e r , W. ( 6 ) 183 R e c k e r s , T. ( 6 ) 183 Beckh, H.-J. (1) 3 7 4 , 375 B e d e r , S.M. (1) 211 B e d n a r s k i , M.D. ( 6 ) 8 3 Been, M.D. ( 6 ) 278 B e e r , P . D . ( 2 ) 27 B e e r n a e r t s , R. ( 6 ) 20 Beg, M . A . A . ( 1 ) 137 Behnke, C . (1) 272 B e h r e n d t , G. ( 6 ) 288 B e i j e r , B. ( 6 ) 2 7 , 28 B e k a s o v a , N.I. ( 8 ) 9 8 , 9 9 , 152
Bekker, A.R. ( 4 ) 54; ( 5 ) 2 2 , 148 B e l a v t s e v a , M. ( 8 ) 177 B e l l , P. ( 1 ) 3 0 1 ; ( 8 ) 5 2 B e l o u s o v a , Z . P . ( 6 ) 116 B e l o v , Yu.P. ( 5 ) 162 B e l t , H.-J. ( 1 ) 79 R e l t e r , R.K. ( 5 ) 196; ( 7 ) 65 B e l y a n o v , R . U . ( 4 ) 45 R e n a t t i , U. (6) 17 Bendayan, A . ( 4 ) 70 R e n e v i d e s , J.M. (6) 462,
463
U e n i y a , Y. (5) 32 H e n j a m i n , A. ( 5 ) 88 B e n j a m i n , R . (1) 117 B e n k o v i c , S . J . ( 6 ) 200 R e n s e l e r , F. ( 6 ) 2 0 8 , 338 B e n t r u d e , W.G. ( 6 ) 69 B e r e n d s e n , H.H. ( 8 ) 86 R e r k , A . J . ( 6 ) 292 R e r k e , H . ( 1 ) 230 B e r k o w i t z , W.F. ( 7 ) 106 Bernacki, R . J . ( 6 ) 9 2 , 93 R e r n e r s - P r i c e , S.J. ( 1 )
130
B e r n i k o v , E . A . ( 5 ) 154 B e r t h a u l t , P. ( 8 ) 70-74 Bertrand, J.-R. ( 6 ) 229 B e r t s c h , B. ( 1 ) 335 B e s p a l ' k o , G . K . (8) 36 Bestmann, H.-J. ( 7 ) 96 Bestrand, G. ( 7 ) 9 B e t h e l l , R.C. (6) 11, 9 7 , 9 9 , 100 B e t t e r m a n n , G . (1) 1 6 4 ; ( 4 ) 53 B e z i a t , Y . (1) 183 B h a r d w a j , R . K . ( 3 ) 4-6 B h a t i a , S.C. ( 6 ) 458 B h o n g l e , N . N . ( 5 ) 89 B i a l a , E. ( 6 ) 3 3 B i d d , I . ( 7 ) 122 B i e d e n b a c h , B. (1) 319 R i e l a w s k i , J . ( 5 ) 47 B i e n i e k , D. (1) 8 B i l l w i t z , H . ( 6 ) 316 B i n d e r , D. (1) 2 3 1 , 232 B i n g e r , P . (1) 317-319, 321 B i n n e w i e s , M. (1) 3 0 2 ; ( 4 ) 74 B i r s e , E.F. ( 3 ) 1, 26 B i r y u k o v , A. ( 6 ) 126 B i s b a l , C . ( 6 ) 247 B i s c h o f , C . ( 8 ) 144 B i s c h o f f , R. (0) 1 5 3 , 431 B i t t n e r , S . ( 1 ) 119; ( 8 ) 23 B l a c k b u r n , G.M. ( 6 ) 1 2 8 , 2 4 7 ; ( 7 ) 58
355
Author Index B l a c k e r , A . J . ( 6 ) 75 Blade, R . J . ( 7 ) 125 Blaser, D. (1) 235, 236 B l a k e , K.R. ( 6 ) 238 Blanchard-Desce, M. ( 7 ) 78 B l a n q u e t , S. ( 6 ) 1 2 3 , 1 2 4 , 308 B l o c h , G . ( 6 ) 451 B l o n s k i , C. ( 4 ) 6 3 ; ( 6 ) 1 7 0 , 469 B l o n s k y , P.M. ( 8 ) 181 Blum, D.M. ( 1 ) 1 2 Bobkov, S.Yu. ( 5 ) 1 3 7 B o b s t , A.M. ( 6 ) 2 6 8 , 269 B o b s t , E.V. ( 6 ) 268 Boche, G . ( 5 ) 199 Boduszek, B. ( 5 ) 122 Bock, A . ( 6 ) 410 BOhm, E. (8) 45-47 Boere, R.T. ( 8 ) 1 2 7 Boese, R . (1) 165, 235-238, 240, 241; (3) 36 Bogachev, V.S. ( 6 ) 149 Bogdanov, V.S. ( 1 ) 7 Bohrnan, C. ( 6 ) 283 B o i s d o n , M.T. ( 4 ) 20 Boldeskul, I.E. ( 1 ) 103 B o l e s o v , I . G . ( 1 ) 176 B o l t o n , P.H. ( 6 ) 1 8 8 , 1 8 9 , 350 Bondarenko, N.A. ( 1 ) 9 7 Bonnet, A. ( 7 ) 9 1 B o n n e t , J.P. (8) 7 0 , 71 Bonora, G.M. ( 6 ) 150 Bookharn, J . L . ( 1 ) 2 7 , 81 Books, J . T . ( 8 ) 176 B o r c h , R.F. ( 5 ) 5 3 B o r c h a r d t , R.T. ( 7 ) 1 1 4 Borchering, D.R. ( 7 ) 114 Borden, W.T. ( 1 ) 222 B o r i s e n k o , A . A . (1) 1 7 3 , 264 B o r i s e n k o v a , E.K. (8) 174 B o r i s o v , E.V. ( 4 ) 5 4 Borm, J . ( 1 ) 230 Borrmann, H. ( 1 ) 3 0 2 ; ( 4 ) 74 B o r t o l u s , P. ( 8 ) 162 Bosman, W.P. ( 8 ) 131 B o s s h a r d , R . ( 6 ) 129 B o t e l h o , L.H.P. ( 6 ) 6 6 B o t t i n , U. ( 6 ) 62 B o t t k a , S. ( 6 ) 6 7 Bourdauducq, P. ( 5 ) 27 B o u r d i e u , C . (1) 3 7 7 ; ( 4 ) 76 B o u v i e r , F. ( 2 ) 3 7 , 38 B o v i n , A . N . ( 5 ) 1 1 8 , 119 Bower, M. ( 6 ) 232 Bowmer, T.N. ( 8 ) 1 4 3
B o x e r , S.G. ( 6 ) 1 8 7 Boyd, B . A . (1) 275, 279 B r a k e l , C.L. ( 6 ) 202 Bramson, H . N . ( 6 ) 79 B r a n d e s , D.A. (1) 1 4 7 B r a n d t , K . (8) 6 2 , 9 7 , 206 B r a t e n k o , M.K. ( 1 ) 1 9 3 Brauer, D.J. (1) 76 B r a u n s t e i n , P. ( 1 ) 2 1 B r e l ' , V . K . (1) 1 5 7 ; (5) 2 0 , 105, 149 B r e n n a n , D . J . ( 8 ) 6 1 , 104 B r e n n a n , J . ( 7 ) 3 6 , 42 B r e n t , T.P. ( 6 ) 392 B r e s l i n , D.T. ( 1 ) 215 B r e s t k i n , A.P. ( 5 ) 2 5 B r e u e r , E. ( 4 ) 7 5 ; ( 5 ) 177 B r e v e t , A. ( 6 ) 123, 124 B r i l l , W.K.-D. ( 4 ) 65, 66, 6 8 ; ( 6 ) 4 4 , 5 2 , 53 B r o c k i e , I . R . ( 6 ) 3 5 , 36 B r o d e r , S . ( 6 ) 235 B r o o k s , P. (1) 2 5 B r o v a r e t s , V.S. ( 1 ) 1 9 6 , 217 Brown, D . E . ( 8 ) 6 7 Brown, D.M. ( 6 ) 1 9 3 Brown, J . W . ( 1 ) 101 Brown, S.J. ( 1 ) 202 Brownbridge, P. ( 4 ) 23 Browner, M.F. ( 6 ) 397 Browse, J . ( 6 ) 3 2 3 B r o z d a , D. ( 6 ) 242 B r u c k , M.A. ( 7 ) 34 B r u c k , T. ( 1 ) 365 B r u i s t , M.F. ( 6 ) 359 B r u n n e r , H . ( 1 ) 6 , 2 8 , 41 B r u s o v , R . V . ( 1 ) 264 B r y s c h , W. ( 6 ) 275 B r z e z i k k a , E. ( 5 ) 3 4 Bubnov, N . N . ( 5 ) 24 R u c h a r d t , 0. ( 6 ) 470 Buck, F. ( 6 ) 1 9 0 Buck, H.M. ( 2 ) 8 , 1 2 ; ( 3 ) 15; ( 4 ) 39; (5) 5, 6 ; ( 6 ) 234 B u c k l e , D.R. ( 7 ) 1 0 8 Buckley, N. ( 6 ) 393 Budding, T.N.W. (6) 191 B u d i l o v a , I.Yu. ( 8 ) 1 2 B u d z i k i e w i c z , H. ( 1 ) 364 Huhro, W.E. (1) 6 7 Bukachuk, O.M. ( 1 ) 214 B u l y c h e v a , E.G. ( 8 ) 9 9 , 152 Bund, J . ( 7 ) 6 7 B u n d e l , Yu.G. ( 1 ) 116 B u n g a r d t , D. ( 1 ) 2 3 6 , 238 Bunya, M . ( 5 ) 1 4 Buono, G . ( 1 ) 1 6 9 , 1 7 2 ;
( 4 ) 1, 7 1 , 72 B u r g h a r d t , R. (1) 8 2 B u r i l o v , A.R. ( 4 ) 4 5 B u r k a r d , U. ( 6 ) 381 B u r k h a r d t , J . (8) 1 2 1 B u r k h o f f , A.M. ( 6 ) 3 7 3 B u r n o u f , D. ( 6 ) 419 B u r n s , G. ( 7 ) 4 3 B u r n s i d e , B.A. ( 5 ) 6 5 B u r t o n , D . J . ( 1 ) 201; ( 5 ) 1 1 1 ; ( 7 ) 1 1 , 72 B u s c a g l i o n i , I. ( 1 ) 206 Bush, R . C . (1) 131 B u s s , A.D. ( 3 ) 2 3 B u t i n , B.M. ( 1 ) 74 B u t k u s , V. ( 6 ) 1 9 4 , 339 B u t s u g a n , J. ( 5 ) 79 B u t t , E. ( 6 ) 6 2 Buwalda, P.L. (8) 207 Bychkova, T . I . ( 5 ) 85 B y e r s , J . H . (3) 2 B y r n e , B.C. ( 6 ) 258 B y s t r o v a , V.M. ( 5 ) 1 5 5 C a e s a r , J . C . (1) 356; ( 3 ) 8 C a i , 2 . ( 7 ) 101 C a i l l a , H.L. ( 6 ) 241 C a i r n s , S.M. ( 1 ) 208 C a l o g e r o p o u l o u , T. ( 5 ) 4 5 C a l v o , K.C. ( 5 ) 165 Cameron, T.S. ( 8 ) 9 3 ( 1 ) 234, Caminade, A.-M. 369 Campana, C.F. ( 8 ) 4 8 C a r e n z a , M. ( 8 ) 1 6 3 C a r r a n o , C . J . (1) 328 Carrera, C.J. (6) 19 C a r r e t e r o , J . C . ( 7 ) 71 C a r s o n , D.A. ( 6 ) 1 9 C a r t e r , C.A. ( 6 ) 391 C a r u t h e r s , M.H. ( 4 ) 6 5 , 6 6 , 6 8 ; ( 6 ) 4 4 , 5 2 , 53 C a s e y , P . J . ( 6 ) 284 C a s i d a , J . E . ( 5 ) 47 C a s t e r , K.C. (1) 3 5 9 ; ( 3 ) 9 C a s t e r a , P. ( 8 ) 80-83 C a t a n i a , J. (6) 435 Cates, L.A. ( 5 ) 189 C a v a l i e r , S.L. ( 6 ) 290 C a v a l l a , D. (3) 24 C a z e n a v e , C. ( 6 ) 2 2 5 , 230 C e a - O l i v a r e s , R . ( 8 ) 205 Ceasar, J.C. ( 4 ) 11 C e c h , D. ( 6 ) 111, 204 Cech, T.R. ( 6 ) 8 , 278, 3 7 7 , 379 Cedergren, R . J . ( 6 ) 158, 329 C e f e l i n , P. ( 8 ) 1 5 3
Organ op h osph oriis Chemistry
356 C e r e g h e t t i , M . (1) 1 6 Cerny, R.L. ( 6 ) 468 C e s a r o t t i , E. ( I ) 1 7 1 C h a i , M. ( 6 ) 201 C h a i , W.-G. ( 5 ) 37 C h a l l i s , B.C. ( 5 ) 54 Chambers, W.R. ( 6 ) 1 9 7 Chan, S. ( 6 ) 58 Chang, C.-N. ( 6 ) 1 9 8 , 448 ( 6 ) 228, 353 Chang, D.-K. Chang, J.-W.A. ( 5 ) 178 Chang, S.C. (8) 1 5 6 , 157 Chaona, S. ( 1 ) 1 9 9 ; (8) 28 Charczuk, R . ( 6 ) 212 C h a r r i e r , C. (1) 351, 353 C h a r u b a l a , R . ( 6 ) 240, 242, 244, 246 C h a s a r , D.W. ( 4 ) 3 0 , 3 5 C h a s e , J . W . ( 6 ) 281 C h a s s i g n o l , M. ( 6 ) 223, 226, 227, 355 C h a s t r e t t e , M. ( 7 ) 22 C h a t t o p a d h y a y a , J. ( 6 ) 1 6 4 , 1 6 8 , 1 7 6 , 177 Chaudhury, M. (8) 49 Chauzov, V . A . ( 1 ) 166 C h a v d a r i a n , C.G. ( 5 ) 181 Cheklov, A.N. (5) 162 Chekroun, I. ( 7 ) 5 3 Chen, A. ( 6 ) 130 Chen, C. ( 6 ) 368, 388 Chen, C.B. ( 6 ) 360 Chen, C.H.B. ( 6 ) 250 Cheng, C.Y. (8) 6 4 Chepakova, L.A. ( 5 ) 20 C h e r c h e s , G.Kh. (8) 115 C h e r k a s o v , R.A. ( 1 ) 127; ( 4 ) 1 3 ; ( 5 ) 179 Chernega, A.N. ( 1 ) 1 7 3 , 293, 298; ( 4 ) 80; (8) 1 2 , 1 9 , 20, 53 Chernyuk, I . N . (1) 1 9 3 C h e r v i n , 1.1. (5) 1 6 4 C h e v r i e r , M. ( 6 ) 230 C h i b a , M. (1) 4 3 C h i c h e , L. ( 7 ) 1 6 C h i c h e s t e r - H i c k s , S.V. (8) 7 7 , 7 8 , 1 4 3 C h i d e s t e r , C.G. (8) 9 C h i d g e a v a d z e , Z.G. ( 6 ) 1 1 7 , 118 C h i e f a r i , J. ( 5 ) 1 4 3 C h i e s a , A. (1) 171 C h i h a o u i , M. ( 1 ) 1 5 8 ( 6 ) 367 C h i n , D.-H. C h i n , J. ( 6 ) 6 0 C h i n , S.M. (6) 371 Chisholm, M.H. (1) 6 7 C h i s t o k l e t o v , V.N. ( 5 ) 144 C h i v e r s , T. (8) 124-126
Chizhov, V.M. ( 1 ) 159 Chladek, S. ( 6 ) 214 Cho-Chung, Y.S. ( 6 ) 7 1 C h o l l e t , A. ( 6 ) 270 (7) 19 Chong, W.K.M. Chopra, A.K. ( 7 ) 7 6 , 77 Choudhury, M.S. (8) 122 Chu, B.C.F. ( 6 ) 383 Chu, C.T. ( 6 ) 399 Chudakova, T . I . (1) 194; (4) 4 Chugunov, Yu.V. ( 4 ) 26 Church, G.M. ( 6 ) 313 Churnusova, S.G. ( 5 ) 31, 136 C i e s l a , J. ( 6 ) 1 5 C i p o l l i n a , J . A . ( 7 ) 116 C l a i r , T. ( 6 ) 71 Clardy, J.C. (2) 7 C l a r k , B.F.C. ( 6 ) 423 C l a r k , J . H . (1) 202, 203 C l a r k , J . M . ( 6 ) 396 C l a u s e n , K . ( 5 ) 180 C l i s s o l d , D.W. ( 7 ) 8 7 C l o s s , K. ( 6 ) 185 C l y n e , J . ( 6 ) 203 Cocks, S. ( 5 ) 6 3 Cocuzza, A.J. ( 6 ) 311 Cohen, J . S . ( 6 ) 235, 236, 267, 447 Cohen, S. ( 6 ) 134 C o l e , W.A. (8) 189 C o l l i n s , F.S. ( 6 ) 324 Colman, R.F. ( 6 ) 305 Colombo, L. ( 1 ) 1 7 1 Comasseto, J. ( 7 ) 129 C o n n o l l y , M.S. (8) 91 C o n r a d i , E. (8) 39 C o n s t a n t , J . F . ( 6 ) 354 C o n t r a c t o r , S.R. ( 8 ) 79 Cook, A.F. (6) 202 Cook, P.F. ( 6 ) 78 Cook, R.M. ( 4 ) 5 7 ; ( 6 ) 156 Cook, S. ( 7 ) 103 Cooke, A . M . ( 5 ) 11, 1 6 C o r b e l , B. ( 3 ) 3 4 C o r d e s , A.W. (8) 6 7 , 7 7 , 127 Corey, D.R. ( 6 ) 1 5 7 , 335, 336 Corey, E.J. ( 7 ) 8 9 , 105 C o s s t i c k , R. ( 6 ) 42 C o s t e , H. (6) 1 2 3 , 124 C o s t i s e l l a , B. ( 7 ) 50, 55 C o u l l , J . M . ( 6 ) 153 C o u r e t , C. (1) 223, 224, 288-290; ( 4 ) 8 5 , 86 C o u t e l l e , C. ( 6 ) 288 C o u t r o t , Ph. ( 5 ) 110; ( 7 ) 119 C o v i t z , F. ( 4 ) 56
Cowie, J.M.G. (8) 154 Cowley, A.H. (1) 6 5 , 9 6 , 221, 265, 306, 316, 320, 3 2 5 , 328, 330, 331, 334, 343, 344, 349 Cox, D.G. (1) 201; ( 7 ) 11 Cox, S.D. ( 5 ) 1 9 3 Cozmiuc, C . (8) 9 2 C r a i g , S.L. (8) 6 7 , 77 Cramer, F. ( 4 ) 61; (5) 4 ; ( 6 ) 34, 41 Cramer, R.E. ( 7 ) 34; (8) 41 Cremers, A.F.M. ( 6 ) 454 Cremo, C.R. ( 6 ) 297 C r i s t a u , H.-J. (1) 183, 209; ( 7 ) 1 6 C r i s t o l , H. ( 1 ) 183 C r o p p e r , P.E. ( 1 ) 187 C r o s , P. ( 4 ) 71 C r o s b y , R.C. (8) 179 C r o s s , N.C.P. ( 6 ) 257 C r o t h e r s , D.M. ( 6 ) 374 Crouch, R.K. ( 7 ) 83 C r u s e , W.B. (3) 24 C r u z , P. ( 6 ) 459 C s a r n y i , A. ( 6 ) 265 C u l l i s , P.M. ( 5 ) 56, 68-70, 77 Cumming, C.U. ( 6 ) 386 Cumminis, D.G. (8) 185, 187 Cunningham, A.F., j u n . ( 4 ) 37 Cunningham, D. ( 6 ) 307 Dabard, R . (1) 136 Dabkowski, W. ( 4 ) 6 1 ; ( 5 ) 3 , 4 ; (6) 3 4 , 41 D a c h i , K. (8) 171 Dahan, F. (1) 234, 369 Dahl, A.O. ( 6 ) 133 Dahl, A.R. ( 5 ) 1 7 3 Dahlenburg, L. (1) 1 7 Dai, D. ( 6 ) 277 Daimon, M. (8) 109-111 Dale, M.P. ( 6 ) 80 D a l l e y , N.K. ( 6 ) 92 Dam, R . J . ( 6 ) 311 Damha, M . J . ( 6 ) 132 Danchenko, M.N. ( 4 ) 46 Dange, V. ( 6 ) 365 D a n i l o v , L.L. ( 6 ) 116 D a r i s h e v a , A.M. ( 5 ) 24, 25 Dartmann, M. (1) 252-254 Darzynkiewicz, E. (6) 104 Dash, P. ( 6 ) 342 Dauben, W.G. ( 7 ) 25 Daune, M. ( 6 ) 419 Davidson, A.H. ( 7 ) 111
357
Author Index
Davidson, D.S. ( 6 ) 136 Davidson, F. ( 4 ) 40; ( 5 ) 15 Davidson, R.S. ( 3 ) 3-6 D a v i s , G . R . ( 6 ) 287 Davis, P.W. ( 6 ) 387 D a y , L.A. ( 6 ) 464 Dean, N . ( 6 ) 292 DeBoer, J . L . ( 8 ) 126, 129 de Bont, H.B.A. ( 4 ) 59 Dechter, J . J . ( 6 ) 24 De C l e r c q , E. ( 6 ) 20, 54, 68, 265 Decout, J.-L. ( 6 ) 221, 223 De F l o r a , A. ( 6 ) 17 De G i o r g i , M. ( 1 ) 204 Degtyarev, A . N . ( 5 ) 118, 119 Dehnel, A. (5) 163; ( 7 ) 54 Dehnicke, K . (8) 3 9 , 40, 42, 43, 45-47 Dehoff, B.S. ( 7 ) 92 Deikhina, N . A . ( 4 ) 1 3 DeJaeger, R. (8) 33 Delmas, M. ( 7 ) 4 Delorme, D. ( 7 ) 8 5 Delpuech, J.J. (8) 34 Del Val, J . J . ( 8 ) 54 Dgmarcq, M.C. ( 5 ) 27 Dembek, J . A . , j u n . (8) 189 Dembirkki, R. ( 5 ) 26 de Meis, L. ( 6 ) 74 Demillequand, M. ( 7 ) 71 D e m i r , T. ( 5 ) 40 de Mul, F.F.M. ( 6 ) 465 De Napoli, L. ( 6 ) 147, 154, 186 Denis, D. ( 4 ) 71 ( 1 ) 247 Denis, J.-M. Denmark, S.E. ( 5 ) 191 Denney, D.B. ( 2 ) 9 , 11 Denney, D.Z. ( 2 ) 9-11 Depezay, J . C . ( 7 ) 91 de Riese-Meyer, L. (1) 54 de R i n a l d i s , P.P.P. ( 6 ) 257 Dervan, P.B. ( 6 ) 318, 357-359, 361 Deschamps, E. ( 1 ) 360 D e Shong, P. ( 7 ) 116 D e s o r c i e , J . L . ( 8 ) 105 Detmer, K. ( 6 ) 291 Deubelly, 3. (1) 69-72; ( 7 ) 12 Deutsch, J. ( 6 ) 134 Deutsch, W.F. (8) 66 Devaud, M. ( 1 ) 87; ( 3 ) 21 de Vries, E.G.E. ( 8 ) 85 de Vroom, E. ( 6 ) 63, 191,
243 Dhathathreyan, K.S. (8) 124, 130, 149 Dhawan, B. ( 5 ) 7 , 160 Dianova, E.N. ( 1 ) 368 D i a s , H . V . R . ( 1 ) 3 7 , 228, 2 29 D i c k i e , P. ( 6 ) 345 Dickinson, L.C. ( 1 ) 345 Dickinson, L.P. ( 5 ) 71 Diekmann, S. ( 6 ) 375 Diel, P . J . ( 5 ) 107 D i e t l , S. ( 1 ) 376 Dimroth, K . ( 1 ) 370, 378; ( 7 ) 18 Divakar, S. ( 6 ) 413 Dmitrichenko, M.Yu. ( 5 ) 85, 8 6 ; (8) 132 D m i t r i e v , V.K. ( 2 ) 39 Doad, G.J.S. ( 7 ) 59 Dobson, C.M. ( 6 ) 443 Dobler, C . ( 1 ) 170 Doherty, R.M. ( 3 ) 20 Doi, J.T. (1) 111 Dolan, M.E. ( 6 ) 392 Dolgushin, G.V. ( 5 ) 85, 8 6 ; (8) 132 Dolinnaya, N.G. ( 6 ) 39, 251, 252, 254 Dolnick, B . J . ( 6 ) 237 Dol'nikova, T.Yu. ( 5 ) 3 0 , 42 Dombou, M. ( 6 ) 122 Donath, Ch. ( 5 ) 28 Dondoni, A. ( 7 ) 20 Donskikh, V . I . ( 1 ) 154; ( 2 ) 39; ( 5 ) 85-87; (8) 132 Dore, I. (6) 165 Dostmann, W. ( 6 ) 62 Dotz, K.H. ( 1 ) 373 Dousset, P. ( 4 ) 63; ( 6 ) 170, 469 Downie, I . M . ( 1 ) 219 Drach, B.S. ( 1 ) 196, 217 Drager, M. (1) 99, 288 D r a p a i l o , A.B. ( 1 ) 293-297, 300; ( 4 ) 31, 79; ( 5 ) 187 D r e e f , C.E. ( 4 ) 41; ( 5 ) 9 D r e w , J. ( 7 ) 132 Dreyfus, M. ( 6 ) 285 Driess, M. (1) 35, 36, 362 D r i g g e r s , P.H. ( 6 ) 273 Driller, H. ( 6 ) 211 Droogmans, L. ( 6 ) 409 D r u t s a , V.L. ( 6 ) 254 Dubovik, 1.1. (8) 177 D u b r o v i t s k i i , V . I . (8) 177 Duchamp, D . J . ( 3 ) 9
Dudchenko, T.N. (8) 27 Dudinov, A . A . ( 1 ) 7 D u e s l e r , E.N. ( 1 ) 337 Duh, J.-L. ( 6 ) 319 Dumont, W. ( 7 ) 120 ( 1 ) 107; du Mont, W.-W. (2) 14 Dunaway-Mariano, D . ( 6 ) 41 1 Duncan, C.H. ( 6 ) 290 Duncan, L. ( 6 ) 213 ( 2 ) 1 , 37, Dupart, J.-M. 38 D u r r a n t , M . C . ( 1 ) 249 D u r s t , H.D. ( 5 ) 65 D u t a s t a , J . P . ( 1 ) 98 Dyatkina, N.B. ( 6 ) 117, 118 Dzik, J . M . ( 6 ) 1 5 Dziwok, K . ( 1 ) 86 E a d i e , J . S . ( 6 ) 136 Eastman, A. ( 6 ) 365, 422 Easwaran, K.R.K. ( 6 ) 413 E b e l , J.-P. ( 6 ) 423 Eberwine, J . H . ( 6 ) 263 E c c l e s t o n , J . F . ( 6 ) 112 E c k s t e i n , F. ( 6 ) 6 4 , 310, 346-348, 375 E c k s t e i n , H. ( 6 ) 185 Edelmann, F. ( 7 ) 34; ( 8 ) 41 Edmonds, M. ( 6 ) 7 E f c a v i t c h , J . W . ( 6 ) 139, 161 E f f e n b e r g e r , F. ( 7 ) 79 E g e r t , E. ( 8 ) 136 Eguchi, S. ( 1 ) 123; (8) 14 Ehresmann, B. ( 6 ) 423 Ehresmann, C. ( 6 ) 423 E i c h i n g e r , P.C.H. ( 3 ) 25 E j i r i , E. ( 7 ) 133 E k i e l , I. ( 6 ) 104 El-Barbary, A.A. (5) 180 E l i e , C . J . J . ( 4 ) 41 E l i s e e n k o v a , R.M. ( 4 ) 34 E l i s e e v a , G.D. ( 5 ) 174 E l l e s t a d , G.A. ( 6 ) 370 E l s c h e n b r o i c h , C. ( 1 ) 11 Endo, E. ( 6 ) 21 Endo, T. (1) 128 Engel, R . ( 1 ) 117; ( 5 ) 88, 169 Engelke, D.R. ( 6 ) 324 E n g e l s , J . W . ( 6 ) 137, 183 Enikeev, K.M. (1) 129 Ephraim-Bassen, H. ( 7 ) 123 E p i s h i n a , T.A. ( 5 ) 18, 1 9 , 149-151
Organophosphorus Chemistry
358 Epstein, W.W. (1) 192; ( 4 ) 12 Erabi, T. (1) 133 Erastov, O.A. (1) 140-142 Ercolani, L. ( 6 ) 205 Erdelmeier, I. ( 7 ) 67 Eriksson, S . ( 6 ) 283, 432 Erin, A.S. (1) 116 Erker, G. ( 7 ) 44 Erlich, H.A. ( 6 ) 255, 260, 261 Erzhanov, K . B . (1) 7 4 Escudie, J. (1) 2 2 3 , 224, 288-290; ( 4 ) 8 5 , 86 Essigmann, J.M. ( 6 ) 210, 418 Eto, M. ( 5 ) 43 Etter, M.C. ( 3 ) 18 herby, M.R. ( 5 ) 21 Evans, R.K. ( 6 ) 296 Evans, S.A. (1) 122 Evertz, K . (1) 144, 230 Ewing, A.G. ( 8 ) 6 3 Facklarn, T. ( I ) 311; ( 4 ) 77 Fackler, J.P., jun. ( 4 ) 30 Fairweather, D.S. ( 6 ) 435 Fanning, J.C. (1) 200 Fantin, G. ( 7 ) 20 Farr, C.J. ( 6 ) 260 Fasan, G . ( 8 ) 34 Faucher, J.P. ( 8 ) 81-83 Faucitano, F. ( 8 ) 163 Faure, R. ( 4 ) 7 0 Fawzi, R. (1) 305; ( 3 ) 37 Fedgenhaeuer, H. ( 5 ) 66 Fedorova, O . S . ( 6 ) 406 Feibush, B. ( 6 ) 436 Femia, J.F. (1) 138; ( 3 ) 17 Feng, W.M. ( 5 ) 44 Feng, Y. ( 6 ) 326 Fenske, D. ( 8 ) 45-47 Fenwick, A.E. ( 7 ) 108 Feorino, P. ( 6 ) 258 Fera, B. ( 6 ) 190 Fernandez, M.J. ( 8 ) 54 Ferrar, W.T. ( 8 ) 180 Feshchenko, N.G. (1) 168; ( 8 ) 18 Feshin, V.P. ( 5 ) 8 6 ; ( 8 ) 132 Fester, V.D. ( 5 ) 35 Fiaud, J.-C. ( 5 ) 41 Fidder, A. ( 6 ) 243 Fild, M. (1) 1 5 6 , 161; (5) 91 Filonenko, L.P. ( 8 ) 3 0 , 37
Fincham, J . K . ( 8 ) 87 Fink, J.F. ( 8 ) 122 Finkelmann, H. ( 8 ) 89 Fischer, G.W. ( 5 ) 66 Fischer, J . (1) 2 1 , 332 Fishel, R.A. ( 6 ) 291 Fisher, K.J. (1) 4 Fitzmaurice, J.C. (1) 177 Fitzpatrick, N.J. ( 8 ) 5 Fitzsimmons, B.J. ( 7 ) 86 Flachmeier, C. ( 6 ) 288 Flamigni, L. ( 8 ) 162 Fleck, T . ( 2 ) 2 1 ; ( 7 ) 13 Flentke, G.R. ( 6 ) 115 Flitsch, W . ( 5 ) 104; 6 7 ) 41 Flora, J.S. ( 5 ) 10 Fluck, E. (1) 155, 227, 380; ( 8 ) 40 Flynn, K.M. (1) 2 2 8 , 229 Folling, P. (1) 273 Fogagnolo, M. ( 7 ) 20 Fohlen, G.M. ( 8 ) 103 Fokin, A.V. (1) 166 Folting, K. (1) 6 7 ; ( 7 ) 35 Fomakhin, E.V. ( 5 ) 51 Ford, R.R. ( 8 ) 1 4 2 , 159 Foresti, E. (1) 9 4 ; ( 4 ) 49 Forster, A.C. ( 6 ) 332 Foss, K. ( 6 ) 408 Foss, V . L . (1) 264; ( 8 ) 26 Foucaud, A. (1) 3 7 7 ; ( 4 ) 76 Foulkes, N.S. ( 6 ) 257 Fourrey, J.L. ( 6 ) 170 Fraenkel-Conrat, H. ( 6 ) 392 Francke, R . (1) 78 Francois, .J.C. ( 6 ) 355 Frank, L.-R. (1) 144 Frase, K.G. ( 8 ) 200 Fraser-Reid, B. ( 4 ) 4 2 ; ( 5 ) 13 Frazier, J . ( 6 ) 266 Frebel, M. (1) 237 Freeman, J.P. ( 8 ) 9 Freeman, S . ( 5 ) 7 4 , 75 Frey, P.A. ( 5 ) 4 8 ; ( 6 ) 9 5 , 115 Frick, K.E. ( 3 ) 37 Fridland, A . ( 6 ) 18 Fridland, S.V. ( 2 ) 15, 1 6 ; ( 5 ) 84 Friedman, J.M. (5) 7 4 , 75 Friedrich, K . ( 6 ) 4 7 4 , 475 Fritsche, E. ( 6 ) 317 Fritz, G. (1) 55-60, 6 3 Froehler, B. ( 6 ) 239
Fromant, M . ( 6 ) 123 Fu, J . M . ( 6 ) 445 Fuchimura, K . ( 6 ) 331 Fuchs, E.P.O. (1) 3 0 9 , 317 Fuchs, R.P.P. ( 6 ) 419 Fuentes, A. ( 7 ) 5 1 , 52 Fueri, J.P. ( 6 ) 241 Fuhrhop, J.H. ( 6 ) 473 Fuji, K . (1) 185 Fujii, M. (5) 2 3 ; ( 6 ) 4 3 , 172, 173 Fujii, S. ( 6 ) 209 Fujimoto, F. ( 7 ) 28 Fujimoto, K. ( 6 ) 1 5 5 , 182 Fujimoto, T. ( 3 ) 27 Fujita, E. (1) 185 Fujita, S . ( 7 ) 133 Fukatsu, S . ( 5 ) 132 Fukuda, T. ( 6 ) 207 Fukui, T . ( 6 ) 3 0 6 , 434 Fukukawa, K. ( 6 ) 2 1 , 23 Fukuyama, K . (1) 84 Fukuzawa, T. ( 6 ) 161 Fukuzumi, K. ( 7 ) 9 3 Funk, A. ( 6 ) 442 Furukawa, A . ( 8 ) 89 Furukawa, M. ( 8 ) 155, 158, 190 Fuzhenkova, A.V. ( 5 ) 172 Gabel, S . A . ( 6 ) 442 Gadru, K. ( 8 ) 7 Gaertner, K. ( 6 ) 119 Gaffney, B.L. ( 6 ) 138 Gafurov, R.G. ( 8 ) 32 Gagnor, C. ( 6 ) 229 Gais, H.-J. ( 7 ) 67 Gait, M . J . ( 6 ) 181 Gajda, T. (5) 138 Galafeeva, M.F. (1) 103 Galanopoulos, S . ( 5 ) 143 Galindo del Pozo, A. (1) 369 Gallagher, M.J. (1) 25 Galle, K. ( 2 ) 4 0 , 4 1 , 42 Galli, R. (1) 216; ( 7 ) 8 Sallyamov, M.R. ( 5 ) 112 Galyantdinov, N.I. ( 5 ) 172 Gamper, H. ( 6 ) 400 Ganapathiappan, S . ( 8 ) 149 Ganushchak, N . I . (5) 29 Garegg, P..J. ( 6 ) 140 Garner, P. ( 7 ) 26 Garrigues, B. (1) 289, 290; ( 2 ) 36 Garrossian, M. (1) 192; ( 4 ) 12 Garvin, G.G. (1) 145
359 Gasar, N . I . (8) 12 Gaset, A. ( 7 ) 4 Gasparyan, G.Ts. ( 1 ) 106 Gasparyan, S.K. ( 1 ) 105 Gautheron, C. ( 6 ) 22 Gauthier, C . ( 6 ) 222, 403 Gavrilova, R.Yu. ( 8 ) 24 Gazizov, T.G. ( 5 ) 170 Gazizov, T.Kh. ( 4 ) 2 6 , 45 Gazizova, L. ( 5 ) 154 Gdaniec, Z . ( 6 ) 33 Geactinov, N.E. ( 6 ) 402 Gebert, P.H. ( 8 ) 202 Geests, R . L . ( 1 ) 331 Gehring, R. ( 8 ) 55 Gelfand, D.H. ( 6 ) 255 Genieser, H.-G. ( 6 ) 6 2 Gerlt, J . A . ( 6 ) 188, 1 8 9 , 350 Germa, R . (1) 134; ( 2 ) 28 Germann, M.W. ( 6 ) 433 Germershausen,,J. I . ( 6 ) 85 Gerrneshausen, J. (1) 5 1 , 53 Gettleman, L. (8) 202 Ghag, S . ( 6 ) 214 Ghosez, L. ( 7 ) 71 Ghosh, S . S . ( 6 ) 286 Gibbons, W.A. ( 5 ) 21 Gibson, D. ( 5 ) 177 Gibson, K . J . ( 6 ) 200 Giege, R. ( 6 ) 423 Gielen, M. ( 5 ) 146 Giese, R. ( 6 ) 436 Gigg, R . ( 5 ) 1 1 , 16 Gilhearny, D.G. (1) 210 Gilje, J . W . ( 7 ) 3 4 ; ( 8 ) 41 Gingeras, T.R. ( 6 ) 287 Giolando, D.M. (1) 65 Giovanetti, M . S . ( 1 ) 102 Gish, G. ( 6 ) 310 Giusti, B. ( 6 ) 139 Gladshtein, B.M. ( 4 ) 10 Glaser, R. ( 3 ) 1 4 ; ( 7 ) 1 Glebova, 2.1. ( 5 ) 117 Gleria, M. ( 8 ) 162 Gloer, K.B. ( 7 ) 66 Goddard, A.J. ( 6 ) 29 Godovikov, N.N. (5) 2 4 , 25 Godovikova, T.S. ( 6 ) 304 Goelet, P. ( 6 ) 342 Goffin, C. ( 6 ) 280 Gol, F. ( 1 ) 61 Gold, R. ( 6 ) 365 Goldbach, M. ( 7 ) 109 Goldberg, I. ( 3 ) 1 9 ; ( 5 ) 167; ( 6 ) 367-369 Goldblum, A. ( 4 ) 7 5 ; ( 5 ) 177
Gol'dfarb, E . I . ( 5 ) 51 Gol'dfarb, Ya.L. (1) 7 Gololobov, Yu.G. (1) 2 1 8 ; ( 8 ) 12 Golovanov, A . V . ( 1 ) 167; ( 5 ) 1 2 7 , 128 Gomelya, N.D. (1) 168 Gonbeau, D. ( 1 ) 92 Gonda, J . ( 1 ) 178 Goodchild, J. ( 4 ) 6 4 ; ( 6 ) 231 Gorbunov, Yu.A. ( 6 ) 142 Gorenstein, D.G. ( 5 ) 178; ( 6 ) 4 3 8 , 445 Goreva, T.V. ( 5 ) 18 Gorshkov, A.V. ( 8 ) 107 Goss, R.L. ( 6 ) 307 Gosselin, G. ( 6 ) 175 Goto, T. ( 8 ) 192 Gottikh, M.B. ( 6 ) 253 Goulart, M . O . F . ( 7 ) 3 Grachev, M . A . ( 6 ) 3 0 1 , 3 0 2 , 304 Graeser, E. ( 6 ) 338 Graf, W. ( 7 ) 32 Graffeuil, M. ( 8 ) 82 Gramatica, P. ( 7 ) 112 Granier, M. ( 8 ) 8 3 Grapov, A.F. ( 5 ) 3 0 , 31, 4 2 , 136 Graskamp, J . M . (8) 104 Gratchev, M . L . ( 4 ) 54 Gratton, E. ( 6 ) 112 Gravel, D. ( 6 ) 329 Graves, D.D. ( 7 ) 117 Gravey, A.M. ( 5 ) 131 Green, C.J. ( 6 ) 381 Green, L . A . ( 6 ) 7 0 Green, M. ( 6 ) 416 Green, R.L. (1) 357 Greeves, N. ( 3 ) 23 Greve, J. ( 6 ) 465 Grey, A . E . ( 8 ) 1 8 5 , 187 Griffin, J.H. ( 6 ) 361 Griffith, J.D. ( 6 ) 3 7 6 , 428 Griffiths, D.V. ( 1 ) 3 5 6 ; ( 3 ) 8 ; ( 4 ) 11 Griller, D. ( 7 ) 54 Grison, C. ( 5 ) 110; ( 7 ) 119 Grobe, J. (1) 1 7 5 , 251-256; ( 4 ) 4 3 Grobelny, D. ( 4 ) 17 Groebe, D.R. ( 6 ) 274 Grollman, A . P . ( 6 ) 1 9 8 , 448 Grosjean, H. ( 6 ) 409 Gross, H.J. ( 6 ) 3 2 5 , 327; ( 7 ) 55 Gross, M.L. ( 6 ) 468 Grotjahn, L. ( 6 ) 468
Gruppe, S. ( 1 ) 287 Gryan, G.P. ( 6 ) 205 Gryazinova, 0.1. ( 6 ) 251 Gryaznov, P.I. ( 5 ) 36 Gryaznov, S.M. ( 6 ) 148 Grzeskowiak, K. ( 6 ) 249 Gubnitskaya, E.S. ( 5 ) 188; ( 8 ) 11 Gudat, D. (1) 299 Gudina, I.V. ( 1 ) 167 Guengerich, F.P. ( 6 ) 395 Guenot, P. ( 1 ) 247 Guerch, G. ( 8 ) 7 2 Guerrier-Takada, C . ( 6 ) 380 Guesnet, J.-L. ( 6 ) 218 Guga, P. ( 4 ) 67 Guida, L. ( 6 ) 17 Guida-Pietrasanta, F. ( 1 ) 209 Guindon, Y. ( 7 ) 85 Guo, H. ( 5 ) 97 Gupta, A . (1) 117; ( 5 ) 88 Gupta, S . C . ( 6 ) 57 Gupta, V . K . ( 1 ) 139 Guranowski, A . ( 6 ) 1 2 5 , 126 Gurarii, L.I. ( 8 ) 29 Gurevich, P . A . ( 4 ) 5 Guseinov, F.I. ( 5 ) 112, 158 Haarburger, D. ( 1 ) 42 Haase, D. ( 1 ) 205 Haase, M. ( 8 ) 48 Haasnoot, C.A.G. ( 6 ) 454 Habener, J . F . ( 6 ) 205 Habhoub, N. ( 6 ) 221, 223 Hacklin, H. (1) 1 5 0 ; ( 2 ) 2 9 , 3 0 , 3 2 ; ( 4 ) 28 Hackney, D.D. ( 6 ) 80 Haddon, R.C. ( 8 ) 7 7 , 7 8 , 143 Hagele, G . ( 5 ) 126 Haelters, J.-P. ( 3 ) 34 Harer, J . (1) 57 Haertle, T. ( 6 ) 19 Hafez, T.S. ( 5 ) 185 Hageman, H.J.H. ( 3 ) 3 Hagendorff, G. ( 6 ) 275 Hagnauer, G.L. ( 8 ) 147 Hahn, J. ( 5 ) 147 Hai, T.-Y. ( 6 ) 382 Haiduc. I. ( 5 ) 146 Haight, G.P. ( 5 ) 57 Hakoshima, T. ( 6 ) 331 Hall, C.D. ( 2 ) 27 Hall, J. ( 6 ) 392 Hall, J.H., jun. ( 6 ) 458 Hall, S.W. (1) 9 6 , 265, 3 0 6 , 316
Orpnophosphorus Chemistry
360 Hamamoto, S. ( 4 ) 6 2 ; ( 6 ) 26, 1 6 7 Hamana, T. ( 6 ) 207 Hambley, T.W. (6) 440 Hamblin, M.R. (5) 10 Hamel, E. ( 6 ) 88 Hampel, K . ( 7 ) 41 Hampton, A. (6) 8 9 , 90 Handke, W. (1) 1 6 1 ; ( 5 ) 91 Handoo, K.L. (8) 7 Hani, R . (8) 142 H a n i k a , G. (1) 70 Hanke, R. (6) 288 Hanlon, S. ( 6 ) 388 Hanna, M.T. (I) 211 Hansen, D.E. ( 6 ) 7 9 Hansen, H.-J. (1) 1 6 Hanson, J . R . (1) 112 Hanvey, J.C. ( 6 ) 24 Happ, E. ( 6 ) 214 H a r a , S. ( 2 ) 21; ( 7 ) 13 H a r a d a , C. ( 7 ) 9 4 Harada, I. ( 6 ) 456 H a r a d a , M. (8) 175 H a r a l a m b i d i s , J. ( 6 ) 201, 213 H a r d i n , C.C. ( 6 ) 387 H a r m s , K. (1) 3 7 3 H a r n e t t , S.P. ( 5 ) 76; (6) 96 Harris, G. ( 6 ) 110 H s r r i s , T.M. ( 6 ) 395 H a r t , D . J . ( 7 ) 75 H a r t l e y , J . A . ( 6 ) 228, 394 Hartmann, C. ( 7 ) 3 0 , 33 Hartmann, G.R. ( 6 ) 302, 303 Harusawa, S. (5) 81 Harvey, R.G. ( 6 ) 402 Harvey, S.C. ( 6 ) 453 Hasagawa, Y. (6) 1 6 3 Hasenbach, J. (1) 52 H a s s e l k u s s , G. (1) 61 Hassler, K . (1) 6 2 H a t a , T. ( 5 ) 23; ( 6 ) 3 2 , 4 3 , 1 4 5 , 1 6 1 , 162, 1 6 9 , 1 7 2 , 174, 178 Hatano, M. ( 5 ) 79 Haumont, E. ( 6 ) 409 Hausen, H.-D. (1) 227 Haw, J . F . (8) 179 Hawkins, E.S. ( 6 ) 24 Hayakawa, J. (8) 118 Hayakawa, T. ( 6 ) 196 Hayase, Y. ( 6 ) 199 H a y a s h i , T. ( 1 ) 100 H a y a s h i , Y. (8) 111 H a y a t s u , H. ( 6 ) 317 H e a l y , L.L. (1) 1 3 8 ; ( 3 ) 17
Heaney, H. (1) 219 H e c h t , S.M. (6) 364, 365 Hecker, R. (6) 430 Heckmann, G. (1) 227, 380 Hees, U. (1) 313 H e i k e n f e l d , G. (1) 11 H e i k k i l a , J. ( 6 ) 1 7 8 Heil, W.G. (6) 61 H e i m g a r t n e r , H. (5) 194 Heine, J. ( 2 ) 25 Heine, J . H . ( 4 ) 22 H e i n i c k e , J. (1) 7 3 Heiser, B. (1) 16 Helene, C. (6) 219-221, 223-225, 227, 230, 355 Hellman, G. ( 7 ) 6 7 Henderson, D. ( 7 ) 103 Hennen, W . J . (6) 9 3 Henner, W.D. ( 6 ) 352 H e n r i c k s e n , U. ( 6 ) 470 H e r b s t , R . (8) 136. 139 H e r c o u e t , A. (1) 212 Hermann, E. ( 5 ) 39 Hermans, R . J . M . ( 4 ) 39; (5) 5 , 6 Hermesdorf, M. ( 1 ) 317 Hernandez, A. ( 7 ) 115 H e r n o t , D. (3) 3 4 H e r o l d , U. (1) 274 Herradon, B. ( 7 ) 115 Herrema, J . K . (8) 208 H e r s c h l a g , D. (5) 58 Hester, L.S. ( 6 ) 81, 8 2 Heubel, J. (8) 33 Heuer, L. ( 4 ) 52 Heumuller, H. (1) 125 Hey, E. (1) 1 4 3 Heydt, H . (1) 304 Heymes, A. ( 7 ) 53 H i g u c h i , M. (8) 170 H i g u c h i , R . ( 6 ) 255, 261 H i g u c h i , T. (1) 258 H i l b e r s , C.W. ( 6 ) 454 H i l l , R.A. ( 7 ) 56 H i l l , W.E. (1) 8 5 Hiller, W. (1) 305; (3) 37; (8) 4 6 , 47 Hino, T. ( 7 ) 126 H i n r i c h s , W. ( 6 ) 6 4 Hirakawa, S. ( 7 ) 104 Hirashima, A. ( 5 ) 4 3 Hirata, K. (5) 157 Hirata, T. (5) 124 Hirayama, M. (5) 132 Hirohama, M. (8) 198 H i r o o k a , S. ( 7 ) 133 H i r o s e , H. ( 8 ) 101 H i r o t s u , K . (1) 258 H i r o y u k i , S. ( 7 ) 63 H i t c h c o c k , C.B. (1) 324 H i t c h c o c k , P.B. (1) 1 9 , 22, 23, 1 1 2 , 268, 323,
326, 361, 363 Ho, M. ( 6 ) 7 9 Hobbs, F.W. (4) 4 0 ; (5) 15; ( 6 ) 311 Hobbs, J.B. (6) 47 Hock, R. ( 7 ) 4 4 H o l z l , W. (1) 263 Hoener, P.A. (6) 324 Honle, W. (1) 59 H o s l e r , K. (8) 4 3 Hoffmann, C. (6) 204 Hoffmann, D.M. ( 7 ) 3 5 Hoffmann, P.U. ( 6 ) 282 Hofmann, F. ( 6 ) 1, 6 1 Hofmann, J. (1) 6 8 , 71 H o h e n h o r s t , M. ( 7 ) 4 1 Holah, D.G. (1) 3 7 1 , 372; ( 3 ) 11 Holdup, D.W. ( 7 ) 122 H o l l e r , E. ( 6 ) 125 H o l t , E.M. ( 1 ) 329 H o l t , M.S. (1) 357 Holy, A. ( 6 ) 4 6 , 48-50, 94 ( 6 ) 407 Hon, Y.-M. Honda, T. ( 7 ) 4 5 Hong, C.I. (6) 1 6 Hong, W.-P. ( 7 ) 75 Honjo, M. ( 6 ) 5 4 Hope, H. (1) 228 Hopf, H. ( 7 ) 8 2 Hopkins, P.B. ( 6 ) 30 Horikawa, M. (6) 5 4 H o r i n o u c h i , Y. ( 6 ) 1 7 3 Horn, G.T. ( 6 ) 255 Horn, T. ( 6 ) 203 H o r n e r , L. ( 5 ) 175 H o r v a t h , S . J . ( 6 ) 359 H o s s e i n i , M.W. ( 6 ) 7 5 , 76 Hostomsky, Z. ( 6 ) 1 8 4 H o u n t o n d j i , C. ( 6 ) 308 Howard, F.B. ( 6 ) 266 H r o v a t , D.A. ( 1 ) 222 H s i e h , B.T. (1) 357 HSU, L.-Y. ( 7 ) 75 Hsu, M.H. ( 7 ) 102 Hsu, Y.H. (8) 1 7 2 , 173 Hu, D. ( 1 ) 362 Hu, J.-S. ( 1 ) 1 9 8 ; ( 7 ) 49 Hua, D.H. ( 5 ) 192; ( 7 ) 6 8 Huang, D.-P. ( 6 ) 386 Huang, E.-S. ( 6 ) 120 Huang, G. ( 5 ) 9 7 Huang, S. ( 4 ) 56 Huang, Y . 4 . ( 7 ) 101 Huber, B. ( 7 ) 31 Huch, V. (1) 335 Hudson, H.R. ( 4 ) 1 6 Hiinerbein, J . (1) 261, 278, 282 Huesken, D. ( 6 ) 183 Huffman, J.C. (1) 67; ( 7 )
Author Index 35 Hugel-Le Goff, C. (1) 284 Hughes, A.N. ( 1 ) 248, 345, 371, 372; ( 3 ) 1 0 , 11; ( 5 ) 71, 72 Hughes, L.R. ( 7 ) 111 H u l l , R . ( 6 ) 385 Hultman, T. ( 6 ) 315 Humar, A. ( 6 ) 267 Hunger, H.-D. ( 6 ) 288 Hunt, J . B . ( 6 ) 103 Hunter, W.E. ( 1 ) 64 Hursthouse, M.B. ( 8 ) 6 5 , 6 6 , 87 Husain, I. ( 6 ) 376 HUSS, S. ( 6 ) 175 Hussong, R . (1) 304 Hutchins, C . J . ( 6 ) 332 Hutchins, L.D. ( 1 ) 337 Hutchins, R.O. ( 5 ) 198 Hutchinson, D.W. ( 5 ) 101, 152 Hutchinson, J.P. ( 6 ) 69 H u t t n e r , G. (1) 144, 230 Huy, N.H.T. ( 1 ) 327, 332 Huynh-Dinh, T. ( 6 ) 152, 222, 269, 451 Hymer, W.C. ( 8 ) 160 I a g r o s s i , A. ( 5 ) 56 Ibanez, F. ( 1 ) 102 I g l o i , G.L. ( 6 ) 295, 317 I g n a t ' e v , Yu.A. ( 1 ) 135; ( 5 ) 92 I g n e r , E. ( 7 ) 121 I g o l e n , J. ( 6 ) 152, 222 I i d a , S. ( 6 ) 317 I i n o , Y. ( 8 ) 15 I i o , H. ( 7 ) 23 I k e d a , K . ( 6 ) 195 I k e h a r a , M. (6) 146, 155, 166, 182, 209, 331, 446 Ilemann, M. ( 8 ) 44 I l e y , J . N . ( 5 ) 54 I l i e s , F. ( 5 ) 146 I l ' i n a , M.N. ( 8 ) 177 I l ' y a s o v , A.V. ( 1 ) 129 Imai, T. (8) 120 I m a i s h i , H. ( 6 ) 434 Imamura, S. ( 6 ) 23 Imbach, J.-L. ( 6 ) 175, 217, 222, 228, 229, 353, 403 Imlay, J . A . ( 6 ) 371 Immenkeppel, M. ( 1 ) 257 Imoto, H . ( 5 ) 114 I m r i c h , J. ( 1 ) 178; ( 7 ) 40 Imura, A. ( 6 ) 199 Inamoto, N . ( 1 ) 258, 267, 268
361 Indzhikyan, M.G. ( 1 ) 105, 106, 184, 213; ( 5 ) 94 I n o u e , H. ( 6 ) 199 Inoue, K. (8) 94 I n o u e , T. ( 6 ) 378 Inshakova, V.T. (1) 160 Ioganson, A.A. ( 4 ) 13 I o n i n , B . I . ( 1 ) 157; ( 5 ) 105 I o n k i n , A.S. ( 1 ) 140 Isaeva, G.M. ( 1 ) 74 I s a g u l y a n t s , M.G. ( 6 ) 251 I s h i b a s h i , K. ( 6 ) 216 I s h i d a , M. ( 5 ) 32 I s h i d o , Y. ( 6 ) 163 I s h i g a m i , K. ( 8 ) 118 I s h i h a r a , K. ( 8 ) 192 I s h i h a r a , T. ( 5 ) 108, 109 Ishmuratov, A.S. ( 1 ) 176 Islam, M.Q. ( 1 ) 8 5 Islam, N.B. ( 6 ) 57 I s m a i l o v , V.M. ( 5 ) 112, 158 Issleib, K. ( 1 ) 44-46, 77, 281; ( 5 ) 129, 142 I t o , H. ( 5 ) 79 I t o , S. ( 8 ) 109, 111, 112, 114 I t o , T. ( 6 ) 6 8 I t o , Y. (1) 100 I t o , Z. ( 8 ) 155, 158, 190 I t o h , H. ( 6 ) 21, 23 I t o h , M. ( 6 ) 216 Ivanchenko, V . I . ( 5 ) 136 Ivanov, A.N. ( 5 ) 18, 19, 149-151 Ivanova, V.N. ( 5 ) 170 Ivanovskaya, M.G. ( 6 ) 251, 253 I v e r s o n , B.L. ( 6 ) 318 Iwai, S. ( 6 ) 179, 199, 206 Iwase, R. ( 6 ) 174 I y e n g a r , R . ( 6 ) 95 I y e r , S.R. (1) 80 I y e r , V.S. (1) 33 I z h b o l d i n a , L.P. (5) 87 I z u t a , S. ( 6 ) 107 Jachow, H. ( 1 ) 51 J a c k s o n , W . R . ( 1 ) 42 J a k e l , E. ( 7 ) 109 Jakubowski, H. ( 6 ) 125, 126 Jamal, H. ( 6 ) 102 James, A.F. ( 8 ) 116 Jameson, D.M. ( 6 ) 112 Jamieson, G.A. ( 6 ) 103 J a n o u t , V . ( 8 ) 153 Janowski, W.K. ( 5 ) 143 Janssen, R.A.J. ( 3 ) 15
J a n u l a i t i s , A . ( 6 ) 194, 339 J a s t o r f f , B. ( 6 ) 62 Ja'szay, Z.M. ( 5 ) 78 J e a n n e , F. ( 8 ) 195, 196 J e d l i n s k i , Z. ( 8 ) 6 2 , 206 J e f f e r s o n , J . R . ( 6 ) 103 J e n c k s , W.P. ( 5 ) 58 J e n k i n s , I . D . ( 1 ) 120 Jenny, C. ( 5 ) 194 J e n s e n , M.A. ( 6 ) 311 J e n t z s c h , R. ( 5 ) 66 J e r i n a , D.M. ( 6 ) 57 J i , G.-J. ( 5 ) 37 ( 6 ) 158 J i a n g , M.-Y. J o b , C. ( 6 ) 87 J o b , D. ( 6 ) 87 J o b e , I . R . ( 4 ) 38 J o h n s , D.G. ( 6 ) 18 J o h n s , R.B. ( 4 ) 29 Johnson, F. ( 6 ) 198 Johnson, J . P . ( 6 ) 259 Johnson, M.A. ( 6 ) 18 Johnson, P.D. ( 7 ) 107 J o h n s t o n , M . I . ( 6 ) 457 J o l l e y , J . G . ( 8 ) 185 J o n a s , K. ( 1 ) 321 Jones, B.K. ( 6 ) 399 J o n e s , C.R. ( 6 ) 445 J o n e s , R.A. (1) 65; (6) 138 J o n e s , R.L. ( 6 ) 450 J o r d a n , A.D., jun. ( 7 ) 113 J o r g e n s e n , E.D. ( 6 ) 303 J o r g e n s e n , T.J. ( 6 ) 352 J o s t e n , B. ( 1 ) 273 J o w e t t , I . C . ( 4 ) 23 J o y c e , G.F. ( 6 ) 3, 378 Jung, M.E. ( 7 ) 128 Juodka, B. ( 6 ) 91, 215 J u r k s c h a t , K . (1) 99 J u s t , G . ( 6 ) 125; ( 7 ) 118 J u t z , P. ( 4 ) 87 J u t z i , P. (1) 1 4 9 , 225, 233 Jwo, J . J . (1) 181 Kabachnik, M . I . (5) 24, 25 Kabachnik, M.M. ( 1 ) 173 K a f a r s k i , P. ( 5 ) 121 K a i s e r , E.T. ( 6 ) 79 Kajiwara, M. ( 8 ) 150, 183, 184, 203 Kakihana, M. ( 7 ) 21 K a l a b i n a , A.V. ( 2 ) 39; ( 5 ) 86, 87 Kalachev, A . I . ( 8 ) 177 Kal'chenko, V . I . ( 5 ) 98 K a l e t s c h , H. ( 1 ) 370,
362 3 7 8 ; ( 7 ) 18 K a l i n i n , V . N . (1) 196 K a l n i c k , M.W. ( 6 ) 4 4 8 K a m , B.L. ( 6 ) 113 Kamachi, M. ( 3 ) 1 6 Kamaike, K . ( 6 ) 163 Kamalov, R.M. ( 5 ) 4 9 , 5 0 Kamikawa, T. ( 7 ) 1 0 4 Kamimura, T. ( 6 ) 1 4 5 K a m i k k i , R. ( 5 ) 2 6 Kamlet, M . J . ( 3 ) 2 0 Kan, %J.H. ( 6 ) 4 5 4 Kan, L. (6) 4 5 2 Kanabus-Kaminska, J . M . (5) 163; ( 7 ) 54 K a n a t z i d i s , M.G. ( 6 ) 4 1 5 K a n a y a , E.N. ( 6 ) 2 6 6 K a n d e l , E.R. ( 6 ) 342 K a n e l l a k o p o u l o s , B. ( 1 ) 322 Kanemasa, S. ( 5 ) 1 1 3 ; ( 7 ) 63 Kang, H.-S. ( 5 ) 1 1 5 , 1 9 7 ; ( 7 ) 29, 6 2 Kao, M. ( 7 ) 21 K a p o o r , P.N. ( 1 ) 29 Kappen, L.S. ( 6 ) 3 6 7 , 368 K a p p l e r , F. (6) 89, 90 Karaman, R . ( 4 ) 7 5 ; (5) 177 K a r a s e v a , E.V. ( 6 ) 1 6 5 K a r e v , V . N . (1) 153 K a r g e r , B. ( 6 ) 436 K a r g i n , Yu.M. ( 1 ) 1 3 5 ; ( 5 ) 92 K a r i k o , K. ( 6 ) 244-246 Karimova, N.M. ( 5 ) 1 5 5 K a r k a s , J . D . ( 6 ) 130 K a r l e , B. (1) 3 0 ; ( 6 ) 1 6 8 K a r p e i s k y , M.Ya. ( 6 ) 45 K a r p o v a , O.V. ( 6 ) 3 4 3 K a r r a n , P. ( 6 ) 392 K a r s c h , H.H. (1) 68-72, 266, 267, 269, 270; ( 7 ) 12 K a r t h i k e y a n , S. ( 8 ) 93 K a s h e m i r o v , B.A. ( 5 ) 130, 164 K a s h t a n o v , S.A. (8) 3 2 Kasmai, H.S. (1) 138; ( 3 ) 17 K a s u k h i n , L.F. ( 1 ) 338 K a s ' y a n , L . I . ( 1 ) 103 K a t o , S. ( 5 ) 3 2 Kato, T. ( 4 ) 3 ; ( 7 ) 133 K a t s a r o s , D. ( 6 ) 7 1 K a t s u t a , M. ( 8 ) 1 5 5 , 1 5 8 , 190 K a t t i , K . V . (8) 136, 1 3 7 , 139 Katz, T . J . ( 5 ) 100 K a t z h e n d l e r , J. ( 6 ) 1 3 4
Kaub, J . ( 8 ) 51 Kaufman, S . ( 6 ) 294 Kawakami, T. (8) 101 Kawamura, M. ( 1 ) 250 Kawase, Y. ( 6 ) 2 0 6 , 446 Kawashima, E . ( 6 ) 270 Kay, P.B. ( 5 ) 1 7 6 Kaye, A.D. ( 5 ) 69, 7 0 Kazankova, M.A. ( 4 ) 3 2 K a z a n t s e v a , T . I . ( 2 ) 39 Keck, G . E . ( 3 ) 2 K e e f e r , L . K . ( 1 ) 200 Keenan, B.C. ( 6 ) 4 3 5 K e g l e v i c h , G. (1) 359; ( 3 ) 9 , 1 2 , 1 3 ; ( 4 ) 16 Kehne, A . ( 6 ) 2 1 1 , 316 Keim, W. ( 1 ) 287 K e i t e l , I . ( 7 ) 50 K e k e l , 4 . P . (8) 130 K e l l e r , G . H . ( 6 ) 386 K e l l e r , H. ( 1 ) 366 K e l l e r , <J. ( 8 ) 4 8 K e l l e r , T..J. ( 6 ) 3 6 6 Kelly, D.J. (7) 123 K e l l y , J.M. ( 6 ) 4 2 7 Kemp, G . ( 1 ) 219 Kennedy, R.M. ( 7 ) 9 5 Kenyon, G.L. ( 6 ) 86 Kern, D. ( 6 ) 423 Kerr, D.I.B. (5) 143 K e r s t i n g , M. ( 8 ) 39 K e y e s , R.S. ( 6 ) 268 Khabou, A . ( 8 ) 3 9 , 4 0 Khachatryan, R.A. ( 1 ) 5 0 , 1 8 4 , 2 1 3 ; (5) 9 4 K h a l i k o v , I . S . (I) 1 2 7 ; (5) 179 K h a l i l , F.Y. (1) 2 1 1 K h a r e , A. ( 7 ) 77 Kharitonov, A.V. (5) 149 K h o k h l o v , P.S. ( 5 ) 1 3 0 , 164 Khomutov, R.M. ( 6 ) 1 2 6 K h r i p a c h , N.B. ( 6 ) 2 4 0 K h u s a i n o v a , N.G. (5) 8 2 K i b a r d i n , A.M. ( 5 ) 36 K i e f e r - H i g g i n s , S. ( 6 ) 313 K i f i , J . (1) 8 4 K i k u c h i , K . ( 6 ) 207 K i l ' d i s h e v a , O.V. (5) 155 K i l i c , Z. ( 8 ) 66, 7 9 Kim, C. ( 8 ) 90 K i m , D.Y. ( 4 ) 7 , 1 4 ; ( 5 ) 139 K i m , H . J . ( 6 ) 331 K i m , J. ( 6 ) 351 K i m , S.-H. ( 6 ) 3 7 7 K i m , S.C. (6) 3 3 7 K i m , T.H. ( 4 ) 7 ; ( 5 ) 1 4 0 K i m , T.V. ( 1 ) 3 3 8 ; (5) 102
K i n g , R.B. ( 1 ) 329 K i n g , R.C.-Y. ( 5 ) 192; ( 7 ) 68 ( 3 ) 15 Kingma, . J . A . J . M . K i r e e v , V.V. ( 8 ) 107 K i r i c h e n k o , L.N. ( 5 ) 1 2 8 K i r k , M.C. ( 5 ) 5 3 ; ( 6 ) 39 1 K i r k p a t r i c k , C.C. ( 8 ) 1 4 8 Kirsanov, A.V. ( 1 ) 298; ( 8 ) 20 Kirsch-De Mesmaeker , A . ( 6 ) 427 K i r v e l i e n e , V . (6) 215 K i s a l u s , .J.C. ( 3 ) 10 K i s c h k e l , H . ( 1 ) 78 Kiselev, V.V. ( 4 ) 5; (5) 106 K i s e l e v a , E . I . ( 5 ) 102 K i s i l e n k o , A . A . ( 1 ) 196 K i s i n , 4.V. ( 8 ) 1 0 7 K i t a b a t a k e , S . ( 6 ) 122 K i t a m u r a , T. ( 5 ) 59 K i z a k i , H . ( 6 ) 106 Klabunovsky, E . I . (1) 42 K l e b a n s k i i , E.O. ( 4 ) 8 0 , 83, 8 4 ; ( 8 ) 19 Kleerniss, W . ( 5 ) 199 K l e i n , G. ( 6 ) 1 2 7 Klepa, T . I . (1) 152 K l i m a s a u s k a s , S. ( 6 ) 1 9 4 , 339 K l i m e n t o v a , G.Yu. ( 4 ) 5 K l i n g e b i e l , U. ( 8 ) 134, 135 K l u g e r , R . ( 5 ) 190 Knapp, M . ( 6 ) 342 K n e b l , R . ( 1 ) 380 K n i e r , B.L. ( 5 ) 6 5 K n i e z o , L. ( 7 ) 4 0 Knoch, F. (1) 2 7 3 , 2 8 2 , 287, 342 K n o l l , F. (1) 226 K n o r r e , D.G. ( 6 ) 406 Knowles, J . R . ( 5 ) 7 4 , 7 5 ; (6) 79 Knudsen, K.L. (1) 3 7 3 7 2 ; ( 3 ) 11 K n u p p e l , P.C. (1) 61 K n u n y a n t s , I . L . ( 5 ) 55 K o b a y a s h i , K. ( 4 ) 3 K o b a y a s h i , T. ( 7 ) 9 7 K o c h i , J.K. ( 2 ) 3 K o c h t a , J. (1) 277 Kodadek, T. ( 6 ) 4 0 0 Kodama, M. ( 7 ) 93, 9 4 K o d a t o , S. ( 7 ) 1 2 6 K o e n i g , J. (6) 111 K o e n i g , W.A. ( 6 ) 4 6 7 K o p f , H. (1) 2 4 K o s s e l , H. ( 6 ) 3 1 7 K o e s t e r , H. ( 6 ) 4 6 7
3 63
Aiithor Index Koh, H.J. (8) 161 K o h l e , R. (1) 207 Kohn, K.W. (6) 394 Kohno, K . (5) 14; (6)
145, 169
K o i d a n , G.N. (8) 30, 36 Koizumi, M. (6) 179 K o j i m a , M. (8) 167-169 K o j i m a , T. (8) 203 K o k i l , P.B. (5) 17 K o l a s a , T. (1) 121 K o l b a s o v , V.I. (1) 160 K o l e s n i k , N.P. (2) 4 K o l l e , P. (1) 291 K o l l i n g , E. (7) 82 K o l o b u s h k i n a , L . I . (6) 45 K o l o d y a z h n y i , 0.1. (1)
K r e b s , B. (1) 252-254 K r e b s , J . W . (6) 258 K r e c h , F. (1) 77 K r e u z f e l d , H.-J. ( 1 ) 170 K r i c k a , L.J. (6) 151 K r i e f , A . (7) 120 K r i e f , P . (1) 119; (8) 23 K r i s h n a m o o r t h y , C.R. (6)
363
K r i s h n a m u r t h y , S.S. ( 8 )
60, 93, 100, 149
K r i s t e n s e n , T. (6) 322 K r i s t i a n , P. (1) 178; (7)
40
K r o e n k e , W . J . (4) 30 K r o l e v e t s , A.A. (1) 162;
(4) 33; (5) 2, 83, 156 K r o t o , H.W. (1) 249 109, 110; (2) 20 K o l o s o v a , T.N. (8) 69 K r u g e r , C. (1) 318, 319, K o m o r o s k i , R.A. (4) 30 321 K o n i s h i , H. (1) 84 K r u p p , G . (6) 325, 327 K o n o v a l o v a , I.V. (2) 31 .Kruppa, V. (1) 32; (3) 33 K o o l e , L.H. (2) 8, 12; K r y n e t s k a y a , N.F. (6) 39, 148, 343 (6) 234 K o p a s z , J.P. (1) 64 K u b l e r , M.-D. (6) 423 Kuchen, W. (1) 207 Kopylov, V.M. (8) 107 K o r k i n , A. 4. (4) 55 Kucsina, M.E. (8) 201 Korrnachev, V.V. (1) 176 Kudyakov, N.M. (1) 75 K o r n i e t s , E.D. (4) 13 Kiihne, U. (1) 44 K o r o t e e v , M.P. (4) 36 Kiindig, E.P. (4) 37 K o r s h a k , V.V. (8) 69, 98, Kuhn, H. (6) 293 Kuhn, N . (3) 36 99, 151, 152 K o r s h i n , E.E. (4) 34 Kukhanova, M. (6) 117 K o r t e , F. (1) 8 K u k h a r ' , V.P. (1) 338; K o s a c h e v , I . P . (5) 92 (5) 161 K o s e r , G.F. (5) 17 K u k h a r e v a , T.S. (5) 148 Koshrnan, D.A. (1) 214 K u l a k , T . I . (6) 240 K o s t e n k o , N . I . (1) 13 K u l i c h i k h i n , V.G. (8) 174 K o s t e r , R. (3) 35 K u l i e v , A . K . (4) 50 K o s t y a n o v s k i i , R.G. (5) K u l i k o w s k i , T. (6) 15 K u l i n k o v i c h , 0.G. (1) 108 164 K o t a k a , T. (8) 165, 171 K u l i s h , V.P. (8) 30 K o t l y a r e v s k i i , I . L . (5) Kumagai, I. (6) 145 Kumar, D. (8) 103 137, 153 K o v a c s , T. (6) 265 Kumar, R. (1) 31, 66 K o v a l e n k o , S.V. ( 4 ) 13 Kumar, S.B. (8) 49 K o v a l e v a , T.V. ,(8) 18 Kumarev, V.P. (6) 149 K o v y a z i n , V . A . (8) 107 K u m a r i , K. (1) 189 Kow, Y . W . (6) 352 Kumar Swamy, K.C. (8) 100 K o z a r i c h , J.W. (6) 362, Kumobayashi, H. (1) 84 K u n i e d a , T. (5) 80 363 Kozhushkov, S . I . (1) 182 K u n i s h i m a , M. (1) 185 K o z l o v , E.S. (2) 13; ( 5 ) Kunz, W. (1) 179; (7) 61 Kunze, U. (1) 32, 82; (3) 95 K o z l o v , V.A. ( 5 ) 30, 31, 33 Kuo, L.Y. (6) 415 42, 136 K o z l o v a , N.Ya. (5) 62 K u p f e r s c h r n i t t , G. (6) 190 K r a s s i g , H . A . (8) 122 K u r c h e n k o , L.P. (8) 88 K r a n n i c h , L.K. (1) 139 K u r i h a r a , T. (5) 81 K r a s o v s k i i , A . N . (8) 30 K u r i t a , E. (1) 250 K r a u s , N. (7) 82 K u r o d a , S. (7) 133 K r a y e v s k y , A. (6) 117 K u r t s , A.L. (1) 116
K u s m i e r e k , J.T. (6) 14 K u t s e n k o , I.F. (4) 32 K u t y a v i n , I.V. (6) 304,
356, 404, 405
K u t y r e v , A . A . (2) 5 Kuwano, E. (5) 43 Kuwata, K. (3) 16 K u z n e t s o v a , T.S. (1) 182 K v a s y u k , E . I . (6) 240 Kwoh, D . Y . (6) 287 Kwok, S. (6) 258 Kwon, C.H. (5) 53 K y p r , J. (6) 472 K y u n t s e l ' , I.A. (2) 13;
(8) 8 L a a s , T. (6) 432 L a b a r r e , .J.F. (8) 70-74,
80-84, 102
Lacombe, S. (1) 92 L a c o s t e , A.M. (5) 131 L a f f a u , D.D.P. (7) 98 L a h a v , N. (6) 58 L a i , M.-D. (6) 272 L a i d l a w , W.G. (8) 123 L a l o r , F . J . (1) 199; (8)
28
Larnandg, L. (2) 35, 36 L a n c e l o t , G. (6) 218 L a n d g r a f , W. (6) 61 L a n d i n i , D. (1) 204 L a n g , B.F. (6) 329 L a n g e n , P. (6) 119 L a n g e r , R. (8) 161 L a n g h a n s , K.P. (1) 40 L a n g l a i s , M. (6) 414 L a n k a t - R u t t g e r e i t , B. (6)
327
Lansdown, M.E.
(1) 138;
(3) 17
L a n s e r , \J.A. (6) 384 L a p i n , A . A . (1) 190 L a p p a s , D. (7) 35 L a p p e r t , M.F. (1) 22, 23,
326
L a p t e v a , Jd.I. (2) 15, 16 L a r o c k , R.C. (7) 102 L a r o v a , E.E. (1) 152 L a r p e n t , C. (1) 136 L a r s o n , J.E. (6) 389 L a s n e s , M.-C. (1) 91, 92 L a s s o t a , P. (6) 1 4 , 104 L a t y p o v , R.R. (5) 186 L a u , C.K. (7) 85 L a u , W. (2) 3 L a u c y s , V. (6) 339 Laundon, C.H. (6) 428 L a u r e n c i n , C.T. (8) 161 L a u r i a , M.R. (1) 138; (3)
17
L a u r i a n , L.G.
(8) 9
Orgari op h ospli or us Chernistry
3 64 L a v a l , F. ( 6 ) 392 L a v a l , J. ( 6 ) 354 L a v i e l l e , G . ( 5 ) 163 L a v r e n t ' e v , A . N . ( 1 ) 167; ( 5 ) 127, 128 Lawesson, S.O. ( 5 ) 180, 184 Lawrence, C.B. ( 6 ) 397 Lazraq, M. ( 1 ) 223, 289, 290; ( 4 ) 86 Le, D.B. ( 6 ) 205 Leader, H. ( 4 ) 75; ( 5 ) 177 Learmouth, M.P. ( 5 ) 21 Lebbe, T. ( 1 ) 76 Lebedev, A.V. ( 6 ) 149 Lebedev, V.B. (1) 167 Le B i g o t , Y. ( 7 ) 4 Leblanc, Y. ( 7 ) 86 Lebleu, B. ( 6 ) 229, 247 L e b l o n d - F r a n c i l l a r d , M. ( 6 ) 285 L e c a t , J.-L. ( 1 ) 87; ( 3 ) 21 Le C o r r e , M. ( 1 ) 212; ( 7 ) 37, 38 L e d e r e r , K . ( 8 ) 122 Le Doan, T. ( 6 ) 221, 223, 227, 355 Ledoux, I. ( 7 ) 78 Lee, B.L. ( 6 ) 209, 238 Lee, C. ( 6 ) 245 Lee, K.M. ( 6 ) 328 Lee, M. ( 6 ) 228, 353 Le Floch, P. (1) 327 L e G o f f i c , F. ( 5 ) 131 Lehmann, C. ( 6 ) 119 Lehmann, U. ( 6 ) 293 Lehn, J.-M. ( 6 ) 75, 76; ( 7 ) 78 L e i b f r i t z , D. ( 6 ) 72 Leimbacher, W. ( 6 ) 129 L e i n f e l d e r , W. ( 6 ) 410 L e i s s r i n g , E. ( 1 ) 45, 46, 281 Lejczak, B. (5) 121 Lernaitre, M. ( 6 ) 229, 247 Lemande, L. ( 2 ) 34 Le Merrer, Y. ( 7 ) 91 Lemmen, P. ( 6 ) 168 Leng, M. ( 6 ) 420 Lensink, C. ( 8 ) 126 Lenz, R.W. ( 8 ) 8 9 L e o n e t t i , J.-P. ( 6 ) 217 Leong, T. ( 6 ) 208 Lepre, C.A. ( 6 ) 421 Le ROUX, J. ( 7 ) 38 Lesnikowski, Z . J . ( 4 ) 67; ( 6 ) 51 L e t e l l i e r , M. ( 7 ) 132 Leung, W.-P. (1) 23, 326 Le Van, D. (1) 175,
251-254 Levene, S.D. ( 6 ) 471 Levin, Ya.A. ( 5 ) 154 L e w i s , R.T. ( 7 ) 60 L e y e r e r , H. ( 1 ) 6 Lhomme, J . ( 6 ) 221, 223, 354 L i , J.-J. ( 6 ) 258 L i , P. ( 6 ) 384 L i , S.W. ( 6 ) 244-246 L i , S.Y. ( 6 ) 130 L i , V.S. ( 5 ) 189 L i , X.-Y. ( 1 ) 198; ( 7 ) 49 Lian, L.-Y. ( 6 ) 443 Liang, W. ( 6 ) 259 L i b l i n g , S.W. ( 8 ) 124, 125 L i g u o r i , A. ( 6 ) 171 L i n , C.-H. ( 7 ) 107 L i n , C.M. ( 6 ) 88 L i n , I . (6) 411 L i n , S.-B. ( 6 ) 238 Linardopulos, S. ( 6 ) 165 L i n d i g , M. ( 8 ) 55 L i n d n e r , E. ( 1 ) 30, 305; ( 3 ) 37 Ling-Chung, S.K. ( 7 ) 3 Linn, S. ( 6 ) 351, 371 L i n t i , G. ( 1 ) 291 L i o r b e r , B.G. ( 5 ) 106, 170 Lippard, S . J . ( 6 ) 417, 418, 421 L i q u i e r , J . ( 6 ) 460, 461 Liskamp, R.M. ( 4 ) 59 L i u , A. ( 1 ) 181 L i u , D.K. ( 6 ) 248 L i u , H.-J. ( 5 ) 44 L i u , R.S.H. ( 7 ) 84 L i u , W. ( 6 ) 326 Livantsov, M.V. ( 1 ) 1-3, 95; ( 2 ) 26; ( 4 ) 6 , 21 Lobanov, O.P. ( 1 ) 196 Lodaya, J.S. ( 5 ) 17 Loeb, L.A. ( 6 ) 271 Logusch, E.W. ( 5 ) 133 Lomakin, A . I . ( 6 ) 142 Lombard, S. ( 8 ) 195, 196 London, R.E. ( 6 ) 442 Lopez, F. ( 1 ) 379; ( 7 ) 2 , 10, 48 Lopez, L. (1) 367; ( 4 ) 78 < o p u s i h s k i , A. ( 5 ) 33, 34 Lora, S. ( 8 ) 163 Loreau, N. ( 6 ) 225 Lotan, I. ( 6 ) 342 Lowe, G. ( 5 ) 76; ( 6 ) 1 1 , 9 6 , 98-100 Lowenstein, J . M . ( 6 ) 284 Lowmaster, N.K. ( 7 ) 116 Lown, J . W . ( 6 ) 228, 353 Lowther, N. ( 2 ) 27
Lu, X. ( 5 ) 96, 9 9 , 135 Lubisch, W. ( 5 ) 104 -kuczak, L. ( 5 ) 34 Ludlum, D.B. ( 6 ) 391 Ludwig, J . ( 6 ) 67 Lucke, E. (1) 239, 241 Luerssen, K. ( 8 ) 55 L u t h j e , J. ( 6 ) 121 Lukhtanov, E.A. ( 6 ) 301 Lutsenko, A . I . ( 4 ) 36 Lutsenko, I.F. ( 1 ) 1-3, 95, 173, 264; ( 2 ) 26; ( 4 ) 6 , 21; ( 5 ) 120 Luzikov, Yu.N. ( 1 ) 3 L u z z a t t o , L. ( 6 ) 257 Lysek, M. ( 1 ) 350; ( 4 ) 79; ( 8 ) 21, 22 Ma, Q. ( 6 ) 86 k a a s , G. ( 1 ) 304, 314 McAllister, W.T. ( 6 ) 303 McAndrew, T.P. ( 8 ) 200 McAtee, R.E. (8) 185, 187 Macaulay, G.S. ( 7 ) 56 McAuliffe, C.A. (1) 85 McBride, L . J . ( 6 ) 139 McCaffrey, R.R. ( 8 ) 185, 187 McCammon, J . A . ( 6 ) 453 McClain, W.H. ( 6 ) 380, 408 McCloskey, J . A . ( 6 ) 353 McConnell, D . J . ( 6 ) 427 McCorkle, G.M. ( 6 ) 382 McCorrnick, F. ( 6 ) 260 MacCoss, M. ( 6 ) 8 5 , 130 McDonald, J.F. (5) 133 McDonnell, G.S. ( 8 ) 106 Macdonnell, J. ( 6 ) 257 McDowell, R.S. (3) 14; (7) 1 McEwen, W.E. (1) 208 McFadden, G. ( 6 ) 345 McFarlane, W. ( 1 ) 27, 81 McGahren, W . J . ( 6 ) 370 McGrath, J.P. ( 7 ) 107 Mack, D.H. ( 6 ) 258 MacKay, R.A. (5) 65 McKenna, E.G. ( 7 ) 17 McKenzie, A. ( 3 ) 26 McKie, J . A . ( 5 ) 192; ( 7 ) 68 McKillop, A. ( 7 ) 87 MacLachlan, W.S. ( 7 ) 56 McLaren, K.L. ( 7 ) 69 McLaughlin, L.W. ( 6 ) 208, 282, 338, 375, 431 McLean, M . J . ( 6 ) 389 McLennan, A.G. ( 6 ) 128 McMurry, J.E, ( 7 ) 27 McOsker, P.L. ( 6 ) 349
365
Aid tlior itrrirx
Macquarrie, D . J . ( 1 ) 202, 20 3 Maddox, M.L. ( 1 ) 118; ( 2 ) 19 Maeda, M. (8) 118 Maeda, S. ( 1 ) 180 Maekawa, T. ( 5 ) 108, 109 Markl, G. (1) 263, 271, 274, 374-376 Mag, M. ( 6 ) 137 Magill, J . H . ( 8 ) 166-169 Mahalakshmi, Y.V. ( 6 ) 344 Maher, J . L . , I11 ( 6 ) 237 Mahran, M.R. ( 5 ) 185 Maia, A. ( 1 ) 204 Maier, L. (1) 179; ( 3 ) 22; ( 5 ) 107; ( 7 ) 61 Maier, S. ( 7 ) 79 Maigrot, N. (1) 351 Mainz, B. ( 8 ) 133 Majewski, P. ( 2 ) 1 8 ; ( 4 ) 27 Majoral, J.-P. ( 1 ) 234, 369 Makino, K . ( 6 ) 434 Malavaud, C. (1) 367; ( 4 ) 78 Maleev, A.V. ( 1 ) 182 Maleki, M. ( 3 ) 1 Maletina, 1.1. (8) 24 Malito, J. (1) 146 Malthete, J. ( 7 ) 78 Malver, 0. ( 6 ) 113 Malvy, C. (6) 229 Mamaev, S.V. ( 6 ) 356 Manak, M.M. ( 6 ) 386 Mandrad-Berthelot, M.-A. ( 6 ) 410 Maneliene, Z. ( 6 ) 194, 339 Manestnikov, V . I . ( 5 ) 144 Manitto, P. ( 7 ) 112 Manoharan, M. ( 6 ) 188, 189, 350 Manojlovic-Muir, L. ( 1 ) 147; ( 4 ) 38 Many, M.N. ( 8 ) 106 Mar, E.-C. ( 6 ) 120 Marchenko, A.P. (8) 35, 36 Margison, G.P. ( 6 ) 392, 435 Marinas, J . M . ( 7 ) 51, 52 Marinetti, A. ( 1 ) 333, 352 Marino, J.P. ( 7 ) 129 Mark, J.E. ( 8 ) 172, 173 Mark, V. ( 4 ) 25 Markhus, F. (1) 186 Markovskii, L.N. ( 1 ) 245, 246, 260, 292-298, 300, 341; (2) 4; ( 4 ) 2 , 31,
79, 8 0 , 8 3 , 8 4 ; ( 5 ) 98, 187; ( 8 ) 3, 4 , 1 9 , 20, 53 Markowska, A. ( 4 ) 24 Marks, T.J. ( 6 ) 415 Markus-Sekura, C . J . ( 6 ) 237 Marlin, J . E . ( 5 ) 191 Marquez, V.E. ( 6 ) 29 Marschall-Weyerstahl, H. ( 7 ) 131 Marschner, T.M. ( 6 ) 113 Marshall, A.G. ( 6 ) 328 Marshall, C . J . ( 6 ) 260 Marshall, J . A . ( 7 ) 92 Marth, C.F. ( 2 ) 2 2 , 23; ( 7 ) 14 Martin, J.-P. (6) 127 Martin, J . C . ( 2 ) 3 Martin-Lomas, M. ( 7 ) 115 Martynov, I . V . ( 5 ) 18-20, 149-151, 162; ( 8 ) 32 Marumoto, R. ( 6 ) 207 Maruyama, I. ( 8 ) 155, 158, 190 Maruyama, T. ( 6 ) 54 Marx, J . L . ( 6 ) 255 Maryanoff, B.E. ( 7 ) 113 Marzilli, L.G. ( 6 ) 440, 450 Masamune, S. ( 7 ) 9 5 Maslennikov, I . G . ( 1 ) 167; ( 5 ) 127, 128 Masnovi, J. ( 7 ) 46 Mason, R . ( 3 ) 23 Masotti, H. ( 4 ) 70 Massa, W. (1) 11 Masschelein, A. ( 6 ) 427 Masuda, S. ( 4 ) 3 Masui, M. ( 1 ) 104, 195 Masuko, T. (8) 167, 168, 186, 194 Masumoto, M. ( 7 ) 133 Mathey, F. ( 1 ) 276, 284, 327, 332, 333, 346-348, 351-355, 360 Mathies, R.A. ( 6 ) 459 Mathieu, R . ( 1 ) 234, 369 Mathieu, S. ( 1 ) 134; ( 2 ) 28 Mathlouthi, M. ( 6 ) 466 Matsuda, A. ( 6 ) 23 Matsuda, I. ( 1 ) 258 Matsukura, M. ( 6 ) 235 Matsumoto, H. ( 8 ) 191 Matsumoto, T. ( 6 ) 434 Matsumura, K. ( 7 ) 94 Matsuo, N. ( 6 ) 182 Matsushita, T. ( 1 ) 132 Matsuura, H. ( 1 ) 250 Matsuzaki, J. ( 6 ) 169 Matsuzaki, K. ( 3 ) 27; ( 7 )
28 Matsuzawa, S. ( 8 ) 170 Matt, D. (1) 21 Mattes, W.B. ( 6 ) 394 Matteucci, M. ( 6 ) 239 Matthes, E. ( 6 ) 119 Matthews, J . A . ( 6 ) 151 Matveeva, E.D. ( 1 ) 116 Matyushecheva, G.I. ( 2 ) 17 Maurer, A. (8) 46, 47 Maver, A. ( 6 ) 72 Mavrin, G . V . ( 5 ) 170 Maxwell, J . R . ( 7 ) 124 Maya, B . J . ( 4 ) 38 Mayamoto, Y. ( 7 ) 9 3 Mayer, M. ( 8 ) 135 Mayer, U. ( 1 ) 225 Mayo, S.L. ( 8 ) 78 Mayol, L. ( 6 ) 147, 154, 186 Mazany, A.M. ( 4 ) 30 Mazumder, A. ( 6 ) 189, 350 Meares, C.F. ( 6 ) 300 Medici, A. ( 7 ) 20 Medina, R . ( 8 ) 116 Medon, P.P. ( 6 ) 384 Medvedev, A.E. ( 5 ) 127 Meek, J.L. ( 4 ) 40; ( 5 ) 15 Meetsma, A. ( 8 ) 126, 129, 131, 206-208 Meguro, H. ( 1 ) 126 Mehrotra, R.C. ( 5 ) 46 Mei, H.-Y. ( 6 ) 426 Meidine, M.F. ( 1 ) 323, 324 Meier, C. ( 5 ) 199 Meijboom, N. (1) 88 Meijers, W.H. ( 8 ) 85 Meijs, G.F. ( 1 ) 48; ( 3 ) 25 Meine, G. ( 1 ) 235, 240 Meinigke, B. (1) 364 Meisel, M. ( 5 ) 28, 7 3 Mel'nichenko, I . V . ( 5 ) 62 Mel'nik, Ya.1. ( 5 ) 29 Mel'nikov, N.N. ( 5 ) 21, 30, 42, 136 Menkhoff, S. ( 6 ) 211 Mercier, F. ( 1 ) 284 Merkler, D.J. ( 6 ) 13 Merrett, J . H . ( 5 ) 134 Metelev, V.G. ( 6 ) 254, 343 Metz, M.H. ( 6 ) 423 Meyer, H. ( 1 ) 77 Meyer, M. ( 8 ) 134 Meyer, S. (1) 30 Meyer, U. (1) 233; ( 4 ) 87 Meyers, W.H. (8) 8 6 Meyring, W. ( 1 ) 252, 253 Mezzina, E. (1) 94; ( 4 )
3663
49 Mhala, M.M. (5) 61 Michaelides, M.R. (7) 19 Michalski, J. (4) 61; (5) 3, 4, 26; (6) 34, 41 Midura, W. (7) 70 Mielewczyk, S. (6) 33 Miftakhov, M.N. (5) 84 Mikhailopulo, I . A . (6) 240 Mikhailov, G.Yu. (4) 32 Mikhailov, S.N. (6) 45 Mikhalin, N.V. (5) 153 Mikityuk, A . D . (5) i30, 164 Miklos, P. (3) 12, 13 Mikolajczyk, M. (1) 300; (7) 70 Milbrath, D.S. (2) 7 Milburn, R.M. (6) 77 Milczarek, R . (1) 318, 321 Miles, H.T. (6) 266 Miller, A . (7) 70 Miller, J.A. (3) 1 Miller, J.M. (6) 416 Miller, M.J. (1) 121 Miller, P.S. (6) 238 Miller, S.L. (6) 3 Miller, T . A . (3) 32 Milligan, J . F . (6) 274 Min, S. (5) 32 Minami, H. (7) 93 Minami, T. (1) 107 Minassian, S. (6) 117 Minasyan, G.G. (1) 106 Minchenkova, L.E. (6) 194 Mindlin, Ya.1. (8) 69 Minowa, N. (5) 132 Minto, F. (8) 162, 163 Mironov, B.S. (1) 135 Mironov, V . F . (2) 31 Mironova, A . A . (8) 24 Misra, R. (5) 68, 77 Mitchell, S.W. (6) 258 Mitchell, T.N. (1) 79 Mitsunobu, 0. (6) 31 Mitsuya, H. (6) 235 Miura, K . (6) 145, 174, 199 Miura, M. (8) 118 Miyachi, Y. (7) 73 Mizuno, Y. (6) 195 Mkrtchyan, G.A. (1) 213 Mlotowska, B . (4) 24 Modro, T . A . (5) 35, 63 Mogelin, W. (5) 129 Moehringer, C. (6) 467 Moller, M. (1) 255 Moesch, C. (1) 220 Mokeeva, V . A . (2) 13; (8) 8
Orgunophosphorus Chemistry Moks, T. (6) 315 Molko, D. (6) 192 Moll, M. (8) 48 Moll, R. (5) 66 Mondeshka, D.M. ( 5 ) 159 Monin, E . A . (1) 173 Montenay-Garestier, T. (6) 219 Montesano, R. (6) 392 Monti, D . (7) 112 Moon, M.-Y. (6) 78 Moore, M.A. (6) 365 Moralev, S.N. (5) 25 Morand, P. (7) 132 Morgan, A.R. (6) 345 Mori, A.L. (8) 41 Mori, K . (3) 19; ( 5 ) 167 Mori, Y. (8) 191 Morimoto, T. (1) 43; (8) 197 Morioka, H. (6) 331 Morris, J. (7) 90 Mortreux, A . ( 1 ) 169; (4) 1, 71 Morvan, F. (6) 217, 222, 228, 229 Moseichuk, M.G. ( I ) 193 Moser, H.E. ( 6 ) 357 Moshnikov, S . A . (2) 26 Moskva, V . V . (2) 5; (4) 5, 50; (5) 112, 158 Moss, G.P. (7) 76, 77 Moss, I . (1) 22 Motherwell, W.B. (7) 60 Motoyoshiya, J . (5) 157 Motsarev, G.V. (1) 160 Mougel, M. (6) 423 Mugge, C. (1) 99 Muller, G. (1) 14, 15, 68-72, 86 Miill-er,U. (8) 39, 40 Mueller, W.B. (8) 193 Munster, H. (1) 364 Mukai, K. (4) 19 Mukhametov, F.S. (4) 34 Mukrnenev, E.T. (8) 29 Mulder, N.H. (8) 85, 86 Muller, G. (7) 5, 12, 30-32 Mullis, K.R. ( 6 ) 255 Munoz, A . (2) 34-36 Murakami, A . ( 6 ) 238 Murata, H . (6) 456 Murphy, E . (6) 442 Murphy, P.J. ( 7 ) 36, 42 Murray, A . W . (3) I., 26 Murray, B . D . (1) 228 Murray, R.E. (I) 5 Murugesan, N. ( 6 ) 364 MUSSO, G.F. (6) 286 Mustdev, A . A . ( 6 ) 301, 302
Myer, L. (5) 192; (7) 68 Mynott, R. (1) 318 Nagamatsu, T. (5) 80 Nagao, Y. (1) 185 Nagaraajan, M. (7) 64 Nagata, R. (7) 89 Nagel, U. (1) 26 Nakagawa, M. (7) 126 Nakagawa, N. (5) 113; (7) 63 Nakahira, H. (5) 14 Nakajima, H. (6) 122 Nakajima, T. (4) 3 Nakamura, A . (8) 41 Nakamura, H. (8) 94 Nakanaga, T. (8) 197, 198 Nakano, M. (8) 94 Nakayama, H. (8) 204 Nakayama, K . (7) 126 Nakayama, M. ( 1 ) 197 Nanishi, K . (8) 204 Narayan, K . (7) 102 Narui, S. (6) 32 Narula, C.K. (1) 291 Naser, L . J . (6) 418 Nasielski, J. (6) 427 Nasri, M. (6) 340 Nataniel, T. (5) 147 Natchev, I . A . (4) 8 Navech, J. (1) 134; (2) 28 Neckers, L. (6) 71 Neenan, T.S. (8) 161, 181 Nefedov, V . D . (1) 188 Neganova, E.G. (1) 264 Negrebetskii, V . V . ( 5 ) 31, 136 Neilson, R.H. (1) 259, 275, 279; (8) 1 , 142 Nelson, .J.H. (1) 357 Nelson, K . A . ( 6 ) 69 Nelson, T..J. (6) 294 Nesterova, S.V. (1) 13 Neuheiser, F. (6) 129 Neumann, * J . M , ( 6 ) 451 Neurnuller, B. ( 1 ) 380 Neuner, P. ( 6 ) 28 Ng, K.S. (2) 6 Ng, P. (6) 239 N'Gando M'Pondo, T. (1) 367; (4) 78 Nguyen, M.T. (8) 5 Niangoran, C.E. (1) 183 Nibert, R . K . (8) 117 Nicholson, A.W. (6) 349 Niclas, H.4. (5) 123 Niebling, K . R . (6) 349 Niecke, E. (1) 18, 226, 299, 350; (4) 69, 79; ( 8 ) 21, 22
367 N i e d e r h o f e r , L . J . ( 6 ) 210 Yiederprum, N. ( 1 ) 240 N i e f , F. ( 1 ) 3 5 4 , 355 N i e g e r , M. ( 1 ) 226, 282, 286, 299 Y i e l s e n , J. ( 4 ) 6 8 ; ( 6 ) 44 Y i e l s e n , P.E. ( 6 ) 470 Niemann, R . (1) 280 N i e n t i e d t , J . ( 1 ) 251, 2 54 N i e w i a r o w s k i , W. ( 4 ) 67 N i f a n t ' e v , E.E. { 4 ) 3 6 , 54; ( 5 ) 22, 148 N i i t s u , T. (1) 258, 267, 268 Nikam, A . R . ( 5 ) 61 N i k i t i n , E.V. (1) 1 3 5 ; ( 5 ) 92 Nikonov, G . N . (1) 1 4 1 , 142 Vishjkawa, A . ( 8 ) 1 1 9 , 199 Vishikawa, S. ( 6 ) 1 8 2 , 331 Nishikawa, T. ( 8 ) 1 1 3 Nishimura, Y. ( 1 ) 1 3 3 N i s h i z a w a , M. ( 6 ) 9 4 N i t t a , M. ( 8 ) 1 5 N i w a , H. ( 7 ) 7 3 Nixon, J.F. (1) 268, 323, 3 2 4 , 3 6 1 , 363 Niyazymbetov, M.E. ( 7 ) 50 Nizamov, I . S . ( 5 ) 1 4 1 No, B.T. ( 1 ) 1 5 3 Nobel, D. ( 1 ) 21 Noth, H. (1) 291; ( 8 ) 205 N o l t e , R . ( 7 ) 44 Nomoto, 11. ( 5 ) 114 Norman, N.C. ( 1 ) 334 Norman, R.E. ( I ) 130 North, G. ( 6 ) 2 N o t t e r , R.H. ( 5 ) 8 9 Novikov, V.P. ( 5 ) 20 Novikova, Z.S. ( 1 ) 1 7 3 ; ( 5 ) 120 Nowell, I . W . (1) 187 Nozawa, Y. ( 7 ) 133 Nuber, B. (1) 3 2 2 , 375, 376 Nunn, C.M. (1) 6 5 , 316, 3 2 8 , 330, 3 3 1 , 349 N u s s t e i n , P. ( 7 ) 7 Nyilas, A. (6) 176, 177 Nyren, P. ( 6 ) 264 O a k l e y , R.T. (8) 127 Obukhova, L.V. (6) 149 Obushak, N . D . (5) 29 O c h i a i , M. (1) 185 O'Connor, B. ( 7 ) 118
O'Connor, T.R. ( 6 ) 354 Oda, D. ( 7 ) 21 Oda, Y . (6) 446 O ' D a y , C.L. ( 6 ) 3 5 O d i n e t s , I . L . ( 5 ) 120 O h l e r , E. ( 5 ) 1 1 5 , 197 O e s t e r h e l t , D. ( 7 ) 8 2 O t v o s , L. ( 6 ) 265, 472 Offermann, W. ( 6 ) 72 O f i t s e r o v , E.N. ( 2 ) 31 Ogabawara, T. ( 5 ) 8 Oganesyan, A . S . (1) 218 O g a t a , N . ( 1 ) 114 O g i l v i e , A. ( 6 ) 121 O g i l v i e , K.K. (6) 1 3 2 , 158 Oh, D.Y. ( 4 ) 7; ( 5 ) 1 3 9 , 140 O h a r a , K. (8) 170 O h a s h i , K . ( 7 ) 104 O h a s h i , M. (8) 101 Ohki, A . (1) 180 O h k i , K . (8) 118 O h l e r , E. ( 7 ) 2 9 , 62 Ohmori, H. (1) 1 0 4 , 195 Ohno, K . ( 1 ) 250 Ohno, M . ( 6 ) 105 O h r u i , H . (1) 126 Ohsaka, F. ( 6 ) 106 O h t a , H . (7) 4 5 O h t a , K . ( 3 ) 27; ( 7 ) 28 O h t s u k a , E. ( 6 ) 1 7 9 , 1 8 2 , 1 9 9 , 206, 331, 446 O h u i g i n , C. ( 6 ) 427 O j i m a , J . ( 7 ) 133 Okamoto, 0. ( 7 ) 7 3 Okano, T. ( 1 ) 8 4 Okawa, K. (8) 176 Okruszek, A. (4) 67 Okuma, K . ( 7 ) 4 5 Okumoto, H. ( 7 ) 9 5 O l d e S c h e p e r , B.C.C.M. ( 2 ) 12 O l m s t e a d , M.M. (1) 228, 2 29 Olornucki, M. ( 6 ) 390 Olsson, A . ( 6 ) 315 Omelanczuk, J. (1) 300 Ona, A . ( 6 ) 196 Onan, K . ( 6 ) 436 O n o r i , G . ( 6 ) 412 Onozato, K . (8) 186 Onys'ko, P.P. (1) 1 9 4 ; ( 4 ) 4 ; ( 5 ) 102 O p e l l a , S . J . ( 6 ) 464 Oppenheimer, N . J . ( 6 ) 113, 366 O r , Y.S. ( 7 ) 83 O r d a , V.V. ( 8 ) 24 O r e n b e r g , J. (6) 58 O r e n d t , A . (1) 221 O r e t s k a y a , T.S. ( 6 ) 1 4 8 ,
251, 254, 343 O r g e l , L.E. ( 6 ) 3, 249, 250, 383 Oro, L . A . (8) 5 4 Orpen, A.G. ( 1 ) 334 Oser, A . ( 6 ) 401 Osowska-Pacewicka, K . ( 5 ) 38 O t t , J. ( 6 ) 211, 346, 375 O t t o , C. ( 6 ) 465 O U , C.-Y. ( 6 ) 258 O u t r e d , D . J . ( 7 ) 108 O u z o u n i s , D. (1) 364 Ovakimyan, M.Zh. (1) 105, 106 Ovchinnikov, V.V. ( 4 ) 13 Ovsepyan, S . A . (5) 9 4 Owens, G.F. ( 6 ) 248 O y , D.Y. ( 4 ) 1 4 O z a k i , H. ( 6 ) 434 O z a k i , K. ( 5 ) 23; ( 6 ) 4 3 O z a k i , S. (5) 8, 1 4 P a c e s , V. ( 6 ) 184 Padyukova, N.Sh. ( 6 ) 4 5 P a e t z o l d , P. ( 1 ) 1 6 5 , 299 P a i n e , R.T. (1) 291, 337 P a k u l s k i , M. (1) 221, 328, 330, 334 P a l a c i o s , F. ( 1 ) 379; ( 7 ) 2 , 10, 4 8 ; ( 8 ) 5 4 P a l i s s a , M. ( 6 ) 111 Palma, G . ( 8 ) 1 6 3 Pandey, R . V . (8) 108 P a n d i t , M.W. ( 6 ) 344 P a n d i t , S. ( 5 ) 6 0 Panosyan, G . A . ( 1 ) 106 P a o l e t t i , C. ( 6 ) 222, 229 P a o l e t t i , J. ( 6 ) 222, 4 0 3 P a r a k i n , O.V. (1) 1 3 5 ; ( 5 ) 92 P a r k e r , J.A. (8) 103 P a r k e s , H.G. (8) 6 6 , 8 7 Parkhomenko, V.S. (5) 188; ( 8 ) 11 P a r k s , R.E., j u n . ( 6 ) 130 P a r k s , T. ( 8 ) 124 P a r t r i d g e , J.J. ( 3 ) 2 8 P a r t r i d g e , L.Z. ( 5 ) 21 P a r v e z , M. (8) 106 P a s a u , P. ( 7 ) 1 2 0 P a s h k e v i c h , K . I . (5) 186 P a s t o r , S.D. ( 2 ) 10, 1 1 ; ( 4 ) 51 P a t e l , D.J. ( 6 ) 448 P a t e r s o n , I. ( 7 ) 9 8 P a t e r s o n , M.C. ( 6 ) 398 P a t i n , H. (1) 136 P a t t e n d e n , G. ( 7 ) 81 P a t t - S i e b e l , U. (8) 3 9 , 40
Orgun oph osp h orus Chernistry
368 P a u l y , G.T. ( 6 ) 268, 269 P a u t a r d , A.M. (1) 122 Pavlenko, N.V. ( 2 ) 1 7 ; ( 8 ) 24 Pavlov, V.A. ( I ) 42; ( 5 ) 106, 170 P a y n t e r , 0.1. (7) 121 P e a r c e , B.C. ( 7 ) 74 Pechkovskii, V.V. ( 8 ) 115 P e d r i n i , P. ( 7 ) 20 Peek, R . J . ( 7 ) 125 Pegg, A.E. ( 6 ) 392 P e i f f e r , G. ( 1 ) 169; ( 4 ) 1, 70, 71 P e l c z e r , I. ( 6 ) 67 P e l l e r i n , B. ( 1 ) 247 Penninger, J. ( 7 ) 131 Penso, M. ( 1 ) 204 Penton, H.R. ( 8 ) 145, 201 PerGe, T.D. ( 6 ) 247 P e r e k a l i n , V.V. ( 5 ) 171 P e r e s y p k i n a , L.P. ( 5 ) 188; ( 8 ) 11 P e r i c h , J.W. ( 4 ) 29 P e r k i n s , C.W. ( 2 ) 3 Perlikowska, W. (1) 300 P e r l y , B. ( 8 ) 70-74, 81 Pernemalm, P.-A. ( 6 ) 432 P e r r i , E. ( 6 ) 171 P e r r i e r , R. ( 1 ) 371 P e r r o t t i , S . J . ( 8 ) 182 P e r r o u a u l t , L. ( 6 ) 221, 227, 355 P e t e , B. ( 1 ) 248; ( 3 ) 10; ( 5 ) 72 P e t e r s , G.E. ( 8 ) 116 P e t e r s , J . ( 5 ) 126 P e t e r s , W. ( 1 ) 207 P e t e r s o n , L.A. ( 6 ) 395 P e t i t , F. ( 1 ) 169; ( 4 ) 1 , 71 PetnehAzy, I. ( 3 ) 1 2 , 1 3 ; ( 4 ) 1 6 ; ( 5 ) 78 P e t r a g n a n i , N . ( 7 ) 129 P e t r a u s k i e n e , L. ( 6 ) 194, 339 P e t r o s y a n , V.A. ( 7 ) 50 P e t r o v , A . A . ( 5 ) 105 P e t r o v , K.A. (1) 159; ( 5 ) 166 P e t r o v s k i i , P.V. ( 8 ) 69, 151
P e t t i g r e w , F.A. ( 8 ) 9 6 , 188, 201 P e y r o n e l , J.F. ( 5 ) 41 P f i s t e r - G u i l l o u z o , G. ( 1 ) 92 P f l e i d e r e r , W. ( 6 ) 1 2 , 240, 242, 244, 246 P i c c i a l l i , G. ( 6 ) 147, 154, 186 P i e l , N. ( 6 ) 208, 338
P i e t r u s i e w i c z , K.M. ( 3 ) 29-31 P i l a t u s , U. ( 6 ) 72 Pinchuk, A.M. ( 5 ) 95; ( 8 ) 30, 35-37 P i n t o , A.L. ( 6 ) 418 P i p e r , U. ( 1 ) 71 Pirozhenko, V.V. (5) 102 P l a t e , N.A. ( 8 ) 174 P l a t e a u , P. ( 6 ) 123, 124 P l e n a t , F. ( 1 ) 209; ( 7 ) 16 P l e s s , R.C. ( 6 ) 319, 320 P l y s h e v s k i i , S.V. ( 8 ) 115 Pochet, S. ( 6 ) 152, 289 Podhajska, A . J . ( 6 ) 337 Podlaha, J. ( 1 ) 20 Podlahova, J. ( 1 ) 20 Podust, L.M. ( 6 ) 406 Podyminogin, M.A. ( 6 ) 405 Poe, M. (6) 8 5 Pohl, S. ( 1 ) 107, 164, 205, 315; ( 2 ) 14; ( 4 ) 53 P o i e s z , B . J . ( 6 ) 258 P o i n d e x t e r , M.K. ( 5 ) 100 P o i s s o n , P. ( 8 ) 56 Pokatun, V.P. ( 1 ) 159; ( 5 ) 166 Polenov, V . A . ( 5 ) 117 P o l l o k , T. ( 1 ) 1 4 , 15; (7) 5, 6 P o l v a n i , C. ( 6 ) 17 Polyachenko, L.K. ( 1 ) 260 Pomerantz, M. (1) 119; ( 8 ) 6 , 23 Pon, R.T. ( 6 ) 132, 135, 159, 433 Pondaven-Raphalen, A . ( 5 ) 168 Ponomarchuk, M.P. ( 1 ) 338 Popkova, T.N. ( 5 ) 148 Popov, A.G. ( 1 ) 162; ( 4 ) 33; ( 5 ) 83, 156 Popov, S.G. ( 6 ) 142 Popov, V . I . ( 8 ) 24 P o r t , H. ( 7 ) 79 P o s s , A . J . ( 5 ) 195, 196; ( 7 ) 65 Postmus, P.E. ( 8 ) 8 5 , 8 6 Potapov, V.K. ( 6 ) 148, I65 P o t e k h i n , K.A. (1) 182 P o t i n , P. ( 8 ) 56 Potrvebowski, M. ( 5 ) 33 P o t t e r , B.V.L. ( 5 ) 10, 11, 16 P o t t e r , P.M. ( 6 ) 392 P o t t s , M.K. ( 8 ) 147 Pougny, J . R . ( 7 ) 100 P o v o l o t s k i i , M . I . (1) 294; ( 4 ) 8 0 , 83; ( 8 ) 19
Powell, C. ( 6 ) 232 Powell, J. ( 2 ) 6 Power, J . M . ( 1 ) 6 5 , 316 Power, P.P. (1) 37, 228, 229 Powietzka, B. ( 1 ) 322 Prabha, S. ( 5 ) 60 P r a c e j u s , H. (1) 170 P r a g e r . R.H. ( 5 ) 143 Pramanik, P. ( 6 ) 452 P r a s e u t h , D. ( 6 ) 221, 223, 227 P r a t i , L. ( 1 ) 171 P r e d v o d i t e l e v , D.A. ( 5 ) 22 P r e s c o t t , B. ( 6 ) 464 P r e s c o t t , M. ( 6 ) 128 P r e s t o n , B.D. ( 6 ) 271 P r i e t o , C.A. ( 1 ) 259 P r i g o z h i n a , M.P. ( 8 ) 9 8 , 99 P r i o u x , 0 . ( 1 ) 220 Prishchenko, A . A . ( 1 ) 1-3, 95; ( 2 ) 26; ( 4 ) 6 , 21 Pritzkow, H. ( 1 ) 35, 36 P r o b e r , J . M . ( 6 ) 311 P r o k o f ' e v , M.A. ( 6 ) 253 P r o s k u r n i n a , M.V. ( 4 ) 48 Provotorova, N.P. ( 8 ) 151, 153 Prudnikova, O.G. ( 1 ) 157; ( 5 ) 105 Puddephatt, R..T. ( 1 ) 145, 147; ( 4 ) 38 Pudovik, A.N. ( 1 ) 127, 129, 190; ( 2 ) 31; ( 4 ) 9 , 26, 45; ( 5 ) 36, 49-51, 8 2 , 141, 179 Pudovik, M.A. ( 4 ) 9 , 45 P u g l i s i , J . D . ( 6 ) 180, 387, 459 Punzalan, R . R . ( 6 ) 319 Purandare, A.V. ( 7 ) 127 Purmal, A . A . ( 6 ) 254 Purygin, P.P. ( 6 ) 116 Pushin, A . N . (1) 157 Q i , Y. ( 4 ) 1 8 ; ( 5 ) 125 Qiu, W. ( 7 ) 39 Quashie, S. (1) 328
Quin, L.D. ( 1 ) 248, 345, 359; ( 3 ) 9 , 10, 12; ( 5 ) 71, 72 Quinnan, G.V. ( 6 ) 237 Quintus, P. ( 8 ) 5 0 , 51 Q u r e s h i , S.S. ( 7 ) 111 Raab, M.N. ( 2 ) 9 Raabe, E. ( 1 ) 318
Author Index Rabanal, R.M. ( 7 ) 115 Rabin, B.A. ( 6 ) 281 R a b o v s k i i , G.V. ( 5 ) 8 5 Raby, C. ( 1 ) 220 Rack, M. ( 6 ) 61 Radchenko, L.G. (8) 177 Raevski, O.A. ( 5 ) 20 Rahmouni, A. ( 6 ) 420 RajBhandary, U.L. ( 6 ) 382 Rajca, A. ( 3 ) 14; ( 7 ) 1 Rajeshwar, K. ( 8 ) 6 Rakhmankulov, D.L. ( 4 ) 4 8 Ramakanth, S. ( 7 ) 26 Ranaivonjatovo, H. ( 1 ) 223, 224, 288; ( 4 ) 85, 86 Ransom, S.C. ( 6 ) 189, 350 Rao, A.V.R. ( 7 ) 127 Rao, J . M . ( 7 ) 47 Rao, R. ( 6 ) 307 Rao, T.S. ( 6 ) 160 Rao, Y.K. ( 7 ) 64 Raphael, A.L. ( 6 ) 425 Rasadkina, E.N. (5) 22 Rashid, A. ( 7 ) 58 Raskina, A . D . ( 1 ) 160 R a t h j e n , P.D. ( 6 ) 332 R a t n e r , V.G. ( 5 ) 186 Rauchberger, W. ( 8 ) 121 Raushel, F.M. ( 6 ) 81, 8 2 Rawson, D . J . ( 7 ) 9 8 R a y , D.G. ( 5 ) 17 Rayner, B. ( 6 ) 217, 222, 228, 229, 353, 403 Reber, G . ( 1 ) 1 4 , 1 5 , 8 6 ; ( 7 ) 5 , 30 Rechavi, G . ( 6 ) 341 Rechka, J . A . ( 7 ) 124 Reddy, A.P. ( 1 ) 47 Reddy, E.R. ( 7 ) 127 Redmore, D. ( 5 ) 7 , 160 Redweik, [J. ( 6 ) 129 Reese, C.B. ( 5 ) 1 2 ; ( 6 ) 160 Reese, P.B. (1) 112 Reetz, M.T. ( 5 ) 103 Regan, J . B . ( 6 ) 232 Regberg, T. ( 6 ) 140 R e g i t z , M. (1) 283, 304, 307-314, 317-319, 321, 358, 362, 366, 373; ( 4 ) 77 R e g n i e r , F.E. ( 6 ) 153 Rehman, H. ( 7 ) 47 Rehwinkel, H. ( 7 ) 67 Reichenbach, N.L. ( 6 ) 244 R e i c h e r t , H.K. ( 1 ) 156 Reid, R. ( 6 ) 120 Reier, F.W. (1) 9 R e i k h s f e l ' d , V.O. (1) 13 R e i l l y , R.M. ( 6 ) 382 R e i l y , M.D. ( 6 ) 440
369 R e i n b o l t , J. ( 6 ) 423 ( 1 ) 266, R e i s a c h e r , H.-U. 267, 269, 270, 337 R e i t i n g e r , S. ( 1 ) 271 R e i t z , A.B. ( 7 ) 113 R e i t z , M. ( 6 ) 235 R e i z i g , K. (1) 238 Remaud, G . ( 6 ) 176, 177 Renk, G.E. ( 7 ) 83 Reuben, J. ( 8 ) 68 R e v e l ' s k i i , I . A . ( 4 ) 10 R i b e i l l , Y. ( 7 ) 16 R i c a r d , L. ( 1 ) 351, 354 Rich, A. ( 6 ) 291 R i c h a r d s , R.L. ( 1 ) 19 Richardson, C.C. ( 6 ) 321 Richardson, J.F. (8) 125 Richardson, K.A. ( 7 ) 103 Richman, D.D. ( 6 ) 19 R i c h t e r , H. (1) 307 R i c h t e r , H.-J. (5) 123 R i c h t e r i n g , V. ( 1 ) 24 Rickenberg, H.V. ( 6 ) 241 R i d e r , P. ( 6 ) 27, 28 Riding, G.H. ( 8 ) 63 Ridoux, J.-P. ( 6 ) 460, 461 Riede, J. ( 1 ) 70 R i e d e l , R . (1) 155, 227 R i e g e r , B. (1) 26 R i e s s , J . G . ( 2 ) 37 R i e t z e l , M. ( 8 ) 137 R i f f e l , H. (1) 380 R i h t e r , B. ( 7 ) 46 R i l l , R.L. ( 6 ) 455 R i n g e l , I. ( 6 ) 134 R i n g q u i s t , S. ( 6 ) 388 R i p o l l , J.-L. ( 1 ) 91, 92 R i s n e r , D. ( 6 ) 430 R i s t , G. ( 1 ) 179; ( 3 ) 22; ( 7 ) 61 Riva, M. ( 6 ) 302 R o b e r t , A. ( 7 ) 107 R o b e r t , F. (1) 354 R o b e r t s , K.A. ( 5 ) 59 R o b e r t s , P.M. (8) 180 Robertson, C.W. ( 6 ) 311 Robertson, H.D. ( 6 ) 349 Robins, R . K . ( 6 ) 71, 9 2 , 93 Robinson, B.H. ( 6 ) 30 Robinson, J.E. ( 7 ) 125 Robson, D.C. ( 7 ) 81 Rocker, M. ( 5 ) 175 Rockwell, C.J.M. ( 7 ) 108 Rode, W. ( 6 ) 15 Rodehuser, L. (8) 34 Rodionova, N.P. ( 6 ) 343 Roelen, H.C.P.F. ( 6 ) 191 Rosch, W. (1) 307, 309, 311-313, 317, 362; ( 4 ) 77
R o s c h e n t h a l e r , G.-V. (1) 78; ( 2 ) 25, 29, 30, 32; ( 4 ) 22, 28 Roesky, H.W. (8) 4 4 , 133, 136-139 Roig, V. ( 6 ) 218, 220 Rokach, J. ( 7 ) 8 6 R o l l i n , P. ( 7 ) 100 R o l l o , F. ( 6 ) 257 Romakhin, A.S. (1) 135; ( 5 ) 92 Romanenko, V.D. ( 1 ) 245, 246, 260, 292-298, 300, 341: ( 4 ) 2 , 31, 79, 8 0 , 8 3 , 8 4 ; (5) 187; (8) 3, 4 , 1 9 , 20, 53 Romanov, G.V. (1) 190 Romanova, E.A. ( 6 ) 343 Romby, P. ( 6 ) 423 Roques, P. ( 6 ) 390 Rosche, J . ( 5 ) 104 R o s c h e n t h a l e r , G.-V. (1) 150 Rosenau, B. ( 5 ) 193 Rosenberg, I. ( 6 ) 46, 48-50, 94 R o s e n t h a l , A . ( 6 ) 204, 312, 316 R o s e n t h a l , H.A. ( 6 ) 119 Ross, R.A. ( 1 ) 33 Roth, S. ( 8 ) 41 Roth, W . K . ( 6 ) 401 Rotherrnel, J . D . ( 6 ) 66 Rougeon, F. ( 6 ) 285 R o u l l e t , F. ( 6 ) 267 ROUS, A . J . ( 5 ) 56 Roush, W.R. ( 7 ) 19 R o u s s i s , V. ( 7 ) 66 ROUX,D. ( 6 ) 241 Rouzaud, D. ( 6 ) 219 Roy, A . K . (8) 142 Roy, S. ( 6 ) 447 Rozengart, V . I . ( 5 ) 25 Rozinov, V.G. ( 5 ) 85-87; (8) 132 Rozovskaya, T.A. ( 6 ) 118 Rub, H.L. ( 1 ) 113 Ruban, A.V. (1) 260, 292-298, 300, 341; ( 4 ) 2 , 31, 79, 8 3 ; ( 5 ) 187; ( 8 ) 3 , 4 , 20 R u b i n i , P. (8) 34 Rudnitskaya, L.S. ( 1 ) 166 Rudomino, M.V. ( 1 ) 97 R i i s s l e r , W. (1) 321 R u t e r j a n s , H. (6) 190 Ruggeri, R . ( 2 ) 22 Running, J . A . ( 6 ) 203 Rutledge, M.C. ( 5 ) 198 R u t t , J.S. (8) 105 Ryabushenko, I.L. ( 6 ) 343 Rycyna, R.E. ( 6 ) 37, 38
3rganoph osph oru.5 Ch emisrry
370
R y d e l , R.E.
(6) 70
S a a k , W. (1) 107, 205, 315; ( 2 ) 1 4 S a b b a t i n i , G.P. ( 6 ) 8 4 Sadaghianizadeh, K. (8) 154 S a d l e r , P . J . ( 1 ) 130 Sadykov, I.S. ( 5 ) 1 5 8 Saenger, W. (6) 64 S a e v a , F.D. (1) 215 S a g a r , V . R . (8) 189 S a g e n , B.L. ( 6 ) 5 6 S a g i , J . ( 6 ) 265, 472 S a h a , M. ( 6 ) 436 S a i k i , N. ( 8 ) 176 S a i k i , R.K. ( 6 ) 255, 260 Saison-Behmoaras, T. ( 6 ) 355 S a i t o , A . (8) 118 S a i t o , H. ( 5 ) 124 S a i t o , K. ( 7 ) 97 S a i z , E . ( 8 ) 164 S a k a i , H. (1) 114 S a k a i , M. (8) 191 Sakamoto, H. ( 6 ) 105 Sakamoto, Y. ( 7 ) 104 S a k a t a , J.-I. ( 7 ) 4 5 S a k a t a , T. ( 6 ) 155 S a k u r a d a , T. ( 6 ) 106 Salama, M . A . ( 5 ) 182 S a l e h z a d a , T. ( 6 ) 247 Salem, G. ( 1 ) 49 S a l g u s a , K. ( 7 ) 21 S a l i s b u r y , S.A. ( 6 ) 1 9 3 Salowe, S.P. ( 6 ) 109 S a l v i , R. ( 6 ) 257 Samejima, M. (8) 113 Samuel, 0. (5) 4 1 Samukov, V.V. (6) 142 S a n c a r , A. (6) 376 S a n c h e z , M. (1) 340; (8) 102 Sanchez-Ferando, F. ( 7 ) 2 , 48 S a n d s t r o m , A . ( 6 ) 177 S a n e y o s h i , PI. ( 6 ) 107 S a n t a c r o c e , C. ( 6 ) 147, 1 5 4 , 186 S a n t e l , H..J. ( 8 ) 55S a n t e l l i , M. (1) 191 S a n t i a g o , A.N. (1) 33 S a n t o , K. ( 5 ) 81 S a n t o s , J . G . ( 1 ) 102 S a n u i , K . (1) 114 S a r a c e n o , R.A. (8) 6 3 S a r i s , C.P. ( 6 ) 191, 243 S a r r o f f , A. (1) 2 5 S a s a k u r a , T. (8) 109-112 S a s n a u s k i e n e , S. ( 6 ) 91 S a t a k e , H. (8) 1 6 7 , 1 7 5
S a t g e , J . (1) 223, 224, 288, 289; ( 4 ) 8 5 , 8 6 S a t o , N.L. ( 6 ) 279 S a t r e , M. ( 6 ) 127 S a u n d e r s , J . ( 7 ) 103 S a v a n t , N . K . (8) 116 S a v i g n a c , P. ( 4 ) 1 5 ; ( 5 ) 116 S a v o i e , R . ( 6 ) 414 Sawai, H. ( 6 ) 216 Sawamura, M. (1) 100 Sawyer, J . F . ( 2 ) 6 Sayadyan, S.V. ( 1 ) 50 S a y e r s , J . R . ( 6 ) 347, 348 S c a l f i - H a p p , C. ( 6 ) 214 Scamrov, A.V. ( 6 ) 262 S c h a f e r , A. ( 1 ) 315 S c h a e f e r , G . ( 6 ) 299 S c h a f e r , H . ( 1 ) 231, 232 S c h a f n e r , A.R. ( 6 ) 302, 303 S c h a u f e l e , H. (1) 362 S c h a l l n e r , 0. ( 8 ) 5 5 S c h a r f , S . J . ( 6 ) 255 S c h e d i e , G.M. (8) 142 Scherbaum, F. ( 7 ) 31 S c h e r e r , O..J. (1) 242, 243, 3 0 1 , 365; (8) 50-52 Schick, H. ( 7 ) 55 S c h i l l i n g , M.B. ( 5 ) 5 6 Schimmel, P.R. ( 6 ) 407 S c h l e m p e r , H. ( 8 ) 31 Schlessinger, R.H. (7) 117 S c h l i n g e n s i e p e n , K.-H. ( 6 ) 275 S c h l i t t e , S. ( 1 ) 5 2 S c h l o s s e r , H. ( 7 ) 79 Schmidbaur, H. (1) 1 5 , 1 4 , 86; ( 7 ) 5-7, 30-34 S c h m i d p e t e r , A . (1) 34 S c h m i d t , B. (1) 9 9 S c h m i d t , E. (8) 195, 196 Schmidt, G . ( 6 ) 143 S c h m i d t , H. (1) 4 5 , 4 6 , 281, 322 Schmidt, H.G. ( 8 ) 136 S c h m i d t , I. (8) 3 9 S c h m i d t , J. ( 6 ) 190 S c h m i d t , R . (1) 1 6 S c h m i d t , R.R. ( 8 ) 5 5 S c h m i d t , T. ( 6 ) 190 Schmidt, W. (6) 3 4 7 , 348 S c h m i e d l , G. ( 7 ) 6 7 ( 6 ) 308 S c h m i t t e r , J.-M. S c h m u t z l e r . R. (1) 93, 163, 164; ( 2 ) 2 4 , 33; ( 4 ) 4 7 , 5 2 , 5 3 ; (8) 10, 13 S c h n a b e l , W. ( 3 ) 16 S c h n e i d e r , M.P. ( 7 ) 109
S c h n o c k e l , H. ( 1 ) 303; ( 4 ) 74 S c h n u r r , W. ( 1 ) 317 Schobert, R. ( 7 ) 96 Schochetman, G . ( 6 ) 258 S c h o n h o l z e r , P. ( 1 ) 1 6 S c h o l l , R. ( 6 ) 323 S c h o l t i s s e k , S. ( 6 ) 338 S c h o l t z , S.4. ( 7 ) 114 S c h o l z , D. ( 6 ) 119 Schomburg, D. ( 2 ) 30 S c h o r e , N.E. ( 1 ) 80 S c h o t t , H. ( 6 ) 185 Schramm, V.L. ( 6 ) 1 3 S c h r e y e r , P. ( 1 ) 165 S c h r o c d e r , S.A. ( 6 ) 445 S c h r u n n e r , H . ( 6 ) 439 Schuhn, W . (1) 273, 280, 285, 286 S c h u l h o f , \J.C. ( 6 ) 192 S c h u l t e , P. (1) 342 S c h u l t z , P.G. ( 6 ) 1 5 7 , 334-336 S c h u l z , B.S. ( 6 ) 1 2 Schumann, H. (1) 9 ; ( 3 )
36
Schunck, S. (1) 3 0 3 ; ( 4 ) 74 Schwager, C. ( 6 ) 3 1 2 , 322 S c h w a r t z , A.W. ( 6 ) 3 Schwarz, K . H . ( 7 ) 50 Schwarz, S. ( 7 ) 55 Schweginger, R . (8) 31 S c h w e l l n u s , K . ( 6 ) 293 S c h y o l k i n a , A . K . ( 6 ) 194 S c o t t , E.V. ( 6 ) 450 S e e l a , F. ( 6 ) 211, 316 S e g i , M. ( 4 ) 3 S e g u i n e a u , P. ( 7 ) 57 S e k i , H . ( 6 ) 31 S e k i n e , M. ( 5 ) 2 3 ; ( 6 ) 3 2 , 43, 145, 161, 162, 169, 1 7 4 , 1 7 8 S e l d i n , M. (8) 57 S e l i g e r , H. (6) 1 4 3 S e l k e , R. ( 4 ) 7 3 S e l l , M. ( 4 ) 5 2 S e l l m a n n , D. (8) 4 8 S e l v e , C. (8) 3 4 S e m e n i i , V.Ya. ( 2 ) 1 7 Semmler, R . ( 6 ) 185 Semple, G. ( 6 ) 98 S e n i o r , A . E . ( 6 ) 307 S e n n e t t , M.S. (8) 95, 140, 141, 1 4 6 , 147 Sensabaugh, G.F. (6) 261 S e n t e n a c , A . (6) 302 S e o u l , D.H. (5) 1 4 0 S e r a f i n o w s k a , H.T. (6) 160 S e r g i e n k o , L.M. (1) 1 5 4 ; (5) 85
371
Author Index S e s e k e , U. ( 8 ) 136 S e t z e r , W.N. ( 6 ) 69 S e u v r e , A.-M. ( 6 ) 466 S e y f e r t h , D. ( 1 ) 83 Shabana, R . ( 5 ) 183-185 S h a b a r o v a , Z.A. ( 6 ) 3 9 , 251-254, 343 S h a g v a l e e v , T.Sh. ( 4 ) 5 ; ( 5 ) 106 Shakya, R.P. ( 1 ) 4 Shang, J . ( 6 ) 277 Sharma, M. ( 6 ) 38 Sharma, R . ( 7 ) 130 Sharmeen, L. ( 6 ) 276 Shaw, L.S. ( 8 ) 6 5 , 6 6 , 87 Shaw, R . A . ( 5 ) 4 0 ; ( 8 ) 2 , 64-66, 7 9 , 8 7 , 100 Shaw, R . R . ( 8 ) 200 S h c h e p i n a , N.E. ( 1 ) 188 S h c h e p i n a , V.A. ( 1 ) 188 S h e a r d y , R.D. ( 6 ) 449 S h e l d t i c k , G.M. ( 8 ) 136, 138, 139 S h e l d r i c k , W.S. ( 8 ) 5 0 , 51 Shen, Y. ( 7 ) 39 Sherman, S.E. ( 6 ) 417 S h e r m o l o v i c h , Yu.G. ( 2 ) 4 S h e r s t i b o t o v , O.E. ( 5 ) 25 Shevchuk, M . I . (I) 193, 2 14 S h i , L. ( 7 ) 101 S h i h a e v , V . N . ( 6 ) 116 S h i k i t a , S. ( 1 ) 197 S h i l o v a , E.V. ( 5 ) 155 Shimada, H. ( 1 ) 104 Shimano, Y. (1) 84 Shimura, Y. ( 6 ) 105 S h i n d e , C.P. ( 5 ) 61 S h i n o z a k i , K . ( 6 ) 145 S h i n o z u k a , K . ( 6 ) 232, 235-237 S h i o b a r a , Y . ( 7 ) 9 3 , 94 S h i o t a n i , N. ( 5 ) 8 S h i r a k i , C. ( 5 ) 124 S h i r e , D. ( 4 ) 6 3 ; ( 6 ) 170, 469 S h i s h k i n , E.V. (1) 153 S h i s h k i n , G.V. ( 6 ) 404, 40 5 S h i s h k o v , I . M . ( 4 ) 10 S h i u e y , S.-J. ( 3 ) 28 Shomburg, D. ( 8 ) 13 Shono, T. ( 1 ) 132 Shoo, H.F.M. ( 8 ) 131 S h r i m a l , A.K. ( 8 ) 108 S h r i v e r , D . F . ( 8 ) 181 S h u b i n a , T.V. ( 5 ) 128 S h u e l y , W . J . ( 3 ) 20 S h u g a r , D. ( 6 ) 1 4 , 15 S h u l ' z i n , V.F. ( 8 ) 53 Shumeiko, A . E . ( 8 ) 88
S h u t o , S. ( 6 ) 2 1 , 23 Shyy, Y.-J. ( 6 ) 441 S i a b a l i s , N. ( 1 ) 278, 280 S i c h e n e d e r , A. ( 1 ) 28 S i c k i n g e r , A. ( 1 ) 30 S i d d i q u i , M.S. ( 1 ) 137 S i e b e r t , W. ( 1 ) 3 5 , 36 S i e v i , R . ( 1 ) 41 S i g e l , H. ( 6 ) 5 5 , 7 3 , 101 Sigman, D . S . ( 6 ) 360 S i l h o l , M. ( 6 ) 247 S i l ' n i k o v , V.N. ( 6 ) 404, 405 S i l v e i r a , C. ( 7 ) 129 S i l v e s t r u , C. ( 5 ) 146 Simmonds, D . J . ( 7 ) 121 Simmoneau, R . ( 5 ) 131 Simmons, A.M. ( 6 ) 114 Simon, E.S. ( 6 ) 83 Simon, J. ( 1 ) 262 Simon, M . I . ( 6 ) 359 Simon, P. ( 1 ) 98 S i n d o n a , G . ( 6 ) 171 S i n g e r , B. ( 6 ) 271, 392 S i n g e r , R..J. ( 1 ) 1 6 3 ; ( 2 ) 2 4 ; ( 8 ) 10 Singler, R . E . ( 8 ) 89, 140, 141 S i n h a , A.M. ( 6 ) 370 S i n h a , N.D. ( 4 ) 5 7 ; ( 6 ) 156 S i n i s t e r r a , J . V . ( 7 ) 51, 52
S i n i t s a , A.D. ( 1 ) 194; ( 4 ) 4 , 4 6 ; ( 5 ) 102; ( 8 ) 25, 27 S i n o u , D. (1) 8 9 , 90 S i n y a s h i n a , T.N. ( 2 ) 31 S i s k o , J . T . ( 8 ) 9 1 , 181 S i v , C. ( 4 ) 70 S k a l s k i , 8 . ( 6 ) 33 S k i n g l e , D.C. ( 6 ) 384 S k l e n a r , V. ( 6 ) 444, 447 S k o l d , S . E . ( 6 ) 432 SkowroAska, A. ( 5 ) 26 Skupsch, J. ( 7 ) 67 S k v o r t s o v , N.K. ( 1 ) 13 Slama, J . T . ( 6 ) 114 S l a w i n , A.M.Z. ( 5 ) 145 S l e i j f e r , D . T . ( 8 ) 85 S l i z k i i , A.Yu. ( 5 ) 106 S l o a n , T.J. ( 1 ) 145 S l o n i m s k i i , G.L. ( 8 ) 177 S l u k a , J.P. ( 6 ) 359 S m a r t , J. ( 6 ) 184 Smirnov, V.N. ( 5 ) 51 S m i t h , L.M. ( 6 ) 309 S m o l i i , O.B. ( 1 ) 217 S m r t , J. ( 6 ) 204 Smyth, M.S. ( 5 ) 195 S n i n s k y , J.J. ( 6 ) 258 So, S. ( 1 ) 197
S o b o l , R.W., j u n . (6) 244, 246 Soderquist, J.A. ( 7 ) 15, 99 S o 1 1 , D. ( 6 ) 381 SoiEer, G.B. ( 2 ) 13; ( 8 ) 8 S o k o l o v , M.P. ( 5 ) 170 S o k o l o v , V.B. ( 5 ) 1 8 , 1 9 , 149- 151 S o k o l o v a , N.I. ( 6 ) 3 9 , 251, 252 S o l o d e n k o , V.A. ( 5 ) 161 S o l o m a t i n a , A.I. ( 8 ) 9 9 , 152 S o m e r v i l l e , C. ( 6 ) 323 Sommer, S.S. ( 6 ) 429 SOO, H.-K. ( 6 ) 374 S o t i r o p o u l o s , J.-M. (7) 9 S o u l i 6 , J.-M. ( 6 ) 87 S o u r n i e s , F. ( 8 ) 72 Sowers, L.C. ( 6 ) 19 S p a l t e n s t e i n , A. ( 6 ) 30 S p e e r , A. ( 6 ) 288 S p e r a n z a , G. ( 7 ) 112 S p i v a c k , J . D . ( 4 ) 51 S p r a g u e , L.G. ( 5 ) 111; ( 7 ) 72 S p r i n g e r , J.P. ( 2 ) 7 S p r o a t , B.S. ( 6 ) 2 7 , 28, 181, 312, 322 Spurden, W.C. ( 5 ) 134 S r d a n o v , G. ( 5 ) 193 S r i v a s t a v a , S.C. ( 8 ) 108 S t a b l e s , C.M. ( 1 ) 206 S t a c k h o u s e , T.M. ( 6 ) 300 S t a f f o r d , J.A. ( 7 ) 27 S t a h l , S . ( 6 ) 315 S t a l l i n g s , W.C. ( 5 ) 190 S t a m b o u l i , A. ( 7 ) 22 S t a n g , P.J. ( 5 ) 59 S t a n g l e , M. ( 3 ) 37 S t a w i n s k i , J. ( 6 ) 140 S t e c , W . J . ( 4 ) 60, 6 7 ; ( 5 ) 55; ( 6 ) 51, 65, 66, 141 Stegemann, J. ( 6 ) 312, 322 S t e g e r , B. ( 1 ) 30 S t e i f a , M. ( 6 ) 64 S t e i n , C.A. ( 6 ) 236 S t e i n , J . M . ( 6 ) 130 S t e i n , S.M. ( 8 ) 77 S t e i n , Z. ( 3 ) 1 9 ; ( 5 ) 167 S t e i n h a u s e r , K.G. ( 6 ) 475 S t e i n h u e b e l , L.P. ( 4 ) 51 S t e l z e r , 0. ( 1 ) 40, 61, 7 6 , 9 3 ; ( 2 ) 3 3 ; ( 4 ) 47 S t e m p i e n , M. ( 6 ) 203 S t e p a n o v a , N.V. ( 1 ) 103 S t e r k , H. ( 6 ) 439 S t e t t e r , J. ( 8 ) 55
Organoph osp h 01-14s Chemistry
372 S t i e b i t z , B. (5) 142 S t o e c k l e r , J.D. (6) 130 S t o f f e l , B. ( 6 ) 255 S t o l a r s k i , R. ( 6 ) 14 S t o l l , K. (1) 55 S t o o d l e y , R . J . ( 7 ) 130 S t o r z e r , W. (1) 163; ( 2 ) 2 4 ; (8) 10 S t r a h l e , J. (8) 4 5 , 4 6 , 47 S t r a n g e , P.G. ( 7 ) 103 Streitwieser, A , , jun. (3) 1 4 ; ( 7 ) 1 S t r e p i k h e e v , Yu.A. (5) I30 S t r o m b e r g , R. (6) 1 4 0 S t r o t h k a m p , K.G. ( 6 ) 421 S t r u c h k o v , Yu.T. (1) 1 7 3 , 182, 298; ( 4 ) 80; (5) 117; (8) 1 2 , 20, 53 S t r u c k , R.F. (5) 5 3 S t r z e l e c k a , T.E. (6) 455 S t u a r t , G.R. ( 6 ) 1 9 7 S t u b b e , J. (6) 108-110, 362, 363 S t u d n e v , Yu.N. (1) 166 S t u r t z , G. (3) 3 4 ; (5) 168 S u b a s i n g h e , C. (6) 236 Suchanova, L.L. (6) 39 Suda, K. (1) 1 9 5 Sudheendra Rao, M.N. (1) 1 2 4 ; (8) 1 2 8 Suga, S. ( 4 ) 3 Suge, H. (5) 113 Sugiyama, H. ( 6 ) 364 S u h a d o l n i k , L. (6) 244 S u h a d o l n i k , R.J. ( 6 ) 2 4 , 2 44- 2 4 6 S u k a l l , S. (5) 1 2 3 Sukhanova, L.L. (6) 165 Sukhorukova, N.A. (5) 174 Sumitomo, H. ( 7 ) 9 4 Sumiyoshi, T. (3) 16 Summers, M.F. ( 6 ) 232 Sun, D.C. (8) 1 6 6 , 168 S u n , G. (5) 93 Sun, H. (1) 222 Sun, J. ( 6 ) 219, 355 Sunitomo, H. ( 7 ) 93 S u t c l i f f e , H. (1) 206 S u t o h , K. (6) 298 S u v a l o v a , E.A. (1) 194; (4) 4 Suvorov, B.A. (1) 160 Suzano, V.A. ( 6 ) 7 4 S u z u k i , F. (8) 186, 194 S u z u k i , T. (1) 126; (8) 120 S v i r i d o v , S.V. (1) 108 Swarowsky, H. (1) 243 Swarowsky, M. (1) 242,
243 Swenberg, J . A . ( 6 ) 392 S y m a l l a , E. (8) 22 Symons, R.H. (6) 332, 384 S y n o r a d z k i , L. (3) 35 Szabo, A.G. ( 7 ) 132 S z a b o l c s , A. (6) 472 Szafraniec, L.J. (4) 44; ( 5 ) 65 S z a j a f i i , B. (5) 7 8 S z a m e i t a t , J . (1) 255, 256 Szemzo, A. ( 6 ) 265, 472 Szewczyk, J. (5) 72 Szmuszkovicz, J. (8) 9 S z y b a l s k i , , W . ( 6 ) 337 T a b o r , S. (6) 321 T a c h i b a n a , Y. ( 7 ) 4 5 Tada, Y. (8) 197, 1 9 8 T a f e s h , A.M. (3) 2 T a f e s s e , F. (6) 77 T a f f e r , I . M . ( 7 ) 88 T a f t , R.W. (3) 20 Tagaya, M. (6) 306 T a g l i a f e r r i , P. (6) 7 1 T a h a r a , S.M. ( 6 ) 1 0 4 , 169 T a i , D.F. (7) 1 9 T a i l l a n d i e r , E. (6) 460, 461 T a i r a , H. (6) 216 T a i r a , K. (6) 330 T a j m i r - R i a h i , H.A. (6) 414 T a k a g i , M. (1) 180; (8) 94 T a k a h a s h i , H. (1) 4 3 T a k a h a s h i , K. (5) 124 Takaku, H. ( 4 ) 62; (6) 25, 26, 6 8 , 160, 167, 172, 1 7 3 Takanami, T. (1) 104, 195 Takashima, M. (8) 1 9 1 T a k a s u g i , J.J. ( 7 ) 2 5 T a k a s u g i , M. (6) 220 Takeda, K. ( 7 ) 9 7 Takeda, T. (6) 195; (8) 118 Takemasa, T. ( 7 ) 95 T a k e s h i t a , M. ( 6 ) 1 9 8 T a k e s h i t a , T. (1) 180 T a k e u c h i , H. (1) 1 2 3 ; ( 6 ) 456; (8) 1 4 T a k e u c h i , T. (6) 434 T a m a t s u k u r i , S. ( 6 ) 1 6 6 , 182 T a m , C. (6) 212 T a m , L.A. (5) 144 Tamura, R. ( 7 ) 21 Tamura, S. (8) 109-111 Tanaka, T. ( 6 ) 1 4 6 , 155,
166, 331 Tancheva, C.N. ( 5 ) 1 5 9 Tang, C. (5) 6 4 T a n i g a k i , T. (8) 9 4 Tanimura, H. (6) 161, 162 Tank, H. (6) 473 T a n n e r , N.K. (6) 379 Taqui Khan, M.M. (1) 47 T a r u s s o v a , N.B. ( 6 ) 126 T a r z i v o l o v a , T.A. (5) 106 Tashman, 2. ( 6 ) 134 T a t e m i t s u , H. ( 7 ) 133 T a t s u m i , K. (8) 4 1 T a y l o r , G.E. (6) 1 2 8 T a y l o r , J. ( 6 ) 276 T a y l o r , J.-S. ( 6 ) 35, 36 T a y l o r , R . J . K . (7) 103 Tchen, P. ( 6 ) 267 Tebby, J . C . (1) 356; (3) 8; ( 4 ) 11 T e c o t t , L.H. (6) 263 T e d d e r , J.B., j u n . (8) 7 5 , 156 T e o u l e , R. ( 6 ) 192 T e r e n t ' e v a , S.A. ( 4 ) 9 T e u l a d e , M.-P. ( 4 ) 15; ( 5 ) 116 T h a t c h e r , G . R . J . (5) 190; (6) 1 2 8 T h e i l , F. ( 7 ) 5 5 T h e n e t , S. ( 6 ) 229 T h e w a l t , U. (1) 164; ( 4 ) 53 Thoma, R . J . (1) 259, 275, 2 79 Thomas, C.J. (1) 124; (8) 128 Thomas, D. (6) 340 Thomas, G . J . , j u n . (6) 462-464 Thomas, I.E. ( 6 ) 269 Thomas, W.A. (5) 134 .Thompson, N.T. (1) 210 Thomson, R.J. (1) 4 2 T h o r a u s c h , P. (1) 4 4 T h o r n t o n , D.M. (5) 101, 152 T h u i l l i e r , A. ( 1 ) 91 Thuong, N.T. ( 6 ) 218-221, 223-227, 230, 355 T i a n , G. (6) 441 T i d w e l l , T.T. ( 5 ) 59 Timko, J . M . ( 7 ) 107 Timokhin, B.V. (1) 154; ( 2 ) 39 T i n g , R. (6) 386 T i n o c o , I . , j u n . ( 6 ) 180, 3 8 7 , 459 T i r i l i o m i s , A. (1) 373 Tishchenko, I . G . (1) 108 T i t s k i i , G.D. (8) 88 T o c i k , Z. ( 6 ) 184
373
Author Index Toda, F. ( 3 ) 1 9 ; ( 5 ) 167 Todesco, P.E. (1) 9 4 ; ( 4 ) 49 Toke, L. ( 4 ) 1 6 ; (5) 7 8 T o h i d i , M. ( 6 ) 250 T o j o , T. (8) 4 4 Toke, L. (3) 1 2 , 13 Tokoroyama, T. ( 7 ) 2 3 Tokunaga, M. ( 6 ) 298 Toldov, S.V. (1) 13 Tolmachev, A.A. ( 5 ) 9 5 Tolman, R.L. ( 6 ) 130 Tomasz, J. ( 6 ) 6 7 Tomer , K.B. ( 6 ) 468 Tomioka, I. ( 6 ) 122 Tomita, K. ( 6 ) 209, 331 Tong, B.P. ( 5 ) 134 Tonge, J . S . (8) 181 T o p a l , M.D. ( 6 ) 120 Toropova, M.A. (1) 188 T o r r e n c e , P.F. ( 6 ) 242 T o r t o r a , G. ( 6 ) 7 1 T o s s i , A.B. ( 6 ) 427 T o t h , G. ( 3 ) 1 2 , 13 T o t o , S.D. (1) 111 Toulme, J.-J. (6) 225 Toyoshirna, C. (6) 298 T o y o t a , K. (1) 258, 267 T r a c h e v s k i , V.V. (1) 103 T r a i n o r , G.L. (6) 311 T r a n Huy, N.H. (1) 276 T r e g e a r , G.W. ( 6 ) 201, 213 T r e h a n , A. ( 7 ) 8 4 T r i b o l e t , R. ( 6 ) 55, 7 3 T r i p p e t t , S. (5) 7 0 , 1 7 6 T r i s h i n , Yu.G. ( 5 ) 144 T r o e t s c h - S c h a l l e r , I. (1) 263 T r o f i m o v , B.A. (1) 7 5 Trommer, W.E. ( 6 ) 299 Trostyanskaya, I.G. (4) 32 T r s i c , M. (8) 1 2 3 T r u j i l l o , M.A. ( 6 ) 241 T r u l s o n , M.O. ( 6 ) 3 8 7 , 459 Truneh, A. (1) 112 T r z e c i a k , A. ( 6 ) 1 4 4 T s a i , E.W. ( 8 ) 6 T s a i , M.-D. (6) 441 T s a r e v , I . G . (6) 304 T s a y , Y.-H. (1) 318; (3) 35 T s u b o i , A . (1) 133 T s u g e , 0. (5) 113; ( 7 ) 6 3 T s u j i n o , M. ( 6 ) 21, 2 3 Tsukarnoto, M. ( 7 ) 23, 9 4 T s v e t k o v , E.N. (1) 9 7 ; (4) 5 5 ; ( 5 ) 118, 119 T s z c h a c h , A. (1) 99 Tuck, D.G. (1) 6 6
T u e t i n g , D.R. ( 1 ) 80 Tuinman, R..J. ( 4 ) 41 T u k a l o , M . A . ( 6 ) 423 T u l l i u s , T.D. (6) 3 7 2 , 373 Tumasheva, N.A. (5) 106 Tunac, J . B . ( 6 ) 24 T u p c h i e n k o , S.K. (8) 2 5 , 27 T u r , D.R. ( 8 ) 1 5 1 , 1 5 3 , 1 7 4 , 177 T u r c o t t e , J . G . ( 5 ) 89 T y a g i , S.C. ( 6 ) 4 0 Tyka, R . ( 5 ) 126 T y u l k i n a , L.G. ( 6 ) 3 4 3 T z s c h a c h , A. (1) 7 3 Uccella, N. ( 6 ) 1 7 1 Ueda, N. ( 7 ) 86 Ueda, S. ( 6 ) 2 3 Ueda, T. ( 6 ) 2 1 , 2 3 , 1 9 5 , 196 Uemura, H. ( 6 ) 182 Ueno, Y. (1) 128 U e s u g i , S. ( 6 ) 1 8 2 , 209, 331, 446 Uges, D.R.A. ( 8 ) 8 5 Ugi, I. ( 6 ) 1 6 8 U h l e n , M. ( 6 ) 315 Uhlenbeck, O.C. ( 6 ) 274, 333 U h l i g , W. (1) 99 Uhlmann, E. (6) 240 U m i , T. (8) 118 U o s a k i , Y. ( 7 ) 7 3 Urakami, K. (6) 1 4 5 Urakawa, C. (5) 1 2 4 U r d e a , M.S. ( 6 ) 203 U r p i , F. (8) 1 6 Uskovic, M.R. (3) 2 8 Usman, N. ( 6 ) 132, 1 5 8 U s t a n o v a , L.N. ( 4 ) 45 U s t i n o v , A.K. (8) 32 U t k i n a , N.S. ( 6 ) 116 U t l e y , J.H.P. ( 7 ) 3 U t v a r y , K. ( 2 ) 40-42 Uvarev, V . I . ( 5 ) 2 0 U z a k i , S. (8) 1 6 5 , 171 Uzlova, L.A. (5) 1 1 7 U z n a n s k i , B. ( 4 ) 6 0 , 6 7 ; (6) 141 Vaahs, T. (1) 56-60 Vagapova, N.N. ( 5 ) 172 V a g h e f i , M.M. ( 6 ) 9 2 , 9 3 V a i n e r , L.M. (5) 1 5 3 V a l c e a n u , N. (8) 9 2 V a l c e a n u , R. (8) 9 2 Valet, G . ( 6 ) 401 V a l v e r d e , S. ( 7 ) 1 1 5
Van, D.L. ( 4 ) 4 3 van Bonn, K.-H. (1) 165 Van Boom, J . H . ( 4 ) 4 1 , 5 8 , 59; ( 5 ) 9; (6) 63, 191, 243, 293, 364, 365, 463 van d e Grampel, J.C. (8) 8 5 , 8 6 , 126, 129-131, 206-208 van d e r H o f s t a d , J . W . M . (2) 8 Van d e r Marel, G.A. ( 4 ) 4 1 ; ( 5 ) 9 ; ( 6 ) 63, 1 9 1 , 243, 3 6 4 , 365, 463 Van d e r Meulen, J . D . ( 8 ) 85 V a n d e r w a l l , D.E. ( 6 ) 363 van d e S a n d e , <J.H. ( 6 ) 433 van d e Ven, L.J.M. ( 2 ) 1 2 van Doorn, J . A . (1) 88 van Genderen, M.H.P. ( 2 ) 1 2 ; ( 6 ) 234 V a n g r z h a n o v s k i i , V.A. ( 5 ) 29 Vanoorenberghe, Y. (1) 172; ( 4 ) 7 2 van Wazer, \J.R. ( 4 ) 2 5 V a p i r o v , V.V. (8) 88 V a r a p r a s a d , C.V.N.S. ( 7 ) 127 V a r a s i , J. (1) 118 V a r a s i , M. ( 2 ) 1 9 Varenne, J. ( 6 ) 170 V a s s e u r , J.-J. ( 6 ) 3 5 3 , 40 3 V a s u d e v a c h a r i , M.B. ( 6 ) 413 Vasudeva Murthy, A . R . (8) 100 V a t h e r , S.M. (5) 3 5 V e d e j s , E. ( 2 ) 21-23; ( 7 ) 13, 1 4 , 110 Veeneman, G.H. ( 4 ) 5 8 , 5 9 Veiko, V.P. ( 6 ) 254 V e i t h , M. (1) 335 Veits, Yu.A. (1) 264; (8) 26 V e n g e l ' n i k o v a , V.N. (1) 154 Verkade, J . G . ( 2 ) 7 V e r l y , W.G. ( 6 ) 280 Verma, S. (6) 353 V i a l , J.-M. (6) 177 Viala, J. ( 1 ) 191 Viari, A. ( 4 ) 6 3 ; ( 6 ) 469 Viduad, L. (8) 71-74, 8 4 V i e r l i n g , P. ( 2 ) 38 Vigny, P. ( 4 ) 6 3 ; ( 6 ) 469 V i k h r e v a , L.A. (5) 2 4 , 25 V i l a r r a s a , <J. (8) 16 V i l l i e r a s , J . ( 7 ) 57
3 74 Vincent, B.R. ( 8 ) 93 Vinogradova, S.V. ( 8 ) 9 9 ,
151-153, 174, 177 Vitkovskii, V.Yu. ( 1 ) 75 Vlassov, V.V. ( 6 ) 356 Vo, C . D . ( 6 ) 205 Volp, K. ( 8 ) 42 Vogel-Claude, P. ( 6 ) 299 Vold, B.S. ( 6 ) 381 Volkov, E.M. ( 6 ) 148 von Beroldingen, C.H. ( 6 ) 26 1 von Holt, C . ( 6 ) 84 von Itzstein, M. ( 1 ) 120; ( 5 ) 103
von Janta-Lipinski, M. ( 6 ) 117-119
von Kitzing, E. ( 6 ) 375 von Schnering, H.G. ( 1 ) 59
Vo-Quang, L. (5) 131 Vo-Quang, Y. ( 5 ) 131 Vorbruggen, H. ( 7 ) 67 Vorlickova, M. ( 6 ) 472 Vorokh, V.S. ( 1 ) 214 Voronkov, M.G. ( 1 ) 75 Voss, H. ( 6 ) 312, 322 Votruba, I. ( 6 ) 94 Vougioukas, A.E. ( 1 ) 4 Vovk, M.V. ( 5 ) 29 Vrudhula, V.M. ( 6 ) 8 9 , 90 Vuocolo, E. ( 6 ) 202 Vural, J . M . ( 1 ) 349 Vyas, K. ( 8 ) 93 Wada, M. ( 1 ) 132, 133 Wagner, F.E. ( 7 ) 33 Wagner, 0 . ( 1 ) 314 Wakabayashi, T. ( 6 ) 298 Waldmann, R. ( 6 ) 325 Walker, B.J. ( 1 ) 210; ( 7 ) 1 7 , 24
Walker, D.M. ( 5 ) 133 Walker, G.A. ( 6 ) 458 Walker, K.A.M. ( 1 ) 118; ( 2 ) 19
Walker, M.D. ( 3 ) 3 , 5 Wallace, J.C. ( 6 ) 38 Wallace, S.S. ( 6 ) 352 Walmsley, J . A . ( 6 ) 56 Walter, R. ( 1 ) 301; ( 8 ) 52
Walther, L . ( 7 ) 131 Walton, D.R.M. ( 1 ) 249 Wamhoff, H. ( 1 ) 113, 115 Wang, A . H . 4 . ( 6 ) 205, 463
Wang, M.L. ( 1 ) 181 Wang, Q. ( 6 ) 277 Wang, T.P. ( 6 ) 326 Ward, J.G. ( 5 ) 12
Organop h osph or us Chemistry Warfield, D. ( 6 ) 258 Warner, B.D. ( 6 ) 203 Warren, S. ( 3 ) 23, 24 Wasgestian, F. ( 1 ) 364 Wasserman, H.H. ( 7 ) 74 Wasson, D.B. ( 6 ) 19 Watanabe, I. ( 8 ) 101 Watanabe, M. ( 1 ) 114 Watanabe, N . ( 1 ) 123; ( 8 ) 14
Watanabe, T. ( 4 ) 6 2 ; ( 6 ) 167
Watanabe, Y. ( 1 ) 128; ( 5 ) 8 , 14
Watkins, C.L. ( 1 ) 139 Watson, W.H. ( 1 ) 279 Webb, G.G. ( 1 ) 221 Webb, T . R . ( 1 ) 85 Weber, A . L . ( 6 ) 59 Weber, E. ( 1 ) 241 Weber, L. ( 1 ) 235-240 Webster, L.C. ( 6 ) 66 Weedon, B.C.L. ( 7 ) 7 6 , 77 Weferling, N. ( 1 ) 9 3 ,
151; ( 2 ) 3 3 ; ( 4 ) 4 7 ; ( 5 ) 90 Wegner, P. ( 1 ) 30 Weidenbruch, M. ( 1 ) 315 Weinfeld, M. ( 6 ) 398 Weissman, S.A. ( 1 ) 336, 339, 349; ( 3 ) 7 ; ( 4 ) 8 1 , 82 Weisz, M. ( 6 ) 134 Welch, C.J. ( 6 ) 164 Weller, F. ( 1 ) 143; ( 8 ) 4 2 , 43 Wellman, D. (5) 193 Wells, R.D. ( 6 ) 6 , 389 Weltermark, U.G. ( 8 ) 142 Wendler, A. ( 6 ) 348 Wenzel, H.V. ( 1 ) 273 Wermuth, U. ( 8 ) 13 Werner, D . ( 1 ) 17 West, C.R. ( 6 ) 16 Westberg, D.S. ( 8 ) 38 Westerduin, P. ( 4 ) 58 Westerhoff, B. ( 8 ) 44 Westermann, H. ( 1 ) 1 8 ; ( 4 ) 69 Westheimer, F.H. ( 4 ) 56 Westman, E. ( 6 ) 432 Weston, J.B. ( 7 ) 125 Wetekarn, W. ( 6 ) 183 Weyerstahl, P. ( 7 ) 131 Whalen, D.L. ( 6 ) 57 Whitcombe, I.W.A. ( 5 ) 134 White, F.H. ( 7 ) 80 White, J.C. ( 6 ) 457 Whitesides, G.M. ( 6 ) 83 Whiting, A. ( 7 ) 130 Whiting, M.C. ( 7 ) 121-123 Wieber, M. ( 1 ) 174
Wieczorek, J.S. ( 5 ) 122 Wieczorek, M. ( 7 ) 70 Wiemer, D . F . ( 5 ) 4 5 ; ( 7 ) 66
Wikmann, F.P. ( 6 ) 423 Wild, S.B. ( 1 ) 49 Wilde, J . A . ( 6 ) 188, 189 Wilk, A. ( 4 ) 6 0 , 6 7 ; ( 6 ) 141
Wilkins, D . J . (5) 6 8 , 77 Will, S. ( 6 ) 198 Willemse, P.H.B. ( 8 ) 85 Williams, A. ( 5 ) 67 Williams, D . J . ( 1 ) 177; ( 5 ) 145
Williams, D.M. ( 6 ) 42 Williams, D.R. ( 7 ) 80 Williams, R. ( 5 ) 193 Williams, L . D . ( 6 ) 369 Williams, R.W. ( 6 ) 457 Williamson, J . R , . ( 6 ) 187 Willingham, R.A. ( 8 ) 8 9 , 140, 141
Willis, I. ( 6 ) 381 Willson, M. ( 8 ) 102 Wilson, B.E. ( 6 ) 92 Wilson, D.A. ( 1 ) 101 Wilson, W.D. ( 6 ) 232, 450 Winkeler, H.D. ( 6 ) 211 Winkhaus, V. ( 1 ) 277 Winter, H. ( 8 ) 129 Wipf, P. ( 5 ) 194 Wishka, D.G. ( 7 ) 90 Wisian-Neilson, P. ( 8 ) 1 , 142, 159
Witczak, M.K.
( 1 ) 119;
( 8 ) 6 , 23
Witherell, G.W. ( 6 ) 274 Withka, J.A. ( 6 ) 188, 189 Witt, M. ( 8 ) 138 Woerner, A.M. ( 6 ) 237 Wohlrab, F. ( 6 ) 389 Wolf, H.C. ( 7 ) 79 Wolf, R. ( 1 ) 340; ( 2 ) 2 Wolfram, P. ( 1 ) 9 Wolfsberger, W. ( 1 ) 3 8 , 3 9 , 148; ( 8 ) 17
Wolkanin, P.J. ( 6 ) 51 Wolmershauser, G. ( 1 ) 242, 243, 365
Wolter, A. ( 6 ) 467 Wood, G.L. ( 1 ) 291, 337 Wood, P.T. ( 1 ) 177; ( 5 ) 145
Wood, T.G. ( 1 ) 83 Woods, M. ( 8 ) 6 0 , 100 Woody, A.-Y.M. ( 6 ) 296 Woody, R.W. ( 6 ) 296 Wooley, P. ( 6 ) 474, 475 Woollins, J . D . (1) 177; ( 5 ) 145
Wreschner, D.H. ( 6 ) 341
Wright, B. ( 7 ) 111 Wright, R.B. ( 8 ) 185 WU, F.-J. ( 1 ) 329 WU, F.Y.-H. ( 6 ) 40 Wu, G. ( 5 ) 64 wu, S.Y. ( 5 ) 43 wu, x.-P. ( 1 ) 345 Wudl, F. ( 5 ) 193 Wunsch, M. ( 1 ) 11 W y a t t , J . R . ( 6 ) 180 Wynne, K. ( 8 ) 57 X i , S. ( 1 ) 119; ( 8 ) 23 Xiang, Y.B. ( 7 ) 105 Xu, C . ( 6 ) 364 XU, W.-P. ( 5 ) 71 xu, Y. ( 5 ) 97 Xue, C.-B. (5) 37, 52
Yaegashi, H. ( 8 ) 186 Yagami, T. ( 6 ) 306 Yagi, H. ( 6 ) 57 Yagupol'skii, L.M. (2) 17; (8) 24 Yamada, K. ( 7 ) 73 Yamada, S. (8) 198 Yamada, Y. ( 4 ) 19; ( 6 ) 146 Yamagiwa, Y . ( 7 ) 104 Yamakage, S. ( 6 ) 172 Yamamoto, I. ( 1 ) 197; ( 3 ) 27; ( 7 ) 28 Yamamoto, S. ( 7 ) 8 6 Yamasaki, Y. ( 5 ) 108, 109 Yamashita, M. ( 5 ) 114 Yamashoji, Y. (1) 132 Yamazoe, 0. (8) 109-111 Yang, J . ( 7 ) 101 Yanovskii, A.I. (5) 117 Yarkov, A . V . ( 5 ) 20 Yarosh, D.B. ( 6 ) 392 Yasnikov, A . A . ( 5 ) 62 Yastrebov, S.I. ( 6 ) 142 Ye, W. ( 5 ) 9 3 Yeung, A.T. ( 6 ) 399 Yin, Y.-W. ( 5 ) 52
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