Organophosphorus Chemistry

Organophosphorus Chemistry Volume 14 A Specialist Periodical Report Organophosphorus Chemistry Volume 14 A Review o...

Author: D. W. Hutchinson | J. A. Miller

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Organophosphorus Chemistry Volume 14

A Specialist Periodical Report

Organophosphorus Chemistry Volume 14

A Review of the Literature published between July 1981 and June 1982

Senior Reporters

D. W . Hutchinson Department of Chemistry and Molecular Sciences, University of Warwick J. A. Miller Medicinal Chemistry Laboratories, The Wellcome Research Laboratories, Beckenham, Kent Reporters

D. W. Allen Sheffield City Polytechnic J. R. Chapman Kratos Analytical Instruments, Manchester R. S. Edmundson University of Bradford

C.

D. Hall King's College, London

J. B. Hobbs The City University, London J. C. Tebby North Staffordshire Polytechnic, Stoke-on- Trent

B. J. Walker Queen's University o f Belfast

The Royal Society of Chemistry Burlington House, London W I V OBN

ISBN 0-85186-126-1 I S S N 0306-0713 Copyright 0 1983 T h e Royal Society of Chemistry

All Rights Reserved No part o f t h i s book may be reproduced or transmitted in any form or by any means - graphic, electronic, including photocopying, recording, taping, or information storage and retrieval systems - without written permission from The Royal Society of Chemistry Printed in Great Britain by Adlard a n d S o n Ltd Bartholomew Press, Dorking

In trod uction This year we welcome an occasional review on the mass spectrometry of organophosphorus compounds by Dr J . R. Chapman of Kratos Analytical Instruments, Manchester. This analytical technique is becoming increasingly useful in the organophosphorus field (particularly for the analysis of insecticides) with the development of chemical ionization and ‘in beam’ evaporation techniques. While mass spectrometry has been little used so far for the analysis of natural products such as oligonucleotides, mainly because of volatility problems, the mass spectra of intact vitamin B 1 2 and vitamin BIZcoenzyme have been obtained, which must be regarded as a minor landmark in the application of this technique. The occasional review which has been commissioned for next year is on phosphazenes, and will be written by Drs van de Grampel and de Ruiter of the University of Groningen, the Netherlands. During the past year, Lawesson’s reagent [ 2,4-bis-(4-methoxyphenyl)1,3-dithia-2,4-diphosphetan 2,4-disulphide] has become the reagent of choice for the replacement of oxygen by sulphur in synthetic reactions. There has been an increase in the number of rearrangement reactions reported which involve organophosphorus compounds and there has been considerable interest in the synthesis of esters of fluorinated phosphorus acids. The explosive expansion in studies of two-co-ordinate phosphorus has continued and, for example, frontier orbital theory has been applied to cyclo-addition reactions of these compounds. The development of automated synthesizers employing solid-phase methods for oligonucleotide synthesis is a significant advance which has been made during the past year, and this has been accompanied by an avalanche of papers detailing improvements in ‘ phosphotriester’ methodology. The latter route has also been used for the synthesis of phospholipids - another area in which many new syntheses have been reported recently. The synthesis of chiral phosphates and thiophosphates and their use for investigating the stereochemical course of enzyme reactions continues t o spur much elegant investigation. Some novel and interesting nucleoside 5’-triphosphate analogues, containing modifications in the tripolyphosphate chain, have been described. The identification of the exact sites of phosphorylation in phosphoproteins has been the subject of much recent research. While the sites of phosphorylation are usually histidine, serine, o r tyrosine, an acyl phosphate has recently been identified as an intermediate during the enzymic hydrolysis of ATP. The Senior Reporters are aware of, and regret, the considerable recent increases in price of this Report. However, new methods for the reproduction of formulae and cheaper typesetting methods should, hopefully, reduce the

vi

Introduction

cost of producing these volumes in the future. This is the last volume with which one of us (J.A.M.) will be associated, and we are pleased to announce that Dr B. J . Walker will become a Senior Reporter from Volume 1 5 onwards.

D. W . Hutchinson J . A . Miller

Contents Chapter 1 Phosphines and Phosphonium Salts

1

By D. W. Allen

1 Phosphines Preparation From Halogenophosphines and Organometallic Reagents From Metallated Phosphines By Addition of P-H t o Unsaturated Compounds By Reduction Miscellaneous Methods Reactions Nucleophilic Attack at Carbon Nucleophilic Attack at Halogen Nucleophilic Attack at Other Atoms Miscellaneous Reactions

2 Phosphonium Salts Preparation Reactions Alkaline Hydrolysis Additions to Unsaturated Phosphonium Salts Miscellaneous Reactions

1

1 1 3 6 7 8 10 10 12 14 17 19 19 24 24 25 26

3 p,-Bonded Phosphorus Compounds

28

4 Phospholes and Phosphorins

32

Chapter 2 Quinquecovalent Phosphorus Compounds

37

By C. D. Hall 1 Introduction

31

2 Structure, Bonding, and Reorganization of Ligands

38

3 Phosphoranes that contain a P-H Bond

40

4 Acyclic Phosphoranes

41

5 Four-membered-ringPhosphoranes

44

6 Five-membered-ring Phosphoranes

45

7 Six- and Seven-membered-ring Phosphoranes

56

8 Hexaco-ordinated Phosphorus Compounds

58

Contents

viii Chapter 3 Halogenophosphines and Related Compounds

60

By J. A. Miller

1 Introduction

60

2 Halogenophosphines

60

Preparation Physical and Structural Aspects Reactions that lead t o p n Bonds t o Phosphorus Reactions with Alkenes o r Dienes Reactions with Carbanions Reactions with Carbonyl Compounds Reactions with Oxygen Nucleophiles Reactions with Phosphorus Nucleophiles Miscellaneous Reactions

60 61 62 63 64 65 68 68 10

3 Silylphosphines

11

4 Halogenophosphoranes

12

Preparation Physical and Structural Aspects Reactions

Chapter 4 Phosphine Oxides and Related Compounds

12 12 13

77

By J. A. Miller

1 Introduction

11

2 Preparation of Acyclic Oxides

11

3 Preparation of Cyclic Oxides

80

4 Structural and Physical Aspects

83

5 Reactions at Phosphorus

84

6 Reactions of the Side-Chain

90

7 Phosphine Oxide Complexes and Extractants

92

Chapter 5 Tervalent Phosphorus Acids

95

By B. J. Walker

1 Introduction

95

2 Phosphorous Acid and its Derivatives

95

Nucleophilic Reactions Attack o n Saturated Carbon Attack o n Unsaturated Carbon

95 95 91

Contents

ix Attack on Oxygen Attack on Halogen Electrophilic Reactions Reactions involving Two- co- ordinate Phosphorus Cyclic Esters of Phosphorous Acid Miscellaneous Reactions

104 107 109 112 118 120

3 Phosphonous and Phosphinous Acids and their Derivatives

122

Chapter 6 Quinquevalent Phosphorus Acids

123

By R. S. Edmundson

1 Synthesis General Phosphoric Acid and its Derivatives Phosphonic and Phosphinic Acids and their Derivatives

2 Reactions General Phosphoric Acid and its Derivatives Phosphonic and Phosphinic Acids and their Derivatives

Chapter 7 Phosphates and Phosphonates of Biochemical Interest

123 123 124 129 139 139 142 149

157

By D. W. Hutchinson

1 Introduction

157

2 Coenzymes and Cofactors

158

3 Sugar Phosphates

161

4 Phospholipids

163

5 Phosphonates

166

6 Enzyme Mechanisms

167

7 Other Compounds of Biochemical Interest

169

Chapter 8 Nucleotides and Nucleic Acids

172

By J. B. Hobbs

1 Introduction

172

2 Mononucleotides

172

Chemical Synthesis Cyclic Nucleotides Affinity Chromatography

172 180 183

Contents

X

3 Nucleoside Polyphosphates

185

Chemical Synthesis Affinity Labelling

195

4 Oligo- and Poly-nucleotides

200

Chemical Synthesis Enzymatic Synthesis Sequencing Other Studies

5 Analytical Techniques and Physical Methods Chapter 9 Ylides and Related Compounds

185

200 214 219 22 1 221

23 1

By 6.J. Walker

1 Introduction

23 1

2 Methylenephosphoranes

23 1

Preparation and Structure Reactions Aldehydes Ketones Miscellaneous

23 1 236 236 243 244

3 Reactions of Phosphonate Anions

248

4 Selected Applications in Synthesis

256

Carbohydrates Carotenoids and Related Compounds p- Lactam Antibiotics Leucotrienes and Related Compounds Pheromones Prostaglandins Miscellaneous Applications Chapter 10 Mass Spectrometry of Organophosphorus Compounds

256 258 26 1 26 1 266 269 27 1

278

ByJ. R. Chapman

1 Introduction

278

2 Techniques

278

Chemical Ionization and ‘In-Beam’ Evaporation Techniques Negative-ion Chemical Ionization Field Desorption and lonization by Energetic Particles Identification of Metastable Ions Liquid Chromatography

218 280 28 1 282 283

xi

Con tents

3 Natural Products Nucleotides Phospholipids Miscellaneous Natural Phosphates

4 Synthetic Compounds Organophosphorus Ester Pesticides Phosphates Phosphonates Phosphites Phosphinates Phosphines Phosphonium Salts Phosphazenes Miscellaneous Chapter 1 1 Physical Methods

283 283 281 289 290 290 292 296 298 298 299 301 302 303

305

By J. C. Tebby

1 Nuclear Magnetic Resonance Spectroscopy Biological, Analytical, and Instrumental Aspects Chemical Shifts and Shielding Effects Phosphorus-3 1 6 p of n' compounds 6 p of 'n compounds 6 p of n 3 compounds 6 p of n4 compounds 6 p of n s compounds Hydrogen-1, - 2 , and - 3 Carbon-1 3 Oxygen-I 7 Fluorine-I 9 Studies of Equilibria, Hydrogen-Bonding, and Shift Reagents Variable-Temperature Studies: Inversion Restricted Rotation and Conformation Pseudorotation Spin-Spin Couplings J(PM) and J(PP) J(PF) JPN) J(PC) 'J(PD) 2 ~ ( ~ ~ ~ ) J(PCC,H) and J(POC,H)

305 305 305 305 3 06 3 06 306 307 308 308 309 3 09 3 09 309 310 310 31 1 31 1 311 312 312 313 313 313 313

Con tents

xii Relaxation, CIDNP, and N.Q.R. Relaxation CIDNP N.Q.R.

314 3 14 314 314

2 Electron Spin Resonance Spectroscopy

315

3 Vibrational and Rotational Spectroscopy

316

Band Assignments and Absorptivity Bonding Stereochemistry Rotational Data

4 Electronic Spectroscopy Absorption Spectroscopy Photoelectron Spectroscopy Optical Kotation 5 Diffraction

X-Ray Diffraction Electron Diffraction

316 316 317 318 319 319 319 320 320 320 325

6 Dipole Moments and Kerr Effects

325

7 Values of pK, and Thermochemical and Kinetic Studies

326

8 Chromatography and Surface Properties

327

Gas-Liquid Chromatography Thin-Layer, Paper, and Gel Chromatographies High-Performance Liquid Chromatography Column Chromatography Surface Properties Author Index

327 328 328 328 328

329

Abbreviations *

AIBN CIDNP CNDO CP DAD DBN DBU DCC DIOP DMF DMSO DMTr EDTA E.H.T. ENU FID g.1.c.-m.s. HMPT h.p.1.c. i.r. L.F. E. R. MIND0 MO MS-C1 MS-nt MS-tet NBS n.q.r. p.e. PPA SCF TBDMS TDAP TFAA TfzO

bisazoisobutyronitrile Chemically Induced Dynamic Nuclear Polarization Complete Neglect of Differential Overlap cyclopentadienyl diethyl azodicarboxylate 1,5-diazabicycIo[ 4.3.01non- 5-ene 1,5-diazabicyclo[ 5.4.01 undec- 5-ene dicy clohexylcarbodi-imide [ ( 2,2-dimethyl-l,3-dioxolan-4,5-diyl)bis( methy1ene)lbis( diphenylphosphine) dimethylformamide dimethyl sulphoxide 4,4’-dimethoxytrityl ethylenediaminetetra-acetic acid Extended Hiickel Treatment N-ethyl-N-nitrosourea Free Induction Decay gas-liquid chromatography-mass spectrometry hexamethylphosphortriamide high-performance liquid chromatography infrared Linear Free- Energy Relationship Modified Intermediate Neglect of Differential Overlap Molecular Orbital mesitylenesulphonyl chloride mesitylenesulphonyl- 3-nitro- 1,2,4-triazole mesitylenesulphonyltetrazole N-bromosuccinimide nuclear quadrupole resonance photoelectron polyphosphoric acid Self-consistent Field t- butyldimethylsilyl tris( diethy1amino)phosphine trifluoroacetic acid trifluoromethanesulphonic anhydride

*Abbreviations used in Chapters 7 and 8 are detailed in Biochem. J., 1970, 1 2 0 , 4 4 9 and 1 9 7 8 , 1 7 1 , 1 .

Abbreviations

xiv THF t.1.c. TPS-C1 TPS-nt TPS-tet TsOH U.V.

tetrahydro furan thin-layer chromatography tri-isopropylbenzenesulphonyl chloride tri-isopropylbenzenesulphonyl- 3-nitro- 1,2,4-triazole

tri-isopropylbenzenesulphonyltetrazole toluene-p-sulphonic acid ultraviolet

1 Phosphines and Phosphonium Salts BY D. W. ALLEN

1 Phosphines Preparation.-From Halogen o p h o s p h ines and Organome tallic Reagents. The reactions o f the Grignard reagent derived from the bromo-ether (1) with halogenophosphines have yielded the phosphino-ethers (2)) which react with bromine to give a series of stable cyclic phosphoranes.' Treatment of alkylor aryl-phosphonous dichlorides with the 'magnesium butadiene' complex gives rise t o the phosphirans (3)) which isomerize to phospholens above 150 O C . * Acetylenic Grignard reagents have been employed in the synthesis of the phosphines (4).3 Methylmagnesium chloride converts the halogenophosphine that was extracted from the residues in the synthesis of bis(dich1orophosphino)methane into the triphospha-alkane ( 5),4 and phenylmagnesium bromide has been used to convert the cyclic halogenophosphines that are obtained from the reactions of diarylamines and phosphorus trichloride at elevated temperatures into the cyclic phosphines (6).'

o\"

HZPh

N0cH2p nPh3 - n

(1)

( 2 ) n = 1 or 2

R-a: H

R ' ~ P (c . - c R ~ )-

CH2PMe

Me P< CH2PMe

( 4 ) R1,

2

R = Ph o r C6F5

n = 0 , 1 , or 2 I

Ph

(5)

I. Granoth, J. Chem. Soc., Perkin Trans. I , 1982, 735. Richter, Angew. Chem., Int. Ed. Engl., 1982, 21, 292. S. A. Krupoder, G. N. Dolenko, G. G. Furin, 0. I . Andreevskaya, and G. G. Yakobson, Izv. Sib. O t d . Akad. Nauk SSSR, Ser. Khim. Nauk, 1981, No. 6 , p. 119 (Chem. Abstr., 1982, 96, 104 401). S. Hietkamp, H. Sommer, and 0. Stelzer, Angew. Chem., Int. Ed. Engl., 1982, 21,

' W. J.

376.

H . S. Freeman and L. D. Freedman,J. Org. Chem., 1981, 46, 5 3 7 3 .

Organophosphorus Chemistry

2

Many examples of the use of organolithium reagents have also been reported. The heteroaryl-phosphine (7) has been prepared by the reaction of 2- thiazolyl- lit hium and phosphorus trichloride. Unfortunately, this route fails for the preparation of the related tris-( 2-benzothiazolyl)phosphine and also for that of tris-[ 2-( 1-methyl)imidazolyl] phosphine. However, phosphines bearing these, and other, heteroaryl groups have been successfully prepared by the reactions of halogenophosphines and the appropriate trimethylsilylsubstituted heterocycle.6 ortho- Lithiation of phenyl sulphides, followed by treatment with diphenylphosphinous chloride, affords the phosphinothioethers (8). The reaction of lithiomethyl phenyl thioether with diphenylphosphinous chloride offers an improved route t o the phosphino- thioether (S).' Treatment of ar-lithiomethyl sulphoxides with halogenophosphines gives the sulphoxide-phosphines ( lo), which are stable only at low temperatures, tending t o undergo transfer of oxygen from sulphur t o p h o s p h o r ~ s . ~ Attempts t o prepare the phosphine (1 1) by the reaction of 2,6-bis(difluoromethy1)phenyl-lithium with phosphorus trichloride are frustrated by sidereactions of the difluoromethyl groups, the desired compound being isolated in only 2% yield." The vinyl carbanions that are formed in the reactions of ketone arylsulphonylhydrazones with the butyl-lithium-TMEDA complex can be trapped with halogenophosphines, giving a general method for the preparation of vinyl-phosphines (1 2).

( 8 ) R = alkyl or

(7)

Ph

CHF2 I

0

II

R'-

1

S-CHR~

9 C ( PPh2 )=CHR2

I

(12)

PPh2 (10)

(11)

Dilithiated reagents have been used in the preparation of a range of potentially chelating diphosphines ( 1 3)-( 15), based on the biphenyl,12 naphthalene,13 and ferrocene l 4 systems.

' S. S. Moore and G . M . Whitesides, J. Ovg. Chem., 1 9 8 2 , 4 7 , 1489.

' L . Horner, A. J . Lawson, and G . Simons, Phosphorus Sulfur, 1982, 12, 353. ' T. Gerdau and R . Kramolowsky, 2. Naturforsch., Teil. B , 1982, 3 7 , 332. ' E.

lo

l3

I4

Vedejs, H . Mastalerz, G. P. Meier, and D. W. Powell, J. Org. Chem., 1981, 46, 5253. E. E. Wille, D. S. Stephenson, P. Capriel, and G. Binsch, J. A m . Chem. SOC., 1982, 104, 4 0 5 . D. G. Mislankar, B. Mugrage, and S. D. Darling, Tetrahedron Lett., 1981, 22, 4 6 1 9 . T. Costa and H. Schmidbaur, Chem. Ber., 1982, 1 1 5 , 1367. T. Costa and H. Schmidbaur, Chem. Ber., 1982, 115, 1374. J . D. Unruh and J. R . Christenson, J. Mol. Catal., 1982, 14, 19.

3

Phosphines and Phosphonium Salts

PMe

Preparation o f Phosphines from Metallated Phosphines. The reactions of metallophosphide reagents with alkyl halides or tosylates (and related sulphonate esters) have found extensive application in the past year for the synthesis of a wide range of new phosphines. Once again, the driving force has been the search for new chiral phosphine ligands for use in transition-metalcomplex-catalysed homogeneous hydrogenation and other reactions. A number of modifications of the DIOP structure have appeared, all involving the reactions of lithiophosphide reagents with tosylate esters. H

H

H

( 1 6 ) Ar2P =

Me

u:DMe \

I

Me

Me

H.+>-, ”””?OH% PhZPT

(18)

PPh2

Ph2P-

PPh

(19)

Ph

CH2PPh2

Y

H

PPh2

(20)

In addition to polymer-supported DIOP systems,’” l 6 the ligands (1 6 ) l7 and (17)18 have been described. The latter - ‘cycloDIOP’ - is an example of a new class of chiral diphosphines, having a P-P bond. The lithiophosphide-tosylate route has also been employed in the synthesis of chiral phosphines that are derived from inexpensive, optically active, natural e.g. ( 1 8).20 Some degree of steric inhibition has been noted in the reactions of lithiophosphide reagents with neopentyl tosylates.’’ An K. Ohkubo, M . Haga, K. Yoshinaga, and Y. Motozato, Inorg. Nucl. Chem. Lett., 1981, 17, 215. l6 l7

I9 2o 21

M . Cerny, Czech. P. 185 139 (Chem. Abstr., 1981, 9 5 , 62 412). C. F. Hobbs and W. S . Knowles, J. Org. Chem., 1 9 8 1 , 4 6 , 4422. S. Y. Zhang, S. Yemul, H. B. Kagan, R. Stern, D. Commereuc, and Y . Chauvin, Tetruhedron Lett., 1981, 2 2 , 3955. G. Comisso, A. Sega, and V. Sunjid, Croat. Chem. Acta, 1981, 54, 375. D. Lafont, D. Sinou, and G. Descotes,J. Chem. R e x , 1982, (S), 117; ( M ) , 1401. D. P. Riley, Eur. Pat. Appl. 3 6 7 4 1 (Chem. Abstr., 1982, 9 6 , 69 2 2 1).

Organ op h 0 s p h or us Ch e m is t ry

4

improved yield of (S,S)-chiraphos (19) results from the use of the mesylate ester, rather than the tosylate of the precursor diol, with lithium diphenylphosphide.22 Mesylates have also been used in the synthesis of a range of chiral bis(diphenylphosphin0)-a-phenyl-alkanes,e.g. (20),23 and of chiral alkyl-diphenylph~sphines.~~ The reactions of lithium organophosphide reagents with alkyl halides have been used to prepare a range of chelating diphosphine ligands, e.g. (2 1)25 and (22).26 Chloromethyldimethylphosphine is converted into bis(dimethy1phosphino)methane on treatment with lithium dimethylp h ~ s p h i d e . ~The ’ reactions of 1,2-dichloroethene with lithium dimethylphosphide appear to involve an addition-elimination mechanism. Whereas the trans-alkene yields the trans-diphosphine (23), the cis-alkene yields only a small amount of the trans-diphosphine and none of the cis-diphosphine.28 Full details of the synthesis of phosphino-macrocycles have now appeared.2g930

Further applications of reagents obtained by lithiation at a carbon atom alpha to phosphorus have been described and a review of such reagents as synthons has appeared.31 The reaction of (1ithiomethyl)dimethylphosphine with methylphosphonous dichloride affords the triphosphine (24),32 and that of the reagent (25) with dimethylphosphinous chloride gives the unusual ligand (26).33 Full details of the reactions of (1ithiomethyl)diphenylphosphine with dimethylfulvene in various solvents have now appeared.34 ( Me2PCH2 ) 2PMe

Li [ C( PMe2 ) J

-*

Me2PC1

Me 3P = C ( PMe2 )

A number of examples of the use of sodium or potassium organophosphides have also appeared. The hitherto unknown phosphine (27) is formed 22

23 24

25

26

27 28 29

30

N. C. Payne and D. W. Stephan, J . Organornet. Chem., 1981, 221, 203. J. M. Brown and B. A. Murrer, J. Chem. Soc.,Perkin Trans. 2, 1982, 489. P. Salvadori, R. Lazzaroni, A. Raffaelli, S. Pucci, S. Bertozzi, D. P h i , and G. Fatti, Chim. Znd. (Milan), 1981, 6 3 , 492. P. W. Clark and B. J . Mulraney, J . Organomet. Chem., 1981, 217, 51. C. S. Kraihanzel, J . M. Ressner, and G. M. Gray, Znorg. Chem., 1982, 21, 879. H. H. Karsch, Chem. Ber., 1982, 115, 823. D. J. Gulliver and W. Levason, Inorg. Chim. Acta, Lett., 1981, 54, L15. E. P. Kyba, R. E. Davis, C . W. Hudson, A. M. John, S . B. Brown, M. J. McPhaul, L.-K. Liu, and A. C. Glover, J. A m . Chem. SOC., 1981, 103, 3868. M. Ciampolini, P. Dapporto, A. Dei, N. Nardi, and F. Zanobini, Inorg. Chem., 1982, 21, 4 8 9 .

31

32 33 34

H.-P. Abicht and K. Issleib, 2. Chem., 1981, 21, 341. H. H. Karsch, Z . Naturforsch., Teil. B, 1982, 37, 2 8 4 . H . H. Karsch, Chem. Ber., 1982, 115, 1956. N. E. Schore and B. E. La Belle,J. Org. Chem., 1981, 46, 2306.

5

Phosphines and Phosphonium Salts

in the reaction of sodium diphenylphosphide with 1 , 4 - d i ~ h l o r o b u t a n eThe .~~ reaction of sodium methylphenylphosphide with 8 -chloroqwinoline gives the chiral phosphine (28).36 Sodium organophosphide reagents have also been used in the synthesis of a range of chiral d i p h o ~ p h i n e s , ~e.g. ~ - ~(29),37 (30),38 and ( 3 1),39 and additionally in the preparation of chiral phosphines derived from carbohydrate^:^ 42 e.g. (32).42 A mixed sodium-potassium diphenylphosphide reagent has been used in the synthesis of the diphosphine (33), which has proved difficult t o purify.43 Potassium diphenylphosphide has been employed in the preparation of the chiral aminophosphine (34).44 Ph ‘PCH

/ 1 PhMeP

CH P 2 \

Ar

(29) Ar = o - t o l , p-tol,

ph2po

H O C H 2 Hy P P h

CH2PPh2

PPh 2

I

COOBut

Ph2PCH(Me)CH2CH(Me)PPhz (33)

CH2PPh

(S)-VeCH(NMez)CH2PPh2 (34)

Metallophosphide reagents continue t o find use in the preparation of heterocyclic systems. Baudler’s group has reported several new ring e.g. (35),45 and the French group has described routes to a 35

36

37 38

39 40

41

42 43 44

45 46

47

E. Lindner, G. Funk, and S . Hoehne, Chem. Ber., 1981, 114, 2465. D. G. Allen, G. M. McLaughlin, G. B. Robertson, W. L. Steffen, G. Salem, and S. B. Wild, Inorg. Chem., 1982, 21, 1007. T. Yoshikuni and J. C. Bailar, Inorg. Chem., 1982, 21, 2 129. G. L. Baker, S. J. Fritschel, J. R. Stille, and J. K. Stille, J. Org. Chem., 1981, 46, 2954. C. Dobler and H.-J. Kreuzfeld, J. Prukt. Chem., 1981, 323, 667. W. Bergstein, A. Kleeman, and J. Martens, Ger. Offen. 3 000 445 (Chem. A bstr., 1981, 95, 187 420).

M. Yamashita, N. Suzuki, M. Yamada, M. Shibata, K. Serizawa, and S. Inokawa, Carbohydr. R e x , 1982, 99, C5. J. P. Amma and J. K. Stille, J. Org. Chem., 1982, 47, 468. J. Bakos, I. T b t h , and L. Mark6,J. Org. Chem., 1981,46, 5427. Hokko Chemical Industry Co. Ltd, Jpn. Kokai T o k k y o Koho 81 29 594 (Chem. Abstr., 1981, 95, 150 890). M. Baudler and F. Saykowski, Z . Anorg. Allg. Chem., 1982, 486, 39. M. Baudler, Y. Aktalay, T. Heinlein, and K.-F. Tebbe, Z . Nururforsch., Teil. B, 1982, 37, 299. M. Baudler, Y. Aktalay, K.-F. Tebbe, and T. Heinlein, Angew. Chem., Znt. Ed. Engl., 1981, 20, 967.

Organophosphorus Chemistry

6

wide range of sila-, germa- and stanna-pho~pholans.~~,~~ A series of heterocyclic diphosphasilanes (36) has been prepared by the reactions of 1,2dilithium- lY2-diphenyldiphosphidewith CY,W- dichloropermethylpolysilanes. 50 The reactions of metallophosphide reagents that are derived from polyphosphines have been employed in the synthesis of the heterocyclic systems (3 7). 51

P-

BU

H

P

x

B

~

~

Me

(35)

( 3 6 ) n = 0 , 1, or 2

(37)

M

=

R

= alkyl

Ti, Z r , o r H f

or Ph

Dimetallophosphide reagents have also been used in the synthesis of new, acyclic di- and p o l y - p h o s p h i n e ~ 53 .~~~

Preparation of Phosphines by Addition of P-H t o Unsaturated Compounds. The formation o f polyphosphines that contain the PCH-CH2P unit by basecatalysed addition of P-H t o vinylphosphines has been reviewed.54 This route has been employed in the synthesis of the new chelating diphosphine (38).55 Irradiation of allylphosphine with light of wavelength 300-600 nm in the gas phase, in a hot-cold reactor, gives rise t o the new diphosphine (39), resulting from head-to-tail addition of P-H t o the allylic double-bond in an

Ph2PCH2CH2P(p-tol)2 (38)

H2C=CHCH2PH(CH2)3PH2 (39)

P-(CH \(

)-P

CH:

12

(40)

anti- Markownikoff fashion. In contrast, the AIBN-induced radical reactions of allylphosphine in benzene solution yield phosphine and the novel bicyclic diphosphine (40).56 A series of P-H functional triphosphine ligands (41) has 4x

49

51

52

53 54

’’ s6

J . D. Andriamizaka, C. Couret, J . Escudi6, and J. Satgd, Phosphorus Sulfur, 1982, 1 2 , 265. J . D. Andriamizaka, J . Escudik, C. Couret, and J . Satg6, Phosphorus Sulfur, 1982, 12, 279. T. H. Newman, J. C. Calabrese, R. T. Oakley, D. A. Stanislawski, and R. West, J . Organomet. Chem., 1982, 225, 21 1 . H. KSpf and R . Voigtlander, Chem. Ber., 1981, 1 1 4 , 2 7 3 1 . M . Baudler, C. Gruner, H. Tschabunin, and J . Hahn, Chem. Ber., 1982, 115, 1739. M. Baudler, G. Reuschenbach, and J . Hahn, 2. Anorg. Allg. Chem., 1981, 482, 27. R . B. King, Adu. Chem. Ser., 1982, 196, 313. N. D. Sadanani, A. Walia, P. N. Kapoor, and R. N . Kapoor, J. Conrd. Chem., 198 1 , 11, 39. B. N. Die1 and A. D. Norman, Phosphorus Sulfur, 1982, 12, 227.

Phosphines and Phosphonium Salts

7

been prepared by free-radical- induced additions of primary or secondary phosphines t o the ally1 group of allylphosphinate esters, followed by reduction of the phosphinic ester grouping with lithium aluminium h ~ d r i d e . ' ~ AIBN-induced additions of primary phosphines t o cyclo-octa-lY5-dienegive rise t o the 9-phosphabicyclononane system (42).58Addition of secondary phosphines t o the terminal double-bond of w-alkenyl-silanes has given the phosphines (43), which may be bound t o an inorganic support via the silane The (aminoalky1)phosphines (44) are formed in the addition of secondary phosp hines to bis(t rifluorome t hy1)ketimine. A metal- t emplat eassisted addition of bis(methy1phosphino)ethane to the carbonyl groups of acetylacetone has given a new macrocyclic quadridentate phosphine ligand, isolated as a palladium complex (45).6'

( 4 1 ) R 1 , R2 R

=

=

0-2

M e o r Ph

(42) R = alkyl

( 4 3 ) R 1 = P r , C y , o r Ph R'=

C1, M e , or OEt

n = 2,

3 , 8 , or 1 4

Preparation of Phosphines by Reduction. Mathey's group has reported a new reduction-complexation-decomplexation procedure for the reduction of phosphine sulphides, involving their reaction with iron pentacarbonyl at 130- 150 "C t o give the phosphine complexes (R3P)Fe(C0)4, from which the phosphines may be isolated by treatment with copper(I1) chloride. This procedure is compatible with a wide range of sensitive functional groups, and is less subject to steric hindrance at phosphorus than is the related nickelocene-ally1 iodide procedure that has been developed by this group in recent 57

6o

M . Baacke, S. Hietkamp, S. Morton, and 0 . Stelzer, Chem. Ber., 1981, 114, 2568. Nippon Chemical Industrial Co. Ltd, Jpn. Kokai Tokkyo Koho 80 122 792 (Chem. Abstr., 1981, 9 5 , 7451). A. A. Oswald and L. L. Murrell, U.S.P. 4 2 6 8 682 (Chem. Abstr., 1981, 95, 150 878). A. E'. Jansen, J . R. Dalziel, S. N . Kay, and R. Galka, J. Inorg. Nucl. Chem., 1981, 43,

61

R . Bartsch, S. Heitkamp, S. Morton, and 0. Stelzer, Angew. Chem., Int. Ed. Engl.,

s9

629. 1982, 2 1 , 3 7 5 .

Orga no p h 0 sph o rus Chemistry

8

years.62 Silane reagents continue t o find wide application. The phosphonin system (46) is formed on reduction of the related phosphine oxide, using p h e n y l ~ i l a n e The . ~ ~ phosphines (47), bearing chiral alkoxy-groups, have been obtained by reduction of the phosphine oxides with trichlorosilane. These phosphines are not accessible via addition of chiral alcohols to vinylphosphines.M [However, the addition of chiral secondary amines to vinylphosphines does take place, giving chiral (~-aminoalkyl)ph~sphines.~~ ] The disilane residue from the direct synthesis of chloro( methy1)silanes can also be used for the reduction of phosphine oxides.66 Lithium aluminium hydride in di-isopropylamine has been used t o reduce bis( trimethylsily1)phosphonous difluoride t o the first recorded primary aminophosphine (48).67

Me

Miscellaneous Methods of Preparation of Phosphines. A scheme for the synthesis of a range of chiral diphosphines (49) has been developed, making use of well-established reactions, i. e. sequential quaternization, alkaline hydrolysis of intermediate phosphonium salts, and reduction of phosphine oxides by trichlorosilane.68 The reactions of N-substituted benzylamines with diphenylphosphine have been used to prepare a variety of benzylphosphines, Treatment of allylic halides with diphenylphosphine under phasee.g. transfer conditions in the presence of aqueous alkali gives (substituted ally1)diphenylphosphines in satisfactory yield. 70 The unusual binucleating 62

63 64 65 66

F. Mercier, F. Mathey, J. Angenault, J.-C. Couturier, and Y . Mary, J. Organornet. Chem., 1982, 231, 237. L. D. Quin, E. D. Middlemas, and N . S. Rao, J. Org. Chem., 1982, 47, 905. G. Markl and B. Merkl, Tetrahedron Lett., 1981, 22, 4463. G . Markl and B. Merkl, Tetrahedron Lett., 1981,22, 4459. R. Calas, J . Dunogues, G. Deleris, and N. Duffaut, J. Orgunomet. Chem., 1982, 225, 117.

67

68 69

E. Niecke and R. Ruger, Angew. Chem., Int. Ed. Engl., 1982, 2 1 , 62. J. C. Briggs and G. Dyer, Chem. Ind. (London), 1982, 163. K. Keller, A. Tzschach, and M. Klepel, Ger. (East) P. 1 4 7 2 4 5 (Chem. Abstr., 1981, 9 5 , 150 893).

70

R. A. Khachatryan, S. V. Sayadyan, G. A. Mkrtchyan, and M. G. Indzhikyan, Arm. Khim. Zh., 1981, 34, 334 (Chem. Abstr., 1981, 9 5 , 169 286).

Phosphines and Phosphonium Salts Ph 2PCH2CONHCHR1COOR2 1

(52) R,

=

M e , P r i , or PhCH'

9 R~ PH ( COOR' (53)

R I P( COOR' (54)

R2= Et or But

chelating ligand (51) has been prepared by a 0-keto-ester synthesis from The reactivity of the carboxylic methyl o-(diphenylphosphin~)benzoate.~~ acid group of diphenylphosphinoacetic acid has been utilized in the synthesis of the chiral phosphino-amino-acid esters (52).72 The reactions of silylphosphines with acyl halides continue t o be used for the synthesis of a c y l p h ~ s p h i n e s , ~ ~whose -'~ thermal and photochemical reactions are of considerable interest. Silylphosphines also react with (a-halogenoalky1)carbonyl compounds to give the related a-phosphinomethylcarbonyl derivat i v e ~ .77~ ~The , reactions of primary phosphines with chloroformate esters in the presence of potassium carbonate lead to the phosphino-esters (53) and (54), depending on the respective mole ratios used.78 Full details have now appeared of the preparation of water-soluble diphosphines, e.g. ( 5 S ) , containing the bis-[ 2-(dipheny1phosphino)ethyllamino-group. 79 0

ButP\,/pBut ( 5 7 ) X = NPri, S , (55)

or S e

A number of new heterocyclic systems have been described. The reaction of white phosphorus with 1,ly2,2-tetramethyldistannanein the dark at 0 "C gives the cage structure (56).80 The three-membered ring systems ( 5 7 ) are formed in the reactions of bis(t-butyl)(chloro)diphosphine with bis(trimethylstannyl)isopropylamine8' or the related bis(trimethylstanny1) sulphide 71

T. B. Rauchfuss, S. R. Wilson, and D. A. Wrobleski, J . A m . Chem. SOC., 1981, 1 0 3 , 6769.

72

73 74

75

F. Job and E. Trdcsanyi, J. Organomet. Chem., 1982, 2 3 1 , 63. M. Dankowski and K. Praefcke, Phosphorus Sulfur, 1982, 12, 131. E. Lindner, M . Steinwand, and S. Hoehne, Chem. Ber., 1982, 115, 2 181. E. Lindner, M . Steinwand, and S. Hoehne, Angew. Chem., Znt. Ed. Engl., 1982, 2 1 , 355.

76

77

H. Brunner, M. E. Dylla, G. A. M. Hecht, and W. Pieronczyk, 2. Naturforsch., Teil. B, 1982, 37, 404. A. Tzschach, S. Friebe, and M . Klepel, Ger. (East) P. 144 265 (Chem. A bstr., 198 1, 95, 62 404).

78

79

**

''

R. Thamm and E. Fluck, 2. Naturforsch., Teil. B, 1981, 3 6 , 910. R. G. NUZZO, S. L. Haynie, M. E. Wilson, and G. M . Whitesides, J . Org. Chem., 1981, 46, 2861. M. Drager and B. Mathiasch, Angew. Chem., Znt. Ed. Engl., 1981, 2 0 , 1029. M. Baudler and G. Kupprat, 2. Naturforsch., Teil. B, 1982, 37, 527.

Organophosphorus Chemistry

10

or selenide.82 Synthetic routes to other three- 83-85 and four-membered phosphorus-containing ring systems have also been reported. The bicyclic system (5 8) is formed in the reaction of tris(diethy1amino)phosphine with bi~-(2-mercaptoethyl)phosphine,~~ and the reaction of o-aminothiophenol with bis(dialky1amino)phosphines gives the benzothiazaphospholine system (59).88 The aminophosphine- functionalized macrocycle (60) has been prepared 8 9 and chiral aminophosphines that are derived from 3-aminopiperidine have also been reported.g0

sgp

s?\

(59)

(58)

‘i

s J N-pR2

R

=

M e , E t , o r Ph

(60)

R

= M e o r Ph

Reactions of Phosphines.-Hints that some accepted mechanistic schemes for the reactions of phosphorus compounds may be in need of revision are to be found in a wide-ranging review of electron-transfer catalysis in organic and inorganic chemistry.” We await developments with interest! Nucleophilic Attack a t Carbon. Second-order rate constants and activation parameters for the reaction of triphenylphosphine with benzyl chloride have been measured in a wide range of solvents, enabling an analysis of medium effects.92 The kinetics of the reactions of a range of alkyldiphenylphosphines with iodomethane have also been studied. The nucleophilicities of the phosphines correlate with the Taft equation, indicating the operation of both inductive and steric effects.93 The reactions of trimethylphosphine with dichloro- and dibromo-methane have been investigated in detail. In alcohol solvents, the products are the tetramethylphosphonium halide, trimethylphosphine oxide, and an alkyl halide, which arise as shown in Scheme 1.” M . Baudler, H. Suchomel, G. Furstenburg, and U . Schings, Angew. Chem., Int. E d . Engl., 1981, 20, 1044. 8 3 E. Niecke, A. Nickloweit-Luke, R. Ruger, B. Krebs and H. Grewe, 2. Natuvforsch., T e d . B, 1981, 36, 1566. 84 E. Niecke, K. Schwichtenhovel, H.-G. Schafer, and B . Krebs, Angew. Chem., Int. E d . Engl., 1981, 20, 963. W. Clegg, M. Haase, M. Hesse, U. Klingebiel, and G. M. Sheldrick, Angew. Chem., Int. E d . Engl., 1982, 21, 445. 86 E. Niecke, A. Nickloweit- Luke, and R. Rueger, Phosphorus Sulfur, 1982, 12, 2 13. ” K. Jurkschat, C. Miigge, A. Tzschach, W. Uhlig, and A. Zschunke, Tetrahedron L e t t . ,

82

’’

1982, 23, 1345. 88

’’ 91 92

93 94

M. A. Pudovik, Yu. B. Mikhailov, and A. N. Pudovik, Izv. Akad. Nauk S S S R , Ser. Khim., 1981, 1108 (Chem. Abstr., 1981, 9 5 , 2 0 4 049). J . Powell and C. J. May, J. A m . Chem. SOC., 1982, 104, 2636. K. Osakada, T. Ikariya, M. Saburi, and S. Yoshikawa, Chem. L e t t . , 198 1, 169 1. M. Chanon and M . L. Tobe, Angew. Chem., Int. E d . Engl., 1982, 21, 1. E. Maccarone, G. Perrini, and M. Torre, Gazz. Chim. Ital., 1982, 21, 1. J. Koketsu and K. Kitaura, Chubu K o g y o Daigaku K i y o , A , 1981, 17, 7 3 (Chem. A b s t r . , 1982, 96, 142 991). J . H. Karsch, Phosphorus Sulfur, 1982, 12, 2 17.

Phosphines and Phosphonium Salts +

i

1

Me PCH2X X-

CH2X2

11

3

Me3PX2

li

Me3P=CH2

+

Me4P+ X-

+

( X = C 1 or B r )

i

+ RX

+

Me3PO-

Me3POR X-

Reagents: i, PMe,; ii, ROH

Scheme 1

Tertiary phosphines attack anodically generated cationic species t o form phosphonium salts.95 On treatment with ethyl acrylate in ethanol solution, A3-phospholens ( 6 1) undergo isomerization to the A*-system (62). The authors propose a mechanism involving, as the key intermediate, a quinquecovalent phosphorane ( 6 3 ) , arising from nucleophilic attack by phosphorus at the &carbon of the acrylic ester, followed by protonation of the resulting zwitterion by the solvent.96 The cyclopropenes (64) undergo ring-opening on reaction with triphenylphosphine, with the formation of the stabilized ylides (65).97 Full details have now appeared of the reactions in aqueous ethanol of the o-alkynyl-phosphines (66), involving intramolecular attack by phosphorus at acetylenic carbon.98 a M ; C ; ; l M E

t

*

Me

#R

3R

(61) R = M e o r Ph

(62)

R1 Ph3P ___z

PPh3

R2

(64)

(651

( 6 6 ) R = H o r CFCPh

(R1= H or COOMe, R 2 = COOMe) 95

S . Nakai, Yuki Gosei Kagaku Kyokaishi, 1981, 39, 154 (Chem. Absrr., 1981, 95, 6 1 045).

96 .y7 y8

P. D. Beer, P. J . Hammond, and C . D. Hall, Phosphorus Sulfur, 1981, 10, 185. G. Hauk and H. Durr, J. Chem. R e x , 1981, (S), 180; ( M ) 2227. T. Butters, I. Haller-Pauls, and W. Winter, Chem. Ber., 1982, 115, 578.

12

Organophosphorus Chemistry

Several papers have reported studies of nilcleophilic attack by phosphines at carbon in molecules that are co-ordinated to transition metals. The investigation of nucleophilic attack by phosphines on co-ordinated cyclobutadiene has been extended with an exploration of the rate effects of ‘noninvolved’ l i g a n d ~ .The ~ ~ relative nucleophilicities of tributylphosphine and tributyl phosphite towards co-ordinated carbenoid systems have been compared, and shown to depend on the nature of the electrophilic centre.lm A study1O1 of the attack of substituted triarylphosphines (RC6H4)3P on the co-ordinated 1-5-q-cyclohexadienyl system has revealed the operation of a significant anchimeric effect in the reaction of the o -methoxyphenylphosphine, implying stabilization of the developing phosphonium centre in the transition state by oxygen 2p-phosphorus 3d interactions of the type previously suggested by McEwen e t al.lo2 The magnitude of this effect is significantly larger than that observed by McEwen e t al. in their studies of the reactions of phosphines with benzyl chloride, implying a greater degree of formation of a P-C bond in the transition of the above reaction.

Nucleophilic A t t a c k at Halogen. Full details have now appeared of the reactions of a-bromo-a-cyano-esters, -nitriles, and -imides with a triphenylphosphine-silver nitrate complex, which lead to replacement of the halogen by a nitro-group under mild conditions. lo3 Halogenophosphonium salts, e.g. (67), are reported to be formed, at low temperatures, in the reactions of sterically hindered phosphines with carbon tetrahalides. The reactions of the cyclic triphosphine (68) with halogens proceed with ring cleavage. lo’

The mechanism of the reaction of the triphenylphosphine-carbon tetrachloride ‘reagent’ with alcohols, leading t o the formation of alkyl halides, has received detailed study. The intermediate that is formed in the reaction of triphenylphosphine, carbon tetrachloride, and neopentyl alcohol decomposes bimolecularly in acetonitrile solution, and not unimolecularly , as occurs in deuteriochloroform. This kinetic order is not consistent with a pericyclic pathway, but is consistent with a mechanism involving the formation of clustered alkoxyphosphonium halide ion-pairs - a two- or three-dimensional array, stabilized by interaction of the alkoxyphosphonium 99 1 no lo’

lo’

Io3 ‘04

lo’

H . S. Choi and D. A. Sweigart, Organometallics (Washington, D . C . ) , 1982, 1 , 60. H . S. Choi and D. A. Sweigart, J . Organomet. Chem., 1982, 228, 2 4 9 . J . G. Atton and L. A. P. Kane-Maguire, J. Organomet. Chem., 1982, 2 2 6 , C43. W. E. McEwen, A. €3. Janes, J . W. Knapczyk, V. L. Kyllingstad, W . - I . Shiau, S. Shore, and J . H . Smith, J. A m . Chem. SOC., 1978. 1 0 0 , 7 3 0 4 . R . Ketari and A. Foucaud, J. Org. Chem., 1981, 4 6 , 4 4 9 8 . 0. I. Kolodyazhnyi, Zh. Obshch. Khim., 1981, 5 1 , 2 4 6 6 (Chem. Abstr., 1982, 96, 122 896). M. Baudler and J . Hellmann, 2. Anorg. Allg. Chem., 1981, 4 8 0 , 129.

Phosphines and Phosphonium Salts

13

cation with a halide ion of another unit. Consistent with this is the incorporation of 'external' nucleophiles into the neopentyl skeleton on addition of, e.g., thiocyanate ion, t o the system. It has also been noted that a change of solvent also affects the steric course of decomposition of intermediates. Reactions conducted in acetonitrile have been found to proceed with predominant racemization at the chiral carbon that bears the alcohol function, rather than with the 'usual' inversion of configuration.'06 The above conclusions are supported by the results of a study of the reactions of a series of alkoxytriphenylphosphonium triflates with nucleophiles, which again indicate the involvement of an ion-pair cluster me~hanism.''~ The reactions of a range of simple diols with the triphenylphosphinecarbon tetrachloride reagent have been investigated. 1,4-Diols, e.g. (69), are smoothly converted into cyclic ethers. However, the corresponding reactions of diols of shorter or longer carbon chain-length lead t o halogeno-alcohols and dichloroalkanes. log Attempted chlorination of the a-hydroxyacetal (70) leads t o a mixture of oligomeric products, e.g. (7 1 Alkenes are formed in the reactions of alcohols with the triphenylphosphine-carbon tetrachloride system at reflux temperatures."' This reagent has also been used for halogenation of methyl gibberellate,"' and its reactions with 5-phenyltetrazole have been investigated. l 2 The reaction of triphenylphosphine with bromotrichloromethane has been used t o generate the ylide (72; X=C1) for use in

& : A cc1 Me

OMe

Ph3P=CX 2 (72)

lo6 lo7 lo*

'lo

"*

x

=

ci

or O

B

~

J . D. Slagle, T. T.-S. Huang, and B. Franzus,J. Org. Chem., 1981, 46, 3526. S. Ramos, and W. Rosen,J. Org. Chem., 1981, 46, 3530. C. N . Barry and S. A. Evans, J. Org. Chem., 1981, 46, 3361. S. David and G. de Sennyey, Tetrahedron Lett., 1981, 2 2 , 4503. T. U. Qazi, Libyan J. Sci.,A , 1980, 10, 39 (Chem. Abstr., 1981, 9 5 , 115 098). J. Z. Duri, B. M. Fraga, and J . R. Hanson, J . Chem. SOC., Perkin Trans. 1, 1981, 30 16.

I . N . Zhmurova, V. G. Yurchenko, and A. M . Pinchuk, Zh. Obshch. Khim., 1981, 51, 2462 (Chem. Abstr., 1982, 96, 162 824).

~

Organophosphorus Chemistry

14

subsequent Wittig reaction^."^ Similarly, the ylide (72; X = OBut) is formed in the reaction of triphenylphosphine and bromoform in the presence of potassium t-butoxide. '14 Combined reagents involving tertiary phosphines and hexachloroethane have also found further applications. The tris(dimethy1amino)phosphinehexachloroethane- 1-hydroxybenzotriazole combined system has been used for the synthesis of arginine-containing peptides. '15 The triphenylphosphinehexachloroethane system has found use for polycondensation reactions leading to polyesters,l16 and has also been used, in the presence of triethylamine, in heterocyclic synthesis for the cyclocondensation of ortho-Nacylamino- est ers. Combinations of triphenylphosphine or tributylphosphine with iodine have been evaluated as reagents for the formation of iodides and esters from alcohols."8 Further reports have appeared of the use of the triphenylphosphine-iodine-imidazole reagent for the modification of carbohydrates."'

Nucleophilic Attack at Other Atoms. The use of the triphenylphosphineborane adduct (73) as a hydroborating agent has been described. Diborane can be liberated from this very stable complex simply by treatment with sulphur or iodomethane in THF under reflux.12' Phosphorus-boron bonds are formed in the reactions of trimethylphosphine with closo-carbaboranes. 12' Ph

Ph

Ph P-BH3 3

PhZ J N P h (73)

ArN3

A

PhX J N P h

/ \N A r

Ph

Ph

(74)

(75)

R3P=NCONHNHCONH2 (76)

The Staudinger reactions of isomeric diazaphospholines (74) with substituded aryl azides to give the As-phosphazenes (75) have been studied. The stereochemistry of the reaction depends on the nature of the substituted aryl 'I3

'I4

W. G . Taylor, J. Org. Chem., 1981, 46, 4290. S. Verma, N. M . Kansal, R. S. Mishra, and M. M. Bokadia, Heterocycles, 1981, 16, 15 37.

'15

'19

R. Appel and E. Hiester, Chem. Ber., 1981, 114, 2649. N. Ogata, K. Sanui, W. Tanaka, and S. Yasuda, Polymer J., 1981, 13, 989. D. Achakzi, M. Ertas, R. Appel, and €4. Wamhoff, Chem. Ber., 1981, 114, 3188. R. K. Haynes and M . Holden, Aust. J . Chem., 1982, 3 5 , 517. P. J . Garegg, R . Johansson, C. Ortega, and B. Samuelsson, J . Chem. Soc., Perkin Trans. 1 , 1982, 681. A. Pelter, R. Rosser, and S. Mills,J. Chem. SOC.,Chem. Commun., 1981, 1014. G. Siwapinyoyos and T. Onak, Inorg. Chem., 1982, 21, 156.

Phosphines and Phosphonium Salts

15

group of the azide.'22 h5-Phosphazenes are also formed in the reactions of triphenylphosphine with diary1 tellurimides. 123 A new class of As-phosphazenes, the N-acylphosphazenes (76), is formed in the reactions of tertiary phosphines with azodicarbonamide.124 Applications of the triphenylphosphine-diethyl azodicarboxylate (DAD) reagent continue to appear. In the past year, it has been used for the alkylation of thioureas 12' and active-methylene compounds,126 and for the alkylation and acylation of N-hydroxy-lactams. 12' There have also been a number of applications in carbohydrate chemistry for the preparation of azidosugars 128 and for epoxidation reactions. 1299 130 This reagent also converts vic-diols in the steroid series into 0x0-steroids by displacement of axial hydrogen and extrusion of triphenylphosphine oxide. These reactions proceed both regio- and stereo-specifically.13' Chiral phosphines have been used t o investigate the mechanism of the high-yield synthesis of phenyl esters from carboxylic acids and phenols in the presence of tertiary phosphineDAD systems. When the reaction is carried out with optically active methylphenylpropylphosphine, the racemic phosphine oxide is produced, indicating the involvement of the intermediate phosphorane (77).'32 Alcohols are converted into the related thiol acetates in 95% yield on treatment with thioacetic acid in the presence of triphenylphosphine and di-isopropyl azodicarboxylate. Subsequent reduction with lithium aluminium hydride, or saponification, leads to the corresponding thiols, the overall conversion of alcohol into thiol proceeding with almost complete inversion of configuration. 133 OA r

I

Me

-P-

PhCOO

/*

\Ph

Pr

(77)

Bis-( p-methoxyphenyl) selenoxide 134 and the related tellurium compound 13' are deoxygenated, on reaction with phosphines, under mild G. Baccolini, P. E. Todesco, and G. Bartoli, Phosphonts Sulfur, 1981, 10, 387. V. I. Naddaka, V. P. Gar'kin, K. V. Obayan, and V. I. Minkin, Zh. Org. K h i m . , 1981, 17, 669 (Chem. Abstr., 1981, 95, 97 258). 1 2 4 S. Bittner, Y . Assaf, and M. Pomerantz, J. Org. Chem., 1982, 47, 99. I Z s H. Nagasawa and 0. Mitsunobu, Bull. Chem. SOC.Jpn., 1981, 54, 2223. '*' T. Kurihara, M. Sugizaki, I. Kime, M. Wada, and 0. Mitsunobu, Bull. Chem. SOC. Jpn., 1981, 54, 2107. 12' E. Grochowski and T. Boleslawska, Pol. J. Chem., 1981, 55, 615. I28 H. H. Brandstetter, E. Zbiral, and G. Schulz, LiebigsAnn. Chem., 1981, 1. 1 2 9 R. D. Guthrie, I. D. Jenkins, R. Yamasaki, B. W. Skelton, and A. H. White, J. Chem. SOC.Perkin Trans. I , 19 8 1, 2 32 8. I 3 O R . D. Guthrie and I . D. Jenkins,Aust. J. Chem., 1981, 34, 1997. 1 3 ' G . Penz and E. Zbiral, Monatsh. Chem., 1981, 112, 1045. 1 3 * E. Grochowski, Bull. Acad. Pol. Sci., Ser. Sci. Chim., 1980, 28, 489 (Chem. Abstr., 12*

1982,96, 12 1 887). 133 134

R. P. Volante, Tetrahedron L e t t . , 1981, 22, 31 19. F. Ogura, H. Yamaguchi, T. Otsubo, and H. Tanaka, Bull. Chem. SOC.Jpn., 1982, 55, 641. S. V. Ley, C . A. Meerholz, and D. H. R. Barton, Tetrahedron, Suppl. 9, 1981, 213.

Organophosphorus Chemistry

16

conditions. Improved yields are claimed for the preparation of the adducts (78) of triarylphosphines and sulphur trioxide in inert organic solvents. 136 An X-ray study has shown conclusively that the triphenylphosphine-sulphur trioxide adduct has the structure (78) rather than a phosphorus-oxygenbonded alternative, 137 Initial nucleophilic attack at sulphur is involved in the reaction of triphenylphosphine with the naphthalene derivative (79), leading to the intermediate betaine (80), which, on heating in decalin, decomposes

to give the heterocycle (8 1) and triphenylphosphine oxide. 138 Tris(diethy1amino)phosphine removes one sulphur atom from the 1,2-dithiolan-3-0ne system (82) to give the thiolactam system (83), whereas the related reactions with triphenylphosphine result in ring-opening.139 The reactions of tributylphosphine with the germadithiolan (84) also result in removal of a sulphur atom from the ring system.’4o The 1: 1 adduct of germanium(I1) chloride with 1,2-bis(diphenylphosphino)ethane has been shown to have a structure which is intermediate between a half-chelate and a double ~ 1 i d e .142 l ~ A~ ~ detailed 31P n.m.r. study of the reaction of P4S9 with triphenylphosphine has revealed the intermediate formation of the hitherto unknown sulphide P4S8, resulting from the removal of a terminal sulphur from the P4S9 cage structure. 143 A. A. Lapin, V. G. Pravdin, Yu. A. Bochkarev, G. V. Romanov, and A. N . Pudovik, USSR P. 859 3 7 1 (Chem. Abstr., 1982, 96, 52 505). 1 3 7 I. J. Galpin, G. W. Kenner, A. Marston, and 0. S. Mills, J. Chem. SOC., Chem. Commun., 1981, 789. 1 3 8 J. L. Kice and K. Krowicki, J . Org. Chem., 1981, 46, 4894. 1 3 9 M. G. Lin’kova, 0. V. Kul’disheva, and I. L. Knunyants, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 1633 (Chem. Abstr., 1981, 9 5 , 150 503). I 4 O J . Barrau, H. Lavayssiere, G. D o u s e , C. Couret, and J . Satgk, J. Organomet. Chem., 136

1981, 2 2 1 , 2 7 1 . 141

N . Bruncks, W.-W. du Mont, J . Pickardt, and G. Rudolph, Chem. Bey., 1981, 114,

14*

W.-W. du Mont. G. Rudolph, and N . Bruncks, Angew. Chem., Int. Ed. Engl., 1981,

143

J . - J . Barieux and M. C. Dkmarcq, J. Chem. SOC.,Chem. Commun., 1982, 176.

3572. 20,475.

Phosphines and Phosphonium Salts

17

Miscellaneous Reactions of Phosphines. 'The reactions of phosphines with organic peroxides continue to be studied. Treatment of the bicyclic peroxide (8 5) with triphenylphosphine leads to the phosphorane (86), which, although reasonably stable in dry benzene solution, undergoes decomposition t o the trans-diol (87) and triphenylphosphine oxide in the presence of water.'44 The reactions of triarylphosphines with tetramethyl- 1,2-dioxetan (88), leading t o the phosphoranes (89), have received further attention. Activation parameters for these reactions, in benzene solution, have now been obtained, and are consistent with the generally accepted biphilic mechanism. 145 The kinetics of the related reactions of a range of A3-phospholens (90) with diethyl peroxide have also been discussed in terms of the biphilic m e ~ h a n i s m . The ' ~ ~ fragmentation reactions of phosphoranes derived from A3-phospholens and sulphenate esters,'47 and from p h e n a n t h r a q ~ i n o n e ,have ' ~ ~ also been studied.

(87)

+

Ph 3P0

uMe

Me

R

The basicities of a range of substituted triarylphosphines have been measured by the nitromethane titration method, together with those of tri-tbutylphosphine and tricyclohexylphosphine. 149 A new selective acidextraction procedure enables the separation of trialkyl- or alkyl(ary1)phosphines from their mixtures with triaryl-phosphines. Chelate complexes of bis(dipheny1phosphino)methane are metallated at the methylene carbon on treatment with the butyl-lithium-TMEDA reagent. The resulting co-ordinated carbanionic diphosphine. undergoes reaction at carbon with a wide range of electrophiles to form complexes of the type ( 9 l ) . l S 1 An

Is'

E. L. Clennan and P. C. Heah,J. Org. Chem., 1981, 46, 4105, A. L. Baumstark, M . Barrett, and K. M . Kral, J. Heterocycl. Chem., 1982, 201. P. J. Hammond, G. Scott, and C. D. Hall, J. Chem. SOC., Perkin TVQnS. 2, 1982, 205. P. J . Hammond, J . R. Lloyd, and C. D. Hall, Phosphorus Sulfur, 1981, 10, 67. P. J. Hammond, J . R. Lloyd, and C. D. Hall, Phosphorus Sulfur, 1981, 10, 47. T. Allman and R. G. Goel, Can. J . Chern., 1982, 6 0 , 716. D. R. Bryant and R. A. Galley, Br. Pat. Appl. 2 0 7 4 166 (Chern. Abstr., 1982, 9 6 ,

151

104 5 19). S. Al-Jibori and B. L. Shaw, J. Chem.

144

14' 147

'41 149

SOC.,Chem. Commun.,

1982, 286.

18

Organophosphorus Chemistry

unusual ring-expansion, involving nucleophilic attack by NH2 on a coordinated phosphorus atom, with C-P fission, occurs in the reaction of the benzoyl derivative (9 1 ; R = PhCO) with hydrazine to form (92).'52 Methylphosphines that are co-ordinated to nickel are selectively metallated at the methyl carbon on treatment with butyl-lithium, even when potentially reactive dimethoxyphenyl co-ligands are present. lS3 The phosphine (93), when co-ordinated to metal carbonyl acceptors via phosphorus, undergoes quaternization at nitrogen on treatment with iodomethane, t o give cationic complexes which are reasonably soluble in aqueous solvents.lS4 Further studies of the cleavage of phosphorus-carbon bonds of co-ordinated phosphines under hydrogenation conditions have been reported. lSs H

Ph PCH CH NMe (93) (91) R = a l k y l , MegSi, Ph,P, or PhCO

The reaction between an aldehyde, an allylic alcohol, and triphenylphosphine in the presence of palladium(I1) acetate leads to the formation of a 1,3-diene and triphenylphosphine oxide. lS6 On treatment with tributylphosphine and methyl thiocyanate, aromatic aldehydes are converted into S-methyl thiobenzoates and phenylacetonitriles.157 (Silylamino)phosphines, e.g. (94), react with carbonyl compounds t o give the X'-phosphazenes (95).'58 The reaction of phenyl(trimethylsily1)phosphine with pivaloyl cyanide leads t o the secondary phosphine (96).'" R CO

(MegSi)ZNPMe2 (94)

2Me3SiN=PMe2(CR2)0SiMe3 (95)

PhPHC( CN) (OSiMe3)But ( 96 )

The heterocyclic phosphines (97) rearrange, on heating in the presence of acid, to form the phosphine oxides (98).160 The reaction of p-bromophenol with carboxylic acids in the presence of triphenylphosphine and triethylamine at high temperatures ( 1 70-200 "C) gives phenyl carboxylates, with 152

S. Al-Jibori, W. S. McDonald, and B. L. Shaw, J. Chem. Soc., Chem. Commun., 1982, 287.

153

M. Wada, J. Chem. Soc., Chem. Commun., 1981, 680. I s 4 R. T. Smith and M. C. Baird, Transition Met. Chem., 1981, 6, 197. S. A . Maclaughlin, A. J. Carty, and N . J. Taylor, Can. J. Chem., 1982, 60, 8 7 . 1 5 6 M. Moreno-Manas and A . Trius, Tetrahedron L e t t . , 1981, 2 2 , 3109. 157 M. Kurauchi, T. Imamoto, and M. Yokayama, Tetrahedron Lett., 1981, 2 2 , 4985. D. W. Morton and R. H . Neilson, Organometallics (Washington D . C . ) , 1982, 1, 289. l S 9 A. N. Pudovik, G. V. Romanov, and T. Ya. Stepanov, Zzv. A k a d , Nauk SSSR, Ser. Khim., 1981, 1675 (Chem. Abstr., 1981, 95, 2 0 4 0 6 6 ) . I6O K. A . Petrov, V. A. Chauzov, and N. Yu. Lebedeva, Zh. Obshch. Khim., 1981, 5 1 , 2142 (Chem. Abstr., 1982, 96, 6807).

19

Phosph in es a n d Ph o s p h o n iu m Salts

Ph (97)

elimination of hydrogen bromide. Only small amounts of the p -bromophenyl carboxylates are formed.16' Full details have now appeared of the use of tris(imidazo1-1 -yl)phosphine in the synthesis of uridine oligonucleotides. 16* E.s.r. studies support the postulate of a radical-ion mechanism for the reactions of tris(dialky1amino)phosphines with 2-bromovinyl phenyl ~ulphones.'~ Limitations ~ to the use of dicyclohexylphosphine as a radicaltrapping agent have now been discovered in the reactions of tributylstannyl anions with alkyl bromides.lM

2 Phosphonium Salts Preparation.-The reaction of the alkyl halide (99) with diphenyl(trimethy1sily1)phosphine leads to the formation of the bicyclic phosphonium salt ( Berlin's group has continued studies of the cyclization of alkenylphosphonium salts and has now reported the synthesis of a range of bisphosphonium salts (101), which exist as mixtures of meso- and (*)-forms in solution.'66 For one of these salts, (101; n = 2 , X=C104), the meso- and

(99)

(100)

(101) n

= 1-6,

X = PF6 or C 1 0 4

(?)-diastereoisomers have been separated by fractional crystallization, and the (*)-form has been partially resolved via the use o f the silver hydrogen dibenzoyltartrates. 16' Prior to this work, no heterocyclic bisphosphonium 16'

163

S. Hashimoto and I. Furukawa, Bull. Chem. SOL'.Jpn., 1981, 54, 2839. T. Shimidzu, K. Yamana, K. Nakamichi, and A . Murakami, J. Chem. SOC., Perkin Trans. 1, 1981, 2294. E. A. Berdnikov, A. A. Vafina, V. L. Polushina, R. M. Zaripova, F. R. Tantasheva, and A . V. Il'yasov, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 2 7 8 5 (Chem. Abstr., 1982.96, 142 041).

164 165

166

M. Newcomb and M. G. Smith, J. Organomet. Chem., 1982, 2 2 8 , 61. Mazhar-ul-Haque, W. Horne, S. E. Cremer, and J . T. Most, J . Chem. SOC.,Perkin Trans. 2, 1981, 1000. N. Gurusamy, K. D. Berlin, D. van der Helm, and M. B. Hossain, J. A m . Chem. SOC., 1982, 104, 3107.

N. Gurusamy and K: D. Berlin, J . Am. Chem. SOC., 1982, 104, 3 1 14.

2

20

Organophosphorus Chemistry

salt containing two asymmetric phosphorus atoms in different rings has been separated into diastereoisomers or resolved into optically active forms. The cyclic salt (1 02) is formed in the reaction of 4-hydroxybutyl(diphenyl)phosphine with hydrogen bromide in toluene solution. 16' +

i,)

Ph'

Br-

'Ph

Whereas triphenylphosphine does not react with the hindered pyrylium salt (103), tributylphosphine reacts readily to give the salt (104).16' A range of heteroaryltriphenylphosphonium salts has been prepared by the direct reaction of t riphenylphosphine with the appropriate 2- halogenoderivatives of pyridine, quinoline, benzothiazole, and b e n z o x a ~ o l e . 'Stabi~~ lized ylides, bearing appropriately sited alcohol functions, can be cyclized t o form the salts (105) and ( 1 06), which have been shown to have analgesic properties. 17'

+

CHPPh3

BF4

-

( 1 0 6 ) R = Me o r Ph

A route to the phosphonium keten acetals (107) has been devised (Scheme 2 ) . These compounds are potential alkylating agents for phosphorus acid anions. 172

Ph3;CH2Ar

Br-

i 9

ii,

Ph P = C ( A r ) C O O M e 3

--

+ Ph 3P

OMe

Ar

Reagents: i, BuLi; ii, ClC0,Me; i i i , M e S 0 , F

Scheme 2 J . M. Muchowski and M. C. Venuti, U.S. P. 4 2 9 6 0 4 2 (Chem. Abstr., 1982, 9 6 , 68 36 1). l60

"O

"' 17'

G. A. Reynolds and C. H . Chen, J . Heterocycl. Chem., 1981, 18, 1235. I. N . Zhmurova, 1. M. Kosinskaya, and A. M. Pinchuk, Zh. Obshch. Khim., 1981, 5 1 , 1538 (Chem. Abstr., 1981, 9 5 , 169 308). R. A . Mueller, U S . P. 4 2 9 7 4 8 7 (Chem. Absrr., 1982, 96, 2 0 2 6 4 ) . A. T. Zaslona and C. D. Hall, J . Chem. SOC.,Perkin Trans. I , 1981, 3059.

-

Phosphines and Phosphonium Salts

21

The synthesis of the allenic bisphosphonium salt (108) has been r e p ~ r t e d . " ~Previous structural assignments 174 for the products of the reaction of triphenylphosphine with 5-bromopent-3-en-2-one have been revised. It has now been shown that this reaction leads t o a 3 : 1 mixture of the protoThe reaction of @-unsaturated meric phosphonium salts (109) and (1 aldehydes with the ylide (1 1 1) leads to the 1,3-dienylphosphonium salts (1 12).176 Treatment of the unsaturated alkyl halides ( 1 13) with tertiary phosphines has given the bisphosphonium salts (1 14) 177 and (1 15).17' The reaction of triphenylphosphine with the halide ( 1 16) leads progressively t o the salts (1 17) and (1 18 ) . l m

+

21-

Ph3P-C=C=C I NMe2

+

+

I-PPh3 NMe2

+ Ph PCH=CHCH2COMe

Ph3PCH2CH=CHCOMe Br-

R1CH=CR2CH0 + Ph3P=CHSiMeg

3

Br-

-

Ph 3kH=CHCR2=CHR1 Br(112) R1= H , Me, or Ph

(111)

R ~ =H or Me

++ +

+

R3PCH=C(Me)CH2CH2PR3

ZBr-

(114) R = Me or Ph

BrCH2CH=C(Z)CH2Br (113) Z

=

+

C1 or Me

R3PCH2CH=C(C1)CH2PR3

2Br-

(115) R = Me o r Ph

+ C1CH2COCH=CHC1 (116)

C1CH2COCH=CHPPh3 (117)

+ C1-

+

Ph3PCH2COCH=CHPPh3

2C1-

(118)

The bisphosphonium salt (1 19) is formed in the reaction of triethylphosphine with carbon disulphide in the presence of hydrated iron(11) tetrafluoroborate.18* Various chloromethyl derivatives of transition metals have been converted into phosphonium salts, e.g. (120), on treatment with 173 174

17' 179

R . Weiss, H. Wolf, U . Schubert, and T. Clark, J . A m . Chem. SOC., 1981, 103, 6142. J. Font and P. De March, Tetrahedron Lett., 1978, 3601. J . Font and P. De March, Tetrahedron L e t t . , 1981, 22, 2391. F. Plhnat, Tetrahedron Lett., 1981, 22, 4705. R. K. Lulukyan, M . Zh. Ovakimyan, and M . G. Indzhikyan, Arm. Khim. Zh., 1981, 34, 563 (Chem. Abstr., 1982, 96, 6803). R. K. Lulukyan, M. Zh. Ovakimyan, G. A. Panosyan, and M . G. lndzhikyan, A r m . Khim. Zh., 1981, 34, 474 (Chem. Abstr., 1981, 9 5 , 169 300). M . I. Shevchuk, V. P. Rudi, I. V. Megera, and F. A. Nadtochii, Zh. Obshch. Khim., 1981, 51, 1024 (Chem. Abstr., 1981, 9 5 , 204053). C. Bianchini, A. Meli, and A. Orlandini, Phosphorus Sulfur, 1981, 11, 335.

22

Organophosphorus Chemistry

triphenylphosphine.181 At tempted arylation of [ ethyl(pheny1)amino 1diphenylphosphine with bromobenzene in the presence of a nickel(i1) bromide catalyst leads t o a mixture of rearranged phosphonium salts, from which (121) has been isolated. This arises from arylation of one of the isomeric phosphines resulting from a nickel-catalysed phospha-semidine rearrangement o f the above aminophosphine.182

2Br-

Ph ,P++

+ PPh

W

,

Ph2PCH2PPh2 Br-

1

SiIePh 2P=C=PPh2

I

(kH2I4

I

Ph2PCH2PPh2 Br-

+

bl ePh P= C= PPh

2

There have been a number of interesting contributions from Schmidbaur's laboratory. The reaction of bis(dipheny1phosphino)methane with 1,4 dibromobutane has been shown t o lead t o two products, the previously characterized cyclic salt ( 122) and also the acyclic salt ( 123), which was used t o generate the new biscarbodiphosphorane ( 124).183 Monoquaternization of bis(dipheny1phosphino)alkanes with 9-bromofluorene gives the salts ( 125), which, o n treatment with base, give the bidentate phosphine-phosphonium ylide ligands (126).lw The new ylidic phosphine (127) has similarly been prepared from bis( dipheny1phosphino)methane. 18' The quaternization reactions of perfluoroalkyl- and pentafluorophenyl-phosphines have been studied and it has been noted that tris(pentafluoropheny1)phosphine under-

'"

C. Botha, J . R . Moss, and S. Pelling, J . Organomer. Chem., 1981, 2 2 0 , C21. J . Cristau, B. Chabaud, A. Chene, and H . Christol, Phosphorus Sulfur, 1981, 11,

''* H.

55.

lR5

H . Schmidbaur and T. Costa, Z.Naturforsch., Teil. B, 1982, 3 7 , 677. N . H o l y , U . Deschler, and H. Schmidbaur, Chem. Ber., 1982, 1 1 5 , 1379. H . Schmidbaur, U. Deschler, and B . Milewski-Mahrla, Angew. Chew., Inr. Ed. Engl., 1981, 20, 586.

Plzosphines and Phosphonium Salts

23

goes dearylation on treatment with iodomethane. 186 Routes to cycIopropylphosphonium salts have also been investigated.‘87 The keto-phosphonium salts (1 28) react with azidinium salts, e.g. (1 29), to form the diazomethylphosphonium salts (1 30). 18’ Hydrazidoyl bromides, e.g. (1 3 l ) , react with triphenylphosphine to give the a-arylazophenacyltriphenylphosphonium salts (1 32).’89 The amidophosphonium salts (1 33) are formed from the related ethoxycarbonylmethylphosphonium salts on treatment with a primary aromatic amine, either in the molten state or in a solvent.’90 The reactions of dicyclohexylcarbodi-imide with carboxymethyltriphenylphosphonium salts also lead to amidophosphonium salts. 19’ + - ‘N’

X(128)

R

Et

No

CH2C1, or Ar

= Me,

+ ArCOC=NNHAr

I Br

ArCOC=NNHAr PPh3 Br-

+I

Ph3PCH2CONHAr

X-

(133)

The reactions between dibromophosphoranes and difluorophosphoranes give rise to products that have been formulated as fluorophosphonium bromides ( 1 34).19* These compounds react with N-trimethylsilylphosphinimines to form the phosphiniminophosphonium salts, e.g. (1 35), which behave as phase-transfer agents for the transport of inorganic ions, e.g. Mn04-, from an aqueous to an organic phase.’93 Migration of a trimethylsilyl group from nitrogen to carbon occurs in the reactions of bis(trimethylsily1)amino(dialky1)phosphines ( 136) with ethyl bromoacetate, giving the phosphonium salts (1 37).’” Ring-opening occurs in the reaction of the oxygen heterocycle (1 38) with triphenylphosphine hydrobromide, giving the salt (1 39).19’ The H. Schmidbaur and C. E. Zybill, Chem. Ber., 1981, 114, 3589. H. Schmidbaur and A. Schier, Chem. Ber,, 1981, 114, 3385. M , Regitz, A. E.-R. Mohammed Tawfik, and H. Heydt, Liebigs Ann. Chem., 1981, 1865.

A. S. Shawali, A . 0. Abdelhamid, H. M . Hassaneen, and C. Parkanyi, Phosphorus Sulfur, 1982, 12, 377. G. P. Pavlov, V. A. Kukhtin, V. V. Kormachev, and A . V. Kazymov, USSR P. 8 0 6 685 (Chem. Abstr., 1981, 9 5 , 8 1 214). N . A. Nesmeyanov, S . T. Berman, N . A. Shorokhov, P. V. Petrovskii, and 0. A . Reutov, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 2152 (Chem. Abstr., 1982, 96,

lH9

190

19’

19 709).

R. Bartsch, 0. Stelzer, and R. Schmutzler, Z.Naturforsch., Teif. B, 1981, 36, 1349. 1 9 3 R. Bartsch, 0. Stelzer, and R. Schmutzler, 2. Naturforsch., Teif. B, 1982, 37, 267. 194 D. W. Morton and R. H . Neilson, Organometallics (Washington, D . C . ) , 1982, 1, 623. 1 9 ’ A . Uijttewaal and R. Snowden, Eur. Pat. Appl. 32 7 1 3 (Chem. Abstr., 1982, 96, lFZ

6866).

Organophosphorus Chemistry

24

+ H3PF

Br-

Me SiN=PR 3

+ 3

Bu3PN=PR3

,4

I-

( 1 3 5 ) R = M e , B u , o r NR’2

(134)

+

BrCH2COOE t ( Me3Si ) 2NPR2

Me3SiNHPR2CH(SiMe3)COOEt

( 1 3 6 ) R = M e or E t

Br-

(137)

CH 2 P P h (138) R = H or M e

Br(139)

(140) n = 2 or 3

macrocyclic aminophosphonium fluorides ( 140) have been claimed as the first examples of completely ionic phosphonium fluorides. 196

Reactions of Phosphonium Salts. --Alkaline Hydrolysis. Compared with previous years, there has been very little activity in this area. Quin has given preliminary details of a study of the influence of bridgehead structural constraints o n the alkaline hydrolysis of the salt (141), which is unaffected o n heating under reflux with 3 M aqueous alkali over a period of 20 hours. However, it does undergo hydrolysis, with cleavage of the exocyclic methyl group, on treatment with 0.3M potassium hydroxide in DMSO, at 25 O C , t o form the

cyclic oxide ( 142). It is argued that in the intermediate hydroxyphosphorane the five-membered-ring component of the bicyclic system exerts the usual apical-equatorial preference, leaving the seven-membered-ring component in its preferred diequatorial disposition. The benzylic component of the ringsystem cannot attain the required apical position for departure without forcing the five-membered ring into the unfavourable diequatorial mode. It is, 196

J . E. Richman and K. B. F l a y , J . A m . Chem. SOC., 1981, 103, 5265.

25

Phosphines and Phosphonium Salts

however, possible t o place the exocyclic methyl group in the apical position of an isomerized phosphorane, from which it leaves, forming methane. In contrast, the salt (143) undergoes alkaline hydrolysis with the expected preferential loss of the benzyl group. 197 (Bromodifluoromethy1)triphenylphosphoniumbromide undergoes hydrolysis under neutral, aqueous conditions, t o form triphenylphosphine oxide and bromodifluoromethane. When the reaction is carried out in the presence of radiolabelled Br-, unequivocal evidence is obtained of the involvement of difluorocarbene as a primary intermediate in the reaction. However, the origin of the carbene is not clear, and as yet it is not known as t o whether it is formed in a concerted reaction from the salt or via loss of bromide ion from the forming bromodifluoromethyl anion.'91 The possible involvement of the bromodifluoromethyl carbanion or difluorocarbene has also been considered for the reactions of (bromodif1uoromethyl)phosphonium salts with halogens in the presence of potassium fluoride, leading t o the formation of (mixed) dihalogenodifluoromethanes. 199

Additions to Unsaturated Phosphonium Salts. Bicyclic phosphonium salts, e.g. (144), are formed in the Diels-Alder addition of cyclopentadiene t o (2 -acylvinyl)phosphonium salts.*" Further examples have been reported of the addition of amidines to (2-acylvinyl)phosphonium salts t o give (imidazolylmethy1)phosphonium salts, e.g. ( 145).*01 0

---3

--

B r-

It

(144)

Nucleophilic additions to vinylphosphonium salts continue to be employed in the generation of ylides for subsequent Wittig reactions. The nature of the 'non-involved' groups at the phosphonium centre affects the stereochemistry of the reactions of vinylphosphonium salts with sodiophthalimide in the presence of aldehydes, leading t o the allyl-phthalimides (1 46). Whereas the use of tributyl(viny1)phosphonium bromide leads to the (E)-isomer, the corresponding triphenylphosphonium derivative leads t o predominant formation of the (Z)-isomer.202 The addition of the anions (147) (the conjugate bases of open-chain analogues of a Reissert compound) '97 '91

201 202

L. D. Quin and S . C. Spence, Tetrahedron Lett., 1982, 2 3 , 2529. R. M. Flynn, R . G. Manning, R. M. Kessler, D. J . Burton, and S. W. Hansen, J . Fluorine Chem., 1981, 18, 525. D. J . Burton, S. Shin-Ya, and H . S . Kesling, J . Fluorine Chem., 1982, 2 0 , 89. I. V . Megera, L. B. Lebedev, and M . 1. Shevchuk, Zh. Obshch. Khim., 1981, 51, 54 (Chem. Abstr., 1981, 9 5 , 4 3 2 2 9 ) . R. L. Webb and J . J. Lewis, J. Heterocycf. Chem., 1981, 18, 1301. A. I. Meyers, J. P. Lawson, and D. R . Carver, J. Org. Chern., 1981, 46, 31 19.

26

Organophosphorus Chemistry

Ar \

&

/C-cN

+ + H C=CHPPh3 2

A r c ) Br--

">o

R

Ph

Ph 3P+ 'C3CH2

c1-

/

MeS

Ph (148)

(14'7)

to triphenyl(viny1)phosphonium bromide leads to the formation of p y r r ~ l e s . ~ The ' ~ a-functionalized vinyl-phosphonium salt ( 148) has been used in the synthesis of members of the prostaglandin D1series.204 Nucleophilic addition of methanol to the salt (149)' leading to the intermediate (1 50), is involved in a scheme for the synthesis of the ketones (1 5 l ) , which are formally the products of an 'umpolung' addition of methanol t o a-allenic ketones (Scheme 3).205

+

n

t

1( 149 1

Reagents: i, LiOMe, MeOH; ii, H'; i i i , Et,N, MeOH

Scheme 3

Miscellaneous Reactions of Phosphonium Salts. The reactions of simple ureas with tetrakis(hydroxymethy1)phosphonium salts in mole ratios lower than 4 : 1 have proved to be rather complex, leading to the formation of condensed (ureidomethy1)phosphonium salts, some of which are polymeric gels, and some (from 1,3-dimethylurea) crystalline cyclic compounds, e.g. (1 52).206,207 Treatment of the allylic phosphonium salt (1 53) with triethylamine gives the butadienylphosphonium salt (1 54).*08 Phosphonium salts, e.g. ( 1 5 5 ) ' that bear a methylketo-group are converted into diquaternary salts, e.g. (1 56), on treatment with iodine followed by a tertiary amine.209 The electrochemical reduction of the (cyanomethy1)phosphonium salts ( 157) has been studied.210 Competition between cleavage and formation of an ylide is observed in the cathodic reduction of benzyl-, allyl-, cinnamyl- and polyenyl-phosphonium salts. In aprotic solvents, these salts undergo an overall one-electron reduction, with formation of up to 50% of the corresponding ylide, this being 203 *04

J . V. Cooney and W . E. McEwen, J . Org. Chem., 1 9 8 1 , 4 6 , 2570. A . G. Cameron, A. T. Hewson, and A. H. Wadsworth, Tetrahedron L e f t . , 1982, 2 3 , 561.

'05 '06

'07

'09

*lo

H.-J. Cristau, J . Viala, and H. Christol, Tetrahedron Lett., 1982, 2 3 , 1569. A. W . Frank, Phosphorus Sulfur, 198 1 , 10, 147. A. W. Frank, Phosphorus Sulfur, 1981, 10, 207. R. I<. Lulukyan, M . Zh. Ovakimyan, and M. G. Indzhikyan, Arm. Khim. Z h . , 1981, 34, 995 (Chem. Abstr., 1982, 96, 199 800). I. N. Chernyuk, M . 1. Shevchuk, P. I . Yagodinets, and E. M. Volynskaya, Zh. Obshch. Khim., 1981, 5 1 , 1020 (Chem. Abstr., 1981, 95, 2 0 4 0 5 2 ) . A . J . Bellamy and I . S . MacKirdy, J. Chem. Soc., Perkin Trans. 2, 1981, 1093.

Phosphines and Phosphonium Salts Me

Me

27

+

+

Ph3PCH2CH=C(C1)CH2Br

0

NJ

Br-

Br-

\--N

Me

Ph3PCH=CHC(C1)=CH2

Me X-

(153)

(154)

(152) X = C1 or HS04

+

I2

Ph3PCH2COMe

I--

+

+

+

Ph3PCH2COCH2NMe3

Ar3PCH2CN

21-

I-

Et3N ( 155 1

(157) Ar

( 156)

=

Ph or mes i t y 1

formed via an initial two-electron cleavage to give a carbanion, which abstracts a proton from a second molecule of phosphonium salt.211A thermogravimetric study of the thermal decomposition of a series of phosphonium salts has shown that thermal stability increases in the order C1-< Br-a I-. Surprisingly, it is claimed that the thermal decomposition of methyltriphenylphosphonium bromide gives methyldiphenylphosphine and bromobenzene.’” Examples of the use of phosphonium salts as phase-transfer agents continue to appear. Applications of polystyrene- bound benzyltributylphosphonium salts in phase-transfer catalysis have been reported,’13 and tetrabutylphosphonium chloride has been used under phase- transfer conditions for the replacement of bromine by chlorine in a sterically crowded halogenosilane.*14 + MeO&eR1R2

OTf-

(158) R 1 , R2= OMe, Et, or Ph

+

MeP(OPh)3 (

159)

I-

Ph3PC(Me)2CSS(160)

The methoxyphosphonium triflates ( 1 5 8 ) , obtained from the reactions of phosphine oxides with methyl triflate, have been shown t o be very powerful alkylating agents.”’ The salt (159) has been used in aprotic solvents, e.g. 1,3-dirnethylimidazolidin- 2-one, t o affect dehydration and dehydrohalogenation reactions under mild conditions.216The 2-(tripheny1phosphonia)ethoxycarbonyl (‘Peoc’) grouping has now been used as a protecting group for alcohols.” Transition-metal carbonyl complexes of the betaine ( 160) undergo a very facile cleavage of the P-C bond on exposure to light.2189 219 211

V. L. Pardini, L . Roullier, J. H. P. Utley, and A. Webber, J . Chem. Soc., Perkin Trans. 2, 1981, 1520.

*I2 213 214 215 216

*I7 21R 21 9

R. G . Ferrillo and A. Granzow, Thermochim. A eta, 198 1, 45, 177. M. Tomoi and W. T. Ford, J. A m . Chem. Soc., 1981, 103, 382 1, 3828. R. Damrauer, J. Organomet. Chem., 1981, 216, C1. E. S. Lewis and K. S. Colle,J. Org. Chem., 1981,46, 4369. C . W. Spangler, D. P. Kjell, L. L. Wellander, and M . A. Kinsella, J. Chem. Soc., Perkin Trans. I, 1981, 2287. H . Kunz and H.-H. Bechtolsheimer, Synthesis, 1982, 303. U . Kunze, R. Merkel, and W. Winter, Angew. Chem., Int. Ed. Engl., 1982, 21, 290. U. Kunze, R. Merkel, and W. Winter, Angew. Chem., Int. Ed. Engl., 1982, 21, 291.

28

Organophosphorus Chemistry 3 p,-Bonded Phosphorus Compounds

The past year has seen a very marked increase in the number of papers published in this rapidly developing area o f phosphorus chemistry. Two review articles have appeared.220’221 The possible modes of reactivity of p,-p,-bonded PrIr compounds have been discussed in terms of a theoretical consideration of the energies of the HOMOS and LUMOs for these systems.222 The reaction of the sterically crowded phosphonous dichloride ( 16 1) with magnesium leads t o the formation of the phosphobenzene (1 62), a thermally stable, orange-red solid.223 This compound is also formed in the reaction o f phosphorus trichloride with two moles of 2,4,6-tri- t- butylphenyl-lithium .224 The reactions of the phosphobenzene with halogens, and also with sodium naphthalene, have been studied, and shown t o involve the formation of radical species that are stabilized by the bulky

The chemistry of mesityl(diphenylmethy1ene)phosphine ( 163) continues to develop. Its reaction with iodomethane provides the first example of a nucleophilic reaction of this type of compound, proceeding via the formation of the intermediate phosphonia-alkene (1 64) t o give the ylide (165) as the major product.226 Full details of a study o f t h e donor properties of (163) t o platinum(l1) halide acceptors have now appeared. An X-ray study shows that the ligand is bound t o the metal by the lone-pair of phosphorus.227 This mode of co-ordination is also observed in a solid-state study of complexes of 220

221 222

223 224

225

?26

227

E. E’luck, Top. Phosphorus Chem., 1980, 10, 193. R. Appel, E’. Knoll, and 1. Ruppert, Angew. Chem., Int. Ed. Engl., 1981, 2 0 , 7 3 1 . W. W. Schoeller and E. Niecke, J . Chem. Soc., Chem. Commun., 1982, 569. M. Yoshifuji, 1. Shima, and N . Inamoto, J . A m . Chem. Soc., 1981, 1 0 3 , 4587. B. Cetinkaya, P. B. Hitchcock, M . F. Lappert, A . J . Thorne, and H . Goldwhite, J . Chem. Soc., Chem. Cornmun., 1982, 691. B. Cetinkaya, A. Hudson, M . F. Lappert, and H . Goldwhite, J. Chem. SOC., Chem. Commun., 1 9 8 2 , 6 0 9 . Th. A. van der Knaap and F. Bickelhaupt, Tetrahedron Lett., 1982, 23, 2037. H . W. Kroto, J . F. Nixon, M . J . Taylor, A . A. Frew, and K. W. Nuir, Polyhedron, 1982, 1, 89.

Phosphines and Phosphonium Salts

29

(1 63) with a platinum(0) acceptor. However, in related solution studies, n.m.r. investigations have revealed an unusually low 31P- 19'Pt coupling constant, which may indicate that, in solution, the ligand is bound sideways on, involving the n-electrons of the P-C bond.228 An X-ray study of a platinum(0) complex of the phospha-alkyne ButCEP shows that this ligand is bound sideways-on to the metal, and that the lone-pair of phosphorus is not involved in ~ o - o r d i n a t i o n . ~ ~ ~ The fluorinated phospha-alkene CF3P=CF2 is believed to be involved in the base-induced dehydrofluorination reactions of bis(trifluoromethy1)phosphine, which lead to the formation of (perfluor~alkyl)diphosphines.~~~ The tetraphosphahexadiene system (166) is formed in the reactions of phenylbis(trimethylsi1yl)phosphine with phenyl isocyanide d i ~ h l o r i d e . ~In~ ' the same paper is reported the formation of the diphospha-alkene (167), from the reaction of succinoyl chloride with phenylbis(trimethylsily1)phosphine, and its Cope rearrangement to form (1 6 8 ) . The P=C system (1 69) is involved in N + P silatropism in solution, with the formation of (1 70) as a mixture of d i a s t e r e o i s ~ m e r s . ~ ~ ~

c;:: OSiMeg

N( SiMe3)Ph PhP hPP'c&

I

PhP

\c/

PPh

QPh

N( SiMe3)Ph (

OSiMe3

OSih?e3

166) Me3Si

1 /

ph/'bC

SiMeg

I

P( SiMe3)Ph

I

Thermally induced and base- and metal-induced 1,2-elirnination reactions of halogenophosphines of the type (1 7 1) have been used for the preparation of the compounds (1 72) with a new substitution pattern at the P=C bond.233 The halofunctional phospha-alkene (1 73) has been used to form a wide range of related compounds by nucleophilic displacement of chlorine. In these reactions, some competition arises from addition reactions to the double228

229

230 231

232 233

Th. A. van der Knaap, F. Bickelhaupt, H. van der Poel, G. van Koten, and C . H . Stam, J. A m . Chem. SOC., 1982, 104, 1756. J. C. T. R. Burckett-St. Laurent, P. B. Hitchcock, H . W. Kroto, and J . F. Nixon, J. Chem. Soc., Chem. Commun., 1981, 1141. A . B. Burg, Inorg. Chem., 1981, 2 0 , 3734. R. Appel, V. Barth, and M . Halstenberg, Chem. Ber., 1982, 115, 1617. R. Appel, H. Forster, B. Laubach, F. Knoll, and I. Ruppert, Angew. Chem., I n f . Ed. Engl., 1982, 21, 448. R . Appel, J . Peters, and A . Westerhaus, Tetrahedron L e t t . , 1981, 22, 4957.

Organophosphorus Chemistry

30

c1 x R1-

Ph

I I

P-CR2R3

R1-

P =CR2R3

Me3Si ( 1 7 1 ) R’=

C1 or Ph

R2,

(173)

R3= H o r M e S i 3

X = H , C 1 , or M e S i 3 heat

(Me3Si)3C-PC12 (174

1

___t

(Me3Si)2C=P-C1 (175)

bond.234 Thermal decomposition of the phosphonous dichloride ( 174) affords an alternative route t o (1 75).235 The P=C compounds that are formed in the reactions of tris(trimethy1sily1)phosphine with acetyl chloride 236y237 are much less stable than those derived from related reactions with pivaloyl chloride, described in detail in recent years by Becker’s group. The reactions of alkyl- or aryl-bis(trimethy1sily1)phosphines with DMF and benzophenone, respectively, lead t o the systems (176) and (1 77), which dimerize readily t o give, e.g. (1 78).238 P=C compounds are also among the products of the reactions of ketens with silylpho~phines.~~~

Two reports have appeared of base-induced dehydrochlorination reactions o f compounds of the type (179) t o give the silylamino-phospha-alkenes (1 80).240’241 Methanol adds t o the P=C double-bond of (180; R=SiMe,) to form ( 18 1).241 Dehydrochlorination of dichloromethylphosphonous dichloride with sodium bis(trimethylsily1)amide gives ( 182). Related attempts to form (1 83) by using triethylamine as the base lead t o the formation of the dimeric system ( 184).242 234

235

236 237

23R 239

240

241

242

R. Appel and U. Kundgen, Angew. Chem., I n t . Ed. Engl., 1982, 2 1 , 219. K. Issleib, H. Schmidt, and C. Wirkner, Z. Chem., 1981, 2 1 , 357. G. Becker, Z.Anorg. Allg. Chem., 1981, 480, 2 1. G. Becker, Z.Anorg. Allg. Chem., 1981, 480, 38. G. Becker, W. Uhl, and H.-J. Wessely, Z. Anorg. Allg. Chem., 1981, 479, 41. 0. 1. Kolodyazhnyi and V. P. Kukhar, Zh. Obshch. Khim., 1981, 5 1 , 2189 (Chem. Abstr., 1982, 96, 2 0 167). 1. E‘. Lutsenko, A. A. Prishchenko, A. A. Borisenko, and 2 . S. Novikova, Dokl. Akad. NaukSSSR, 1981, 256, 1401 (C‘hem. Abstr., 1981, 95, 8 1 109). K. H. Neilson, Inorg. Chem., 1981, 20, 1679. A . A. Prishchenko and 1. F. Lutsenko, Zh. Obshch. Khim., 1981, 5 1 , 2 6 3 0 (Chem. Abstr., 1982, 96, 104 395).

Phosphines and Phosphonium Salts

RCH2P( C l ) N ( S i M e g ) Z

-[

-

31 OM e

HC1J

RCH=PN(SiMe

( 179)

)

I

Me3SiCH P - N ( S i M e 3 ) 2 2

(181 1

(180)

( R = P h , COOMe, o r S i M e 3 )

(Me3Si )2NP=CC1 (

ClP=

2

182 1

CC12

c1-P

(183)

Xl

The reactions of phosphorus trichloride (and of alkylphosphonous dichlorides) with lithium chlorobis( trimethylsily1)methane initially yield P=C systems, e.g. ( 185), which rearrange t o form bis(methylenephosphoranes), e.g. (1 86), involving trico-ordinate phosphorus.2437244

-

(MegSi ),C=PC(C1)(SiMe3)2

(Me3Si)2C=P=C(SiMe3)2

I

A number of hJ-P=N p,-p,-bonded systems have also been reported. The synthesis of the highly polar compound (187) has been described. This compound, an intense yellow liquid, is very sensitive t o air and water and is stable only at low temperatures. When warmed above O’C, it dimerizes by [ 2 + 1 ] cycloaddition t o give the 1,2 h3,3 h5-azadiphosphoridine ( 1 88).245 Cycloaddition reactions of t h e iminophosphines ( 189) with alkyl azides and diazoalkenes have also been investigated.246*247 An X-ray study of the ability o f these compounds t o act as bridging ligands has appeared.248

But t,P=N/ Bu

But P‘

RNBu N ‘ID -ut

R’~N-P=NR’

/ (189)

(187)

R 1 , R2= Me3Si o r a l k y l

(188)

There has also been considerable interest in the chemistry of phosphenium ions, R,P+. A new route t o these systems is afforded by elimination of a dimethylamino-group from (dimethy1amino)phosphines with triflic acid.249 243 244 245

R. Appel and A. Westerhaus, Tetrahedron Lett., 1982, 2 3 , 2017. R. Appel, J . Peters, and A. Westerhaus, Angew. Chem., Int. Ed. Engl., 1982, 2 1 , 80. E. Niecke, R. Riiger, and W. W. Schoeller, Angew. Chem., Znt. Ed. Engl., 1981, 2 0 , 10 34.

246 241

E. Niecke and H.-G. Schafer, Chem. Ber., 1982, 1 1 5 , 185. E. Niecke, A. Seyer, and D.-A. Wildbredt, Angew. Chem., Int. Ed. Engl., 1981, 2 0 , 675.

248

249

0. J. Scherer, R. Konrad, E. Guggotz, and M . L . Ziegler, Angew. Chem., Int. Ed. b’ngl., 1982, 2 1 , 297. 0 . Dahl, Tetrahedron L e t t . , 1982, 2 3 , 1493.

Organophosphorus Chemistry

32 Me

+ ( Pri2N)

( Pri2N)2P+

n

A1C14Sn

Ph2P \p/+PPh2

(193)

The phosphenium ion system is stabilized by the presence of bulky groups at phosphorus, as in, e.g., (190), obtained by the reaction of the related phosphinous halide with aluminium t r i ~ h l o r i d e . ~The ~ ' reaction of the phosphinous chloride (191) with aluminium chloride at - 78 OC gives the multi-hapto-phosphenium ion (1 92).251 The reactions of stannocene (or plumbocene) with the salt (193) do not lead to the formation of P=Sn or P=Pb compounds but involve oxidative addition of a C-H bond to the twoco-ordinate cation to give the phosphonium salt (194), which has been deprotonated to give the first monosubstituted derivatives of the stannocene and plumbocene systems.252The diphos complex of P+ (195) is formed in the reaction of phosphorus trichloride and stannous chloride in the presence of d i p h ~ s . ~ ~ ~ 4 Phospholes and Phosphorins

There has been a marked increase in the number of publications in this area over the past year. Phosphole chemistry has been reviewed,254 The Mathey dehydrohalogenation procedure, using the base DBU, has been used for the conversion of McCormack cyclo-adducts, e.g. (1 96), into multicyclic phospholes, e.g. (1 97), which have been found to undergo C-protonation on addition of anhydrous hydrogen chloride, giving, e.g., ( 198).255Mathey has now found it advantageous to replace DBU as the dehydrohalogenation agent

"'

A . H. Cowley, M . Lattman, and J . C. Wilburn, Inorg. Chem., 1981, 2 0 , 2916. S. G. Baxter, A. H. Cowley, and S . K. Mehrotra, J. A m . Chem. Soc., 1981, 103, 5572.

252 253

A . H. Cowley, R. A. Kemp, and C. A. Stewart, J . A m . Chem. SOC., 1982, 104, 3239. A. Schmidpeter, S. Lochschmidt, and W. S . Sheldrick, Angew. Chem., Int. Ed. Engl., 1982, 2 1 , 63.

254

255

F. Mathey, Top. Phosphorus Chem., 1980, 10, I . L. D. Quin, K. A. Mesch, and W. L. Orton, Phosphorus Sulfur, 1982, 12, 161.

Phosphines and Phosphonium Salts

33

by other nitrogen bases, e.g. 2-methylpyridine, in the synthesis of simple phospholes from McCormack c y c l o - a d d u c t ~ .257 ~~~’ Mathey’s group has reported several applications of phospholyl anions in synthesis. Such anions are readily accessible by cleavage of P-phenyl bonds of phenylphospholes, using lithium in THF or sodium-naphthalene in THF. Conversion of (199) into the related magnesium or cadmium derivat ives , f ollowed by re act ion with appropriate halo f un ct ion a1 co mpounds , enables the synthesis of the functionalized phospholes ( 200).258 The sulphides of related (a-bromoalky1)phospholes (prepared by the reactions of phospholyl anions with &,a-dibromoalkanes) undergo Diels- Alder reactions with N-phenylmaleimide to give the phosphanorbornene system (201).

(200)

( 1 9 9 ) M = L i or N a

&J( 2 0 1 ) n = 4-6

S

11

Br(CH2)nPH

I

n = 1 or 2 ; Z = COOEt, CN, C O R , or OH

NaH

THF

OM e

(202)

(203)

On photolysis in methanol, these compounds undergo fission to form (202), which may be cyclized, on treatment with sodium hydride in THF, t o form the heterocyclic systems (203).259 Protonation of phospholyl anions yields unstable 1H-phospholes, which spontaneously rearrange through 1,s-proton shifts to give 2H-phospholes (204). These systems undergo spontaneous Diels-Alder dimerization t o give [ 4 + 2 ] dimers (205), involving a P-P 256

A. Breque, F. Mathey, and P. Savignac, Synthesis, 1981, 983.

258

(Chem. A b s t r . , 1982, 96, 143076). G. Muller, H . Bonnard, and F. Mathey, Phosphorus Sulfur, 1981, 10, 175. S. Holand and F. Mathey, J. Org. Chem., 1981, 46, 4386.

”’ A. Breque, G. Muller, H. Bonnard, E‘. Mathey, and P. Savignac, Eur. Pat. Appl. 4 1 4 4 7 lS9

0rga PI o p h o sp h or us Ch e mist ry

34

bond.260 The reaction of the 2,5-diphenylphospholyl anion with phosgene gives the biphospholyl (206; R = H).261 When heated for several days at 230 OC, 1,2,5-triphenylphospholeyields the biphospholyl (206; R = Ph),262 via a transient 2H-phosphole, in which phenyl migration from phosphorus t o carbon has taken place. These intermediates can be trapped with appropriate dienophiles t o give the l-phospha8,9-dinorbornadiene system, e.g. (207).263 Prolonged heating of l-phenyl3,4-dimethylphosphole gives a complex mixture of products, from which the H

H

Ph (205)

Ph

( 2 0 6 ) R = H o r Ph

tetramer (208) has been isolated in 20% yield. It is possible t o cleave this compound reductively t o a biphospholyl dianion, which may then be alkylated at phosphorus to give 2,2'-biphospholes (209).264 The reversible yellow-red colour change that is observed when 1,2,5-triphenylphosphole is heated, in carbon tetrachloride solution, has been attributed t o the incipient formation of the chlorophospholium trichloromethanide salt.265 H

cj

u-u ""rnPh

Ph

I

U

P

h

I

Ph

Ph

Ph

Ph

R

R

Further studies of the co-ordination chemistry of phospholes have been riported. With metal carbonyls, simple phospholes form bimetallic sandwich complexes which involve both 0-and 71 -bonded phosphole ligands.266 DielsAlder addition of dimethyl acetylenedicarboxylate t o simple phospholes that are co-ordinated via phosphorus t o a Group 6 transition-metal carbonyl 260

G. de Lauzon, C. Charrier, H . Bonnard, and F. Mathey, Tetrahedron Lett., 1982, 2 3 , 51 1.

263

C. Charrier, H. Bonnard, and F. Mathey, J. Organomer. Chem., 1982, 2 3 1 , 361. C. Charrier, H. Bonnard, and F. Mathey, J. Org. Chem., 1982, 47, 2376. F. Mathey, F . Mercier, C . Charrier, J . Fischer, and A. Mitschler, J . A m . Chem. SOC.,

264

F. Mathey, F. Mercier, F. Nief, J . Fischer, and A. Mitschler, J. A m . Chem. SOC.,

261

262

1981, 1 0 3 , 4 5 9 5 . 1982, 1 0 4 , 2 0 7 7 . 265 266

M. B. Hocking and T. A. Smyth, Can. J. Chem., 1982, 60, 138. C. C. Santini, J . Fischer, E'. Mathey, and A. Mitschler, Inorg. Chem., 1981, 2 0 , 2848.

35

Phosphines and Phosphonium Salts

R ( 2 1 0 ) H = Me o r Ph

(211)

H (212)

acceptor lead to related complexes of the 7-phosphanorbornadiene system (2 Mathey’s group has continued to explore the chemistry of phosphaferrocene system^.^^^-*^' Routes to the 1,3-benzodiphosphole (2 1 1) and 1,3-benzazaphosphole systems (2 12) have been developed.271’ 272 The ketone hydrazone-phosphorus trichloride reaction has been employed in the synthesis of (2 1 3).273 Diaminomaleodinitrile and tris(dimethy1amino)phosphine condense at room temperature to give the salt ( 2 14), containing the ambidentate 1,3,2-diazaphospholide anion, which undergoes methylation at nitrogen (on treatment with iodomethane) to give (215).274 There have been a number of investigations of the reactivity of di- and tri-azaphospholes with a ~ i d e s , ~ 276 ~d ” i a ~ o a l k a n e sand ,~~~ nitrile oxides.278Only for the latter reagents have cycloadditions t o the P=C bond been observed.

R (214) ( 2 1 3 ) R = H o r Me

A previously established route from phospholes to h3-phosphorins, involving ring-expansion and reduction steps, has been optimized by careful selection of starting materials and reagents, and applied to the synthesis of 267

268

A. Marinetti, F. Mathey, J. Fischer, and A. Mitschler, J. Chem. Soc., Chem. Commun., 1982, 667. B. Deschamps, J. Fischer, F. Mathey, and A. Mitschler, Znorg. Chem., 1981, 2 0 , 3252.

269

270

271

’I2 273

274

275

276 277

”’

B. Deschamps, J. Fischer, F. Mathey, A. Mitschler, and L. Ricard, Organometallics (Washington, D.C.), 1982, 1, 312. R. Wiest, B. Rees, A. Mitschler, and F. Mathey, Znorg. Chem., 1981, 20, 2966. K. Issleib, E. Leissring, and H. Meyer, Tetrahedron Lett., 1981, 22, 4475. K. Issleib and R. Vollmer, Z. Anorg. Allg. Chem., 1981, 481, 22. N. Ayed, R. Mathis, F. Mathis, and B. Belgacem, C. R. Hebd. Seances Acad. Sci., Ser. 2, 1981, 2 9 2 , 187. A. Schmidpeter and K. Karaghiosoff, Z. Naturforsch., Teil. B, 1981, 36, 1273. B. A. Arbuzov, E. N. Dianova, and S. M. Sharipova, Zzv. Akad. Nauk SSSR, Ser. Khim., 1981, 1600 (Chem. Abstr., 1981, 9 5 , 2 0 4 0 6 5 ) . M. R. Marre, M. T. Boisdon, and M. Sanchez, Tetrahedron Lett., 1982, 23, 853. B. A. Arbuzov, E. N. Dianova, and S. M. Sharipova, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 1113 (Chern. Abstr., 1981, 9 5 , 9 7 9 1 9 ) . R . Carrik, Y. Y. C. Yeung Lam KO, F. de Sarlo, and A. Brandi, J. Chem. SOC.,Chern. Commun., 1981, 1131.

0rga n o p hos p h or us Ch e mist ry

36

( 2 16), which is of considerable potential interest as a chelating ligand.279 Cycloaddition of a-pyrones and cyclopentadienones with the phospha-alkyne PhCGP leads t o the formation of X3-phosphorins, following elimination of carbon dioxide o r carbon monoxide from the intermediate cyclo-adducts.280 The reactions of 2,4,6-triphenyl-X3-phosphorinwith zerovalent nickel compounds lead mainly t o complexes in which the phosphorus is a-bonded t o the metal, although a few polynuclear complexes involving both a - and n-co-ordination have also been characterized.281 282 Temporary anionic states of phosphabenzene have been studied in the gas phase by electrontransmission spectroscopy.283

The chemistry of Xs-phosphorins has been reviewed by Dimroth,2R4who has made a number of other contributions t o this field in the past year.285-289 The consensus of opinion is that Xs-phosphorins should be regarded as cyclic phosphonium ylides (2 17), involving the 6n-delocalized pentadienyl anion, rather than fully delocalized heterocyclic 28s Dimroth has, however, pointed o u t that t h e high stability and strong tendency of ASphosphorins t o regenerate the ylide unit in reactions shows that they have much in common with aromatic compounds. It is considered that the dipolar ylide structure is probably an oversimplified view of the true state of the phosphorus-carbon bonding in these compounds, and further studies are awaited. A series of fairly stable radicals, derived from Xs-(and A3-)phosphorins by chemical o r electrochemical oxidation, has been described.286 Methyl groups that are attached t o the phosphorus of As-phosphorins undergo metallation o n treatment with butyl-lithium at - 70 "C to form the salts (218), which are then able to be alkylated at carbon.287 Structural studies of a range of metal tricarbonyl complexes of As-phosphorins have shown that the metal acceptor is n-bonded t o the delocalized pentadienyl anion of the cyclic ylide.288y289 J.-M. Alcaraz, A . Breque, and F. Mathey, Tetrahedron L e t t . , 1982, 2 3 , 1565. G. Markl, G. Y . Jin, and E. Silbereisen, Angew. Chem., Int. Ed. Engl., 1982, 21, 370. 2 8 1 H. Lehmkuhl, R. Paul, and R. Mynott, Liebigs Ann. Chem., 1981, 1139. 2 8 2 H. Lehmkuhl, R. Paul, C. Kruger, Y.-H. Tsay, R . Benn, and R . Mynott, Liebigs A n n . Chem., 1981, 1147. 2 R 3 P. D. Burrow, A. J. Ashe, tert., D. J. Bellville, and K. D. Jordan, J . A m . Chem. SOC., 279

1982, 1 0 4 , 4 2 5 . 2R4

2R5 286 2R7 288

289

K. K. K. K. K. K.

Dimroth,Acc. Chem. Res., 1982, 15, 58. Dimroth, S. Berger, and H . Kaletsch, Phosphorus Sulfur, 1981, 10, 305. Dimroth, and W. Heide, Chem. Ber., 1981, 114, 3004, 3019. Dimroth and H. Kaletsch, Angew. Chem., Int. Ed. Engl., 1981, 20, 871. Dirnroth, M. Luckoff, and H . Kaletsch, Phosphorus Sulfur, 1981, 10, 285. Dimroth, S. Berger, and H. Kaletsch, Phosphorus Sulfur, 198 1, 10, 295.

2 Quinquecovalent Phosphorus Compounds BY C. D. HALL

1 Introduction

During the past year, the volume of work in this area appears t o have reached a plateau, with most of the effort being focused on the synthesis, structure, and properties of phosphoranes that contain small (four- or five-membered) rings. Attention is drawn to the A.C.S. report of the International Conference on Phosphorus Chemistry (held at Duke University, North Carolina, in 198 1) in which several papers deal directly with the chemistry of hypervalent phosphorus and numerous contributions invoke such molecules as reaction intermediates. The theoretical contribution of the year goes to Kutzelnigg and Wasilewski, who point out that the pseudorotational and turnstile processes for reorganization of ligands within PH5 are topologically equivalent.2 Both are of the (eeaa) (aaee) type, and, by computing various structures between the transition states of the Berry and the turnstile mechanisms, it is clear that the transition state for the turnstile process is not a transition state at all, since it has n o stationary properties and lies on the slope of a valley at a position that is approximately 30 kJ mol-' (7 kcal mol-') above the bottom of the valley which represents the Berry, pseudorotational path. In the same paper, calculations on the fragmentation of PH5 [reaction ( l ) ] are shown t o be very

'

PH5

PH3

5

+

H2

(1)

sensitive to the level of computational sophistication. Using SCF with polarization functions, two saddle-points are found, one of which corresponds to the Woodward-Hoffman-allowed, concerted reaction from two equatorial sites and the other t o a non-least-motion variant of a Woodward-Hoffmanforbidden process that is better described as a zwitterionic reaction, going via PH4' and H-. The barrier to the concerted process is slightly lower than that for the zwitterionic path, but the potential-energy surface between the two saddle-points is extremely flat. It follows (by microscopic reversibility) that the contribution of polarized species may also be of fundamental importance to the mechanism of formation of pentaco-ordinate phosphorus compounds from trico-ordinate phosphorus and various 0-bonded species (e.g. peroxides, disulphides, sulphenate esters, and halogens - see below). Using more 'Phosphorus Chemistry', ed. L. D. Quin and J. G. Verkade, A. C. S. Symposium Series N o . 171, 1981. W. Kutzelnigg and J . Wasilewski, J. A m . Chcm. SOC.,1982, 104, 9 5 3 .

37

Orga no p h 0 s ph or us Ch ernis t ry

38

sophisticated calculations (CEPA and polarization functions), only the concerted saddle-point ‘survives’, but the saddle-point region remains very flat, and the barrier height is 150 kJ mo1-l ( 3 6 kcal mol-’) above PH5, so that the latter should be metastable as an isolated molecule. Catalytic amounts of Lewis acids, and even of PHS itself, may be expected, however, t o lower the barrier for decomposition considerably.

2 Structure, Bonding, and Reorganization of Ligands A single-crystal X-ray diffraction study of the novel spirocyclic X5P-O-X5P oxydiphosphorane ( 1)3 reveals that the geometries of both phosphorus atoms may be described as distorted trigonal-bipyramidal (tbp), with the sixmembered ring in a boat conformation and the methyl groups cis with respect t o the ring.

‘cF3

Ph

The crystal structures of two phenyl-spiroarsoranes ( 2 ) and ( 3 ) show the first truly rectangular-pyramidal (rp) structure for an arsenic(v) compound (2), which contains two independent molecules per asymmetric unit, showing 97.5 and 92.8% displacement along the Berry co-ordinate towards the rp D. Schomberg, N. Weferling, and K. Schrnutzler, J. Chem. SOC., Chem. Commun., 1 9 8 1 , 810.

39

Quinquecovalent Phosphorus Compounds

~ t r u c t u r e Molecule .~ ( 3 ) is a distorted tbp (21.5% towards rp), and comparisons between pentaco-ordinated compounds of Group SA show that the principles that have been established for phosphoranes also apply to the analogous AsV and SbV compounds. A H n.m.r. study of some phenyl-substituted pentaco-ordinated compounds of phosphorus, arsenic, and antimony (and, incidentally, including analogous compounds of Si, Pb, S, Te, and I ) reveals a consistent shift of the ortho-protons of the phenyl ring, relative to the meta- and para-protonsY5 which is diagnostic for the presence of the pentaco-ordinated state of these elements in solution. The use of phosgene allows the preparation of triphenyldichlorophosphorane [reaction (2)] that is free of impurities, and the 3 1 P n.m.r. shift of the product varies from - 47.4 (in p-xylene) t o + 63.7 p.p.m. +

Ph3P

C0Cl2

-

+

Ph3PC12

CO

(2)

(in MeCN). This is explained by the usual equilibrium between ionic and pentaco-ordinate structures [equation ( 3 ) ] being dependent upon the dielectric permeability of the medium.6 Specific solvation of the ions apparently has an insignificant effect on the chemical shift, however, and hence the changes may also be explained by changes in contributions from the ionic form (5) t o a resonance hybrid, (4)++(5), (cf. Chapter 2 of Vol. 13 of these Reports). The variable-temperature Raman spectra of PC15 and PBr5 that had been sublimed on to a copper plate at 15 K showed that PC15 is pentaco-ordinated (tbp) whereas PBrS is ionic (PBr: Br3).7 Further studies of apicophilicity have shown that in some phosphorane systems, e.g. ( 6 ) , the 2-fury1 group is more apicophilic than phenyl [by ca

OMe

Me

(6)

'

(7)

R . 0 . Day, J . M . Holmes, A. C . Sau, J . R. Devillers, R. R . Holmes, and J . A. Deiters, J. A m . Chem. SOC., 1982, 104, 2127. A. C. Sau and R . R. Holmes, J . Organomet. Chem., 1981, 217, 157. B. V. Timokhin, V. K. Dmitriev, V. I . Dmitriev, B. I . Istomin, and V . I. Donskikh, J . Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 1711. A. Finch, P. N. Gates, and A. S . Muir, J . Chem. Soc., Chem. Commun., 1981, 812.

Organophosphorus Chemistry

40

ci'2:o& @x

0-P'

0

( 9 ) X = O a l k y l o r OPh

(8)

'

13 kJ rnol- (3 kcal mol- ') 3, whereas in others, e.g. (7), the reverse is true (by 2 kJ mol-').8 The phenylseleno-group has a similar apicophilicity to phenylthio- and phenoxy-groups, but sulphur within a benzoxathiaphosphole ring, e.g. in (8), shows no tendency to adopt an apical position.' In phosphoranes of the type (9), the phenoxy-group is more apicophilic than alkoxy by ca 10 kJ mol-', and the 13C n.m.r. spectrum indicates that reorganization of ligands involves a diequatorial dioxaphospholan ring."

3 Phosphoranes that contain a P-H Bond Condensation of (R,R)-tartaric acid with PC13 gave oligomers, e.g. (lOa), and a cyclic dimer ( 1 la), which, on oxidation, gave hydroxyphosphoranes ( 1Ob) and (1 1 b); a similar reaction with malic acid ( I 2a) or citric acid (1 2b) gave the phosphoranes (1 3)."

(10) a ; X = H b ; X = OH

(11) a ; X = H b ; X = OH

(12) a ; R = H

b ; R = CH2COOH

lo

'*

M . P. Johnson and S. Trippett, J . Chem. SOC.,Perkin Trans. 1, 1982, 191. M. P. Johnson and S. Trippett, J . Chem. SOC.,Perkin Trans. I , 1981, 3074. V. V. Ragulin, V. I. Zhakarov, and N . A. Razumova, J . Gen. Chem. USSR (Engl. Transl.), 1981, 51, 1897. A. Munoz, K. Lamand6, M . Koenig, and R. Wolf, Phosphorus Sulfur, 198 1, 1 1 , 7 1.

Quin quecova len t Phosphorus Co m po unds

(neo-C5H110)2PH +

41

-

HOCH~CR~~NHCH~CHR~OH (15) a ; R1= R2= H b ; R1= M e , R2= Ph

(14)

Bicyclic phosphoranes with two P-H bonds are obtained by the reaction of the dialkoxy-phosphine (14) with the aminediols (15). The ‘ H and 13C n.m.r. spectra indicate tbp structures of the (aea) type and in (1 6b), since the PH2 protons are non-equivalent, the 31P signal has the characteristic pattern of the X part of an ABX system.12 the bicyclic phosphorane (17) reacts with borane-dimethyl sulphide to give the adduct ( 18),13 and the preparation of the first Pv-Pv compound (20) - a bis-cyclenphosphorane - has been described, through the condensation of (1 9; X = H) with (1 9; X = F).I4 The pentaco-ordinate geometry is displaced 33% from the idealized tbp.

(19; X = H)

(20)

4 Acyclic Phosphoranes

Good yields (60-80%) of trialkyldifluorophosphoranes have been obtained from the corresponding trialkylbromophosphonium bromides by heating under reflux with sodium fluoride in dry acetonitrile, l 5 Phenoxyfluorophosphoranes ( 2 1) and ( 2 2 ) and some novel alkoxydifluorophosphoranes, e.g. (23), were prepared by the direct fluorination of the corresponding organyll2

K. Bruzik, W. Stec, D. Houalla, and R. Wolf, J . Chem. Res. (S), 1981, 348. *’ R. Contreras, Tetrahedron Lett., 1981, 2 2 , 3953. l4 15

J . E. Richman, R. 0 . Day, and R. R. Holmes,Znorg. Chem., 1981, 20, 3378. R. Bartsch, 0 . Stelzer, and R. Schmutzler, J. Fluorine Chem., 1982, 20, 85.

Organophosphorus Ch em istry

42

oxy(fluoro)phosphanes, and the tbp structure of all the pentaco-ordinate structures was confirmed by multinuclear ( 19F, 3 1 P, and 13C) n.rn.r.l6 The reaction of phenol with phosphorus pentaiodide gives (Ph0)3PIg, through a series of disproportionation reactions,' and not the anticipated PhOPI4, as reported earlier.18 On the other hand, perfluorophenol with phosphorus pentachloride in hexane, in the presence of y -collidine, gave perfluoropentaphenoxyphosphorane (24) - with some phosphite and perfluorodiphenyl ether - but perfluorobenzyl alcohol gave only phosphate

(24)

(25)

via d e a l k y l a t i ~ n . ' ~An analogous attempt to form penta(thiopheny1)phosphorane gave only triphenyl trithiophosphite (25) and diphenyl disulphide, and the reaction between bis-(perfluoropheny1thio)lead and phosphorus pentachloride again gave the trithiophosphite and a disulphide, probably via a pentathiophosphorane [reaction (4)]. l9 Furthermore, the

condensation of phosphorus pentachloride with thiocatechols produced the chloro- thiophosphite (27) and oligomeric disulphide (28), almost certainly via fragmentation of the desired thiophosphorane ( 26).20 The tendency for diaryl-thiophosphoranes to fragment has also been invoked to explain the formation of substantial quantities of diary1 disulphide in the reactions of (polyf1uoroalkoxy)phosphoranes (29) with arenethiols, and reactions of

l6

l7

I . Ruppert, Z.Anorg. Allg. Chem., 1 9 8 1 , 477, 5 9 . V. G. Kostina, J . Gen. Chem. USSR (Engl. Transl.), 1 9 8 1 , 5 1 , 1 6 8 8 . V. G. Kostina and N . G . Feshchenko, J. Gen. Chem. USSR (Engl. Transl.), 1 9 7 9 , 49, 2165.

l9 2o

D. 8. Denney, D. Z. Denney, and L.-T. Liu, Phosphorus Suljur, 1 9 8 2 , 1 3 , 1 . D. B. Denney, D. Z . Denney, and L.-T. Liu, Phosphorussulfur, 1 9 8 2 , 13, 243.

43

Quin quecovalen t Phosphorus Compounds [H(CF2),CH20I5P

+

2 ArSH

+

ArSSAr

[H(CF2)4CH2012P(@)Cl

(29) n = 2 or 4

2 PhSCl

[H(CF2)nCH201 3P

[H(CF2)4CH201 3PC12 +

PhSSPh

[ n = 41

[50R]

(30)

polyfluoroalkyl phosphites (30) with benzenesulphenyl chloride.21 Likewise, the reaction of (3 1) with methyl benzenesulphenate ( 3 2 ) gave substantial quantities (ca 50%) of ( 3 4 ) and (35), presumably via (33).22 In the same

m o > P O M e

m o > p - s Ar ‘

0

‘

( 3 1 ) Ar = p - t o 1

+

PhSSAr (35)

0

(34)

/

pr O-P‘*

I

SAr

‘SPh

OMe (33)

paper, Denney reports that substituents in the aryl ring of sulphenate esters (36) have virtually no effect on the rate of reaction with trimethyl phosphite [reaction ( 5 ) J except when X is p - N 0 2 , which in fact retards the rate. Clearly ‘gH12 2 XC6H4SOMe

+

(Me013P at -78’~

-

(Me015P

+

(XC6H4S)2

(5)

(36) ( X = pMeO, H I

**

m-CF3, or p N 0 2 )

Yu. G. Shermolovich, N . P. Kolesnik, V. V. Vasil’ev, V. E. Pashinnik, and L. N . Markovskii, J. Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 423. D. B. Denney, D. Z. Denney, and D. M. Gavrilovic, Phosphorus Sulfur, 1981, 11, 1.

Organ o p h 0 sph or us Ch em istry

44 X

Ph

127.4

- 31.7

- 82.6

40.1

6.3

2.0

Me 1 5 ( ~ l P )( p . p . m . ) (37)

lo5

k :!/drn3

mo1-l

H

OEt

this is not consistent with displacement of the thiol anion, and the author goes on to present a convincing argument in favour of a concerted, biphilic insertion into the S - 0 link. In support of this concept, a kinetic study of the reaction of 1-substituted-A3-phospholens(37) with diethyl peroxide reveals a broad correlation between rate and the 31Pchemical shift of (37), with deshielding at phosphorus giving rise to higher rates.23 With 1-arylphospholens (37; X=para-substituted C6H4) the value of p is -0.5, which signifies very little development of charge in the transition state, in line with the negligible effect of the solvent on rate, and in agreement with the results obtained for the reaction of triarylphosphines with d i ~ x e t a n . ~ ~ 5 Four- membered-ring Phosphoranes

The decomposition of triphenyl phospite ozonide (38) above - 30 "C in the presence of a nitrone (40)gave the biradical (4 l), thus providing evidence for the existence of (39), and in contrast to the decomposition of (38) at - 78 "C (in m ethanol- py rid h e ) , which generated singlet oxygen.25

0

-

I

PhCH=yBu

(PhO)3P-O0.

>

P-

Photolysis of 1,3-di-t-butyltriazene (42) in the presence of trimethyl phosphite, in cyclopropane solution, gave the paramagnetic phosphorane (43), in which exchange of apical and equatorial nitrogen atoms by pseudo24

P. J . Hammond, G. Scott, and C. D. Hall, J . Chrm. SOL'.,Perkin Trans. 2, 1982, 205. A. L. Baumstark, C. J. McCloskey, T. E. Williams, and D. R . Chrisope, J. Ovg. Chem.,

2s

W. A. Pryor and C. K. Govindan, J. Org. Chem., 1981, 46, 4679.

23

1980,45, 3593.

Quinquecovalent Phosphorus Cornpounds

45 OMe I

BU

NH- N= N B ~ (42)

lh

BU

-

- N- N-

2

1

(43b)

(MeO) 3P

N-BU

-

OMe

2

3

rotation was monitored by variable- temperature e.s.r.,26 t o reveal kexchmge for (40a)*(40b) =4.4 x l o 7 s-' at 225 K, with AG* = 22 kJ mol-'. Proton, 19F, and 31P variable-temperature n.m.r. studies on three types of fluorodiazaphosphetidines (44)-(46) produced data on the barriers facing This led to five types of pseudorotational process within these the conclusion that the PFR2 group is substantially more rigid than the PF2R group. In particular, the steric hindrance that is brought about by an increase in the size of R from Me to But was shown to be the dominant factor in determining the thermodynamic ratio of trans- : gauche-isomers in (44) and also the energy barrier to pseudorotation. The condensation of the amidophosphite (47) with a-keto-nitriles (48) gave the cyclic dimer (5 l ) , presumably via (49) and

I

Me

I

Me

I

Me

6 Five- membered-ring Phosphoranes Chlorination of ethylene chlorophosphite ( 5 2) at - 100 "C gives the trichlorophosphorane (53) [S(31P)=- 29 p.p.m.1 as an intermediate en route t o the 26

27

28

J . C. Brand and B. P. Roberts, J . Chem. SOC.,Chem. Commun., 1981, 1107. R . K. Harris, M . I . M . W a x e r , 0. Schlak, and P. Schmutzler, Phosphorus Sulfur, 1981, 11, 2 2 1 . I . V . Konovalova, M . V. Cherkina, L. A. Burnaeva, and A . N . Pudovik, J. Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 1419.

Organophosphorus Chemistry

46 (Me0)2PN=CPh(OEt) (47)

+

RCOCN

R

(48)

N-P' Ph

bEt

OMe (51)

t

[

( Me0)2P-N=CPh(

a-&(CN)

OEt )

]

(49) 0

II

(53)

(52)

cMe OCH2Ph

o ;@

PPh2

P h / 'Ph

p- chloroethyl

phosphorodichloridate ( 54).29The reaction of the phosphine ether ( 5 5 ) with bromine generates the bromophosphorane (56) [6 (31P)= - 17.8 p.p.m.1, which is remarkably stable to water but reacts with AgBF4 to 29

J . Gloede, M . Pakulski, A. Skowronska, H. Gross, and J. Michalski, Phosphorus Sulfur, 1982, 1 3 , 163.

Quin q ue co vale n t Ph osph orus Corn po unds

47

P-Ph

\ Me Me

(59)

form the salt (57) [ 6 ( 3 1 P ) = + 7 5 . 6p.p.m]. An analogous reaction of (58) with bromine gives the macrocyclic phosphonium bromide (59) [ 6 (31 P) = + 70.9 p.p.m.1 , which, on heating, forms the spirophosphorane (60).30Treatment of the phosphine oxide (61) with sodium hydride deprotonates the OH function, and generates the oxide anion (62), which is in equilibrium with its phosphorane oxide anion (63) [ 6 ( 3 1 P ) =- 30.3 p.p.m.1. The exceptional reactivity of (62) towards methyl iodide, which results in (64), is ascribed t o intramolecular solvation of the sodium cation by the P=O Me Me

cMe

Me

Me Me

PPh2

PPh2

II 0

It

b Na+

O***Na+

woMe'> P( O)Me,

(64)

30

I . Granoth, J. Chem. SOC.,Perkin Trans, 1, 1982, 735.

31

1. Granoth, R. Alkabets, and E. Shirin, J. Chem. SOC.,Chem. Cornmun., 1981,981.

Organ oph osph or us Che m istry + -

Me2C=CHN02

n , PhnP(OR):j - nCMe2-CHN02

Me hle (68)

a ; fi(31~)= -263 p . p . m . b ; 6(31P) = -14 p . p . m . c ; 6('lp) = -20 p . p . m .

The reaction of trico-ordinated phosphorus compounds (65) with 1-nitro2-methylpropene (66) in ether gives the pentaco-ordinqted structures (68), which are in equilibrium with the betaines (67) and the starting P"' comp o u n d ~ With . ~ ~ an acetylenic substrate (69), the position of the equilibrium between the ylide (70) and the pentaco-ordinated product (71) is dependent upon the solvent.33 Addition of a cyclic phosphite (72) to dicarbomethoxyethyne gives a 1,l ,I-trialkoxyphosphole (74) via the betaine (73).34

c":i'

OMe

e .. > " ( 0

PhCOOH, C C 1 4

+

- 0(i __COPh PC=CHCOOMe

0

Me00C-CZC-COOMe

COObff2

C-CHC00Me

I

OCOPh

COOE4e (69)

(71)

(70)

[s(31p) = +69 p . r s . m . 1

LS("P)

=

-49 p.p.m.1

The reaction of 1,3,2-dioxaphospholans (75) with diols, 2-(N-methylamino)ethanol, or a-hydroxy-acids, in the presence of diphenyl disulphide, gives three series of spirophosphoranes (76)-(78), with the disulphide behaving as a proton acceptor to form ben~enethiol.~'Spirophosphoranes (8 1) may be obtained in yields as high as 60% from the reaction of phosphonous dichlorides (79) with butane- 2,3-diols (80) in the presence of ~ y r i d i n e . ~ ~ 32

33 34

35 36

R . D. Gareev, G. M . Loginova, E. E. Borisova, A. V . Il'yasov, A. N. Pudovik, and I. M. Shermergorn, J. Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 2265. R . Burgada, Y . Leroux, and Y . 0 . El Khoshnieh, PhosphorusSulfur, 1981, 10, 181. R . Burgada, Y . Leroux, and Y . 0. El Khoshnieh, Tetrahedron L e t t . , 1981, 22, 3533. Y . Kimura, M. Miyamoto, and T. Saegusa, J. Org, Chem., 1982, 47, 916. W. J. Richter, Phosphorus Sulfur, 1981, 10, 395.

Quinquecovalent Phosphorus Compounds

49 COOMe

Me0

I

xo>POMe 0

1

2 Me00C-C:C-COOMe

COOMe (73)

+

H O ( CH2) 2NHMe, PhSSPh

J

2 PhSH

-

+

2 PhSH

(75) (77)

R. +

( H = P h , OMe, o r O E t )

B U L J

o r Ph

‘gHll’

2 PhSH

(78)

(80)

(81)

l S ( 3 1 ~ ) = -12.6 t o -27.5 p . p . m . 1

Organophosphorus Chemistry

50

In a more conventional approach, spirophosphoranes (83) with two dioxaphospholen rings and an exocyclic P-N bond are obtained in high yield (87-89%) by the reaction of the phosphoramidites (82) with b e n ~ i l . ~ ' NEt2

I

(82) R = M e or E t

o r RR

=

(CH2l4

( 8 4 ) Y = H o r OMe

X-

L

0

\+/O

/4

0

x

X

(85)

Br

(87) 37

T . N. Kudryavtseva, M . V. Proskurnina, and I . F. Lutsenko, J . Gen. Chem. USSR (Engl. Transl.), 1981, 51, 1418.

Quinquecovalen t Phosphorus Compounds

51

The halogenation of aryl o -phenylene phosphites (84) gives stable dihalogeno-phosphoranes (8 5), in equilibrium with the phosphonium salts (86), except where X = B r and Y=OMe, in which case the intermediate rearranges, even at - 100 'C, to the spirophosphorane (87).38 Solvolysis of halogenospirophosphoranes (88) produces the stable spirophosphoranes (89) [(89) may be sublimed from sulphuric acid] and the isolable potassium phosphoranoxide (90), all in high yield. The 19F n.m.r spectra reveal that two sets of CF3 groups are present in (88) and ( 9 0 ) , and hence at least one step of the reorganization of ligands is slow on the n.m.r. t i r n e - ~ c a l e . ~ ~

(89) a ; R = H

b: R

20&OH

'' 39

3

=

Me

+

PhPC12

(92)

J . Gloede, H. Gross, J . Michalski, M. Paluski, and A. Skowronska, Phosphorus Sulfur, 1982, 13, 157. G.-V. Roschenthaler and W. Storzer, Angew. Chem., Int. Ed. Engl., 1982, 21, 208.

Organophosphorus Che mis try

52

Condensation of phenylphosphonous dichloride with 2-keto-phenols (9 1) gives tricyclic phosphoranes (93), via the phosphonous diesters (92), provided that R does not possess unfavourable electronic or steric chracteri~tics.~' An analogous reaction with N-methylbenzylideneamine gives head- to- tail cyclization to form the tricyclic phosphorane (94). The synthesis of the spirophosphorane (95) by the route shown is enantiospecific, and the configuration of the enantiomerically pure diastereoisomer has been established by X-ray d i f f r a ~ t i o n . ~ '

6::

H

\

2

+

PhPC12

The 31P and "F n.m.r. data for compounds of the type (96) offer convincing evidence of a change from a pentaco-ordinate t o an ionic structure, brought about by the ability of phosphorus to adopt a tetrahedral geometry as the size of the ring increases.42 A spirocyclic phosphorane (97), with a P-P bond between penta- and tetra-co-ordinate phosphorus, has been prepared as shown and exhibits a value of 709 Hz for 'Jpp, consistent with the proposed structure.43 Addition of chloranil to the diphosphabicyclo [ 3.3.0loctane (98) has led t o the first diphosphorane (99) that contains an axial X5P-X5P bond.44 A number of spirophosphoranes of the types ( loo)-( 102) have been prepared.45 Variable- temperature H n.m.r. spectra reveal that reorganization of ligands is not due to an irregular process, and that the NN-dimethylaminogroup and the phenylamino-group have similar apicophilicities but are less apicophilic than hydrogen by 17-21 kJ mol-'. On the other hand, spirophosphoranes, formed as a diastereoisomeric mixture of (1 05a) and ( I 05b) by the condensation of dioxaphospholans ( 103) with 3-benzylidenepentane2,4-dione (104), are alleged to interconvert by an irregular process through the dipolar species ( 1 06). The fact that in several cases the initial condensation gives a larger proportion of the syn -isomer (1 05a) than is present in the thermodynamically equilibrated mixture is cited as evidence for a synchronous mechanism for the 1 , 4 - a d d i t i 0 n . ~ ~

'

10 41

42 43 44

45

46

S . D. Harper and A . J . Arduengo, II1,J. A m . Chem. SOC., 1982, 104, 2 4 9 7 . M. R. Marre, J. F. Brazier, R. Wolf, and A. Klaebe, Phosphorus Sulfur, 1981, 1 1 , 8 7 . J . E. Richman and R. B. Flay,J. A m . Chem. SOC.,1981, 103, 5265. H. W. Roesky and H. Djarrah, Znorg. Chem., 1982, 2 1 , 844. H. W. Roesky, D. Amirzadeh-Asl, and W. S . Sheldrick, J. A m . Chem. SOC., 1 9 8 2 , 104,2919. B. M. Dahl, 0. Dahl, and S. Trippett, J. Chem. Soc., Perkin Trans. I , 1981, 2 2 3 9 . V. V. Ragulin, V. I. Zakharov, A. A. Petrov, and N . A. Razumova, J. Gen. Chern. USSR (Engl. Transl.), 1981, 5 1 , 2 8 .

Quinquecovalent Phosphorus Compounds

53

OH +

Me

AC*

P(N?lez)3

> 125 kJ mo1-I

NHMe NMe

H

Me

I

c1

I

c1

Ph

0

Me MeN.,

\

n 6(3lP)* 6(19F)* 2,2,2,2 3,2,2,2 3,3,2,2 3,2,3,2 3,3,3,2 3,3,3,3

-14.2 -32.2 -42.8 -46.3 +25.2 +15.1

JpF /Hz

-75.4 -82.6 -67.2 -93.3 -126.7 -127.4

( * Values quoted are i n p . p . m . )

793 872 872 927

0 0

0rga n op h osphorus Che m istry

54

A

Me N

/NMe p-1

\

0

MeNvNhle 1

0

0 0 Cl c1 c1

7$(

\ /

P-°CR

I \”\ ;-to1 ( 1 0 1 ) R = O P h , NHPh ,

(100) R = Ph, NMe2,

OPh,

or H

(102) R

=

NVe2 or NHPh

NHPh, o r H

The reaction of the oxazaphosphole ( 107) with a variety of carbonyl compounds (including formamides) gave high yields of the phosphinates (109) via t h e cyclic phosphinimine (108), itself a precursor t o the diazadiphosphetidine ( 1 47

J. I. G. Cadogan, J. B. Husband, and H. McNab, J. Chem. SOC., Chem. Cornrnun., 1981, 1054.

Quin q ue co valen t Phosphorus Co mpo unds

55

(105b)

( X = OMe, N E t 2 ,

E t , or SPh)

0

(

,COMe

o>f-CHPh-c x

‘COMe

py PPh HN-P’

,ePh

OMe

L

(MeOH)

1

c$

0-P( O)Ph2

56

Organophosphorus Chemistry

Amines and hydrogen phosphonates add to the P-carbon atom of the vinyl-spirophosphorane (1 1 1) t o form (1 12), which are susceptible to an unusually facile cleavage of the P-C bond by methoxide ion or methan01.~’ Addition of amines to the vinyl bond of the spirophosphorane (1 13) (derived from propiolic esters), however, occurs at the a-carbon, to form (1 14).

- (“s‘.0.

XH

C=CHCOOMe

I

COOMe

I

P-CH-CH( 0

x

COOM~

LOMe 0 II

( 1 1 2 ) X = Me2N o r (MeO)zP-

Me 2 NH P

A variety of polymerization processes involving spiroacyloxy-phosphoranes (1 15) have been described, all of which involve zwitterionic intermediates, e.g. (1 16), leading to polymers that contain phosphorus, or containing the a-ester unit, in which the PI1’component serves as a de-oxygenating agent.49 Finally, for purposes of comparison with phosphorus chemistry, conductometric studies show that the reactions of the spiroarsoranes (1 17) with alkyl halides to form (1 19) and ( 1 20) probably occur via intermediate arsonium salts ( 1 18).”

7 Six- and Seven-membered-ring Phosphoranes The reaction of triphenylphosphine with 2,5-dioxabicyclo[ 2.1.1 .I heptane gave the phosphorane (121), which, in the presence of water, hydrolysed to phosphine oxide and cyclopentane- 1,3-dioLS1 In line with previous e ~ p e r i e n c e ,24~ ~the ’ second-order rate coefficients for the reaction in benzene and methylene chloride were virtually identical, suggesting once again the operation of a biphilic insertion mechanism into the peroxide link to form (1 2 1 ). Introduction of trichloromethyl groups into the ring structure of phosphatrioxabicyclo [ 2.2.2.1octanes ( 122) allows reaction with halogens to 4a 49

’’

R . Burgada and A. Mohri, Phosphorus Sulfur, 1982, 13, 85. S. Kobayashi and T. Saegusa, Pure Appl. Chem., 1981, 53, 1663. V. S. Gamayurova, V. K. Kuz’min, and B. D. Chernokal’skii, J. Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 285. T. C. T. Chang, and M. Rosenblum,J. Org. Chem., 1981, 46, 4105.

Q uin q ue co vale n t Phosphorus Co m p o un ds

57

n

0

\+

/O

R1

X-CHCOO-

i

R2

(115) X

=

0 o r CH,

L

(119)

ia

“‘is

+ R2 X

[6(

RHC-0 /,H P-C\‘R RHC-

\ 0-P / 0

(122)

c12

31 P ) = - 63.9 p . p . m . 1

RHC/,H P-C-

a t -6OOC

RHC

0

\

O-PC12

(123)

( R = CCl,)

-

RHC

-0

2 PhOH Et3N

(124 1

Organophosphorus Chemistry

58

form relatively stable dihalogenophosphoranes (1 23), which may be allowed to react with phenol to form the corresponding diphenoxyphosphoranes (1 24).'*

8 Hexaco-ordinated Phosphorus Compounds The insertion of COYCOSYor CS2 into the P-N bond of (1 25) gave moderate to excellent yields of the hexaco-ordinated carbamates ( 1 26), which were also prepared by the reaction of the halogenophosphorane (127) with trimethylsilyl carbamates (1 28).53 An X-ray structure determination on (126; E = 0) revealed a slightly distorted octahedron, with the carbamate ring, the methyl group, and the trifluoromethyl group coplanar.

&le(CF3)3PNMe2

+

( 125)

(127) X = F or C1

CE2

t

( E = 0 o r S)

Me+>+ F 3 C '

NMe E'I

(138)

( 1 2 9 ) Ar = p-FC6H40 F& ., 0-P-x

(X

=

T F C ~ H ~ or O F)

'I b (132)

s2

53

L. N. Markovskii, A. V. Solov'ev, V. V. Pirozhenko, and Yu. G. Shermolovich, J. Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 1 6 7 8 . R. G. Cavell, K. I. The, and L. V. Griend, Inorg. Chem., 1981, 20, 3 8 1 3 .

Quinquecovalent Phosphorus Compounds

59

F3C

(133)

I xX

(137)

(136) ( X = p-FC6H40)

CF3

(138)

Treatment of the thiophosphorane ( 129) with sodium p-fluorophenoxide at - 80 "C gave the trans-anion (130), which at - 60 "C isomerized to a mixture of cis-isomers (1 3 1) and (1 32). With fluoride ion, the trans-isomer was again formed initially, but it isomerized t o only one cis-isomer. The multiplicity of six-co-ordinate anions obtained from the aminophosphorane (1 33), one trans-isomer giving rise to four cis-isomers with X = p-FC6H40, is explained either by a non-planar ring nitrogen, as shown in (134)-( 137), or by a planar nitrogen associated with a twisted oxazaphospholidine ring, as described for (1 36) by the Newman projection (1 38). The conclusions were reached by a subtle combination of variable-temperature 19F and 31P n.m.r. spectra.54 54

J. J. H. M. Font Freide and S. Trippett, J. Chem. R e x (S), 1981,2 18.

3 Halogenophosphines and Related Compounds BY J. A. MILLER

1 Introduction This year's survey covers a particularly unexciting literature. In the main, halogen derivatives continued to be valued more as synthetic intermediates than as ends in themselves. No new reactions have been reported, and little progress in theoretical or mechanistic problems is evident.

2 Halogenophosphines Preparation.- 1,3-Dihalogeno-l,2,3-tri-t-butyltriphosphines ( 1) have been prepared by ring- cleavage of the corresponding cyclotriphosphine, using phosphorus pentachloride, phosphorus pentabromide, bromine, or iodine. The 1,3-dichloride (1 ; X = C1) is particularly stable, and has been shown by 31P n.m.r. t o form as two diastereoisomers.' But

I

P B~LP-L'P-BU~

But

I

-.

x-P-P-P-x

(1) X

c1 C12PCH2PC12 (2)

I

C12PCH2PCH2PC12 ( 3 )

=

C1, Br, or I c1

I

Cl2PCH2PCH2C1 (4)

The formation of bis(dichlorophosphiny1)methane (2) from phosphorus trichloride has been studied in more detail, and the triphosphine (3) found to be a significant by-product ( 16%) and the chloromethyl derivative (4)a minor by-product. (Trichloromethy1)trimethylsilane has been used to introduce a trichloromethyl group into dichlorophosphines to form the compounds ( 5 ) in good yield.4 Stabilization of tetrabromodiphosphine with

'

*

M. Baudler and J . Hellman, 2. Anorg. Allg. Chem., 1981, 480, 129. Z. S. Novikova, A. A. Prishchenko, and I . F. Lutsenko, Zh. Obshch. K h i m . , 1 9 7 7 , 4 7 , 775. S. Hietkamp, H . Sommer, and 0. Stelzer, Angew. Chem., Int. Ed, Engl., 1982, 21, 376.

A . P. Marchenko, G. K. Bespal'ko, E. S. Kozlov, and A. M . Pinchuk, J . Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 1422.

60

Halogenophosphines and Related Compounds

61

chromium in the complex ( 6 ) has been reported.' Inisolation, the diphosphine is not stable, relative t o phosphorus tribromide. c1 RPC12 + MegSiCClg-

I

heat

RPCC13 ( 5 ) R = C1 [ 6 0 % ]

R

=

Ph [ 8 2 % ]

R

=

NMe,

[65%1

'2

R

=

OBu [70%1

( CO)5Cr.Br2PPBr2.Cr(CO)5

(61

Difluoro-(2-trifluoromethylphenyl)phosphine (7) has been prepared by the standard sequence shown in Scheme 1, and extensive coupling data have been discussed in relation to conformation.6

Reagents: i, (Et,N),PCl; ii, HCl; iii, NaF, sulpholane Scheme 1

Physical and Structural Aspects of Ha1ogenophosphines.-Various combinations of isotopically labelled (I3C, 2H, and 37Cl) forms of the phospha-alkene (8) have been studied by microwave spectroscopy, and bond angles and lengths ~ a l c u l a t e d .The ~ same technique has been used to obtain dipole moments and conformational information for difluoro(viny1)phosphine (9), in which the lone-pair on phosphorus lies in the same plane as the vinyl group.'

Photoelectron-spectroscopic studies of the borane adducts (10) and (1 1) have revealed an explanation for the instability of the fluorophosphine

'

A. Hinke, W. Kuchen, and J. Kutter, Angew. Chem., Int. Ed. Engl., 1981, 2 0 , 1060. T. Schaefer, K. Marat, A. Lemire, and A. F. Janzen, Org. Magn. Reson., 1982, 18, 9 0 . B. Bak, N. A. Kristiansen, and H. Svanholt, A c t a Chem. SCQnd.,Sect. A , 1982, 36, 1. G. D. Fong and R. L. Kuczkowski, Inorg. Chem., 1981, 2 0 , 2 3 4 2 .

Organophosphorus Chemistry

62

adduct ( 10; n = 1).9 In essence this is ascribed t o fluorophosphine having lower basicity than expected o n the basis of interpolation, and this, in turn, is the result of destabilization of the HOMO, and hence a relatively low ionization potential. Reactions of Halogenophosphines that lead to p n Bonds to Phosphorus.-In a year of several significant 'firsts', the most surprising was perhaps the preparation lo of t h e diphosphene (12), reported t o be stable, and even handlable in air. Otherwise this field continues t o be a German monopoly, But

But ( i ) P C 1 3 , THF

-

But

But

But

( i i ) M g , THF

But

LiC(SiMe3)2C1 + RPC12

-

But

RP4 C SiMe 3 \CS i Me (13)

with Appel's group again t o the fore. These workers have prepared the first bis(methy1ene)phosphorane (1 3), by a route which depends upon a silicon t o phosphorus migration of chlorine, as modelled in the conversion of (14) into ( 1 5)." Further evidence of this migration follows from the isolation of (1 6) in the sequence leading t o (1 7).'*

c1 I

( Me2N)2PC( SiMe

312

( ? l e S i ) C=PC1(NMe2)2 3 2

/ - ,

(15)

(14)

c1 PC13 +

3 LiCC1(SiMe3)3-

2O0C

I

(Me

Si) C=P-C(SiMe3)2 3 2

[100%]

(16)

i

1 4OoC

c1 I (Me3 Si)2 C = P = C ( S i F l e 3 ) 2

[lOO%J

(17)

lo

"

'*

A . H. Cowley, R. A. Kemp, M . Lattman, and M. L . McKee, Inorg. Chem., 1 9 8 2 , 21, 85. M . Yoshifuji, I. Shima, and N . Inamoto, J . A m . Chem. Soc., 1981, 1 0 3 , 4 5 8 7 . R . Appel, J . Peters, and A. Westerhaus, Angew. Chem., Int. Ed. Engl., 1 9 8 2 , 21, 8 0 . R . Appel and A. Westerhaus, Tetrahedron L e t t . , 1 9 8 2 , 2 3 , 2 0 1 7 .

Halogenophosph ines and Related Co m po unds

63

Three different starting materials (1 8; X = H, C1, or SiMe3) have been used in routes to phospha-alkenes, depending on whether the 0-elimination uses lithium, heat, or base respe~tively.'~ The chemistry of some of these alkenes (R=C1) that has been reported over the year includes displacement of halogen l4 and further 0-elimination and [4+ 2lcycloaddition to give the phosphorin (1 9).15

[Ph-C E P ]

Reactions of Halogenophosphines with Alkenes or Dienes.-The incorporation of phosphorus into heterocyclic rings via 1,n-diene cycloadditions has long been a source of spectacular new reactions, which unfortunately often proceed in low yields. Much light has been cast on this subject by a major paper l6 which not only reveals new examples, where n is varied over a wide range, but also discussed mechanistic features in relation to experimental detail. Other examples concern the heterocycles (20) and ( 2 l ) , prepared in only moderate ~ i e 1 d s . I ~

Synthesis of phospholes via 1,3-dienes has been further studied and valuable details of the relationship between the ligands on phosphorus, the base that is used, and the yield of product have been described." The authors l3 l4 15

l6 l7 l8

R. Appel, J. Peters, and A. Westerhaus, Tetrahedron L e t t . , 1 9 8 1 , 2 2 , 4 9 5 7 . R. Appel and U . Kundgen, Angew. Chem. S u p p l . , 1 9 8 2 , 5 4 9 - 5 5 8 . G. Markl, G. Y . Jin, and E. Silbereisen, Angew. Chem., Int. Ed. Engl., 1 9 8 2 , 2 1 , 370. A. Rudi and Y . Kashman, Tetrahedron, 1 9 8 1 , 37, 4 2 6 9 . Y . Kashman and A . Rudi, Tetrahedron L e t t . , 1 9 8 1 , 2 2 , 2 6 9 5 . A. Breque, F. Mathey, and P. Savignac, Synthesis, 1 9 8 1 , 9 8 3 .

Organophosphorus Chemistry

64

Reagents: i , R 2 P X 2 . AIX,; ii, ArN=C=S; iii, H,O

Scheme 2

+MexMe i, i i

PhPBr2

/

\

Ph

(22) [88%1 Reagents: i, 30 minutes at 2OoC; ii, a-picoline

Scheme 3

stress the individuality of each system (a fair description of much of halogenophosphine chemistry!) and details are provided for the l-phenylphosphole (22), as shown in Scheme 3.

0

II

R'SCR~ [57-84%]

Reactions of Halogenophosphines with Carbanions.-Sulphoxide- st abilized anions can be phosphinylated and the intermediate rearranged into an a sulphenylphosphine oxide (23). l 9 Subsequent oxidative cleavage of the phosphinoyl group leads to the thiolesters in moderate to good yields. The anions of tosylhydrazones can be trapped by chlorodiphenylphosphine, and hence lead to substituted vinylphosphine oxides (24),20 as shown in Scheme 4 .

Reagents: i, BuLi, TMEDA; ii, Ph2PCI; iii, oxidation

Scheme 4 l9

'O

E. Vedejs, H . Mastalerz, G. P. Maier, and D. W. Powell, J. Org. Chem., 1981, 46, 5253. D . G.Mislankar, B. Mugrage, and S . D. Darling, Tetrahedron L e t t . , 1981,22, 4619.

65

Ha logen op h o s ph in es and R elated Co mpo u nds

t-Butyldichlorophosphine (25) reacts with the Grignard reagent (26) to produce, after oxidation at phosphorus, both a tertiary phosphine oxide and the diphosphine dioxide (27), formed as one diastereoisomer only.”

( i) h e a t

ButPC12

+

ButCH2MgC1

(ii)H202

(25)

(26)

iBu (28)

(R

=

B u t , P h , C6Hll,

[25-40%1

o r Me)

The complex of magnesium with buta-1,3-diene has been used to prepare a range of isomeric 2-vinylphosphirans (28), each of which has the cisisomer predominant.22 Alkenyl-lithium species that have been generated in situ can be trapped by various dichlorophosphines t o give the heterocycles (29). These are rearranged by acid to form h5-phosphorins,23 as shown in Scheme 5 .

OMe (29)

Reagents: i, BuLi; ii, R*PCI,, at - 78OC; iii, H +

Scheme 5

xhanistic Reactions of Halogenophosphines with Carbony Compounds.aspects of halogenophosphine-carbonyl interactions continue t o attract attention, although real understanding seems as elusive as ever. Thus a further kinetic study 24 of the reaction between chlorodiethylphosphine (30) and cyclohexanone has resulted in hesitant identification of the salt (31) as an intermediate - previously suggested25 some years ago. A ” 22

23 24

’’

H. Quast, M. Heuschmann, W. Von-der-Saal, W. Buchner, K. Peters, and H . G . VonSchnering, Chem. Ber., 1 9 8 2 , 1 1 5 , 1 1 5 4 . W. J. Richter, Angew. Chem. Suppl., 1 9 8 2 , 739-743. G. Markl, H. Baier, R . Liebl, and D. S. Stephenson, Chem. Ber., 198 1 , 1 1 4 , 8 7 0 . S. Kh. Nurtdinov, R . €3. Sultanova, S. S. Nurtdinova, T. V. Zykova, G . M. Doroshkina, and V. S. Tsivunin, J . Gen. Chem. USSR (Engl. Transl.), 1 9 8 0 , 5 0 , 1 5 9 2 . S. Kh. Nurtdinov, N. M. Ismagilova, T. V. Zykova, R . A. Salakhutdinov, and V. S . Tsivunin, Zh. Obshch. Khim., 1 9 7 6 , 47, 1256.

Organophosphorus Ch em is try

66

+

Et2PC1 (30)

c1-

0

reinvestigation of the reactions of diacetone alcohol (32) with dichlorophosphines has revealed that A3-1,2-0xaphospholen 2-oxides (33) are formed, along with the known A4-phospholen 2-oxides (34).26 The 1 : l intermediate (35; R = M e ) has been identified, but its relation to the final products remains obscure. This chemistry resembles that which leads to the stable tricyclic phosphoranes (36), for which structural details have now been reported.27

(32) (34)

(33)

( R = Ph o r M e )

KO PhPC12

Et3N

+

-78OC

RC

,PhP

I:'o]2

\O

Trapping of various phosphine-carbonyl adducts by other carbonyl compounds contines to provide new synthetic reactions. N-Acetylaminoalkylphosphine oxides (37) are formed28 in fair yield, as shown, although 26

27

"

K. Moedritzer and R. E. Miller, J. Org. Chem., 1982, 47, 1530. S . D. Harper and A . J . Arduengo, J. A m . Chem. SOC., 1982, 104, 2497. J . Oleksyszyn, Synthesis, 1981, 444.

Halogenophosphines and Related compounds

-

R’CH ( NHCOhle )

-

0

II

AcOH

P h 2 P C 1 + R I C H 0 + R2CONH2

67

Ph,PCHH’(NHCOMe)

1

(38) +

i

(37)

R1= Ph o r a l k y l R2= P h , M e , o r C H 2 C 1

Ph2PH

[R1=

P h : 63x1

the authors provide a minor surprise in their speculation that the pathway involves the intermediate aldehyde derivatives ( 3 8). Related reactions with carbarnates yield the oxides (39), or (40), according to the value of n.29 0

(39) 0

Et00C(CH2),COR1

[R

AcOH

II

= Me: 42-55501

+ H2NCOCH2Ph + R2PC12

2 ( R = C 1 , P h , Me, or E t ) 0 (40)

0

RCH ( OCOMe )

(42)

+ Me2N=CHI

I-

(43)

(411

Phosphorus trichloride and 2’,3’-isopropylideneguanosine react in acetone to give the phosphonate (41) as the only product, and the authors discuss possible interrnediate~.~’The 1,l-diacetates (42) of a/3-unsaturated 29

J. Oleksyszyn, E. Gruszecka, P. Kafarski, and P. Mastalerz, Monatsh. Chew., 1982,

30

M. Honjo, T. Maruyama, S. Sato, and R. Marumoto, Tetrahedron Lett., 1981, 2 2 ,

11 3, 59.

2663.

68

Organophosphorus Chemistry

aldehydes and of aromatic aldehydes are formed 31 from acetic anhydride and catalytic quantities of phosphorus trichloride. Dimethylformamide should be avoided as a solvent for iodophosphine chemstry, in view of the isolation of the complex (43) from solutions of either phosphorus tri-iodide or tetraiododiphosphine in DMF.32 The latest trapping experiments with the organomagnesium derivative (44) lead to the phosphoranes (45), as shown in Scheme 6 . These appear to be on the borderline between phosphoranes and phosphonium halides.33

i

(44)

( 4 5 ) R = CH2Ph or Me

Reagents: i , Me1 o r PhCH,Cl; ii, aq. NaHCO,

Scheme 6

Reactions of Halogenophosphines with Oxygen Nucleophi1es.- Examples of quite standard substitution reactions of chlorophosphines, using silyl ether,35 or carboxylate 3 6 nucleophiles, have been described, and are summarized in Scheme 7. Reactions of Halogenophosphines with Phosphorus Nucleophiles. -The reactivity of phosphorus trihalides with phosphites has been monitored by 31P n.m.r., and a regular increase from fluoride through to iodide observed.37 31

32 33 34

35

36

37

J . K. Michie and J. A. Miller, Synthesis, 1981, 824. A. B. Shortt and H. S. Mosher, Synth. Commun., 1981, 11, 733. I . Granoth and J . C. Martin, J . A m . Chem. SOC., 1981, 103, 271 1. S. Kh. Nurtdinov, I. V. Tsivunina, V. G. Zaripova, and V. K. Khairullin, J. Gen. Chem. USSR [Engl. Transl.), 1981, 51, 248. I. F. Lutsenko, M . V. Proskurnina, T. N . Kudryavtseva, N. B. Karlstedt, and T. G. Shestakova, J. Gen. Chem. USSR [Engl. Transl.), 1981, 51, 802. E. Lindner and J. C. Wuhrmann, Chem. Ber., 1981, 114, 2272. R . U. Belyalov, A. M. Kibardin, T. Kh. Gazizov, and A. N . Pudovik, J. Gen. Chem. USSR [Engl. Transl.), 198 1, 5 1, 19.

69

Halogenop h osph ines and Related Compounds

Me

I

HO-CCCC13

+

I Me

x

OSiMe3 + RPC12

'400c ZnCl 2

OSiMe3

+

RICOO-

C1PR22

c1

i

1';P-R

-

R1COOPR22

0

(RICO),O + R22PCl

0

R1!-PR2

II

0

Scheme 7

Although simple exchange reactions dominate, other processes, such as isomerization to P=O compounds, are found to compete. A more theoretical approach 38 t o redistribution between halogenophosphines and various phosphorus(1v) esters leads t o 'redistribution free energies', and hence predicts equilibrium constants. Often, AS* terms more or less cancel, and hence enthalpy data can be used in many predictions. Other exchanges of halogenophosphines include those with pyrocatechol derivatives at both three- 39 and five-co-ordinate levels. 0

0

II Ph2PPPh2

II Ph2PC1 + Ph2PH

+

HC1

(48) Ph2PC1

H

I +

Ph2PPPh2 c1-

4

HC 1 2O0C

]I

Ph2PPPh2

0

+

Ph2PC1 II

-

Ph2PH It

0

II Ph2POH

(47)

Scheme 8

Chlorodiphenylphosphine and diphenylphosphine oxide have been shown 41 t o form diphenylphosphinic acid (46) and tetraphenyldiphosphine (47), or its hydrochloride, as shown in Scheme 8. Under basic conditions, 3R 39 40

J.-C. Elkaim and J. G. Riess, Tetrahedron, 1981, 37, 3 2 0 3 . J. Gloede and B. Costisella, Z . Anorg. Allg. Chem., 1981, 480, 142. J. Gloede, J. Prakt. Chem., 1981, 3 2 3 , 621.

70

Organophosphorus Chemistry

the same reactants are known42 to form the diphosphine monoxide (48), but, in the absence of base, this is not stable to chlorodiphenylphosphine. Miscellaneous Reactions of Ha1ogenophosphines.-The fascinating chemistry of small rings that contain phosphorus has now been extended to the thiadiphosphiran (49; X = S ) and its selenium analogue (49; X Z S ~ ) In . ~com~ parison to cyclotriphosphines, these are extraordinarily stable compounds. t-Butyl groups on phosphorus also seem to be critical in the formation of the bicyclo [ 3.1 .O] hexaphosphine ( 5 0). Phosphorus- 3 1 n.m.r. studies reveal the four shifts expected for this structure.w

X

X = S e [33%1

Bu

The complex polyiodides (51) are formed as shown, from alkyl iodides and diphosphorus tetraiodide, or from trialkylpho~phines.~’ [ Bis(trimethy1silyl)amino]phosphine (52) is the first compound of its type to be prepared.46

LiAlH

(Me3Si)2NPF2

4

P

(Me3Si )2NPH2 (52)

4’

[53%1

D. Hunter, J. K. Michie, J . A. Miller, and W. Stewart, Phosphorus Sulfur, 1981, 10, 267.

42 43

44

4s

J . McKechnie and D. S. Payne, J. Chem. SOC., 1965. 3500. M. Baudler, H. Suchomel, G. Furstemberg, and U. Schings, Angew. Chem., Int. Ed. Engl., 1981, 2 0 , 1044. M. Baudler, Y . Aktalay, K.-F. Tebbe, and T. Heinlein, Angew. Chem., Int. Ed. Engl., 1981, 20, 967. Yu. P. Mokovetskii, N. G. Feshchenko, V. V. Malovik, V. Ya. Semenii, I . E., Boldeskul, V. A . Bondar, and N . P. Chernukho, J. Gen. Chem. USSR (Engl. Transl.), 1980, 5 0 , 1967.

46

E. Niecke and R. Ruger, Angew. Chem., Znt. Ed. Engl., 1982, 21, 62.

71

Halogeno phosph ines and Related Compounds

3 Silylphosphines The silylated tetraphosphine (5 3) has been prepared 47 as shown. Detailed 31Pn.m.r. studies have revealed that it is a mixture of four diastereoisomers.

pen tane

2 Me3SiCl + K2(PPh)4

Me3Si(PPh)4SiMe3 (53)

(Me3Si)3P

+

MeCOC1

[56’%1

/Me

MeCO-P=C

‘0s i M e (54)

(55)

-

OSi14e3

20°C

( MeCO)

3P

( E4eCO ) 2P<

CH2

Several acylation reactions of silylphosphines have been reported. When tris(trimethylsily1)phosphine (54) is treated with acetyl chloride, the intermediate ( 5 5 ) , analogous t o the first phospha-alkenes, is formed, but it reacts further t o give t r i a c e t y l p h ~ s p h i n eOther . ~ ~ acylating agents include halogenoacetyl chloride^,^' which have been used as a source of chloro-ketens (56), and pivaloyl cyanide.50

-

+

hk3SiPPh2

8OoC

-8OOC

HCOCl

RCOPPh2

R’ )c=C=O

c1

(56) R’=

w e , H , o r ~1

200c ButP-P(But

ButP(SihZe3)C1

1

( 5 7 ) [1OOc“Cl

)C1

S i fle

3

(58)R = M e [39C.l

R

= Ph

R

=

[71rC]

CH B r [417] 2

Halogenation of t-butylbis(trimethylsily1)phosphine yields the first silylated halogenophosphine (5 7),” which was fully characterized spectroscopically, despite its ready decomposition. 0-Keto-phosphines (58) have been prepared as shown.

’*

47 4* 49

M. Baudler, G. Reuschenback, and J. Hahn, Z . Anorg. Allg. Chem., 1981, 482, 21. G. Becker, Z . Anorg. Allg. Chem., 1981, 480, 21. E. Lindner, M . Steinwand, and S. Hoehne, Angew. Chem., Int. Ed. Engl., 1982, 21, 355. A. N. Pudovik, G. V. Romanov, and T. Ya. Stepanova, Izv. Akad. Nauk SSSR, Ser.

’’

Khim., 1981, 1675. R. Appel and W. Paulen,Angew. Chem., Int. Ed. Engl., 1981, 20, 869. Brunner, M. E. Dylla, G. A. M. Hecht, and W. Pieronczyk, Z. Naturforsch., Teil. B, 1982, 37, 404.

’* H.

Organo p h 0sp h o rus Ch em istry

72 4 Halogenophosphoranes

Preparation.-For the first time, a direct oxidative addition of fluorine t o phosphorus(II1) esters has been achieved. 53 The fluorophosphoranes thus formed belong to the series (59)-(6 l), and their bipyramidal structures are confirmed by multinuclear n.m.r. Dimethyl ether is a surprise decomposition product from (61 ; n = 0, R’ = Me).53 A simple and efficient route to fluorophosphoranes (62) from bromophosphonium bromides has been de~cribed.’~Related structures have also been prepared from phosphine sulphides or selenides, using sulphuryl chloride fluoride (63).”

+ R3PBr

2 NaF v

Br-

i n MeCN

R3PF2 (62)

R

=

Et

[62(1]

R = Pri

K = Uu”

R P=X 3

+

FS02C1

(X = S or S e )

(63)

[70?1

[8!5’”,1 R,PF . ! I

2

[ 70-90‘

1

f1 /-\

A ( X = CH2 o r 0 )

(64)

[ 48-69? ]

The phosphoranes (64) are reported t o be the first acyclic (a1koxy)a m i n o p h o ~ p h o r a n e s .A ~ ~series of related cyclic oxyphosphoranes, bearing halogen ligands at phosphorus, have been prepared via ring- closure reactions, as shown in Scheme 9. Of these, the alkoxyphosphoranes are bordering on phosphonium salts in character,33, whereas the acyloxyphosphorane (65) is very stable.” Physical and Structural Aspects of Ha1ogenophosphoranes.-A very detailed gas-phase electron-diffraction study of the phosphoranes (66) provides some new answers to the problem of the relative apicophilicity of fluorine and trifluoromethyl ligands.” For (66; n = l), two conformers are present, and that

’’

” 54

’’ 56

57

’’ 59

I. Ruppert, 2. Anorg. Allg. Chem., 1981, 477, 59. R. Bartsch, 0. Stelzer, and R. Schmutzler, J. Fluorine Chem., 1982, 2 0 , 85. A. Lopusinski and J. Michalski, J. A m . Chem. SOC., 1982, 104, 290. L. N. Markovskii, A. V. Solov’ev, and Yu. G. Shermolovich, J. Gen. Chem. USSR (Engl. Transl.), 1980, 50, 1757. I. Granoth, J. Chem. SOC.,Perkin Trans. I , 1982, 735. I. Granoth, R. Alkabets, and Y. Segall, J . Chem. SOC.,Chern. Cornmun., 1981, 622. H . Oberhammer, J . Grobe, and D. le Van, Inorg. Chem., 1982, 21, 275.

73

Halogenophosphines and Related Compounds

0

Reagents: i, Br, ; ii, R X ; iii, SOCl,

Scheme 9

with equatorial trifluoromethyl is predominant. The phosphoranes ( 6 6 ;n = 2, CF3 axial) and ( 6 6 ;n = 3 , CF3 equatorial) reveal the basis for existing confusion on apicophilicity, and the authors discuss in detail the factors which control apicophilicity, and why these depend upon the nature of the other ligands in any one structure.59 Raman spectra have revealed new aspects of the dissociation of phosphorus pentahalides.60 Reactions of Ha1ogenophosphoranes.-Further attempts have been made t o unravel the mechanistic complexities of the reactions of phosphorus pentachloride with electron-rich alkenes. Sometimes these reactions are highly regio- and stereo-specific, and give good yields of vinylphosphonic dichlorides, but these features have so far failed t o attract the interest of synthetic chemists in general. Typical of better-yielding reactions is that of styrene, t o give the phosphonic dichloride (67).61 This example is one of several from a study of reactions between phosphorus pentachloride and styrenes, enol ethers, or dienes, in which paraldehyde or dimethoxymethane is used as a 6o 61

A. Finch, P. N. Gates, and A. S. Muir, J. Chem. SOC.,Chem. Commun., 1981, 812. V. V. Kormachev, Yu. N . Mitrasov, V. A. Kukhtin, T . M . Yakovleva, and Yu. A. Kurskii, J. Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 801.

0rga no p h osp h o r us Ch e m ist ry

74 Ph CH =CH2

0

( i ) PC15

II

PhCH=CHPC12

c

( i i ) (Me0)2CH, 0 II

PC15

+

(71)

BuO-CH=CHPC12

-

J

[65%1

novel quenching agent for the initial adduct. In a more mechanistic study, the first products in the phosphorus pentachloride-butyl vinyl ether system are the salts (68).62 It is only after the stage of quenching with sulphur dioxide that addition t o the initial vinyl group occurs, and small amounts of product (69) are formed. A similar profile was found with the ether (70).63 The amide ( 7 1) reacts with phosphorus pentachloride as shown, although most other amides give mainly polymer.64 0

(ref .65)

1

(F:t0I3P

0

II

(Et0)2PC1

(ref .66)

Scheme 10 62 63

64

V. V. Rybkina, V. G. Rozinov, V. I . Glukhikh, and A. V. Kalabina, J. Gen. Chern. USSR (Engl. Transl.), 1980, 5 0 , 2 1 4 8 . V. G . Rozinov, V. V. Rybkina, V. E. Kolbina, V. I . Glukhikh, V. I. Donskiich, and S. G. Seredkina, J . Gen. Chem. USSR (Engl. Transl.), 1981, 51, 1494. G. A. Pensionerova, V. G. Rozinov, and V, I . Glukhikh, J. Gen. Chem. USSR (Engl. Transl.), 1981, 51, 1015.

75

Halogeno p h osph ines and Re la ted Compounds

Chlorination reactions 65 66 of phosphorus pentachloride have been used in the reactions shown in Scheme 10. Reactions of the iodophosphoranes (72) with primary and secondary alcohols and of (72; R’ = B u ) with acids have been reported,67 and the fluorophosphonium bromide (73) has been shown t o convert allylic and benzylic silyl ethers into the corresponding b r omid es .68

2

( R = p r i m a r y o r secondary a l k y l )

(

73)

Details have appeared6’ of the complexities of the reactions of gibberellate esters with triphenylphosphine in the presence of carbon tetrachloride or tetrabromide. The reaction leading t o the ester (74), as shown in Scheme 1 1, is typical, in that allylic rearrangement and stereoselective delivery of bromide is observed.69 6H-1,3-Oxazin-6-ones (75) are formed by cyclization of heterocyclic P-amino-esters with triphenylphosphine and hexachloroethane .70

Reagents: i, Ph,P, CBr,, acetone

Scheme 11

I

COR 65

( 7 5 ) [60-854]

S . L. Smith, W. J. Layton, M . Govindan, and H. W. Pinnick, J. Org. Chem., 1981, 4 6 , 4076.

66

61 68

69

J . Gloede, 2. Anorg. Allg. Chem., 1982, 484, 231. R . K. Haynes and M. Holden, Ausr. J. Chem., 1982, 3 5 , 5 17. R. Bartsch, 0. Stelzer, and R. Schmutzler, Synthesis, 1982, 326. J . Z. Duri, B. M. Fraga, and J . R . Hanson, J . Chem. Sac., Perkin Trans. 1 , 1981, 3016.

70

D. Achakzi, M. Artas, R . Appel, and H. Wamhoff, Chem. Ber., 1981, 114, 3188.

0rga n op h osp h or us Ch e m istry

76

Two very thorough and informative studies of the mechanism and applicaIn the first tions of reactions of alcohols with Ph3P-CC14 have of these,71 neopentyl alcohol is used as the substrate, and this allows a study of intermediates and of their reactions with external nucleophiles that are added to the system. The authors favour ion-pair pathways to the normal

(76)

Reagents: i, Ph,P, CCI,; ii, Ph,P, CCl,, K,CO,, base

Scheme 12

h i g h e r saccharides

halogenation products. In the second study,72 the 1,2-diols (76) are used as substrates, and the formation of epoxides, or of 2- chlorocycloalkanols, has been found to depend upon the presence or absence of base, and upon the size of the ring (Scheme 12). The nature of R in the sugars (77) determines the outcome of chlorination using Ph3P-CC14.73

71 72

73

J. D. Slagle, T. T.-S. Huang, and B. Franzus, J. Org. Chem., 1981, 46, 3 5 2 6 . C. N. Barry and S. A. Evans, J. Org. Chern., 1981, 46,3361. S . David and G. de Sennyey, Tetrahedron L e t t . , 1981, 2 2 , 4503.

4 Phosphine Oxides and Related Compounds BY J. A. MILLER

1 Introduction The current literature reveals a good deal of solid progress, mainly in established areas. Once again, many of the highlights arose in the field of cyclic phosphine oxides, with new syntheses and some new reactions, at least two of which were far from predictable.

2 Preparation of Acyclic Oxides N-Tosylhydrazones feature in two new syntheses of phosphine oxides, shown in Scheme 1. In one route, a phosphinyl group is introduced by trapping the anions of tosylhydrazones (l), and subsequent oxidation gives good yields of vinylphosphine oxides.' The other example involves initial addition of diphenylphosphine oxide to tosylhydrazones, followed by decomposition of the intermediate (2).* NNHTs

II

R1CH2CR2

i-iii

0

II

P h 2 P C =CHR1

I

R2 (1)

0

II

P h 2 P H + R2C=NNHTs

[63- 78%]

0

II

I Ph2PCR2NHNaTs

-

0

iv

II

Ph2PCHR2 [ 21-90%

Reagents: i, BuLi, TMEDA; ii, Ph, PCl; iii, oxidation; iv, heat Scheme 1

The site of carbonyl addition of diphenylphosphine t o monocyclic 1 3 diketones (3) is dependent upon the size of the ring in which one of the keto-groups is sited, as shown in Scheme 2.3 a-Acylaminophosphine oxides

'

*

D. G. Mislankar, B. Mugrage, and S. D. Darling, Tetrahedron L e t t , 1981, 2 2 , 4619. S. H. Bertz and G. Dabbagh,J. A m . Chem. SOC., 1981, 103, 3932. S. M. Kalinov, V. I . Vysotskii, and N . M. Tilichenko, J. Gen. Chem. USSR (Erigl. Trunsl.), 1981, 5 1 , 1426.

77

Organophosphorus Chemistry

78

[53%1

Reagents: i, Ph, PH, HCI, dioxan

Scheme 2

(4) are formed by a complex reaction, involving four components, in which the phosphorus is provided by ~hlorodiphenylphosphine.~ Further examples of the rearrangement of (acy1oxy)phosphines ( 5 ) into acylphosphine oxides have been reported.' A more novel rearrangement is that leading to a-sulphenylphosphine oxides (6) from the isomeric aphosphinyl sulphoxides ( 7 ) . 6 Lithiation and subsequent oxygenation of the oxides (6) leads t o the thiolesters.

- 0

II

P h 2 P C 1 + A c O H + R I C H 0 + R2CONH2

RCOO-

+

0

It

Ph2PCHR1SR2

Ph2PC1

Ph2PCHR1(NHCOR2)

RCOOPPh

-

500c

2

II

II

0

-

0

II

(i) RLi

Ph2PCHR1SR2

0

11

R1CSR2

(ii) 0

('7)

[57-84%1

(6) 0 II

0

RC-PPh2

(5)

2O0C

R' 2

[35-63%1

(4)

~

0 II

~

~

2

~

~

~

2

(8)

Phosphine oxides ( 8 ) 7 and (9)' have been prepared, the latter by rearrangement of intermediate hydrazides (lo), as shown in Scheme 3 . Details have appeared of the cyclization of the phosphines (1 1) in the presence of J. Oleksyszyn, Synthesis, 1981, 444. E. Lindner and J . C. Wuhrmann, Chem. Ber., 1981, 114, 2272. E. Vedejs, H . Mastalerz, G. P. Maier, and D. W. Powell, J. Org. Chem., 1981, 46, 5253.

T. Ya. Medved', M. K. Chmutova, N. P. Nesterova, 0. E. Koiro, N . E. Kochetkova, B. F. Myasoedov, and M. I . Kabachnik, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 2121.

P. A. Gurevich, A. I. Razumov, R . L. Yavarova, T. V. Komina, and F. Kh. Kutumova, J. Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 1424.

79

Phosphine Oxides and Related Compounds

RL

(10)

1 2 (9) R = Et, R = H

[47-70%]

R1=

P h , R2= H

[28%]

[30%]

Reagents: i, PhNR’NH,; ii, 2 5 0 ° C

Scheme 3

H2°

trap

OJ H ‘

( 1 3 ) R = H o r CECPh i n t r amo 1e c u 1ar trap

[R

= CECPh]

80

Organophosphorus Chemistry

water.’ Isolation of the oxides (12) is suggestive of a mechanism (outlined in Scheme 4) in which cleavage of the initial phosphole ring may result in intramolecular trapping, t o give ( 1 2), o r external protonation, t o give the normal products ( 1 3).’ The oxides (1 4) and ( 1 5) have been isolated from a Grignard reaction with t-butyldichlorophosphine, followed by oxidation. lo The a-keto-phosphine oxides (1 6 ; R = chloro-alkyl) have been prepared and found to undergo standard facile addition t o the keto-group.” A hydrolytic route t o the oxides (1 7) has been described.12 0

(i)ButPC12 BU M ~ 1C

( i i ) [OI (15)

0 II

RC- PPh I1 0

&H

QPPh 0

3 Preparation of Cyclic Phosphine Oxides Details of routes to and of the spectroscopic properties o f derivatives o f phosphonan and phosphonin 1-oxide have appeared.13 The basic recipe in these syntheses involves construction of bicyclic phospholen 1-oxides, followed by ozonolysis o f the double-bond (see Scheme 5 ) . This work is

Reagents: i, R’PCI,, AlCl,; ii, H,O; iii, ozonolysis; iv, hv, I , , 0,

Scheme 5 10

l3

T. Buttars, I . Haller-Pauls, and W. Winter, Chem. Ber., 1982, 115, 578. H. Quast, M. Heuschmann, W. von der Saal, W. Buchner, K. Peters, and H . G. von Schnering, Chem. Ber., 1982, 115, 1154. E. Lindner and M. Steinwand, 2. Naturforsch., Teil. B, 1982, 37, 407. I. Granoth and J. C. Martin,J. A m . Chem. SOC., 1981, 103, 2711. L. D. Quin, E. D. Middlemas, N . S . Rao, R. W. Miller, and A . T. McPhail, J . A m . Chem. SOC., 1982, 1 0 4 , 1893.

81

Phosphine Oxides and Related Compounds

characterized by elegant interpretation of extensive multinuclear n.m.r. data on the various phosphonans. Scheme 6 illustrates a number of reactions of the diketones (18) (ozonolysis products, as in Scheme 5 ) , including facile aldol reactions leading t o (19) and (20).14

(19)

(20)

Reagents: i, BF,, HSCH,CH,SH; ii, Raney nickel; iii, BH,-; iv, POCI,, pyridine

xo R

Ph

Ph

(22) R

Scheme 6

=

H o r Me

Ph

X ( 2 1 ) X = 0 or S

(21a)

Ph is equatorial

The phosphorinan-4-one 1-oxides (2 1) have been prepared from the dienone (22). l5 Thermal isomerization of the initial products yields the alltrans structure (21a), and the individual isomers were characterized by a blend of U.V.and n.m.r. data and a novel application of liquid-crystal circular dichroism. l5 The preparation and some simple reactions of the diphosphorin disulphide (23) have been described 1 6 , and are summarized in Scheme 7. Treatment of the phosphinoyl chloride (24) with azide ion in dimethylformamide and pyridine yields the A2-benzophospholen 1-oxide (25).” The phosphinoyl azide corresponding t o (24) is claimed not to be an intermediate, l4 15

l6 17

L. D. Quin, E. D. Middlemas and N. S. Rao, J. Org. Chem., 1982, 47, 905. J. B. Rampal, N. Satyamurthy, J . M. Bowen, N. Purdie, and K. D. Berlin, J. A m . Chem. Soc., 1981, 1 0 3 , 7 6 0 2 . T. Kawashima, M . Shimamura, and N. Inamoto, Heterocycles, 1982, 17, 341, A. Baceiredo, G. Bertrand, P. Mazerolles, and J.-P. Majoral, J. Chem. SOC.,Chem. Commun., 1981, 1197.

Organophosphorus Chemistry

82

(23)

I

[53%:1 [ 7 2 % trans]

vi

Reagents: i, ClCH,CH=CHCH,Cl; ii, S , ; iii, BuLi; iv, BrCCl,, HCl; v, E t , N , MeCN; vi, Br, o r py - HBr,

Scheme 7

But1 !4e

M e

m 0& p \ R

R (28) n = 2

01^

3

R = Me o r Ph

Phosphine Oxides and Related Compounds

83

but the authors leave us with a nice puzzle - what is the pathway t o ( 2 5 ) ? Further examples of 1,n-diene cycloadditions lead to the phosphine oxides (26)-(29), and substituent effects are rationalized via carbo-cationic intermediates.18 Other related reactions of alkenes lead to the oxides (30) and (3 1): see Chapter 3 for details. 4 Structural and Physical Aspects

Determination of crystal structure by X-ray methods continues to dominate physical aspects of phosphine oxides. Simple tertiary phosphine derivatives whose structures have been reported are (32; X = O),20p21(32; X = S or Se),22 the complexes ( 3 3 ) 23 and (34),24 and the benzyl(pheny1)phosphine oxides ( NCCH2CH2 ) 3P=X

(32)

2 ( Ph3P=O)

*

MePh2As=S. ( E d e 2 N ) 3P=0

( COOH)2

(33)

(34)

R“ ( 3 5 ) R = -C=CHCOOH I Me

( 3 7 ) R1=

( 3 6 ) R = -C(OH)Me

I

Ph

R1=

R

1

=

X

H , R2= C 1 , X

=

S

E t , R2= P h , X = S

Me, R

2

=

Ph, X =

R1= M e , R2= P h , X = 0

t i l t 138O t i l t 145O

t i l t 149O

(35) 25 and (36).26 Of more novelty are the cyclic derivatives (37),27 in which the dihedral angle made by the benzene rings is dependent on the functionality at phosphorus. The e m - o x i d e (38) has been compared with other bicyclic structures.28 X-Ray data have also been reported for the diphosphines

*’A. Rudi and Y . Kashman, Tetrahedron,

1981, 37, 4269. 1981, 2 2 , 2695.

l9

Y. Kashman and A. Rudi, Tetrahedron L e t t . ,

lo

A. J. Blake, R. A. Howie, and G . P. McQuillan, A c t a Crystallogr., Sect. B, 1981, 37,

’’

997.

l2

F. A. Cotton, D. J . Darensbourg, M. F. Fredrich, W. H. Ilsley, and J . M. Troup, Inorg. Chern., 1981, 2 0 , 1869. A. J. Blake, R. A. Howie, and G . P. McQuillan, A c t a Crystallogr., Sect. B, 1981, 37, 1959.

23 24

lS

26 27

28

4

D. Thierbach and F. Huber, 2. Anorg. Allg. Chern., 1981, 477, 101. D. H. Brown, A. F . Cameron, R . J . Cross, and M . McLaren, J. Chern. Soc., Dalton Trans., 1981, 1459. M. L. Glowka, Acta Crystallogr., Sect. B, 1981, 37, 1780. M. L. Glowka and 2. Galdecki, A c t a Crystallogr., Sect. B, 1981, 37, 1783. A. I. Bokanov, A. I. Gusev, N . I . Demidova, M. G. Los’, I. R . Segel’man, and B. I . Stepanov, J . Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 1216. Mazhar-ul-Haque, W. Horne, S. E. Cremer, and J. T. Most, J . Chern. Soc., Perkin Trans. 2, 1981, 1000.

Organ op h 0 sp h or us Chemistry

84

0 II M e P CH h a 1 (41)

x x

II II Ph 2P-PPh

2

0 0 Ph2PCH2PPh2 II II

0

(45) X

= 0, S,

o r NMP

(39; X = 0) 29 and (39; X = S).29930 Conformational studies o n the bis-oxide (40) 31 and the oxides (41 ) 32 and studies of the stability towards radiation of the bis-oxide (42) 33 have been described. Mass-spectroscopic work o n triarylphosphine oxides 34 and on diphenyl(styry1)phosphine oxides (43) 35 36 has been described. Vibrational data for the telluride (44)37 have yielded information on the P-Te bond. Amongst n.m.r. studies, 'J(77Se-31P) coupling for the selenides (45) 38 and shift tensors, from solid-state spectra of various tertiary phosphine derivative^,^^ have been evaluated.

5 Reactions at Phosphorus Dibenzylphosphine oxide (46) may attack alkyl halides at the halogen o r at carbon:' in the presence of methoxide ion, these reactions lead to the products shown in Scheme 8. Diphenylphosphine oxide reacts with chlorodiphenylphosphine t o give tetraphenyldiphosphine (47), o r its hydrochloride, depending upon the reaction temperature:' see Chapter 3 for the pathway. 29

30

31

32

33

34

35 36 31

38 39 40

41

A. J. Blake, G. P. McQuillan, I. A. O x t o n , and D. Troy, J. Mol. Struct., 1 9 8 2 , 7 8 , 265. A. J . Blake, R. A. Howie, and G. P. McQuillan, Actu Crystullogr., Sect. B, 1 9 8 1 , 37, 966. A. P. Baranov, V. G. Dashevskii, T. Ya. Medved', G. M. Petov, E. I. Matrosov, and M. I. Kabachnik, Teor. Eksp. Khim., 1 9 8 1 , 8 3 3 . 0 . A. Raevsky, N . G. Mumzhieva, T. E. Kron, and E. N . Tsvetkova, Izw. A k u d . Nauk SSSR, Ser. Khim., 1 9 8 1 , 1292. N . E. Kochetkova, M. K. Chmutova, I. A. Lebedev, a n d B. F. Myasoedov, Rudiokhimiyu, 1 9 8 1 , 2 3 , 4 2 0 . G. Marshall, S . Franks, a n d F. R. Hartley, Org. Muss. Spectrom., 1 9 8 1 , 16, 2 7 2 . L. Adler and D. Gloyna, J. Prukt. Chem., 1 9 8 1 , 3 2 3 , 5 7 8 . K. G. Berndt, D. Gloyna, and H. G. Henning, J. Prukt. Chem., 1 9 8 1 , 323, 4 4 5 . F. Watari, Inorg. Chem., 1 9 8 1 , 2 0 , 1776. D. W. Allen and B. F. Taylor, J. Chem. SOC.,Dalton Trans., 1 9 8 2 , 5 1 . J . B. Robert and L. Wiesenfeld, Mol. Phys., 1981, 44, 319. K. A. Petrov, V. A. Chauzov, and I. V. Pastukhova, J. Gen. Chem. U S S R (Engl. Trunsl.), 1 9 8 1 , 5 1 , 1 4 2 5 . D. Hunter, J . K. Michie, J. A. Miller, and W. Stewart, Phosphorus Sulfur, 1 9 8 1 , 10, 267.

Phosphine Oxides and Related Compounds

-

0

II

i,ii

(PhCH2) ZPBr

85

-

0

]I

i,iii

( PhCHZ) 2PH

0

i1

( PhCH2) 2PCH2CH=CH2

Ii

" II

0

Reagents: i, MeO-; ii, BrCH,Br; iii, ClCH,CH,CH,CI

Scheme 8 0

II

2 Ph2PH

+

Ph2PC1

2O0C

-

H

I

Ph2P-PPh2 C 1 -

+

0

+

II

Ph2POH

Ph2P-PPh2 (47)

Three papers 42-44 have appeared on the generation and reactions of phosphiran 1-oxides. Thus the oxide (48; R = B u t ) has been isolated as an intermediate in the conversion of the oxide (49; R = B u f ) into the vinylphosphine oxideP2 see Scheme 9. The t-butyl groups of (48; R = B u t ) are held to be responsible for its lack of r e a ~ t i v i t y ,and ~ ~ a similar effect is described for the diazaphosphiridine 3-oxide ( Thermolysis of (48; R = B u t ) leads to [ 2 + l]-cycloelimination,44and the presumed phosphinidene oxide intermediate (51) can be trapped as shown in Scheme 9. The effect of the t-butyl groups in (48; R = B u t ) is critical in the trapping by solvent, because less-substituted phosphiran 1-oxides normally undergo ring- fission, by nucleophilic attack at phosphorus, to give (52). The tricyclic phosphine sulphides ( 5 3) generate phosphinidene sulphides by photolysis, and new phosphorus heterocycles result from trapping of the 42

43 44

H . Quast and M . Heuschmann, Liebigs Ann. Chem., 1981, 9 7 7 . H. Quast and M . Heuschmann, Liebigs Ann. Chem., 1981, 9 6 7 . H. Quast and M . Heuschmann, Chem. Bet-., 1 9 8 2 , 1 1 5 , 901.

Organophosphorus Chemistry

86

0

0

II

RCH2PCHC1R

I R

- AR- YPH I1

But

i

ii

y

[R = B u t ]

R

(49)

RO-P-B~~

O

But

(48)

iv s -

B ~ ~ P = O

I

I

iii

[ 100%1

Reagents: i, base; ii, heat; iii, 3,5-di-t-butyl-o-benzoquinone; iv, R O H ; v , MeO-

Scheme 9

(R

=

87

Phosphine Oxides and Related Compounds 0

II

0

0

II

ii

PhP=CPh2

.Ph

* [11%1

(54)

iv/

It

Ph

t 7%1 Reagents: i, hv; ii, tropone; iii, heat at 180 C; iv, tetracyclone

Scheme 10

latter.45 Further trapping reactions of the phosphine oxide (54) have been d e ~ c r i b e dThese . ~ ~ are summarized in Scheme 10. Diels- Alder reactions of phosphole oxides and sulphides have become commonplace in recent years - e.g. see Volume 13, Chapter 4,pages 67 and 72 respectively. However, it is now reported 47 that, with alkyne dienophiles, the phosphole (55a), and its sulphide (55b), each undergo prior rearrangement - t o 2H-phosphole sulphide ( 5 6 ) in the latter case - and subsequent [ 4 + 21 cycloaddition leads to the 7-phospha-8,9-dinorbornadienes (57), as shown in Scheme 1 1 . There is some analogy in earlier work 48 for the key 1,sshift of aryl groups in phospholes.

ii

Me Ph

6

Ph

I

'Ph

I

( 5 5 ) a ; X is

X

L

(57)

[loo%]

b ; X i s =S

Reagents: i, heat (1,s-shift of phenyl, then 1,3-shift of H); ii, PhC-Ph

Scheme 1 1 S. Holand and F. Mathey, J. Org. Chem., 1981, 46, 4386. G. Maas, M. Regitz, K. Urgast, M. Hufnagel, and H. Eckes, Chem. Ber., 1982, 115, 669. F. Mathey, F. Mercier, C. Charrier, J. Fischer, and A. Mitschler, J . A m . Chem. SOC., 1981, 103,4595. J. I. G. Cadogan, R. J. Scott, R. D. Gee, and I. Gosney, J. Chem. SOC.,Perkin Trans. 1, 1974, 1694.

88

Organophosphorus Chemistry

Studies of the mechanism of the Perkow reaction continue t o attract attention, and two rearrangements of phosphine oxides in this year’s literature the oxide (58) is heated at low are relevant to this theme. In one pressure and thereby fragmented t o the ester (59). The lack of chloral in the product is taken as evidence of an intramolecular pathway t o (59) - the authors favour ‘ three-centre’ rearrangement, involving migration of phosphorus t o oxygen from carbon,49 as shown in Scheme 12. Base-catalysed hydrolysis of the esters (60; R = O M e ) leads t o vinyl esters,” whereas the oxides (60; R = E t or Ph) fragment, possibly by the route shown. Under thermal conditions, the oxides (60; R = Et o r Ph) rearrange t o p h o ~ p h i n a t e s . ’ ~ 0

II

-

0s i ?!e

Bu2P-CHCC13

I

0s i Me

OSiMeg

~

I

i

three-centre

I

*

BU2P-O-CHCCl3

+

rearrangement

-

/

/

0

II Bu2POCH=CC12 (59)

+

Me,,SiCl

[60%1

168x1

Reagents: i, heat at 100°C, at 10 mmWg, for I hour.

Scheme 12

0

II R,P-CHCC1 I

aq. OH-

0

II

( MeO) 2POCH=CC1

[ R = OMe]

2

OH

0

0

II R2P-CCCl3

1 OH

II R2P-CCHC12

II 0

-

0

II

R2PH

+

HOOCCHC12

Solvent and substituent effects o n the tautomerism of the oxides (61) have been reported,’l and both forms were found t o coexist under many conditions. New reactions of the oxides (62) 52 and (63) 53 have been described. 49

50

52

53

T. Kh. Gazizov, Yu. I. Sudarev, A. M . Kibardin, R. U . Belyalov, and A . N . Pudovik, J. Gen. Chem. USSR (Engl. Transl.), 1981, 51, 5 . G. Aksnes and R. 0. Larsen, Liebigs Ann. Chem., 1981, 1967. 0 . I. Kolodiazhnyi, Tetrahedron Lett., 1982, 2 3 , 499. I. Granoth, R. Alkabets, and E. Shirin, J. Chem. SOC.,Chem. Commun., 1981, 981. I. Granoth, R. Alkabets, and Y . Segall, J. Chem. SOC., Chem. Commun., 1981, 622.

89

Phosphine Oxides and Related Compounds OH Ph 2PCH ( S O 2

(611

(62)

COOH S 0 C l 2 , CHC13

-

;iP%

0

d). +Ph

0

Ph

c1

Reduction of triphenylarsine oxide (64) by titanium tetrachloride in the presence of hydride o r metal reducing agents,54 and of the bis-sulphides (65), ( 6 6 ) , and (67) 55 by radical anions, have been described. Difluorophosphoranes (68) are formed from the corresponding phosphine sulphides o r ~ e l e n i d e s . ~ ~

( 6 5 ) m or p

S02C1F

R.P=X 3

54

55

56

-*

R3PF2

( 6 8 ) X = S or S c Y. D. Xing, X. L. HOU,and N . 2. Huang, Tetrahedron Lett.,

1981, 2 2 , 4727. W. Kaim, P. Haenel, U . Lechner-Knoblauch, and H. Bock, Chern. Ber., 1981, 115, 1265. A. Lopusinski and J . Michalski, J. Am. Chem. SOC., 1982, 104, 290.

Organophosphorus Chemistry

90

6 Reactions of the Side-chain But- 2-enyl(diphenyl)phosphine oxide (69) has been converted into the vinylphosphine oxide (70), and two Diels-Alder cycloadditions of the latter have been studied 57 (see Scheme 13). Analysis of the products shows that the regiochemistry of the cycloadditions is controlled by the diphenylphosphinoyl moiety, but that it is the acetyl unit of (70) that prefers an endo-orientation in t h e transition state leading t o t h e adduct with acetoxybuta- 1,3-diene. COMe

0Ac

0

0 [80%1

Reagents: i , MCPBA; ii, KOBut; iii, 0 0 , ; iv, H,C=CHCH=CHOAc; v, isoprene

Scheme 13 0

II

Ph2PCH=CH2

+

€

I

(711

N

3

-

0

3

Ph2PCH2CH2N II

/

/

CH,,OH

CH20H

Y

(72)

Several additions of chiral amines58 o r of chiral alcohols5’ t o vinyldiphenylphosphine oxide (7 1) have been reported. The reaction is illustrated for L-prolinol, which yields the oxide (72), and other substrates include methyl(a-phenylethyl)amine,58 3-pinanylmethylamine,58 (-)-borneol,” (-)-menthol,59 and (-)-myrtanol. 59 s7

SR

59

S. D. Darling and S. J . Brandes, J . Org. Chem., 1982, 47, 141 3. G . Markl and B. Merkl, Tetrahedron L e t t . , 1981, 2 2 , 4459. G. Markl and B. Merkl, Tetrahedron Lett., 1981, 2 2 , 4463.

91

Phosphine Oxides and Related Compounds

Allylic phosphine oxides continue to be used in the stereospecific synthesis of polyenes.60 The stereochemical control arises from the fact that the allylic double-bond in the oxide and the double-bond in the apunsaturated carbonyl component retain their configuration during these Wittig-Horner reactions. Furthermore, the threo -intermediate [ (73) in Scheme 141 eliminates rapidly (relative t o the erythro-adduct), and hence the new double-bond has E geometry.60 The only drawback in these reactions is the generally low yield, as is illustrated in Scheme 14 for the oxide that is derived from nerol(74). Anions derived from a-methoxyallyl(dipheny1)phosphineoxides (75) may react either at the &-carbon or at the y-carbon, depending on the electrophile that is used.61 The regiochemistry also depends o n the ligands on the allylic moiety, and o n reaction conditions, and two illustrative examples are given in Scheme 15. The anions of a-aminoalkyl(dipheny1)phosphine oxides (76) give a-amino-ketones (77) after quenching with aldehydes.62 Diphenylphos-

1

iv,v

-+ e r,q t h r o - i some r [74% ( b o t h isomers)]

[74%1

Reagents: i, MeSO,CI, pyridine; ii, Ph,PLi; iii, H , O , ; iv, BuLi; v, (E)-citral; vi, crystallization; vii, NaH, DMF on threo-isomer

Scheme 14 6o 61 62

J . M . Clough and G. M. Pattenden, Tetrahedron, 198 1 , 37, 39 1 1. M. Maleki, J . A. Miller, and 0. W. Lever, Tetrahedron Lett., 1 9 8 1 , 2 2 , 3789. N. L. J. M . Broekhof and A. Van der Gen, Tetrahedron Lett., 1981, 22, 2 7 9 9 .

Orga n o p h osp h or us Chem is try

92 0

0

Ph2PCHCR1=CHR2 II

I

OMe

P h zIIP y 2 y C H ( O H ) n " l i

i ,ii [ R ' = H, R

2

=

Me]

Me

OMe

(75)

0

II

,OM e

Ph2POLi

/c

PhCH=C 'CH~CHP~

+

v

PhCH2COCH=CHPh

(E or Z)

Reagents: i, LiNPri,, at - 7 8 ° C ; ii, MeCHO; iii, PhCHO, at

-

78OC; iv, at 2 O o C ; v, H,O'

Scheme 15 0

II

-

.R21

heat

Ph2PCHNR1R2

+

R3CH0

I

Li

_z

P3COCH,NR1R2

-

Y

(77) [ 58-86%1

X

X

(X

=

S o r 0) [ 6 1 - 7 3C:1

phinoylstilbenes (78) are formed, as shown, from the corresponding toluene

derivative^.^^ 7 Phosphine Oxide Complexes and Extractants Complexes of phosphine oxides or sulphides with electron-pair acceptors remain an active field of research. Sometimes the aim is purely preparative, but more often the aim is a spectroscopic or thermodynamic study. Protonation of triphenylphosphine oxide (79a) or sulphide (79b) in highly acidic media, e.g. oleum, occurs prior to sulphonation of the ring.@ 63 64

G. P. Schiemenz and M . Finzenhagen, Liebigs A n n . Chem., 1 9 8 1 , 1 4 7 6 . K. B. Dillon, M. P. Nisbet, and T. C . Waddington, J . Chem. Soc., Dalton Trans., 1982,465.

93

Phosphine Oxides and Related Compounds

Complexes of (79b), of tri-p-tolylphosphine sulphide (80), or of the disulphide (81) with iodine in halocarbon solvents are reported t o exist in several competing s t o i c h e i o m e t r i e ~ . Other ~~ tertiary phosphine sulphides complex with cobalt(I1) halides.66 Copper(I1) complexes with (79a) have been fully ~ h a r a c t e r i z e d . ~ ~

b; X = S

0

0

II

II

R 3 P =O

P h 2 P [ C H 2 1 nPPh2

(82) a; R = Et b ; R = CH2Ph

(83)

R

= 2

or 4

c ; R = Me

Complexes of zinc(II), cadmium(Ir), and mercury(11) dichlorides with triethylphosphine oxide (82a) or with tribenzylphosphine oxide (82b) have been the subject of thermochemical studies.68 A huge compilation of '13Cd n.m.r. data on a series of tertiary alkyl- or aryl-phosphine oxides has been p ~ b l i s h e d . ~Protonation ' of trimethylphosphine oxide (82c) has been the subject of a quantum-mechanical in~estigation.~'The oxides (83) complex with dialkyltin(1v) dichlorides." 0

(C8H17)3P=0 (84)

(C H

) As=O 8 17 3

(85)

R'

II

PC H NHCOOR' (86)

Trioctylphosphine oxide (84) remains the most popular extractant for various cations, although mixed extractant systems in which (84) is a component are now more in evidence. Ions whose extraction has been reported in the current year are zirconium(~v),~* uranium,73 lead(I1) from molar aqueous sodium ~erchlorate/thiocyanate,~~ c a d m i u r n ( ~ r ) ,ammo~~ n i ~ m ,europium( ~ ~ I I I ),77 silver( I ) (assisted by dibenzo- 18-crown- 6),78 65 66

67 611

69 70

71 12

73 74 75

16

71 78

S . Kaur and T. S. Lobana, J. Inorg. Nucl. Chem., 1981,43, 2439. J. C. Pierrard, J . Rimbault, and R. P. Hugel, J. Chem. Res. ( S ) , 1982, 52. M. Melnik and J. Mrozinski, J. Mol. Stnict., 1982,7 8 , 85. J. C. De Queiroz, C. Airoldi, and A . P. Chagas, J. Inorg. Nucl. Chem., 1981,43, 1207. P. A. W.Dean, Can. J. Chem., 1981,59, 3221. V. V. Pem'kovskii and M. M. Konoplya, Teor. Eksp. Khim., 1982, 18, 25. G. K. Sandhu, H. Singh, and S. S. Sandhu, Indian J. Chem., Sect. A , 1981, 20, 5 18. Y. Shigetomi and T. Kojima, Bull. Chem. SOC.Jpn., 1981, 54, 1887. K. Krishima and T. Yanagi, J. Nucl. Sci. Technol., 1982, 19, 83. S. Kusakabe and T. Sekine, Bull. Chem. SOC. Jpn., 1981,54, 2533. H. Akaiwa, H. Kawamoto, T. Koizumi, and P. W. Schindler, Bunseki Kagaku, 1982, 31, 151E. T.Sekine, H. Hishikura, and S. Kusakabe, Bunseki Kagaku, 1982,31, 157E. T. Taketatsu, Chem. Lett., 1981, 1057. Y . Hasagawa, K. Suzuki, and T. Sekine, Chem. Lett., 1981, 1075.

94

Organophosphorus Chemistry

m a n g a n e s e ( ~ ~ )alkaline ,~~ earths,80 and tervalent lanthanides." Acids that have been extracted b y (84)include acetic acid 82 and perchloric acid,83 and the extraction of rhenic and of technetic acids by trioctylarsine oxide (85) has also been r e p ~ r t e d . ' The ~ extraction of transplutonium elements from nitric acid by the carbamate (86) has been i n ~ e s t i g a t e d . ' ~

l9

O'

'' "

84 R5

T. Aoki, Bull. Inst. Chem. Res., K y o t o Univ., 1 9 8 1 , 5 9 , 191. S. Umetani, K. Sasayama, and M . Matsui, Anal. Chim. Acta., 1 9 8 2 , 34, 3 2 7 . H . E'. Aly, S . M . Khalifa, N . Zakreia, and A. A. Abdel-Rassoul, Radiochem. Radioanal. L e t t . , 1 9 8 1 , 48, 31. J . Goiob, V . Grilc, and B. Zadmik, Ind. Eng. C h e m . Process Des. Dev., 1 9 8 1 , 20, 1 3 3 . A. M. Rozen, A. S. Skotnikov, and L. G. Andrutskii, Zh. Neorg. Khim., 1 9 8 2 , 2 7 , 732. A . M. Rozen, A . S . Skotnikov, and E. G . Teterin, Zh. Neorg. Khim., 1 9 8 2 , 2 7 , 7 3 9 .

M. K. Chmutova, N . P. Nesterova, N . E. Kochetkova, 0. E. Koiro, and B. F. Myasoedov, Radiokhimiya, 1 9 8 2 , 2 4 , 3 1 .

5 Tervalent Phosphorus Acids BY B. J. WALKER

1 Introduction The explosive expansion in studies of two- co-ordinate phosphorus continues, to such an extent that this year it has been allocated a separate section in this Chapter.

2 Phosphorous Acid and its Derivatives Nucleophilic Reactions.--A ttack on Saturated Carbon. The use of phasetransfer catalysis in the Michaelis-Becker reaction has been reported.' Under these conditions, neither strong base nor anhydrous conditions are required, and so the scope of the reactions is broadened. An initial Michaelis-Becker reaction to give the phosphonate ( I ) is apparently involved in the reaction of dialkyl phosphites with 1-bromocarboxylic acids in the presence of base and a carbonyl compound, which ultimately gives acrylic acids (see Chapter 9). 0

II

(R0)2PH

+

2NaH

BrCHRCOOH

0

II

( RO)2PCH2COO-

Ma'

-NaBr

The Arbusov reaction has been r e ~ i e w e d ,and ~ examples of its use include the synthesis of the phosphono-analogue (2) of a-D-glUCOSe 1-phosphate and substituted aminomethylene-bis(phosphonates)( 3 ) and -bis(phosphinates) (4)' and reactions of 1- and 2-adamantyl phosphites with alkyl halides to give diadamantyl alkylphosphonates ( 5 ) . 6 Fluoroalkyl halides do not generally undergo the Arbusov reaction (although the phosphonation of telomers of chlorotrifluoroethylene has been reported) and so this route is not available for the formation of perfluoroalkyl-phosphorus bonds. However, such bonds can be formed by the reaction of tetraethyl pyrophosphite (6) with perfluoroalkyl halides in the K. M. Kern, N. V. Nguyen, and D. J . Cross, J. Ovg. Chem., 1981, 46, 5 188. D. R. Britelli,J. Org. Chem., 1981, 46, 2514. A . K. Bhattacharya and G. Thyagarajan, Chem. Rev., 1981, 8 1 , 4 1 5 . E'. Nicotra, F. Ronchetti, and G. RUSSO,J.Chem. SOC.,Chem. Commun., 1982, 4 7 0 . L. Maier,PhosphorusSulfur, 1981, 11, 311. R. I. Yurchenko, T. I . Klepa, 0. B. Bobrova, A. G. Yurchenko, and A . M . Pinchuk, Zh. Obshch. Khim., 1981, 51, 7 8 6 (Chem. Abstr., 1981, 9 5 , 133 0 3 1 ) . B. Boutevin, Y. Hervaud, and Y . Pietrasanta, PhosphorusSulfur, 1981, 1 1 , 373.

95

Organophosphorus Chemistry

96

0 Ve2NCHC1

2 +

II

+

Me2NCH [PR1(0R2)],

2R1P(0R’)2-

2R”Cl

( 3 ) R1= OR2 ( 4 ) R1=

alkyl

presence of di-t-butyl peroxide, thus providing a synthesis of perfluoroalkylphosphinites (7) and -phosphonates (8) (Scheme 1).8 The Michaelis-Becker reaction proved unsatisfactory for transforming benzylic secondary phosphine oxides (9) into tertiary phosphine oxides (1 l).9 However, conversion of (9) into the corresponding trimethylsilyl phosphinite (1 0), followed by an Arbusov reaction, gave much better results (Scheme 2), and these have been added to the transform file of a program for computer-aided synthesis.

Reagents: i, (ButO),, CF,CICFCI,; i i , ButOOH, MeOH, C F , CICFCl, Scheme 1 Me

I ArCHP(0)H

Me ,0sih!e3

1

I

Me

ArCHP,

I

Me

I

ii

ArCHP(0)H

vp

1

Me

Reagents: i, ClSiMe,, E t , N ; ii, KX Scheme 2

Yet more details of the reaction of 2-chloro-oxirans (as an alternative t o 2-chloro-ketones) with tervalent phosphorus have appeared. l o

lo

M. Kato and M. Yamabe, J. Chem. SOC.,Chem. Commun., 1981, 1173. C . Laurenco, L. Villien, and G. Kaufmann, J . Chem. Rex ( S ) , 1982, 12. J. Gasteiger and C. Herzig, A n g e w Chem., I n t . Ed. Engf., 1981, 2 0 , 8 6 8 ; C. Herzig and J. Gasteiger, Chem. Ber., 1 9 8 2 , 115, 6 0 1 ; B. J . Walker, in ‘Organophosphorus Chemistry’, ed. D. W. Hutchinson and J . A . Miller (Specialist Periodical Reports), The Koyal Society of Chemistry, London, 1982, Vol. 13, u. 7 9 .

Tervalent Phosphorus A cids

97

Dicationic tris(trialky1 phosphite) complexes, e.g. ( 12)) undergo Arbusov reactions with iodide or cyanide ions to give anionic phosphonate complexes, e.g. (1 3)." The latter complexes act as ligands towards a variety of transition metals.

R'NCHR~OM~

I

COOhlIe

+

-

0

II

Lewis

( R ~ O 3~ )

acid

a

R~NCHR'P( OR"

I

C OOMe

(14)

A new synthesis of (aminoalky1)phosphonates (1 4) is provided by the reaction of a-methoxyurethanes with trialkyl phosphites in the presence of Lewis acids. l 2 A detailed study of the kinetics and equilibrium of reactions of alkoxyphosphonium triflates (1 5) has provided data that will be very useful to those interested in the mechanism of the Arbusov r e a ~ t i o n . The ' ~ alkylating ability of (1 5 ) , towards triflate, changes by up to six orders of magnitude, depending on the substituents.

(16)

Full details have appeared l4 of the synthesis and chemistry of the thermally and hydrolytically stable phosphorane ( 16), which is offered as a useful model for the long-postulated Arbusov reaction intermediate. The involvement of dialkyl phosphite and thiophosphite anions in aliphatic SRN1 reactions with a-halogeno- and Q- tolyl-sulphonyl nitroalkanes has been investigated and mechanistic details have been proposed." Nucleophilic Attack on Unsaturated Carbon. Activated vinyl halides undergo normal Arbusov reactions, and such a reaction of ethyl (2)-2,3-dibromopropenoate, followed by treatment of the vinylphosphonate product with base, has been used l 6 to prepare a useful, new dienophile (17) (Scheme 3). W. Klaui, H. Otto, W. Eberspach, and E. Buchholz, Chem. Ber., 1982, 115, 1922.

'* T . Shono, Y . Matsumura, and K. Tsubata, Tetrahedron L e t t . , 1981, 2 2 , 3249. l3 l4

E. S . Lewis and K. S. Colle,J. Org. Chem., 1981, 46,4369. I . Granoth, J . Chem. Soc., Perkin Trans. I , 1982, 735. G. A. Russell, F. Kos, J . Hershberger, and H. Tashtoush, J . Org. Chem., 1982, 47, 1480. R. G.Hall and S . Trippett, Tetrahedron L e t t . , 1982, 2 3 , 2603.

Organophosphorus Chemistry

98 0

Reagents: i, (EtO), P; ii, Et,N

Scheme 3

Unactivated vinyl halides generally require catalysis t o accomplish the same reaction, and full details have appeared of the use in this way of copper(1) halide complexes ( 18) of trialkyl phosphites t o prepare v i n y l p h o ~ p h o n a t e s . ' ~ Under certain conditions, halide- exchange reactions occur as well as phosphonate formation, and this reaction has been developed as a method of converting vinyl bromides into vinyl chlorides in excellent yield. Further studies of the similar copper-promoted phosphonation of aryl halides by trialkyl phosphites have been reported. l 8 Phosphite complexes of copper(I), e.g. ( 1 9), have been prepared which will phosphonylate certain aryl halides even at room temperature.

(20b) K1=

( RO) 3PCuC1

(EtO)3PCu(OOCMe)

(18)

(19)

Et

The 1,4-dihydropyridylphosphonate (2 l a ) is a useful intermediate in the synthesis of 4-alkyl-pyridines, and in an attempt t o obtain (21a) rather than the 1,2-isomer (21b), trimethyl phosphite was allowed t o react with the sterically hindered acylpyridinium salt (2Oa). l 9 However, the ratio of isomers was essentially the same as when the simple acylpyridinium salt (20b) was "

'' l9

G. Axelrad, S. Laosooksathit, and R. Engel, J. Org. Chem., 1981,46, 5200. G. Axelrad, S. Laosooksathit, and R. Engel, Synth. Comrnun., 1980, 10,9 3 3 (Chern. Abstr., 1981,95, 62 309); J . A. Connor, D. Dubowski, A. C. Jones, and R. Price, J. Chem. Soc., Perkin Trans. I , 1981, 1143. K.-Y. Akiba, H. Matsuoka, a n d M. Wada, Tetrahedron Lett., 1981,22, 4093.

TeY vale n t Ph 0 sp h orus A cids

99

used. Steric hindrance in the phosphite was much more effective, and the 1,4isomer ( 2 1a) was obtained predominantly from reactions of triethyl or triisopropyl phosphites with (20b). The corresponding quinolinium salts (22) and isoquinolinium salts (24) 21 undergo specific 2-phosphonylation, irrespective of the bulkiness of the alkyl phosphite, to give (23) and (25), respectively.

*’

COOH

COOR

Secondary phosphites add to vinylphosphoranes to give adducts, e.g. (26);22 however, owing to the presence of strongly electron- withdrawing substituents, it is impossible to assess the influence of the Pv atom. Further investigations of the reactions of tervalent phosphorus esters and amides with activated double- bonds are unremarkable, except that in one case prolonged reaction times led t o ring-expansion of the initial product (27) t o give (28).23 The results of an investigation of the reactions of phosphites with dimethyl acetylenedicarboxylate 24 are essentially the same as those reported by T e b b ~ . ~As ’ might be expected, the stability of the initial phosphorane product (29) depends on the nature of the phosphite used; (29a) is stable, but (29b), derived from trimethyl phosphite, rearranges to the cyclic ylide (30). Many, mostly routine, reports of additions of phosphites to imino-groups have appeared. Asymmetry is induced in the product (32) that is formed 2o 21

22

23 24

’’

K.-Y. Akiba, T. Kasai, and M. Wada, Tetrahedron L e t t . , 1982, 2 3 , 1709. K.-Y. Akiba, Y. Negishi, K. Kunimaya, N . Ueyama, and N. Inamoto, Tetrahedron L e t t . , 1981, 2 2 , 4977. R. Burgada and A. Mohri, Phosphorus Sulfur, 1982, 1 3 , 85. Y. Leroux, D. E. Manouni, and R . Burgada, Tetrahedron L e t t . , 1981, 22, 3393. R . Burgada, Y. Leroux, and Y. 0. El Khoshnieh, Tetrahedron L e t t . , 1981, 2 2 , 3533. J. C. Tebby, S. E. Willetts, and D. V. Griffiths, J . Chem. SOC., Chem. Commun., 1981,420.

Organophosphorus Chemistry

100

PhCO

0

H

\C’

II

+

0),NMe2

H’ C‘COPh

-

Ph

Ph

( RO)

2POMe

+

X c 2

111

C V

(X

= COOMe)

( 2 9 b ) R = Me

X

from tris(trimethylsily1) phosphite and the imine (3 l), followed by hydrolysis and hydrogenation (Scheme 4).26 Diphenylphosphine oxide will react with arenesulphonylhydrazones in ether over several days t o give the acid- and base-sensitive adducts (33).27 Brief heating converts (33) into starting materials. However, prolonged heating in T H F gives the tertiary phosphine oxides (34) (Scheme S ) , thus providing a new mild method for their synthesis under neutral conditions. 26

27

J. Zon, Pol. J. Chem., 1981, 5 5 , 643 (Chem. Abstr., 1982, 9 6 , 199 793). S . H. Bertz and G. Dabbagh,J. A m . Chem. SOC., 1981, 103, 5932.

Tervalent Phosphorus Acids

-

101

i-iii

( + )-(R 1 - R C H B N C H M e P h

( + )-(S ) - M e C H P ( 0 ) ( O H ) 2

i

(31 1

NH2 (32)

Reagents: i, (Me,SiO),P; ii, H,O*; iii, H,,catalyst Scheme 4 0

II

Ph 2PH

0

11

i

+

R~R'C=N-NH-SO,,A~

Ph ?P C R ~ R ~ N H N H S O ~ A ~ Y

li

(33) i

Ph2P( O)CHR1R2

(34) Reagents: i, heat at 25 'C; ii, heat Scheme 5

n

n

Examples of Mannich- type reactions of phosphites include the formation of substituted l-[(phosphonyl)methyl]-2-imidazolidinones (35) and 1,3bis [ (phosphonyl)methyl]-2-imidazolidinones.28 An analogous reaction of phosphorous acid has been used t o prepare ( 1-aminoalkyl)phosphonic acids (36) (Scheme 6).29

( H O ) ~ P ( O ) H+

R'CHO

+

(36)

Reagents: i , Ac,O; ii, H30+ Scheme 6

Potassium or caesium fluoride catalyse the formation of phosphonates from the reaction of secondary phosphites with aldehydes and ketones in the absence of solvent.30 Di-(2-acylphenyl) phenylphosphonites (37) undergo 19

30

J . A. Mikroyannidis, Phosphorus Sulfur, 1982, 12, 249. J. Oleksyszyn and E. Gruszecka, Tetrahedron Lett., 1981, 22, 3537. F. Texier-Boullet and A. Foucaud, Synthesis, 1982, 165 (Chem. Abstr., 1982, 96, 217927).

Organophosphorus Ch em istry

102

R2 heat _L

(38)

I R'CO

$O

k$-

1

Me0

(37)

OMe

,OMe1

OMe

fJ

Ohle

\

OM e

thermally induced intramolecular cyclization to the tricyclic phosphoranes (38).3' The reaction does not occur when one acyl group is sterically hindered, or with ester functions, and, although a phosphorane is formed from di- [ 2-( 2,4 - dimethoxybenzoy1)- 5- methoxyphenyl] phenylphosphonite (39), it is in solvent- and temperature-dependent equilibrium with the phosphonite form. The addition products of diethyl trimethylsilyl phosphite (40) and aldehydes have been converted (by consecutive treatment with base and an alkylating agent, followed by hydrolysis) into aldehydes, ketones, 07-unsaturated ketones, and carboxylic acids (Scheme 7).32 The formal adducts (43) of benzil and (44) of phenacyl chloride are not formed by 0

i-iii

MegSiOP(OEt,)Z + R'CHO

-R1CHP(0)(OEt)2

R1R2C0

+

II

(EtO)ZPH

(40)

( R1= H or a l k y l ; R 2 = H , a l k y l , R 3 C H = C H C H 2 ,

or OH)

Reagents: i, LiNPri2;ii, R'X; iii, H 3 0 f Scheme 7 3'

32

S . D. Harper and A. J . Arduengo, 111, J. A m . Chem. SOC., 1982, 104, 2 4 9 7 . M. Sekine, M . Nakajima, A. Kume, A. Hashizume and T. Hata, Bull. Chem. SOC.J p n . , 1982, 55, 224.

Tervalent Phosphorus Acids

103 + OSiMe3

( E t O ) 2 P O S i M e 3 + PhCOX'CXPh

I

0-

II

11

(EtO)2P-O-C=CH

( E t O ) 2P-O-C=CPhOSiMe

I

1

Ph

Ph

2

reaction with (40), since the initial addition product (4 1) undergoes migration of phosphorus t o oxygen more rapidly than of silicon to oxygen.33 However, (43) and (44) can be prepared via the phosphonate carbanion (42). Pyrolysis of (43) and (44) gives the Perkow products (45) and (46) respectively (Scheme 8),and since the pyrolysis is thought to take place via the adducts (41; X=COPh) and (41; X=CH2C1), this is suggested t o provide further evidence that the Perkow reaction occurs via initial attack at carbonyl carbon. 0

II

-

( Iit0)2P-CPh

I

0s iMe

OSiMeg

0

OSiMeg

0

I

II

II I (Et0)2P-CPh

( Et0)2P-CPh

I

I I COPh

kH2C 1

(43)

(44)

I

I

iii

iii

Ph

C/OsiMe

1I Ph/

'\O-P(

3

0

II

OEt )

(45)

Reagents: i , PhCOCI; i i , ClCH,I; iii, heat Scheme 8 33

M. Sekine, M . Nakajima, and T. Hata, J. Org. Chern., 1981, 46, 4030.

104

Organophosphorus Chemistry

oc:OCHXY

4-

[X

=

Ha1.Y

=

HI

(48)

(47)

1

[X

=

+

Y = Hal]

c’ocl

( RO)ZP(

( R 0 ) 2 P ( O)OC=CHX

I

O)OC=CH2

I

The reaction of 2,6-dichlorophenacyl halides with phosphites gives both Arbusov (48) and Perkow (49) products, while 2,6-dichlorophenacylidene dihalides give only the Perkow product (50).34 Kinetic studies are claimed to support the postulate that there is initial attack of phosphorus on bromine for (47; X = Y = B r ) and o n carbonyl carbon for (47; X = Y = C l ) , but the validity of this cannot be judged from the abstract. In a correction of earlier N-benzoylphenylglyoxanilide (5 1) has been shown36 t o react with triethyl phosphite t o give the meso-ionic structure (5 2).

L

J

(52)

The reactions of 4-nitro- and of 3,4-dinitro-benzoyl chloride with trimethyl phosphite give (54), containing two phosphorus atoms, rather than the a-keto-phosphonate (53) that was previously obtained from similar reactions, although (53) does appear to be an intermediate in the formation of (54).37 Nucleophilic Attack on Oxygen. Reported desulphurization reactions, using trialkyl phosphites, include the novel conversion of the cyclic dicyanothioesters (5 5) into vinylcyclopropane dicarbonitriles (56), presumably by the (5 7) mechanism shown.j* 1,3-Dimethyl-2-phenyl-1,3,2-diazaphospholidine 34

3s 36 37

38

B. Mlotkowska, P. Majewski, A. Koziara, A. Zwierzak, and B. Sledzinski, Pol. J . Chern., 1981, 5 5 , 631. M. L. Scheinbaum, Tetrahedron Lett., 1969, 4221; H. 0 . Larson, K. Y . W. Ing, and D. L. Adams,J. Heterocycl. Chern., 1970, 7, 1227. M. J. Haddadin, A . M. Kattan, and J. P. Freeman, J . Org. Chern., 1982, 47, 723. D. V . Griffiths, H. A. R . Jamali, and J . C. Tebby, PhosphorusSulfur, 1981, 11, 95. K . Friedrich and H. J . Gallmeier, Tetrahedron Lett., 1981, 2 2 , 2971.

Tervalent Phosphorus Acids

(Me0)3P

+

ArCOCl

-

105 0

+

0

11 11

(Me0)2P-CAr

O-P(OMe)3

(Me0)3P _ _ _ _ f

)

MeCl [ A r = 4-N02C6H4

I

ArC_-P( 0 ) ( OMe )

+

(53)

ArC=O

or 3,5-(N02)2C6H31 0 - P ( 0 ) ( OMe l 2

I 1

A r c - P ( 0 ) ( OMe ) ArC=O

R2

I R'

( RO)3P

C ( C N I 2 -C R1% ..

+

(R0)3PS

R1 R2

CN

(56)

(55)

Ph

1

is a superior reagent t o phosphite for converting thionocarbonates into the corresponding alkene in that it is effective at much lower temperatures (25-40 0C).39Penicillin sulphoxides are known to undergo deoxygenation on treatment with trimethyl phosphite, t o give thiazolines (58) and small amounts of the desulphuration products.40 It is now reported that the addition of catalytic amounts of organic acid t o this reduction leads to the formation of the oxazoline (59) as the major product (Scheme 9); optimum yields were obtained by using a triphenylphosphine-squaric acid mixture. The reaction of 1,3,2-dioxaphospholans (60) with glycols, amino-alcohols, and a-hydroxy-acids in the presence of diphenyl disulphide provides new routes t o spirophosphoranes (62) and (63).41 The reaction is thought t o take place via initial formation of phosphonium benzenethiolate (6 1). 39 40 41

E. J . Corey and P. B. Hopkins, Tetrahedron Lett., 1982,2 3 , 1979. S. Yamamoto, S. Kamata, N . Haga, Y . Hamashima, and W. Nagata, Tetrahedron Lett., 1981, 22, 3089. Y . Kimura, M. Miyamoto, and T. Saegusa, J . Org. Chem., 1982,47, 916.

Organophosphorus Chemistry

106

R1 0-

R1coNu> I

R1

0

OH

HN

I

A00R2

i

OH

I

I

\

R1coNE> ;1°0R2

R1

0

8',

0

I

'COOR2 (59)

Reagents: i , R , P ; ii, RCOOH

Scheme 9

+

PR'

PhSSPh

-

( 6 0 ) R3= P h , O E t , o r OMe

(62) X

=

(61)

NH or O H ,

Y = NH o r OH

A re-investigation of the reaction of thiocyanogen with a variety of secondary phosphine oxides and secondary phosphorous esters has shown that the initial product (formed with retention of configuration at phosphorus) is the thiocyanate structure (64).42 These compounds rearrange to the isothiocyanidates ( 6 5 ) at a rate that is dependent on the substrate. 42

A. Lopusinski, L. luczak, and J . Michalski, Tetrahedron, 1982, 38, 679.

Tervalent Phosphorus A cids

-

R1

R1

‘Pyx R 2’ \ H R1,

107

+

(SCN)2

-

X

>P/

R

R2= a l k y l o r O a l k y l

‘SCN

R1 \p/x

H2’

\N=C=S

(65)

(64)

X = O o r S

The mechanism of the reaction of phosphites with alkyl benzenesulphenates to form penta-alkoxyphosphoranes or phosphates has been i n ~ e s t i g a t e d . ~ ~ The data support initial direct insertion into the S - 0 bond t o give an intermediate (66). Phosphites that contain 8-quinolinyl substituents form hexaco-ordinate ozonides (67).44

RlgP

+

R20SAr

-

r [R1

1 P/sAr] \OR2

(67)

Nucleophilic Attack on Halogen. Details of the use of the tris(dimethy1amino)phosphine-hexachloroethane condensation reagent in the synthesis of arginine-containing peptides have appeared.45 Trialkyl phosphiteor triphenylphosphine-silver nitrate complexes can be used to replace positive halogen atoms by nitro-groups; for example, in the synthesis of a-nitronitriles (68).& The reaction probably involves initial attack of phosphorus on halogen, and both the nitro- (68) and the nitroso-compounds (69) are formed. However, the former appears t o be favoured at room temperature and the latter decomposes by loss of nitrosyl cyanide. Both 1,l -dibromocyclopropanes and 1,I-dibromo-alkenes can be reduced to the monobromo-derivatives (70) and (7 l), respectively, by diethyl hydrogen phosphite and t r i e t h ~ l a m i n e ? ~presumably via attack of phosphorus on halogen (dichlorides d o not react under the same conditions). 43

44

45

46 47

D. B. Denney, D. Z . Denney, and D. M. Gavrilovic, Phosphorus Sulfur, 1981, 11, 1. M. Koenig, F. El Khatib, A. Munoz, and R . Wolf, Tetrahedron Lett., 1982, 2 3 , 421. R . Appel and E. Kiester, Chem. Ber., 1981, 114, 2649. R. Ketari and A. Foucaud, J . Org. Chem., 1981, 4 6 , 4 4 8 9 . T. Hirao, T. Masunaga, Y . Ohshiro, and T. Agawa, J. Org. Chem., 1981, 4 6 , 3745.

108

Organophosphorus Chemistry CN

I I

R1-C-Br

+

RZ3P.AgN03

X

- [I" R1-C-

Ag+

( X = C N , COOR, o r CONR2)

1

CN

I H~-C-NO l 2

CN

I

+

RI-C-ONO

1

- x

X

.

(69)

I

R'COX

+

[NCNO]

RCH = CB r

\2

RCH =C H B r

( X = C1 or B r )

Do/, x-

\+,OAr

0

X

(72)

The reaction of halogens with aryl o-phenylene phosphites at low temperature gives the adducts (72), which have been shown by 31P n.m.r. spectroscopy to exist as a mixture of phosphorane and phosphonium forms,48 while the intermediate in the chlorination of ethylene chlorophos-

'*

J . Gloede, H. Gross, J . Michaslki, M. Pakuslki, and A. Skowronska, Phosphorus Sulfur, 1982, 13, 157.

Tervalent Phosphorus A cids

109

Br (75) (74)

phite is entirely in the phosphorane form (73).49 Perhaps the most surprising aspect of this work is that the adduct (74) undergoes ether cleavage t o give (75), even at - 100 “c. Dialkyl phosphites can be converted into the corresponding fluorides (76), under mild conditions, by treatment with sulphonyl chloride fluoride.”

at -4OOC

(76)

Electrophilic Reactions.-The chemistry of diazadiphosphetidines (77) has been r e ~ i e w e d . ’ The ~ first example of a primary aminophosphine (78) has been obtained by reduction of the corresponding difluoro(amino)phosphine with lithium aluminium h ~ d r i d e . ’ ~

I

R2

49

52

J . Gloede, M. Pakulski, A. Skowronska H. Gross, and J . Michalski, Phosphorus Sulfur, 1982, 13, 163. A. lopusinski and J . Michalski, Angew. Chern., Int. Ed. Engl., 1982, 2 1 , 294. A. F. Grapov, L. V. Razvodovskaya, and N . N . Mel’nikov, Usp. Khirn., 1981, 5 0 , 6 0 6 (Chern, Abstr., 1981, 9 5 , 4 3 203). E. Niecke and R. Ruger, Angew. Chern., Znt. Ed. Engl., 1982, 21, 62.

Organ op h o sp h or us Che m is try

110

OH

bH

"\ /"

+

PIm

0

CJ

B =

HO

0

0

I

Im = 1-imidazolyl

Uridine oligonucleotides have been synthesized by the reaction of uridine with tris(imidazo1-1 -yl)phosphine followed by hydrolysis of the intermediate (79).53 Evidence has been provided that the single enantiomer that is formed in the reaction of tris(dimethy1amino)phosphine with (-)-ephedrine is the trans-isomer (SO).54 This isomer reacts with chloranil t o give a phosphorane, again as only one diastereoisomer (81) (Scheme lo), this structure being confirmed by X-ray diffraction. The 1,3,2X3-benzoxaphospholes( 8 2 ) are formed by transamination of bis( dimethy1amino)methylphosphine with 2-( methy 1amino)-phenols and -anilines.55 Ph

&.

H I

H /OH

NMe

i

I

C

Me/

'NHMe H

Me

NMe H

c1

Reagents: i, (Me,N),P; ii, c1

Scheme 1 0 53

54

55

T. Shimidzu, K. Yamana, K. Nakamichi, and A. Murakami, J. Chem. SOC.,Perkin Trans. I , 1981,2294. M. R. Marre, J . F. Brazier, R. Wolf, and A. Klaebe, Phosphorus Sulfur, 1981, 11, 8 7 .

M.Wieber, 0. Mulfinger, and H . Wunderlich, Z . Anorg. Allg. Chem.,

1 9 8 1 , 477, 108.

Tervalent Phosphorus Acids

111 XH

Me

( X = 0 or NMe)

(82)

In a continuation of their work on large-ring tervalent phosphorus esters, Robert and his co-workers have investigated the synthesis of eight-membered rings that contain two phosphorus atoms.56 Partly on the basis of 31Pn.m.r. evidence, the reaction of P-methyldiethanolphosphine (83) with dichloro(methy1)phosphine is reported to give, in addition t o the two isomeric eightmembered rings (84), a mixture of dimeric isomers (85). The reaction of dimercaptoethylphosphine with tris(diethy1amino)-phosphine or -arsine gives the corresponding 1,5-diphospha- (86) and 1-phospha- 5-arsa- 2,8-dithiabicyclo [ 3.3 .O]octane derivatives (87).” These derivatives react with electrophiles preferentially at carbon-bonded phosphorus in each case. Me

MeP(CH2CH20H)2

+

MePC12

-

Me +

Me-P

Me

1 10°C

./) \

(86) E = P (87) E = As

Transesterification reactions of dialkyl phosphites have been investigated. 58 Similar reactions with tertiary amine hydrochlorides cause monodealkylation of the phosphorus esterYs9while reactions with triethanolamine hydrochloride give products arising from both dealkylation, e.g. (88), and ester exchange, e.g. (89). 56 57

’* 59

J. P. Dutasta, K. Jurkschat, and J . B. Robert, Tetrahedron Lett., 1981, 2 2 , 2549. K. Jurkschat, C. Mugge, A. Tzschach, W. Uhlig, and A. Zschunke, Tetrahedron Lett., 1982, 2 3 , 1345. K. Troev, E. Tasher, and G. Borisov, Phosphorus Sulfur, 1982, 1 2 , 313. K. Troev, E. Tasher, and G. Borisov, Phosphorus Sulfur, 1981, 11, 3 6 3 .

Orga no p h o s p h or us Ch e rnistry

112

0

II

ROP-O(CH,),N(CH,CH,OH)~

YH I

0

+

II

+

( RO 1 2PH

( HOCH2CH2 ) 3NH

c1-

ki ROP-0-

( 89 1

+ HN(CH2CH20H)3

I

H

(88)

Reactions involving Two- co-ordinate Phosphorus.--The chemistry of compounds that contain two- co-ordinate phosphorus has been reviewed.60 The direction of addition of nucleophiles to P=N in iminophosphines, and hence the nature of the anion that is formed, is of current interest. On the basis of the quenching, with deuterium oxide, of anions that are formed from the reactions of the aminoiminophosphine (90) with lithium aluminium hydride and with methyl-lithium, the quinquevalent anions (9 1) and (92) are suggested as intermediates.

P 'N~R

-P

\NR~

( 9 0 ) R'=

SiMe

R'

(R-= 3 A1H 4 o r Me)

I$/

2

\NH7

( 9 1 ) R2= H

3

(92) R2= Me

Frontier orbital theory has been applied to the cycloaddition reactions of two-co-ordinate phosphorus compounds (93).62 Two situations are visualized, ( a ) where the HOMO is the n-orbital and the LUMO is the n*-orbital of P=X, and ( b ) where the HOMO is a n-orbital (the phosphorus lone-pair) and the LUMO is the n*-orbital of P=X. In the former case [ 2 + 2 ] , and in the -X

R-I?

7 I

o

X-P-R

R P' (93) X

-X

R-P I

r I R-P-X

I

=x =

CH2, NR, or 0

\ P H ~

/ /

or

P-x 12 "

62

E. Fluck, Top. Phosphorus Chem., 1 9 8 0 , Ruppert, Angew. Chem., Int. Ed. Engl., 1 9 8 1 , A. H. Cowley a n d R . A. Kemp, J . Chem. Soc., W. W. Schoeller and E. Miecke, J . Chem. Soc.,

+

I1

[4

+

11

10, 193; R . Appel, E'. Knoll, and I . 2 0 , 731.

Chem. Commun., 1 9 8 2 , 3 1 9 . Chem. Commun., 1 9 8 2 , 5 6 9 .

Tervalent Phosphorus Acids

113

latter case [ 2 + I] or [4+1], cycloadditions are followed. The effect of changing X is explained by the crossing of 0- and .rr-orbitals favouring the [ 2 + 11 or [ 4 + 11 paths when X is an electronegative atom. Frontier orbital theory is also invoked to explain the [2 + 11 cyclodimerization of t-butylimino- t- butylphosphine (94), when aminoiminophosphines (95) are known ~ ,3 h3-Azadiphosphiridines (96) t o undergo [ 2 + 21 c y c l ~ d i m e r i z a t i o n . 1~,2X3 are available from [ 1 + 21 cycloadditions of phosphinidenes with aminoiminophosphines, and are unusual in that they decompose by [ 2 + 11 cycloreversion t o phosphinidenes.64 The remarkably air-stable 1,2,3X3-diazaphosphoridines

-

Bu'\

4 N B u L

a t O'C

2 B ~ ~ P = N B ~ ~

R2N-P=NR

;))NBut

(95)

R~P- PNR'~ RI2N-P=NR2

\/

[R3P]

+

N

(97) have been prepared from NN'-di- t- butylhydrazine and their stereochemistry has been determined by ' H and 13C n.m.r. spectroscopy and, in one case, by X-ray crystallography.6s When (97) is heated in toluene, the isomeric di-iminophosphoranes (98) are formed initially, but these rapidly form the dimer (99) or the di-iminophosphorane (100) (Scheme 11). The

A NR2 (97)

But Pri2N,p,N,

4 N B ~t

P ButN4

N '/

'NPri But

(99

,NHu 2

Me 3 S i N = P

1

N N B U ~

(100 1

Reagents: i, BunLi; ii, R,NPF, ;iii, MeLi; iv, heat at 1 0 0 ° C Scheme 11 63

E. Niecke, R. Ruger, and W. W. Schoeller, Angew. Chem., I n f . Ed. Engl., 1981, 2 0 ,

64

E. Niecke, A. Nickloweit-Luke, R. Ruger, B. Krebs, and H. Grewe, 2. Nctuvfovsch., Teil.B, 1981, 36, 1566 (Chem. Abstr., 1982, 96, 162 825). E. Niecke, J. Schwichtenhovel, H.-G. Schafer, and B. Krebs, Angew. Chem., Int. Ed. Engl., 1981, 2 0 , 963.

10 34. 65

0rga n o p h o sp h o r us Ch e m is try

114

aminophosphine ( 102), formally a trimer of N-phenylimino-N-phenylaminophosphine, has been prepared both by thermolysis of (10 1) at 80 "C and by the reaction of phosphorus trichloride with aniline.66 Heating ( 102) above 8 0 ° C results in an equilibrium mixture of (102) and the dimer (103) of N-phenylimino-N-phenylaminophosphine. The authors draw analogies between this reaction and the oligomer-interconversion reaction of the quinquevalent phosphazenes. Iminophosphines undergo [ 2 + 3 ] cycloaddition reactions with both t-butyl azide67 and with diazoalkanes.68 In the former case, the initially formed A3-tetra-azaphospholines ( 104) can be decomposed H 2

[(PhNH)2P]2NPh

-,

Ph

Ph

" ' Ph

PhN' H

(1011

Ph

H

2PhN\p/N\p/N\,/Np~

8OoC

PhNHP/N\

>x

Ph

R2 B

~3 ~

R' 2 ~ - ~ = -~m ~ 2

NR1

N

/N\N

\P

11

N R ~

-N 2 -R',N-P~

N

R1=

B

~

SiMe3 o r P r i (105)

R2= SiMe3 or But (104)

thermally or photochemically to give di-iminophosphoranes (105) or the dimers of (105), depending on the substituents present.67 The cyclo-adducts (1 06) that are formed with diazoalkanes readily lose nitrogen, on heating, to give the iminomethylenephosphorane (107) and the dimer ( 108). Further heating of (108) gives the stable isomer (109), and 31Pn.m.r. studies indicate that (107) is an intermediate in the formation of (109)? Among the first two- co-ordinate phosphorus compounds to be prepared were those with the phosphorus atom in a five-membered, potentially aromatic, ring, and these compounds continue to be the subject of many publications. The diazaphosphole ( 1 10) undergoes regiospecific cycloaddition with 4-chlorobenzonitrile oxide to give (1 1 1).69 The diaza-arsenole (1 12) gives an analogous product (1 13) in a kinetically controlled reaction, but the isomer (1 14) as the thermodynamic product. Treatment of 2-phenyl (or -acetyl)- 5-methyldiazaphospholes ( 1 15) with phenyl azide gives trimers (1 1 6),70 while the reaction of the triazaphosphole ( 1 17) with azido-alcohols 66

67

68

M . L. Thompson, A. Tarassoli, R . C. Haltiwanger, and A. D. Norman,J. A m . Chem. SOC., 1981, 103, 6770. E. Niecke and H.-G. Schafer, Chem. Ber., 1982, 115, 185. E. Niecke, A. Seyer, and D . - A . Wildbredt, Angew. Chem., I n t . Ed. Engl., 1981, 20, 675.

69

70

R . Carri6, Y . Y. C. Y. L. KO, F. De Sarlo, and A. Brandi, J. Chem. SOC., Chem. Cornmun., 1981, 1131. B. A. Arbusov, E. N. Dianova, and S. M . Sharipova, Izv. A k a d . Nauk S S S R , Ser. Khim., 1981, 1600 (Chem. Abstr., 1981, 95, 204065).

~

Tervalent Phosphorus Acids

115 NR’ R’~N--P@ CHR’

R2

R’ 2~ -P = N R ~ +

R3CHN2

R12N,p

4CHR3

2 / \NR2

R N

P ’‘ \NR1

R3HC4

2

(108)

MeCON

+

ArCNO

-

MeCON”\CMe

\

/

P

Ph N/

\CMe

\ AS-

C-H

/

\

ArC \N/

I

0

(113)

gave phosphazenes (1 19).71 This latter reaction is thought t o involve the tautomeric pair (1 18) as intermediates. 4,s-Dicyano-1 ,3,2X3-diazaphospholate ( 1 20) is formed from the condensation of diaminomaleonitrile with tris(dimethy1amino)phosphine at room t e m p e r a t ~ r e Methylation .~~ of ( 120) gave 71

72

5

M. R. Marre, M. T. Boisdon, and M. Sanchez, Tetrahedron L e t t . , 1982, 2 3 , 853. A. Schmidpeter and K. Karaghiosoff, Z. Naturforsch., Teil. B, 1981, 36, 1273 (Chem. Abstr., 1982, 96, 1 2 2 874).

Organ op h osp h or us Ch e mis try

116

+ NN‘

P Me

H

-

HOCHR~CH~N~

N3

N‘

N3

N‘

Me

Me

Me

the 1,3,2X3-diazaphosphole ( 12 1). 1,3-Benzazaphospholes ( 123) have been synthesized by cyclization reactions and by oxidation of the secondary phosphine ( 122). 7’ Zerovalent platinum complexes of the h3-phosphazene (1 24) have been prepared by reaction with platinum dicyclo-octadiene followed by 73

K. Issleib and R. Vollmer, 2. Anorg. Allg. Chem., 1981, 481, 2 2 .

Tervalent Phosphorus Acids

117

X ‘Pt

-P t /x

/y\

X ( 1 2 5 ) X = Y = CNR //NR ( 1 2 6 ) X = CNR, Y = P \NR~

progressive substitution of l i g a n d ~ . X-Ray ~~ structures confirm that complexes (1 25) and (1 26) provide the first examples of X3-phosphazenes participating in p-P co-ordination. 75 Phosphorus-3 1 n.m.r. evidence indicates that the reaction of aminophosphines with trifluoromethanesulphonic acid gives an equilibrium mixture involving phosphenium ions (1 27).76 The ionic form predominates in this equilibrium only when it is stabilized by two amino-groups (i.e. X = Y =NR2). Similar cations (128) have been prepared by treatment of the corresponding chlorophosphine with aluminium t r i ~ h l o r i d e . ~ ~ ‘\P-NMe2 Y/

+

2 CF 3S O 3H

Y/ “P+

CF3S0 3 -y/

P-

0sO2 C F

(127 1

+ Me2NH2

Ph ‘c=pc1 Me3Si / (129)

-

+ CF3S03

-

Ph ‘C=PX Me3Si’

(130) X = BuL, NR2,

PR2,

OR, or SR

Appel’s group reports that P-chloro(methy1ene)phosphine (1 29) is a useful intermediate for the synthesis of a wide range of P-substituted(methy1ene)74

75

76 77

0. J . Scherer, R. Konrad, C. Kriiger, and Y.-H.Tsay, Chem. Ber., 1982, 115, 414. 0. J . Scherer, R . Konrad, E. Guggolz, and M. L. Ziegler, Angew. Chem., Int. Ed. Engl., 1982, 21, 297. 0. Dahl, Tetrahedron Lett., 1982, 2 3 , 1493. A. H. Cowley, M. Lattman, and J . C. Wilburn, Inorg. Chem., 1981, 20, 2916.

Organophosphorus Chemistry

118

phosphines ( 130).7s t -Butylphosphinidene oxide (1 32) has been generated by heating tris-(t-buty1)phosphiran (1 3 1) and trapped by water and alcohols to give (1 33) and (134) respectively, and by [ 4 + 11 cycloaddition to orthoquinones to give (135).79 In the absence of trapping agents, the water- and alcohol-sensitive poly(metaph0sphinite) (1 36) was formed (Scheme 12). 0

M e 3C'

CMe3

&

i +

___f

[Me3CP=Ol

Me3C

-

[Me3CP=Oln

(132)

CMe

(136)

(131)

II

( 1 3 4 ) R = alkyl

Reagents: i , heat at 50--60°C;

ii, ROH; iii,

Scheme 1 2

CMe3

Me3C

(137)

Two groups

have reported the first syntheses of a true phosphobenzene

( 137) and in one case confirmed the structure by X-ray diffraction.

Cyclic Esters of Phosphorous Acid.-A large number of 2H- 1,3,2-dioxa(1 38), dithia- (1 39), -diaza- (140), and -oxaza-phosphorinans (141) have been prepared by reduction of the corresponding chlorides with tributyltin hydride, arid their H, 13C, and 31Pn.m.r. parameters have been determined." Proton, I3C, and 31P n.m.r. have also been used t o investigate the conforma7x 79

xo

R. Appel and U. Kundgen, Angew. Chem., Znt. Ed. Engl., 1982, 21, 219. H . Quast and M.Heuschmann, Chem. Ber., 1982, 1 1 5 , 901. M. Yoshifuji, I . Shima, and N. Inamoto, J. A m . Chem. Soc., 1981, 103, 4 5 8 7 ; B. Cetinkaya, P. B. Hitchcock, M . F. Lappert, A. J . Thorne, and H. Goldwhite, J. Chem. Soc.,Chem. Commun., 1982, 6 9 1. E. E. Nifantiev, S . F. Sorokina, A. A. Borisenko, A. I . Zavalishina, and L. A. Vorobjeva, Tetrahedron, 198 1 , 37, 3 183.

119

Tervalen t Phosphorus A cids

I

R1

(138) X = Y = 0

( 1 4 2 ) R 1 = P h , Me, E t , OMe, o r C 1

(139) X = Y = S ( 1 4 0 ) X = Y = NR2 ( 1 4 1 ) X = 0 , Y = NR2

tion of a series of 1,3,2-dithiaphosphorinans (142) and their 2-0x0- and 2 - t h i o n o - d e r i ~ a t i v e sThe . ~ ~ results, which are confirmed by X-ray studies in many cases, indicate a chair conformation with a strong axial preference for a wide variety of P-substituents, although equatorial is strongly preferred by P-t-butyl. X-Ray diffraction shows that the thermodynamically unstable form (143) (with the lone pair of phosphorus axial) of the phosphorinan ligand co-ordinates t o molybdenum with retention of configuration at phosphorus. 83

(1431

The high-yield, AIBN-initiated, molecular oxygenation of phosphites has been shown to be highly stereoselective, with retention of configuration at phosphorus.@ Replacement of l 6 0 2 with I8O2or " 0 2 offers a convenient method for the regio- and stereo-selective introduction of isotopic oxygen, and has been applied t o the synthesis of labelled 3,s-cyclic monophosphates (1 44) and (145) of thymidine (Scheme 13). +

x

B

~

~

N

H

~

@I

and ( 1 4 5 ) X =l80,Y = l 6 0

Reagents: i, AIBN, ' * 0 2benzene; , ii, resolution by MPLC; iii, ButNH, Scheme 13 " B. E. Maryanoff, A. T. McPhail, and R. 0. Hutchins,J. A m . Chem. SOC., 1981, 103, '3

R4

44 32. R . A. Jacobson, B. A. Karcher, R. A. Montag, S. M. Socol, L. J. Vande Griend, and J. G. Verkade, Phosphorus Sulfur, 1981, 11, 2 7 . T. M. Gaida, A. E. Sopchick, and W. G. Bentrude, Tetrahedron L e t t . , 1981, 2 2 , 4 1 6 7 .

Organop h osp h or us Che m is try

120

A study of the stereochemistry of nucleophilic substitution at phosphorus in the aminophosphonite (146) has been carried Proton and 31Pn.m.r. spectroscopic evidence indicate that while the initial substitution is stereoselective, to give (1 47), with inversion at phosphorus, the final product is an equilibrium mixture of the isomers (147) and (148). The authors suggest that the reactions may involve a pentaco-ordinate phosphorus intermediate (149), rather than the S N ~ ( Pmechanism ) commonly suggested.

r,o m7 Me

0 + H

\

CDC13 9 S 25OC

P

i NMe

+

\

\X

2

+

\

(X

=

I:

‘x

(147)

(148)

(146 )

Me2NH

OPh, OMe, o r

( 149

1

Miscellaneous Reactions.-Silyl phosphites (1 5 1) can be generated by treatment cf the readily available 2,2,2-trichloroethoxycarbonylphosphonates (1 50) with zinc and trimethylchlorosilane.86 Since ( 15 1) are particularly sensitive to moisture, this provides a useful method for their preparation in situ. 1

0

0

II II OR ) 2

Cl 3CCH20C-P(

-co*

-

M e 3 S i O P ( OR )

Me S i c 1 3

(151 1

(152)

There is a developing interest in hybrid ligands, e.g. (152), for stabilizing bimetallic species that contain two different metal atoms.87 The first R5 86 87

0. Dahl, Tetrahedron L e t t . , 1 9 8 1 , 22, 3281. M. Sekine, H. Yamagata, and T. Hata, J. Chem. SOC., Chem. Commun., 1981, 9 7 0 . J . Powell and C. J . May, J. A m . Chem. SOC., 1 9 8 2 , 104, 2636.

Tervalen t Phosphorus A cids

121

examples of cyclic secondary aminophosphines (1 54) have been synthesized (Scheme 14) by 6 -elimination of trimethylchlorosilane from acyclic precursors (153).88 Compounds (154) show the lowest direct P-H coupling constant ever reported.

H R2N-P-NHR

i,ii

H iii

H R2N-P-NR

I

C 1si M e 2 (R = SiMe ) 3

-

RN

/p\

\ s
'Me

Me

(153)

(

154 )

Reagents: i, BuLi; ii, Me,SiCI,; iii, heat

Scheme 1 4

NHPh Ph

0

II R'C-O-PR~~

30-60°C

0

0

II II R'C-PR~~

(157)

1 ( R = Me o r R F ,

R2=

Ph o r M e )

At temperatures above 100 O C , the 3H-2,l-benzoxaphosphole (1 5 5 ) disproportionates t o give ( 1 56).89 A number of rather unstable acyloxyphosphines (157) have been prepared and a kinetic investigation of their rearrangement t o acylphosphine oxides has been carried out.g0 The phosphines (1 57) can be stabilized by co-ordination t o metal carbonyls. The stable triphenyl phosphite-borane complex (1 5 8 ) is reported t o be a convenient , high- yielding hydroborating agent ." Tertiary phosphites rapidly reduce mercuric acetate t o metallic mercury, and this reaction has been developed as a method of quantitatively determinine phosphorous esters, using potentiometric titration with a platinum e l e ~ t r o d e . ' ~ 89

90 91 92

E. Niecke, A. Nickloweit-Luke, and R. Riiger, Phosphorus Sulfur, 1981, 12, 213. B. M. Dahl, 0. Dahl, and S. Trippett, J . Chem. SOC., Perkin Trans. I , 1981, 2239. E. Linder and J. C. Wuhrmann, Chem. Ber., 1981, 1 1 4 , 2272. A. Pelter, R. Rosser, a n d S . Mills,J. Chem. SOC. Chem. Commun., 1981, 1014. M. C. Demarcq, Phosphorus Sulfur, 1982, 1 3 , 9.

122

Organophosphorus Ch em istry

3 Phosphonous and Phosphinous Acids and their Derivatives The alkylation of (+)-(R)-isopropyl methylphosphonate ( 1 59 j with methyl trifluoromethanesulphonate occurs stereospecifically and entirely on oxygen to give the phosphonium salt (160), which can be converted (Scheme 15) into the somewhat stereochemically labile (+j-(R )-isopropylmethyl methylphosphonite (1 6 l), with retention of configuration at phosphorus, by treatment with a base.93

0

Reagents: i, M~O!!CF~ ; ii, R,N

II

0

Scheme 1 5

S

I\

OMe

'Cb

(163)

CH ( CHMeOPPh ) (164

1

A variety of secondary phosphinothioates (163) have been prepared by photocleavage of the cyclo-adducts (1 62) in methanol." Both enantiomers of the chiral phosphinite ( 164) have been prepared from the corresponding optically active diols and used as ligands in homogeneous catalytic hydrogenat ion.95

93 94 95

L. J. Szafraniec, L. L. Szafraniec, and H. S . Aaron, J. Org. Chem., 1982,47, 1936. S. Holand and F. Mathey, J. Org. Chem., 1981,46, 4386. J . Bakos, I . Toth, and L . Marko, J. Org. Chem., 1981,46, 5427.

Quinquevalent Phosphorus Acids BY R . S . EDMUNDSON

The proceedings of two symposia on organophosphorus chemistry have been published. Each report contains many short papers and reviews of relevance to the present chapter.IT2Other subjects which have received the attention of reviewers during the year include phosphorylated and thiophosphorylated amino-heterocycles (1 70 refs.), a-alkoxyalkyl phosphorus compounds and their analogues (305 ref^.),^ the preparation of spin-labelled phosphorus compounds (77 ref^.),^ and the quantitative analysis of the effects of structure of tetraco-ordinate phosphorus compounds on their reactivity ( 104 refs.).6 An extensive discussion (148 refs.) of the chemistry of reactive metaphosphate (1), metaphosphonate (2), and metaphosphinate ( 3 ) species has been p ~ b l i s h e d .A~ review of the enzymatic reactions of phosphates will also be of interest t o those concerned with the stereochemistry of reactions of phosphorus compounds.8 As in the Reports for previous years, the sections headed ‘General’ cover papers which describe work on phosphonic or phosphinic acid derivatives as well as those of phosphoric acid, or which describe compounds possessing more than one type of ‘phosphyl’ group.

1 Synthesis General.-In its first application to organic chemistry, sulphuryl chlorofluoride has been shown t o convert phosphorothionates, phosphonothionates, and the corresponding seleno-analogues into phosphoro- and phosphonofluoridates, although with little stereospe~ificity.~ The first 00-dialkyl thio-

’ ‘Phosphorus Chemistry’, A.C.S. Symposium Series No. 171, ed. L. D. Quin and J . G. Verkade, The American Chemical Society, Washington D.C., 1981. ’ Khim. Primen. Fosfororg. Soedin., Tr. Yubileinoi K o n J , 6th, 1977 (publ. 1981), ed. A. V. Kirsanov. L. V. Razvodovskaya, A. F. Grapov, and N . N. Mel’nikov, Usp. Khim., 1982, 51, 239. (Chem. Abstr., 1982, 96, 181 323). K. A . Petrov, V. A. Chauzov, and S. V. Agafonov, Usp. Khim., 1982, 51, 412 (Chem. Abstr., 1982, 96, 181 328). M. Konieczny and G. Sosnovsky, Synthesis, 1981, 682. ‘ B. I. Istomin and V. A. Baranskii, Usp. Khim., 1982, 51, 394 (Chem. Abstr., 1982, 96, 181 327).

’ ’

M. Regitz and G. Maas, Top. Curr. Chem., 1 9 8 1 , 9 7 , 72. P. A . Frey, Tetrahedron, 1982, 38, 1541. A. Lopusifiski and J . Michalski, J, A m . Chem. SOC., 1982, 104, 290.

123

Organophosphorus Chemistry

124

phosphoro- and thiophosphono-sulphenyl bromides (4) have been prepared (by conventional reactions) and their reactions examined briefly." Further examples of macrocyclic polyether compounds that contain phosphorus as a ring heteroatom have been recorded l 1 (see 'Organophosphorus Chemistry', Vol. 1 1, p. 1 12; Vol. 13, p. 106). The reactions between t h e hydrazides (5; X = 0 o r S, R' = Ph o r PhO) and ap-unsaturated compounds give, with exceptions, t h e tetra-azaphosphocines ( 6 ) ; mesityl oxide and ( 5 ; R' = P h , X = S) give a similar product, but, otherwise, the compounds (5) react with mesityl oxide t o yield the tetra-azaphosphorines ( 7 ) with loss of acetone. It is perhaps relevant mechanistically that t h e compound (8) will not undergo cyclization.12 Z

(1)

z= x =

I

I

HP\

X

R

R

I

OW, OR, or N R ~

HP\

NPN0

Y

X (2)

x

=

o

or N R

0 , S , or N R ~

(H2NNMe)

CR2

(3) X = 0 or S

HX

P

\R1 (5)

X

"'>( )<; HN-NMe

Me

HN-NMe

Me

(7) (4)

R1= R 2 = a l k o x y or a r y 1o x y

PhO

NM e N =CH C H =C H M e

'P\ R1= B u t , R 2 = M e 0

s@ \

N M ~ N H ~ (8)

Synthesis of Phosphoric Acid and its Derivatives.--Mixtures of phosphorus pentoxide and phosphoric acid have been used t o convert alcohols and phenols into t h e corresponding dihydrogen phosphates,13 and this procedure has also been used t o prepare 32P-labelled mono-, di-, and tri-octyl phosphates. l4 The poor nucleophilic activity shown by potassium salts of dialkyl phosphates towards alkyl halides can be overcome since they may be alkylated by treatment with alkyl( dipheny1)sulphonium t e t r a f l u o r ~ b o r a t e s . ' ~ The reactive cyclic enediol phosphates [ 10; R ' , R2 = dialkyl o r (CH2)3] are obtainable from the enediol disilyl ethers (9) and phosphoryl halides. The only product from (9; R' =Me) and methyl phosphorodifluoridate is ( 1 0 ; in

J . Michalski, M. Potrzebowski, and A. topusihski, A n g e w . Chern., Znt. E d . Engl., 1982, 21, 135.

12

I3

A. V. Kirsanov, V. A. Zasorina, A. S. Shtepanek, and A. M. Pinchuk, D o k l . A k a d . Nauk SSSR, 1981, 2 5 9 , 11 12 (Clzem. A b s t r . , 1981, 95, 169 310). H. J . Merrem, J. P. Majoral, and J . Navech, PhosphorusSulfur, 1981, 11, 241. H . Yamaguchi, F. Ogura, T. Otsubo, and Y . Ikeura, Bull. Chem. SOC.J p n . , 1981, 54, 1891.

I4

M. Walewski and J . Dobrowolski, Zesz. N a u k . Politech. Gdansk, C h e m . , 1980, 318, 37 (Chem. Abstv., 1982, 96, 51 748). B. Badel, M. Julia, and C . Rolando, Synthesis, 1982, 291.

Quinquevalent Phosphorus A cids

125

R1= R2 = Me), but the corresponding phosphorodichloridate gives a mixture of the same product and ( 1 0; R 1= Me, R2 = SiMe3). Similarly, (1 1 ; R = CF3 or 4-@NCsH4), with the difluoridate, yield the corresponding compound (1 2), the difluoridate also acts as a source of ( 1 3 ; R = Me or SiMe3).16

H

Full details have appeared of the synthesis of chiral [160,'70,'801phosphate monoesters of known absolute configuration via the cyclic esters (1 4), derived from m e w - h y d r ~ b e n z o i n , ' and ~ a further discussion of the analysis of chirality in such phosphate esters by phosphorus n.m.r. spectro(see also ref. scopy contributes to the growing literature on the subject 120). The syntheses of a variety of triseleno- and selenodithio-esters of phosphoric acid have been r e p ~ r t e d . '00-Diethyl ~ S-chloromethyl phosphorodithioate is prepared from diethyl hydrogen phosphorothioite by reaction with chloromethyl sulphenyl chloride or chloromethyl isothiocyanate in the presence of Na2C03 and also from the hydrogen dithioate and dichloromethane in the presence of 20-40% DMF.20 SS-Diary1 hydrogen phosphates are obtainable, using the reactions indicated in Scheme 1; they are more stable than the mono S-aryl derivatives.*' 0

II

H2P-OH

0

0

i

HP( OSiMeg)2-(

ii

II

ArS)2POSiMe3-

iii

II

( ArS)2POH

Reagents: i, Me3SiC1, E t 3 N ; ii, ArSSAr; iii, H Z O

Scheme 1 l6 17

18

R. Schwarz and I . Ugi, Angew. Chem., Int. Ed. Engl., 1981, 2 0 , 789. P. M. Cullis, and G. Lowe, J . Chem. SOC., Perkin Trans. I , 19 8 1, 2 3 17. R. L. Jarvest, G. Lowe, and B. V. L. Potter, J. Chem. SOC., Perkin Trans. I , 1981, 3186.

l9 'O

Ya. I. Mel'nik and Ya. I. Kolodii, Ukr. Khim. Z h . (Russ.Ed.), 1981, 47, 1289 (Chem. Abstr., 1982, 96, 85 674). W. W. Brand, J . M . Gullo, and M . C. Carr, Phosphorus Sulfur, 1981, 10, 183; W. W. Brand and M. C. Carr, ibid., 1981, 11, 323. M . Sekine, K. Hamaoki, and T. Hata, Bull. Chem. SOC. Jpn., 1981, 54, 3815.

126

Orga n o p h 0 sp h or us Che mist ry

0 - E t h y l 0-phenyl hydrogen phosphorothioate has been resolved as its quinine salt .22 Further examples of the preparation of 1,3,2-0xathiaphospholans and of the analogous seleno-esters (1 5 ) from oxirans, via hydroxyethyl esters, have been recorded.23

( 1 5 ) R'=

H or

X = S o r Se

R ~ =P r i o r

R7f!

ti

'P-Ar

0

(16)

Ph (18) n = 4 o r 5

(17)

0

II

RC-

XH

I

CHR

V

R

'

Ar

2,4 - Di-(4-methoxyphenyl)- 1,3,2,4-dithiadiphosphetan 2,4 -disulphide (Lawesson's reagent; for a convenient preparation see ref. 66) has been employed t o prepare 1,3,2-oxathiaphosphorinan-4-ones (1 6; Ar = 4MeOC6H4) from P - p r o p i o l a ~ t o n e s ,a~mixture ~ of the isomeric 1,3,2-oxathiacompounds (17; X = O , Y = S ) and (17; X = S , Y = O ) from benzalacetophenone, and t h e trithiaphosphorinans ( I 8) from unsubstituted cyclic ketones, as well as the 1,3,2-oxathiaphospholes and t h e 1,3,2-0xazaphospholes (1 9; R = Ph o r Pr, X = 0 or NPh).25 Other anhydrides (20; R = a l k y l o r Ph) have been used in similar syntheses. Thus, their reactions with the alkynols (2 1) lead ultimately t o the methylene1,3,2-0xathiaphospholan 2-sulphides (22) rather than t h e 6H- 1,3,2-oxathiaphosphorins (23). Imino-l,3,2-oxathiaphospholans can be obtained similarly, and t h e other imino-compounds (24) have been prepared from 2-hydroxy- or 22

23

24

''

Chu-Chi Tang, Gui-Ping Wu, and You-Xin Chai, K a o Teng Hsueh Hsiao Hua Hsueh Hsueh Pao, 1981,2, 70 (Chem. Abstr., 1981, 95, 61 689). 0.N. Nuretdinova and B. A. Arbuzov, I z v . Akad. Nauk SSSR, Ser. Khim., 1981, 1130 (Chern. Abstr., 1981,95, 1 1 5 408). R. Shabana, J. B. Rasmussen, and S . 0 . Lawesson, Bull. SOC. Chim. Belg., 1981,90, 103 (Chem. Abstr., 1981,95, 97 905). S . Scheibye, R. Shabana, and S. 0. Lawesson, Tetrahedron, 1982, 38, 993.

Quinquevalent Phosphorus A cids

127

(24)

(25)

2-amino-benzonitriles. Other types (25 ; X = CH2 o r C=O) are prepared from 2- hydroxybenzyl chloride o r 2-hydroxybenzoyl chloride, respectively.26 The compounds (26), prepared by the reaction between trialkyl phosphites and amidines from trichloroacetic acid, undergo tautomerism along a course (and t o an extent) depending upon the presence of free hydrogen o n either nitrogen atom, as shown in Scheme 2.27 The addition of sulphur t o the bicyclic system (27; X = Z = l o n e electron pair) yields the expected dithione (27; X = 2 = S), but oxidation by permanganate affords (28). The diazadiphospholidine (30) is obtained when (29) is heated.28 0

[R

1

0 =

HI

0

Reagents: i , P(OR4), ; ii, R’ R ~ N H

Scheme 2 0

0

MeN

\ p/PPh

0

(27) 26

*’

28

(28)

\Ph

(29)

G. Salbeck, Phosphorus Sulfur, 1980, 9, 175. A. D. Sinitsa, V. S. Krishtal’, V. I. Kal’chenko, and L. N. Markovskii, Zh. Obshch. Khim., 1980, 50, 2 4 0 9 (Chem. Abstv., 1981, 9 5 , 2 4 191). W . S . Sheldrick, S. Pohl, H. Zamankhan, M . Banek, D. Amirzadeh-Asl, and H. W. Roesky, Chem. Ber., 1981, 1 1 4 , 2132.

0rga n op h osp h orus Che m ist ry

128

The reaction of isocyanatophosphites (3 1; M = 0) with esters of halogenopyruvic acids to yield cycloaddition products as well as Perkow products has been recorded in previous Reports. When acted on by the same esters, the isothiocyanatophosphite (3 1 ; M = S) has now been shown to give the Perkow products (32) exclusively. However, ( 3 1 ; M = 0) and (3 1 ; M = S) each react with hexachloroacetone to yield mixtures of cycloaddition (33; X = C1) and Perkow products (34) whereas with hexafluoroacetone, only (33; X = F) is formed.29 The products obtained from (35) and ethyl benzoate or diethyl phenylphosphonate have been shown to be structurally similar t o ( 33).30 0

II

( MeO) 2PNCM

(31)

( x 3 c ) i

U I

O

)(

OMe)2

NCM

CC13

I

(34)

N

MeOP-0 -C=CH2 NCS

-C=CC1

I

0

0

MeOP-0

(Me0)2PN=CPh2

I

COOEt

(33)

(35)

(32)

Lawesson’s reagent converts afl-unsaturated carboxamides (analogous esters are simply thiated) in HMPA, at 60 OC, into the 1,3,2-thiazaphosphorinan-4-ones (36; Ar = 4-MeOCsH4, X = 0);these, by further reaction with the reagent, yield the 4-thiones. The stereochemistry of the trans-isomer of (36; R’ = H, R2 = Me, X = 0, Ar = 4-MeOCbH4) has been determined by X-ray t e c h n i q ~ e s . The ~ ~ same reagent converts N-nitrosamines into the novel 1,3,2-thiazaphosphetidines(37).32

YH X

(36)

Ar-P-

II S

S

(37) 29

30 31

I . V. Konovalova, L . A. Burnaeva, N . K. Novikova, 0. S. Kedrova, and A. N . Pudovik, J. Gen. Chem. U S S R (Engl. Transl.), 1981, 51, 831. I . V. Konovalova, M. V . Cherkina, L. A. Burnaeva, and A. N. Pudovik, Zh. Obshch. Khim., 1981, 51, 4 7 1 (Clzem. Abstr., 1981, 95, 97 904). S. Scheibye, S. 0. Lawesson, and C . Roemming, Acta Chem. Scand., Ser. B, 1981, 35, 239.

32

K. A. Joergensen, R . Shabana, S. Scheibye, and S. 0. Lawesson, IARC Sci. Publ., 1980, 31, 129 (Chern. Abstr., 1981,95, 220098).

Q u in q u e valen t Ph 0 sp h orus A cids

129

Compound (38) is formed from t h e hydrazine (5; X = S, R = PhO) by its reaction with f ~ r m a l d e h y d e . ~ ~ Synthesis of Phosphonic and Phosphinic Acids and their Derivatives.- Studies on the reactions between PC15 and alkenes o r alkynes continue t o be reported. Two papers discuss t h e nature of the reaction intermediate. The intermediate (39; R = C1) from phenoxyethyne is not formed following t h e addition of HCl t o (39; R Z H ) , ~nor does the phosphorylation of 2-ethoxybut-1-ene proceed via (40).35 The intermediate adducts in such reactions can be decomposed with paraldehyde, acetone, o r d i m e t h ~ x y m e t h a n e ,and ~ ~ they can also be converted into phosphonic difluorides by treatment with AsF3 under oxidative condition^.^^ + PhOC=CHPC 1

I

PC 1

c1

I

+

EtO-C-CH2PC13

PC16

I

R

Et (39)

(40)

A combination of (Ph3P)4Pd and triethylamine catalyses the arylation (using bromo- o r iodo-benzene) and vinylation (using vinyl bromide) of dialkyl hydrogen phosphonates t o give esters o r phenyl- o r vinyl- phosphonic acids.38 2-Hydroxyphenylphosphonic acid esters are produced by the isomerization of dialkyl phenyl phosphates by lithium di-isopropylamide in THF.39 A drawback t o the preparation of (arylmethy1)phosphonates from N N diethylbenzylamines and hydrogen (thio)phosphonates is t h e possible isomerization of t h e initial product (41) into (42), a process which is catalysed by the liberated d i e t h ~ l a m i n e . ~Trialkyl ' phosphites have been used t o phosphonate aryl halides in the presence of copper([) salts,41 and the dihydroquinolinephosphonic acid esters (43), also obtained using trialkyl

I

COOEt

0

(43) 33 34

35

36

31

M. Benhammou, J . P. Majoral, and J . Navech, Phosphorus Sulfur, 198 1, 11, 2 11. V. V. Rybkina, V. G. Rozinov, V. I. Glukhikh, G. S. Lyashenko, and A. Kh. Filippova, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 898 (Chem. Abstr., 1981, 9 5 , 204048).

V. G. Rozinov, V. V. Rybkina, V. E. Kolbina, V. I. Glukhikh, V. I. Donskikh, and S. G . Seredkina, J. Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 1494. V. V. Kormachev, Yu. N. Mitrasov, V. A. Kukhtin, T. M. Yakovleva, and Yu. A. Kurskii, J . Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 801. S. V. Fridland and N . V . Dmitrieva, J . Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 1016.

38

39 40

41

T. Hirao, T. Masunaga, N . Yamada, Y. Ohshiro, and T. Agawa, Bull. Chem. SOC.Jpn., 1982, 5 5 , 909. L. S. Melvin, Tetrahedron Lett., 1981, 22, 3 3 7 5 . V. V. Ovchinnikov, 0. A. Cherkasova, N . A. Mukmeneva, A. G. Liakumovich, and A. N . Pudovik, J . Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 834. J. A. Connor, D. Dubowski, A. C. Jones, and R. Price, J . Chem. SOC., Perkin Trans. I , 1982, 1143.

Organophosphorus Chemistry

130

Reagents: i, (-)-(S)-PhCHMeNH,;ii, R 3 0 H , 0 . 5 M-H,SO,

Scheme 3

phosphites, are important intermediates in a regioselective synthesis of 4 - a l k y l - q ~ i n o l i n e s Optically .~~ active phosphonate esters have been prepared by utilizing t h e chirality of (-)-(S)-a-methylbenzylamine (Scheme 3).43 An increased interest has been directed towards the synthesis of fluorinated phosphonic esters. Tri-isopropyl phosphite reacts with iodotrifluoroethene, initially by replacement o f fluorine, but in the second stage by replacement of iodine, with the formation of the symmetrical compound (44).@ (Perfluoroalky1)phosphonite esters have been oxidized t o t h e corresponding phosphonates by t-butyl hydroperoxide at low t e m p e r a t ~ r e Two .~~ 0

0

II II . ( Pri0)2PCF=CFP( OPr’ ) 2 groups have reported o n t h e use of perchloryl fluoride in the preparation of mono- and di-fluoromethylenebis(phosphonic acid) derivatives (Scheme 4);46747such compounds may co-distil under vacuum, but they can be separated by partition techniques. The reaction between diethyl sodio

Reagents: i, KOBut or NaH; ii, CIFO, in THF

Scheme 4

phosphonate and dialkyl (bromodifluoromethy1)phosphonate at low temperatures is reported t o be a more satisfactory procedure for the preparation of the difluoro-compounds,47 but other authors have indicated that unsymmetrical diphosphonates so prepared tend t o disproportionate into symmetrical corn pound^.^^ Scheme 5 indicates an improved mode of preparation of some dialkyl [ ( 1,l -difluoro-2-hydroxy)alkyl]phosphonates.49 Interaction of t rialkyl phosphites, chlorotrimethylsilane, and (rp- unsaturated carboxylic esters yields dialkyl [ 3- alko xy- 3- (trimethylsilyloxy)prop42 43 44

4s 46

41

K. Akiba, T. Kasai, and M. Wada, Tetrahedron Lett., 1982, 2 3 , 1709. T. Otsuki, Y. Okamoto, and H. Sakurai, Synthesis, 1981, 81 1. R. Dittrich and G. Haegele, Phosphorus Sulfur, 198 1 , 10, 127. M. Kato and M . Yamabe, J . Chem. SOC., Chem. Commun., 1981, 1173. C. E. McKennaand P. Shen, J . Org. Chem., 1981, 46, 4573. G. M . Blackburn, D. A. England, and F. Kolkmann, J . Chem. SOC.,Chem. Commun., 1981,930.

4’ 49

D. J . Burton, T. Ishihara, and R. M . Flynn, J . Fluorine Chem., 1982, 2 0 , 121. M . Obayashi and K. Kondo, Tetrahedron Lett., 1982, 23, 2327.

Quinquevalent Phosphorus A cids 0

II

( Et0)2PCF2SiMe3

- ‘t i

( Et0)2PCF2

OSiMeg-

131 ii (

Ar

Ar

Reagents: i, RC(O)Ar, CsF in THF; ii, H , O +

Scheme 5

2-enyl] phosphonates (45).” Diethyl trimethylsilyl phosphite cannot be used in this reaction, but the adduct from this phosphite and an aldehyde may be hydrolysed t o a [( l-hydroxy)alkyl]phosphonate.51 Some (0-keto-alkyl)phosphonates, e.g. (46), have been obtained, free from enol phosphate, by the reaction between trialkyl phosphites and a-chloro~ x i r a n s . ’Mono~ and di-peroxy esters of phosphonic and phosphinic acids have been prepared by the reaction between the appropriate phosphorus chloride and the sodium derivative of the h y d r ~ p e r o x i d e . ’ ~

Two papers describe aspects of the chemistry of [a-alkyl-thio(or -seleno)alkyl]phosphonates (Scheme 6). Oxidation of (49; X = Se, R = Me), prepared from (47; R = Me), affords ( 5 0 ; X = Se), which readily undergoes an elimination process to give (51); this can then be oxidized t o the sulphoxide (52) and thence to the sulphone (53). The latter can also be prepared, as indicated, from the sulphone (54).54 Compound (48; R = allyl), obtained by alkylation of the anion from (48; R = H ) , is similarly convertible into (50; X = S ) , and this undergoes ‘easy’ elimination to form the diene phosphonate (55). A final C-methylation gives (56).” The optimum conditions for the preparation of di(hydroxymethy1)phosphinic acid from formaldehyde and HzPOzNa have been determined.56 An attempt has been made to formulate a mechanism to explain the formation of the isomeric 1,2-oxaphospholen 2-oxides (57) and (58) when phosphorus dichlorides react with diacetone alcohol. The reaction is thought t o proceed through a 4 -chloro- 1,3,2-dioxaphosph(111)orinan; this undergoes isomerization t o a mixture of chloro- 1,3,2-dioxaphospholans, which are then dehydrohalogenated t o the l,2-oxaphospholens.57 Other examples of the j0

Y. Okamoto, T. Azuhata, and H. Sakurai, Chem. Lett., 1981, 1265.

’’ M. Sekine, H. Yamagata, and T . Hata, J. Chem. SOC., Chem. Commun., 1981, 970.

52

s3 54

’‘ st,

’’

C. Herzig and J . Gasteiger, Chem. Ber., 1982, 115, 601. B. I. Kaspruk and A . N . Karpenko, Visn. L’viv. Politekh. Inst., 1981, 149, 5 0 (Chem. Abstr., 1982, 96, 104409). M. Mikolajczyk, S. Grzejszczak, and K. Korbacz, Tetrahedron Lett., 1981, 22, 3097. S. F. Martin and P. J. Garrison, Synthesis, 1982, 394. Yu. V. Nazarov, A. A. Muslinkin, and A. A. Kutuev, Z h . Prikl. Khim., 1981, 5 4 , 21 15 (Chem. Abstr., 1982, 96, 681 1). M. Moedritzer and R . E. Miller, J . Org. Chem., 1982, 4 7 , 1530.

Organophosphorus Chemistry

132 0

0

II

-

SMe

II I

1

( Et0)2PCH2R

(47)

SMe

0

II I

ii

( Et0)2P-CHR

( Et0)2P-CR

i

XMe

(48)

(49) X = S or Se

iii 0

S(0)Me

I1 I

-

(Et0)2P-C=CH2

S02Me

I1 I

SMe

(Et0)2P-C=CH2v

II( 5 1 )I

(52)

0

0

iii

-

p5i:i)M]

0

II

V

(EtO),P-C=CH2

[

(Et0)2P-CR

(Et0)2P-CHCH20H

(53)

iv -(Et0)2PCH2S02Me

(54)

O=P( OEt )2

(55) Reagents: i , BuLi, S , Mel; ii, BuLi, Se, Me1 or methyl methanethiolsulphonate; iii, 10,( X = S ) or H z O , , pyridine ( X = S e ) ; iv, H,CO, MeCOOH; v, piperidine, vi, Me,CuLi

Scheme 6

A4-1,2-oxaphospholen system (59) are claimed t o be formed when isocyanates or isothiocyanates of tervalent phosphorus react with ethylideneacetylacetone o r related compounds; MeXCN (X = 0 o r S ) is eliminated from a dipolar h ~ t e r r n e d i a t e . ' ~3,3,5,5-Tetramethyl-2-phenyl- 1,2-0xaphospholan 2-oxide is the suspected product when 2,4-dimethylpenta-l,.l-dienereacts with t h e PhPC12--A1C13 complex.59 The 1,3-dihydro-2,1-benzoxaphosphole 1-oxides (61; R' = O E t o r Me) are formed when the esters (60; R 1= O E t o r Me, R2 = Et, X = Br) are distilled or, alternatively, when the compounds (60; R ' = M e o r Ph, R2 = H , X = C 1 o r Br) o r (60; R' =Me, R 2 = E t , X = O A c ) are heated in 10% perchloric acid. The exocyclic ester bond is easily cleaved in moist air.60 A further synthesis of the system involves treatment of the 58

'9 60

I. V. Konovalova, N . V. Mikhailova, R . D. Gareev, L. A. Burnaeva, T. V. Anufrieva, and A. N. Pudovik, J . Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 826. A. Rudi and Y . Kashman, Tetrahedron, 1981, 37, 4269. J. A. Miles, R . C. Grabiak, and C. Cummins, J. Org. Chem., 1982, 47, 1677.

133

Quinquevalent Phosphorus Acids

‘>fK OH

0

1

RPCl

( Me0)2PNCX

+

MeCH=CC(O)R

I

COMe

(X = 0 or S)

[Meo)2fNcxii~ MeCH-C‘CMe

]- MeXCN

eM: RC :MQM

( 5 9 ) R = Me o r E t O

Me

phosphinic amide ( 6 2 ) with Ag+ and DBU, and subsequent hydrolysis of an imine intermediate .61 61

J. A. Miles, R. C. Grabiak, and M. T. Beeny, J. Org. Chern., 1981,46, 3486.

Organophosphorus Chemistry

134

Imidazolidine- 2-thione has been used to decompose chlorophosphinealkyl halide---A1C13 complexes t o give phosphinothioyl chlorides;62 these are also obtainable by the action of thiophosphoryl chloride o n phosphinic acids.63 In a superior procedure for the preparation of dihydrogen (alky1)phosphonothioates, sulphur is added t o bis(trimethylsilyl)phosphonites, and the products are hydrolysed under acidic conditions.@ X

Ar

Ar

( 6 3 ) R = B u t o r Ph i

/

R

iii

S

II

S Reagents: i , P,S,,, Et,N; ii, heat; iii, H,C=CHCN Scheme 7

2,9-Dithia-l-phosphabicyclo[4.3.0lnona-3,7-diene 1 -sulphides (64) (see Scheme 7 ) are novel heterocyclic systems that are obtained when the enones ( 6 3 ) are treated with phosphorus pentasulphide and triethylamine in carbon disulphide. When heated, they undergo a retro-Diels-Alder reaction, and the products may be trapped by reaction with acrylonitrile, thus providing a route t o the new bicyclic thiophospholan (65).65 A convenient preparation of 2,4-di(methoxyphenyl)-1,3,2,4-dithiadiphosphetan 2,4 -disulphide (Lawesson’s reagent) involved heating a mixture of red phosphorus, sulphur, and anisole in the molar proportions of 5 : 2 : 2.66 The usual crop of papers dealing with various types of (aminoalky1)phosphonic acids and their derivatives has appeared, but attention appears t o be 62

63

64

65

66

M. P. Kaushik and R. Vaidyanathaswamy, Indian J . Chem., Sect. B, 1981, 20, 9 3 2 . G. K. Fedorova, A. G. Matyusha, and N . G. Feshchenko, Zh. Obshch. Khim., 1982, 52, 2 1 4 (Chem. Abstr., 1982, 96, 181 355). E. E. Nifant’ev, R. K. Magdeeva, N. P. Shchepet’eva, and T. A. Mastryukova, J . Gen. Chem. USSR (Engl. Transl.), 1 9 8 0 , 5 0 , 2 1 5 9 . H . Yamaguchi, S. Kametani, T . Karakasa, T. Saito, and S. Motoki, Tetrahedron Lett., 1 9 8 2 , 2 3 , 1263. F. N. Mazitova and V. K. Khairullin, J . Gen. Chem. USSR (Engl. Transl.), 1981, 51, 799.

Quinquevalent Phosphorus A cids

135

turning towards phosphorylated amino-acids and phosphonic analogues of amino- acids.67 The reaction of C-phosphorylated aldehydes with benzylamine in the presence of NaBH3CN yields [ 1-(benzylamino)alkyl]phosphonates,68 also formed under asymmetric conditions from trialkyl phosphites and chiral a l d i m i n e ~ in ; ~ ~both cases, hydrogenolysis of the products yields (1 -aminoalky1)phosphonic esters. Diethyl hydrogen phosphonate reacts with benzimidazole-2-carboxaldehydein the presence of aniline t o give the phosphonate (66), and the related N-alkylated derivative (67) is obtained from benzimidazole and diethyl phosphite in the presence of ben~aldehyde.~'

mN> '

fHi( O E t ) 2

NHPh

N

X

0 (R 'O

(68) R (69) R

1

=

1

=

)

II

Ph, R2= CH SR, X 2

Ph, X

= 0,

0

II~

Z

Z

=

=

~

~

~

S, Z

=

NHPh

OCH 2 Ph

II

(2 H0)2PCHCH2SR ~ ~

~

~

I NH2 (70)

The diphenyl esters (68), obtained from N-phenylthiourea, triphenyl phosphite, and alkylthioacetaldehyde, are hydrolysed by hydrogen chloride in acetic acid to phosphonic acids (70);71 the related diphenyl [ 1-(benzyloxycarbonylamino)alkyl]phosphonates (69) undergo transesterification with alcohols in the presence of K F and 18-crown-6 ether." R1

\

MeOOC

R2

/

7-T

OMe

(i) TiC14

-

(ii> ( R ~ o ) ~ P

0

R1

III I

( R30)2PCHNCOOMe

N [.H2i( OH

)j3

R2 (72)

(71)

In the preparation of (1-aminoalky1)phosphonic acid derivatives, a new method for creating carbon-phosphorus bonds involves the activation of the a-methoxyurethanes (71) by Lewis acids such as Tic14 or BF3 EtzO, *

67

C. Wasielewski and K. Antczak, Synthesis, 1981, 540; J . Oleksyszyn, E. Gruszecka, P. Kafarski, and P. Mastalerz, Monatsh. Chem., 1982, 113, 59; J . Rach6n and U. Schollkopf, Liebigs Ann. Chem., 1981, 1693; P. Kafarski and M. Soroka, Synthesis,

1982,219. G. Fabre, N. Collignon, and P. Savignac, Can. J. Chem., 1981, 59, 2864. 6 y J . Zon, Pol. J . Chem., 1981, 5 5 , 643. 70 G. L. Matevosyan, R. M . Matyushicheva, S. N. Vodovatova, and P. M. Zavlin, J . Gen. Chem. USSR (Engl. Transl.), 1981, 51, 636. 71 Z. H. Kudzin, Synthesis, 1981, 643. l 2 J . Szewczyk, B. Lejczak, and P. Kafarski, Synthesis, 1982, 409.

68

Organophosphorus Chemistry

136

followed by reaction with a trialkyl phosphite.n The electrochemical oxidation of nitrilotri(methy1enephosphonic acid) (72) affords a new one-step preparation of (aminomethy1)phosphonic acid itself.74 Both the electrochemical and the thermal dealkylation of (72) have been used to obtain iminodi(methy1enephosphonic acid) (73; R = H), also obtainable by treatment of the hydrazine derivative (73; R = NH2) with nitrous acid.75 R1

I

0

II

HOOCCH2NCH' P O 'H

( 7 5 ) R1= H o r CH2Ph

CH2Ph o r H

( 7 4 ) R1=

(73)

R2

RL= a l k y l o r a r y l

[N-(Carboxymethyl)aminomethyl] -alkyl- and - aryl-phosphinic acids have been prepared from tervalent phosphorus starting material^.^^ Reactions between aminomethylene dichlorides and phosphonites, and between primary amines, orthoformates, and the half esters of phosphonous acids, provide routes to N-substituted aminomethylenedi(phosphonates) (75; R2= Et).77 Geminal di(phosphonic acids) (76) are obtained when carboxamides or nitriles react with mixtures of phosphorous acid and trichloride: a-amidino-

+ NH2 R RNHC( CH2

II 0

I

-c-P(

0 )( O E t

n

,P(OEt)

BuLi [( E t O ) 2 i ] y N R 1 R 2

-R3CH=C R 3 ~ H ~

\

0

0

II II 2A R3CH2C-P( H O+

OEt )2

NR' R~

(77)

[z, or

E , or Z & E l

methylenedi(phosphonic acids) suffer degradation t o aminoalkyldi(phosphonic acids) when treated with alkali.78 Other aminomethyldi(phosphonic esters) react with base followed by an aldehyde to give (1-aminoetheny1)T. Shono, Y. Matsumura, and K. Tsubata, Tetrahedron Lett., 1981, 22, 3249. J . K. Wagenknecht, F. S. Stover, W. G. Wagner, and R. S. Mitchell, Synth. React. Inorg. Metal-Org. Chem., 1982, 12, 1. 7s N . V. Tsirul'nikova, V . Ya. Temkina, T. M . Sushitskaya, and S. V. Rykov, J. Gen. Chem. USSR (Engl. Transl.), 1981, 51, 859. 76 L. Maier, Phosphorus Sulfur, 198 1, 11, 139. 77 L. Maier, PhosphorusSulfur, 1981, 11, 311. K.-H.Worms and H. Blum, Liebigs Ann. Chem., 1982, 275.

73

74

''

Quinquevalent Phosphorus A cids

137

phosphonic esters (77), which are hydrolysable t o (1 -oxoalkyl)phosphonic esters 79 (see also refs. 149, 150). Phosphonates possessing more strongly activated methylene groups are converted into (2-aminoethy1)phosphonates when heated with the disilylimines (78).80 0

0

II

(Et0I2PCH2CN +

CN

II I

heat

Me3SiOCH=NSiMe3-

(EtO)2PA=CHNH2

(78) Ph

PhNCO ( E t 0 ) 2 P N H P h -(

11

0 EtO)2P*

NPh

PhNCO

~

o<:>NHPh P( OEt ) 2

NHPh Ph

(79)

II 0

The reaction between phenyl isocyanate and diethyl N-phenylphosphoramidate yields initially the aminophosphonate (79) and, ultimately, the phosphonic ester (80); the kinetics of this process have now been determined, using infrared spectroscopy.81 Compound (80) is also the ultimate product in the reactions between phenyl isocyanate and diethyl hydrogen phosphonate or hydrogen phosphorothioite; during the course of this sequential process, COX (X = 0 or S) is eliminated and (79) and N'N*-diphenylcarbodiimide have been recognized as intermediates.82

Reagents: i, PCl,; ii, Cl,, CCl,; iii, RNH,; iv, DBU

Scheme 8

The two isomeric 2,3-dihydro-benzazaphospholeshave been prepared as their oxides and sulphides. A multi-step sequence (Scheme 8) from 0-ethyl (methyl)( 2 - methylpheny1)phosphinat e leads t o 2- aryl- 1-methyl- 2,3-dihydro2,l -benzazaphosphole 1-oxides (8 1): alternative pathways were examined but were not successfuL6' 2-Phenyl- 2,3-dihydro- 1H - 1,2-benzazaphosphole 2-oxide (83; X = 0)and the corresponding 2-sulphide have been prepared B. Costisella, I. Keitel, and H. Gross, Tetrahedron, 1981, 37, 1227. V. A. Kozlov, N. I. Burashkina, A. F. Grapov, and N. N . Mel'nikov, Zh. Obshch. Khim., 1981, 51, 1674 (Chem. Abstr., 1981, 95, 150793). *' M. I. Bakhitov, V. V. Zharkov, E. V. Kuznetsov, and Z. Kh. Khazeeva, J. Gen. Chem. USSR (Engl. Transl.), 1981, 51, 432. 8 2 M. I. Bakhitov, V. V. Zharkov, E. V . Kuznetsov, and F. L. Kligman, J . Gen. Chem. USSR (Engl. Transl.), 1981, 51, 864. 79

Organop h osp h or us Ch ern istry

138

from the (2-aminobenzyl)(phenyl)phosphinates (82).83 The compounds (83; R = H , X = O o r S) are formed when (82; R = H, X = 0 or S) are heated; (83; R = M e , X = O ) is similarly formed, and, in this case, the same result is obtained by t h e action of DCC. In addition, sulphides were converted into oxides when acted upon by peroxy-acids, and t h e reverse process was achieved by the use o f phosphorus p e n t a ~ u l p h i d e . ~ ~ X

\Ph

NH,R

R ( 8 3 ) X = 0 or S

( MeO)

2PNCX

LtesyN\p//O R2N& R

‘OMe (86)

Reactions between unsaturated carbonyl compounds o r other similarly polarized compounds with tervalent phosphorus isocyanates o r isothiocyanates provide a route t o 1,2-azaphospholidinones and related substances, e.g. (84) and ( 8 5 ) , which are obtained as mixtures of stereoisomers from alkylidene malonic esters.58 The reactions between the same phosphoruscontaining starting materials and N-substituted aldimines yield the diazaphospholines (86), whereas those possessing a free NH group yield only the iminium isothiocyanate.84 Other 1,2-azaphospholine 2-oxides (87) have been obtained from phosphonous dichlorides and a l d i m i n e ~ . ~ ’ 83 84

D. J . Collins, P. F. Drygala, and J . M. Swan, Tetrahedron Lett., 1982, 2 3 , 11 17. I . V . Konovalova, M . V. Cherkina, E. G. Yarkova, L. A. Burnaeva, and A. N. Pudovik, J . Gen. Chem. USSR (Engl. Transl.) 1981, 5 1 , 829. S. Kh. Nurtdinov, I. V. Tsivunina, V . I . Savran, N . M. Ismagilova, T. V. Zykova, and V. S. Tsivunin, J. Gen. Chem. USSR (Engl. Transl.), 198 1, 5 1, 13 13.

Quinquevalent Phosphorus A cids

139

0

0

\R1O )PCHOCNH~ R O

I

Ar

Aromatic aldehydes react with phosphorus(rr1) isocyanates in the presence of alcohols or water, evidently through the intermediacy of similar compounds (88), t o give C-phosphorylated carbamate esters.% 2 Reactions General.-Several redistribution reactions have been considered from a Earlier attempts to support theoretical viewpoint in terms of bond energie~.~’ the principle of additivity of substituent effects in the basic hydrolysis of nitrophenyl esters have been criticized.88 Features of the electronic and steric structure of phosphorus esters have been discussed.89 The reactivity of compounds that possess the P(0)F grouping has been examined and discussed. The hydrolysis of phosphoryl and phosphonic fluorides under basic phase- transfer conditions proceeds about 500 times faster in the presence of traces of hydrogen peroxide, which acts as a supern ~ c l e o p h i l e .A~ ~study of the kinetics of the acid hydrolysis of phosphates, phosphonates, and phosphinates derived from the 2,3-dihydro-l,4-dioxin (89) has shown that the rate-determining step is the breakdown of the initially formed cyclic oxonium system.” The reactivity of monothio phosphorus acids towards diazo-compounds has been the subject of continued investigations. Their reactions with diazoacetic ester yield a mixture of the S-alkyl ester and the 0-alkyl ester, but the R. I. Tarasova, T. V . Zykova, T. A. Dvoinnikova, N . I. Sinitsyna, and R. A. Salakhutdinov, J. Gen. Chem. USSR (Engl. Transl.), 1981, 51, 1289. J . C . Elkaim and J . G. Riess, Tetrahedron, 1981, 37, 3203. ” M. G. Gubaidullin, J . Gen. Chem. USSR. (Engl. Transl.), 1981, 5 1 , 1018. 8 9 L. N. Mazalov, G. N. Dolenko, and V. D. Yumatov, Zh. Srrukr. Khim., 1981, 22, 18 (Chem. Abstr., 1981, 9 5 , 2 3 7 1 0 ) . 90 L. Horner and H. W. Kappa, Phosphorus SuZfur, 1981, 11, 339; L. Horner and R. Gehring, ibid, 1982, 12, 295. 9 1 V. S. Tsivunin, V. G. Zaripova, I. N . Zaripov, and Sh. A. Nasybullin, J. Gen. Chem. USSR (Engl. Transl.), 19 8 1 , 5 1 , 2 5 6. Cb

140

0

Organophosphorus Chemistry

GSH

0

OPR’

bH = H or SiMe3 ;

X = 0 or

II x

relative proportions (ca 9 : l in E t 2 0 ) depend on the reaction medium.92 Hydrogen phosphates and, to a lesser extent, hydrogen phosphonates and phosphonodithioates, are alkylated by phosphonium or pyridinium keten acetals in both aqueous and non-aqueous media; these systems could also be used under phase-transfer conditions, but other keten acetals were of no value under such condition^.^^ In the ieactions of p-yuinones with S-trimethylsilyl phosphoro-thioates or -dithioates, or with analogous phosphonates, the products are evidently obtained via ‘phosphylatropic’ rearrangements, the extent of which depends on the nature of the groups R’ and R2 in (90).% The thiocyanation of the compounds R’R2P(X)H ( X = O , R1=MeO or Ph, R 2 = B u t : X = S , R ’ = R 2 = ButCH20) and subsequent change of the thiocyanate form [P(O)SCN] into its isothiocyanate [P(O)NCS] isomer are both highly stereospecific reactions, and they proceed with retention of configuration at p h o s p h ~ r u s . ’ ~ Lawesson’s reagent has proved t o be very useful for the conversion of many types of ‘ phosphyl’ esters and amides into the corresponding ‘thiophosphyl’ compounds, often in high yields: there are, as yet, no reports of the stereospecificity of the reaction.96 Metaphosphate, derived from either 2,4-dinitrophenyl dihydrogen phosphate dianion or erythro -( 1,2-dibromo-l-phenylpropyl)phosphonate dianion, in each case by treatment with NN-di-isopropylethylamine, yields alkyl or aryl phosphates when generated in the presence of t-butyl alcohol or phenol; and in neither case was there any formation of enol phosphate when the generation took place in the presence of acetophenone or ethyl pyruvate. However, in the absence of added nucleophile, the phosphatederived metaphosphate leads (through aryl pyrophosphate and aryl tripolyphosphate) to cyclic trimetaphosphate whereas the more quickly generated phosphonate-derived metaphosphate undergoes a true polymerization because it does not encounter high concentrations of source compound.97 The ease of cleavage of the P-N bond and the lack of preponderance of fission of P-0 bonds during the alkaline hydrolysis of 1,3,2-oxazaphosphol-

’’ T. ” 94

’’ 96

”

A. Mastryukova, A. B. Uryupin, M. Orlov, D. Jeremic, and M . I . Kabachnik, J . Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 1251. A. T. Zaslona and C . D. Hall, J. Chem. SOC.,Perkin Trans. 1 , 1981, 3059. G. A. Kutyrev, A. A. Kutyrev, R. G. Islamov, R. A. Cherkasov, and A. N . Pudovik, Dokl. Akad. Nauk. SSSR, 1981, 2 5 6 , 601 (Chem. Abstr., 1981, 95, 2 4 4 3 2 ) . A. Lopusinski, L. Luczak, and J . Michalski, Tetrahedron, 1982, 38, 679. L. Horner and H . Lindel, Phosphorus Sulfur, 1982, 12, 2 5 9 . F. Ramirez, J. F. Marecek, and S. S. Yemul, J. A m . Chem. SOC., 1982, 104, 1345; Tetrahedron Lett., 1982, 2 3 , 1515.

Quinquevalent Phosphorus A cids

141

idines contrast markedly with the stability of the P-N bond during similar treatment of acyclic phosphoramidates and related compounds. The stability of phosphates and phosphonates that are derived from (-)-ephedrine and (+)-norephedrine has been discussed in two papers,98'99 in which a new term, 'apical potentiality', has been introduced. This term is intended t o refer t o the apical preference of a group during the course of a reaction as distinct from the term apicophilicity, which is used to describe positional preference of groups in stable oxyphosphoranes. The results obtained in the study of the ring-opening reactions of compounds derived from (-)-ephedrine are consistent with a process of nucleophilic attack at phosphorus opposite N rather than 0. Thus, the alkaline hydrolysis of (91 ; R = OEt) to (92; R = OEt) proceeds with retention of configuration at phosphorus during cleavage of endocyclic P-0 bonds. However, in the case of (91; R=Me), the fission of the P - 0 bond proceeds with preponderant inversion of configuration; fission of a P-N bond to give (93) occurs with inversion of configuration. When (94; R = OEt) is treated with a catalytic amount of sodium methoxide in methanol, ring-closure occurs (with retention of configuration) to give (96; R = O E t ) , and the use of AgN03-Na2C03 produces the epimer of (96; R = O E t ) as the main product. A mixture of (96; R=Me) and its epimer results from the cyclization of (94; R=Me). Treatment of (94; R = O E t ) with dry HC1 rapidly affords the rearrangement product (95; R = OEt).98

Me

Me

(91) X = R ,

Y

= S

(96) X = 0,

Y

=

Me

(92)

(93)

R

Me--

Me Me

HN Me

SMe

N H

By using the derivatives (97; X , Y = S , 0, Me, or OEt) of (+)-norephedrine as substrates in alkoxide-initiated reactions, it was shown that the kinetically controlled product is formed by fission of P - 0 bonds in the ring and the thermodynamically controlled product by fission of ring P-N bonds, both processes occurring with inversion of configuration at phosphorus; in the former case, an elimination addition process is considered feasible.99 98

99

C . R . Hall and T. D. Inch, J . Chem. SOC., Perkin Trans. 1 . 1 9 8 1 , 2 3 6 8 . C . R . Hall, T. D. Inch, and N. E. Williams, J. Chem. SOC.,Perkin Trans. I , 1982, 639.

Organophosphorus Chemistry

142

r Me (98)

L

+ 1 Me

J

Me (99)

Rearrangement o f 1,3,2-oxazaphospholidine-2-thiones (98) yields the 1,3:2thiazaphospholidine 2 -oxides (9 9). loo Reports have appeared o n the selectivity of diphenylphosphino- and diphenoxyphosphino-derivatives and their analogues towards hydroxy, mercapto, and amino nucleophiles in competition. Both the nature of the 'phosphyl' group (i.e. P=O us P=S) and the nature of t h e substituent (Ph vs PhO) have little influence o n t h e extent of the selectivity. On the other hand the other groups (Cl, F, CN, N3, o r 4-02NC6H4) may be displaced highly selectively, depending o n the base present. Thus for the leaving groups F, CN, and 4-nitrophenoxy, 0-esters are formed virtually exclusively, and amides are formed only when Ci" is displaced; such differences in selectivity are noticeable even when the two nucleophilic groups are in the same substrate molecule. As a result, Ph2P(X)CN are considered good protecting reagents for thiol groups, whereas t h e corresponding chlorides are valuable for N-protection purposes. lo'

Reactions of Phosphoric Acid and its Derivatives.-A further example of equilibration between a pentaco-ordinate compound (1 00) and a tetracoordinate ester (101) has been reported; in solution, the equilibrium is shifted towards ( 101).'O2 New phosphorylating agents include SS-diary1 hydrogen phosphorodithioates,21 di-[(2,2,2-trichloro-1,1 -dimethyl)ethyl] phosphorochloridate,103 and the morpholino phosphoryl chloride (1 02).'04 Earlier experiments on loo lo' 102

lo4

C . R. Hall and N. E. Williams, J . Chem. SOC., Perkin Trans. I , 1981, 2746. L. Horner and R. Gehring, PhosphorusSulfur, 1981, 1 1 , 157; L. Horner, R. Gehring, and H. Lindel, ibid., p. 349. L. N. Markovskii, V. I . Kal'chenko, A. D. Sinitsa, Yu. A. Serguchev, V . V. Negrebetskii, and L. Ya. Bogel'fer, Dopov. A k a d . Nauk. Wkr. R S R , Ser. B, Geol., Khim. Biol. Nauki, 1981, No. 2 , p. 5 6 (Chem. Abstr., 1981, 9 5 , 132 839). H. A. Kellner, R . G . K. Schneiderwind, H. Eckert, and I . K. Ugi, Angew. Chem., 1981, 93, 581. J . A. J . den Hartog and J . H. van Boom, R e d . T ~ Q vChirn. . Pays-Bus, 1981, 100, 2 8 5 .

Quinquevalent Phosphorus A cids

143

potential uses for the phosphorus chlorides ( 103) have continued; best results in the synthesis of carboxamides and carboxylic anhydrides are obtained when R is H and X is Ph011°5 Continued exploitation of the compound (104) (the Palomo--Coll reagent) as a reagent for the preparation of carboxylic anhydrides is reported.'& It is also employed, in the presence of triethylamine, t o prepare 0-lactams by annelation of imines."' The related substance (105) has also been used to activate carboxyl groups.lo8 Diethyl phosphorocyanidate converts sodium aryl- or heteroaryl-sulphinates into t hiocy anat es .lo9 4-0 NC H 0 2

k

6 4 \

(102)

0

( 1 0 3 ) X = P h N H o r PhO R = H or Me

(105)

(104)

(106) R = M e or OEt

X = O o r S

The ( E ) isomers of the products (106) are formed predominantly from pentane-2,4 -dione, and exclusively from ethyl acetoacetate, when these are phosphorylated under phase- transfer conditions. 'lo The alkylation or arylation of dialkyl hydrogen phosphates by trialkyl or triphenyl phosphite occurs via an intermediate consisting of a mixed anhydride.''l Reactions of diethyl arylphosphonates with alkyl, alkenyl, aryl, or trimethylsilylmethyl Grignard reagents in the presence of nickel acetylacetonate result in coupling and the formation of the appropriately substituted arene.l12 A similar process has been observed for the enol phosphates (1 O7).ll3 Two notes describe coupling reactions involving allylic phosphates and Grignard reagents, using CuI as the ~ a t a 1 y s t . l ' ~ lo'

R . Mestres and C. Palomo, Synthesis, 1982,288.

J. Cabrk-Castellvi, A . Palomo-Coll, and A. L. Palomo-Coll, Synthesis, 19811616. lo' D. R. Shridhar, B. Ram, and L. V. Narayana, Synthesis, 1982, 63. lo* T. Kunieda, Y . Abe, T. Higuchi, and M. Hirobe, Tetrahedron Lett., 1981, 22, 1257;

Io6

Io9 'lo 111

112

113

114

see also A. Arrieta and C. Palomo, Bull. SOC.Chim. Fr., Part 2, 1982,7. S. Harusawa and T . Shioiri, Tetrahedron Lett., 1982,2 3 , 447. R. A. Jones and S. S . Badesha, Synth. Commun., 1981, 11, 557. A. Markowska, J . Olejnik, B. Mlotkowska, and M . Sobanska, Phosphorus Sulfur, 1981, 10, 143;A. Markowsa and J . Olejnik, ibid., p. 245. T. Hayashi, Y. Katsuro, Y . Okamoto, and M. Kumada, Tetrahedron Lett., 1981,2 2 , 4449. T. Hayashi, T. Fujiwa, Y. Okamoto, Y. Katsuro, and M . Kumada, Synthesis, 1981, 100. S . Araki, T. Sato, and Y . Butsugan, J . Chem. SOC., Chem. Commun., 1982, 285; S . Araki and Y. Butsugan, Chem. Lett., 1982, 177.

Organophosphorus Chemistry

144 0

R1

ll

OP( OEt ) 2

-

R1

A

MegSiCHR'MgX

\

/CHR4siMe3

"0-Labelling experiments have shown that in the metal-hydroxidecatalysed hydrolysis of acetyl phenyl phosphate, reaction occurs exclusively by fission of a C-0 bond.'I5 Bunton has continued his work o n micellecatalysed dephosphorylations with a study on that of diphenyl4-nitrophenyl phosphate by benzimidazole and related ions, in which cetylammonium bromide activates the reaction by a factor o f l o 3 t o 104,116 whereas the dephosphorylation that is mediated by benzamidoxamate at pH 10 is only weakly catalysed.'" Hydroxamate nucleophiles, in the presence of tetraalkyl-ammonium salts, cleave both 4 -nitrophenoxy-groups from ethyl di-(4nitrophenyl) phosphate. l 8

-0

The compounds (1 08; X = CH2, S, SO2, o r Me,") undergo significant hydrolysis only in basic solution, whereas hydrolysis occurs under a wider pH range for ( 1 0 8 ; X = NMe); in this last case, the process is subject t o specific acid and base catalysis, and an explanation based upon the involvement of the P-N bond in the formation of a pentaco-ordinate intermediate has been advanced Methanolysis of the dianions from phenyl and 2,4 -dinitrophenyl ( R ) [ 1 6 0 , 1 7 0 , 1 8 0 ] - p h o s p h a tproceeds, e~ in both cases, with complete inversion of configuration at phosphorus.120 Using substrates based upon the 5-chloromethyl- 5-methyl- 2-0x0- 1,3,2-dioxaphosphorinan system, Wadsworth has shown that methanolic displacement of a 4-nitrophenoxy-group is catalysed by Zn2+, t h e product ratio (60% inversion) being similar t o that obtained by proton catalysis. When the concentration of effective catalyst is very low, the reaction of the trans -compound occurs with retention of configuration. 12'

'I7

121

D. A. Buckingham and C. R. Clark, Aust. J . Chem., 1981, 34, 1769. C. A. Bunton, Y . S . Hong, L. S. Romsted, and C. Quan, J. A m . Chem. SOC., 1981, 103, 5784, 5788. C. A. Bunton, S. E. Nelson, and C. Quan, J. Org. Chem., 1982, 47, 1157. Y . Okahata, H. Ihara, and T. Kumitake, Bull. Chem. SOC.J p n . , 1981, 54, 2072. R. K. Sharma and R . Vaidyanathaswamy, J . Org. Chem., 1982, 47, 1741. S. L. Buchwald and J. R , Knowles,J. A m . Chem. SOC., 1982, 104, 1438. W. S. Wadsworth, jr., J. Org. Chem., 1981, 46, 4080.

Quinquevalent Phosphorus Acids

145

Also using phosphoryl halides derived from the same system, a study of the displacement of halogen by aryloxy anions has illustrated the importance of electronic effects of the para -substituents in the aryloxy-group in controlling the stereochemistry of the reaction; predominant retention of configuration is observed for donor groups, and inversion for electron-withdrawing groups. Lithium salts generally direct the replacement towards retention of configuration at phosphorus, but tetramethylammonium chloride has the opposite effect.'22 According t o other authors,'23 lithium salts have no effect on the outcome of the displacement of C1- or of 4-nitrophenoxide anion from acyclic esters by 4 -nitrophenoxide or phenoxide, respectively; such is also the case for some carbohydrate-derived cyclic phosphorus esters, when, depending on the conformation of substituents o n phosphorus and the nature of the group undergoing displacement, retention or inversion may occur. Phosphorus-3 1 n.m.r. spectroscopy, now the standard technique for following stereochemical changes in reactions of phosphorus compounds, has also been used to show that the acid-catalysed 172-phosphorylmigration that occurs with 2-(R)-[ 1 6 0 , 1 7 0 , 1 8 0 ] - phosphopropanediol proceeds with quantit ative retention of configuration, and is best represented by a pseudorotation mechanism. 124 A study of the kinetics of isotope exchange between C1- and 00-diphenyl phosphorochloridate and phosphorochloridothionate has been reported in two papers dealing with the effects of added cations 125 and solvents.'26 Carbohydrate epoxides are deoxygenated to unsaturated sugars when treated wth salts of 00-dialky phosphoroselenoic and 00-diethyl hydrogen phosphorotelluroate has been employed to dehalogenate a-halogeno-ketones.'28 The reaction between 0 0 - d i e t h y l S-hydroxymethyl phosphorodithioate and diazomethane yields a mixture of the S-methoxymethyl and S-methyl esters, whilst the S-hydroxymethyl ester, when acted upon by ZnC12, gives an ether derivative 12' (see also ref. 20). Complex mixtures of phosphorus-containing compounds may result when sulphur-containing compounds are oxidized with peroxy-acids. Thus the phosphorothiolate (1 09; R' = MeO, R2= NH2, R3 = Me) gives twenty products with 3-chloroperoxybenzoic acid. An important feature in the reaction shown in Scheme 9 appears to be the formation of thiolate S-oxides and their rearrangement; the high reactivity of phosphoramidothiolates is also noteworthy. 13*

R. J . P. Corriu, J . P. Duthell, and G. Lanneau, Tetrahedron, 1981, 37, 3681. C. R. Hall, T. D. Inch, and C. Pottage, Phosphorus Sulfur, 1981, 10, 229. S. L. Buchwald, D. H. Pliura, and J . R. Knowles, J. A m . Chem. SOC., 1982, 104, 845. 12s W. Reimschuessel, S. Tilk, M. Mikolajczyk, and H . Slebocka-Tilk, Int. J. Chern. Kinet., 1981, 13, 417. 126 M . Mikolajczyk, H . Slebocka-Tilk, and W. Reimschuessel, J . Org. Chem., 1982, 47, Ia3 124

1188.

129 130

W. Kudelska and M . Michalska, Tetrahedron, 1981, 37, 2989. D. L. J . Clive and P. L. Beaulieu, J. Org. Chem., 1982, 47, 1124. H. G. Corkins, L. Storace, D. Weinberger, E. Osgood, and S. Lowery, Phosphorus Sulfur, 1981, 10, 133. Y. Segall and J. E. Casida, Tetrahedron Lett., 1982, 2 3 , 139.

Organophosphorus Chemistry

146

0

0

J

MCPBA

Scheme 9

The ability of trialkyl phosphites to alkylate hydrogen phosphates has already been commented upon in this and in earlier Reports in this series. In a reversal of this approach, 00-diethyl hydrogen phosphorodithioate has ~ ~ same been employed to cleave P-S bonds in tervalent c o m p o ~ n d s . 'The dithio-acid converts a0-unsaturated ketones into 2,4-disubstituted thietans (as mixed stereoisomers) through the sequence indicated in Scheme 1O;13* S- -+0-phosphoryl migration is further exemplified by the conversion of (1 10) into (1 1 1) 133 and in the reaction between 00-dialkyl phosphorothiolate salts and thiocarbamoyl chlorides, when the rearrangement of (1 12) (the major product of initial reaction) t o (1 13) takes place once the reaction mixture is heated.IM 1 A r CH=CHAr2

li

Ar1CH-CH2COA

r2

1

S-P(OEt)Z

II

S

\i

Reagents: i, (EtO)?PS,H; ii, NaBH,; iii, NaH Scheme 10

Initial treatment of 1,2,3,4-tetrahydroisoquinolinewith bis(dimethy1amino)phosphoryl chloride, followed by butyl-lithium, allows subsequent alkylation at position 1 and ultimately, after acidolysis, the isolation o f the 1-alkyl- 1,2,3,4- tetrahydrois~quinolines.'~~

134

E. N. Ofitserov, 0. G. Sinyashin, E. S. Batyeva, and A. N . Pudovik, J . Gen. Chem. U S S R (Engl. Transl. ), 19 8 1, 5 1, 602. Y. Ueno, L. D. S. Yadav, and M . Okawara, Synthesis, 1981, 547. G. Sturtz and M. Baboulene, Tetrahedron, 1981, 37, 3067. M . G. Zimin, M . M. Afanas'ev, A. V. Mironov, and A. N. Pudovik, Zh. Obshch,

13'

Khim., 1981, 5 1 , 470 (Chem. Abstr., 1981, 9 5 , 6 1 432). D. Seeback and M . Yoshifuji, Helv. Chim. Acta, 1981, 64, 643.

13' 133

147

Quinquevalent Phosphorus A cids 0

0

II

L iKCHMe

(Et0)2PSCH2COMe (110)

II

( Et0)2POCMc=CH(Sllc)

THF, - l O ° C

(111)

0 s

0 .

II

Me 1

P

E t 2NCSC1

( Pr10)2P-S-

’

II II

( PrlO)ZP-SCNEtg +

(Pr’O)

2P-O-CNEtZ

N H ~ +

(113)

During the acidolysis of the aziridine derivatives (1 14) and (1 15), the formation of 2-hydroxyethyl-phosphoramides and their subsequent cyclization t o 2-amino- 1,3,2-oxazaphospholidine2-oxides have been detected. 136

0

0

( i ) PhNCS ( PriO)2PONa

( i i ) Me1

.

ii

.

s

ii

ii

( Pr10)2P-SC=NPh + ( PrlO)ZP-N-CMe

I

I

Methylation of the reaction product from phenyl isothiocyanate and diisopropyl sodio phosphite yields a mixture of (1 16) and (1 17). Lack of details does not allow a decision t o be made on whether this might be the result of an S + N migration,137 but this process, as well as O + N migration of phosphoryl groups, has been observed in the reactions between carbodiimides and hydrogen phosphates or phosphorodithioates. Such processes have been considered as models for the biotin system. The addition of sterically hindered 0 0 - d i a r y 1 hydrogen phosphates o r phosphorodithioates t o DCC was found t o be acid-catalysed. The reaction between the protonated carbodi-imide and t h e phosphorus acid anion (1 18; X = O o r S) affords t h e intermediate ( 1 19), whose structure was confirmed by an X-ray study o n (1 19; X = 0). T h e rearrangement of (1 19) t o (1 20) is hindered by steric effects in the acid anion and also, when X is oxygen, by the presence o f excess acid. Other isolable products are the mixed ester (122) and the pyrophosphate (123), the formation of both of which is controlled by the relative 136

137

J . B. Stokes, C. W. Woods, and A. B. Berkovec, PhosphorusSulfur, 1981, 10, 139. M. G . Zimin, A. K. Burilov, and A. N . Pudovik, Zh. Obshch. Khim., 1981, 5 1 , 469 (Chem. Abstr., 1981, 9 5 , 80418).

6

Organophosphorus Chemistry

148

X X R

rO ) 2

(Ar0)2P=X

II

~

~

~

2

I

'

t i

VN H RX~

OAr

2P-O-P(

(123) X = 0 o r S

nucleophilicity of the nitrogen atoms, i.e. by the substituents on each nitrogen atom, in ( 12 1). 13' N' + N 2 migration of the (EtO),P(X) group has been observed in the dimethylbenzamidine derivatives ( 1 24; X = 0 o r NPh),'39 and a P + N migration, the result of insertion of an imino-group between two phosphorus atoms, is observed when (125) is heated t o temperatures higher than 150 O C . 1 4 0 S

(Et0)2F"Me-CPh

II

heat

( R0)2P-P(OR)2-

II

( R0)2P-N-P(OR)

I

NMe (124)

2

Ph (

125)

S

( 127)

II

(EtO)2P-O-P(OEt)2 (

126 1 (Et0)2P-O-P(OEt)2

II

NR

II S

(128) 138

139

+ EtO-P-0-P(

I

OEt )

NREt

(129)

C. Blonski, M. B. Gasc, A. Klaebe, a n d J. J. Perie, Tetrahedron Letr., 1982, 23, 2773; C. Blonski, M. B. Gasc, A. Klaebe, J. J. Perie, R. Roques, J. P. Declercq, and G. Germain, J. Chem. SOC.,Perkin Trans. 2, 1982, 7 . V. V. Negtebetskii, L. Ya. Bogel'fer, A. D. Sinitsa, V. S. Krishtal, V. I. Kal'chenko, and L. N. Markovskii, Zh. Obshch. Khim., 1980, 5 0 , 2 8 0 6 (Chem. Abstr., 1981, 94, 120 602).

140

Yu. G. Gololobov, E. A. Suvatova, and T. I. Chudakova, Zh. Obshch. Khim., 5 1 , 1433 (Chern. Abstr., 1981, 95, 1 5 0 0 8 1 ) .

1981,

Quinquevalent Phosphorus A cids

149

In the Staudinger imination of (1 26) with aryl azides, the product compo sition depends o n t h e nucleophilic activity of the nitrogen atoms in (1 29), which is obtained, together with (128), when the nitrogen is weakly basic; when R is Ph, (1 29) evidently rearranges t o (1 27) 14' (see 'Organophosphorus Chemistry', Vol. 12, p. 1 17). Reactions of Phosphonic and Phosphinic Acids and their Derivatives.. --The asymmetric hydrogenation of enol diphenylphosphinates is catalysed by rhodium complexes and gives products which, when cleaved by methyllithium, yield optically active secondary alcohols;'42 the addition of optically active amines, e.g. prolinol, t o vinylphosphonates and vinylphosphinates gives optically active derivatives of 2-aminoethyl phosphorus compounds. 143 The Diels-Alder additions of cyclopentadiene t o (2-nitroviny1)phosphonates and t o both ( E ) and ( 2 ) isomers of (3-oxopropeny1)phosphonates have been de~cribed.'~' The course of the reaction between ethenylphosphonates and aryl azides via the triazolines (1 30) depends upon the nature of t h e aromatic substituent, which, if an electron donor, favours t h e formation of the aziridine (131), whereas the enamine-imine ( 132) is favoured for electron-attracting groups. 146 Nitrosyl chloride adds t o (2-ethoxyetheny1)phosphonic dichloride t o give (1 33).'47 Following the direct chlorination of (propa-l,2-dienyl)phosphonic dichlorides, t h e subsequent elimination of hydrogen chloride from the cyclo0

II / N

-

ii

( RO) 2P-CH-CH

0

II

( RO ) 2PCH=CH2

\2

\N/NAr

0

0

II ( EtO)CH-CHPC12

ll

(R0)2PCH=CHNHAr

( 131)

0

II

(RO)2PCH2CH=NAr

I I

C1 NO (133) I 4 ' S . K. Tupchienko, T. N . Dubchenko, and Yu. G. Gololobov, J . Gen. Chem. USSR (Engl. Transl.), 1981, 51, 847. 14' T. Hayashi, K. Kanehira, and M. Kumada, Tetrahedron Lett., 1981, 22, 4417. 1 4 3 G. Mark1 and B. Merkl, Tetrahedron L e t t . , 1981, 22, 4459, 4463. 144 T. K. Kostina, G. M . Baranov, and V. V. Perekalin, J . Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 578. 145 E.Ohler, E. Haslinger, and E. Zbiral, Chem. Ber., 1982, 115, 1028. 14' N. G. Khusainova, %. A. Bredikhina, E. A. Ishmaeva, A . A. Musina, and A. N. Pudovik, J . Gen. Chem. USSR (Engl. Transl.), 198 1, 51, 409. 147 V . M. Ismailov, Kh. Ya. Al-Khaidar, and A. N . Guliev, Azerb. Khim. Zh., 1980, NO. 3 , p . 5 8 (Chem. Abstr., 1981, 9 5 , 97 9 1 1).

Organophosphorus Chemistry

150

hexane derivative (134) via t h e proposed intermediate is much easier than that from many other examples previously examined.148 Several papers have described the synthesis and properties of (enamine)phosphonates. These, e.g. (1 35 ; Nu = NEt2), are readily obtained from (propa1,2-dienyl)phosphonates,and they yield t h e (2-oxoalkyl)phosphonates (1 36) o n acid01ysis.l~~ Another study has concentrated o n the addition of amines t o the [ ( 1-vinyl)allenelphosphonates (1 37); whilst two modes of addition are recognizable, only one product, i.e. (1 38), is actually isolable. For compounds from primary amines, rearrangement of (138) t o the imine form (139)

R1

>

R2

.=(,3

r( us. L

HNu

RZ'

occurs.15o Secondary (2-aminoetheny1)phosphonates undergo addition reactions with acrylonitrile o r methyl acrylate to give (1 40), acid-catalysed hydrolysis of which, as for (1 3 5 ) , affords (2-oxoalkyl)phosphonates. The reaction between an oq3-unsaturated carbonyl compound, e.g. (141), and a primary (2-aminoetheny1)phosphonate can give the ( 1,4-dihydr0-3-pyridyl)phosphonic esters (1 42)."' 1,4-Dihydropyridine derivatives are also the 148

Kh. Angelov, V . Khristov, and B. I. Ionin, J. Gen. Chem. USSR (Engl. Transl.), 1981,

149

H. J . Altenbach and R. Korff, Tetruhedron L e t t . , 1981, 2 2 , 5 1 7 5 . Yu. M.' Dangyan, G. A. Panosyan, M. G . Voskanyan, and Sh. 0. Badanyan, J . Gen. Chem. USSR (Engl. Transl.), 1981, 51, 628. A , Yu. Alikin, M. P. Sokolov, B. G. Liorber, A. I . Razumov, T . V . Zykova, and V. V. Zykova, J . Gen. Chem. USSR (Engl. Transl.), 1981, 5 1 , 428.

5 1 , 1041. 150

151

151

Quinquevalent Phosphorus A cids 0 ( R'O ) 2

If

,R2 ~

H C=CHX

~

\NHR3

~2

=

~

(R1O),P

No

(X = CN or COOMe)

:1R3

XCH2CH2

0

\NH2

(R2 = Me or O E t )

H (142)

result of heating (2-aminoetheny1)phosphonates and acrolein in the presence of alcohols.'52 Methylenephosphonates may be C-nitrosated in a variety of ways, when the products are C-phosphorylated oximes.lS3 A novel disproportionation reaction occurs when the methylenedi(ph0sphinic acid) esters (143) are treated with magnesium methoxide in methanol.'54

0

II

( EtO)ZPCOCHR1R2

*

0

0

0

II

PhCMe ( E t 0 ) 2 PUC O P h -PhECHZCPh

II

+

( 144 1

I PhCH-OP( O E t ) 2

II

0 (1451

The extent of keto-enol tautomerism in the (1-oxoalky1)-phosphonates (144) depends on the nature of the groups R' and R2, which, if aromatic, favour the enolized form. lS5 Diethyl benzoylphosphonate C-benzoylates acetophenone in the presence of lithium di-isopropylamide, or preferably LiN( SiMe3)2, and is, at the same A. Yu. Alikin, M . P. Sokolov, B. G. Liorber, A. I . Razumov, T. V. Zykova, V. V. Zykova, and I . N . Suleimanova. J . Gen. Chem. USSR (Engl. Transl.), 1981, 51, 435. B. A . Kashemirov, P. S. Khokhlov, and Yu. A. Strepikheev, Zh. Obshch. Khim., 1982, 52, 442 (Chem. Abstr., 1982, 96, 199 799); Yu. A. Strepikheev, P. S. Khokhlov, and B. A. Kashemirov, J. Gen. Chem. USSR (Engl. Transl.), 1981, 51, 1020; P. S. Khokhlov, B. A. Kashemirov, and Yu. A. Strepikheev, Zh. Obshch. Khim., 1981, 51, 2145 (Chem. 4bstr., 1981, 95, 2 2 105); V. M . Berestovitskaya, D. A. Efremov, G . A. Berkova, and V. V . Perekalin, ibid., p. 2418 (Chem. Abstr., 1982, 96, 85 670).

A. A. Prishchenko, G. G. Kolesnikova, 2 . S. Novikova, and I . F. Lutsenko, Zh. Obshch. Khim., 1981, 51, 480 (Chem. Abstr., 1981, 95, 6 3 313). I55

C. C. Tam, K. L. Mattocks, and M . Tishler, Proc. Natl. Acad. Sci. USA, 3301.

1981, 7 8 ,

Organophosphorus Chemistry

152

time, reductively 0-phosphorylated t o ( 145).'56 The same phosphonate also selectively benzoylates primary alcohol groups in the presence of DBU.'57 Other (1 -0xoalkyl)-phosphonic esters also act as good acylating agents for ketones.' 5 7 The usefulness of [ a-(trimethylsilyloxy)alkyl]phosphonates and related compounds in synthesis is being increasingly explored by Japanese Anions from the compounds (146) may be alkylated or acylated (best at room temperature) and the products cleaved under basic conditions t o afford various types of ketones (Scheme 11). The products OSiMe3

I

RICH-P(

i , ii

II 0

O E t ),

I

iii

RIC-P(

OEt )2

R1CR2

I, II

R

(146)

-

OSiMe3

II

O (147)

0

'

0

i,iv

#O

Ph ph[ OSiMe3 RIC-P(OEt),

I I

R'CO

II

iii 0 0 [ R A= pl hh ] e - ! R 2

0

(149) 0 OH + ThC-CHR'

II I

(148)

0/ 9 O E t (150 1

OH 0 PhCH-CR2) I

II

+ v

[66-824%1

[O-10x1

R' R~ CH

OSiMe3

I

i , ii

R'CH=CHCHP( O E )~2

X F 3 YH *

II

0

0

II

0

II

R1R2CHCH2C-P(0Et (

151)

)2

-

P(OEt

vii

l2

R1R2CHCH2COOR3 (152)

Reagents: i, LiNPri,; ii, R 2 X ; iii, HO-; iv, R*COCI; v, heat; vi, H , O f ; vii, R 3 0 H , H+

Scheme 11

(147; R' = P h , R2 = CH2C1) and (147; R' = R2 = Ph) cannot be obtained directly from diethyl trimethylsilyl phosphite and phenacyl chloride or benzil, respectively. Pyrolysis of (148; R' = R2 = Ph) gives t h e enediol cyclic phosphate (1 50) via the enol phosphate (1 49). When R' is an unsaturated group, hydrolysis of t h e initial products yields (1 -oxoalkyl)phosphonates (151), from which t h e carboxylic acid esters (152) may be obtained by acid- cat aly sed hydrolysis . A study of t h e Perkow reaction was also the source for the observation that when the phosphates (146; R' = CC13) are heated, diethyl 2.2-dichloroM . Sekine, A. Kume, M . Nakajima, and T. Hata, Chem. Lett., 198 1, 1087. M . Sekine, A. Kume, and T. Hata, Tetruliedron Lett., 1981, 2 2 , 3617. M . Sekine, M. Nakajima, and T. Hata,J. Org. Chem., 1981, 46, 4030. M . Sekine, M . Nakajima, A. Kume, A. Hashizume, and T . Hata, Bull. Chem. SOC. J p n . , 1982, 5 5 , 2 2 4 ; M. Sekine, M . Nakajima, and T . Hata, ibid., p. 218.

153

Quinque vden t Ph osph orus A cids

ethenyl phosphate is formed after an initial migration of the trimethylsilyl group between oxygen atoms.'60 The hydrolysis of [(2,2,2-trichloro-lhydroxy)ethyl] phosphinates proceeds along the same course as that of the phosphonate analogue, Dipterex.16' The bicyclic 1,4-dioxa-2,5-diphosphorinan (1 53), formed from ethylphosphonous dichloride and acetylacetone, is hydrolysed by moist air t o the 1,2-oxaphospholan (1 54).85 Me I

Me

The kinetics of the alkaline hydrolysis of 0-aryl (dimethy1)phosphinothioates have been determined.162 The derivatives (1 55; R=PhCH2, HOCH2CH2, and H2NCH2CH2) of hexadecyldimethylammonium bromide have a significantly greater catalytic effect o n the rate of alkaline hydrolysis of 0-isobutyl 0-4-nitrophenyl methylphosphonate than does the derivative (1 55; R = Me).'63 Under acidic conditions, compounds (1 56; R = Ph or 2-py; n = O or 1) hydrolyse by selective S - 0 bond fission whereas under neutral conditions fission takes place at P-0 bonds, and intramolecular catalysis by the 2-pyridyl group is observed for (1 5 6 ; n = 1, R = 2-py).la Ring fission occurs when A3-2-chloro-5,5-dimethyl-2-oxo- 1,2-0xaphospholen is treated with methyl-lithium. Notwithstanding the earlier observation by Machida and Saito (see 'Organophosphorus Chemistry', Vol. 11, p. 1 1 1) that the ester (161) undergoes spontaneous cyclization to (1 58), and hydrolysis t o (1 59) is then rapid, a new study of the hydrolysis of (1 60) has confirmed that, in neutral or acidic media, the (autocatalytic) hydrolysis of (160) yields only (159) with no ring-opening, and that even under basic conditions, only the salts of (159) are found, again with no evidence for ring-0~ening.I~~ 160

T. Kh. Gazizov, Yu. I. Sudarev, A. M . Kibardin, R. U . Belyalov, and A. N. Pudovik, Zh. Obshch. Khim., 1981, 51, 8 (Chem. Abstr., 1981, 94, 173 883). 1 6 ' G.Aksnes and R. 0. Larsen, Liebigs A m . Chem., 1981, 1967. 1 6 2 B. I. Istomin, M . G. Voronkov, E. L. Khdanovich, and B. N . Bazhenov, Dokl. A k a d . N a u k SSSR, 1 9 8 1 , 2 5 8 , 659 (Chem. Abstr., 1981, 9 5 , 131 876). 163 A. V. Begunov, G . V. Rutkovskii, and S. G . Kuznetsov, Zh. Org. Khim., 1981, 17, 1668 (Chem. Abstr., 1981, 95, 186272). 164 T. Eiki, T. Horiguchi, M . Ono, S. Kawada, and W. Tagaki, J . Am. Chem. SOC., 1982, 104, 1986. 16'

R. S. Macomber and G. A. Krudy, J . Org. Chem., 1 9 8 1 , 4 6 , 4038.

Organophosphorus Chemistry

154

CPH0

0

II

(BuO)~PCH=CHCH~OH

R2

\

X'

(161

(157) R = M e , X = C1 ( 1 5 8 ) R = H , X = OBu ( 1 5 9 ) R = M e , X = OH

(160) R = M e , X = OMe

The 0-phosphinyl ester (162) not only undergoes a predictable [3,31 sigmatropic shift t o give (1 63), but a further [ 3,3] sigmatropic rearrangement in the presence of excess base, and involving the benzyl group of (1 64) as its anion, is a prelude t o the ultimate (prototropic) shift which leads to ( 1 65).'66

P h LPh

Ph

/cH2ph

\

NS

0 //p\s

PPh-h

b In the reactions between the nitrones (1 66)--( 168) and the phosphonates (169) and (170), the nature of the products is determined essentially by the size of the phosphonate ring; the smaller of these leads t o aziridines whilst the compound with the larger ring leads completely or predominantly to enamine~.'~'For other nitrones (1 71), acted upon by various organophosphorus compounds, the nature of the products appears t o depend somewhat on R' and R 2 . Thus (17 1 ; R' = R2 =aryl) and PhPSClz yield benzothiazoles, whereas (17 1 ; R' = aryl, R2= Me), under similar conditions, eventually give 166

167

J . Monkiewicz, K. M . Pietrusiewicz, and R . Bodalski, Bull. Acad. Pol. Sci., Ser. Sci. Chim., 1980, 2 8 , 3 5 1 (Chem. Abstr., 1982, 96, 85 678). S. Zbaida and E. Breuer, J . Org. Chem., 1982, 47, 1073.

155

Quinquevalent Phosphorus A cids

( 1 6 9 ) X = C N o r COOEt

(170)

X = CN o r C O O E t

N - methylbenzamides, also obtained by using Ph2PSC1.168 Other nitrones (1 71 ; R' = R2 = aryl) and Ph2P(S)OMe, at 150 OC, give b e n z o x a z ~ l e s . ' ~ ~ A study of the kinetics of the reaction between alkyl cyanides and diphenylphosphinodithioic acid supports the two-stage mechanism illustrated in Scheme 12.17" S II

R\

RCNH2

+

S II >cp

s II

Ph

s II

Scheme 12

The potential of Lawesson's reagent in synthesis continues t o be explored. In addition to its value for the synthesis of various phosphorus-containing heterocyclic ring systems discussed earlier,24-2693' 32 the reagent converts 2-substituted cyclohexanones into t h i ~ l s , ~unsaturated ' esters into thioesters (in contrast t o the analogous a m i d e ~ ) , C-nitroso-compounds ~' into azoand a z o x y - ~ o m p o u n d sand , ~ ~ ' phosphyl' into 'thiophosphyl' compounds;% it has also been used in a synthesis of thiadiazoles from diazo-ketones."l The Zwierzak synthesis of amines, using diphenylphosphinic amides, has been adapted t o the asymmetric synthesis of opticallv active amines from oximes (Scheme 13), production of excess of the (R)enantiomer of the R1R2C=NOH

i

0 0 ii 11 II Ph 2 PN=CR1P12-Ph2PNHCHR1R2

iii R'R'ZHNH,

Reagents: i , Ph,PCl, Et,N; ii, LiAlH,, (-)-quinine, Et,O, THF; iii, HCI, EtOH

Scheme 13 16'

M . Yoshifuji, R. Nagase, T. Kawashima, and N . Inamoto, Bull. Chem. Soc. J p n . ,

16'

M . Yoshifuji, R. Nagase, and N . Inamoto, Bull. Chem. SOC.J p n . , 1982, 55, 873. S. A. Benner, Tetrahedron Lett., 1981, 2 2 , 1855. M . I. Levinson and M . P. Cava, Heterocycles, 1982, l Y , 241.

1982, 5 5 , 870. I7O

17'

156

Organophosphorus Chemistry

amine being observed. Diphenylphosphinic hydrazide has similarly been used for the preparation of unsymmetrical disubstituted h y d r a z i n e ~ . ' ~ ~ The full paper o n the reaction between diphenylphosphinic chloride and hydroxylamine t o give the 0-phosphinylated compound has appeared.'74 For the reaction between (172; X=C1; R' = E t , Pri, or But) and the amines R2NH2 (R2 =Pri o r But), the rate of reaction shows a low sensitivity t o t h e

(172)

size o f R2, suggesting an associative mechanism involving a rate-limiting attack of N o n P. The chlorides react readily with aniline, and it thus appears that the nature of the attacking amine is of importance. It was suggested that an elimination-addition mechanism operates, in which the intermediate discriminates poorly between different nucleophiles. 17'

173

I74

'I5

B. Krzyzanowska and W. J . Stec, Synthesis, 1982, 270. M. Kluba and A. Zwierzak, Synthesis, 1981,537. M . J. P. Harger, J . Chem. SOC.,Perkin Trans. I , 1981, 3284. M. J. P. Harger, Tetrahedron Lett., 1981,22, 4741.

7 Phosphates and Phosphonates of Biochemical Interest BY D. W. HUTCHINSON

1 Introduction

The proceedings of the International Conference on Phosphorus Chemistry which was held last year at Duke University, North Carolina have now been published.' One session at this conference was devoted t o the biochemistry of phosphorus compounds and was dedicated to Professor F. H . Westheimer, who is also the author of a recent review * o n monomeric metaphosphate, a species often invoked by biochemists and others. One compound which has attracted considerable interest in the past year is fructose 2,6-bis(phosphate) (1). This compound has been identified only

H203p0y0 OP0gH2

OH

W eS

n

CONH

I

R

OHH2°

1

DCCD

I

R

[ R = a d e n o s i n e 5'-pyro~hosphoryl-5-(@-D-ribofuranosyl)]

'Phosphorus Chemistry, Proceedings of the 1981 International Conference', ed. L. D. Quin and J . G. Verkade, A.C.S. Symposium Series N o . 171, American Chemical Society, Washington, 1981. I-'. H. Westheimer, Chem. R e v . , 1981, 81, 313.

157

158

Organophosphorus Chemistry

recently and can be synthesized from fructose 1,6-bis(phosphate) (2) by cyclization of the latter with DCCD followed by hydrolysis of the cyclic intermediate with alkali,3y4o n a scale which is sufficiently large for a sample t o be obtained for analysis by 31P and 13C n.m.r. s p e c t r o ~ c o p y Naturally .~ occurring (1) is t h e 0-anomer, and is synthesized ir, the liver from ATP and fructose 6 - p h ~ s p h a t e Phosphofructokinases .~ from both liver and yeast are stimulated by ( 1),7 which also regulates the functions of fructose 1,6-bisphosphatase and inorganic pyrophosphate: D-fructose 6-phosphate 1-transferase.' Another component of this complex regulatory system has been identified as fructose 2,6-bisphosphatase, which copurifies with phosphofructokinase, suggesting the presence of a single, multifunctional enzyme." The methodology for the synthesis of phospholipids has been improved considerably in recent years. Individual methods that have been published recently will be discussed in more detail in Section 4 of this Chapter.

2 Coenzymes and Cofactors The large-scale use o f nicotanamide coenzymes in organic synthesis is limited by the problem of regenerating NAD(P)H from NAD(P)+. Recently. several methods have been published by the same laboratory for carrying o u t this regeneration o n a large scale. 'These include t h e combined electrochemicalenzymatic reduction of disulphides," electrochemical reduction in the presence of methyl viologen and flavoenzymes,'* reduction using hydrogen and a h y d r ~ g e n a s e , 'and ~ reduction by glucose 6 -phosphate dehydrogenase and glucose 6-sulphate (the latter being more stable than glucose 6phosphate). l4 5-Thiomethylnicotinamide-adenine dinucleotide (3) has been prepared from NAD' and 5-thiomethylnicotinamide with the aid of a transglycosidase.I5 The dinucleotide ( 3 ) can be converted into 5-methylnicotinamide3

4 5

S. J . Pilkis, M. R. El-Maghrabi, J . Pilkis, T. H. Claus, and D. A. Cumming, J . Biol. Chem., 1981, 256, 3171. E. Van Schaftingen and H.-G. Hers, Eur. J . Biochem., 1981, 117, 319. A.-M. Hesbain-Frisque, E. Van Schaftingen, and H.-G. Hers, Eur. J . Biochem., 1981, 117, 325.

6

I R

9

L. Hue, P. F. Blackmore, and J. H. E x t o n , J. B i d . Chem., 1981, 256, 8900; E. Van Schaftingen and H.-G. Hers, Biochem. Biophys. Res. Commun., 1981, 101, 1078; M. R. El-Maghrabi, T. H. Claus, J . Pilkis, and S. J. Pilkis, ibid., p. 1071. E . Van Schaftingen, M. F. J e t t , L. Hue, and H.-G. Hers,Proc. Natl. Acad. Sci. USA, 1981, 78, 3483; G. Avigad, Biochem. Biophys. Res. Commun., 1981, 1 0 2 , 985. S. J . Pilkis, M. R. El-Maghrabi, M. M. McGrane, J. Pilkis, and T. H. Claus, J. B i d . Chem., 1981, 256, 1 1 4 8 9 ; E. Van Schaftingen and H.-G. Hers, Proc. Natl. Acad. Sci. USA, 1981,78,2861. D. C. Sabularse and R. L. Anderson, Biochem. Biophys. Res. Commun., 1981 103, 848.

10 11

12

13

14

15

E. Van Schaftingen, D. R. Davies, and H.-G. Hers, Eur. J . Biochem., 1982, 124, 143. Z . Shaked, J. J . Barber, and G. M . Whitesides, J. Org. Chem., 1981, 46, 4100. R. DiCosimo, C. H. Wong, L. Daniels, and G. M . Whitesides, J. Org. Chem., 1981, 46, 4622. C. H. Wong, L. Daniels, W. H. Orme-Johnson, and G. M . Whitesides, J . Am. Chem. Soc., 1981, 103, 6227. C. H. Wong, J. G o r d o n , C. L. Cooney, and G. M. Whitesides J . Org. Chem., 1 9 8 1 , 4 6 , 4676. J . P. Samama, A. D. Wrixon, and J . F. Biellmann, Eur. J. Biochem., 1981, 118, 479.

159

Phosphates and Phosphonates of Biochemical Interest

adenine dinucleotide and 3-cyano-5-methylpyridine-adenine dinucleotide. Both of these compounds have been used t o probe the binding of NAD“ coenzymes t o liver alcohol dehydrogenase, and while neither compound was active as a coenzyme, both bound t o the enzyme. The kinetic properties of eighteen NAD’ analogues that have modified nicotinamide moieties have been studied, using lactate dehydrogenase.16 The size of the substituent at C-3 does not appear t o be critical; however, substitution at C-5 can hinder binding of the coenzyme t o the dehydrogenase. As might be expected, substitution at C - 4 prevents hydride transfer. 3-Chloroacetylpyridine-adenine dinucleotide (4), an NAD+ analogue with a considerable conservation of coenzyme structure, is active as a coenzyme for liver alcohol dehydrogenase but irreversibly inactivates the enzyme, presumably by binding covalently t o it .17 Diazotized 3-aminopyridine-adenine dinucleotide phosphate has been used as an affinity label for NADPH-cytochrome P - 4 5 0 ( c ) reductase.18 Spinlabelled analogues of NAD’ ( 5 ) in which the perdeuteriated nitroxide radical 4-amino-2,2,6,6- tetramethylpiperidine-1 -oxyl is connected t o either C-6 o r C-8 can be prepared from NMN+ and the corresponding adenine nucleotide, using DCCD.19 Perdeuteriated spin-labels give e.s.r. spectra with a decreased linewidth compared with spectra obtained with the fully protonated spinlabels, and hence the study of enzyme-bound versus freely tumbling coenzymes is facilitated. R

(5) K

=

-

c?3

The 31P n.m.r. spectrum, at 50.5 MHz, of commercial riboflavin 5’phosphate (FMN) (6) consists of a major signal (80%) due t o the 5’-isomer together with signals due t o the 2’-, 3’-, and 4‘-isomers, which are presumably l6

l9

J . P. Samama, N . Marchal-Kosenheimer, J . F. Biellmann, and M. G. Rossmann, Eur. J. Biochem., 1981, 120, 563. B. Foucaud and J . F. Biellmann, Eur. J. Biochem., 1981, 119, 3 1 I . R. E. Ebel, Arch. Biochem. Biophys., 1981, 2 1 1, 2 2 7 . K. G . Gloggler, K. Balasubramanian, A. Beth, T. M. Fritzsche, J . H. Park, D. E. Pearson, W. E. Trommer, and S . D. Venkatamu, Biochim. Biophys. Acta, 1982, 701, 224.

Organophosphorus Chemistry

160

artefacts of isolation or of storage.20 The 31P n.m.r. spectrum of FMN that is bound to the apoflavodoxin of Megasphaera elsdenii shows that the phosphoryl group is in the dianionic form and is buried in the protein. The distance between the phosphoryl group and N-10 of the isoalloxazine moiety of the enzyme-bound FMN is similar to that in the related flavodoxin from Clostridium MP. 21 8a-(O-Tyrosyl)flavin-adenine dinucleotide (7) is the prosthetic group of p -cresol methylhydroxylase from Pseudomonas putida. 22 + H NCHCOO3 1

H

0

I

While several flavoproteins are known in which the riboflavin residue is linked by the 8a-position to cysteine or histidine, this is the first instance of the involvement of a tyrosine residue. The modified tyrosine is at the N-terminus of a protein chain and the sequence of a section of theN-terminal end of the protein has been determined. Compound (7) can be prepared by treating 8CY - bromotetra- 0 - acetylribo flavin with a copper- tyrosine complex, followed by deprotection of the product. A cyclopropane analogue (8) of phosphoenolpyruvate (PEP) has been prepared by phosphorylating the methyl ester of l-hydroxycyclopropanecarboxylic acid with 2-cyanoethyl phosphate and DCCD (see Scheme l).23 Removal of the protecting groups is readily achieved in alkaline solution. Compound (8) is a much more potent inhibitor of PEP-requiring enzymes than either phospholactate or phosphogycolate, and it is presumed that the stereochemistry and electronic structure of (8) resemble those of PEP more closely than do those of either of the other analogues. Two other PEP analogues, ( E ) - (1 0) and (2)-2-phosphoenolbutyrate (9), have been examined as inhibitors of PEP c a r b o ~ y k i n a s e sExperimental .~~ details for the preparation o f (9) and (10) are given only in outline, but the key steps (see Scheme Moonen and F . Miiller, Biochemistry, 1982, 2 1 , 408. *’ CR.. TM.. W.Burnett, G. D. Darling, D. S. Kendall, M . E . LeQuesne, S. G. Mayhew, W. W. 22

’’ 24

Smith, and M. L. Ludwig, J . Biol. Chem., 1974, 249, 4383. W. M. Mclntire, D. E. Edmondson, D. J . Hopper, and T. P. Singer, Biochemistry, 198 1 , 2 0 , 3068. M . H. O’Leary, W. J . DeGooyer, T . M. Dougherty, and V . Anderson, Biochern. Biophys. Res. Commun., 1981, 100, 1320. T. H. Duffy, P. J . Markovitz, D. T. Chuang, M. F. Utter, and T. Novak, Proc. Natl. Acad. Sci. USA, 1981, 7 8 , 6680.

Phosphates and Phosphonates of Biochemical Interest

161

M e CHB r COCOOH

1

iii

OH

I I O=P(

MeCHBrCCOOH OEt )

(11)

iv

-

Me

/P( OH 1 2

‘c=

’H

‘ \ O H (9)

Reagents: i, dicyclohexylcarbodi-imide (DCCD); ii, NaOH, H,O; iii, (EtO), POH; iv, NaOH; v, hu Scheme 1

1) are the treatment of 3-bromo-2-ketobutyric acid with diethyl phosphite t o give (1 l ) , which was converted into the (2)-isomer (9) by treatment with sodium hydroxide. Ultraviolet irradiation of (9) gave a mixture of both isomers. The (E)-isomer was the more powerful inhibitor of the carboxykinases. While the mechanisms of reactions that are catalysed by thiamine diphosphate are understood in principle, little is known about their steric course. The preparation of (1R)- and ( lS)-[l-2H1,1-3H1]fructo~e 6-phosphate has enabled the stereochemistry of the reaction that is catalysed by phosphoketolase to be studied,25 as the product of this reaction is chiral acetyl phosphate, whose absolute configuration can be readily determined.26

3 Sugar Phosphates The chromatographic separation of isomeric pentose phosphates on dihydroxyboronyl columns has been described and this technique has been used to obtain pure samples of D-XyhlOSe 5-phosphate and D-ribulose 5 p h ~ s p h a t e . ~An ‘ isosteric analogue of glucose 6-phosphate, 6,7-dideoxy-ar-D gluco-heptopyranose 7-phosphonic acid (1 2), has been prepared by the basecatalysed reaction between tetraethyl methylenebis(phosphonate) and the aldehyde (1 3), followed by treatment with trimethylsilyl bromide and then catalytic hydrogenation (Scheme 2).28 Glucuronate 6-phosphate dehydrogenase will convert (12) into the open-chain glucuronate (14).29 The 25 26

27

28 29

I. Merkler and J. Rktey, Eur. J. Biochem., 1981, 120, 593. J . W. Cornforth, J . W. Redmond, H. Eggerer, W. Bucknel, and C. Gutschow, Nature (London), 1969, 2 2 1 , 1212; J . Liithey, J . Rktey, and D. Arigoni, ibid., p. 1213. A. Gascon, T. Wood, and L. Chitemerere, Anal. Biochem., 1981, 118, 4. D. J. W. Roach, R. Harrison, C . R. Hall, and T. D. Inch, Biochem. J., 1981, 197,735. D. J. W. Roach and R. Harrison, Biochem. J., 1981, 197, 731.

Organophosphorus Ch ernistry

162

*R o

i-iii

-

RO

H o * 0 3;2

OR

OH

(12)

(13)

Reagents: i, CH, [ P(O)(OEt), ] *,base; ii, Me,SiBr; iii, H,/Pd

Scheme 2

phosphonate analogue of a - D -glucose 1-phosphate, 2,6- anhydro-1 - deoxy-Lglycero-D-glum-heptopyranose 1-phosphonic acid ( 15), has been prepared by t h e Arbusov reaction from t h e bromide (1 6).30 This is the first report of the synthesis o f a phosphonate analogue Of CY-D-glUcOSe 1-phosphate, and an investigation of the interaction of (1 5 ) with enzymes that are involved in the synthesis of nucleoside diphosphate sugars would be interesting.

HO

UDP-N-acetylhexosamines have been synthesized by the reaction between fully protected hexosamine phosphates and the mixed anhydride formed from UMP and diphenyl p h o ~ p h o r o c h l o r i d a t e Pyridoxal.~~ 5’-diphospho-aD-glUCOSe (17), also prepared by the mixed anhydride method, has been used t o examine the interaction between pyridoxal 5’-phosphate and CY-D-glUCOSe 1 -phosphate in the active site of glycogen p h o s p h o r y l a ~ e .The ~ ~ evidence suggests that the two phosphoryl groups are close together at the catalytic site. A number of new nucleoside diphosphate sugars have been synthesized 33 30 31

32

33

I?. Nicotra, F. Ronchetti, and G . Russo,J. Chem. Soc., Chem. Commun., 1982, 470; T. Yamazaki, C. D. Warren, A. Herscovics, and R. W. Jeanloz, Can. J. Chem., 1981: 5 9 , 2247. S. G. Withers, N. B. Masden, B. D. Sykes, M. Takagi, S. Shimomura, and T. Fukui, J. Biol. Chem., 1981, 256, 1 0 7 5 9 . H. A. Nunez, J. V. O’Connor, P. R. Rosevear, and R. Barker, Can. J. Chem., 1981, 59, 2086; V . N . Shibaev, G. I. Eliseeva, M. A. Kraevskaya, and N. K. Kochetkov, Bioorg. Khim., 1981, 7, 376 (Chem. Abstr., 1981, 95, 8 1 3 8 1 ) ; V. N. Shibaev, N. S. Utkina, L. L. Danilov, and G. I. Eliseeva, ibid., 1980, 6, 1778 (Chem. Abstr., 1981, 9 5 , 7662).

Phosphates and Phosphonates of Biochemical Interest

163

Me

CH20H

I

I

HO

CHO

0-P-0-P-0

I

HO

I

OH

and the identification of ADP-D-glycero-D-manno-heptose 34 and of UDP-Nacetylglucose 4 -sulphate 35 has been reported. The lipopolysaccharides of Pseudomonas aeruginosa have a very high phosphorus content, and it is claimed (from 31P n.m.r. evidence) that triphosphate residues are present.36 This claim has been q u e s t i ~ n e d , ~and ' it is suggested that the triphosphates may arise during the isolation of the lipopolysaccharides. 4 Phospholipids As mentioned in the Introduction, descriptions of a number of new, specific syntheses of phospholipids have been published in the past year. The phosphotriester approach, so popular in the nucleotide field, has been used to prepare a-glucosylated mono- and di-phosphatidylglycerols 38 and 2-0acetyl-3-0 - hexadecyl-sn -glycero( 1) p h o s p h o ~ h o l i n e . ~ Phospholiponucleo~ sides have been synthesized by a simple procedure, using the cyclic enediol pyrophosphate (1 8) as phosphorylating agent.40 However, the most interesting development is the use of oxazolines as protecting groups. In the synthesis

of the enzyme-inhibitory compound 2-sn -deoxy-2-amidophosphatidylcholine (19),41 serine is first converted into the oxazoline (20) before phosphorylation of the alcohol function with 2-chloro-2-0x0- 1,3,2-dio~aphospholan.~~ 34 35

T. Kontrohr and B. Kocsis, J . Biol. Chem., 1981, 256, 7715. A. L. Fluharty, J . A. Glick, G. F. Samaan, and H. Kihara, Anal. Biochem., 1982, 121, 310.

36

37 38

39

40

41

42

S. G. Wilkinson,Biochem. J., 1981, 199, 833. D. Horton and D. A. Riley, Biochem. J., 1981, 199, 855. C. A. A. van Boeckel, J . J . Oltvoort, and J. H. van B o o m , Tetrahedron, 1981, 37, 3751. C. A. A. van Boeckel, G. A. van der Marel, P. Westerduin, and J . H. van B o o m , Synthesis, 1982, 399. F. Ramirez, S. B. Mandal, and J . F. Marecek, Synthesis, 1982, 402. N . S. Chandrakumar and J . Hajdu, J . Org. Chem., 1982, 4 7 , 2144; Tetrahedron Lett., 1981, 2 2 , 2 9 4 9 . N . S. Chandrakumar, V. L. Boyd, and J. Hajdu, Biochim. Biophys. Acta, 1982, 711, 357.

164

Organophosphorus Chemistry 0

COO-

II

CH20H

I

\

i-iii

CH,O-P-OH,C fH2

I “

iv,v

I

-0

“I R

+

I

CH20H

NMe 3

I (20)

0

-

II CH20-F-OH2C I - 10 H-C-NCOR I H CH2

vii

I

+I

CH 2 0 R

NMe 3

0

II -I0

CH 20-F-

OH2C

CH2

HcC-NH2

I

+ Nb4e I

(19)

I I CH20R

(21)

Reagents: i, MeOH, HC1; ii, RC(OEt)=NH. HCI; iii, LiAlH,; iv, vi, HCI, H,O; vii, RCOOOCOR

Scheme 3

Treatment of the phosphorylated product with trimethylamine opens the dioxaphospholan ring and then acid hydrolysis leads to the aminophosphatidylcholine (2 l), which can be acylated to (1 8). The oxazaphospholidine group has been used to protect phosphoryl oxygens in a synthesis of P-chiral phospholipids 43 and an analogue (22) of cytidine diphosphate 1,2-diacyl-sn glycerol which contains three carbon-phosphorus bonds has been prepared ROCH2

I

ROCH

I

CH2 ii CH2-

P -CH

I

OH

2-

0 P

II-0 I OH

y07; t

OH

OH

( 2 2 ) R = Me(CH2)16

in a nine-step synthesis.44 N o details of the biochemical properties of this unusual compound are given, however. The stereochemical requirements for the platelet-activating factor l-O-hexadecyl-2-O-acetyl-sn-glycero(3)phosphocholine (23 ; R = OCOMe) have been determined:’ and analogues, e.g. 43

44

4s

K. Bruzik and M. D. Tsai,J. A m . Chem. SOC., 1982, 104, 863. A. F. Rosenthal and L. A. Vargas, J. Chem. SOC., Chem. Commun., 1981 9 7 6 . R. L. Wykle, C. H. Miller, J . C . Lewis, J . D. Schmitt, J . A. Smith, J . R. Surles, C. Piantadosi, and J . T. O’Flaherty, Biochem. Biophys. R e x Commun., 198 1, 100, 1651.

Phosphates and Phosphonates of Biochemical Interest

165

CH20R

I

R ~ H

ROCH

+

(23)

(24)

(23; R = Pr”), have been prepared from the corresponding 1-0-hexadecyl-2alkyl- 3 - p r 0 p a n o l s . ~ ~1,2-Diacyl-rac-glycero(3)thionophosphocholines (24) can be prepared by condensation of the diacylglycerol with thiophosphoryl chloride and choline toluenesulphonate. Differences in chemical shifts in the 31 P n.m.r. spectra of naturally occurring phospholipids are small compared with linewidths, and as thionophospholipids have 31P n.m.r. chemical shifts that are well removed from those of the natural compounds, the aggregation of a particular phospholipid in a mixture can be investigated by using the thionophospholipid~?~ Acyl migration in lysophospholipids has been studied by 31P n.m.r. because, at 40.3 MHz, the chemical shifts of the three isomeric lysophosphatidylcholines are well resolved.48 Conformational differences between sn - 2and sn -3-phospholipids have been studied by both neutron and X-ray diffraction methods 49 and the preferred conformations and molecular packings of phosphatidylethanolamine and phosphatidylcholine have been determined.”

L

J 18

A sensitive assay for dolichyl phosphate (25; R = H ) has been developed which makes use of the reaction between [14C]phenyl chloroformate and alkyl monophosphates, when a carbonic-phosphoric acid anhydride is formed.” The latter can then be separated from the reaction mixture by t.1.c. and the radioactive content assayed. This method is not specific for dolichyl phosphate, as any phosphornonoester will react in this way with 46

47

R. L. Wykle, J. R. Surles, C. Piantadosi, W. L. Salzer, and J. T. O’Flaherty, FEBS Lett., 1982, 141, 29. I . Vasilenko, B. De Kruijff, and A. J . Verkleij, Biochim. Biophys. Acta, 1982, 685, 144.

4a 49 50

51

A. Pluckthun and E. A. Dennis, Biochemistry, 1982, 2 1 , 1743. G. Biildt and G. H. de Haas,J. Mot. Biol., 1982, 158, 5 5 . H . Hauser, 1. Porchev, R. H. Pearson, and S. Sundell, Biochim. Biophys. Acta, 1981, 6 5 0 , 21. R . K. Keller, J . W. Tamkun, and W. L. Adair, Jr., Biochemistry, 1981, 2 0 , 5831.

166

Organophosphorus Chemistry

phenyl chloroformate. However, the separation step allows some specificity t o be achieved. A new class of acidic glycolipids have been isolated from plants which are analogous t o the acidic gangliosides found in the membranes of animal cells.52 The major glycolipid is a glycophosphoceramide in which the phosphoryl moiety is joined t o C-1 of myoinositol in the tetrasaccharide Gal(a 1 4)GlcNAc(a 1 4)GlcUA(a 1+ 2)myoinositol. -+

-+

5 Phosphonates

The recognition of the effects of pyrophosphate analogues such as phosphonoacetic acid (26) and C-substituted methylenebis(phosphonates) (27) o n the replication of viruses s3 and the calcification of bone 54 has stimulated the search for new compounds with biological activity. For example, details of two syntheses of mono- and di-fluoromethylenebis(phosphonic acids) (27; R 1= F , R2 = H ) and (27; R 1= R2 = F) have been published.559s6 The electronegativity of the fluorine atoms leads t o withdrawal of electron density from the bridging carbon atom, making the dissociation constants of t h e phosphoryl hydroxyl groups more like those of pyrophosphoric acid than methylenebis(phosphonic acid). ( HO)2P( O)CH2COOH

(

E t 0 ) 2 P ( 0) CH2CONHCHRCOOH

( HO)2 ~O)CR’R~( ( O)P(

OH)

H, 0

2 3

N-(Phosphonoacety1)amino-acids (28) are analogues of the transition states of several enzymes, and hence the recently published synthesis of this class o f compound by the Arbusov reaction from N-(halogenoacety1)aminoacids should be valuable.57 Angiotensin-converting enzyme cleaves the precursor protein, angiotensin I, t o the vasodepressor angiotensin 11. The enzyme has a zinc ion at its active site and can be inhibited by a number of phosphoramides, phosphonamides, and phosphates, e.g. (29), which have been synthesized recently .58 52 53

54

55

56 57

58

T. C . - Y . Hsieh, R: L. Lester, and R . A. Laine, J . Biol. Chem., 1982, 256, 7 7 4 7 . B. Eriksson, B. Oberg, and B. Wahren, Biochim. Biophys. A c f a , 1982, 696, 1 1 5 ; D. Grossberger and W. Clough, Biochemistry, 1982, 2 0 , 4049: L). W. Hutchinson, A . C . S . Symposium Series 171, ed. L . D. Quin and J . G. Verkade, American Chemical Society, Washington, 1981, p. 135; E. De Clercq, Biochem. J . , 1982, 2 0 5 , 1. H. Fleisch and R. Felix, CuZcif Tiss. Znt., 1979, 2 7 , 91. C . E. McKenna and P . D . Shen, J . Org. Chem., 1981, 46, 4 5 7 3 . G. M . Blackburn, D. A. England, and F. Kolkman, J . Chem. Soc., Chem. Commun., 1981,930. P. Kafarski and M . Soroka, Synthesis, 1982, 2 19. E. D. Thorsett, E. E. Harris, E. R . Peterson, W. J . Greenlee, A. A. Patchett, E. H. Uhn, and T. C. Vassil, Proc. Natl. A c a d . Sci. U S A , 1982, 79, 2176.

Phosphates and Phosphonates of Biochemical Interest

167

6 Enzyme Mechanisms

The mechanism of action of fructose 1,6-bisphosphatase has been reviewed,59 as has the stereochemistry of enzymatic reactions of phosphates.60 The latter review summarizes the use of 160,'70,180-labelled phosphates and thiophosphates in the study of over 30 enzymes. Among enzymes that are not included in this latter review but whose stereochemistry of phosphoryl transfer has been determined during the past year are phosphofructokinase,6' phosphoglucomutase,62 glucose 6 - ~ h o s p h a t a s e ,and ~ ~ liver acid phosphatase.64 The hydrolysis of ATP by myosin and actomyosin has also been studied in this way.65 Full details have been published for the synthesis of chiral l 6 0,l 70,l80labelled phosphate esters from meso - hydrobenzoin , correcting an earlier erroneous stereochemical assignment, and a method for the analysis of the chirality of phosphate esters by 31P n.m.r. has been described .67 The thermodynamics, kinetics, and mechanism of yeast inorganic pyrophosphatase have been the subject of much recent interest. Previous studies have indicated that two bivalent metal ions are required for maximum enzymic activity.68 On this basis, a mechanism for the enzymic reaction has been put forward in which the active substrate is the fully ionized P ' , P2-bidentate [ Mg(H20)4 J2+-pyrophosphate complex and the second metal ion, which binds close to this complex, binds the water molecule that is involved in the h y d r o l y ~ i s . Flowever, ~~ 31P n.m.r. spectroscopy has revealed that a third bivalent metal ion is necessary for full catalytic a ~ t i v i t y , ~and ' this observation is supported by kinetic data.71 Thus, the proposed mechanism of action, requiring only two metal ions, requires modification. During the kinetic work described above,71 two methods were developed for determining inorganic orthophosphate in the presence of large excesses of inorganic pyrophosphate. One method relies on the selective extraction of orthophosphate into 2-methylpropan-1-01, while the other relies on twodimensional t.1.c. The acid phosphatase from tubers of the sweet potato is unique in that it naturally contains Mn'II. Phosphorus-3 1 and 170n.m.r. studies indicate that there is direct metal-phosphate interaction in the

59

6o 61

62

63 14

S . J . Benkovic and M. M. de Maine, A d v . Enzymol., 1982, 5 3 , 45. P. A. Frey, Tetrahedron, 1982, 38, 1541. R. L. Jarvest, G. Lowe, and B. V. L. Potter, Biochem. J . , 1981, 199, 427. G. Lowe and B. V. L. Potter, Biochem. J., 1981, 199, 693. G. Lowe and B. V . L. Potter, Biochem. J . , 1982, 201, 665. M. S. Saini, S . L. Buchwald, R. L. Van Etten, and J . R. Knowles, J . B i d . Chem., 1981, 256, 10453.

65

66

67

M. R. Webb and D. R. Trentham, J . Biol. Chem., 1982, 256, 10910. P. M . Cullis and G. Lowe, J. Chem. SOC., Perkin Trans. I , 198 1, 23 17. R. L. Jarvest, G . Lowe, and B. V . L. Potter, J . Chem. Soc., Perkin Trans. 1, 1981, 3186.

68

69 70

B. S. Cooperman and N . Y . Chin, Biochemistry, 1973, 12, 1670; T. A. Rapoport, W. E. Hohne, P. Heitman, and S . J . Rapoport, Eur. J . Biochern., 1973, 33, 341. W. B. Knight, S . W. Fitts, and D. Dunaway-Mariano, Biochemistry, 1981, 20, 4079. B. S. Cooperman, A. Panackal, B. Springs, and D . J. Hamm, Biochemistry, 1981, 20, 6051.

71

B, Springs, K. M . Welsh, and B. S. Cooperman, Biochemistry, 1981, 20, 6384.

168

Organophosphorus Chemistry

phosphatase and that there is exchange of oxygen between water and inorganic orthophosphate which is catalysed by this enzyme.n The presence of an acyl phosphate intermediate, possibly at an aspartyl residue, during the hydrolysis of ATP by the calcium-activated ATPase of skeletal muscle has been inferred from 31P n.m.r. data.73 The formation of a covalent phosphoenzyme intermediate during the hydrolysis of phosphodiesters by either snake venom phosphodiesterase or a 5’-nucleoside phosphodiesterase from Sinapis alba has been demonstrated, using radioactively labelled s ~ b s t r a t e s .Since ~ ~ reduction of the phosphoenzymes with borohydride did not liberate radioactivity from the protein, they do not seem to be acyl phosphates. However, the hydrolysis of ATP by enzymes of the plasma membrane of Neurospora crassa does lead to the formation of a phosphoenzyme that is an acyl phosphate.75 DNA type I topoisomerase catalyses the relaxation of superhelical DNA by the introduction of a singlestrand break and it forms an intermediate in which the DNA is covalently bound to the enzyme. In view of the stability of the protein-DNA bond towards acid, base, hydroxylamine, or iodine, it appears that the DNA is bound t o a tyrosine residue in this intermediate.76 The properties of a phosphatase which specifically dephosphorylates phosphotyrosine rather than phosphoserine residues in histones has been described .77

1-0-Pyrenebutyl phosphorochloridates and phosphorofluoridates (30; R’ = OEt, R2= Cl), (30; R’ = OEt, R2= F), and (30; R’ = R2= C1) have been prepared and treated with acetylcholinesterase to give fluorescent phosphorylated enzymes, which have been used as models for ‘aged’ and non-aged’ enzymes.78 Fluorescence measurements indicate that the phosphoryl residue in the aged enzyme is more deeply buried within the enzyme than in the nonaged counterpart. The difference in accessibility of the phosphoryl residue may be an important factor in the resistance of the aged enzyme to dephosphorylation by nucleophiles. The interaction of nine trialkyl phosphorothiolates with acetylcholinesterase has been studied and it appears that displacement of an S-alkyl rather than an 0-alkyl group is favoured when PO ssible ,79 72

H. Kawabe, Y . Sugiura, and H . Tanaka, Biochem. Biophys. Res. Commun., 1981,

73

E. T. Fossel, R. L. Post, D. S. O’Hara, and T. W. Smith, Biochemistry, 1981, 2 0 ,

103, 327.

7215. 74

7s 76 77

78

79

C. U . Rugevics and H. Witzel, Biochem. Biophys. R e x Commun., 1982, 106, 7 2 . J. B. Dame and G. A . Scarborough, J. Biol. Chem., 1981, 256, 10 724. J . J . Champoux, J. Biol. Chem., 1981, 256, 4085. G. Swamp, S. Cohen, and D. L. Garbers, J . Biol. Chem., 1981, 256. 8197; D. L. Brautigan, P. Bornstein, and B. Gallis, ibid., p. 65 19. G . Amitai, Y . Ashani, A . Gafni, and I . Silman, BiochPmistry, 1982, 21, 2 0 6 0 . B. Clothier, M . K. Johnson, and E. Reiner, Biochem. Biophys. A c t u , 1981, 6 6 0 , 306.

169

Phosphates and Phosphonates of Biochemical Interest

2-Bromoacetylaminopentitol 1,5-bisphosphate ( 3 1) has been prepared by the reductive amination of ribulose 1,5-bisphosphate followed by bromoacetylation of the resultant amine.80 Compound ( 3 1) acts as an affinity label for ribulose 1,5-bisphosphate carboxylase/oxygenase from Rhodospirillum rubrum, as does the related compound 2-bromo- 1,5-dihydroxypentan-3-0ne 1,5-bisphosphate (32).81 CH OPO H

I HCNHCOCH2B r I HCOH I HCOH I CH20P03H2

CH2 OP03H

I I c=o

CHB r

b'.

I

7H2 CH20P03H

The catalytic site of prenyl transferase, the enzyme which catalyses headto- tail condensations between isopentenyl pyrophosphate and an allylic pyrophosphate, can be inactivated by irradiating the enzyme in the presence of 2'-azidophenylethyl pyrophosphate (33).82 Degradation of the transferase which has been inactivated in the presence of radioactive ( 3 3 ) indicates the presence of at least eleven different radioactive peptides, reflecting the non-selective nature of photoaffinity labelling.

HO ( 3 4 ) R = C6Hll;

HO 0 =l80

Evidence for a rigid geranyl cation-pyrophosphate ion pair during the formation of farnesyl pyrophosphate by farnesyl synthetase has been obtained when ( 1 -"O)geraniol pyrophosphate (34) was used as the substrate for the enzyme.83 There is no incorporation of the l80label into farnesyl pyrophosphate, and hence it is probable that the geranyl cation, which is an intermediate in this condensation,@ does not become fully separated from the pyrophosphate ion during the synthesis until the final stages.

7 Other Compounds of Biochemical Interest The hydrolysis of geranyl pyrophosphate is catalysed by Mn*I salts and involves cleavage of a C-0 bond.s5 While the products of this hydrolysis are 'O

"

B. Fraij and F. E. Hartman,J. Biol. Chem., 1982, 2 5 7 , 3501. M . I . Donnelly and F. C. Hartman, Biochem. Biophys. Rex Commun., 1981, 103, 161.

82

83 84

"

D. N . Brems, E. Bruneger, and H. C. Rilling, Biochemistry, 1981, 20, 371 1. E. A. Mash, G. M . Gurria, and C. D. Poulter,J. Am. Chem. SOC., 1981, 103, 3927. C. D. Poulter, P. L. Wiggins, and A. T. Le,J. Am. Chem. SOC.,1981, 103, 3926. M . V. Vial, C . Rojas, G. Portilla, L. Chayet, L. M . Phrez, 0. Cori, and C. A. Bunton, Tetrahedron, 1981, 37, 2351.

Organophosphorus Chemistry

170

similar to those obtained in the acid-catalysed reaction, more cyclic products are formed, and the metal-ion-catalysed hydrolysis may be the better model for many enzymic reactions. Other bivalent metal ions can catalyse the hydrolysis of geranyl pyrophosphate, the order of effectiveness being Cu2+> Mn2+> Zn2+> Co2+> Mg2+= Ca2+. A combination of fast-atom-bombardment mass spectrometry and n.m.r. spectrometry has been used to demonstrate the presence of ecdysone 22phosphate (35; R = O H ) and 2-deoxyecdysone 22-phosphate (35; R = H ) in the eggs of the desert locust.86 The 22-hydroxyl group had previously been shown t o be required for hormonal activity in ecdysones, and essential phosphorylation may be the reason for this. Alternatively, the 22-phosphates may be a way in which the organism stores large quantities of the hormone, which is then released by slow, enzymic hydrolysis. 5-[(Hydroxymethy1)0-pyrophosphorylluracil ( 3 6 ; R = CH20P207H3)has been identified as an intermediate in the biosynthesis of a-putrescinylthymine [ 36; R = CH2NH(CH4)4NH2 ] in bacteriophage @W-14.87 The displacement of the pyrophosphoryl group takes place at the polynucleotide level, but the origin of the putrescinyl moiety is unknown.

H 0 (35)

(36)

In addition to the methods that have been developed for the estimation of orthophosphate in the presence of a large excess of pyrophosphate which were mentioned above,m a simple method for the estimation of pyrophosphate in the presence of a large excess of orthophosphate has been described.88 The latter method relies on the activation of inorganic pyrophosphatase by fluoride ion in the presence of pyrophosphate, as pyrophosphate acts as a 'suicide substrate' for the enzyme under these conditions. An alternative method for the estimation of pyrophosphate involves selective precipitation in the presence of calcium chloride/potassium fluoride. The precipitate is then redissolved in sulphuric acid and any orthophosphate is removed by precipitation as the phosphomolybdate-triethylamine complex. Finally, the 86

87

88

R. E. Isaac, M. E. Rose, H. H. Rees, and T. W. Goodwin, J . Chem. Soc., Chem. Commun., 1 9 8 2 , 2 4 9 . K. L. Maltman, J . Neuhard, and R. A. J . Warren, Biochemistry, 1 9 8 1 , 2 0 , 3586. A. A. Baykov and S. M . Avaeva, Anal. Biochem., 1982, 119, 2 1 1 .

Phosphates and Phosphonates of Biochemical Interest

171

pyrophosphate is estimated as the green pyrophosphomolybdate in the presence of m e r c a p t o e t h a n ~ l .Nucleotides ~~ and phosphate esters do not interfere; other inorganic polyphosphates give a green colour at this stage, but it is claimed that they do not interfere with the assay, as their rate of formation of colour is very much slower than that of pyrophosphate. Details of a method for the selective precipitation of orthophosphate, involving a mixture of tungstate, tetraethylammonium ion, and procaine, have been publishedY9' as have those of a modified version91 of the Hanes and Isherwood spray 92 for the detection of phosphorus compounds on chromatograms.

89 90 91

92

J . K. Heinonen, S. H. Honkasalo, and E. I. Kukko, Anal. Biochem., 1981, 117, 293. B. R. Bochner and B. N . Ames, Anal. Biochem., 1982, 122, 100. B. K. Bochner, D. M . Maron, and B. N . Ames, Anal. Biochem., 1981, 117, 81. C. S. Hanes and F. A. Isherwood, Nature (London), 1949, 164, 1107.

Nucleotides and Nucleic Acids B Y J. B. HOBBS

1 Introduction

The past year has seen considerable progress in the area of oligonucleotide synthesis, including the description of automated synthesizers employing solid-phase ‘phosphotriester’ methods, and a general high level of activity throughout the field. Two volumes of symposium reports 1 9 2 contain a number of papers relevant t o the field which are not cited elsewhere in this Report.

2 Mononucleo tides Chemical Synthesis.-The phosphorylation of nucleosides, by reagents both old and new, has come under scrutiny. Upon heating inosjne with an equivalent quantity of trimetaphosphate at 7 0 ‘C, at pH 12, for a week, 3’-IMP is formed in 26% yield, and another product, thought t o be 2’-IMP, in 33% yield.3 Isomerically pure nucleoside 5‘-monophosphates may be obtained by treating with nuclease P I t h e mixture of products formed from t h e reaction between a 2’-deoxynucleoside and phosphoryl chloride in trialkyl phosphate solution (Yoshikawa’s m e t h ~ d ) This . ~ approach also succeeds with 0*-and 04-methyldeoxythymidine, which are poor substrates for phosphorylation by carrot phosphotransferase. The 0 6-alkyl-deoxyguanosines are best phosphorylated in triethyl phosphate solution, since a larger quantity of a by-product, possibly t h e result of alkylation at N-7 o r N-1, arises when trimethyl phosphate is used. Treatment of adenosine, 2’-deoxyadenosine, and 2’,3’-0,O-isopropylideneadenosinewith diphenyl phosphorochloridate in pyridine affords the corresponding 5 ‘-(diphenyl phosphates) in yields of 32%, 5 7%, and SO%, respectively. When 5’- 0-monomethoxytrityl- 2’-deoxyadenosine is treated similarly, however, the major product is t h e N6,3’-bisphosphorylated species ( I ) , the structure of which was confirmed by unambiguous synthesis.’ If phenyl o r 2-chlorophenyl phosphorodichloridates are employed, the analogous phosphoramidochloridate intermediates may be allowed t o react further with 2-cyanoethanol t o afford N6-aryl cyanoethyl phosphoramidates, which are stable t o treatment with ammonia. Phosphorylation o f 2’,3’-0,0-isopropylidene-nucleosides with bis-(2,2,2-tribromoethyl)

’ Nucleic Acids Symp. Ser., 198 I , Vol. 9. ’ ACS Symp. Ser., 1981, Vol. 171. M . Tsuhako, M . Fujimoto, and S. Ohashi, Chcrn. Lett., 1981, 849. R. Saffhill and J. Hall, J . Carbohydr., Nucleosides, Nucleotides, 1981, 8 , 573. R. Charubala and W. Pfleiderer, Heterocycles, 198 1, 15, 761.

172

Nucleotides and Nucleic Acids

173

phosphorochloridate in pyridine in the presence of 1,2,4-triazole and 1-methylimidazole gives good yields of the corresponding 5'-[ bis-(2,2 >2tribromoethyl) phosphates]. Electrochemical deprotection affords good yields of the nucleoside 5'-monophosphates after subsequent removal of the isopropylidene group with acid.6 Bis-(2,2,2-trichloro- 1,l-dimethylethyl) phosphorochloridate has been prepared and used with 4 -dimethylaminopyridine in pyridine solution as a selective agent for the simultaneous phosphorylation and protection of the 5'-hydroxy-group in nucleosides, the reagent attacking this position with a specificity comparable to that of trityl ~ h l o r i d e The . ~ deblocking process, employing cobalt(1) phthalocyanine anion, is rather slow, but eventually affords good yields of 5'-monophosphates. 4-Nitrophenyl phosphorochloridomorpholidate attacks suitably base- and sugar-protected nucleosides in acetonitrile in the presence of 1-methylimidazole to afford nucleoside 5'-(4-nitrophenyl phosphoromorpholidates) such as (2).8 The analogous 2,4-dichlorophenyl compound (3) is formed similarly. After removal of the aryl group with syn -4-nitrobenzaldoximate, the result ant 5 '-phosphoromorpholidat e may be treated with ort hophosphate, pyrophosphate, methylenediphosphonate, etc., to afford the corresponding 5'-diphosphate, -triphosphate, -[/3,y-methylene]triphosphate, e t c . Treatment of 2',3'-O,O-isopropylideneguanosinewith excess phosphorus trichloride in

Rib-5 '-p

'

c1

J . Engels and U . Krahmer, Synthesis, 1981, 485. H. A. Kellner, R. G. K. Schneiderwind, H. Eckert, and I . K. Ugi, Angew. Chem., Int. Ed. Engl., 1981, 20, 577. J . A. J . den Hartog and J . H. Van Boom, Recl.: J . R . Nerh. Chem. Soc., 1981: 100, 285.

Organophosphorus Chemistry

174

acetone, followed by hydrolysis and removal of the protecting group, gives N 2 -( 1-methyl- 1-phosphono)ethylguanosine 5’-monophosphate (4).’ The same substituent at N-2 is obtained when 2’,3‘,5‘-tri-O-acetylguanosine reacts with the same reagents under nitrogen. It is supposed that the nucleophilic amino-group attacks a reactive species such as ( 5 ) during these reactions. Unusual nucleosides which have been converted into their 5’ -monophosphates by using phosphoryl chloride in trialkyl phosphates include 1-(2deoxy-/3-~-ribofuranosyl)-2( 1H)-pyrimidine, -2( 1H)-pyridinone, and -4amino-2( 1H)-pyridinone l o and a series of l-(~-D-ribofuranosyl)-3-acetyl-5alkylpyridinium nucleosides. l 1 The three deoxynucleoside 5’-monophosphates were further converted into their 5’-triphosphates by the phosphoroand 1-(6morpholidate method. 1-(6-Deoxy-~-~-allofuranosyl)cytosine deoxy-a-L-talofuranosy1)cytosine have been converted into their 5’-mono,phosphates via condensation of their 2’ .3’-0,0-isopropylidene derivatives with 0-cyanoethyl phosphate and DCC, followed by deblocking. l 2 The corresponding 5 ’-diphosphates were prepared from the monophosphates, using diphenyl phosphorochloridate and orthophosphate. 3’-Amino-3’deoxyguanylic acid has been prepared by phosphorylation of 3’-(t-butyloxycarbonyl)amino-3’-deoxyguanosine with phosphoryl chloride in triethyl phosphate, followed by deblocking, and cyclized to the 3’,5’monophosphate, using a water-soluble carbodi-imide.I3 0

(10)

( 6 ) R1= (7)

R2= NH 2 ; B

= Ade,

R1= O H ; R 2 = N H 2 ; B

, C Me (9) R1=

R2= N

,,

\I

’

’

’

I?

Cyt, U r a , G u a ; K3= OH

= Ade,

Cyt, U r a , G u a ; R3= OH

= Thy;

R3= H

CH2

If a ribonucleoside is treated with phosphoryl chloride in trimethyl phosphate, and 7 M ammonia is added t o the resultant 5’-phosphorodichloridate, the nucleoside 5‘-phosphorodiamidate (6) is formed, and, being lo

‘I

I* l3

M. Honjo, T . Maruyama, S . Sato, and R . Marumoto, Tetrahedron Lett., 1981, 22, 2663. P. Kohler, M . Wachtl, and C. Tamm, Helv. Chim. Acta, 1980, 6 3 , 2 4 8 8 . E. J . Freyne, E. L. Esmans, J . A . Lepoivre, and F. C. Aldenveireldt, J. Carbohydr., Nucleosides, Nucleo tides, 1 9 8 1 , 8 , 2 6 1 . S. David and G. de Sennyey, J . Chem. SOC., Perkin Trans. I , 1982, 3 8 5 . M . Morr., Liebigs Ann. Chrm., 1 9 8 2 , 666.

175

Nucleotides and Nucleic Acids

electrically neutral, is easily separated from charged by-products on an ionexchange resin.14 Controlled hydrolysis of ( 6 ) in weak acid affords the phosphoramidate (7), which gives the corresponding nucleoside 5’-diphosphate on heating with orthophosphate in DMF. When 2’-deoxyribonucleosides, such as 5-flUO1-0- and 5-alkyl-2’-deoxyuridine, are subjected t o the same initial procedure, 3‘- and 5’-phosphorodiamidates as well as the 3’3’bis(phosphorodiamidates) are formed, and may be cleanly separated by partition chromatography on c e l l ~ l o s e Acidic . ~ ~ hydrolysis t o the corresponding phosphates then gives a convenient method for separating the isomeric phosphates in pure form. If 3’-O-acetyl-2’-deoxythymidine is first phosphorylated, as above, and the phosphorodichloridate is treated with aziridine or 2,2-dimethylaziridine in glyme and then deblocked with methanolic ammonia, the 5’-thymidinyl bis-( 1-aziridiny1)phosphonates (8) and (9), active against murine leukaemias, are formed.16 Adenosine 5‘-phosphoramidate seems to occur naturally in cells of Chlorella pyrenoidosa; its function there is unknown.” When 5’-AMP is treated with sterically hindered aromatic carboxylic acid chlorides such as 0-toluoyl chloride, 2-nitrobenzoyl chloride, or 2,4,6- tribromobenzoyl chloride, the mixed carboxylic phosphoric anhydrides are formed, and these react with alkyl- or aryl-amines to give the corresponding 5‘-phosphoramidates, or with alcohols to give phosphodiesters.’ In a study of the hydrolyses of uridylyl(5’ +N)-amino-acid esters and uridylyl( 5’ +N)-amino-acids in acid media, it was found that the former afforded 5’-UMP and amino-acid esters while the latter gave some uridine and orthophosphate, in addition to UMP and a m i n o - a ~ i d . ’ ~While ~ the former seem t o be hydrolysed following protonation at the phosphoamide nitrogen, thermodynamic measurements suggest that when an a-COOH group is present in the uridylyl(5‘ +N)-amino-acids, it participates in intramolecular nucleophilic catalysis, and uridine is !ost, with the formation of a reactive intermediate such as (1 0), which is then hydrolysed. If d(TpT) is treated first with diphenyl phosphorochloridate in DMF, in the presence of base, and then with ammonia or dimethylamine, the corresponding phosphoramidates (1 1) or (1 2) are formed.21 While treatment of (1 1) with acid leads to the re-formation of d(TpT), alkaline hydrolysis affords 2’-deoxythymidine and equal quantities of its 3’- and 5’-phosphoramidates. In contrast, (12) is stable t o alkali; alkaline breakdown of (1 1)

*’

l4 l5 l6 17

J . Tomasz, J . Carbohydr., Nucleosides, Nucleotides, 1981, 8 , 557. J . Ludwig and J . Tomasz, Synthesis, 1982, 32. L. Y. Hsiao and T. J . Bardos, J . Med. Chem., 1981, 24, 887. H. Fankhauser, G. A. Berkowitz, and J . A. Schiff, Biochem. Biophys. R e x Commun., 1981, 101, 524.

“ S . S. Tret’yakova, N . I. Sokolova, V. M. Risnik, E. V. Petushkova, and 2. A. Shabarova, Bioorg. Khim., 1981, 7 , 1218 (Chem. Abstr., 1981, 9 5 , 220255). l 9 B. Juodka, S. Sasnauskiene, V. Kirveliene, and Z. A. Shabarova, Bioorg. Khim., 1981, 7 , 2 4 0 (Chem. Abstr., 1981, 9 5 , 115 961). 20 B. Juodka, S. Sasnauskiene, and Z . Shabarova, J. Cai-bohydv., Nucleosides, Nucleotides, 1981, 8 , 519. 2 1 J. Tomasz and A. Sirnoncsits, Tetrahedron L e t t . , 1981, 2 2 , 3905.

176

Organophosphorus Chemistry B

Thy

B

I

( 1 1 ) B = T h y ; R1=

R2= H

(12) B

H ; R = Me

= Thy;

R1=

2

might thus involve the formation of metaphosphorimidate intermediates, e.g. (1 3).

The analysis of the chirality of [160,'70,'80] phosphate esters, using 31P n.m.r. spectroscopy, has been detailed." Treatment of meso -[ l-'80]hydrobenzoin with [ ' 7 0 ] p h o ~ p h o r y lchloride in pyridine, and then with 2',3'-di0 - acetyladenosine, affords separable diast ereoisomeric phosphotriest ers, e.g. ( 1 4) [the (Rp)-isomer] , which on hydrogenolysis and deacylation with ammonia yields adenosine 5'-[(S)-'60,'70,'s0]pho~phate ( 1 5 ) . When (15) is treated first with diphenyl phosphorochloridate and then potassium t-butoxide, cyclization t o CAMP occurs, and methylation using methyl iodide in DMSO then affords N'-methyladenosine 3',5'-phosphate methyl ester, in which the methyl group may be on either axial o r equatorial oxygen o n the 1,3,2-dioxaphosphorinan ring. Since 1 7 0 produces considerable broadening of the phosphorus resonance, only those isomers of the cyclic phosphate that are formed by elimination of 170in the cyclization process give strong signals in the 31P n.m.r. spectrum and t h e shift of the signal of phosphorus that is bonded t o " 0 allows the position of the oxygen to be assigned as equatorial o r axial. Since the absolute stereochemistry of (14), and hence of (1 5), was already known from X-ray data, the determination of the stereochemistry in the cyclic phosphate shows that the process of cyclization proceeds with > 94% inversion of configuration at phosphorus. When each of the separated diastereoisomers of 5'-0-monomethoxytrityl2'-deoxythymidine 3'-[ 1 7 0 ]phosphoranilidate 4 -nitrophenyl ester ( 16) is treated with sodium hydride and C"02, the anilino-group is replaced by " 0 with retention of configuration; after detritylation, the resulting compound (17) is a substrate for bovine spleen exonuclease. The 2'-deoxythymidine 3'-[ 1 6 0 , ' 7 0 , ' 8 0 ] p h o ~ p h a t ethat is formed has been analysed by cyclization, methylation, and 31P n.m.r. spectroscopy, as described above, t o show that the configuration at phosphorus is retained during the enzymic hydrolysis. Interestingly, if the analogous nitrophenyl thiophosphate is used as substrate, a different product, i.e. d [Tp(S)Tp(S)(C,II4N0,)], is formed, the 5'-hydroxygroup of one molecule having displaced the 4-nitrophenyl group o n a n ~ t h e r . ' ~2'-Deoxythymidine 5'-(4-nitrophenyl ['70,'80]phosphate), prepared and used in a similar way t o the 3'-isomer, has been employed as a sub-

'' R. 23

L. Jarvest, G . Lowe, and B . V . L. Potter, J . Chem. Soc., Perkin Trans. I , 1981,

3 186. S . Mehdi and J . A. Gerlt,J. A m . Chem. Soc., 1981, 103, 7018.

177

Nucleotides and Nucleic Acids

0

\,P-O-(

Ado-5’)

H

R1ovT 0

I

0=P-R2

1

a-j 0

OC6H4N02-4 I ( 1 6 ) R1=

MMTr; R2= NHPh

(17)

H ; R’=180

II

dThd-5’ 1

0-P-O-(

AH

H

(20)

J?/& 0

O-P-O-(dThrl-Fi’)

I

, RL-i

/CH,CH,R‘ A

\

0

(fJ NI

Rib-5

NH- N=N

’-p

(21) X

=

Rib-5’( 2 2 ) R1=

NO2 o r S03H

p

P(0)(NH2)(0H):

R2= C1

( 2 3 ) 9.1= H ; R 2 = C 1

(24) R 1 = P(O)(NH?)(OH);

R2= N 7 - G W

strate for snake venom phosphodiesterase (when hydrolysis occurs with retention of configuration at phosphorus) 24 and for staphylococcal nuclease (when hydrolysis occurs with inversion at p h o s p h o r ~ s ) . ~In ’ the latter case, 24

25

S. Mehdi and J. A. Gerlt,J. Biol. Chem., 1981, 256, 12 164. S . Mehdi, a n d J. A. Gerlt, J. A m . Chem. SOC., 1982, 104, 3223.

178

Organophosphorus Chemistry

the chiral phosphoryl group of the 4-nitrophenyl phosphate that is released by the enzyme is transferred t o chiral propane-l72-dio1 by using alkaline phosphatase, and the resultant phosphate is cyclized, methylated, and analysed as above. Nucleoside 3’-(S- methyl phosphorothioates) have been prepared by treatment of base- protected 2 ’ 3 ’-di- 0-(4 - methoxytetrahydropyran-4-y1)ribonucleosides with 2-( methylthio)-4H-l,3,2-benzodioxaphosphorin 2-oxide (18) and aniline in DMF at elevated temperature, followed by deblocking in acid.26 The phosphorothioate esters are substrates f o r ribonucleases, and estimation of the methylthiol that is released by using Ellmann’s reagent allows these compounds t o be used by quantitate ribonuclease activity. When t h e 1-naphthyl ester of 5’-[ m e t h ~ l - ~thymidylic H] acid is incubated briefly with snake venom phosphodiesterase from Crotalus durissus terrificus or 5’-nucleotide phosphodiesterase from Sinapis alba, radioactivity is bound t o the protein.27 Hydrolytic studies suggest that a histidinyl- o r a tyrosylthymidylate intermediate may have been formed, an observation which accords well with a double-displacement mechanism for snake venom phosphodiesterases that is suggested by the results described above.24 2’-Deoxythymidine 5’-(4-methylumbelliferyl phosphate) ( 1 9) is a substrate for snake venom phosphodiesterase, and the corresponding 3’-phosphate ester is a substrate for spleen phosphodiesterase.28 Hydrolysis releases 4-methylumbelliferone in each case, with an accompanying increase in fluorescence, affording a convenient method f o r detecting nucleotide 3’- and 5’-phosphodiesterases. 2’-Deoxythymidine 5‘-(5-iodoindol-3-yl phosphate) (20), prepared by esterifying 3‘-0-acetyl-2’-deoxythymidine 5’-phosphate with 5-iodoindolol (using DCC) and subsequent d e b l ~ c k i n g ,is~ ~reportedly a useful anti- tumour agent. In an investigation of potential pro-drugs of ara-cytidylate, a series of lipophilic 5‘-(alkyl phosphate) esters of ara-cytidine and its N4-palmitoyl and N4-stearoyl derivatives has been synthesized by treating the nucleosides with phosphoryl chloride in trialkyl phosphate, and the resulting 5 ’-phosphorodichloridates with the appropriate alcoh01.~’ A similar series of cytidine S’-(alkyl phosphate) esters was transformed into the corresponding 3 ‘ - 0 acyl- 2,2 ’-anhydrocy tidine 5’- (alkyl phosphate) esters by treatment with acyl chlorides and boron trifluoride etherate in acetonitrile. ara -Cytidine 5’-(glyceryl phosphate) showed toxicity t o L1210 murine leukaemia cells in culture that was comparable t o that of ara-cytidylate. Novel dinucleoside monophosphates that are worthy of mention include adenyly 1( 3 ’ -5 ’ )-3 ’-0 - met hy lguanosine and guany ly 1(3 ’-5 ’ )-3 ‘-0 -methylguanosine, prepared as potential inhibitors of replication in RNA viruses,31 and 2’-deoxy-2’-fluoroguanylyl( 3’-5 ’ )uridine, prepared as a non-hydrolysable 26

27 28 29

30 31

D. Saba and C. A. Dekker, Biochemistry, 1981, 2 0 , 5461. C.U. Rugevics and H. Witzel, Biochem. Biophys. Res. Commuri., 1982, 106, 7 2 . D. M. Hawley, K. C . Tsou, and M . E. Hodes, Anal. Biochem., 1981, 1 1 7 , 18. L. Pan, C. Ding, and Q. Guan, Shengwu Huaxue Y u Shengwu Wuli Jinzhan, 198 1 , 4 0 , 6 4 (Chem. Abstv., 1 9 8 2 , 9 6 , 85 926). A. R o s o w s k y , S.-H. Kim, J . Ross, and M . M . Wick, J . Med. Chem., 1982, 2 5 , 171. G . Ekborg and P. J . Garegg, A c t a Chem. Scand., Ser. B, 1980, 34, 7 5 3 .

Nucleotides a n d Nucleic A cids

179

substrate analogue for RNase T I .32 Phosphotriester syntheses were employed in each case. 5‘-0-Monomethoxytrityl-02,2’-anhydrouridine 3’-monophosphate and 3’-O-acetyl-02,2’-anhydrouridine have been coupled, using 2,2‘dipyridyl diselenide arid triphenyl phosphite, t o give, after deprotection, 02,2’-anhydrouridylyl(3’-5’ )-02,2’-anhydrouridine, which, on alkaline ara-Uridylylhydrolysis, in turn afforded ara-~ridylyl(3’-5’)ara-~ridine.~~ (3 ’-5 ’ )adenosine was prepared similarly. Other novel ara-nucleosidecontaining species include ara-adenylyl(3’-5‘ )ara-adenylyl(3 ‘-5‘ )araadenosine 34 and its 2’-5’-linked a n a l ~ g u e , ~both ’ o f which were synthesized unambiguously by phosphotriester methods. The monoanionic form of guanylic acid exhibits general acid catalysis in the hydrolysis of the diastereoisomeric benzo [a]pyrene-7,8-diol9,1O-epoxides in aqueous dioxan, and is much more efficient in this respect than orthophosphate monoanion, which has a similar pKa value.36 The difference may be due t o charge-transfer association between the purine base and the aromatic rings of the carbocycle. When guanylic acid is treated with 4-nitroo r 4-sulpho-benzenediazonium ion in weakly alkaline solution, at room temperature, benzenediazonium phosphate salts (which explode o n drying) seem t o be formed initially, but N2-triazenes (21) are formed, in low yield, o n prolonged i n c ~ b a t i o n .At ~ ~ 95 ‘C, the corresponding 8-aryl-guanylic acids are formed in similarly low yields, via free-radical reactions. Guanylic acid reacts with phosphoramide mustard, in weakly acidic media, t o yield unstable N-alkylated products, viz. (22)-(24), in low yield.38 Mechanism-based inhibitors of thymidylate synthetase continue t o stimulate interest, and investigators employing 1-(2’-deoxy-P-~-ribofuranosy1)-8-azapurin- 2-one 5 ’-m o n ~ p h o s p h a t e ,5-nitro~~ 2 ’-deoxyuridine 5 ’-phosphate ,40 and 5-fluoro-ara -uridylic acid 41 have all reported time-dependent inactivation of the enzyme under appropriate conditions. The last-named inhibitor was prepared by treating 5-fluoro-O2,2’-anhydrouridine with pyrophosphoryl chloride in acetonitrile, followed by acidic hydrolysis of the product. Thymidylate synthetase is also inhibited by certain 5-alkynyl- 2’deoxyuridylates, some of which cause time-dependent i n a ~ t i v a t i o n 43 .~~ 32

33 34

35

36

31 38 39 40

M. Ikehara and J . Imura, Chem. Pharm. Bull., 1981, 29, 2408. H . Takaku and Y . Enoki, Chiba K o g y o Daigaku K e n k v u Hokoku, Riko-hen, 1980, 2 5 , 45 (Chem. Abstr., 1981, 9 5 , 25 476). C. Gioeli, J . B. Chattopadhyaya, A. F. Drake, and B. Oeberg, Chem. Scr., 1982, 19, 13 (Chem. A b s t r . , 1982, 96, 2 1 8 175). M . Kwiatkowski, C. Gioeli, B. Oeberg, and J. B. Chattopadhyaya, Chem. Scr., 1981, 18, 95 (Chem. Abstr., 1981, 9 5 , 2 2 0 2 5 8 ) . S . C. Gupta, T. M . Pohl, S . L. Friedman, D. L. Whelan, H . Yagi, and D. M . Jerina, J. A m . Chem. SOC., 1982, 104, 3101. M.-H. Hung and L. M . Stock, J. Org. Chem., 1982, 47, 4 4 8 . V . T. Vu, C. C. Fenselau, and 0. M . Colvin, J. A m . Chem. Soc., 1981, 103, 7 3 6 2 . T . I . Kalman and D. Goldman, Biochem. Biophys. Res. Commun., 1981, 102, 652. L. Maggiora, C. T.-C. Chang, P. F . Torrence, and M . P. Mertes, J . A m . Chem. Soc., 1981, 103, 3192.

41

42

43

C. Nakayama, J . Wataya, D. V. Santi, M . Saneyoshi, and T. Ueda, J. Med. Chem., 1981, 24, 1161. P. J . Barr, P. A. Nolan, D. V . Santi, and M. J. Robins, J. Med. Chem., 1981, 24, 1385. P. V . Danenberg, R. S . Bhatt, N . G . Kundu, K. Danenberg, and C . Heidelberger, J . Med. Chem., 1981, 24, 1537.

7

180

Orga no p h osph orus Che mis try

5-Ethynyl- 2’- deoxyuridylate was prepared from the corresponding nucleoside by employing deoxythymidine kinase from Escherichia coli, and 5-(3hydroxypropyny1)- and 5-(4 -hydroxybut-l-ynyl)-2’-deoxyuridylateby using carrot p h o s p h ~ t r a n s f e r a s e . A ~ ~ large number of 8-arylthio-, 8-aralkylthio-, and 8-alkylthio-derivatives of AMP and IMP have been prepared, using 8-bromoadenylic acid as starting material, and they proved t o be competitive inhibitors of inosinic acid dehydrogenase from E. coZi.44 Cyclic Nuc1eotides.-Some novel derivatives of adenosine 2 ’ 3 ’-cyclic phosphate and 3’,5’-cyclic phosphate have been d e ~ c r i b e d . ~When ’ 3’-iodo-3’deoxy-xylo -adenosine is treated with thioohosphoryl chloride in triethyl phosphate, and then with alkali, 3’-thio-3’-deoxy-xylo-adenosine 3’,5’cyclic phosphate (25) is formed, in good yield, via ring-closure of the intermediate 2’,3’-anhydro-ribo-adenosine 5 ’-thiophosphate. If 3’-thio- 3‘-deoxyadenosine is phosphorylated similarly, and the resultant phosphorodichloridate is treated with alkali under nitrogen, the corresponding 3’,5’-cyclic phosphate is formed in low yield. Similar phosphorylation of 2’,3’-anhydrolyxo-adenosine leads, after alkaline treatment, t o formation of a mixture of 3’- chloro- 3’- deoxy-am-adenosine 2’,5’-cyclic phosphate (26) and 2‘-chloro2’-deoxy-xylo -adenosine 3’,5’-cyclic phosphate (27). Here the hydrogen chloride that is released by attack of the 5’-OH o n phosphoryl chloride opens the epoxide ring t o afford the chloro- sugar nucleoside phosphorodichloridates, and alkali effects ring-closure. Similar treatment of 3’-azido-3’-deoxyara-adenosine yields the corresponding 2’,5’-cyclic phosphate (28), which is easily reduced t o (29). Phosphorus-3 1 n.m.r. evidence indicates that, unlike its 3’-oxygen analogue, ( 2 5 ) does not have the cyclophosphate ring in a chair conformation, but rather a twisted boat, a deduction confirmed by X-ray data. Starting from 8-bromoadenosine 3 ’,S‘-cyclic phosphate, and using standard methods t o alter substitution on the rings of the base and of the sugar, 2’-azido-, 2‘-amino-, and 2’-N-acylamino-2’-deoxy-8-hydroxyadenosine 3‘,5’-cyclic phosphates (30)-(32) have been ~ y n t h e s i z e d Phosphoryla.~~ tion of 7-deazaguanosine by Yoshikawa’s method and ring-closure of the resultant 5 ’-monophosphate with DCC affords 7-deazaguanosine 3’,5’-cyclic phosphate, which is hydrolysed by cyclonucleotide phosphodiesterase rather more rapidly than c G M P . ~ ~ Methyl 2’-deoxythymidine 3’,5‘-cyclic phosphite (33) is conveniently oxidized, using azobisisobutyronitrile and l 8 0 2 in benzene, t o afford methyl 2’-deoxythymidine 3’,5’-cyclic [“O]phosphate (34) as a mixture of diastereoisomers that are separable by m.p.1.c. o n silica. Demethylation, using t-butylamine, then affords the individual diastereoisomers of 2’-deoxythymidine 3’,5‘-cyclic [‘‘O]phosphate (35).48 Similar nearly quantitative reactions were 44

45 46

47

E. B. Skibo and R . B. Meyer, jun., J . Med. Chem., 198 1, 2 4 , 1 1 5 5 . M. Morr, L . Ernst, and R. Mengel, Liebigs A n n . Chem., 1 9 8 2 , 65 1 . N . N . Gulyaev, L. A. Mazurova, and E. S. Severin, Bioorg. K h i m . , 1 9 8 1 , 7, 552 (Chem. Abstr., 1981, 9 5 , 9 8 196). Q.-H. Tran-Thi, D. Franzen, and F. Seela, A n g ~ w Chem., . Znt. Ed. Engl., 1982, 2 1 , 367.

4R

T. M . Gajda, A. E. Sopchik, and W. G . Bentrude, Tetrahedron Lett., 1981, 2 2 , 4 1 6 7 .

Nucleotides and Nucleic Acids

181 Ade

Ade

(25) X

I

I

OH

R

R = S ;

R = OH

(26) R,

( 2 7 ) X = 0;R = C 1

= C1

( 3 8 ) R = N3

(29) R

=

NH2

Thv

(30)

R

=

N3

( 3 1 ) R = NH

( 3 3 ) X a b s e n t ; R = OMe (34) X

2

( 3 2 ) R = NHCOCH3,

NHCOCH2C1,

o r NHCOC6H4S02F-4

=I8O; R

=

OMe

( 3 5 ) X =l8O; F = OH ( 3 6 ) X a b s e n t ; R = WMe2

observed for (36), which affords (33) o n methanolysis, and thus, by using isotopically labelled methanol, a convenient route t o 2’- deoxythymidine 5’-[’60,’70,’80]pho~phate~ of known chirality is available. The stereochemical courses of the hydrolyses of cAMP and o f the (Sp}and (Rp)-diastereoisomers of adenosine 3’,5’-cyclic thiophosphate (CAMPS) by cAMP phosphodiesterases from bovine heart and baker’s yeast have been e ~ t a b l i s h e d . ~Essentially, ’ (37) and its 170-containing isomers were prepared by cyclization of (15), and used as substrates for the enzymes in [170]H20. The chirality of the resultant AMP was analysed by the method described above.22 Using CAMPS, the (Sp)- (38) and (Rp)-isomers (39) were used as substrates for the enzymes in H2I80 [the bovine enzyme hydrolyses only (38)] and t h e resultant adenosine 5’-[180]thiophosphate was converted into adenosine 5 ’ - [ ~ ~ - ’ ~ 0 , c r - t htriphosphate, io] using adenylate kinase, which phosphorylates only the pro-R oxygen of AMPS, and pyruvate kinase; the chirality at P, was analysed by using 31P n.m.r. Using both enzymes, inversion of configuration at phosphorus was established, suggesting ‘in- line’ mechanisms of hydrolysis in each case. This was observed for both (38) and (39) in the case of the enzyme from baker’s yeast; for the first time, it has 49

R . L. Jarvest, G . Lowe, J . Baraniak, and W. J . Stec, Biochem. J . , 1982, 203, 461.

182

Organophosphorus Chemistry

been shown that both diastereoisomers of a phosphorothioate are hydrolysed by t h e same stereochemical course. A re-investigation of the reaction o f cAMP with ethylene oxide has shown that alkylation occurs at N-1 of t h e base rather than o n the cyclic phosphodiester group.’’ The interaction of cAMP analogues that are modified in base, sugar, and cyclophosphate moieties with the ‘stable’ CAMP-binding site of CAMP- dependent protein kinase type I suggests that specific hydrogen- bonds t o 3‘-oxygen, 5’-oxygen, and the 2’-OH group, and an ion-pair interaction between an equatorial oxyanion o n the cyclophosphate ring and a positively charged amino-acid side-chain, are involved: (38) was bound much more strongly than (39).”

OH

(37)

x

=%;

(38)

x

=

Y

= 160

s;

Irradiation of 5’- deoxy- 5’-( pheny1thio)guanosine 2’,3‘-cyclic phosphate with U.V. light affords 5’- deoxy- 8,5 ’-cy cloguanosine 2 ’,3 ’-cyclic phosphate, giving the corresponding 3’-phosphate which is a substrate for ribonuclease T1, (40) as product.52 Since (40), which is fixed in the anti conformation, interacts with RNase T 1 in an identical manner t o 3’-guanylic acid, as indicated spectrophotometrically, a previous suggestion that the enzyme interacts only with t h e syn form of 3’-guanylic acid may require revision. An unusual cyclic nucleotide phosphodiesterase which appears t o hydrolyse both purine and pyrimidine nucleoside 2‘,3’- and 3’,5’-cyclic phosphates at a single species of catalytic site has been reported.53 Hydrolysis of the 2’,3’-cyclic nucleotides afforded both 2’- and 3’-phosphate products in varying proportions, depending o n the substrate, but only 5’-monophosphates were obtained from 3‘,5’cyclophosphate substrates. Discontinuities in the van’t Hoff and Arrhenius plots of the rate of hydrolysis of cytidine 2’,3’-cyclic phosphate at pH 7 and pH 5 . 5 , at 4 OC, catalysed by bovine pancreatic ribonuclease A, are thought t o result from a change in structure of the protein, resulting from the alteration in the structure of water a t this t e m p e r a t ~ r e . ’ ~ so ” 52

J . Beres, E. Moravcsik, a n d L . Radics, Heterocycles, 1981, 16, 195 1. R. J . W. d e Wit, J . H o p p e , W. J . S t e c , J . Baraniak, a n d B. Jastorff, Eur. J. Biochem., 1982, 1 2 2 , 95. A. Matsuda and T . Ueda, N i p p o n Kagaku Kaishi, 1981, 845 (Chem. A b s t v , , 1981, 9 5 , 169 660).

53 54

D. M . Helfman a n d J . F. K u o , J . B i d . Chem., 1982, 2 5 7 , 1044. J . A . Biosca, F. Travers, a n d C. M. Cuchillo, Eur. J . Biochern., 1982, 1 2 4 , 151.

Nucleotides and Nucleic A cids

183

Affinity Chromatography.-In a new general method for the immobilization of enzymes and affinity ligands o n hydroxy-group-carrying supports (e.g. agaro se , cellulose, dio 1- silica, glycophase-glass, o r hydro xye t hyl me thacrylate), t h e support is treated with 2,2,2-trifluoroethanesulphonylchloride (tresyl chloride) in dry acetone, washed with acetone and dilute HC1, and the desired affinity ligand is then coupled t o the activated support in neutral conditions, at low temperature.” N6-(6-Aminohexyl)-AEIP, coupled t o tresylsilica in this way, showed good affinity properties, separating albumin, lactate dehydrogenase, and horse liver alcohol dehydrogenase with high efficiency. Two N7-alkylated GDP affinity columns have been d e ~ c r i b e d . ’2‘,3‘-0,0~ [ 1-(2-Carboxyethyl)ethylidene]guanosineethyl ester was converted into its 5’-pyrophosphate by standard methods, saponified, and methylated at N-7, using methyl iodide, t o afford (41). Also GDP was alkylated at N-7 by 6-iodohexanoic acid in DMSO t o give (42). Both (41) and (42) were coupled t o Sepharose 4B, using a water-soluble carbodi-imide, and the resultant resins were used for the purification of 24K ‘cap7-binding protein from rabbit reticulocytes, protein retained o n the resins being eluted by washing with N 7-met h y 1- G DP.

Affinity chromatography is now so widely employed, frequently using commercially available affinity media, that it would be superfluous merely t o list t h e instances of its use. Some cases in which the technique has affected a particularly tricky separation, o r afforded a spectacular degree of purification in a single step, are worthy of mention, however. N6-(6-Aminohexyl)-5‘AMP-Sepharose has been used t o separate rat sperm lactate dehydrogenase isozyme C4 from other LDH isozymes that are present in the tissue.57 Orotidylic acid, when oxidized (using periodate) and coupled t o adipic dihydrazide which had previously been allowed t o react with CNBrSepharose, affords a column that allows rapid purification of orotate ” 56 57

K. Nilsson and K. Mosbach, Biochem. Biophys. Res. Commun., 1981, 102, 449. K. M. Rupprecht, N . Sonenberg, A. J . Shatkin, and S . M . Hecht, Biochemistry, 1981, 20, 6570. A . A. Ansari, Biochem. J., 1 9 8 1 , 1 9 9 , 75.

184

Organophosphorus Chemistry

phosphoribosyltransferase from E. coli K 1 2.58 8-(6- Aminohexy1)amino-GMP, bonded t o 4% beaded agarose, was employed t o purify a hypoxanthinexanthine-guanine phosphoribosyltransferase activity that is present in Eimeria tenella, s9 and guanylic acid that is linked via 3,3’-iminobis(propy1amine) t o Sepharose 4B has been used t o purify hypoxanthine-guanine phosphoribosyltransferase from baker’s yeast.60 8-( 2-Aminoethy1amino)CAMP-Sepharose 4B facilitated the purification of a phosphodiesterase from porcine liver that hydrolyses cCMP, CAMP, and cGMP,~’and cGMP, bound t o epoxy-activated Sepharose, could be used t o purify a cGRIP- stimulated cyclic nucleotide phosphodiesterase from bovine tissues.62 2’,5’-ADP-Sepharose has been used t o isolate hexose 6-phosphate dehydrogenase of rat liver microsomes, the enzyme being eluted by washing with its cofactor, NADP+.63 ATP, when linked t o agarose via adipic dihydrazide as a spacer arm, has been used t o probe different ATP-binding domains in myosin subfragment 1 (SF-1) and the modulation of their behaviour by alkali light chains.@ Ribosomal 5s RNA, or its fragments UI-G41 and C42-U120, immobilized o n epoxy-activated Sepharose 2B, have been used t o deduce the specificity of binding of 50 S ribosomal proteins t o different domains o n 5s RNA.65

(44) (43)

Cellulose may be conveniently activated for coupling by treatment with butane-l,4-diol diglycidyl ether (43) in alkali at room temperature, in the presence of borohydride ion. When the resulting material is incubated with DNA in weak alkali at room temperature, the nucleic acid is bound t o the cellulose, supposedly via attack by imino- o r amino-groups o n the bases, with high efficiency and relatively little degradation.66 Double-stranded DNA, coupled t o cellulose by this method, could be used t o purify complementary RNA from total poly(A)-enriched RNA by affinity chromatography. If cellulose papers, activated as described above, using (43) or an epihalohydrin 1e.g. (44)], are treated with an aminophenol or an arninothiophenol in alkaline solution, arylamine---cellulose papers are formed which, after diazotization, are useful for coupling and hybridization of nucleic acids.67 In terms of DNA-binding capacity, diazo-paper that was derived via treatment with 2-aminothiophenol gave the best results, binding being optimal at pH 4. 58 59

6o 61 62

63 64 65 66

67

G . Dodin, F E B S Lett., 1981, 1 3 4 , 2 0 . C. C. Wang and P. M. Simashkevich, Proc. Natl. Acad. Sci. U S A , 1981, 7 8 , 6618. R . L. Nussbaum and C. T. Caskey, Biochemistry, 1981, 20, 4 5 8 4 . D. M . Helfman, M . Shoji, and J . F. Kuo, J. Biol. Chem., 1981, 2 5 6 , 6 3 2 7 . T . J . Martins, M . C . Mumby, and J . A. Beavo,J. Biol. Chem., 1982, 2 5 7 , 1973. Y . Hino and S. Minakami, J. Biol. Chem., 1982, 2 5 7 , 2 5 6 3 . M. Burke, H . L. Wang, and M. Sivaramakrishnan, Eur. J. Biochem., 1981, 118, 389. J . Sedman, T. Maimets, M.Ustav, and R . Villems, FEBS Lett., 1981, 1 3 6 , 2 5 1 . L. G . Moss, J . P. Moore, and L . Chan, J. Biol. Chem., 1981, 2 5 6 , 12 6 5 5 . B. Seed, Nucleic Acids Res., 1982, 1 0 , 1799.

Nucleotides and Nucleic Acids

185

Such activated paper is useful for the detection of electrophoretically separated RNA by blot transfer and hybridization. DNA that is immobilized o n cellulose may be used t o determine restriction endonuclease activity, if other nucleases are absent. The DNA fragments that are cleaved from the immobilized material are quantitated spectrophotometrically.68 Oligo(deoxyribonucleotides) that are linked t o cellulose have been used t o probe specificity at the DNA-binding sites of receptors of steroid hormones in the Protected oligomers of 2’-deoxyguanylic acid that have a free 3’-OH terminus have been coupled t o cross-linked poly(viny1 alcohol), using TPS-C1, and then deacylated, in order t o prepare oligo(dG) columns for isolating cytidylate-rich DNA fragment^.^' Poly(A)-Sepharose has been used t o isolate uridylate-rich RNA fragments from a population of RNA molecules from which 3‘-poly(A) tails had been removed by incubation with oligo(dT) and ribonuclease H.71 Antipoly(1) - poly(C) antibodies from rabbits, bound t o CNBr-activated cellulose, may be used for t h e specific separation o f double-stranded RNA.72 An account of quantitative studies in affinity elution chromatography of enzymes includes examples in which nucleotides are utilized as eluting l i g a n d ~ .As ~ ~an example of affinity elution, rec A protein from E. coli, which is required for homologous genetic recombination, is quantitatively eluted from the population of protein molecules that are retained by a single-stranded- DNA-cellulose column by washing with ATP. 74

3 Nucleoside Polyphosphates Chemical Synthesis.-In a search for novel, isopolar analogues o f ATP, adenosine 5’-phosphoromorpholidate was treated with the bis(tributy1ammonium) salts of dichloromethylenebisphosphonic acid, fluoromethylenebisphosphonic acid, and difluoromethylenebisphosphonic acid t o afford (45), (46), and (47), respectively. 75 The introduction o f electronegative groups

( 4 5 ) R1= ( 4 6 ) tll=

(47)

F; R = H

( 4 9 , ) R = Ado-5‘

(50) R

=

Guo-5’

R1= R 2 = F

( 4 8 ) R1= 68

R2= C 1 2

R2= H

A. A. Janulaitis and D . P Vaitkevitchius, Anal. Biochem., 1981, 116, 116.

S. C. Gross, S. A. Kumar, and H . W. Dickerman,J. Biol. Chem., 1982,257,4738. ’’ H.Schott and H. Watzlawick, Makromol. Chem., 1981,182,825. 7 1 M. W. Wood and M. Edmonds, Biochemistry, 1981,20, 5359. 72 Y. Kitagawa and E. Okuhara, Anal. Biochem., 1981,115, 102. l 3 R. K. Scopes, Anal. Biochem., 1981, 114, 8. 7 4 M. M. Cox, K. McEntee, and I . K . Lehmann, J. Biol. Chem., 1981,256, 4676. 7 s G. M. Blackburn, D. E. Kent, and F. Kolkmann,J. Chem. SOC., Chem. Commun.,

69

1981, 1188.

186

Organophosphorus Chemistry

at the methylene bridge shifts the value of pKa of the fourth ionization constant from 8.4 in the methylenebisphosphonate (48) t o 7.0, 7.4, and 6.7 in (45), (46), and (47), respectively, and hence t o values more comparable with the value of 7.1 exhibited by ATP; the chemical shifts of Pp and P, in the 31P n.m.r. spectra indicate that the electronegativity of the bridge group has altered in such a direction as to make (45), (46), and (47) more realistic analogues of ATP than (48), in terms of charge distribution. Treatment of adenosine and of guanosine 5’-phosphorimidazolidates with peroxodiphosphate affords the py-peroxy analogues of ATP and GTP, (49) and (SO), r e ~ p e c t i v e l y The . ~ ~ 31P n.m.r. spectra of these compounds exhibit the anticipated changes in chemical shift and coupling constant at Pp and P,. The analogues are stable in neutral or basic solution, and oxidation of (49) at N-1 , for instance, does not seem to occur. Analogue (49) forms a far less stable complex with Mg2+ than does ATP, but it is not clear whether this is due to altered electron distribution in the polyphosphate chain or because the seven-membered ring which the formation of a P,y-chelate (which is the normal co-ordination mode in MgATP) would require would be sterically disfavoured. Steric reasons may also account for (49) being a generally poorer substrate than ATP in reactions involving adenylyl transfer and phosphoryl transfer, and comparative leaving-group efficiencies may also be involved. The GTP analogue (50) inhibits ribosome-dependent synthesis of peptides. A review of the stereochemistry of enzymatic reactions of phosphates, covering the field up to early 1981, has appeared.77 Diastereoisomers of guanosine 5 ’ - 0 - ( 1-thiotriphosphate) and guanosine 5’-0-(2-thiotriphosphate) have been ~ y n t h e s i z e d . Guanosine, ~~ when treated with thiophosphoryl choride in trimethyl phosphate, with an aqueous work-up, yields its 5’-phosphorothioate, GMPS, which o n treatment with diphenyl phosphorochloridate and orthophosphate affords (Rp)- and (Sp)-GDP&S as a mixture, separable by h.p.1.c. Incubation of the mixture with phosphoglycerate kinase and a quantity of 173-diphosphoglycerateequal to the proportion of (Sp)-GDPaS in the mixture affords (Sp)-GTPaS of 95% purity. (Rp)-GTP&S of 85% purity may be prepared by incubating the GDPaS mixture similarly with succinylCoA synthetase, succinyl-CoA, and orthophosphate. Ion-exchange chromatography may then be employed t o obtain pure samples of each isomer. Incubation of GDPPS with acetate kinase and acetyl phosphate affords only (Rp)-GTPPS, together with a GTP contaminant which may be removed by treatment with myosin t o give the pure diastereoisomer. When used as a substrate for pyruvate kinase and phosphoenolpyruvate, GDPPS yields (Sp)-GTPPS and (Rp)-GTPPS in a ratio of 7 : 3, and the (Rp)-isomer may be preferentially removed with glycerol kinase, leaving the pure (Sp)-isomer. These nucleotides were examined as substrates for acetate kinase, RNA polymerase, and succinyl-CoA synthetase. The full paper detailing syntheses IATPyS and [ P - l 8 0 1IADPPS has of the diastereosiomers of [ py-180,y-1801 76 l7 78

M . S. Rosendahl and N . J . Leonard, Science, 1982, 2 1 5 , 81. P. A. Frey, Tetrahedron, 1982, 38, 1541. B. A. Connolly, P. J. Romaniuk, and F. Eckstein, Biochemistry, 1982, 2 1 , 1983.

187

Nucleotides and Nucleic Acids

now appeared,79 but the salient features have already been covered in other Reports in this series,s0 and will not be repeated here. (Sp)-[y-"Ol]ATP$3, upon incubation with ApA and T4 polynucleotide kinase, transfers the thiophosphate group t o the 5'-OH of ApA. Cleavage of the product with snake venom phosphodiesterase gives [ C Y - ~ ~ O I A Mwhich P~S, is phosphorylated (using adenylate kinase and pyruvate kinase) t o (Sp)[a-'80]ATPaS.81 Analysis of this material by methods described previously shows that l80is in the ap bridge position, and thus phosphoryl transfer that is catalysed by T4 polynucleotide kinase proceeds with P~S, inversion, probably via an in-line displacement. ( S P ) - [ ~ - ~ ~ S ] A Tprepared from [35S]AMPS in the same way, is a substrate-for adenylate cyclase from bovine brain, affording ( R p ) - [ 35S]cAMPS, and cyclization thus occurs with inversion of the configuration at phosphorus.82 (Sp)-dATPaS has been copolymerized, together with dTTP, on a poly[ d(A-T)] template, using bacteriophage-T7-induced DNA polymerase, and the configuration in the product has been analysed, using 31P n.m.r., t o show that polymerization is accompanied by inversion at Pa.83 S

o

NC( C H

\

11 ,P-0-( ~2 0 - ~ - ~ f l @ I 0

0

Ado-5' )

i

11

ey P-0-(

A

N C ( C H ~) 2 ~ - ~ - ~ ~ '

____)

I

OH

OH

(51)

Ado-5' )

(57)

0

0

(53)

(54)

Reagents: i, CNBr; ii, H, " 0 ; iii, O H Scheme 1

Treatment of AMPS with diphenyl phosphorochloridate and 0-cyanoethyl phosphate affords the (Rp)- and (Sp)-diastereoisomers of adenosine 5'-(pcyanoethyl a-thiodiphosphate) [(S 1) is the (Rp)-isomer], which are 79 80

J. P. Richard and P. A. Frey, J. Am. Chem. SOC., 1982, 104,3476. J. B. Hobbs in 'Organophosphorus Chemistry' (Specialist Periodical Reports), ed.

D. W. Hutchinson and J. A. Miller, The Royal Society of Chemistry, 1980,Vol. 1 1 , p.150; 1981,Vol. 12,p. 164; 1982,Vol. 13,p. 175. F. R. Bryant, S. J. Benkovic, D. Sammons, and P. A. Frey, J. Biol. Chem., 1981, 2 5 6 , 5965. '' F. Eckstein, P. J. Romaniuk, W. Heideman, and D. R. Storm, J. Biol. Chem., 1981, 256,9118. 8 3 R. S. Brody, S. Adler, P. Modrich, W. J . Stec, Z. J . Lesnikowski, and P. A. Frey, Biochemistry, 1982,21, 2570.

Organophosphorus Chemistry

188

separable by reverse-phase h.p.l.c.p4 When (5 1) is treated with cyanogen bromide in H2180, the thiocyanate group that is formed in (52) is displaced by the isotopically substituted water t o give adenosine 5 f - ( 0-cyanoethyl [a-1801Idiphosphate) (5 3); o n alkaline deblocking, this affords (Sp)[a-1801]ADP (54) (Scheme 1). Analysis of the absolute configuration of (54) shows that the displacement of sulphur is accompanied by inversion o f configuration at P,, as indicated. The sulphur is displaced smoothly and in good yield. Clearly, by starting from chiral [170]AMPS, the method can be applied t o yield chiral [160,'70,'80]phosphates. The (Rp)-diastereoisomer of (54),i.e. compound ( 5 5 ) , has been prepared by treating (Sp)-ADPaS with NBS in the presence of H2 l 8 0 , and similar oxidative removal of sulphur with accompanying inversion at phosphorus was also observed when using (Sp)CAMPS.^^ However, this process is not absolutely stereospecific: when (Rp)-cdTMPS is oxidized in this way in H 2 1 8 0 , the inversion product, (Sp)-["O]cdTMP, is obtained in 77% yield and its (Rp)-isomer in 23% yield.86 When (Sp)-ADPaS is oxidized by using bromine in [ 1 7 0 ] H 2 0at room temperature for four minutes, ( R ~ ) - [ a - ' ~]ADP o ~ (56) is the predominant product, 31P n.m.r. evidence indicating 93% inversion at P, and 7% retention. No bromination at C-8 of adenosine is observed. On hydrolysis of ( 5 6 ) , using snake venom phosphodiesterase in H2180, (15) is obtained, this being a result which was used t o establish the stereochemistry in ( 5 6 ) . % Oxidation of ATPaS with NBS o r bromine in H 2 1 8 0 results in incorporation of l80at P, and P,, with the latter predominating.8s386 Incorporation at P, probably takes place in an analogous manner t o that shown in Scheme 1, and at P, by attack of H2180 o n adenosine S'-trimetaphosphate, which is formed as an intermediate. Oxidative removal of sulphur, using NBS in water, has also been demonstrated for ATPPS, ATPyS, GTPPS, CDPaS, dTDPaS, and UTPaS, but the stereochemistry o f these reactions has not yet been e l ~ c i d a t e d . ~ ~ S

I

,P-O-(

OH

(55) (56)

x =l80 x =l7o

Ado-5')

(57)

Phosphorylation of [ 5'-'80]adenosine with thiophosphoryl chloride, followed by work-up in [ 1 7 0 ] H 2 0 ,affords ( 5 7 ) ; o n phosphorylation using adenylate kinase, coupling t o 2',3'-protected activated ADP, periodate cleavage, and basic elimination of the unprotected adenosine residue, followed by deblo cking, ( 5 7) gives ( R p)- [fly-' 0,y-' 70,l 8O3 ATPyS ( 5 8).87 This is a substrate for sarcoplasmic reticulum ATPase, and analysis of the chirality of the thiophosphate that is released by the enzyme, using methods 84

g6 87

R . D. Sammons and P. A. Frey, J. Biol. Chem., 1982, 257, 1138. B. A. Connolly, F. Eckstein, and H . H. Fuldner, J. B i d . Chem., 1982, 257, 3382. G. Lowe, G . Tansley, and P. M . Cullis, J. Chem. SOC., Chem. Commun., 1982, 595. M . R . Webb and D. R. Trentham, J. Biol. Chem., 1981, 256, 4884.

Nucleotides and Nucleic Acids

189

described previously," has shown that the configuration at phosphorus is retained. The similar GTP analogue, (Sp)-[ ~y-'70,y-'70,1801GTP+yS, has been used to show that hydrolysis by the GTPase activity of EF-G of E. coli proceeds with inversion at phosphorus,88 and the same result has been obtained for the GTPase activity of EF-Tu of E. coli in the presence of antibiotic X-5 108, using the same a n a l ~ g u e . ~If, ' in the method described above22 for the synthesis of ( 1 5), 2',3'-O,O-diacetyladenosineis replaced by ADP, exclusive formation of trans- 2- (adenosine-5'-diphospho)-4,s- diphenyl- 1,3,2dioxaphospholan-2-one (5 9) is observed, which on hydrogenolysis yields (Sp)-adenosine 5'-[y-'60,'70,180]triphosphate.90 Using this material, and determining the chirality of the products by methods identical or similar t o those described above,22 phosphoryl transfer with inversion of configuration has been shown t o occur for reactions that are catalysed by yeast hexokinase," rat liver g l u c ~ k i n a s e , ~and ' T4 polynucleotide kinase,92 while phosphoryl transfer with retention of configuration is observed with creatine kinaseg3 and in the hydrolysis that is catalysed by snake venom phosphodi] triphosphate has been prepared by a method esterase.% Adenosine 5'-[ /3-1802 in which P '-diphenyl P2-bis(diphenylmethy1) [P2-1804Ipyrophosphate is first elaborated, starting from tris(diphenylmethy1) [I8O4]phosphate, then monodealkylated with iodide, and treated with AMP t o afford the diphenylmethyl ester of [P-1803]ADP, which in turn is hydrogenolysed and the [ P-I8O3IADP that is thus obtained treated with carbonyldi-imidazole and orthophosphate to afford the desired p r ~ d u c t . ~ ' H

I

H

OH

(0 =

I

OH

(59)

18

0 ; 0 =I7O) 'I'h y

OH

'' M.

OH

OH

OH

OH

R. Webb and J . F. Eccleston, J. Biol. Chem., 1981, 256, 7 7 3 4 . J . F. Eccleston and M. R. Webb, J. Biol. Chem., 1982, 257, 5046. . G. Lowe and B. V. L. Potter, Biochem. J . , 1 9 8 1 , 199, 227. 9' D. Pollard-Knight, B. V. L. Potter, P. M. Cullis, G. Lowe, and A. Cornish-Bowden, Biochem. J., 1982, 201, 4 2 1 . 92 R. L. Jarvest and G . Lowe, Biochem. J., 1981, 199, 2 7 3 . 93 D. E. Hansen and J . R. Knowles, J. Biol. Chem., 1981, 256, 5 9 6 7 . 94 R . L. Jarvest and G. Lowe, Biochem. J., 1981, 199, 4 4 7 . 95 G. Lowe and B. S . Sproat, J. Chem. SOC.,Pevkin Trans. I, 1981, 1874. 89 90

190

Organophosphorus Chemistry

A number of P’,P3-bis-(5’-nucleosidyl) triphosphates have been prepared as analogues of mRNA 5‘-terminal ‘cap’ structures by treating a nucleoside 5‘-phosphorimidazolidate with the 5’-diphosphate of another nucleoside molecule.96 In the presence of zinc and magnesium ions, ATP, L-phenylalanine, and pyrophosphatase, and in the absence of tRNAPhe, the phenylalanyl-tRNAPhe synthetase from yeast and that from E. coli both produce A(S’)pppp(S’)A. This unexpected product is presumably formed by the reaction of enzyme-bound phenylalanyl adenylate with ATP instead of with pyrophosphate in the reverse of the first stage of the enzyme-catalysed reaction, and its appearance may be significant in terms of its putative role in controlling Compounds of general formula G( 5‘)pppp(5 ’ )N (N = A , C, U, o r G), derived by the displacement of pyrophosphate from GTP by a molecule of nucleoside triphosphate, are formed during the transcription, in vltro, of cytoplasmic polyhedrosis virus of Bombyx r n ~ r i . ~ This ’ reaction, not unlike ‘cap’ formation, may involve the interaction of a viral guanylyltransferase-guanylate complex with a nucleoside triphosphate. A(S’)ppppp(S’)A and its mono-(8-thioethyladenosine) analogue have been prepared by treating adenosine 5 ’ - trimetaphosphate with ADP and %thioethyl-ADP, respectively; they have been shown t o be potent two-site inhibitors, preventing binding of the natural substrates t o the AMP- and ATPbinding sites of adenylate kinase and displaying selective inhibitory effects at these sites f o r different i s o ~ y m e s . 2’-Deoxythymidine ~~ 3’-diphosphate 5’- [ (phosphonomethyl)phosphonyl phosphate] (60) has been synthesized, using phosphotriester techniques, viu 2’-deoxythymidine 5’-(2,4 -dichlorophenyl phosphoromorpholidate) 3’- (2,2,2- trichlorethyl phosphoromorpholidate). loo The P 3 - ( 2 4 (2,4-dinitrophenyl)amino]ethyl)-esters of the common ribonucleoside 5’-triphosphates (6 1) have been prepared by treating 2-[(2,4dinitropheny1)aminolethyl phosphoromorpholidate with the appropriate nucleoside diphosphate in DMSO.”’ The corresponding P3-methyl esters (62) were formed from the nucleoside 5’- triphosphates, using diphenyl phosphorochloridate and methanol. Using RNA polymerase from E. coli and a poly [ d(A-T)] template, (6 1 ; R2 = Ado) can initiate transcription, but only the pyrimidine species of ( 6 1) were elongation substrates, releasing 2-[(2,4dinitropheny1)aminolethyl pyrophosphate o n utilization. Elongation was also supported by (62; R2 = A d o or Urd). By initiation using (61; R 2 = Ado), the useful hapten 2,4-dinitrophenyl is introduced at the S‘-terminus of RNA. N-( p-D-Ribofuranosy1)formamide (‘F’), obtained by treating uridine with peroxytrifluoroacetic acid, has been converted into its 5 ‘-mono-, di-, and - triphosphates by standard methods, and has also been used to construct two S. Bornemann and E. Schlimme, Z. Naturforsch., Teil. C.,1 9 8 1 , 36, 1 3 5 . P. Plateau, J.-F. M a y a u x , a n d S. Blanquet, Biochemistry, 1 9 8 1 , 20, 4 6 5 4 . K. E. Smith and Y . Furuichi, J. Biol. Chern., 1 9 8 2 , 257, 4 8 5 . ’’ A . Hampton, F. Kappler, a n d D. Picker, J . Med. Chern., 1 9 8 2 , 2 5 , 6 3 8 . l o o J . A. J . den Hartog, M . P. Lawson, E. W. P. de Jong, a n d J . H. van Boom, R e d : J . R . N e t h . Chern. Soc., 1 9 8 1 , 100, 3 1 7 . I o 1 W. J . Smagowicz, J. V. Castell, K. M . Clegg, and K.-H. Scheit, Biochemistry, 1 9 8 1 , 20, 5538. 96

97 91

Nucleotides and Nucleic Acids

191

dinucleoside monophosphates, FpA and Fp(Zin -benzo-A), by phosphodiester methods.lo2 The compounds were prepared as foreshortened nucleotide analogues which might be base-pairing complements for Zin - benzoadenosine. FDP was n o t a substrate for polynucleotide phosphorylase, but the dinucleoside phosphates were cleaved by phosphodiesterase I to give the expected products. 0

(61) R 1 = 2,4-(N0,),C,H,RH(CH,)2 ( 6 3 ) $1

=

Vg2+:

R1=

5'-AMP: R 2 = 0

(62) R1= MP

R3= Ado-5 ' , U r d - 5 ' ,

( 6 4 ) M = Mg2+, R1= 0 : R2= 5'-AvfP C s d-5 ' ,

or Guo-5'

A large number of derivatives of ATP, bearing iodoacetyl groups at the ends of spacer arms of varying length, attached at N-6 o r C-8 of t h e base, have been prepared, starting from 6-chloropurine riboside 5 '-monophosphate o r 8-bromo-ATP, as a p p r ~ p r i a t e , " ~and their kinetic parameters with adenylate kinases, pyruvate kinases, hexokinases, and thymidine kinase have been evaluated.lM Judged by the results, the introduction of the alkylating groupspacer arm moiety with a view t o effecting irreversible binding at a nucleophilic site that is external t o the active site of thz enzyme is a chancy business. N 6 -(2,2,6,6-Tetramethylpiperidin4 -yl- 1-0xy1)-AMP and t h e analogously C-%labelled derivative have been converted into their corresponding 5'-triphosphates and 5'-[ 0,y-methyleneltriphosphatesby treatment with dibutylphosphinothioyl bromide, followed by pyrophosphate o r methylenediphosphonate and silver acetate in dry pyridine.'" The C-%spinlabelled ATP derivative binds tightly t o glyceraldehyde 3-phosphate dehydrogenase, probably at t h e NAD+-binding site, and the N6-labelled derivative is a substrate for Ca2+-ATPase of sarcoplasmic reticulum. New derivatives of 1,N6-etheno-ADP and -ATP, with anilino-, 4-azidoanilino-, and benzylamino-groups forming amidates at t h e terminal phosphates, have been 5 'described. lo6 Both ( R ) - and ( S)-N6-Benzoyl-2',3'-0,0-isopropylidene[ 2Hlladenosine have been converted into ( R ) - and (S)-[5'-2Hl]ATP by standard methods and used as substrates for yeast metiiionine adenosyltransI03

I 04

105

A. W. Czarnik and N . J . Leonard, J. Am. Chem. Soc., 1982, 1 0 4 , 2 6 2 4 . A. Hampton, A. D. Patel, M. Maeda, T. T. Hai, C.-D. Chang, J . B . Kang, F. Kappler, M. Abo, and R . K. Preston, J . Med. Chem., 1982, 2 5 , 373. A. Hampton, D. Picker, K. A. Nealy, and M . Maeda, J. Med. Chem., 1982, 2 5 , 3 8 2 ; A . Hampton, A. D. Patel, R. R. Chawla, F. Kappler, and T. T. Hai, ibid., p. 386. K. G. Gloggler, T. M. Fritzsche, H. Huth, and W. E. Trommer, Hoppe-Seylev's 2. Physiol. Chem., 1981, 362, 1 5 6 1 . G. A. Nevinskii and A . Yu. Denisov, Bioovg. Khim., 1 9 8 1 , 7 , 1 6 9 3 (Chpm. A b s t v . , 1982, 96, 85 9 1 2 ) .

192

Organophosphorus Chemistry

ferase. lo7 Isolation and degradation of the S-adenosylmethionine that is produced and establishment of the chirality at the 5'-position, using H n.m.r., shows that the methylthio-group of methionine displaces triphosphate from ATP by an in-line mechanism. (Sp)- [ T - ~ ~ATPaS P] has been prepared by equilibration of (Sp)-ATPaS with [ 32P]orthophosphate, 3-phosphoglycerate kinase, and glyceraldehyde 3-phosphate dehydrogenase in the presence of Mg2+;( R P ) - [ ~ - ~ ~ P ] A T has P~S been labelled by using the same method, with Co2+ replacing Mg2+. (Sp)-[y32P]ATPPS was prepared similarly, using Mg2+. An investigation into the substrate efficiencies of ( R p)- and (Sp)-ATPaS and -ATPPS for acetate kinase in the presence of bivalent metal ions suggests that P,y-bidentate MgATP in the A configuration (63) is the normal substrate for acetate kinase, and similar studies of the reverse reaction, using ADPPS, indicate that MgADP is bound in the reverse reaction and released in the forward reaction as a 0-unidentate complex.'08 Similar studies with myosine subfragment 1 (SF-1) ATPase indicate that this uses MgATP, as the A,P,y-bidentate chelate (64), as its s ~ b s t r a t e . ' ~Another ' investigation, monitoring the rates of release o f the complexes of bivalent metal ions with (Rp)- and (Sp)-ADPaS from myosin SF-1, has concluded that the metal ion is not co-ordinated t o Pa, but rather as the 0-unidentate complex, when it is bound t o SF-I .ll' The P-unidentate chromium complex of ADP, formerly considered t o be substitution-inert, has been found t o decompose at neutral pH at an appreciable rate t o form free ADP, and any deductions regarding an enzyme mechanism that were based o n the use of P-CrADP and a,P-CrADP should be treated circumspectly."' A 31P n.m.r. study of the rates at which oxygen is exchanged in [ ' 8 0 ~ ] ~ r t h o p h o ~ p h by a t e myosin SF-1 in the presence of (Rp)- and (Sp)ADPaS and magnesium ions has been described."' The structure of the complex that forms between EF-Tu (from Escherichia coli and Bacillus stearothermophilus), GDP, and bivalent metal ions has been investigated by observing the inhomogeneous broadening in the e.p.r. signal of Mn2+ that is caused by unresolved superhyperfine coupling t o 1 7 0 in [ c u , ~ 17 0 , p - 1 7 0 3 GDP, ] [d 7 0 2 ] GDP, and [a-'703]GDP.''23 l 3 The results indicate that the metal ion is mono-co-ordinated t o Pp of GDP. Studies o n the stereoselectivity of EF-Tu for the diastereoisomers of GDPaS, and 31P n.m.r. studies on GDP and GDPPS that are bound t o EF-Tu, support this view.'I3 In a comparable investigation, in which the broadening of the e.p.r. signal of Mn2+ by [a-'702,a/?-170]ADPor [,B-l703IADP, bound t o myosin sub-

'

'

Io7 Io9

"" 'I1

113

R. J . Parry and A. Minta,J. A m . Clzern. Soc., 1 9 8 2 , 104, 871. P. J . Romaniuk and E'. Eckstein, J . Biol. Chem., 1981, 256, 7322. B. A. Connolly and F. Eckstein, J. Biol, Chem., 1981, 256, 9450. R. S. Goody, W. Hofman, and M. Konrad, FEBS Lett., 1981, 129, 169. P. Rosch, K. S . Goody, H.-R. Kalbitzer, and H. Zimmermann, Arch. Biochem. Biophys., 1981, 2 1 1 , 622. J . F. Eccleston, M . R. Webb, D. E. Ash, and G. H. Reed,J. Biol. Chem., 1981, 256, 10 774. A. Wittinghofer, R . S. Goody, P. Roesch, and H. R . Kalbitzer, Euv. J. Biochem., 1982, 1 2 4 , 109.

Nucleotides and Nucleic Acids

193

fragment 1, was observed, it was also concluded that ADP is a 0-unidentate ligand for the metal ion in the M2+-ADP-SF-l ~ o m p l e x . " ~ The diastereoisomers of ADPaS have been tested as substrates for the polymerization reaction de novo that is catalysed by Form I polynucleotide Using ( R p)-[ 2-3H]ADPaS and phosphorylase from Micrococcus luteus. (Sp)-ADPaS, it was found that the former is used selectively t o form the 5'-termini of the polynucleotides that are produced, while the latter is preferentially used for chain elongation, suggesting that the enzyme possesses two stereochemically distinct subsites for initiating polymerization. When ADPaS was used as substrate, the average chain-length of the product was smaller than that obtained when ADP or ADPPS was used, indicating possible competition between the rate of polymerization and the rate of dissociation of the growing chain from the enzyme. The characteristics of the diastereoisomers of ATPclS and ATPPS in supporting the reactions that are catalysed by methionyl-tRNA synthetase have been investigated.l16 Studies with bivalent metal ions indicate that the nucleotide is bound as a P,y-chelate. A study of the mechanisms of hydrolysis of ATP in 3M perchloric acid, and of ADP and of pyrophosphate in 1-5M perchloric acid, has been r e p ~ r t e d . " Working ~ in H2180 medium, no reaction involving the exchange of oxygen isotopes in the substrates without hydrolysis was observed, and no isotopic exchange was found in the orthophosphate that was formed on hydrolysis. Hydrolysis of ADP afforded both [l8O ]AMP and orthophosphate and AMP and [1801lorthophosphate, since lysis could occur at either end of the oy-oxygen bridge. The hydrolyses of ADP and of pyrophosphate show large negative values for the entropy of activation, suggesting the involvement of a water molecule in the rate-determining step. It is thought that a trigonalHO

I I

O=P-OK

0

0

0

II

II

II

HO-P-0-P-0-P-0

A

( 6 5 ) R = H or Ado-5'

R

C

i"!

- (Ado-5 ' )

D

(66)

bipyrimidal intermediate (65) is formed, which loses phosphate faster than it can undergo pseudorotation t o bring the phosphate group to an equatorial position, since isotopic exchange would otherwise be observed. The hydrolysis of ATP, as expected, is more complicated, with isotope data indicating that hydrolysis can occur at A and B and c and/or D in (66), with lysis at A and B

'I5

M. R. Webb, D. E. Ash, T. S. Leyh, D. R. Trentham, and G. H . Reed, J . B i d . Chem., 1982, 257, 3068. J . F. Marlier and S . J. Benkovic, Biochemistry, 1982, 21, 2349. L. T. Smith and M. Cohn, Biochemistry, 1982, 2 1 , 1530. G. J. Hutchings, B. E. C. Banks, M. Mruzek, J . H. Ridd, and C . A . Vernon, Biochemistry, 1981, 2 0 , 5809.

194

Organophosphorus Chemistry

being preferred. The observation that n o exchange of isotope accompanies hydrolysis is of prime importance, since many investigations o n the incorporation of a tracer oxygen isotope into ATP involve acid hydrolysis t o AMP and orthophosphate. Enthalpy data for the hydrolyses of anhydride and ester bonds in GMP, GDP, and GTP have been redetermined, and yield values close t o those previously found for ATP.Il8 Calorimetric studies of the hydrolysis of ATP by heavy meromyosin have also been reported."' [y-1803]ATP, prepared by transfer of the phosphoryl group from NH2C0'80P180:t o ADP, using carbamate kinase, has been used in quenched-flow investigations of the exchange of oxygen with H2160 that is catalysed by rabbit skeletal muscle myosin SF-1 ATPase.I2' The same synthetic method could be used t o prepare [y-1803]GTP. Adenylyl imidodiphosphate, not generally a substrate for enzymes that catalyse the transfer of the y-phosphoryl group of ATP, is hydrolysed by the Ca2+-ATPase of sarcoplasmic reticulum t o orthophosphate and, apparently, adenylyl phosphoramidate, with accompanying vesicular accumulation of Ca2+ ions. 12' Guanylyl imidodiphosphate, guanylyl methylenediphosphonate, and GTPyS have been shown t o be substrates for guanylate cyclase from rat lung, while periodate-oxidized GTP and guanosine 5'- tetraphosphate are powerful com pet it ive in hibit ors. 122 In a new model for the mechanism of oxidative phosphorylation it is proposed that the process be regarded as involving a set of directly energycoupled enzymes, without the requirement of storage of energy in the form of a membrane p 0 t e n t i a 1 . l ~The ~ reactive species which phosphorylates ADP o n the inner side of the mitochondrial membrane, having been formed by loss of hydroxide ion from orthophosphate at the outside of the membrane, is formulated as (67). It seems inherently unlikely that this species, formally a metal salt of monomeric metaphosphate that is co-ordinated t o a second metal monocation, would survive long enough for passage across t h e membrane, in view of its extreme reactivity, though it is tempting t o speculate whether such a species might 'migrate' through a stack of orthophosphate molecules via transfer of hydroxide ions. However, the proposal is attractive and demands serious consideration. When arsenate is added t o submitochondrial particles from beef heat that are supplied with succinate as an oxidizable substrate, ADP arsenate appears t o be formed instead of ATP, and is a substrate for hexokinase, leading t o the formation of glucose 6 - a r ~ e n a t e . I The ~ ~ ADP arsenate that is formed in unstable, and is very rapidly hydrolysed back t o ADP and arsenate, providing a rationale for the apparent 'uncoupling' effect of arsenate o n oxidative phosphorylation. 11'

H . - J . Hinz, P. Pollwein, R . Schmidt, and F. Zimmermann, Arch. Biochern. Biophys., 1981, 212, 72.

119

''I

T. Yamada, H . Shimizu, and H . Suga, Biochemistry, 1 9 8 1 , 2 0 , 4 4 8 4 . M. K. Webb and D. R . Trentham, .I. Biol. Chem., 1 9 8 1 , 2 5 6 , 10 9 1 0 . J . S. Taylor, J. Biol. Chem., 1 9 8 1 , 2 5 6 , 9 7 9 3 . H . J. Brandwein, J . A. Lewicki, S. A. Waldman, and F. Murad, J. Riol. Chetn., 1 9 8 2 , 257, 1309.

124

D. E. Green and H . Van de Zande, Proc. Natl. Acad. Sci. U S A , 1 9 8 2 , 7 9 , 1064. M . J . Gresser, J. Biol. Chem., 1 9 8 1 , 2 5 6 , 5 9 8 1 .

Nucleotides and Nucleic Acids

I/"-M+ +p \ 0-

195

+n+

M+

9-(2- Hydroxyethoxymethy1)guanine triphosphate and ara - ATP are substrates for herpes-simplex-virus-coded DNA polymerases, resulting in the addition of the corresponding monophosphates at the 3'-termini of growing DNA chains, where their presence suppresses further elongation. 12', 126 These findings suggest a rationale for the antiviral activities of the parent nucleosides. xyb-Adenosine, when added t o CHO cells, appears to cause premature termination of RNA chains by a similar m e ~ h a n i s m . Amongst '~~ other studies worthy of mention, 2'(3')-O-trinitrophenyl derivatives of adenine nucleotides have been used t o study the structure and the mechanism of action of soluble mitochondrial ATPase;'28 tubercidin (i.e. 7-deaza-adenosine) 5'-mOnO-, -di-, and -triphosphates have been investigated as potential substrates for mitochondrial phosphotransferases from rat liver and beef heart;'*' a number of ribose-modified ADP analogues have been tested as substrates or inhibitors of photophosphorylation by spinach chloroplasts;'30 and the substrate specificities of many aminoacyl-tRNA synthetases from various sources have been investigated, using an array of ATP ana10gues.l~'' 132 Upon alkylation (using stearyl iodide), 1,4-diazabicyclo[2.2.2]octane affords (68). This lipophilic diammonium cation can be used t o extract nucleotide anions from an aqueous solution into chloroform, and can act as a nucleotide carrier, transporting nucleotides across a chloroform liquid membrane. 133 It both extracts and transports nucleoside polyphosphates, in the order NTP > NDP > NMP, and the pH dependence of the extraction process shows that geminate or vicinal dianions o n the polyphosphate chain interact most strongly with (68), accounting for this selectivity. Affinity Labelling.-For the most part, studies of affinity labelling have employed tried and tested reagents during the past year, but some novelties have been reported. In the presence of promoter template, adenosine 5'-trimetaphosphate behaves as an affinity label towards the initiation site of 125 126

127 12R

129

130

131

I32

133

D. Derse and Y.-C. Cheng,J. Biol. Chem., 1981, 2 5 6 , 8 5 2 5 . D. Derse, Y.-C. Cheng, P. A. Furman, M. H. St. Clair, and G. B. Elion, J. Biol. Chem., 1981, 2 5 6 , 1 1 447. B. A. Harris and W. Plunkett, Biochem. Biophys. Res. Commun., 1982, 106, 5 0 0 . Z. S. Kormer, I. A. Kozlov, Ya. M. Milgrom, and I. Yu. Novikova, Eur. J. Biochem., 1982, 121, 4 5 1 . I . Petrescu, I. Lascu, I . Goia, M. Markert, F. H. Schmidt, I . V. Deaciuc, M. Kezdi, and 0. Bbrzu, Biochemistry, 1982, 2 1, 886. K. S. Boos, B. Dimke, E. Schlimme, H. Wiedner, K. Edelmann, and H . Strotmann, FEBS Lett., 1981, 130, 7 3 . W. Freist, H. Sternbach, and F. Cramer, Hoppe-Seyler's Z . Physiol. Chem., 1981, 362, 1247. E. Gerlo, W. Freist, and J . Charlier, Hoppe-Seyler's Z . Physiol. Chem., 1982, 3 6 3 , 365. I. Tabushi, Y. Kobuke, and J.-I. Imuta,J. A m . Chem. Soc., 1981, 103, 6152.

196

Organophosphorus Chemistry

DNA-dependent RNA polymerase from E. coZi.'34 The presence of UTP markedly accelerates the inactivation of the enzyme, and it appears that the true affinity label is 5'-trimetaphosphorylated ApU. The p-subunit is labelled, and hydrolytic studies suggest that a histidine residue is phosphorylated. The disulphides of 6-thioinosine 5'-triphosphate and 6-thioinosine 5'-[ 0 , ~ methylene] triphosphate have been used as affinity labels for Na+,K+-ATPase, and the effects of monocations on the labelling process determined. '35 A detailed study of the preparation, structure, and properties of periodateoxidized ATP (oATP) has been made.136 The material appears (from ' H n.m.r. evidence) to exist in aqueous solution as a mixture of three dialdehyde monohydrates [which are diastereoisomeric substituted 1,4 -dioxans, (69)(71)] and a dihydrate (72), with little free aldehyde present. Thus, from the point of view of affinity labelling, oATP does not behave as an opened ribose ring, but rather more nearly resembles a hexopyranosyl nucleotide from the aspect of conformation. The different diastereoisomers (69)-( 7 1) would presumably interact differently with an ATP-binding site, and the concentration of the species that is performing affinity labelling is likely t o be different from that of the oATP that is added to an incubation.

A further cautionary note has been sounded concerning the interpretation of the inactivation of nucleotide-metabolizing enzyme functions by periodate-oxidized nucleotides as 'affinity labelling'. Catalysis of the transfer of the aminoacyl group from aminoacyladenylate to tRNA by aminoacyltRNA synthetases is inhibited by oATP, but the ATP-pyrophosphate exchange reaction that is catalysed by these enzymes is not!137 Moreover, oATP and oGTP inhibit aldolase, which has an essential lysine group at its active site but does not use a nucleoside 5'-triphosphate as substrate. Thus, periodate-oxidized nucleoside triphosphate species are not necessarily nucleotide-site-specific reagents. A study of the reaction of oADP with bovine glutamate dehydrogenase, in which both active- site-specific and non-specific labelling occurs,138 serves to reinforce this view. While UMP is an allosteric inhibitor of carbamyl phosphate synthetase, oUMP, like IMP, is an activator 134

13'

'37

M. A. Grachev and A. A. Mustaev, FEBS Lett., 1982, 137, 89. R . Patzelt-Wenczler and W. Mertens, Eur. J. Biochem., 1981, 121, 197. P. N. Lowe and R. B. Beechey, Bioorg. Chem., 1982, 11, 55. A. H. Mehler, J.-J. P. Kim, and A. A. Olsen, Arch. Biochem. Biophys., 1981, 212, 475. R. Favilla and P. M . Bayley, Eur. J. Biochem., 1982, 125, 209.

Nucleotides and Nucleic A cids

197

'''

for the enzyme! Nevertheless, oATP appears t o be a valid affinity label for rabbit skeletal muscle phosphorylase kinase 140 and for the large-T proteins of polyoma and SV40 v i r u ~ e s , ' ~and ' oAMP for human placental alkaline p h o ~ p h a t a s e . 'Moreover, ~~ tRNAPhe from yeast 143 and tRNAMet from sheep liver have been oxidized at the 3'-terminus, using periodate, and found t o behave as affinity labels for their corresponding aminoacyl- tRNA synthetases. Upon oxidation of rat liver ribosomal 6 0 s subunits with periodate, followed by reduction with borohydride and ribosomal dissociation, 5s RNA became bound covalently to protein L5, suggesting their close association in intact 6 0 s subunits.'45 Lastly, a series of compounds ~ n ( A 2 ' p ) , [ ~ ~ P ](n p C= 1-3), prepared by ligating [32P]pCp to the terminus of '2-5A' followed by limited treatment with bacterial alkaline phosphatase, has been oxidized at the 3'-terminus, using periodate, and used for the affinity labelling of '2--5A'-dependent endoribonuclease from different mammalian sources.146 Once again, photoaffinity labelling using azido- derivatives of nucleotides has found favour. 8-Azido-CAMP has been used for photoaffinity labelling of CAMP-dependent protein kinase of yeast,I4' and 8-azido-GTP t o label a putative GTP- binding regulatory factor of adenylate cyclase in membranes of Dictyostelium discoideum 148 and GTP- binding components in highly purified preparations of GTPase from bovine rod outer segments.'49 Analogues of ATP and GTP with azidoaryl groups attached at P, have been ~~ used with [cI-~*P]UTPor CTP as substrates for RNA p o l y m e r a ~ e . ' Once transcription has begun, irradiation of the preparation attaches the 5 ' terminal of the transcript to the protein, where the label is mainly bound t o the p and o subunits. The photoaffinity label 3'-0-[ 3-(4-azido-2-nitropheny1)propionyll ATP, prepared by esterification of ATP at the 3)-position with 3-(4-azido-2-nitrophenyl)propionic acid, has been used to characterize and label ATP-binding sites on (Na' + K+)-ATPase lS1 and coupling factor CF-1 of ~ h l o r o p l a s t s . ' ~A~ novel photoaffinity probe, 3'-0-(4-benzoylbenzoy1)ATP (73), prepared by treating 4-benzoylbenzoic acid with carbonyldi-imidazole followed by ATP, has been used to label ATP-binding sites of rat liver mitochondria1 F1-ATPase.lS3 Several P1-[w-(5-diazonium 139

I4O

14' 14' 143

144

145 146

147

14'

14'

Is' 152

Is3

B. Boettcher and A. Meister, J. Biol. Chem., 1981, 256, 5977. M. M. King and G. M. Carlson, Biochemistry, 1981, 20, 4 3 8 2 , 4387. P. Clertant and F. Cuzin, J. Biol. Chem., 1982, 257, 6300. G.-G. Chang, S.-C. Wang, a n d F. Pan, Biochem. J., 1981, 199, 281. M . Renaud, F. Fasiolo, M. Baltzinger, Y. Boulanger, and P. Remy, Eur. J. Biochem., 1982, 123, 267. A. Brevet, C. Geffrotin, and 0. Kellermann, Eur. J. Biochem., 1982, 124, 4 8 3 . K. Terao, T. Uchiumi, a n d K. Ogata, Biochim. Biophys. Acta, 1982, 697, 20. D. H. Wreschner, R. H. Silverman, T. C. James, C. S. Gilbert, and I. M. Kerr, Eur. J. Biochem., 1982, 124, 2 6 1 . J. S y and M. Roselle, FEBS Lett., 1981, 135, 9 3 . B. H. Leichtling, D. S. Coffman, E. S. Yaeger, H. V. Rickenberg, W. Al-Jumaliy, and B. E. Haley, Biochem. Biophys. Rex Commun., 1981, 102, 1187. D. J. Takemoto, B. E. Haley, J. Hansen, 0. Pinkett, a n d L. J. Takemoto, Biochem. Biophys. Res. Commun., 1981, 102, 341. M. A. Grachev and E. F. Zaychikov, FEBS Lett., 1981, 130, 23. G. Rempeters and W. Schoner, Eur. J. Biochem., 1981, 121, 131. M. F. Bruist and G. C. Hammes, Biochemistry, 1981, 20, 6298. N. Williams and P. S. Coleman, J. Biol. Chem., 1982, 257, 2834.

0rga n op h o sp h or us Ch e mist ry

198

benzimidazol-2-yl)alkyl] P 2 - (5’-adenosyl) pyrophosphates (74) have been prepared by treatment of adenosine 5’-phosphoromorpholidate with the appropriate o-(5-nitrobenzimidazol-2-yl)alkyl phosphate, followed by catalytic reduction and diazotization, and 1-(5-phospho-P-D-ribofuranosyl)benzimidazole-5-diazonium salt ( 7 5 ) was synthesized from l-(fl-D-ribofuranosyl)-5-nitrobenzimidazole by phosphorylation of the isopropylidene derivative by Tener’s method, followed by reduction and d i a z o t i ~ a t i o n . ’ ~ ~ These diazonium compounds rapidly inactivate a number of dehydrogenases, apparently by binding t o the NAD+-binding site followed by covalent modification of t h e enzymes.

(Arlo-5’ ) Ade

6

OH

0-t R.NA

COPh

(73)

I

Rib-5

’- F

(75)

( 7 7 )n

=

1 or 3

Several methods have been devised t o turn tRNA into an affinity-labelling species. Oxidation of the 3’-terminal adenosine of tRNAPhe by periodate, followed by reaction with 4-azidobenzoylglycylhydrazide, modifies the 3’-terminus t o (76), and this tRNA analogue binds t o 7 0 s ribosomes and is irradiated t o label the sequence of 2 3 s tRNA that is thought t o interact with the 3’-terminus of native tRNA.15’ tRNAfMef has been treated with bisulphite and propane-173-diaminet o introduce N 4 - ( 3 -aminopropy1)cytidine residues in different structural regions of the molecule, and these then react with dithiobis(succinimidy1 propionate) t o introduce an acylating group that lS4

15’

A. Burkhard, A. Dworsky, R. Jeck, M. Pfeiffer, S. Pundak, a n d C. Woenckhaus, Hoppe-Seyler’s 2. Physiol. Chem., 1981, 3 6 2 , 1079. M . Leitner, M. Wilchek, and A . Zamir, Eur. J. Biochem., 1 9 8 2 , 125, 49.

Nucleotides and Nucleic A cids

199

contains a cleavable disulphide bridge at the 4-position of the modified cytidine resid~es.’’~If the degree of modification is limited (ca one crosslinking group per tRNA molecule), these compounds are effective affinity labels for methionyl-tRNA synthetase, while subsequent reduction of the disulphide bridge with a thiol reagent releases the tRNA and restores activity. An alternative route to similar functionalization consists in treating tRNAPhe with 4 - [ N - (2-chloroethyl)-N- methylamino]benzylamine (when statistical alkylation of N-7 of the guanine bases takes place, t o introduce aliphatic amino-groups on the molecule) and subsequent reaction of these aminogroups with 2,4-dinitro-5-fluorophenylazide.ls7 The resulting tRNA derivative is competent for binding to the P site of ribosomes, and upon irradiation it becomes attached to 30s and 50s ribosomal proteins. Two oligodeoxyribonucleotides that are complementary t o a segment of bacteriophage MS2 RNA have been converted into affinity reagents, one (bearing a 3’-terminal phosphate) by treatment with mesitoyl chloride, conversion into a 2-aminoethyl phosphoramidate with ethylenediamine, and acylation by a 4-bromomethylbenzoyl derivative t o give an alkylating species, and the other (terminating in riboguanosine) by acylation with 4-azidobenzoylimidazole to afford a photoaffinity reagent. Adenosine 5’-trimetaphosphate, on treatment with 4 - [ N - (2- chloroethy1)-N- methylamino] benzylamine, yields the correspondingly substituted ATP y-phosphoramidate (77; n = 3), and both this and the analogous AMP derivative (77; n = 1) have been used t o label the PI isozyme of yeast hexokina~e.’’~ Many studies have sought to cross-link nucleic acid to nucleic acid or nucleic acid to protein to gain information on their topography and interaction in complex systems. In some cases, cross-linking has been effected by chemical reagents. 4 - Azid 0-2,3,5,6- tetrafluoropyridine and 4 - azido- 3 3 dichloro-2,6-difluoropyridine have been used to cross-link 1 6 s RNA to 3 0 s ribosomal proteins, the active halogens on the reagents being attacked and replaced by amino-groups on the protein, and subsequent irradiation resulting in cross-links to the nucleic acid.’@) 2-Iminothiolan has been used similarly, to cross-link 2 3 s RNA to 50s ribosomal proteins.161 However, the majority of cross-linking studies involving nucleic acids have employed direct photochemical methods. Irradiation using a laser was effective in linking T7 DNA to RNA polymerase from E. coli. N-Acetylvalyl-tF.NAVal, bound to the P sites, has been cross-linked photochemically to a nonanucleotide sequence of 1 6 s rRNA of 30s ribosomal subunits of E. coli 163 and t o 18s tRNA in L. H. Schulrnan, D. Valenzuela, and H. Pelka, Biochemistry, 1981, 2 0 , 6018. S. N. Vladimirov, D. M. Graifer, and G. G. Karpova, FEBS L e t t . , 1981, 135, 155. 15’ M. B. Gottikh, M. G. Ivanovskaya, V. P. Veiko, and Z . A. Shabarova, Bioorg. Khim., 1981, 7 , 1310 (Chem. Abstr., 1982, 96, 85 895). 159

V. N. Buneva, E. Yu. Dobrikova, D. G. Knorre, I. 0. Pacha, and T. A. Chimitova,

16*

FEBS Lett., 1981, 135, 159. R. Millon, J.-P. Ebel, F. le Goffic, and B. Ehresmann, Biochem. Biophys. Res. Commun., 1981, 101, 784. I. Wower, J. Wower, M. Meiken, and R. Brimacombe, Nucleic Acids Res., 1981, 9,

16’

4285. C. A. Harrison, D. H. Turner, a n d D.

163

B. H.

C. Hinkle, Nucleic Acids Res., 1982, 10, 2399. Taylor, J . B. Prince, J . Ofengand, and R. A. Zirnmerrnann, Biochemisrry, 1981,

20, 7581.

200

Organophosphorus Chemistry

the 40s subunit of yeast ribosomes.la Non-aminoacylated tRNA binds to the N-acetylphenylalanyl-tRNAPhe- poly(U) 7 0 s ribosomal (E. coli) complex, and upon irradiation it becomes attached to a set of proteins that are different from those attached to irradiated tRNA that is bound in the ‘A’ or ‘P’ sites; this observation may be significant in stringent control of metab01ism.l~~ The allosteric effector dTTP appears to be bound directly to an allosteric site on protein M1 of mouse ribonucleotide reductase upon irradiation. A timely warning has been sounded concerning such photochemical studies of cross-linking of nucleic acids by workers who compared the rate of formation of UMP photohydrate in irradiated 3 0 s ribosomal subunits (of E. coli) with the rate of formation of RNA-protein cross-links, and who deduced that more than two UMP photohydrate residues were formed per cross-link that was created. If the rate of formation of photohydrate exceeds the rate of cross-linking t o the extent that base-pairs are disrupted and the conformation of the nucleic acid is changed, artefactual contacts might be formed, leading t o spurious cross-linking, and the experimental findings must be carefully reviewed, taking this into consideration. 167

4 Oligo- and Poly-nucleotides Chemical Synthesis.-The past year has seen enormous activity in this area. In a promising new method for ‘phosphotriester’ intermediates, an aryl or alkyl phosphorodichloridate is treated with two equivalents each of 1-hydroxybenzotriazole and pyridine in THF to give the corresponding bis(N’-benzotriazolyl) phosphate (78), which phosphorylates base-protected 5‘-O-silylated 2‘-deoxynucleosides t o give phosphotriesters of the type (79) in good yields, without the formation of bis-nucleosidyl products, and without by-products formed by attack of ( 7 8 ) on the guanine or thymine [or, in oligo(ribonuc1eotide) synthesis, uracil] rings.16’ Moreover, treatment of ( 7 9 ) with an alcohol in the presence of N-methylimidazole results in replacement of the oxybenzotriazole function by the appropriate alkoxy residue, allowing the introduction of cyanoethyl, tribromoethyl, etc. groups, or, if the alcoholic function is the 5‘-hydroxy-group of a 3’-blocked nucleoside, the formation of a (3’-5’)-internucleotidic bond, without any further requirement of a condensing agent. Otherwise, the oxybenzotriazole group is easily removed with aqueous triethylamine. Furthermore, intermediates of type ( 7 9 ) will react with alkyl- and aryl-amines and thiols in the presence of triethylamine or N-methylimidazole to afford the corresponding 164

J. Ofengand, P. Gornicki, K. Chakraburtty, and K. Nurse, Proc. Natl. Acad. Sci. U S A ,

165

G. G. Abdurashidova, M. F. Turchinsky, and E. I. Budowsky, FEBS Lett., 1981, 129,

1982,79,2817. 166

59. S. Eriksson, I. W. Caras, and D. W. Martin, jr., Proc. Natl. Acad. Sci. USA, 1982, 7 9 , 81.

167 168

L. Gorelic and S. A. Shain, Biochemistry, 1982, 21, 2 3 4 4 . G. van der Marel, C. A. A. van Boeckel, G. Wille, and J . H. van Boom, Tetrahedron Lett., 1981, 2 2 , 3887.

Nucleotides and Nucleic A cids B

0 N

/N\

II N-0-P-0-N

( 7 8 ) R = 2-C1C

20 1

/N\N

C

H 0 or 6 4

CBr3CH20,

etc.

H

( 7 9 ) R1= TBDMS;

R2= 2 - C 1 C 6 H 4 ;

R 3= N 1- 0 x y b e n z o t r i a z o l e

A

(80) R = 0

WN

phosphoramidates and phosphorothioates. 169 Reagents of the type (78; R = tribromoethoxy) are capable of phosphorylating relatively hindered hydroxy-groups, such as the 3'-OH in 5'-O-laevulinyl-2'-O-methoxytetrahydropyranyluridine, which does not react with 2,2,2-tribromoethyl phosphorochloridomorpholidate. Lastly, (78) or (80) [formed in the same way as (78), but starting from morpholinyl phosphorodichloridate J are convenient reagents for phosphorylating the 5'-OH function of fully protected oligonucleotides, and the products can be converted into 5 '-phosphotriesters, thiophosphates, phosphoramidates, or [if (80) was employed] used t o form a 5'-terminal polyphosphate.'m Phosphotriesters such as (8 1) have been developed as intermediates in the triester synthesis of oligo(ribonuc1eotides). Treatment of 4-chlorophenyl phosphorodichloridate with 5-chloro-8-hydroxyquinolineand triethylamine in THF affords 4-chlorophenyl 5- chloro-8-quinolyl phosphorochloridate, which reacts with base-protected 5'-O-dimethoxytrityl-2'-O-tetrahydropyranyl nucleosides in the presence of N-methylimidazole to give (8 1 ) . 1 7 ' The corresponding phosphorotetrazolide, prepared in situ by adding tetrazole and triethylamine to the phosphorochloridate prior t o addition of the protected nucleoside, is similarly effective for the preparation of (8 1),lz but both these reagents suffer from the drawback that by-products resulting from phosphorylation at 0 - 6 of guanine are observed. However, if the protected nucleoside is coupled with 4- chlorophenyl 5- chloro- 8- quinolyl hydrogen phosphate, using quinoline-8-sulphonyl-tetrazole or - 3-nitro- 1,2,4-triazole as condensing agent, (81) is formed in high yield, without unwanted byproducts from guanine derivatives.'73 In a limited comparative study of cyanoethyl, 4 -chlorophenyl, and 8-quinolinyl groups as protecting groups for phosphotriester synthesis, in which ease of introduction, stability, yields in 169

S. A. A. van Boeckel, G. van der Marel, G. WilIe, and J. H. van Boom, Chern. Lett.,

I70

G . A. van der Marel, C. A. A. van Boeckel, G. Wille, and J. H . van Boom, Nucleic Acids R e x , 1982, 10, 2337. H . Takaku, M . Yoshida, K. Kamaike, and T. Hata, Chern. Lett., 1981, 197. H. Takaku, T. Nomoto, and K. Kamaike, Chern. Lett., 1981, 543. H. Takaku, K. Kamaike, and K. Kasuga, Chem. Lett., 1982, 197.

1981, 17'5. 171

172 173

Organ up hosp h or us Che m ist ry

202

condensation reactions, and ease of removal were considered, the 8-quinolyl group, which is easily removed with aqueous ammonia, was preferred Another novel group of compounds that may be utilized for phosphotriester synthesis are the SS-diary1 phosphorodithioates. Treatment of bis(trimethy1silyl) phosphite with diphenyl disulphide in THF, and subsequent work-up in aqueous base, affords SS-diphenyl phosph~rodithioate,"~which may be coupled to a base-protected 5'-O-dimethoxytrityl-2'-O-tetrahydropyranyl (if ribo-) nucleoside, using a novel condensing agent, 4,6-dimethoxybenzene1,3-disulphonyl chloride (82), to give the nucleoside 3'-( SS-diphenyl phosphorodithioate) (83). One phenylthio-group can be removed from (83), using pyridinium hypophosphonate, to give the corresponding 3'-(S-phenyl

P

so2c1

B

R1 RIO

0-P-OR2

I

\

R2

s o p

OH3

IIMTr; R2= 4 - C 1 C 6 H 4 ;

(82)

R3=

5-chloro-8-quinolgl ;

(8.5) R'=

R4=

t e t r a h y d r o p y r a n v l (Thp)

( 8 1 ) R1=

R1= OMe; R2= H R?= Me

B

(83) K

1

=

( 8 4 ) R1=

OThp o r H ; R 2 = DMTr

( 8 6 ) R1=

B

OThp

OThp or H ; R 2 = H

phosphorothioate), and the dimethoxytrityl group is removed with 2% toluene-4-sulphonic acid, to give (84); the two products are then coupled, using mesitylenedisulphonyl chloride (85) in the presence of tetrazole, t o form (86). Repetition of deblocking and coupling allows construction of an oligonucleotide. During deblocking, the internucleotidic and one of the terminal thiophenyl groups are removed with alkaline dioxan, and the second terminal thiophenyl group with silver acetate in aqueous pyridine. The use of (82) and (85) means that the disulphonates that are generated upon exposure 174

175

S. C. Srivastava and A. L. Nussbaum, J . Carbohydr., Nucleosides, Nucleotides, 1981, 8,495. M. Sekine, H. Hamaoki, and T. Hata, Bull. Chem. SOC. Jpn., 198 1 , 5 4 , 3815.

203

Nucleo tides and Nu cleic A cids

to water during work-up are easily extracted into aqueous media and thus separated from the apolar products in an organic phase.’76y177 Among the custom-built phosphorylating agents designed to afford useful monomer building-blocks for the ‘phosphotriester’ synthesis of oligonucleotides are 2-chlorophenyl phosphoro-(4-anisido)chloridate (87) 17’ and 4-chlorophenyl 2-cyanoethyl phosphorochloridate (88).lm Both (87) and (88) phosphorylate the 3’-hydroxy-group of base-protected 5’-0-dimethoxytrityl-2f-deoxyribonucleosides to give the corresponding phosphotriesters in good yield. Similarly, building-block monomers of the general pattern of (81) have been prepared by treating base-protected 5f-U-monomethoxytrityl-2f0 - t- butyldimethylsilyl-ribonucleosides with 2- chlorophenyl or 2,5- dichlorophenyl phosphorodichloridate and subsequent treatment of the aryl nucleosidyl phosphorochloridate that is formed with 2-cyanoethanol or with 4 -nitrophenylethanol. ‘O 0

II I

R1O-P-C1

R2

( 8 7 ) R’=

2-C1C6H4;

R2= 4-MeOC6H4NH ( 8 8 ) R1=

4-C1C6H4;

R2= N C ( C H 2 ) 2 0 0

1

H

O= P-OC6H 0

II

C 1- 4

1 OCH2CH2CM

0-.P-0

MMT r 0

‘J

0

89 1

B

C H MMT r 0

0- P - S - CNM e

OCH CH,, CN

176

M . Sekine, J. Matsuzaki, and T. Hata, Tetrahedron Lett., 1981, 2 2 , 3209. S. Honda, K. Terada, Y.Sato, M. Sekine, and T. Hata, Chem. Lett., 1982, 15. E. Ohtsuka, Y . Taniyama, R. Marumoto, H. Sato, H. Hirosaki, and M. Ikehara, Nucleic Acids Res., 1982, 10, 2597. 179 S. De Bernardini, F. Waldmeier, and C. Tamm, Helv. Chim. Acta, 1981, 64, 2 1 4 2 . G. Silber, D. Flockerzi, R. S. Varma, R. Charubala, E. Uhlmann, and W. Pfleiderer, Helv. Chim. Acta, 1981, 6 4 , 1704. 177 178

204

Organophosphorus Chemistry

Treatment of 5f-0-dimethoxytrityl-2'-deoxythymidinewith excess 4-chlorophenyl phosphorodichloridate and 1,2,4-triazole, and the subsequent reaction of the product with 2-cyanoethanol, generates the 4 - triazolopyrimidinone nucleotide triester (89), which may be used for the synthesis of oligonucleotides by the usual phosphotriester methods. If aqueous ammonia is then used for terminal deblocking, the triazolopyrimidinone is converted into 5-methylcytosine, establishing a convenient method for the synthesis of oligonucleotides that contain this base. If an oximate is used instead t o deblock t h e internucleotidic aryl phosphates, thymine is regenerated. A related strategy for synthesizing DNA fragments that contain 5-methyldeoxycytidine has used 4-(3-nitro)triazolopyrimidinoneintermediates. lg2 Novel protecting groups for phosphate have again received attention. Treatment of 5'-0-monomethoxytrityl-2'-deoxythymidinewith 2-chloro2-0x0- 1,3,2-dioxaphospholan gives a high yield of (90), which reacts with thiophenol in the presence of triethylamine t o give the 2-(pheny1thio)ethyl nucleosidyl phosphate (9 I ) , ready for coupling t o a free 5f-hydroxy-group.183 Following the synthesis of an oligonucleotide the phenylthioethyl group is oxidized t o the sulphone with N-chlorosuccinimide and removed by P-elimination with alkali. In an extensive study in which n o less than 24 compounds of the 5 ' - 0 -trityl- 2'- deoxythymidine 3 '-(chlorophenyl 0-phenylethyl phosphate) type were synthesized and investigated for their stability and utility in oligonucleotide synthesis, it was concluded that the 5'-monomethoxytrltyl and 3'-(2,5-dichlorophenyl 4-nitrophenylethyl phosphate) functions conferred optimal properties o n t h e monomeric b ~ i l d i n g - b l o c k s . ' ~ ~ The monomethoxytrityl group is easily removed with trifluoroacetic acid in chloroform, t h e dichlorophenyl group with oximate ion (see below), and the substituted phenylethyl group by 0-elimination, using diazabicyclo[ 5.4.01undecane. The 2-bromophenyl group, introduced by phosphorylating 5'- and base-protected 2'-deoxynucleosides with 2-bromophenyl phosphorochloridate, has also been investigated as a phosphate-protecting Following the synthesis of an oligonucleotide by standard phosphotriester methods, the group is removed, using cupric acetate in aqueous pyridine at room temperature, under which conditions the 2-chlorophenyl group is stable. A specific complexation by C u 2 + bridging between the bromine atom and the phenolic oxygen is thought t o mediate the deblocking reaction. Treatment of base5'-0-monomethoxytrityl-2'-deoxynucleoside 3'-(cyanoethyl protected phosphate) with bis(dimethylthiocarbamoy1) disulphide and triphenylphosphine effects t h e introduction of the (dimethylthiocarbamoy1)thio-group, as in (92).Ig6 Following oligonucleotide synthesis using (92) as a basic monomeric building-block, the (dimethylthiocarbamoy1)thio-groups are removed by using boron trifluoride in aqueous dioxan, conditions which also

'"

W. L. Sung, Nucleic Acids R e x , 1 9 8 1 , 9 , 6 1 3 9 . G. A. van der Marel, G. Wille, H. Westerink, A. H.-J. Wang, A. Kich, J . K . Mellema, C. Altona, and J . H . van Boom, Recl.: J. R . Neth. Chem. Soc., 1 9 8 2 , 101, 7 7 . l S 3 Nguyen Thanh Thuong, M. Chassignol, U . Asseline, and P. E. Chabrier, Bull. Soc. Chim. Fr., Part 2, 1 9 8 1 , 51. 184 E. Uhlmann and W. Pfleiderer, Helv. Chim. Acta, 1 9 8 1 , 64, 1 6 8 8 . l X 5 Y. Stabinsky, R . T. Sakata, and M. H. Caruthers, Tetrahedron I,ett., 1 9 8 2 , 2 3 , 2 7 5 . H. Takaku, M . Kato, and S . Ishikawa, J. Org. Chem., 1 9 8 1 , 46, 4 0 6 2 . la2

205

Nucleotides and Nucleic Acids

remove the monomethoxytrityl group. The 2-pyridylmethyl group has also been utilized as a protecting group for internucleotidic phosphate and subsequently removed by using cupric chloride. 187 Reagents that are used for the removal of groups that protect the internucleotidic link have come under scrutiny. While thiophenol and toluene-4 thiol in the presence of base have often been utilized t o remove the methyl groups and the 4-nitrophenyl group from phosphotriesters, it has been found that treatment of (93) with toluene-4- thiol and triethylamine in acetonitrile at room temperature gives significant quantities of 5 ’-deoxy-5’-(4-tolylthio)3’-O-methoxytetrahydropyranyl-2’-deoxythymidine, resulting from nucleophilic attack at the 5’-position of the 3‘-residue, and thus that internucleotidic cleavage has occurred. 188 Deblocking with thiols must be undertaken with caution. No such stigma attaches to the use of oximates t o unblock oligonucleotide aryl esters. In a study in which the N’ ,N’,N3,N3-tetramethylguanidinium salts of a number of oximates were used to unblock (93) and (94) in aqueous dioxan, syn-2-nitrobenzaldoxime was found t o be the reagent of choice, and 2-chlorophenyl the blocking group most rapidly removed.’” No accompanying internucleotidic cleavage was detected. S

J,

JH! R1

0-PRU”

0-P-0

OH

OR?

( 9 3 ) R2= 4 - C l C

H

6 4

( 9 4 ) RL= 2 - C 1 C 6 H 4 1

(R’= m e t h o x v t e t r a h y d r o p y r a n y l )

OH

OThp (95)

Side-reactions of phosphorylating and condensing agents with nucleosides and nucleotides (particularly those that contain guanine), resulting in the formation of unwanted by-products, have long bedevilled oligonucleotide synthesis. This problem has now been addressed, and methods have been described for the protection of guanine-containing nucleosides at 0 - 6 by alkyl and substituted alkyl group^,"^ o r by aryl groups,191 or by phosphoryl or phosphinothioyl groups,192y193 and of uracil at 0 - 4 by aryl groups,191 prior to oligonucleotide synthesis, and their subsequent deblocking. In a notable example,193 treatment of N2-benzoyl- 5 ’-0-monomethoxytrityl-2’- O-tetraH. Tskaku and T. Oishi, Chiba K o g y o Daigaku K e n k y u Hokoku, R i k o - h e n , 1980, 25, 61 (Chem. Abstr., 1981,94, 209 127). C. B. Reese, R. C. Titmas, and L. Valente, J. Chem. SOC., Perkin Trans. 1, 1981, 245 1. 18’ C. B. Reese and L. Zard, Nucleic A c i d s Res., 1981,9, 461 1. 190 B. L. Gaffney and R . A. Jones, Tetrahedron L e t t . , 1982, 23, 2 2 5 3 , 2257. I 9 ’ S . S. Jones, C. B. Reese, S. Sibanda, and A. Ubasawa, Tetrahedron Lett., 1981, 22, 4755. H. P. Daskalov, M. Sekine, and T. Hata, Bull. Chem. SOC. Jpn., 1981, 54, 3076. f 9 3 M . Sekine, J . - I . Matsuzaki, M . Satoh, and T. Hata, J. Org. Chem., 1982,47, 571.

206

Organophosphorus Chemistry

hydropyranylguanosine with di-n-butylphosphinothioyl bromide and triethylamine, using a catalytic quantity of 4-NN-dimethylaminopyridine, afforded (95) in nearly quantitative yield, without appreciable attack occurring at the 3’-OH group, and (95) was subsequently coupled t o 2,2,2trichloroethyl S-phenyl phosphorothioate, using (82). After removal of the dibutylphosphinothioyl group with 80% acetic acid, the desired phosphotriester was obtained, in high yield, representing a dramatic improvement over results obtained using unprotected guanosine. Novel proiecting groups for the nitrogen of the base and hydroxy-functions of the sugar of nucleosides during oligonucleotide synthesis have again been described. A number of aryl-substituted 2-phenylsulphonylethoxycarbonyl chlorides have been prepared and used t o acylate 2’-deoxythymidine at the 5’- o r 3’-hydroxy-groups, and the phenylsulphonylethoxycarbonyl groups were then evaluated with regard t o ease of introduction, stability under conditions of oligonucleotide synthesis, and ease and selectivity of removal under conditions in which other common oligonucleotide-protecting groups are stable. 194 The 2-(4-chlorophenyl)sulphonylethoxycarbonyl group fulfils these requirements and is easily removed, using triethylamine in dry pyridine or aqueous potassium ~ a r b 0 n a t e . I The ~ ~ fluoren-9-ylmethoxycarbonyl group, introduced at hydroxy-groups of the sugar of a nucleoside by using fluoren-9-ylmethoxycarbonyl chloride in pyridine, also meets these requirements, and is also removed by using triethylamine in dry ~ y r i d i n e . ‘The ~ ~ applicability of both of these groups in the synthesis of oligonucleotides was shown by their use in the construction of oligothymidylates. The 4-methoxybenzyl group has been used t o protect the 2’-OH function. It is introduced, apparently specifically at the 2’-position, by treating unprotected adenosine with sodium hydride and 4-methoxybenzyl bromide, and removed at the completion of the synthesis of the oligonucleotide by treatment with triphenylmethyl fluoroborate in dichloromethane.197 Higher yields and better selectivity in introducing the laevulinyl moiety at the 5’-position are obtained when “-protected ribonucleosides are treated with laevulinic acid and 2-chloro- 1-methylpyridinium iodide as the condensing agent, in the presence of 1,4-diazabicyclo[ 2.2.2]octane, than when DCC is used.’98 Protection of the 5’-position is, however, most commonly performed by introducing trityl o r alkoxytrityl groups. The addition of 6-nitroquinoline as base t o reactions in which adenosine and cytidine 3‘-phosphates are tritylated by using monomethoxytrityl chloride improves the yields for 5’- tritylation and suppresses reactions at 2’-OH and at amino-groups of the n ~ c l e o s i d e . ’ ~ ~ N . Balgobin, S. Josephson, and J. B. Chattopadhyaya, Tetrahedron Lett., 1981, 22, 3667. I9’S. Josephson, N . Balgobin, and J. B. Chattopadhyaya, Tetrahedron Lett., 1981, 22, 45 37. 1 9 6 C. Gioeli and J. B. Chattopadhyaya, J. Chem. SOC., Chem. Commun., 1982, 672. 197 H. Takaku and K. Kamaike, Chem. Lett., 1982, 189. 19* J. A. J. den Hartog, G. Vv‘ille, and J. H. van Boom, Recl.: J . R . Neth. Chem. SOC., 1 9 8 1 , 1 0 0 , 320. 199 J. Okupniak, R . W. Adamiak, and M. Wiewiorowski, Pol. J. Chem., 1981, 5 5 , 679 (Chem. Abstr., 1982, 96, 143 252).

194

Nucleotides and Nucleic Acids

20 7

A series of novel 4-alkoxytrityl chlorides, containing long-chain ( C B - C ~ ~ ) alkyl groups, has been prepared and used to protect the 5’-position of 2‘-deoxythymidine, and the blocked thymidines have been used in turn to construct a series of fully protected oligonucleotides.200The high lipophilicity of the 4-hexadecyloxytrityl group allows the ready separation of oligonucleotides that bear this group at the 5’-terminus from others (such as non-coupled fragments of a coupling reaction, which contains a 5’-OH terminus) by using reverse-phase h.p.1.c. This useful property has also been applied t o separate the products of the solid-phase phosphotriester synthesis of oligonucleotides.201 Trityl groups (including the long-chain alkoxy- derivatives) are readily removed with 80% acetic acid, or by using zinc bromide. Since the latter has low solubility in dichloromethane and nitromethane (the solvents previously recommended), solutions of zinc bromide in methanol- chloroform have been investigated; while trityl groups are rapidly removed from protected nucleosides, N-aryl groups on the bases are also removed at a significant rate!202 However, a 1 M solution of zinc bromide in isopropyl alcohol-methylene dichloride removes trityl groups very rapidly, without appreciable concomitant N-deacylation or depurination. Di-isobutylaluminium chloride in toluene and diethylaluminium chloride in hexane also effect rapid, quantitative detritylation of base- and sugar-protected oligonucleotides that are dissolved in methylene dichloride, without depurination or unwanted reactions with other protected Removal of a 3 ‘ - 0 acetyl group from a base-protected 2‘-deoxynucleoside 5’-(cyanoethyl phosphate), a process frequently required in ‘phosphodiester’ synthesis of oligonucleotides, is achieved by using aqueous ammonia in pyridine, with minimal removal of the cyanoethyl group.2“ The methoxyacetyl group has also been used to protect nucleotide components in a ‘phosphodiester’ synthesis.205 The 2,2,2-trichloro- t-butoxycarbonyl group has been introduced as a new protecting species for NH2 of the base in oligonucleotide synthesis.206 The intermediate reactions in the formation of phosphotriesters, as effected by coupling agents, have been investigated, using 31Pn.m.r. and kinetic methods. When the 4-chlorophenyl esters of 5’-O-trityl-2’-deoxythymidine 3’-phosphate or 3’-O-acetyl-2’-deoxythymidine 5’-phosphate are mixed with arenesulphonyl chlorides or arenesulphonyltetrazoles, the symmetrically tetrasubstituted pyrophosphate is formed.207,208 In the case of condensation using toluene-4-sulphonyltetrazole, this condensation is

*”’ 202

’03 ’04 ’05

’06

’07

’08

H.-H. Gortz and H. Seliger, Angew. Chem., Int. Ed. Engl., 1981, 20, 681. H. Seliger and H.-H. Gortz, Angew. Chem., Int. Ed. Engl., 1981, 20, 683. R. Kierzek, H. [to, R. Bhatt, and K. Itakura, Tetrahedron Lett., 1981, 22, 3761. H. Koster and N. D. Sinha, Tetrahedron Lett., 1982, 23, 2641. S. C. Srivastava,Bioorg. Chem., 1981, 10, 161. V. V. Konstantinov and A. Yu. Misharin, Bioorg. Khim., 1981, 7, 365 (Chem. Abstr., 1981, 95, 8 1 380). R. G. K. Schneiderwind and I . Ugi, Z . Naturforsch., Teil. B, 1981, 36, 1173.

V. F. Zarytova, L. M . Khalimskaya, and E. V. Yarmolinskaya, Izu. Sib. Otd. Akad. NaukSSSR, Ser. Khim. Nauk, 1980, N o . 6, p. 7 8 (Chem. Abstr., 1981, 9 5 , 8 1 377). L. I . Drozdova, V. F. Zarytova, and L. M . Khalimskaya, Izu. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk, 1 9 8 1 , No, 1, p. 125 (Chem. Abstr., 1981, 95, 9 8 192).

20 8

Organophosphorus Chemistry

catalysed by pyridine 209 and by the presence of toluene-4-sulphonic acid. If mesitylenesulphonyltriazole is used, the formation of a phosphodiester triazolide is observed.208 Formation of the internucleotidic bond by the reaction of a hydroxy-group with the pyrophosphate is slower for nucleoside 3'-OH than for 5'-OH groups, and the process is catalysed by nucleophiles such as pyridine o r t e t r a ~ o l e . ~ ' ~ The efficacy of arenesulphonyl chlorides as coupling agents is improved if 4-dimethylaminopyridine is used in place of the pyridine that is usually and is particularly good if N-methylimidazole is employed instead, when fewer unwanted by-products resulting from sulphonation of the 5'-OH component of t h e coupling mixture are seen than when using arenesulphonyltetrazoles.211 Coupling is rapid, yields are high, and the products are purer. Quinoline-8-sulphonyltetrazole 212 and quinoline- 8-sulphonyl-3-nitro- 1,2,4triazole 2 1 3 have both been described as coupling agents for oligonucleotide synthesis, the latter affording better yields in a shorter time when compared with TPS-3-nitro- 1,2,4-triazole (TPS-nt) and mesitylenesulphonyl-3-nitro1,2,4 -triazole (MS-nt). 4-Nitrobenzenesulphonyl-4'-nitroimidazolehas also been developed as a new condensing agent for phosphotriester synthesis, performing coupling reactions in good yield and more rapidly than 4-nitrobenezenesulphonyltriazole and mesitylenesulphonyl-4'-nitroimidazole,witho u t significant s i d e - r e a ~ t i o n s . ~Arenesulphonyl-[5-(pyridin-2-yl)]tetrazoles '~ have also been prepared and used for the same purpose.215 Curiously, when 5'- 0 - dimethoxytrityl- 2'- deoxythymidine 3'-(2- chlorophenyl phosphate) is coupled t o 3'-0-acetyl-2'-deoxythymidine by using MS- o r TPS-[ 5-(pyridin2-yl)l tetrazoles, only a single stereoisomer of the resultant phosphotriester seems t o be produced, while using MS-nt affords both. It is thought that the pyridinium cation that is attached t o the tetrazole may interact somehow with the phosphate ion of the phosphodiester t o impose stereospecificity , but t h e reaction requires further study. The general strategy of ' phosphotriester' synthesis of oligonucleotides has been described in previous reviews and needs n o reiteration. For syntheses in solution, it is convenient t o build up a chain, using protected dimer blocks,216 These can be prepared by sequential phosphorylation of properly substituted components that bear 3'-OH and 5'-OH groups, in a 'one-pot'

'"' 'lo

'I1 'I2

'14 'Is

V. F, Zarytova, G . V. Shishkin, and L. M. Khalimskaya, Bioorg. Khim., 1981, 7 , 9 0 0 (Chem. Abstr., 1 9 8 1 , 95, 2 0 4 334). V. F. Zarytova, E. M . Ivanova, D. G. Knorre, and H. Vorbriiggen, Dokl. Akad. Nauk SSSR, 1980, 255, 1 1 2 8 (Chem. Abstr., 1981, 95, 8 1 378). V . A. Efimov, S. V. Reverdatto, and 0. G . Chakhmakhcheva, Tetrahedron L e t t . , 1982, 2 3 , 9 6 1 . M . Yoshida and H. Takaku, Chiba K o g y o Daigaku K e n k y u Hokoku, R i k o - h e n , 1980, 2 5 , 5 3 (Chem. Abstr., 1981, 9 4 , 2 0 9 126). J. Engels, U . Krahmer, L. Zsolnai, and G. Huttner, Liebigs Ann. Chem., 1982, 745. C. A. Leach, F. Waldmeier, and C. Tamm, Helv. Chim. Acta, 1981, 64, 2 5 1 5 . E. Ohtsuka, Z . Tozuka, and M. Ikehara, Tetrahedron Lett., 1981, 22, 4 4 8 3 . N . Balgobin, S. Josephson, and J. B. Chattopadhyaya, A c t a Chem. Scand., Ser. B , 1981, 35, 2 0 1 .

Nucleotides and Nucleic Acids

209

reaction, without isolation of intermediate^.^" Noteworthy synthetic feats reported during the past year include the total synthesis of an RNA molecule with a sequence that is identical t o that of tRNAfMetof E. coli except that it lacks the modified bases of the native species218 and the total synthesis of a human leukocyte interferon gene, which is a fragment that consists of 5 14 b a ~ e - p a i r s ! ~The ’ ~ latter study involved the rapid solid-phase synthesis of 67 oligo(deoxyribonucleotides), followed by enzymatic ligation to assemble the gene. An oligonucleotide that contains 06-methylguanine has been prepared as a model of a mutagenically transformed sequence of bacteriophage $X 174 DNA,220 and an octanucleotide that contains a recognition site for the restriction endonuclease Eco R I , but containing an ara-adenosine residue close to the point of cleavage, has also been made, using phosphotriester methods.221 Automated solid-phase synthesis of oligonucleotides has arrived. Several of the accounts of automated synthesizers show considerable unity of approach,222-226which may be summarized as follows (see Scheme 2): silica gel (h.p.1.c. grade) is treated with (3-aminopropy1)triethoxysilane and the resulting aminopropylsilica is then succinylated, using succinic anhydride, t o give a support phase (96). Unreacted OH groups on the silica are blocked, using trimethylsilyl chloride. A base-protected 5’-0-dimethoxytrityl-2’deoxynucleoside is then coupled to (96), using DCC, to give (97), which is detritylated, by using zinc bromide 2233 224 or trichloroacetic acid,222y226 to give (98). The internucleotidic bond is made by coupling a base-protected 5’-0 - dimethoxy trityl- 2‘-deoxy- nucleoside 3’-(methyl phosphorochloridit e or phosphorotetrazolidite) 223 to afford (99), which is oxidized t o the corresponding phosphotriester (100) by using aqueous iodine, any unreacted 5’-OH groups that have not been consumed in the coupling reaction being eliminated by blocking with acetic anhydride 224 or diethyl p h o s p h o r ~ t r i a z o l i d i t e . ~ ~ ~ Detritylation of ( 1 00) is performed as before t o complete the addition cycle. Flushing is necessary between the stages of the addition cycle in order t o change solvents o r t o remove traces of moisture following the oxidation step. The time taken to perform a single elongation cycle varies according to the individual procedure, but ranges from 125 minutes223 t o as few as 13 minutes,226 and there are indications that even faster synthesizers will

218

’I9

K. L. Sadana, F. E. Hruska, and P. C. Loewen, Tetrahedron Lett., 1981, 22, 3367. E. Ohtsuka, S. Tanaka, T. Tanaka, T. Miyake, A. F. Markham, E. Nakagawa, T. Wakabayashi, Y . Taniyama, S. Nishikawa, R. Fukumoto, H. Uemura, T. Doi, T . Tokunaga, and M. Ikehara, Proc. Natl. Acad. Sci. USA, 1981, 78, 5493. M. D. Edge, A. R. Green, G. R. Heathcliffe, P. A . Meacock, W. Schuch, D. B. Scanlon, T. C. Atkinson, C. R. Newton, and A. F. Markham, Nature (London), 1981, 292, 7 5 6 .

’O

K. W. Fowler, G. Buchi, and J. M. Essigmann, J. Am. Chem. SOC., 1982, 104, 1050.

’” E. Ohtsuka, H. Morisawa, and M. Ikehara, Chem. Pharm. Bull., 1982, 30, 874. ”’ G. Alvarado-Urbina, G. M. Sathe, W.-C. Liu, M . F. Gillen, P. D. Duck, R . Bender, and 223 224

225

K. K. Ogilvie,Science, 1981, 214, 270. M . D. Matteucci and M. H. Caruthers,J. Am. Chem. SOC.,1981, 103, 3 1 8 5 . F. Chow, T. Kempe, and G. Palm, Nucleic Acids Res., 1981, 9, 2807. A. Elmblad, S. Josephson, and G. Palm, Nucleic Acids Res., 1982, 10, 329 1. T. Tanaka and R . L. Letsinger, Nucleic Acids Res., 1982, 10, 3249.

Organophosphorus Chemistry

210 HOOC( CH2 ) 2CONH( CH2 ) (

Z

(96)

)

HOOC

@

@

=

-

B

s i l i c a gel

DMTr

(97) R =

( 9 8 ) H = OH

(99) Reagents:

(96)

(100) (97);

X is a b s e n t

x

= 0

and DCC DMT r 0

OH

3X C13CCOOH i n C H C 1 3 or Z n B r 2 i n M e N O

B‘

B’

DMTrO d : - l - O M e

Or

c1 (99)-

(100);

2

I

i n THF

D M T i - O ~ ~ - P - O M e tet r a z o l e

I2 i n H,O

Scheme 2

appear.227 The completed oligonucleotide is demethylated at the internucleotidic links (using thiophenol and triethylamine), cleaved from the silica support with ammonia, and generally purified, using reverse-phase h.p.l.c., before final acidic removal of the 5’-dimethoxytrityl group. Claims of the yields of desired product vary between accounts, and some appear ambitious, but t h e synthesis of a decamer in overall isolated yield of 30% is typical and creditable. The use of 3-chloroperoxybenzoic acid in dichloromethane €or 227

T. H , Maugh,jr., Science, 1982, 216, 398.

Nucleotides and Nucleic A cids

21 1

performing t h e phosphite oxidation step (99) + (100) has been suggested 228 and criticized 226 o n the grounds that N4-benzoylcytidine and N6-benzoyladenosine residues are attacked under these conditions. However, a freshly prepared solution of 3-chloroperoxybenzoic acid in pyridine effected rapid, quantitative oxidation of the phosphite without side-reactions.226While automated synthesizers are certain t o attract customers with large research budgets, Letsinger’s simple but attractive approach,226 in which the derivatized silica-nucleoside template (97) is placed in the barrel of a syringe that is fitted with a filter at its base, and all the processes of synthesis are performed by drawing reagent and flush solutions into the syringe and expelling them after t h e necessary reaction, must appeal t o the impecunious researcher. Other approaches t o solid-phase synthesis which can be automated have employed polydimethylacrylamide resin 229 or polystyrene that is crosslinked with 1 % di~inylbenzene,’~’ derivatized in each case t o afford an aminoalkyl ‘handle’ which is coupled t o a 3’-O-succinylated 5’-O-dimethoxytrityl-2’-deoxynucleoside t o give a template for elongation that is strictly analogous t o (97). Following detritylation, the elongation procedure (98) +. (100) is performed in a single stage by coupling the barium salt of a baseprotected 5’-O-dimethoxytrityl-2’-deoxynucleoside 3’-(4-chlorophenyl phosphate) t o (98), using MS-nt in pyridine, each elongation cycle taking about one hour. At the completion of synthesis of the oligomer, the aryl groups are removed (using oximates Is’) prior t o cleavage from the support and deblocking of the base with ammonia, and detritylation with acetic acid. An almost identical approach has been used t o synthesize oligo(ribonuc1eotides) o n aminoalkylated controlled-pore glass.231 During the coupling reactions, an excess of the 3’-phosphorylated component is required in order t o maintain effective concentrations for coupling, and the unreacted excess is subsequently conveniently recovered from the pyridine reaction solution by adding water ( t o destroy unreacted coupling agent), evaporation t o a small volume, and addition t o ice-cold barium chloride solution, when the nucleotide is precipitated. Once again, the syntheses of ‘2-5A’ (pppA2’pS’A2’p5‘A) and its ‘core trimer’ (A2’p5’A2‘p5’A) and their analogues have received attention. Core trimer has been prepared in modest yield by polymerization of adenosine 2’(3’)-phosphate, using diphenyl phosphorochloridate, followed by enzymic cleavage of 3’-5’ internucleotidic links and the 3’-terminal phosphate and separation o f the resulting mixture of products.232 However, most syntheses of core trimer have used standard phosphotriester and these

229

230 231 232

233 234

8

K. K. Ogilvie and M. J. Nemer, Tetrahedron Lett., 1981, 2 2 , 2 5 3 1 . M . J . Gait, H . W. D. Matthes, M. Singh, and R. C. Titmas, J. Chem. SOC., Chem. Commun., 1982, 37. H . Ito, Y. Ike, S. Ikuta, and K. Itakura, Nucleic Acids Res., 1982, 10, 1755. G. K. Gough, M . J . Brunden, and P. T. Gilham, Tetrahedron Lett., 1981, 2 2 , 4 1 7 7 . M. Yu. Karpeisky, L. N . Beigelman, S. N . Mikhailov, N . Sh. Padyukova, and J . Smrt, Collect. Czech. Chem. Commun., 1982, 47, 156. R. Charubala, E. Uhlmann, and W. Pfleiderer, Liebigs .4nn. Chem., 1 9 8 1 , 2 3 9 2 . E. Ohtsuka, A. Yamane, and M. Ikehara, Chem. Pharm. Bull., 1982, 3 0 , 376.

21 2

Organophosphorus Chemistry

were also used in preparations of A2’p5’A3’pSfA, A3‘p5‘A2’p5‘A,233 and xylo -(A2‘p5’A2‘p5’A).235 Some of these procedures employed novel protecting groups and phosphorylating agents: t h e 3’-OH group was protected as its tetrahydrofuranyl derivative, which was introduced at t h e nucleoside level (using 2,3- dihydrofuran and toluene-4 -sulphonic acid) and removed, after synthesis of the oligonucleotide was complete, with 80% acetic bis-(2,2,2-trichloroethyl) phosphorochloridite in T H F , at - 78 O C , was used t o effect 5’-phosphorylation of oligonucleotides that had been protected at internucleotidic links by trichloroethyl groups but which contained unprotected adenine residues in a synthesis of pA2’pS’A2’pS’A and ‘2-5A’.236 T h e trichloroethyl groups were removed quantitatively, using zinc-copper couples (containing 16% o r 32% copper) in pentane-2,4-dioneDMF. T h e 5’-monophosphate of ‘core trimer’ has been shown t o antagonize the inhibitory effect o n protein synthesis that is displayed b y ‘2-5A’ by preventing activation of t h e ‘2-SA’-activated ribonuclease (RNase L) which degrades mRNA.237 T h e bisphosphoramidate analogue of ‘core trimer’ has reportedly been formed by treating t h e protected 2’-5‘-linked oligonucleotide that bears 4 -chlorophenyl gI oups at the internucleotidic phosphate residues 232 with tetrabutylammonium fluoride and methanolic This analogue was slightly less effective than ‘core trimer’ in inhibiting protein synthesis in intact mouse cells following its exogenous application. T h e terminal sequence of tRNA, i.e. CpCpA, fully protected apart from a 2’- terminal hydroxy-group, has been prepared by phosphotriester methods, amino-acylated (using N-benzyloxycarbonyl-amino- acids and MS-tet), and subsequently deblocked t o afford 2’(3’)-O-aminoacyl-CpCpAspecies as model compounds for investigating t h e synthesis of proteins.23g In a study of t h e formation of oligoguanylates from guanosine 5‘-phosphorimidazolidate o n oligocytidylate templates, it has been found that increasing efficiency in catalysing the oligomerization of guanylate is shown in the absence of added metal ions o r in t h e presence of Pb2+ as the oligocytidylate is increased in length from two t o six residues, while in t h e presence of Zn2+, catalysis is first observable with the pentacytidylate, becoming maximal with the h e p t a ~ y t i d y l a t e . ~ In ~ ’ the presence of Pb2+, 2’-5’ internucleotidic links are formed predominantly, while Zn2+ catalyses t h e preferential formation of 3’-5’ links, and uncatalysed reactions give a mixture of linkages. A dramatic improvement in the efficiency of poly(C)directed oligomerization at pH 7, at 0 OC, is seen when guanosine 5‘-phosphorimidazolidate is replaced by guanosine 5’-phosphoro(2-methylimidazolidate), with high yields of predominantly 3’-5‘-linked oligomers of mean chain-length 1 4 being formed.241It is thought that orientation of the substrate 235

236 237

23R

239 240 24’

G . Gosselin and J.- L. Imbach, T e t r a h e d r o n Lett., 1981, 2 2 , 4699. J. Imai and P. E‘. Torrence, J. Org. Chem., 1981, 46, 4015. P. E’. Torrence, J. Imai, and M. I . Johnston, Pvoc. Natl. Acad. Sci. U S A , 1981, 78, 5993. M. Jurovcik and J. Srnrt, FEBS Lett., 1981, 133, 178. G. Kumar, L. Celewicz, and S. Chladek, f. Org. C h e m . , 1982, 47, 634. H. Fakhrai, J. H. G. van Koode, a n d L. E. Orgel, J . Mol. E u o f . , 1981, 17, 295. T. Inoue and L. E. Orgel,.J. Am. Chetn. Soc., 1981, 103, 7666.

213

Nucleotides and Nucleic Acids

o n poly(C) ( n o polymerization is seen in its absence) and a steric effect due to t h e methyl group may combine t o line u p the attacking 3’-OH and the P-N bond that is t o be broken in a favourable geometry. The corresponding 5‘-phosphoro( 2-ethylimidazolidate) does not display comparable ability to oligomerize. The condensation of the 5’-phosphorimidazolidates of GpG and G2’p5’G in the presence of poly(C) has also been Metal ions influence both the yield of oligomers and the distribution of linkage isomers, notably with Zn2+ increasing the yield of oligomers of the 3’-5’-linked isomer with the formation of predominantly 3’-5’ links, but failing t o catalyse the formation of long oligomers from the 2’-5‘-linked isomer. The formation of 2’-5’-linked oligoinosinates 243 and oligouridylates 244 from the corresponding nucleoside 5 ’-phosphorimidazolidates in neutral imidazole buffers in the presence of Pb2+ ions has been studied. In these conditions, 2’-5’ internucleotidic links are formed preferentially, and small yields of oligomers (up t o the pentamer) are isolable. The many products that are formed in each case were identified by chemical and enzymic degradative methods. When unprotected uridine is treated with tris(imidazo1-I-y1)phosphine in pyridine-TI-IF at - 7 8 ” C , selective attack at the 2‘- and 3’-OH groups t o generate an intermediate uridine 2’,3’-cyclic phosphorimidazolidite ( l O l ) , followed by oligomerization t o ( 1 02)) is thought t o occur, and subsequent oxidation with aqueous iodine generates two series of products of the

Ura

(10.2)

type (Up), and (Up),U (n < 6).245No 5‘-UMP o r 2’,3’-UMP was found in the products, nor could any 3’-3’ o r 5‘-5’ linkages be detected. The oligomers that were formed contain both 2’-5’ and 3’-5’ links, the proportion in the UpU fraction being about 2 : I but this ratio of linkage isomers is markedly influenced by the presence of bivalent metal ions or polynucleotides. The self-complementary decanucleotide d(TGGCCAAGCTp) undergoes selfassociation in aqueous solution t o form a pseudopolymeric duplex with B-type DNA geometry, and treatment of the concatemeric duplex with a water-soluble carbodi-imide results in efficient polymerization t o give d(TGGCCAAGCTp)2-lo, containing only 3‘-5’ internucleotidic bonds.246 )

242

243 244

245

24h

R. Lohrmann, P. K. Bridson, and L. E. Orgel, J. Mol. Evol., 1981, 17, 303. H. Sawai and M . Ohno, Bull. Chem. Soc. Jpn., 1981, 54, 2 7 5 9 . H. Sawai and M. Ohno, Chcm. Pharm. Bull., 1 9 8 1 , 2 9 , 2 2 3 7 . T. Shimidzu, K. Yamana, K. Nakamichi, and A. Murakami, J . Chem. Soc., Perkin Trans. 1, 1981, 2 2 9 4 . Z. A. Shabarova, N. G. Dolinnaya, V. L. Drutsa, N . P. Melnikova, and A . A . Purmal, Nucleic Acids R e x , 198 1 , 9, 5 7 4 7 .

214

Organo p h osph or us Ch em is t ry

Enzymatic Synthesis.-5-Methoxycytidine 5'-diphosphate has been prepared from t h e nucleoside, using the phosphoramidate method described above,I4 and polymerized, using polynucleotide phosphorylase f r o m M . luteus, t o give poly-(5-methoxycytidylic acid), which forms a 1 : 1 hybrid with poly(1) that is of higher stability than poly(1) * poly(C), but which fails t o induce interferon in human cell lines.247 Polymers of adenylic acid which contain tubercidin residues, prepared similarly, form double-stranded complexes with poly(U) whose stabilities increase with their adenosine content, and which can also form triple-stranded complexes with a second molecule of poly(U), while poly(tubercidy1ic acid) forms only a 1 : 1 complex with p 0 1 y ( U ) . * ~Poly(tubercidy1ic ~ acid) is cleaved very rapidly by the singlestrand-specific nuclease S 1 , and it has been speculated that the antibiotic activity of tubercidin may in part be due to misincorporation of tubercidin in RNA, providing a weak point for preferential cleavage by nucleases. Copolymerization of CDP o r of ADP with N6-methoxyadenosine 5'-diphosphate, using polynucleotide phosphorylase, has allowed t h e preparation of a series of polymers poly(C,mo6A) and poly(A,mo6A), containing N 6 - m e t h o x y adenosine.249 When these were used as transcription templates for RNA polymerase of E. coli, uridine and cytidine were incorporated opposite N 6 methoxyadenosine in t h e newly synthesized strands, showing that the analogue can be read as A o r G , but not as U o r C. This has been rationalized o n t h e basis of tautomeric equilibrium between N6-amino- and -imino-forms of t h e modified base. When N4-methoxycytidine, which is misread only as U in transcription, is incorporated into copolymers poly(U,mo4C) and transcribed with RNA polymerase and ATP, t h e resulting duplex with the newly formed poly(A) is more stable t h a n that formed when poly(U,mo4C) is annealed t o pre-formed poly(A), but b o t h are less stable than ~ ~ ~ changes in stacking and disruption of adjacent poly(A) * p ~ l y ( U ) .While base-pairs by N4-methoxycytidine probably account f o r the overall change in stability, it has been suggested that only t h e syn rotamer of the analogue can function in transcription, and thus that t h e poly(U,mo4C) poly(A) duplex that is generated by transcription is more ordered and thus exhibits higher stability. Poly-( 2'- fluoro-, poly-(2'- chloro-, and poly-(2'- bromo- 2'deoxyadenylic acid) all behave as mRNA- t y p e templates in proteinsynthesizing systems in vitro, directing t h e formation of polylysine, with poly-(2'-fluoro-2'-deoxyadenylic acid) directing its formation even faster than p ~ l y ( A ) . ~ ~ ' When UTP and dUTP are converted firstly into their 5-mercuriacetates, and these are treated with allylamine in acetic acid in the presence of potassium tetrachloropalladate t o form 5-( 3-aminoallyl)-UTP and -dUTP respectively, and these are then allowed t o react with biotinyl N-hydroxysuccinimide ester in DMF, the biotinyl nucleotides ( 1 0 3 ) and (104) are 247

248 249 250

251

C . F. Hui and D. W. Hutchinson, Biochim. Biophys. A c t a , 1981, 656, 129. F. Seela, J . Ott, and D. Franzen, Nucleic Acids R e x , 1982, 10, 1389. B. Singer and S . Spengler, FEBS I,ett., 1982, 139, 69. S. Spengler and B. Singer, Biochemistry, 1981, 2 0 , 7290. T. Fukui, N. Kakiuchi, and M . Ikehara, Biochim. Biophys Acta, 1982, 697, 174.

215

Nucleotides a n d Nucleic Acids

formed.252 These are efficient substrates for a number of DNA polymerases and RNA polymerase, and the resulting biotin-labelled polynucleotides are selectively and quantitatively bound t o avidin-Sepharose. Polynucleotides that contain < 5% of biotin-U show denaturation, re-association, and hybridization characteristics similar t o those of untreated controls, and the biotinyl residues may serve as useful affinity probes for the sequestration of specific DNA and RNA sequences.

H40gp il 0

H

H

OH

( 1 0 3 ) R = OH

(104) R = H

0

x

19

0

HoY? OH

OH

(105) X (106)

x

= 0

=

s

Copolymerization of the 5'-diphosphate of ( 1 05) with UDP, using polynucleotide phosphorylase from M. luteus, affords 5- nitroxide- labelled poly(U), and if the content of spin-label in the copolymer is restricted t o I%, complexation with poly(A) and thermal melting transitions are unaltered by 252

P. K. Langer, A . A. Waldrop, and D. C . Ward, Pt-oc. Natl. Acad. Sci. U S A , 1 9 8 1 , 18, 6633.

216

Organophosphorus Chemistry

t h e presence of t h e Further, poly(U) that contains 1% of residues of (1 0 5 ) o r (106) can direct the synthesis of poly(phenyla1anine) o n E. coli ribosomes in vitro as efficiently as poly(U), although copolymers that contain 1% of residues of (107) [formed b y treating 4-thio-UDP with 4-(a-iodoacetamido)-2,2,6,6-tetramethylpiperidin-l-oxyl and copolymerizing the product with UDP, as above] showed reduced synthesis of p ~ l y p h e n y l a l a n i n e . ~T’h~e spin-labelled analogues were also used t o monitor competitive binding of polynucleotides t o ribosomes. Copolymers that are formed from t h e 5‘diphosphate of (1 07) and CDP b y the action of polynucleotide phosphorylase have been prepared and annealed t o p o l ~ ( I ) The . ~ ~correlation ~ time of the nitroxide moiety indicates t h a t t h e spin-labelled residues are non-intrahelical, and thus divide t h e duplex into double-helical segments. Duplexes in which t h e ratio of the residues of C : (107) 2 16 induced similar interferon titres t o poly(1) . poly(C) in various cell cultures, suggesting that double-helical segments that are about 16 base-pairs long suffice to trigger the interferon response. Poly(C) has also been spin-labelled by treatment with 3-carboxy2,2,5,5-tetramethylpyrrolin-1 -oxyl anhydride t o give samples containing 0.1% and 6% of labelled residues, and the duplexes that are formed with poly(1) were also capable of inducing interferon in cell cultures.255 Poly(A) has been spin-labelled with 3-(2-iodoacetamido)-2,2,5,5-tetramethylpyrrolidin- 1-oxyl, and t h e encapsidation of t h e polynucleotide by tobacco mosaic virus protein t o form pseudovirus has been followed by monitoring the e.p.r. signals .256 The synthesis of nanomole quantities of oligo(deoxyribonucleotides), using T 4 RNA ligase, has been reported, the enzyme being used in t h e presence o f ATP b o t h t o catalyse single addition of d(pNp) t o the 3’-OH terminus o f an oligo(deoxyribonuc1eotide) (which must be three o r more residues long) and t o join t w o oligoniers together.257 However, the reactions are very slow, and yields are variable and usually modest. Incubation of oligo(deoxyribonuc1eotides) that terminate with a 3’-phosphate with t h e enzyme and high concentrations of ATP resulted in the formation of an unusual product in which t h e adenylyl group had become linked t o the 3’-terminal phosphate, dNp . . . dN3’ppS’A, presumably because the 3’-end of the donor binds t o t h e site that is normally occupied by the 5’-terminal phosphate of the acceptor and becomes adenylylated. In a reaction that was catalysed by T4 RNA ligase, and which was meant t o join ApCpG and pGpApUp, both the expected product (ApCpGpGpApUp) and two unanticipated by-products (ApCpGpUp and ApCpGpGpApGpApUp) were obtained. Formation of these by-products can be explained if the terminal p u p is removed from t h e expected hexamer product and ligated t o ApCpG, the 253 254

255

P. W. Langemeier and A. M . Bobst, Arch. Binchem. Biophys., 1981, 208, 2 0 5 , A. J. Ozinskas, P. D. Devanesan, S. J. Keller, and A . M . Bobst, Nucleic Acids Res., 1981, 9 , 5 4 8 3 . A . M . Bobst, P. W. Langemeier, P. F. Torrence, and E. de Clercq, Biochemistry, 198 1 , 2 0 , 4 7 9 8 .

256 257

H. W. M. Hilhorst, U . D. Postma, and M . A. Hemminga, FEBS Lett., 1 9 8 2 , 1 4 2 , 301. D. M. Hinton, C. A. Brennan, and R. I . Gumport, Nucleic Acids Res., 1 9 8 2 , 1 0 , 1877.

Nucleotides and Nucleic Acids

217

remnant from the hexamer then becoming ligated t o pGpApUp. The implication, of course, is that the reaction that is catalysed by T 4 RNA ligase is reversible, and this has been shown t o be the case, with the enzyme preferentially catalysing t h e phosphorolysis by AMP o f 3 ’-terminal phosphodiester bonds of oligonucleotides that terminate in 3 ’ - p h o ~ p h a t ePhosphate .~~~ is thus a poor choice for the blocking group at the 3‘-terminus of the donor component in syntheses o f oligomers that are catalysed by T 4 RNA ligase, and other groups should be employed. T 4 RNA ligase has also been used t o probe the accessibility of the 3’-termini of ribosomal RNA molecules in intact mammalian ribosomes and ribosomal subparticles by investigating their ability t o be labelled with [32P]pCpat the 3 ’ - t e r m i n ~ sA. ~novel ~ ~ RNA ligase activity, found in wheat germ, converts linear poly(ribonuc1eotides) into covalently closed circles, apparently by condensing a 2‘,3‘-cyclic phosphate at the 3’-terminus with a 5’-phosphate at the 5I-terminus t o form a 2’-phosphomonoester, 3’-5’-phosphodiester linkage a t the point o f joining.2607261This enzyme may be a new type involved in RNA processing, the 2’,3‘-cyclic phosphate substrate having been formed during cleavage of a longer precursor. Terminal deoxy-nucleotidyl transferase may be used t o add homopolymer tails t o duplex DNA with 3’-protruding, even, o r 3’-recessed ends, and optimum conditions for adding oligo(dG) o r oligo(dC) tails that are 10-25 nucleotides long, and oligo(dA) o r oligo(dT) tails that are 25-40 units long (the optimal lengths for subsequent hybridization f o r cloning purposes) t o all types of 3’-termini have been determined.262 Complementary DNA may be transcribed from RNA molecule templates with reverse transcriptase, using a specific complementary oligo(deoxyribonucleotide) as primer, and the full-length cDNA transcript corresponding t o potato-spindle-tuber viroid has been synthesized in this way.263When bovine prolactin mRNA from a single pituitary gland was transcribed in this way, in the presence of dideoxynucleoside 5 ’-triphosphates, for gel sequencing purposes, it was found that several different primers, of sequence d[(pT)8pNpN’ 1, were active in promoting transcription, and that the resulting sequencing gels showed shifted patterns of identical sequence, indicating that the length of the 3’-non-coding sequence between the prolactin coding sequences and the poly(A) tail varies between mRNA molec u l e ~ Oligothymidylate . ~ ~ ~ analogues that contain stereoregular, alternating methylphosphonate-phosphodiester backbones, d [ Tp(Me) {TpTp(Me)) 4 IT and d [Tp(Me)(TpTp(Me)),T(pT),_, 1, prepared by using methods indicated 258

2s9 260

261

M. Krug and 0. C. Uhlenbeck, Biochemistry, 1982, 21, 1858. J. M . Kelly and R. A. Cox, FEBS L e t t . , 1981, 133, 79. M . Konarska, W. Filipowicz, H . Domdey, and H . J. Gross, Nature ( L o n d o n ) , 1981, 2 9 3 , 112. M . Konarska, W. Filipowicz, and H . J. Gross, Proc. Natl. Acad. Sci. USA, 1982, 79, 1474.

262 2.5 3

264

G. Deng and R. Wu, Nucleic A c i d s Res., 1981, 9, 4173. W. Rohde, M . Schnolzer, H . - R . Kackwitz, B. Haas, H . Seliger, and H. L. Sanger, Eur. J. B i o c h e m . , 1981, 118, 151. N . L. Sasavage, M . Smith, S. Gillam, K. P. Woychik, and F. M. Rottman, Pvoc. Natl. Acad. Sci. USA, 1 9 8 2 , 79, 2 2 3 .

218

Organophosphorus Chemistry

previously,80 and containing either one o r the other diastereoisomer exclusively at the methylphosphonate links, have been tested as primers for DNA polymerase I from E. coli and DNA polymerase a from calf thymus, but only those molecules with a 3’-oligothymidylate tail that was longer than TpT displayed activity, which increased as the tail was lengthened.265 The stereochemistry at the methylphosphonate links also affected the efficiency of the analogues in acting as primers, and markedly influenced the stability of complexes formed with poly(A). The 5’- triphosphate of (E)-5-(2-bromovinyl)-2’-deoxyuridine, a potent agent in infections by herpes simplex virus 1, is an analogue of dTTP and a substrate f o r DNA polymerase I from E. coli, but its presence in incubation mixtures does not seem t o depress the net rate of synthesis o f DNA, and it has thus been suggested that the drug exerts its effect at the level of a nucleic acid, by affecting replication of the virus.266 The ability of the 5’-triphosphate of the mutagen 9-(P-~-ribofuranosyl)-2-aminopurine t o be incorporated into DNA by DNA polymerases is principally dependent o n the efficiency of the 3’-exonuclease ‘proofreading function’ associated with these enzymes.267 The DNA polymerase activity that is induced by Epstein-Barr virus (a herpes virus) shows little discrimination between dATP and 2-aminopurine riboside 5‘-triphosphate, incorporating substantial amounts of the latter into DNA, and suggesting that modern antiviral drugs require careful study as viral mutagens.268 The 3’-exonuclease proofreading function that is associated with most prokaryotic DNA polymerases is unable t o cleave a phosphorothioate 3’-terminal link that has been formed at the end of a growing DNA chain by incorporation of a dNMPS molecule by the polymerase function, using d N T P a S as substrate.269 As a consequence, if a mismatched dNTPaS is added t o the 3’-terminus of prokaryotic DNA in error, it cannot be removed, and thus misincorporation o f dNTPaS leads t o enhanced mutagenesis. Exonuclease I11 is also unable t o digest DNA chains with a phosphorothioate link at the 3‘-terminus, and thus this enzyme, which normally hydrolyses double-stranded DNA from the 3’-termini o f both strands, can be used t o digest completely the non-thiophosphorylated strand of an asymmetrically thiophosphorylated duplex fragment.270 Alternatively, if limited digestion of such a duplex is followed by treatment with the singlestrand-specific nuclease S 1, the result is asymmetric shortening of the duplex from the end which does not contain the phosphorothioate link, and thus restriction fragments can be shortened at will from a chosen end. If phosphorothioate forms the link in one strand of the recognition sequence that is normally hydrolysed by restriction endonucleases, cleavage is inhibited, and thus recognition sequences can be selectively protected against 265

266

267 26R

269

270

P. S. Miller, N . D. Annan, K. B. McParland, and S. M . Pulford, Biochemistry, 1982, 21, 2507. J. Shgi, A. Szabolcs, A. Szemzo, and L . Otvos, Nucleic Acids R e x , 1981, 9, 6985. R. C. Pless, L. M. Levitt, and M. J . Bessman, Biochemistry, 1981, 20, 6235. D. Grossberger and W. Clough, Proc. Natl. Acad. Sci. USA, 1981, 7 8 , 7271. T. A. Kunkel, F. Eckstein, A. S. Mildvan, R. M . Koplitz, and L. A. Loeb, Pvoc. Natl. Acad. Sci. USA, 1981, 7 8 , 6734. S. D. Putney, S. J. Benkovic, and P. R. Schimmel, Proc. Natl. Acad. Sci. USA, 1981, 78, 7350.

Nucleotides and Nucleic Acids

219

cleavage by base-specific introduction of phosphorothioate at the point of cleavage, by using the appropriate dNTPaS as a substrate for DNA polymerase I when replication is performed in vitro.271 ‘2-5A’ has been labelled at its 3’-terminus, using [32P]pCp and T4 RNA ligase, and the resulting material has been used in assays to characterize the binding of ‘2-5A’ to ‘2-5AY-activated endoribonuclease 272 and t o establish the formation of ‘2-5A’ in interferon-treated cells in response to exposure t o double-stranded RNA.273 (2’-5’)-Oligoadenylate synthetase, the enzyme responsible for the formation of ‘2-5A’, can also use ATP t o add adenylate residues in 2’-5’ linkage t o NAD+, ADP-ribose, and AS’ppppS’A, resulting in the formation of NAD+2‘p5’AYNAD’ 2’p5’A2’p5’AYand analogous 2‘-5‘linked oligoadenylates that are attached to ADP-ribose and A 5 ’ ~ 4 5 ‘ A . ~ ~ ~ While some of these unusual analogues mimic the properties of ‘2-5A’, no evidence for their natural occurrence has yet been reported. An increasing number of papers has appeared dealing with the generation of site-specific mutations and their effects. Most commonly, an oligonucleotide that contains a single base mismatch is synthesized, annealed to its complementary strand on the circular gene of interest, and used as the primer for DNA polymerase I from E. c01i.2759276Following ligation, the newly synthesized strand contains a single mutated site. Other methods for sitespecific mutagenesis have included the transformation of cytosine residues into uracil by bisulphite ion in specifically created single-stranded regions 277 and the use of error-prone DNA polymerases that lack 3’-exonuclease activity t o incorporate mismatched bases.278 The references cited are representative; more extensive discussion of this topic lies further into the area of molecular biology than is the purview of this Report, Sequencing.-Reviews by Sanger 279 and Gilbert ,280 effectively their Nobel Prize lectures, describe the development of their gel-sequencing methods. Sanger’s review also describes the basis of ‘shotgun sequencing’ ,281 which requires cloning techniques 282 and which, although beyond the scope of the present Report, must be appreciated by anyone seeking a grasp of modern sequencing methods. In an improved enzymatic method for sequencing DNA,283 partial digestion of a duplex DNA fragment with exonuclease I11 is H.-P. Vosberg a n d F. Eckstein, J. Biol. Chem., 1982, 2 5 7 , 6595. T. W. Nilsen, D. L. Wood, and C. Baglioni, J. Biol. Chem., 198 1, 256, 10 75 1. T. W. Nilsen, P. A. Maroney, and C. Baglioni, J. Biol. Chem., 1981, 256, 7806. 2 7 4 P. J. Cayley and I. M. Kerr, Eur. J. Biochem., 1982, 1 2 2 , 601. 2 7 5 R. B. Wallace, M. Schold, M. J. Johnson, P. Dembek, and K. Itakura, Nucleic A c i d s Res., 1981, 9 , 3647. 2 7 6 G. F. Temple, A. M. Dozy, K. L. Roy, and Y. W. Kan, Nature (London), 1982, 2 9 6 , 537. 277 M. S. Ciampi, D. A. Melton, and R. Cortese, Proc. Natl. Acad. Sci. USA, 1982, 7 9 ,

271 272

273

1388.

R. A. Zakour and L. A. Loeb, Nature (London), 1982, 2 9 5 , 708. 2 7 9 F. Sanger, Science, 1981, 214, 1205. ”O W. Gilbert, Science, 1981, 2 1 4 , 1305. S. Anderson, Nucleic A c i d s R e x , 1981, 9 , 3015. 2 R 2 U. Ruther, M. Koenen, K. O t t o , and B. Muller-Hill, Nucleic Acids Res., 1981, 9, 4087. 283 L.-H. G u o and R. Wu, Nucleic Acids R e x , 1982, 1 0 , 2065. 278

Organophosphorus Chemistry

220

first performed, in order t o provide an array of shortened 3‘-ends in each chain in t h e duplex, the resulting DNA is divided into four portions, and repair synthesis is then performed, using either a different labelled dideoxynucleoside 5’-triphosphate with the deoxynucleoside triphosphate mixture for each portion, o r else a single [ C I - ~ ~ P I ~ N for T P each portion.279 Following asymmetric cleavage, using a restriction enzyme, the labelled products are separated and sequenced o n denaturing polyacrylamide gels. T h e use of dimethyl sulphate t o effect depurination, particularly the removal of adenine residues, in the original Maxam-Gilbert technique 280 was superseded by t h e use of acid, which is less specific but more controllable.284 The addition of silver ions t o a solution of DNA in 0.02M-nitric acid suppresses depurination by 80% overall, but t o a much greater extent at guanine residues than at adenine, thus creating conditions for the specific removal of adenine residues prior t o cleavage of the chain and its sequencing.285 It is argued that the charged state of the purine following the binding of the silver ion at N-1 accounts for the specificity of loss of base. Diethyl pyrocarbonate has also been used t o sequence adenines and guanines in DNA.286 At p H 5 , both of these bases are attacked t o give carbethoxyderivatives in which the imidazole ring has been opened, and subsequent treatment with base leads t o loss of t h e remnants of the base and cleavage of t h e chain; at p H 8 , only guanine is attacked appreciably, there being weak attack at cystosine and none at adenine. The formation of stable secondary structures such as duplexes, hairpin loops, etc., during sequencing using polyacrylamide gel electrophoresis gives rise t o ‘band compression’ and obscures resolution, but can be largely or wholly eliminated by using gels that contain 16M o r 20M f ~ r m a m i d e . ~ ~ ~ Another useful ploy t o relieve band compression is t o treat the nucleic acid with chloroacetaldehyde,288which reacts specifically with adenine and with cytosine residues t o form etheno-derivatives 289 that cannot participate in normal base-pairing. A pentacytidylate sequence in a tRNAVal from a species of Drosophila has been resolved by this method 288 which requires only partial modification of the sequence in order t o suppress the secondary structure, since complete modification would render the base-specific cleavage reactions (in this case, treatment with RNase A) ineffective. T h e Maxam-Gilbert sequencing technique utilizes reactions which render a particular set of phosphodiester bonds, adjacent t o certain specific bases, susceptible t o cleavage. Much useful information can be obtained regarding the conformation of nucleic acids and the interactions between nucleic acid and protein molecules by determining which portions of the polynucleotides are attacked by chemical and enzyme reagents, resulting in direct or indirect chain cleavage, and which are not. F o r instance, methylation of folded and M. Maxam a n d W. Gilbert, Methods Enzyniol., 1980, 65, 4 9 9 .

284

A.

286

A . S. Krayev, FEBS Lett., 1 9 8 1 , 130, 19.

2R7

R. Frank, D. Muller, and C . Wolff, Nucleic AcidsRes., 1981, 9, 4 9 6 7 .

’” D. E. Pulleyblank, FEBS Lett., 1982, 1 3 9 , 2 7 6 .

”’ W. R. A d d i s o n , I. C. Gillam, a n d G . M. Tener, J . B i d . Chetn., 1982, 2 5 7 , 6 7 4 . 2R9

W. J. Krzyzosiak, J . Biernat, J . Ciesiolka, K. G u l e w i c z , and M.Wiewiorowski, Nucleic Acids Res., 1981, 9, 2 8 4 1 .

Nucleotides and Nucleic Acids

22 1

unfolded end-labelled tRNA molecules, using ethylnitrosourea, followed by brief treatment at 9OoC, at p H 9 , t o split the phosphotriesters that are formed, and subsequent comparison of the resultant fragments after their separation o n polyacrylamide gels, indicates which phosphate groups are unavailable for alkylation in folded tRNA.290 Similar approaches t o investigating the structure of a tRNA have utilized double-strand-specific ribonucleases from cobra venom 291 and nuclease P 1;292 the conformational changes that are induced in tRNAPhe upon binding intercalators have been monitored, using nuclease S 1 and ribonuclease T1.”’Similar agents, and also diethyl p y r ~ c a r b o n a t e , ~have ’ ~ been used t o investigate the topography o f ribosomal RNA in ribosomes and its interaction with ribosomal proteins.294’295 Another investigation has employed a set of synthetic oligo(deoxyribonucleotides), complementary to part of the 1 6 s rRNA sequence of E. coli, t o test the ability of different areas of the rRNA t o form hybrids; these were cleaved, using the double-stranded-hybrid-specificiibonuclease H, and the cleavage sites were determined o n sequencing gels.296 Based o n the finding that the non-exchangeable aromatic and anorneric protons of RNA nucleosides exhibit chemical shifts which, at 7OoC, are a function of the nature of their nearest and next-nearest neighbours in the RNA sequence, a formula for calculating chemical shifts as a function of sequence has been devised and shown t o be applicable for sequencing some short RNA 01igomers.~’~The method requires less than one milligram o f RNA, and spectra are run at 7 0 “C t o minimize secondary structural effects.

Other Studies.-RNA o r DNA that contains 4-thiouracil residues (which can be introduced by treatment of the native nucleic acid with liquid hydrogen sulphide in aqueous pyridine) can be labelled by successive treatment with cyanogen bromide in phosphate buffer and sodium [ 35S]sulphide in water, the 4-thiocyanatouracil residues that are formed being attacked by the sulphide to give 4-[35S]thio~ra~i1.298 The labelled nucleic acids can be used t o provide a sensitive assay for nucleolytic enzymes. Poly(U) has been acetoxymercuriated at the 5-position and then treated with styrene o r 3-nitrostyrene in the presence of lithium tetrachloropalladate t o give poly [ U,S(E)-styryl-U] and poly [ U,S(E)-( 3-nitrostyryl)U], respectively, in moderate yield^.^'' The styryl analogue contained some 10%o f 5-[ (E)-styryll290 291

292

293 294

295

296

297

29R 299

V. V. Vlassov, R. GiegC, and J . P. Ebel, Eur. J. Biochem., 1981, 119, 5 1 . R. E. Lockard and A. Kumar, Nucleic Acids Res., 1981, 9, 5 1 2 5 ; A . S. Butorin, P. Remy, J. P. Ebel, and S . K. Vassilenko, Eur. J . Biochem., 1 9 8 2 , 121, 5 8 7 . K. S. Aultman and S . H. Chang, Eur. J. Biochem., 1982, 1 2 4 , 4 7 1 . P. E. Nielsen, Biochim. Biophys. Acta, 1981, 6 5 5 , 89. T. A. Walker. K. D. Johnson, G. J . Olsen, M. A . Peters, and N . R . Pace, Biochemistry, 1982, 21, 2 3 2 0 ; A. C. Lo and R . N . Nazar, J. B i d . Chem.. 1982, 2 5 7 , 3516. S. Douthwaite, A. Christensen, and R. A . Garrett, Biochemistry, 1 9 8 2 , 21, 2 3 1 3 ; A. S. Mankin, A. M. Kopylov, and A. A . Bogdanov, FEBS Lett., 1981, 134, 1 1 . A . S . Mankin, E . A. Skripkin, N . V. Chichkova, A . M. Kopylov, and A . A. Bogdanov, F E B S L e t t . , 1 9 8 1 , 131, 2 5 3 . P. A . Hader, T. Neilson, D. Alkema, E. C. Kofoid, and M . C . Ganoza, FEBS I x t t . , 1981, 1 3 6 , 6 5 . K. Miura, S. Sato, K. Takagi, J . Tohyama, and T. Ueda, Chem. Phavm. Bull., 1982, 30, 1 0 6 9 . C . F. Bigge, K. E. Lizotte, J . S. Panek, and M . P. Mertes, J. Carbohydr., Nucleosides, Nudeotides, 1 9 8 1 , 8 , 2 9 5 .

222

Organo p h o s p h o r us Ch ern istry

uridine residues, and t h e 3-nitrostyryl analogue u p t o 24% of 5-[(E)-3-nitrostyryl] uridine. T h e modified polymers did not display ordered structure in solution, o r hydridize with poly(A). Similar treatment of UpU, followed by alkaline degradation of t h e styrylated products, showed that both 5'- and 3'-residues were modified equally, without preference. The ease of transition from the B conformation of DNA t o t h e Z conformation of poly[d(G-Cj] molecules has been studied as a function of increasing methylation of the guanine residues at N-7 by dimethyl s ~ l p h a t e Methylation .~~ accelerates the B + Z conversion in salt solutions, possibly because t h e positive charge that is introduced at N-7 upon methylation will tend to lower t h e inter-strand repulsion between the negatively charged phosphate groups, and, since the phosphate groups are closer together in the Z structure o f DNA than in the B structure, the energy that is involved in bringing the strands together will be lowered. Treatment of d(TpT) and d [ ( T p j S T ] , protected at the internucleotidic links by chlorophenyl groups, with fluoride and 6-aminohexanol results in replacement of the chlorophenyl groups with 6-aminohexyl groups, and the resulting species are consequently positively charged in neutral solution.301 Upon formation of a complex with poly(A), that formed by t h e positively charged d {[Tp(H3N'[ CH2 1 6 ) 1 S T } displays higher thermal stability than those that are formed by t h e neutral d { [ T p ( E t ) l S T ) and t h e negatively charged d [ ( T p ) s T ] . Both tRNA and 1 6 s rRNA have been treated with N-(2-aminoethyl)-2,4-dinitroaniline in t h e presence of excess triphenylphosphine and 2,2'-dipyridyl disulphide t o afford t h e corresponding 5'terminal phosphoramidates in high yield."' The sensitivity of t h e aminoacylation reaction of bovine tRNATrp t o t h e conversion of exposed cytidine residues in the structure into uridine has been investigated.303 T h e tRNA, modified (using bisulphite) until only 50% of it was chargeable, was divided into charged and uncharged fractions, which were sequenced t o determine t h e sites of modification. While cytidine residues in the second position of t h e anticodon loop and the CCA terminus could be modified without loss o f activity, t h e o t h e r cytidine residues in t h e anticodon loop could not. An ingenious method for t h e chemical excision of apurinic acid from RNA has been developed3w and demonstrated o n a model compound as follows: guanylyl(3'-5' )-7-methylguanosine 3'-( methyl phosphate) was depurinated t o afford ( 1 08), which was treated with 2-aminopyridine at pH 4.5 for five days, at 45 OC, t o afford 3'-GMP almost quantitatively. If aniline was used instead of 2-aminopyridine, n o 3'-GMP was formed. T h e putative course of t h e reaction is indicated in Scheme 3. It is thought that t h e pyridine ring stabilizes the enol ( 109) by hydrogen- bonding, thus rendering t h e proton A. Moller, A. N o r d h e i m , S. R. Nichols, a n d A . R i c h , Proc. N a t l . Acad. Sci. U S A , 198 1, 78, 4777. 30' N . K. D a n i l y u k , V . A . P e t r e n k o , P. I . P o z d n y a k o v , G. F. Sivolobova, a n d T. N . S h u b i n a , Biooug. K h i m . , 1981, 7, 703 (C'hern. Ahstv., 1981, 9 5 , 1 3 3 293). j o 2 L. V . Mochalova, 1. N . Shatskii, a n d A . A . Bogdanov, Bioorg. K h i m . , 1982, 8, 239 (Chern. Ahstr., 1982, 96, 163 108). 303 V. S h . S c h e i n k e r , S. E'. Beresten, T. D. Mashkova, A . M. M a z o , and L. L Kisselev, FEBS Lett., 198 1 , 132, 349. 304 K. Nishikawa, B. L. A d a m s , a n d S. M . H e c h t , J . A m . Chcm. Soc., 1982, 104, 326. '0°

Nucleotides a n d Nucleic A cids

223

Cruo- 3’ -0

I

0

I O=P-OH

I

OH

\

Guo- 3 ’ -0

I I

O=P-

OH

(109)

L/

\ t

:1‘ - G V P

Scheme 3

at C-4 of t h e ribose remnant more acidic, and promoting a second 0-elimination t o release 3’-GMP. T h e method was applied t o excise the Y residue of tRNAPhe: t h e Y base is easily removed in acid, and removal of the ribose remnant (as described above), followed by removal of the flanking phosphates o n the resultant tRNA half-molecules (with alkaline phosphatase),

224

Organ o p h o s ph or us Ch e m istry

phosphorylation of the 5’-OH at the gap (with polynucleotide kinase), and ligation with T 4 RNA ligase resulted in a novel t R N A species with six nucleotides (instead of seven) in t h e anticodon loop. T h e facile removal of t h e Y base a t pH 2.9 has also been used as t h e starting point of an enzymic and t h e method for excision and replacement of t h e anticodon dependence upon the anticodon sequence that is inserted of t h e ability of t h e t R N A species that is formed t o be aminoacylated was investigated. DNA has been alkylated with N-[’4C]methyl-N-nitrosourea and with N - [‘‘C]ethyl-N-nitrosourea,these being t w o reagents which alkylate t h e internucleotidic link, and sedimentation analysis of the alkylated DNA, before and after hydrolysis, was used to determine the number of single-strand breaks that are produced o n hydrolysis of the resulting triesters. Also, vacuum distillation of t h e alkylated DNA solutions before and after hydrolysis was used t o estimate (using scintillation counting) t h e proportion of phosphotriester hydrolyses which resulted in release of the labelled alcohol. A substantial amount of alkylation at t h e phosphodiester link was observed with both reagents, and in each case around 70% of t h e phosphotriesters that were formed were hydrolysed in alkali t o give single-strand breaks.306 T h e covalent adducts that are formed upon exposure of DNA t o mutagens may be detected by hydrolysis of t h e modified DNA t o 2’-deoxynucleoside 3’-phosphates, using micrococcal nuclease and spleen exonuclease, followed b y labelling with T4 polynucleotide kinase and [y-”PIATP, t o afford a mixture of d-[32P]pNp species, which are separated by two- dimensional chromatography o n PEIcellulose plates and detected by autoradiography. T h e pattern of spots produced, showing both chemically altered nucleotides as well as t h e normal DNA constituents, is characteristic of the mutagen employed, and the method gives a convenient procedure for detecting mutagenic damage in DNA.307 In t h e presence of Fe2+ and oxygen, bleomycin causes strand scission in DNA, accompanied by the release of free bases and of f o u r compounds, of low molecular weight, which afford the free bases if hydrolysed with formic acid and which react with phenylhydrazine t o give 1-phenylpyrazole. Two of these intermediates have been shown t o be 3-(adenin-9’-yl)prop-2-enal and 3-(thymin-1 ’-yl)prop-2-enal, structures which have been confirmed by chemical synthesis. Also, oligonucleotides that are formed upon bleomycininduced strand scission contain glycollic acid residues esterified t o t h e 3’-terminal phosphates.308 O n the basis of these findings, a n interesting mechanism for t h e cleavage has been proposed (Scheme 4), in which the vital requirements are abstraction of a hydrogen atom at C-4’ , followed by reaction with oxygen and a Fenton-type reaction t o give t h e peroxide (1 10). A simple 1,2-shift, with hydration of t h e intermediate cation, generates ( 1 1 l ) , which dissociates t o give (1 12) and a 5’-phosphate- terminated 305

306 307

A. G. Bruce and 0. C . Uhlenbeck, Biochemistvy, 1 9 8 2 , 21, 8 5 5 . A. R. C‘rathorn and K. V . S h o o t e r , Biochim. Biophys. Actu, 1982, 6 9 7 , 2 5 9 , K. Randerath, M . V. Keddy, and R. C. Gupta, Pvoc. Nutl. Acud. Sci. U S A , 1981, 7 8 , 6126.

308

L. Giloni, M . Takeshita, F. Johnson, C. Iden, and A. P. Grollman, J. B i d . Chem., 1981, 2 5 6 , 8 6 0 8 .

Nucleotides and Nucleic Acids

225

0

0

II

R1O-P-O OH

1

0

0

I O=P-OH I

1

O=P-OH

1

OR

OR2

;HvOy

0

0

R10-P-0

iii

P

0

0

'0

HO 0

0

1 1OR^

1

O=P-OH

O=D-OM

1

/ y

OR2

0

0

I1

-

R1O-P-O OH 0

R1 0-7-0 II

(110)

O y n

OH 0

HO 0

I

O=P-OH

I

ORZ 0

II 1

/

R'O-P-OCH~COOH

+

R-CH=CH-CHO

OH Reagents: i, bleomycin-b'e*+-O, or O H ; i i , 0,; i i i , E'e2+;iv, H'; v, OH

Scheme 4

DNA fragment, and p-elimination in ( 1 12) gives the observed products. The chromophore of the antitumour drug neocarzinostatin also degrades DNA in the presence of oxygen and mercaptoethanol, and 2'-deoxythymidine-S'aldehyde has been identified at the breaks in t h e strands.309 Selective oxidation at the 5'-carbon has therefore taken place, and it is tempting t o speculate that a process that is not unrelated t o the initial stages of Scheme 4 309

L. S. Kappen, I. H. Goldberg, and J . M . Liesch, Puoc. Natl. A c a d . Sci. U S A , 1982, 79, 744.

226

Organ op h nsp h or us Ch em is try

operates here also. DNA can be cleaved b o t h at a p u r i n i ~ " ' ~ and ~~~ apyrimidinic 3 1 2 sites by the tripeptides Lys-Trp-Lys and Lys-Tyr- Lys, with 3'-OH and 5'-phosphoryl termini being formed at the nick. The reaction is not light-dependent, and DNA that lacks such sites is not cleaved. Lys-LysLys and Lys-Ala-Lys-Oh4e can also nick apurinic DNA, b u t with much lower efficiency. It is thought that efficient stacking o f t h e aromatic aminoacids with t h e base residues that flank t h e de-based site may bring t h e primary amino-groups of t h e lysine residues into close proximity with t h e site, thus facilitating t h e formation of a Schiff-base and/or 0-elimination (cf. Scheme 3).311 If the damage t o DNA that is induced by exposure t o U.V.light occurs at or near their recognition sequences, cleavage by restriction endonucleases is suppressed, with the degree of inhibition corresponding roughly t o t h e relative frequency of formation of pyrimidine dimers in t h e recognition sequence^.^'^ From t h e distance between potential sites for formation of dimers and restriction sites in DNA of known sequence, it can be deduced that t h e range of influence of t h e pyrimidine dimers stretches for 1-3 basepairs along the DNA molecule. N-(Guanin- 8-yl)-l-naphthylamine has been identified in an acid hydrolysate of a nuclease P I digest of calf thymus DNA that had been exposed t o l-naphthylhydr~xylamine.~~~ Since this agent is believed t o be t h e activated form of t h e urinary bladder carcinogen l-naphthylamine, this observation may be significant with respect t o its carcinogenic action. Condensation of dAMP with d( [ 32PlpTpT) by phosphodiester methods, followed by lengthening of t h e oligothymidylate tail (using dTTP and terminal deoxynucleotidyl transferase) and depurination in acid, affords d {pRib [ 32P]pT[poly(T)]} [with 2-deoxy-5-phosphoribose at the 5'-terminus of poly(dT)]; treatment of this with alkaline phosphatase gives d(Rib[32P]pT[poly(T)l) . 3 1 5 These compounds are modelsubstrates for the repair products resulting from excision of a uracil base from DNA; o n treatment with alkali, both predictably afford [ 5'-"P]poly(dT) (cf. Scheme 3). This result indicates that the origin of a population of small DNA fragments with 5'-phosphorylated termini that was isolated from an 6: coli mutant after alkaline treatment lies in uracil repair fragments, rather than in intermediates that were formed during discontinuous replication. T h e valuable antitumour drug cis-diamminedichloroplatinum(1I ) has been bound t o a plasmid DNA restriction fragment of known sequence, in which one (5'-end-labelled) strand contained several oligo(dG) segments, and the sites of binding were determined by digestion (using exonuclease 111) followed by removal of t h e drug with cyanide, and separation of the resulting 310 311

3'2 313

314

315

J. Pierre, and J . Lava1,J. Biol. Chern., 1981, 2 5 6 , 1 0 2 1 7 . T. Behmooras, J . - J . Toulmk, and C. H k l h e , Nature ( L o n d o n ) , 1981, 2 9 2 , 8 5 8 . N. Duker and D. M . Hart, Biochem. Biophys. Res. Commun., 1982, 1 0 5 , 1433. J . E. Cleaver, L. Samson, and G. H. Thomas, Biochinz. Biophys. Actn, 1 9 8 2 , 6 9 7 , 255. Y . Murofushi, Y . Hashirnoto, K. Shudo, and T . Okamoto, Chem. Phann. Bull., 1981, 29, 2730.

Y . Machida, T. Okazaki, T. Miyake, E. Ohtsuka, and M . Ikehara, Nucleic Acids R e x , 1981, 9 , 4 7 5 5 .

227

Nucleotides and Nucleic Acids

fragments o n sequencing gels.3i6 The resulting pattern indicates that the drug binds specifically to (dG), (dC), sequences ( n > 2), and other evidence suggests binding at N-7 of adjacent guanine bases. If the drug binds within three base- pairs’ distance of the recognition sequence of the restriction endonuclease Barn H1, cleavage by the enzyme is eliminated.317The drug will also bind t o the trinucleotide d(GpCpG), and a ‘ H n.m.r. study of the chemical shifts of the protons of the base as a function of pH indicates that platinum is bound at N-7 of both guanine bases.318 It thus seems that the platinum atom can form a bridge between two guanines that are separated by a third base, at least at the trinucleotide level. Studies of enhancement of the fluorescence of Tb3+ in the presence of polynucleotides show that it does not occur exclusively in the presence o f single-stranded polynucleotides, as previously reported, but is also observed, t o a lesser extent, with double-stranded helices.319 The degree of enhancement varies with base composition,320 and poly(deoxyribonuc1eotide) duplexes also enhance the fluorescence, albeit at higher ratios of Tb3+ t o P. It is therefore thought that Tb3+ binds t o the phosphate group in polynucleotides (with possible co-ordination to 2’-OH in ribo-polymers) and possibly also t o electron-donating groups on the nucleoside bases, *

5 Analytical Techniques and Physical Methods

A recent article, discussing results of single- crystal X-ray analyses of doublestranded DNA molecules of predetermined sequence, exemplifying the A, B, and Z structures of DNA, provides a useful update.32’ The X-ray structure of d(pApTpApT), determined at 1 resolution, shows that the ApT and TpA sequences have different phosphodiester conformations, and that deoxyribose pucker and sugar orientation alternate along the chain, depending o n the base (3’-endo for A , 2’-endo for T).322 Extrapolating these results suggests that poly [d(A-T)] has B- type structure, with sequence-dependent alternations of deoxyribose pucker and conformation of the phosphodiester bridge. Phosphorus-3 1 n.m.r. studies o n adenosine 5’-[a,P-methyleneltriphosphate, adenosine 5’-[ 0,y-methyleneltriphosphate,adenosine 5’-methylened i p h ~ s p h o n a t e ,324 ~ ~ ~adenosine , 5’-[ P-fluoroldiphosphate, and adenosine 5’-[y-fluoro]triphosphate 324 at varying values of pH and concentrations of Mg2+ have been performed, and the values of PKa for the dissociations of phosphate determined. Using high magnetic fields, a high temperature, and a solvent of low viscosity allows useful 1 7 0 n.m.r. spectroscopic data o f

a

316 317

318

3!9 320 321

322

323 3 24

T. D. Tullius and S. J. Lippard,J. A m . Chem. SOC., 1981, 103, 4620. H. M. Ushay, T. D. Tullius, and S. J . Lippard, Biochemistry, 1981, 2 0 , 3744. A. T. M. Marcelis, J. H . J. den Hartog, and J . Reedijk, J. A m . Chem. SOC.,1982, 104, 2664. T. Haertli, J . Augustyniak, and W. Guschlbauer, Nucleic Acids Res., 1981, 9, 6191. D. S. Gross and H. Simpkins,J. Biol. Chem., 1981, 256, 9 5 9 3 . R. E. Dickerson, H. R. Drew, B. N . Conner, R. M. Wing, A. V. Fratini, and M. L. Kopka, Science, 1982, 2 16, 475. M. A. Viswamitra, Z. Shakked, P . G. Jones, G. M . Sheldrick, S. A . Salisbury, and 0. Kennard, Biopolymers, 1982, 2 1, 5 13. L. H. Schliselfeld, C. T. Burt, and R. J. Labotka, Biochemistry, 1982, 21, 317. H. J . Vogel and W. A . Bridger, Biochemistry, 1982, 2 1, 394.

Organ o p h o sph or us Che m is try

228

appropriately labelled nucleotides t o be obtained, and the I7O chemical shifts and one-bond 31P-170 coupling constants in [170]AMP, [ ( u - ~ ~ O I A D P , [P-170]ADP, [(u-'~O]ATP, [ p-170]ATP, and [y-170]ATP have been measured.325 An investigation of the I7O n.m.r. spectra of ADP and ATP, variously labelled with the isotope in both bridge and non-bridge positions, in the presence and absence of Mg2+, has been made t o determine the mode of co-ordination in the metal-nucleotide complexes.326 The metal ion interacts with P, and Po of ADP, and predominantly with Pp and P, of ATP, as judged by line-broadening of the 170n.m.r. resonances. The interaction of DNA with Mg2+, Mn2+, and Co2+has been studied, using 31 P n.m.r. spectroscopy. The paramagnetic ions significantly alter the rates of relaxation of the phosphorus nuclei, allowing calculation of the metalphosphorus internuclear distances.327 Since each phosphorus nucleus in an oligonucleotide is coupled t o H-S', H-5", H-4', and H-3' of its flanking sugar residues, the 31P n.m.r. resonances may be assigned unambiguously, for any oligonucleotides whose H resonances in the furanose- backbone region have been completely resolved and assigned, by specific irradiation of the 31P resonance and observation of the resulting changes in the ' H n.m.r. spectrum.32s The temperature dependence of the 31P n.m.r. spectra of poly[d(G-C)], [d(G-C)]4, yeast tRNAPhe, and mixtures of poly(A) and oligo(U) in various proportions has been examined, with a view t o gaining torsional information o n the conformations of phosphate esters in double-, triple-, and 'Z'-helical nucleic acids.329 Since random coil and double and triple helices exhibit different 31P n.m.r. signals, the technique can be used t o estimate the fractions of the different strand forms in the solution. While the acidic form of poly(A) exhibits only a single phosphorus resonance in its 31P n.m.r. spe9trum below the melting temperature, poly(A) - poly(U) displays two, of similar intensity, and poly(A) 2poly(U) shows three."' Again, it is thought that the multiplicity of resonances results from the strands in the complexes having different conformations of the phosphate backbone. Specific labelling o f the phosphate groups in individual strands with 1 7 0 might go far towards resolving uncertainties. The equilibrium between the B and Z forms of poly[d(G-C)l in LiCl solutions as a function of temperature has been monitored, using 31P n.m.r.331 Once again, 31P n.m.r. has been used t o study nucleotide-protein interactions such as the energetics and interconversion of two myosin SF-1-ADP complexes,332 the binding of the phosphate groups in a complex of ATP with a nitrated derivative of G - a ~ t i n and , ~ ~the ~ metal ion-phosphorus distances *

328

J . A . Gerlt, P. C . D e m o u , and S . Mehdi, J. A m . Chem. SOC., 1982, 104, 2848. S. L. Huang, and M.-D. Tsai, Biochemistry, 1982, 21, 95 1 . J. Granot, J . Feigon, and D . R. Kearns, Biopolymevs, 1982, 21, 181. D. M. Cheng, L.-S. Kan, P. S. Miller, E. E. Leutzinger, and P. 0. P. T'so, Biopolymers,

329

D. G. Gorenstein, B. A . L u x o n , E. M . Goldfield, K. Lai, and D. Vegeais, Biochemistry,

330

331

J . L. Alderfer and G. L. H a z e l , J . A m . Chem. SOC., 1981, 103, 5925. D . J. Patel, S. A. Kozlowski, A. Nordheim, and A . Rich, Proc. Natl. Acad. Sci. U S A ,

332

J. W. Shriver and B. D . Sykes, Biochemistry,

333

M. Brauer and B. D . Sykes, Biochemistry, 1981, 2 0 , 6767.

325

326 327

1982, 2 1 , 697. 1982, 2 1 , 580.

1982, 79, 1413. 1981, 20, 6357.

h’ucleotides and Nucleic Acids

229

between Mn2+ and ATP that is bound t o RNA polymerase from E. coli under simulated transcription conditions.334 Metabolic studies employing the technique have included t h e determination of the steady-state rate of synthesis of ATP in perfused rat heart (using 31P n.m.r. saturation transfer),335 the measurement of photophosphorylation in intact cells o f Chromatium v i n o ~ u m and , ~ ~the ~ internal pH and state of compartmentalization of ATP in synaptic vesicles.337 In the binding of several mono-, di-, and oligo-nucleotides that bear 5’-phosphate groups t o the gene 5 protein of bacteriophage fd, 31P n.m.r. data suggest that different phosphodiester conformations occur in the bound oligomers, and that binding of the 5’-terminal phosphate is of critical importance.338 DNA is effectively immobilized by tight binding t o histones in eukaryotic chromosomal complexes, and solid-state 31 P n.m.r. methods are required t o obtain useful data, but results obtained using magicangle spinning suggest that the packaging of DNA by the proteins does not introduce major distortions in most of the phosphodiester links that are present.339 The effects of various intercalating drugs o n the 31P n.m.r. spectra of DNA preparations have been ~ h a r a c t e r i z e d . ~ ~ ’ Acriflavin-agarose displays excellent resolution in the chromatographic separation of nucleotides o r oligonucleotides, working in sodium acetate buffer, at pH 4.M1While the separation time is slightly longer, the results are superior t o those obtainable with the widely used RPC-5. A phenazinium dye, covalently bound t o poly(ethy1ene glycol), which shows specific affinity for G-C pairs, has been used t o effect DNA fractionation in aqueous twophase partition systems.342 Novel polyacrylamide-bound nitrobenzeneboronic acid species with pKa values close t o 7.0 have been prepared and used t o purify isoaccepting t RNA speciesM3 Sulphydryl- cellulose has been described as an effective new medium for the affinity chromatography of mercuriated polynucleotides.344 A novel method for the determination of t h e length of oligonucleotide chains consists in treating the oligomer first with alkaline phosphatase, then with snake venom phosphodiesterase, and separating t h e resulting mixture, using reverse-phase ion-pair h.p.1.c. A single nucleoside (the 5’-terminus) is observed, and determination of the mole fractions of the other, nucleotidic products allows the length of the chain and the composition t o be d e d ~ c e d . ~ ’ I . A. Slepneva and L. M. Weiner, FEBS Lett., 1981, 130, 283. P. M. Matthews, J . L. Bland, D. G. Gadian, and G . K. Radda, Biochem. Biophys. Res. Commun., 1981, 103, 1052. 3 3 6 K. Nicolay, K. J . Hellingwerf, H . van Gemerden, R . Kaptein, and W. N. Konings, FEBS Lett., 1982, 138, 249. 3 3 7 H . H. Fuldner and H. Stad!er, Eur. J. Biochem., 1982, 121, 519. 3 3 R T. P. O’Connor and J . E. Coleman, Biochemistry, 1982, 21, 848. 3 3 9 J . A. Di Verdi, S. J . Opella, R.-I. Ma, N . R. Kallenbach, and N . C. Seeman, Biochem. Biophys. Res. Cornrnun., 1981, 102, 885. 340 W. D. Wilson, R. A. Keel, and Y . H. Mariam, J. A m . Chem. Soc., 1981, 103, 6267; W. D. Wilson and R. L . Jones, Nucleic Acids R e x , 1982, 10, 1399. 3 4 1 E. Boschetti, P. Girot, A. Staub, and J.-M. Egly, FEBS Lett., 1982, 139, 193. 3 4 2 W. Muller and A. Eige1,Anal. Biochem., 1981, 118, 269. 3 4 3 B. J . B. Johnson, Biochemistry, 1981, 20, 6103. 344 P. L. Feist and K. J . Danna, Biochemistry, 1981, 20, 4243. 34 5 J. B. Crowther, R. Jones, and R . A. Hartwick, J. Chromatogr., 1981, 217, 4 7 9 .

334 335

230

Organophosphorus Chemistry

Fluorimetric h.p.1.c. assay procedures have been developed for assaying enzymic activities for which nucleotides derived from t h e strongly fluorescent formycin (8-aza-9-deaza-adenosine) are substrates.M6 The sensitivity of the method is claimed t o equal that of radiochemical assays. The effect of the removal of 5‘-terminal phosphate groups upon the electrophoretic mobilities of poly( deoxyribonucleotides) in high-resolu tion polyacrylamide gels has been investigated and found t o vary with chain length, the marked change in mobility being observed with shorter oligonucleotides (< 30-mer) upon 5’-dephosphorylation, dropping almost t o zero with long (> 50-mer) oligonucleotides.M7 Several new double-stranded RNA polymers have been synthesized and their c.d. spectra used, together with previous data, t o establish that the c.d. spectra are essentially dictated by nearest-neighbour interactions, and t o provide a data library that allows the approximate spectra of other RNA species t o be calculated.M8 Laser Raman spectroscopy has been used t o measure the kinetics of exchange of hydrogen isotopes at C-8 in IMP and cIMP, and the more rapid exchange in the latter has been ascribed t o an influence of the ribosyl phosphate g r o ~ p . ~Raman ’ spectroscopy has also been used t o investigate the hydrogen-bonded self-aggregates of GMP 350 and t o attempt t o characterize t h e geometry at t h e junction between one segment of DNA in the B-type double-helical form and another that is in the Z form.351

346 341

34R 349

350

351

E. F. Rossomando, J. Jahngen, and J. F. Eccleston, Anal. Biochem., 1 9 8 1 , 116, 8 0 . D. P. Tapper and D. A. Clayton, Nucleir Acids Res., 1 9 8 1 , 9, 6 7 8 7 . D. M. Gray, J.- J . Liu, K. L. Katliff, and F. S. Allen, Biopolymevs, 1 9 8 1 , 2 0 , 1 3 3 7 . S. A. Ferreira and G. J . Thomas, jr., J . Rarnan. Spectvosc., 1 9 8 1 , 1 1 , 5 0 8 (Chem. Abstu., 1 9 8 2 , 96, 1 4 3 2 3 7 ) . 0 . F. Nielsen, P. A. Lund, and S. B. Petersen, J . A m . Chem. Soc., 1 9 8 2 , 104, 1 9 9 1 . R . M . Wartell, J . Klysik, W. Hillen, and K . L). Wells, Pvoc. Natl. Acad. Sci. USA, 1 9 8 2 , 79, 2549.

Ylides a n d Related Compounds ~~

B Y B. J. W A L K E R

1 Introduction During the past fifteen years, many publications have appeared detailing conditions for the Wittig reaction which will produce a particular stereochemistry of an alkene. Although the broad principles of stereochemical control are well established (although nut well understood), a word of warning is probably overdue t o synthetic chemists from those groups who find the more subtle effects difficult t o repeat. In most cases the original work is sound; the problems probably arise from the very precise conditions required and the lack of that undefinable skill developed by chemists who work for a prolonged period with a particular compound o r reaction.

2 Methylenephosphoranes Preparation and Structure.-The 13C, 'H, and 31P n.m.r. data obtained from a salt-free sample of cyclopropylidenetriphenylphosphorane ( 1) suggest a pyramidal geometry for t h e carbanion in solution and rapid inversion at room temperature.' An X-ray crystal structure confirms a pyramidal geometry in the solid and, despite this, the ylide P-C bond length of 169.6 pm suggests significant double-bond character. Ylides derived from methylcyclopropylphosphonium salts exist entirely as methylene ylides (2) rather than as cyclopropylidene ylides, except of course for (3).* N.m.r. studies of ( 3 ) indicate rapid exchange between the @-protonsof the cyclopropyl group. t

&yOh3

-.

(1)

(Me13 - n II pK$n

CH2

g p X ] x (3)

(2)

Schmidbaur's group continues t o investigate carbodiphosphoranes and t o produce some interesting results. The cyclic example (4) has been prepared from the corresponding diphosphonium salt and shown t o react in a predictable way with methyl iodide and borane, and t o form 1: 1 complexes with dimethylzinc and dimethylcadmium (Scheme lX3 X - Ray structures o f

'

H. Schmidbaur, A. Scheir, B. Milewski-Mahrla, and U . Schubert, Chem. Ber., 1 9 8 2 , 115, 722. H. Schmidbaur and A. Scheir, Chem. Ber., 1981, 114, 3385. H. Schmidbaur and T. Costa, Chem. Ber., 1 9 8 1 , 114, 3 0 6 3 .

23 1

0rga n op h os p h or us Ch e rn is t ry

232

Br-

(4)

n

MePh2P4C+PPh2Me

(5)

(M

=

Zn o r C d )

Reagents: i, Ph,P=CH,; ii, Me,M (M = Z n or Cd)

Scheme 1

i

M e Me

[MeP=CH2]

-

(9)

Reagents: i, MeLi; ii, 2 KH, T H F

Scheme 2

(4) 3 1 4 and of the acyclic analogue ( 5 ) demonstrate the smallest bond angles (1 16.7" and 12 1.8", respectively) yet found for carbophosphoranes. The cyclic diquaternary salt (6) is converted into the ylide (7) o n treatment with one equivalent of methyl-lithium.' However, attempts t o form the cyclic carbodiphosphorane (8) from either (6) or (7) lead t o 9,9-dimethyl-9hsphosphaphenanthrene (9), probably via (8) as shown in Scheme 2. The effects U. S c h u b e r t , C. Kappenstein, B. Milewski-Mahrla, and H. Schmidbaur, Chem. B e r . , 1981, 114, 3070.

T. Costa a n d H. Schmidbaur, Chem. Ber., 1 9 8 2 , 115, 1367.

Ylides and Related Compounds

--

Ph2P=C=PPh2

I

I

RCH2

233 H Ph2P=C-PPh2

I

CH2R

\

RCH2

\ CHR

(11)

(10)

of substituents o n the equilibrium of carbodiphosphoranes ( 10) with di-ylides (1 1) have been investigated.6 In general, the results are readily explained by t h e carbanion-stabilizing ability of a particular substituent; for example ( 10; R = Me) exists entirely as the carbodiphosphorane, whereas ( 1 1; R = CHZPh) is entirely in the di-ylide form. The primary adduct (13) is reported t o be an intermediate in the reaction of hexaphenylcarbodiphosphorane ( 12) with s ~ l p h u r which ,~ gives the phosphacumulene ylide (14) and phosphine sulphide as the final products. The adduct (13) decomposes at room temperature, but can be isolated at - 50 "C as a red solid and can be trapped by alkylation t o give the stable salts (1 5 ) . An analogous adduct (1 6) is formed S-

+ Ph2P=CH-PPh2

I

J

R2N

NR2 (17)

base

c1-

Ph2P= C =PPh2

I

J R2N

NR2

(18)

with selenium, and in this case the structure has been confirmed by X-ray analysis. The previously unreported diaminocarbodiphosphoranes ( 18) have been prepared from the ylide salt (17), which in turn was synthesized by t w o separate routes.8 Various other multi- phosphorus-substituted ylides have been prepared. Bis( dimethy1phosphinyl)methylenetrimethylphosphorane (20), which acts as a bidentate Iigand, is available b y a number o f routes, including methylation of t h e phosphine-stabilized carbanion ( 19).9 An analogous ylide (21), and not the expected tetraphosphine, is obtained from the reaction of H. Schmidbaur and U . Deschler, Chem. Ber., 1981, 114, 2491. H. Schmidbaur, C. E. Zybill, and D. Neugebauer, Angew. Chem., Int. Ed. Engl., 1982, 2 1 , 310. K. Appel a n d K. Waid, 2. Naturforsch., Teil. B, 1981, 36, 131 (Chem. Abstr., 1981, 9 5 , 8 1 104). H. H. Karsch, Chem. Ber., 1982, 115, 1956.

Organophosphorus Chemistry

234 Me1

L i [C(PMe2)31

c Me3P=C(PMe2)2 (20)

\

Me2PC1

(19)

MI e Me2P-P=C(PMe2)2 I M e (21)

(1 9) with chlorodimethylphosphine. The novel anionic ylidic ligand (22) has also been synthesized as shown in Scheme 3, and its co-ordination properties towards nickel have been investigated."

-

H

i,ii

(Ph2P)2CH2

-

H

iii

Ph2P //'\PPh2

I

Me

PhZPflc->PPhZ

1: -

CH2

Na+.THF

(22)

Reagents: i, Mel; ii, Me,P=CH,; iii, Na, T H F Scheme 3

The bicyclic ylide (23) can be further deprotonated by methyl-lithium t o give (24),' which reacts with bis(trimethy1phosphine)nickel dichloride in a molar ratio of 2 : 1 t o form the polyspirocyclic nickel ylide complex ( 2 5 ) , the structure of which was confirmed by X-ray analysis. Both cyclic (27) and lo

H. Schmidbaur, U . Deschler, and B. Milewski-Mahrla, Angew. Chem., f n t . Ed. Engl., 1 9 8 1 , 20, 586. H. Schmidbaur, A. Morte, and B. Zimmer-Gasser, Chem. Ber., 1 9 8 1 , 1 1 4 , 3 1 6 1 .

235

Ylides and Related C o m p o u n d s

N C ( C H ~ )CN

+

2 H

A

B-

~

~1 ~

~

3:

1

(26) 2/

I

Ph3P=CH [n

=

6-81

n (CH 1 W H

t

Ph 3 P=CH2

[n = 4 or 51

C =CH-CH=PPh -

I

C

H =PPh

(27)

acyclic bisphosphoranes (28) have been prepared by the reaction of methylenetriphenylphosphorane with the polymeric products (26), obtained from CY, w -dinitriles and di-isobutylaluminium hydride. l 2 The phosphoranes undergo Wittig reactions with mono- and di-aldehydes to give a variety of novel products, e.g. (29). A number of new cyclopentadienylidene and fluorenylidene ylides [for example, (30) and (31)1, in most cases containing

Ph

I i

P-( CH2

Ph

Ph

(30) n = 1 , 2 , or 3

R

l2

B. Bogdanovik, A. Hullen, S. Konstantinovic, B. Krawiecka, and R . Mynott, Chem. Ber., 1981, 114, 2261.

23 6

Organophosphorus Chemistry

phosphine centres, have been prepared and their properties as ligands investigated . Attempts t o generate methylene ylides from perfluorophenyltrimethyl(32) and di(perf1uorophenyl)dimethyl-phosphonium salts (33) gave dark red solutions which oligomerized, while (perfluorohexy1)trimethylphosphonium iodide reacted with strong base t o give pentaco-ordinate phosphorus compounds rather than t h e corresponding ylide. l 4 However, stable ylides (34) were obtained from pentafluorobenzylphosphonium salts. The formation of ylides has been confirmed in the cathodic reduction of allylic and benzylic phosphonium salts in aprotic solvent^.'^ The unusual and relatively stable ylide (36) is reported t o be formed by the reaction of mesityldiphenylmethylenephosphine (35) with methyl iodide.16 That (36) does not undergo a Wittig reaction nor react with methyl iodide is not t o o surprising. However, the two alternative structures (37) and (38) are not satisfactorily excluded.

MesP=CPh2

Me1

I

Mes,+

,P=CPh2

Me

(35)

(37)

I--

I

Mes-P=CPh2

1

Me (36)

M e s -P-

I Me

C I Ph

Reactions of Methy1enephosphoranes.--A ldehydes. A Wittig reaction of p-chlorobenzaldehyde with t h e 1-phosphabicyclo[ 3.2.lloctane-based salt (39) gave p-chlorostyrene, suggesting that the ylide involved was (42) rather than the benzylic form (40).17 This result is explained in terms of the high energy barrier for pseudorotation of the oxaphosphetan ( 4 1) to the form with apical benzylic carbon that is required t o complete the Wittig elimination, whereas (43) does not have this problem (Scheme 4). Attempts t o prepare cinnoline derivatives (45) by intramolecular Wittig reaction o f the arylazomethylenetriphenylphosphoranes (44) unexpectedly gave the methyl quinazoline-2-carboxylate (46) and triphenylphosphine." In some cases, a l3 l4

l6 17 18

N. Holy, U. Deschler, and H. Schmidbaur, Chem. Ber., 1982, 1 1 5 , 1379. H. Schmidbaur a n d C. E. Zybill, Chern. Ber., 1981, 1 1 4 , 3589. V. L. Pardini, L. Roullier, J . H. P. Utley, and A . Webber, J . Chern. Soc., Perkin Trans. I , 1 9 8 1 , 1520. Th. A. Van der Knaap and F. Bickelhaupt, Tetrahedron Lett., 1982, 2 3 , 2037. L. D. Quin a n d S. C. Spence, Tetrahedron Lett., 1982, 2 3 , 2529. A. Alemagna, P. D. Buttero, E. Licandro, a n d S. Maiorano, J . Chern. Soc., Chem. Commun., 198 1 , 8 9 4 .

237

Ylides and Related Compounds

Reagents: i, base; ii, ArCHO

Scheme 4

phosphorus- containing intermediate was is0 la t ed , but not identified ; one possibility for this intermediate is the resonance-stabilized structure (47). Although Wittig alkenylations of carbonyl functions in molecules that contain silylated hydroxy-groups are possible, yields are often low, and epimerization at the carbon that carries the siloxy-group frequently occurs.

238

Organophosphorus Chemistry

These problems, which arise from the presence of trace amounts of base in the reaction mixture, have been largely resolved by addition of a large excess of (2-chloroethoxy)trimethylsilane (48), and this new procedure has been used in t h e methylenation of 16-ket0-gibberellins.'~ Me 3S i OCH 2CH2 C 1 (48)

Ph3P=CH(CH2)3COO(49)

Based o n the initial observation that Wittig reactions of the phosphorane (49) with aromatic aldehydes gave, for an unstabilized ylide, unusually high proportions of trans-alkenes, an extensive investigation of the effect of solvent, base, temperature, and the nature of the aldehyde o n the stereochemistry of t h e alkene has been carried out.20 It is clear from these results that the major factor in obtaining high proportions of trans-alkene is t h e carboxylate end-group in (49), although the use of lithium hexamethyldisilazide as t h e base and ether as the solvent at room temperature provided the very highest proportions. Perhaps surprisingly, a Wittig reaction of D-glyceraldehyde acetonide ( 5 0 ) with methoxycarbonylmethylenetriphenyl-

phosphorane gives a 7 : 1 predominance of ( 2 ) - ( 5 1 ) over the corresponding ( E )-alkene.21 Bestmann's group has investigated the synthetic applications of various 2-ethoxy-alkylidene and -alkenylidene ylides. These include a new method for the synthesis of 2-ethoxybutadienes ( 5 3 ) and (55) via the 2-ethoxyalkylidenephosphorane (52).22 On the basis of 31Pn.m.r. evidence, the ylides (54), which are formed by acylation of (52), appear t o be in equilibrium with t h e 1 ,2h5-oxayhosphorins (56), and this is supported by the formation of N-methylphthalimides ( 5 7 ) and triphenylphosphine oxide when (54) is treated with N-phenylmaleimide (Scheme 5). A new stereoselective (> 85%) route t o (2)-crp-unsaturated aldehydes is provided by t h e addition o f ethoxide ion t o t h e vinylphosphonium salt (58), followed by Wittig reaction and h y d r o l y s i ~ .T~h~e method has been used t o synthesize ethyl ( 2 E , 4 2 ) deca-2,4-dienoate ('pear ester') (Scheme 6).24 Attempts t o introduce the dienoic acid side-chain of tirandamycic acid directly, using the reaction of 4-carbomethoxybut-3-en-2-ylidenetriphenylphosphoraneor methyl 4-(di-

'' O' 21

22

23 24

L. N. Mander a n d J . V, Turner, Tetrahedron Lett., 1981, 2 2 , 4 1 4 9 . B. E. Maryanoff a n d B. A. Duhl-Emswiler, Tetrahedron Lett., 1 9 8 1 , 2 2 , 4185. N . Minami, S. S. KO, a n d Y . Kishi,J. A m . Chem. Soc., 1 9 8 2 , 104, 1109. H. J. Bestmann and K . K o t h , Angew. Chern., Int. Ed. Engl., 1 9 8 1 , 2 0 , 575. H. J. Bestmann, K. R o t h , and M. Ettlinger, Chrm. Ber., 1 9 8 2 , 1 1 5 , 161. H. J. Bestmann a n d J. Suss, Liebigs A n n . Chem., 1 9 8 2 , 3 6 3 .

239

Ylides and Related Compounds R1 R3CH=C i -C=CHR2 Ph 3Lx1= cI -CHR2

+ -

4 (1

Ph3P-CS1-C

OEt

I

=CHR2

7

i OEt

(53)

+ -

1

Ph 3P-CR1-

OEt

C =CR2 COR4 1 OEt

(52)

_.z

R3CH=CR1C=CR1COR4 1

OEt

(55) 1

R1

ph373 0

R4 H

J +

Ph 3P0

(57)

9

[

C

Reagents: i, K3CHO; ii, R”COC1; iii,

>NMe

5 Scheme 5 H

Br-

Ph3;HC=C<

Ph3P=CHCH(

OEt

)z -%

-H Me ( CH2 1C

OEt

(O E t )

(58)

’COOEt

Reagents: i, NaOEt; ii, C , H , , C H O ; iii, H*; iv, P h , P = C H COOEt

Scheme 6

ethy1phosphono)crotonate with t h e aldehyde ( 5 9 ) , led t o predominant decomposition of t h e bicyclic r i n g - ~ y s t e r n . ~Eowever, ’ step-wise introduction through t h e use of t w o Wittig reactions was highly efficient and highly stereo25

R. E. Ireland, P. G. M. Wuts, and B. Ernst, J. A m . Chem. SOC., 1981, 103, 3 2 0 5 .

Organ o ph osph o m s Chemistry

240 R

R

-

OHC H (59)

MeOOC

Me

Me MeOOC

R =

Me Reagents: i, Ph,P=CMe C O O E t ; ii, D I B A L , E t , O , at 0 ° C ; iii, (COCI),, Me,SO, at - 6 0 ° C ; iv, Ph,P=CHCOOMe Scheme 7

1/ base

[Ph3PCH2HC=CHCOMe

+ Ph3;HC=CHCH2COMe

(60)

+

- -:-/'I

0

Ph3P-CHCHCHCMe

ArCHO

COMe

7

+

Ph

OMe Ar

selective (Scheme 7). Although a mixture of phosphonium salts (60) is obtained from quaternization of ( E ) -5-bromopent-3-en-2-one, a single ylide is formed o n treatment with a base.26 This ylide reacts with aromatic aldehydes t o give two alkenes, apparently derived from a - and y-condensation reactions. One possible route for the latter reaction is elimination of water followed by hydrolysis of t h e dienylphosphonium salt that is formed. The stereoselective synthesis of 1,4-dienes, using a variety of methods, has been reported.27 Reactions of stabilized ylides with lactols have been used t o synthesize The lactones (Scheme 8) 28 and 2-substituted tetrahydrofurans (6

oa

A ii iii Me

COOE t

H

Reagents: i, Ph,P=CHCOOEt; ii, H 2 , catalyst; iii, H 3 0 f Scheme 8 26

J . Font and P. De March, Tetvuhedroti, 1 9 8 1 , 37, 2 3 9 1 . 2 1 H. J . Bestmann, K.-H. Koschatzky, A . Plenchette, J . Suss, and 0 . Vostrowsky, Leibigs A n n . Chem., 1 9 8 2 , 536. A. G. M. Barrett a n d H . G . S h e t h , J . Cheni. Soc., Cizem. Commun., 1 9 8 2 , 170. '' N . Katagiri, K. Takashima, and T . Kato, J . Cbcm. SOC.,Chern. Comrriun., 1 9 8 2 , 664.

24 1

Ylides and Related Compounds

""(IY":

Ph 3P=CHCOCH2COOEt

#

/

O

\

X

\

0

rn

Ro

/

O

CH2

\

X

0

Me

Lo 0

1

+ Me

HO HO

0-

PPh ;Ph

X-

(65)

reaction of the protected galactose (62) with acetonyltriphenylphosphorane gave a mixture of the expected vinyl ketone (64) and the furan (63).30 The yield of (63) increases with increasing the proportion of phosphorane in the reaction, and this supports the suggestion of an intramolecular Wittig reaction via (65) as the route t o (63). j0

K. Olejniczak and R. W. Frank, J . Ovg. Chem., 1982, 47, 380.

Organophosphorus Chemistry

24 2

-

c lo4

Ph

( 6 7 ) n = r) or 7

, 3xii

+

3

Keagents: i,

/

c104-

0

CH2 (HC=CH),040

r

1

; iv, heat at 200°C' for 30 minutes

Scheme 9

Polymethylenes, e.g. (67), that contain heptafulvenyl terminal groups have been prepared by Wittig reactions of the cycloheptatrienylmethylene ylide (66) (Scheme 9).31 Wittig reactions of the azine ylides (68) and (69) with aromatic aldehydes occur normally t o give azines (70) and (7 l ) , respectively, although in t h e latter case spontaneous cyclization t o pyrazoles takes place.32 The reaction of terminally functionalized long- chain alkylidenephosphoranes Ar CHO

Ph

31

32

Ph

( 6 8 ) R = Me

(70)

(69) R

( 7 1 ) R = Ph

=

Ph

R

=

Me

N . Ott and D. Rewicki, A n g e w . Chern., Int. Ed. Engl., 1 9 8 2 , 2 1 , 6 8 . E. E. Schweizer and S . N . Hirwe, J. Org Chem., 1 9 8 2 , 4 7 , 1 6 5 2 .

Ylides and Related Compounds

(72)

243

X = OTHP

n = 8,

n = 9 , X = CN

( 7 2 ) with aromatic 1,3-dialdehydes has been used t o prepare precursors for the synthesis of ~ a t e n a n e s . ~ ~ A one-pot palladium-catalysed olefination, involving the reaction of an aldehyde, triphenylphosphine, and an allylic alcohol ( 7 3 ) , has been reported 34 and may involve an ylide intermediate.

-

R 2 Pd(acac12 R’CHO

+ Ph3P +

R1HC=CHHC=CHR2

+ Ph3P0 + H 2 0

HO (73)

Reactions of Ketones with Methylenephosphoranes. A new, general one-pot synthesis of substituted acrylic acids is provided by the reaction of dialkyl phosphites with 1-bromo-carboxylic acids in the presence of a ketone or a l d e h ~ d e . ~The ’ reaction presumably involves the phosphonate dianion ( 7 4 ) (Scheme 10). 0

II

(R’O),PH

-

0

i

+

B~CHR~COOH

R3R4C=CR2COOH

Reagents: i, 3 equivalents of NaH; ii, R Z R 3 C 0

Scheme 10

In order t o define the parameters that are important for asymmetric induction in the intramolecular Wittig reaction to give ( 7 5 ) , a variety of phosphonium ylides derived from optically active phosphines have been used (Scheme 1 l).36 The largest induction [76% enantiomeric excess in (75)l is obtained from those phosphines where the chirality is at phosphorus rather than at carbon. The variation in induction with the structure of the phosphine has been explained in terms of the phosphetan intermediates leading to ( S ) - and ( R ) - ( 7 5 ) .The betaines ( 7 6 ) , obtained from the reaction of silylated ylides with carbonyl compounds, can eliminate either phosphine oxide (the normal Wittig reaction) or siloxy anion, t o give vinylphosphonium 33 34

35 36

E. Logemann, K. Rissler, G. Schill, and H . Fritz, Chem. Ber., 1981, 114, 2245. M. Moreno-MBnas and A. Trius, Tetrahedron L e t t . , 1981, 22, 3109. D. R. Brittelli,J. Org. Chem., 1981, 46, 2514. B. M. Trost and D. P. Curran, Tetrahedron Lett., 1981, 22, 4929.

9

Organophosphorus Chemistry

244

Br

0

*

Reagents: i, R,P; ii, K,CO,

Scheme 11 + H Ph,P\l/SiR1, A

P h 3 h C = C R 4 R 3 C=CHR2

Br-

+

[R13SiOH]

(77)

salts;37 this reaction has been applied to the synthesis of 1,3-dienylphosphonium salts (77). The synthesis of 2-methyleneindane from indan- 2-one and methylene ylide is not successful, owing to enolization of the ketone, and attempts to carry out the reaction in the opposite sense gave 1-methyleneindane, since 2-bromoindane and triphenylphosphine give 1- and not 2-indanyltriphenylphosphonium bromide.38 A potential new route to 7bH-cyclopent[cdlindene derivatives is provided by cyclization of triene ylides, e.g. (78), the products of which undergo spontaneous intramolecular 01efination.~~ Miscellaneous Reactions of Methylenephosphoranes. Ylide chemistry has been incorportated into an interactive computer program for the mechanistic evaluation of organic reactions.m 37 3R

39 40

F. Plenat, Tetrahedron L e t t . , 1981, 22, 4705. K. J. McCullogh, Tetrahedron L e t t . , 1982, 2 3 , 2 2 2 3 . R. H. Bradbury, T. L. Gilchrist, and C. W. Rees, J. Chem. SOC.,Perkzns Trans. I , 1981, 3234. T. D. Salatin, D. McLaughlin, and W. L. Jorgensen, J . Org. Chem., 1981, 46, 5284.

245

Ylides and Related Compounds 0

0

P h 3 P = C ( OBut ) 2 (79)

It has been reported 41 that di- t-butoxymethylenetriphenylphosphorane (79) is the product from treatment of triphenylphosphine and bromoform with potassium t-butoxide. However, some of the reactions proposed for (79) are highly unlikely, and a re-investigation seems worthwhile. R

-

‘CO

Arc ( CN) NRCOPh

-Ph3P0

Ar

-HCN

Ar

Ph

Br-

(80)

R Ph gP

An intramolecular Wittig reaction of the ylides (8 I), generated by treatment of the cyano-carbanion (80) with vinyltriphenylphosphonium bromide, is the basis of a synthesis of substituted p y r r ~ l e s in , ~ spite ~ of the fact that NN-disubstituted amides have not previously been observed t o undergo the Wittig reaction. Regioselective thiocarbonyl olefination of N-acetylated thioamides with methoxycarbonylmethylenetriphenylphosphorane has been used as the key step in a new synthesis of P - a m i n o - a ~ i d s . ~ ~

heat

OCOR

41

S. Verma, N. M. Kansal, R. S . Mishra, and M. M. Bokadia, Heterocycles, 1981, 1 6 , 1 5 37.

42

43

J. V . Cooney and W. E. McEwen, J. Org. Chem., 1981, 46, 2570. M. Slopianka and A. Gossauer, Liebigs Ann. Chem., 1981, 2258.

Organophosphorus Chemistry

246

+

Ph3P0

OCOR

Ph 3P0

[n

-

Ph 3”-“(

=

31

,COR Ph 3P0

CH2 ) 30COR (84)

A detailed investigation of the thermal decomposition of w-acyloxyalkylidene- (83) 44, 46 and u -acyloxybenzylidene-triphenylphosphoranes (82) 45 has been reported. The ylides (8 2) give benzofuran in refluxing toluene,45 while the corresponding alkylidene ylides (83; n = 2 ) give 2,3-dihydrofurans under similar conditions, but cyclopropyl ketones when they are heated in t-butyl alcohol. Lengthening the alkyl chain changes the reaction pathway in that (a-acyloxy-n-buty1idene)triphenylphosphoranes(83; n = 3) d o not give cyclobutyl ketones in t-butyl alcohol, but rather the 1-acylated ylide (84). However, 3,4-dihydro-2H-pyrans are obtained from (83; n = 3) in toluene.& Ph 1 2 [R = R = R3= P h ]

R1HC=CHR2C=PPh3

(85)

1

+ R3NC0

[R’= P h ]

R2

f

\NPh

Ph

pm:

0

Ph

(87)

Allylic phosphonium ylides (85) react with isocyanates at the a- and/or y-positions in the ylide chain, depending o n the substituent at the carbanionic centre.47 Reaction at the a-position leads t o vinylketenimines (86) via a normal Wittig reaction, while reaction at the y-position ultimately gives the pyrrolone (87). The protected formylidene ylide (88) reacts with isocyanates 44

45 46

47

A. Hercouet a n d M. Le Corre, Tetrahedron, 1981, 37, 2855. A. Hercouet a n d M. Le Corre, Tetrahedron, 1981, 37, 2867. A. Hercouet a n d M. Le Corre, Tetrahedron, 1981, 37, 2861. L . C a p u a n o a n d A. Willmes, Liebigs A n n . C h e w . , 1982, 80.

247

Ylides and Related Compounds 0

R (89) X = 0

x

(90)

=

s

and isothiocyanates to give, after hydrolysis, the pyrimidine- 2,4( 1H,3H ) diones (89) and -dithiones (90), r e ~ p e c t i v e l y . ~ ~ 3a-Aza-azulenes, e.g. (9 l ) , undergo Michael addition of P-ketomethylene ylides, followed by cyclization and elimination of phosphine oxide, to give cyclohexa-1,4 -diene derivatives, e.g. (92).49 The stable phosphonioborates (93), prepared from phosphonium ylides and borane, provide a convenient source of monoalkylb~ranes.’~

a

+

-

Ph3P=CHCOR

X ( 9 1 ) X = 0 , CHCN, o r CHCOMe

heat

R1R2C-;Ph3 -1

I

R R CHBH2PPh3

= R1R2CHBH2

BH3

(94)

Ph3P

0

II

(93) 5 111 - C P F ~ ( C O ) ~ I

+

+

Ph3P=CHR

T

/“\

Cp(C0)Fe

\ CH’/ F e (‘Rc o ) c p (95)

A new type of reaction between an ylide and a metal complex is displayed by the formation of (95) as the major product from treatment of the iron complex (94) with alkylidenetriphenylpho~phoranes.’~The reactions of ylide-carbon disulphide adducts (96) with transition-metal carbonyls have been investigated.’* In the absence of light, pentacarbonyl-manganese and 4R 49 50

H. J. Bestmann a n d R. W. Saalfrank, Chem. Ber., 1981, 114, 2661. W. Flitsch a n d E. R. F. Gesing, Chem. Ber., 1981, 1 1 4 , 3146. H. J. Bestmann, K. Siihs, and T. Roder, Angew. Chern., Int. Ed. Engl., 1981, 2 0 , 1038.

’’ R.

Korswagen, R. Alt, D. S p e t h , a n d M. L. Ziegler, Angew. Chem., Int. Ed. Engl.,

1981, 2 0 , 1049. 52

U. Kunze, R. Merkel, a n d W. Winter, Angew. Chem., Int. Ed. Engl., 1982, 2 1 , 290, 291.

Organophosphorus Chemistry

248

S

+ 4 Ph3PCMe2C1 \\S

(96)

Me

Me

-rhenium halides form complexes (97). However, under the action of light, the reaction with pentacarbonylrhenium bromide gives the 1,2,4 -trithiolan (98). The compound was previously erroneously reported 53 as having struc ure (99).

3 Reactions of Phosphonate Anions The ris(dimethylthiophosphiny1)methane carbanion ( 100) has been synthesized and shown t o be approximately as basic as methoxide ion.s4 On the basis of 31 P n.m.r. and chemical evidence, the [ di(arylsulphonyl)methyl]phosphine oxides (1 0 1) have been shown to exist in solvent- and temperaturedependent equilibrium with the ylides (102).”

OH

0

II Ph2PCH(S02C6H4X)2 ( 1 0 11

I

Ph2P=C( S0,C6H4X), ( 102 1

Olefination using the ylide-phosphonate ( 103) proceeds entirely by the phosphonate route and so provides a synthesis of unsaturated acylphosphoranes ( 104)? Catalytic amounts of crown ether facilitate the olefination of 53 54

55 56

E. Schaumann and F.-F. Grabley, Liebigs Ann. Chem., 1979, 1702. H. H. Karsch, Chem. Ber., 1982, 115, 818. 0. I. Kolodiazhnyi, Tetrahedron L e t t . , 1982, 2 3 , 4 9 9 . M. Cooke, Jr. and K. P. Biciunas, Synthesis, 1981, 2 8 3 .

Ylides and Related C o m p o u n d s COOEt

0

II

I

+

(Et0)2PCH2COC=PPh3

R1R2C0

-

249 COOEt

I

R1R2C=CHCOC=PPh3 ( 104 1

(103) 0=P(0?.Je)2

\

(105)

aryl and fury1 aldehydes and ketones with the phosphonate ( 105).57Diethyl oxazolyl- ( 107) and thiazolyl-phosphonates (1 08) have been prepared by the reactions of diethyl isocranomethylphosphonate carbanion ( 106) with acid chlorides and carbon disulphide, re~pectively.'~ Compounds (107; R = OR' or NR;) can be hydrolysed to (1-glyciny1)phosphonic acid or esters (109), and 0

II

( EtO)2PCH-C:-

0 ( Et0)2!-cHCN

I 9s

;r

- )=(- H

,;

(EtOy)+

N

A

S

SMe

,P(OEt)2

S-

0

NC

0 '

(108)

j"i-

iii

(lo6)

ii

NS-

\

II

( E t 0 ) 2 POC H ( NC)COR

0

II

( R0)2PCHCOOR

I R (

O 'ZPNO

NH2 (109) R = H or

(107)

iv (107; R = OEt)

___t

alkyl

i"p

OEt

( E t 0 )2 8 ,

JI NC

I

Ar\C=C/

y

H'

(Et0)2P--C-COOEt

ll

0

(110) Reagents: i, CS,; ii, M e I ; iii, RCOC1; iv, base; v, H'; vi, ArCHO

Scheme 12 c7 5R

R. Baker and R. J. Sims, J. Chem. Soc., Perkin Trans. 1, 1981, 3087. J . Rachoh and U . Schollkopf, Liebigs Ann. Chem., 1981, 1186.

NC 'COOEt

(111)

0rga n op h osph or us Chem is try

250

metallation of ( 1 07; R = OEt), followed by reaction with aromatic aldehydes, gives (Z)-3-aryl-2-isocyanoacrylates (1 1 1) via the phosphonate carbanion (110) (Scheme 12).59 In a synthesis of hydroxy-y-lactones from apunsaturated aldehydes, whether epoxidation or phosphonate olefination is carried out first is reported to be unimportant.60 However, evidence from work on the synthesis of leucotrienes at Lilly Research6' indicates that a$-epoxy-functions greatly activate aldehydes t o attack by formyl-stabilized ylides. The isopropyl ester function appears t o be an important factor in the success of olefination reactions using ( 1 12) (Scheme 13).62 (1-Mercaptoalky1)phosphonates have been used to convert 1,3-dicarbonyls into 1,4dicarbonyls and hence into cyclopentenones (Scheme 14).63

-

CHR

CH2R

0

(112) Reagents: i, BuLi; ii, RCHO; iii, HCI

Scheme 13 SMe

II

0

(

EtO)zPCH( SVe)R- i-iii Ro+

W

iv

RCO( CHz ) 2COMe

0

J ..-

Reagents: i,

.>(\,,, , BunLi; ii, H,O; iii, NaH, 18-crown-6; iv, TsOH, H,O; v, U0 NaOH, EtOH

Scheme 14

Attempts to generate diazoethenes by olefination, using dimethyl (diazomethy1)phosphonate (1 13), gave acetylenes in moderate to excellent yield 59 60 61

62

63

J. Rachoh and U. Schollkopf, Liebigs Ann. Chem., 1981, 1693. H. Marchall, J. Penninger, and P. Weyerstahl, Liebigs Ann. Chern., 1982, 49. S. R. Baker, personal communication. K.-Y. Akiba, Y. Negishi, K. Kurumaya, N . Ueyama, and N. Inamoto, Tetrahedron Lett., 1981, 2 2 , 4977. M. Miko4ajczyk, S. Grzejszczak, and P. Lyzwa, Tetrahedron L e t t . , 1982, 2 3 , 2237; M. Miko*ajczyk, S. Grzejszczak, and K. Korbacz, ibid., 1981, 22, 2097; H.-J. Altenbach and R. Korff, Angew. Chem., Int. Ed. Engl., 1982, 2 1 , 371.

25 1

Ylides and Related Compounds

(113)

Reagents: i, BunLi; ii, R'R'CO; iii, eliminate N,

Scheme 15

(Scheme 15).64 The results are consistent with initial formation of diazoethenes, which decompose to alkylidenecarbenes even at - 78 "C.Support for this is available from the reaction of (1 13) with the en-5-ones (1 14) 65 and (1 16) 66 to give the highly reactive bicyclo[ 3.1 .O]hex-1-ene (1 15) and the bicyclo[ 2.1 .O]pentane (1 17), respectively, presumably through intramolecular trapping of the alkylidenecarbene in each case (Scheme 16).

R (114) R = But

[

R&R]

i

R

R

\

( 1 1 6 ) R = But

(117)

Reagents: i, (1 13), ButOH, T H F , at - 30 "C

Scheme 16 64

65

66

J . C. Gilbert and U. Weerazooriya, J. Org. Chem., 1982, 4 7 , 1837; E. W. Colvin and B. J . Hamill, J. Chem. SOC.,Perkin Trans. I , 1977, 869. R. F. Salinaro and J . A. Berson, Tetrahedron L e t t . , 1982, 23, 1447. R. F. Salinaro and J . A. Berson, Tetrahedron L e t t . , 1982, 2 3 , 1451.

Orga n op h os p h orus Ch e m istry

252

(118) X = H (119) X

=

NO2 or M e 0

Olefination of aldehydes with the anion (1 18) of diphenyl 1-(4-nitroani1ino)-1 -arylmethylphosphonate gives t h e expected enamines. However, the (2-substituted aryl) analogues (1 19) d o not react with aldehydes, and an X-ray crystal structure indicates that this is due t o steric effects.67 Thermolysis, at 150 O C , of the adducts (1 20), derived from carbanions of a-aminomethylphosphine oxides and aldehydes, gives a-amino-ketones and diphenylphosphine oxide, although, as expected, enamines are formed o n treatment of (1 20) with base (Scheme 17).68 A variety of evidence is presented that the formation of a-amino-ketones takes place by an intermolecular mechanism. 0

I1

-

0

II

i-iii

Ph2PCH2NR1R2

R

iv

Ph2PCHNR1RB

I R~ COH

1

R3R4C=CHNR1R2

(120) V

[R4 = H I

R3COCH2NR1R2

0

II

+

FhZPH

Reagents: i, BuLi; ii, R 3 R " C O ;iii, NH,' C1-; iv, KOBut; v, heat at 1 5 0 " C

Scheme 17

0

U

( Et0)2PCH2COOEt (

i-iv

121)

Reagents: i, NaH, DME; ii, Me,SiCH,I; iii, NaH, RCHO; iv, LiAlH,

Scheme 18

Silylated allylic alcohols have been prepared, using a one-pot silylationolefination reaction of the phosphonate (1 2 1) as the key step (Scheme 1 8).69 Routes t o vinyl selenides (1 22) are available from both phenylselenomethyl67

6R 69

M. D. Grenshaw, S. J . Schmolka, H. Zimmer, R . Whittle, and R . C. Elder, J. Org. Chem., 1 9 8 2 , 4 7 , 101. N . K. J . M . Broekhof a n d A. Van der G e n , Tetrahedron Lett., 1981, 2 2 , 2799. R. Henning and H . M. R . Hoffrnann, Tetrahedron L e f t . , 1982, 2 3 , 2305.

253

Ylides and Related Compounds NaOH, CH2C12

c @-CH2SePh

@

RHCxCHSePh

RCHO

(122)

0

= Ph3;

II o r ( E t O ) 2 P-

phosphonium salts and -phosphonates. In the latter case, phase-transfer conditions are used.70 0

MeOOC

0

II ( Et0)2PCH2COOMe

+

___c

R

R

(124)

(123) 0

0

II

+

(EtO),PCH2R7 R1=

COOMe, CONH,, C N ’ Me3CC07 o r PhCO

HO

H

( 1 2 5 ) R2= B r o r Me

(126)

Cyclic 2-en-1-ones (124) have been prepared in one step from enol lactones (1 23) by reaction with methyl diethylphosphonoacetate and base.71 Similar reactions with 5-hydroxy-furanones ( 125) gave (2,E)-dienoic acids

Me

Me

/,iii

Po Me

II

Reagents: i, (EtO),PCH,Li; ii, H , O + ; iii, NaH, DME, a t 6 0 ° C

Scheme 19 70 71

J. V. Comasseto and C. A. Brandt, J. Chem. R e x ( S ) , 1982, 56. J. C. Canevet a n d F. Sharrard, Tetrahedron Lett., 1982, 2 3 , 181.

254

Organophosphorus Chemistry

(1 26). Another example of the synthetic application of intramolecular phosphonate olefination is provided by the preparation of bicyclo[ 3.3.0 loctA‘92-en-3-ones,e.g. (1 27), from 2,5 -diketo-phosphonates (Scheme 19).” n

n

COOEt

COOE t

I

I

(128) Reagents: i, BuLi, at - 7 8 ° C ; ii, RX

Scheme 20 R2

\

R2

(OR1), COOE t

COOE t ( 1 2 9 ) R1=

H

Me, E t , o r P r i

Reagents: i, BuLi, at

-

7 8 ° C ; ii, R 2 X

Scheme 2 1

Regioselective syntheses of 4-alkyl-pyridines (Scheme 20) 73 and o f 4-alkylquinolines (Scheme 2 1) 74 by alkylation of the phosphonates (128) and (129), respectively, have been reported. An example of a sigmatropic rearrangement which formally involves a phosphorus-stabilized carbanion (1 30) provides the key step in a new synthesis of medium-sized ring lactones; however, t h e driving force is provided by the sulphonium ylide contribution (Scheme 22).75 Compounds with one less carbon undergo intramolecular alkylation t o give ( 13 1). The course of the reaction between the carbanions of five- and sixmembered-ring cyclic phosphonates and nitrones depends o n the size of the ring.76 In general, the compounds with a five-membered ring, e.g. (132), give aziridines, while those with a six-membered, e.g. ( 1 33), give enamines. An explanation of this is provided in terms of the stability of the pentacoordinate intermediates involved (Scheme 23). The anions (1 34) of (cr-methoxyally1)phosphine oxides react with electrophiles, generally in a highly regio72 l3 74

75 76

M. J . Begley, K. Cooper, and G . Pattenden, Tetrahedron, 1981, 37, 4 5 0 3 . K.-Y. Akiba, H . Matsuoka, and M. Wada, Tetruhedron L e t t . , 1981, 22, 4 0 9 3 . K . - Y . Akiba,T. Kasai, and M. Wada, Tetruhedron L e t t . , 1 9 8 2 , 23, 1 7 0 9 . E. Vedejs and D. W. Powell, J. Am. Chem. SOC., 1 9 8 2 . 104, 2046. S. Zbaida and E. Breuer, J. Org. Chern.? 1982, 4 7 , 1 0 7 3 .

255

Ylides and Related Compounds I

\;1

[n = I ]

(130)

Reagents: i, K,CO,, at 2 0 ° C ; ii, K,CO,, at 8 0 ° C

Scheme 22 R1 i,ii

Me

(133) R’

Reagents: i, NaH; ii,

\

H

( X = COOEt or C N )

/R2

=N\o Scheme 23

selective manner, t o give products of 0 - o r y-attack, depending o n the . ~ ~ reactions of substituents o n ( 1 34) and the nature of the e l e ~ t r o p h i l e The difluoromethylphosphonate carbanions with electrophiles have also been investigated, with a view t o developing synthetic methods for the introduction of the difluoromethyl and difluoromethylene groups. 78 ”

M. Maleki, J. A. Miller, and 0. W. Lever, Jr., Tetrahedron Lett., 1981, 22, 3789. M. Obayashi, E . Ito, K. Matsui, and K. Kondo, Tetrahedron L e f t . , 1982, 2 3 , 2 3 2 3 ; M. Obayashi and K. Kondo, ibid., p. 2 3 2 7 .

Organophosphorus Chemistry

25 6

OMe

0

E

I

/ y-attack

R1

COOMe

qCHO 0

II (MeO) 2PCH2COOMe

NaH, DME, at 2 5 O C , 1 hour

F e ( CO 1

Fe(COl3

(135)

The co-ordinated aldehydic diene (1 35) undergoes normal phosphateolefination in excellent yield.79 4 Selected Applications in Synthesis

Carbohydrates.-Wittig reactions of ethoxycarbonylmethylenetriphenylphosphorane with 2-, 3- and 4-keto-derivatives of a-D-hexopyranoses have been used t o prepare the corresponding alkenes, e,g, ( I 3 6 ) , as single isomers in each case.8o The use of the Wittig and Knoevenagel-Doebner reactions for chain-extension of aldoses, e.g. (1 37), has been compared.” The latter reaction apparently causes epimerization at C-4 in (138), to give (140), which explains why this reaction, unlike the Wittig, is not followed by cyclization, to produce (1 39) (Scheme 24).

MeOOC

.3

OMe

(136)

’’ D. Martina and F. Brion, Tetrahedron L e t t . , 1982, 2 3 , 8 6 5 .

80

B. Fraser-Reid, R. Tsang, D. B. Tulshian, and K. M o Sun, J. Org. Chem., 1981, 46,

3764. M. Collins, W. G. Overend, and T. S. Shing, J. Chem. SOC., Chem. Commun., 1982, 297.

*’ P.

257

Ylides and Related Compounds COOE t

x:vLyLX(;

."

(137)

ii

COOMe

(138)

xzkL> CH2COOR

OH

(139) O

x

(140) Reagents: i, Ph, P=CHCOOEt; ii, HOOCCH,COOMe, pyridine, piperidine

Scheme 24

'\

-

Ph P

K\R

(three) [fast]

(143)

[slow]

R [

=L]

R""--i R

R+

CHO

(142) Reagents: i, BuLi, at - 6 O o C ; ii, (142)

Scheme 25

R

258

Organophosphorus Chemistry

Carotenoids and Related Compounds.-The use of phosphine-oxide-stabilized carbanions in the stereochemically controlled synthesis of conjugated polyene isoprenoids has been reported. 82 Reactions of allylic phosphine oxides, e.g. (141), with citrals, e.g. (142), take place with complete preservation of stereochemistry of the alkene in the starting materials to give polyenes, e.g. (143), where olefination is > 98% ( E ) . The yields in these reactions are very low, and separation of the intermediate diastereoisomeric 0-hydroxyphosphine oxides shows that this is related t o the stereospecific olefination, in that the rate of elimination from the erythro- is very much slower than that from the threo-intermediate (Scheme 25). However, as has been shown before, it is possible to generate (2)-alkenes by separating the intermediate diastereoisomeric 0-hydroxyphosphine oxides and treating the erythro -form, e.g. (144), with sodium hydride. In this report,82 this method is used to synthesize (145) (Scheme 26), which is spectroscopically very similar to di-(Z)-phytofluene ( 146).

0

II

Ph2P

-

R

[

R

=

i,ii

4

R (erythro)

threo-isomer

Reagents: i, BuLi, THF, at - 60 OC; ii, V

c

Scheme 26

H

'' J. M . Clough and G . Pattenden, Tetrahedron, 1 9 8 1 , 37, 391 1.

O ; iii, NaH

259

Ylides and Related C o m p o u n d s

(146) R =

The Wittig reaction has been used to synthesize the retinoic acid metabolite (148) from the all-trans phosphonium salt (147) (Scheme 271, although the method is not without d i f f i ~ u l t i e s Fiuorinated .~~ analogues of retinal have been prepared from 0-ionylideneacetaldehyde. 1 3-(Trifluoro-

Reagents: i, NaOMe; ii,

OHCy-COOR

Scheme 27

( 150)

Reagents: i, NaH; ii, LiAlH,; iii, MnO, 83

Scheme 28 M. Rosenberger and C. Neukom, J. Org. Chem., 1982, 47, 1782.

Organ op h osph or us Chem is try

260

methy1)retinal (1 50) is available from olefination, using the phosphonate (149) (Scheme 28),84 while ll-cis-l2-fluororetinal (15 1) has been prepared by a route analogous to that previously used for fluorinated vitamin A, using the ethyl diethylphosphonofluoroacetate ( 152).85 The naphthyl analogue (153) has been synthesized from methyl 2-naphthyl ketone by multiple phosphonate olefinations.86 Compound (1 53), which has the 0

II

(Et0)2PCHFCOOEt (152)

carbons 5 , 6, 7, 8, and 18 of retinal held conformationally rigid as part of the naphthyl ring, has optical properties, when combined with bacterio-opsin, which suggest that present theories for the red shift in bacteriorhodopsin require modification. The nitroxide retinal (1 54) has been prepared, for use in studies of the bonding site of the visual pigment, by consecutive phosphonate olefinations of 2 , 2 3 3 - tet ramethyl- 3- pyrrolin- 1 -0xyl-3- carboxaldehyde (Scheme 29).87

Reagents: i, (EtO) tEOO 2C&' P

, NaNH,; ii, L M H , ; iii, MnO, Scheme 29

(+)-Faranal (156) has been prepared by a Wittig reaction of 5-carboxypentylidenetriphenylphosphorane with the ketone ( 155) followed by a reduction-oxidation sequence (Scheme 30).88 It is noteworthy that ylides that contain functional groups other than carboxy at C-5 gave only poor yields of alkenes on reaction with a model ketone (see also ref. 20). R4 W.

Gartner, D. Oesterhelt, P. Towner, H. Hopf, and L. Ernst, J. A m . Chem. SOC.,

1981, 103,7642. 85

86 8' 88

R . S. H. Liu, H. Matsumoto, A. E. Asato, M . Denny, Y. Shichida, T. Yoshizawa, and F. W.Dahlquist,J. A m . Chem. SOC., 1981, 103,7195. M . Akhtar, L. Jallo, and A. H. Johnson, J. Chem. SOC., Chem. Commun., 1982, 44. R. K. Crouch, T. G. Ebrey, and R. Govindjee,J. Am. Chem. SOC., 1981, 103,7364. D.W. Knight and B. Ojhara, Tetrahedron Lett., 1981, 22, 5101.

261

Ylides and Related Compounds

Me

Me (. 156) .

; ii, LiAlH,; iii, pyridinium chlorochromate; iv, g.1.c.

Reagents; i, ( 155)

Scheme 30

p- Lactam Antibiotics.-The

phosphorane ring-closure technique has been used t o form the six-membered ring in a synthesis of the 1-carbadethia-2oxocephem-4-carboxylate (1 57) 89 and the five-membered ring in a general synthesis of optically active penams (1 5 8 ) . 9 0 The reaction of elemental sulphur with phosphonate carbanions to give a-phosphoryl sulphides has been used t o generate intermediates (159), (161), and (162), which spontaneously cyclize t o the isopenam [e.g. (1 60)l and cephalosporin analogue^.^' Clavulanic acid derivatives ( 163) and penicillin V esters undergo Wittig reactions at the 0-lactam carbonyl and, since the P-lactams can be regenerated by ozonolysis, this provides a means of protection, although the yields of alkene are very low.’* Leucotrienes and Related Compounds.-The biological activity of leucotrienes and the difficulties of obtaining them from natural sources (a thousand tons of guinea pigs would only give a milligram or so!) have made C. W. Greengrass and D. W. T. Hoople, Tetrahedron Lett., 1981, 2 2 , 5335; C. W. Greengrass and M. S. Nobbs, ibid., p. 5339. 90 V. M. Girijavallabhan, A. K. Ganguly, S . W. McCombie, P. Pinto, and R. Rizvi, Tetrahedron Lett., 1981, 2 2 , 3485;S. W. McCombie, A. K. Ganguly, V. M. Girijavallabhan, P. D. Jeffrey, S. Lin and R. Pinto, ibid., p. 3489. 9 1 G . H. Hakimelahi and A. Ugolini, Tetrahedron Lett., 1982, 2 3 , 913. 9 2 M. L. Gilpin, J . B. Harbridge, T. T. Howarth, and T. J . King, J. Chem. SOC., Chem. Commun., 1981,929. R9

262

Organophosphorus Chemistry 0

OMS

0

II H PhCH2C-

II

I

PhCHZC-

0

II

PhCH2C-

ROOC

-/'sHll HO

H,

OCOPh \

+

COOMe OHC

H

11

H

OH

(166) R = H

them popular targets for synthesis. (SS,1 2S)-Dihydroxy-(6E78Z,1OE,14Z)eicosatetraenoic acid (166), a geometric isomer of leucotriene Bq, has been synthesized, using a Wittig reaction between the phosphonium ylide ( 1 64) and t h e aldehyde (1 65) as t h e key step.93 Leucotriene B4 ( 1 68) itself has been 93

E. J. Corey, A. Marfat, a n d B. C. Laguzza, T e t r a h e d r o n L e t t . , 1981, 2 2 , 3339.

263

Ylides and Related Compounds

1

2

( 1 6 8 ) R = R = R3= H

prepared, using a similar reaction of the vinylogous ylide (167).94 The trio1 (169), which is a key intermediate in many of these syntheses, has been prepared in high yield from the reaction of 2-deoxy-D-ribose with one equivalent of carbethoxymethylenetriphenylphosphorane,9s while a similar reaction with two equivalents of ylide and a longer reaction time gives the C-glycoside ( 170) (Scheme 3 l).96 The 7-cis-9-trans-undecadienoate( 173)

(170)

Reagents: i, Ph,P=CHCOOEt, 6 hours; ii, 2Ph,P=CHCOOEt, 5 days

Scheme 3 1

has been prepared directly by a Wittig reaction of the aldehydic ylide (1 72) with the epoxy-aldehyde (1 7 1) and converted, by further Wittig reaction with cis-non-3-enylidenetriphenylphosphorane,into 7-cis-stereoisomers of leucotriene A4 methyl ester (174) and D4 (175) (Scheme 32).97 Stereo94

95

9b

97

Y. Guidon, R. Zamboni, C.-K. Lau, and J. Rokach, Tetrahedron Lett., 1 9 8 2 , 2 3 , 7 3 9 ; R. Zamboni a n d J. Rokach, ibid., p. 2631. D. P. Marriott and J. R. Bantick, Tetrahedron L e t t . , 1 9 8 1 , 2 2 , 3657; J. Rokach, R. Zamboni, C.-K. Lau, and Y. Guindon, ibid., p. 2759. J. Rokach, C.-K. Lau, R. Zamboni, and Y. Guindon, Tetrahedron L e t t . , 1 9 8 1 , 2 2 , 2763. I. Ernest, A. J. Main, and R. Menasse, Tetrahedron Lett., 1 9 8 2 , 2 3 , 167.

264

Organophosphorus Chemistry

'gH1

-~ W - -

1

Reagents: i, Ph3PwCH0

; ii, Ph -3P

'gHI 1

( 172)

Scheme 32

-Y -

'sHll\-A

H

COOH SCH2CHCONHCH2COOH

I

NH2

(175)

CT \

II

0

(

176 1

OHC

P(OEt)2

COOMe

+

(177)

I-.

H

COOH H (178) Reagents: i, LiNPri,, a t - 78 "C, T H F ; ii, heat at 2 5 "C for 2 4 hours; iii, chromatography (AgNO,, S O , ) ; iv, H,, Lindlar catalyst; v, LiOH, THF, H,O, at 2 5 "C

Scheme 33

265

Ylides and Related Compounds

e: 0 0

n N

3:

u 3: u

W

3:

u 3: u

0: 0

“ll

3:

u u

I

3: 0

3:

I

u? z u

+ l-l

3:

3z

43:

10

u

X 0

u

r( r(

X 10

0

u

l-l

X 10

I U

u

X

0

+ am fi

a

u

+ am G

a

266

Organophosphorus Chemistry

selective olefination [ > 90% ( E ) ]of the aldehyde ( 177) with the phosphonate (1 76) is t h e key step in a total synthesis of 5,6-methanoleucotriene A4 (178) (Scheme 33).98 The blood-platelet-aggregation metabolites ( R , S ) - ( 5 Z,8E, 1OE)-12hydroxyheptadeca-5,8,lO-trienoicacid (180; R = H ) , ( R , S ) - and ( S ) - ( 5 2 , 8 Z , 1OE,1 4 2 ) - 1 2-hydroxyeicosa- 5,8,10,14 - tetraenoic acid ( 182; R = H), and their racemic 5,6,8,9-tetradeuterio-isomers have been prepared by Wittig reactions of the salts (179) and (181), respectively (Scheme 34).99 In each case, the salts appeared t o contain a triphenylphosphine hydroiodide impurity, and the products (180) and (182) were each contaminated with some (102)-isomer. The stereospecific total synthesis o f the (1 l R ) - l l hydroxytetraene ( 183) has been achieved, using n-hexylidenetriphenylphosphorane t o introduce the ( 1 4 2 ) - d o u b l e - b 0 n d . ' ~ ~

The synthesis of various analogues of arachidonic acids, which are the biosynthetic precursors of leucotrienes and prostaglandins, has been reported. 1 1,12-Dehydro- and 5,6-dehydro-arachidonic acids ( 185) and ( 186), which are effective inhibitors of this biosynthesis, are available from Wittig reactions of the acetylenic phosphonium salt ( 184) (Scheme 35).Io1 The iodo-allenes (1 88) and (1 89), which are intermediates in an alternative synthesis of ( 186) and (1 85), have been prepared by Wittig reactions of S-trimethylsilylpent-3ynylidenetriphenylphosphorane (1 87) followed by iodination (Scheme 36). lo2 Pheromones.-The eight possible isomers of allofarnesene have been synthesized by Wittig reactions and separated by chromatography. lo3 Isomer (190) is identical t o that obtained from the Dufour glands of Solenopsis invicta, the red fire ant, but all (4Z)-isomers exhibited trail-following activity. Wittig reactions of a number o f ylides ( 192) with various aldehydes have been used t o prepare t h e functionalized dienes (1 93), these being useful in the synthesis of bis-olefinic sex pheromones.lM In a comprehensive study,lo5 Bestmann has applied similar principles (his so-called 'unitized 98

K. C. Nicolaou, N . A. Petasis, and S. P. Seitz, J. Chem. SOC., Chem. Commun., 1981, 1195.

S. W. Russell and H. J. J . Pabon, J. Chem. SOC.,Perkins Trans. I , 1982, 545. l o o E. J . Corey and J. Kang, J. A m . Chem. Soc., 1981, 103, 4618; G. Just, C. Luthe, and P. Potvin, Tetrahedron Lett., 1982, 2 3 , 2285. l o ' E. J. Corey and J . E. Munroe, J. A m . Chem. Soc., 1982, 104, 1752. lo' E. J . Corey, and J. Kang, Tetrahedron Lett., 1982, 2 3 , 1651. l o 3 H. J. Williams, M . R. Strand, and S. B. Vinson, Tetrahedron, 1981, 37, 2763. I o 4 H. J. Bestmann, K.-H. Koschatzky, W. Schatzke, J. Suss, and 0 . Vostrowsky, Liebigs 99

Ann. Chem., 1981, 1705. H. J. Bestmann, J . Suss, and 0. Vostrowsky, Liebigs Ann. Chem., 1981, 2 1 17.

267

Ylides and Related Compounds

.+

rl

+,JIa L a:

. I

>

.I)

m

c a > P

zu

m v)

in

a

lJ

X

E 0

0

z u

rl

II

I

X

10

n

v rl Q) v

jI

II

I

c1

---

cu :=I

268

Organophosphorus Chemistry

i,ii

Ph3P=CHCH2CsCCH2SiMe3

-

/I

H 2 C = C = C v

(187)

(189)

\

iii,ii

H2C=

C =C

/I

COOMe

Reagents: i, C , H , , C H O ; ii, I , , AgBF,; iii, OHC(CH,),COOMe

Scheme 36

Me '

;

d

M

e

( R = Ye2C=CHCH2CH2-

+

H/'C=PPh3

-

Me

+

)

Me ( 190)

Ph3P=CHR1

+

Me [ C H 2 ] =HC=CI! [CH ] HC=CH [ C H 2 ] x R 3

R2CH0

(193)

[CH ] H C = C H [ C H 2 1 x R 3 o r [ C H Z l x R3 2 Y [CH 1 M e o r [ C H 2 ] H C = C H [ C H 2 1 Z M e 2 2

C H 2 0 0 C M e , C H 2 0 H , C H 2 0 T H P , CHO, COOR, e t c . x

=

3 , 4 , or 5 ;

:

2 Y

(192)

y = z

= 0 ,

1 , 2 , or 3

Ph 3P= CHR

( 1 9 4 ) R = HC=CHMe, C z C M e , a l k y l ,

o r [ C H 2 ] nOOCMe

construction' method) t o the synthesis of all four geometric isomers o f various conjugated diene systems, known to be sex pheromones of female butterflies and moths, through reactions of the ylides (1 94). The pheromones (1 95) and (1 96) have been prepared, virtually stereospecifically, by using a combination of Wittig and hydroboration reactions.lo6 lo6

H. J . Bestmann and K. Li, Tetrahedron L e t t . , 1981,22, 4941.

269

Ylides and Related Compounds

Prostaglandins.- Examples of the use of 4- carboxybutylidenetriphenylphosphorane (1 97) to introduce the P-side-chain into prostaglandins include the syntheses of (+)-prostaglandin E2 methyl ester,'" of analogues, e.g. (1 98), o f prostacyclin,'08 and of 10-aza-pro~taglandins.'~~ Similarly, the use of the 2-oxoheptylphosphonates (1 99)''' and of the 2-oxoheptylidene ylides (2O0)ll1 continues as the method of choice for the introduction of the p-side-chain. A modification of this traditional approach is the use of 2-hydroxyheptylidenetriphenylphosphorane (20 1) ' I 2 , 'I3 t o introduce the

Ht)

bH

0 (RO)2P-cHCO(CH2)qMe

II

(199)

OLi Ph3P-CHCH(

I

CH2)qMe

(201)

C. Howard, R. F. N e w t o n , D. P. Reynolds, and S. M. Roberts, J. Chem. SOC., Perkin Trans. 1, 1981, 2049. R. F. N e w t o n , a n d A. 11. Wadsworth, J. Chem. SOC.,Perkin Trans. 1, 1982, 823. '09 R. W. King, Tetrahedron Lett., 1981, 22, 2837. W. F. Berkowitz, S. C. C h o u d r y , a n d J. A. Hrabie, J. Org. Chem., 1982, 47, 824; H. Disselnkotter, F. Lieb, H. Oediger, a n d D. Wendisch, Liebigs Ann. Chem., 1982, 150; A. Barco, S. Benetti, P. G. Baraldi, F. Moroder, G. P. Pollini, a n d D. Simoni, ibid.,

lo'

p. 960. 112

'13

S . Ohuchida, N. Hamanaka, a n d M. Hayashi, J. A m . Chem. SOC., 1981, 103, 4597. S. Schwarz, G. Weber, J. Depner, J. Schaumann, H. Schick, and H. P. Welzel, Tetrahedron, 1982, 38, 1261. F. Johnson, K. G. Paul, D. Favara, R. Ciabatti, and U. Guzzi, J. Am. Chem. Soc., 1982, 104,2190.

270

Organophosphorus Chemistry

0-side-chain directly; however, in a synthesis of PGF2, the old favourite (199) gave better yields.' l 3 One new Wittig-based method of introducing the P-sidechain into prostaglandins has been r e p ~ r t e d . " The ~ reaction of the aldehyde precursor (202) with t h e thioacetal ylide (203), followed by hydrolysis, gives the aldehyde (204). The reaction of (204) with alkyl Grignard reagents allows the synthesis o f a variety of different 0-side-chains (Scheme 37); however,

n

-

n ,CH2COOMe

i-iii

U

(204)

iv/

n

9

,CH2 COOMe

OH Ph P=CH 3

Reagents: i,

; ii, separation of (E)-isomers; iii, H , O + ; iv, RMgX

U

(203)

Scheme 37

the method appears t o have a number of disadvantages compared with the use of (199) and (200). The 15-deoxy-16-hydroxy-16-methy1side-chain, for example in 8-aza-l l-deoxy-l 5-deoxy-l6-hydroxy-l6-methylprostaglandin (205), can be efficiently introduced by a one-pot reaction, using the ylide that is generated from methylenetriphenylphosphorane and 2- methylhex1-ene oxide by treatment with butyl-lithium (Scheme 38).l15 The cyclic enone (207), a n intermediate in a synthesis of prostaglandin D methyl ester, has been prepared via an intramolecular Wittig reaction, using the vinylphosphonium salt (206) t o generate the keto-ylide intermediate (Scheme 39).'16 'I4

J . Brugidon, J . Poncet, C.-T. B. Huong, and H. Cristol, Tetrahedron L e t t . , 1981, 2 2 , 4709. C.-L. J . Wang, Tetrahedron L e t t . , 1982, 23, 1067. A . G . Cameron, A. T. Hewson, and A. H. Wadsworth, Tetrahedron Lett., 1982, 23, 561.

27 1

Ylides and Related Compounds

b,, ( CH2)

Reagents: i, Ph,P=CH,; ii, BunLi; iii,

6COOBut

Scheme 38

Me S,

i ,ii

SMe

I

Reagents: i, NaH; ii, (206)

Scheme 39

Miscellaneous Applications.-A bis-Wittig reaction of the diphosphorane (208) and (EYZ)-5-methylhepta-2,4-dien-6-ynal provides the key step in a very short synthesis of the [ 16lannulenobiphenylene derivative (209) (Scheme 40).'17 Olefination of 17-0x0-steroids with diethyl a-isocyanatoethylphosphonate has been used as the key step to construct the dihydroxyacetone side-chain of corticosteroids efficiently.'" The acarbocyclic monosubstituted epoxide (21 1) has been prepared, for use in sterol synthesis by non-enzymic cyclization, via a Wittig-Schlosser coupling of the ylide (210) (see Scheme 41)."' The reaction of vinyltriphenylphosphonium bromide with the enolate ( 2 12; R2 = Me), readily available from tetralone, gives the ylide (2 13), which 'IR

F. Sondheimer and R. J . K. Taylor, J. Org. Chem., 1981, 46, 4594. D. H. R. Barton, W. B. Motherwell, and S. Z. Zard, J. Chem. Soc., Chem. Commun.,

'I9

E. E. Van Tamelen, and T. M. Leiden, J. A m . Chem. Soc., 1982, 104, 2061.

1981,774.

27 2

WPPh3+ 21cH Organophosphorus Chemistry

Me

i,ii

PPh3

Me

CS C H

(208)

Me (209 )

Reagents; i, THF, at 5 0 ° C for 2 hours; ii, Cu(OAc), . H,O, pyridine

Scheme 40

R. Me

I

C

L ii .

/O\

(210)

( 2 1 1 ) R = CH-CH2

Reagents: i, PhLi, THF, Et,O; ii, Me,S=CH2

Scheme 4 1

undergoes an intramolecular Wittig reaction under these conditions to give the tetracycle (214);l2O this is claimed t o be the shortest known total synthesis of a steroid, albeit in fairly low yield. If the same reaction sequence is applied to the bromo-enolate (2 12; R2= Br), the major product is the 9 , l l seco-steroid (2 15), and this is found to be a general reaction for a-halogenoketones. An intramolecular Wittig reaction is also involved in the synthesis of the insecticide ajugarin-IV (2 17);12' ketenylidenetriphenylphosphorane (216) 122 is used as a highly effective method of forming the butenolide group. Intramolecular phosphonate olefination is the basis for forming the 6 -1actone side-chain in a synthesis of (22R)-3P-acetoxyergosta-5,24-dien22,26-olide (2 18).123 I2O 12'

lZ2

G. H. Posner, J. P. Mallamo, and A. Y . Black, Tetrahedron, 1981, 37, 3921. A. S. Kende and B. Roth, Tetrahedron Lett., 1982, 2 3 , 1751. K. Mickisch, W. Klose, and F. Bohlmann, Chem. Ber., 1980, 113, 2038. E. Glotter, M . Zriely, and I . Kirson, J. Chein. Res. ( S ) , 1982, 32.

273

Ylides and Related Compounds

0

0

n

In rl v N

0

0 n

m rl v N

Organophosphorus Chemistry

274 OH

+

Ph3P=C=C*

> -

(216)

Me OOC

OCOMe

MeOOC

OCOMe

0 0

II

H

AcO

(222)

Polyene and enyne constituents of algae have been synthesized, using the Wittig reaction. Octa-2,5-dienylidenetriphenylphosphorane(2 19) was used to introduce the 32-double-bond in a synthesis of the isomer (220) of ( 3 E 3 2,8Z)-l,3,5,8-~ndecatetraene(222), which is the odoriferous principle of the gametes of the brown alga Spermatochnus paradoxus. 124 Although the '24

F.- J. Marner, W. Boland, and L. Jaenicke, Liebigs Ann. Chem., 1982, 5 7 9 .

Ylides and Related Compounds

275

reaction is not stereospecific, the (3E)-isorner (221) can be removed by preferential Diels- Ald er reaction with t e t racy anoe t hylene . Lauren cenyne (224) and neolaurencenyne (226), constituents of red algae of the genus Laurencia, are available from Wittig reactions of propargylaldehyde with the phosphonium salts (223) and (225), respectively (Scheme 42).12'

(224)

) PPh3 Ii

M e ( CH?

I

\-

(225 1

i,ii

-

Me(CH2))

-

C mCH

(226 1

Reagents: i, 1.2 equivalents of BuLi, THF, HMPT, at - 78°C;ii, HC-CCHO, at - 78'C

Scheme 42

(228) R =

Mey Mef Mey=Mey (229) R =

M e OOC

(230) R =

MeOOC

'"

MeOOC

. ' O R

(231) R

COOMe

H.Kigoshi, Y. Shizuri, H. Niwa, and K. Yarnada, Tetrahedron Lett., 1981, 22, 4729.

10

276

Organophosphorus Chemistry

With a view t o the synthesis of the acyclic chains o f verrucarins A and J, the reactions of phosphonate carbanions and of phosphoranes with malealdehydic acid (227) have been studied. 126 Phosphonate olefination gave much better yields, and the method was used t o prepare (228), (229), (230), and (23 1) with good stereoselectivity. In similar work, involving the synthesis of (230),12' benzoic acid was used t o catalyse 128 olefinations of ketones with the stabilized compound methoxycarbonylmethylenetriphenylphosphorane. Phosphonate olefin synthesis has been used extensively in investigations of possible routes to polyene macrolide mimics.129 The reaction of the diphos-

(233)

R

R

R

( 2 3 4 ) R = H or OAc

phonate (232) with dialdehydes (233) in the presence of base gave a good yield of the macrocycles (234), whereas poor yields were obtained from dilactonization methods.

( 236)

Reagents: i, KO(t-amyl), PhH; ii,

()o 0

,at92"C

'

(235)

Scheme 4 3 lZ6 127

W. R. Roush, T. A. Blizzard, and F. Z. Basha, Tetrahedron Lett., 1982, 2 3 , 2331. J. D. White, J. P. Carter, and H. S. Kezar, III,J. Org. Chem., 1982, 47, 9 2 9 . W. Keller-Schierlein, J . Widmer, and B. Maurer, Helv. Chim. Acta, 1 9 7 2 , 55, 198. D. M . Floyd and A. W. Fritz, Tetrahedron Lett., 1 9 8 1 , 22, 2 8 4 7 .

Ylides and Related C o m p o u n d s

277

A Wittig reaction at high temperature, using potassium t-amylate as the base, has been used to convert the hindered ketone (235) into (236), and hence into modhephene (237) (Scheme 43), after attempts under more normal conditions had failed.13' It was important ( a ) to use a large excess of ylide, ( b ) to use a minimum of solvent, and (c) to add the ketone t o a preheated solution of ylide. 0

II I OPh

Ph3P=CHPCH2C1

+ RCHO

-

1

(Et0l3P

RHC=CHPCH2C1-

R =

I OPh

RHC=CEPCH2P(OEt)2

I

OPh

C18H370CH2

I

C1 8H370CH-

Key steps in a multi-step synthesis of a phosphinate-phosphonate liponucleotide analogue are olefination of the diether aldehyde (239) with the novel phosphinate-stabilized phosphonium ylide (238), followed by an Arbusov reaction with triethyl phosphite, to give the phosphinate-phosphonate

(240). 13'

I3O

13'

A. 8.Smith, 111, and P. J. Jerris, J. Org. Chem., 1982, 47, 1845. A. F. Rosenthal and L. A. Vargas, J. Chem. SOC.,Chem. Commun., 1981, 976.

Mass Spectrometry of Organophosphorus Compounds BY J. R. CHAPMAN

1 Introduction

The history of the application of mass spectrometry t o the analysis of organophosphorus compounds provides many illustrations of the shortcomings of conventional electron-impact ionization and the advantages t o be gained from newer ionization techniques. In the area of synthetic chemistry, electronimpact ionization has been widely used for the analysis of phosphorus compounds and has often been able t o provide considerable structural information. However, a wide range of compounds based o n the oxyacids of phosphorus undergo extensive fragmentation under electron-impact conditions, so that the percentage of ion current that is carried by the molecular and other high-mass ions is very low, making complete identification difficult. Ionic compounds such as phosphonium salts are not amenable t o analysis under electron-impact conditions. Thus, electron-impact ionization on its own is a less than suitable method for over half the compounds recorded in synthetic phosphorus chemistry. Chemical ionization and, t o a lesser extent, field desorption are now increasingly used as ionization techniques in this field. In the field of natural products, the presence of ionic phosphate groups and the larger molecular size of these materials, together with the presence of more labile sugar moieties in some cases, has underlined shortcomings in both mass-spectrometric ionization and the techniques for introducing a sample into the spectrometer. Thus, earlier applications of mass spectrometry t o nucleoride analysis employed structural elucidation based on the fragmentation that is induced by a combination o f electron-impact and pyrolytic techniques. Alternatively, chemical degradation o r derivatization techniques had t o be used prior t o mass-spectrometric analysis. However, the application of techniques such as field desorption and, more recently, energetic- particle bombardment, has provided a means by which the direct analysis of these natural products may be simply achieved. Because of the considerable importance of ionization techniques in the analysis of organophosphorus materials, Section 2 of this Report is devoted to a more detailed discussion of their availability, applications, and limitations.

2 Techniques Chemical Ionization and ‘In- Beam’ Evaporation Techniques.-Under standard electron-impact (EI) conditions, the interaction in the ion source of 27 8

279

Muss Spectrometry of Organophosphorus Compounds

energetic electrons with sample molecules that have ionization potentials of 7-1OeV produces molecular ions that contain a considerable amount of excess energy. This energy is largely dissipated through fragmentation processes. If the ion source now also contains a high pressure (0.1 - 1 Torr) of a reagent gas such as methane, so that the ratio of reagent gas t o sample is in the order of 1O3 or 1O4 t o 1, then the principal process carried out by the electrons becomes the ionization of the reagent gas. In the case of methane, ionization followed by ion-molecule reactions eventually produces two dominant ionic species, CHS+ and C2Hs+. Both of these reagent ion species can now act to ionize the sample molecules present in the source. This is chemical ionization (CI).' A major reaction with methane reagent gas is ionization by proton transfer [reaction ( 1) I .

M + CH,'

+

MH+ + CH,

(1)

Proton transfer is a considerably less energetic process than ionization by electron impact, with the overall result that whilst some fragmentation does occur, the percentage of the ion current that is carried by the so-called quasimolecular ion MH+ is generally much greater than that carried by the molecular ion M+, formed under electron-impact conditions. The spectra of parathion as obtained by EI and CI are given in Table 1 for comparison.

Table 1 Major ions in the CI spectrum (using methane)2 and the El spectrum o f parathion (mol. w t = 2 9 1 ) CI

EI

mlz

Rel. int.

Composition

mlz

Rel. in 1.

mlz

R el. in t.

292 320

100

(M+ H)' (M +C2H5)+

63 64 65 75 76 81 93

36 21 50 15 11 25 20

97 109 125 137 139 155 29 1

100 96 33 41 36 26 15

19

A further advantage of chemical ionization is that, by the use of different reagent gases, reagent ions of differing reactivity may be produced. For example, the use of isobutane as the reagent gas produces a t-butyl ion as the principal reagent ion. As this ion is a considerably weaker proton donor than the CHS+ ion, isobutane can be used t o form quasi-molecular ions which undergo much less fragmentation. Still milder ionization conditions may be achieved by the use of ammonia, which provides protonated molecular ions MH+ or adduct ions (M +NH4)+, depending on the basicity of the sample r n o l e ~ u l e .Such ~ milder reagent gases are also more selective, so that, for example, saturated hydrocarbons will not be ionized by ammonia.

' M. S. B. Munson and F. H . Field, J. A m . Chem. SOC., 1966, 88, 2621. R. L. Holmstead and J. E. Casida, J. Assoc. Off Anal. Chem., 1974, 5 7 , 1050. J . M . Desmarchelier, D. A. Wustner, and T. R. Fukuto, Residue Rev., 1976, 6 3 , 77. T. Keough and A. H. DeStefano, Org. Mass Spectrom., 1981, 16, 527.

28 0

Organo p h 0 sp h or us Che rnis try

The use of a very mild reagent gas, giving little o r no fragmentation, can be particularly advantageous when the detection of a particular compound by monitoring a relatively intense specific ion is t o be accomplished. The use o f a gas that gives more fragmentation o r the complementary use o f electronimpact ionization may be preferred where more information, for complete structural analysis, is required. More detailed applications of the technique of chemical ionization will be found in Sections 3 and 4. The use of chemical ionization does not itself remove the necessity for vaporization of the sample, either from a conventional heated probe that is introduced into the ion source or o n injection into a coupled gas chromatograph. Obviously, many materials are sufficiently thermolabile that decomposition occurs during evaporation. The use of modified techniques for evaporation of the sample can be helpful in these cases. All of these modified techniqes involve evaporation of the sample very close t o t h e point of ionization, and therefore may be spoken of as 'in-beam' techniques. In many cases, high rates of heating ( 2 10 "C s- ') have been used, so that evaporation takes precedence over thermal d e c o m p ~ s i t i o n Evapora.~ tion of the sample from an inert support material, such as gold6 or a polyimide-coated wire,7 is an important feature in many cases. Instrument manufacturers provide facilities for these specialized evaporation techniques under the acronym DCI (direct o r desorption chemical ionization). Rapid in-beam evaporation is also a viable technique under EI conditions (see p. 288). Negative-ion Chemical Ionization.-Until recently, analysis of negative ions was little used in mass spectrometry. This was principally because the negative ions that are produced under the conditions of electron-impact ionization are those corresponding t o structurally uninformative low-mass fragments, and even these are produced only in low yield. More useful spectra can be produced by dissociative electron-capture processes, using a less energetic electron beam, but, even in these cases, information o n molecular weights is absent and t h e sensitivity is low. An impetus t o the analysis o f negative ions was provided by the realization that a reagent gas for chemical ionization, e.g. methane, interacts with a primary beam of energetic electrons t o provide not only positive reagent ions but also a large population of secondary electrons, having only thermal energy [reaction (2)]. These electrons may be captured by sample molecules that have a positive electron affinity, in a non-dissociative process, t o provide molecular anions M-. This process, commonly referred t o as negative-ion chemical ionization, has the advantages of being selective for electroncapturing compounds, providing an extremely mild form of ionization, and achieving high sensitivity.8 In certain cases, electron-capture ionization can

*

G. B. Daves, Jr.,Acc. Chem. Res., 1979, 12, 359. E. Constantin, Y . Nakatini, G . Ourisson, R. Hueber, and G. Teller, Tetrahedron L e t t . , 1980,21,4745. V . H . Reinhold and S. A . Carr, Anal. Chem., 1982,54, 499. D. F. Hunt, G . C. Stafford, Jr., F . W. Crow, and J . W. Russell, Anal. Chem., 1976,48, 2098.

Mass Spectrometry of Organophosphorus Compounds

28 1

offer sensitivity that is higher by orders of magnitude than positive-ion chemical ionization.

In addition t o electron-capture ionization, negative-ion operation provides the possibility of ionization through ion-molecule reactions, in a manner analogous to the positive-ionization methods described earlier. An important anionic reagent ion is C1-, generated from a number of alternative sources, such as carbon tetrachloride, d i c h l ~ r o m e t h a n e ,or ~ dichlorodifluoromethane (Freon 12)." The C1- ion reacts principally by the formation of (M+Cl)- adduct ions. Not only is the chloride ion a very mild CI reagent, producing virtually no fragmentation, it is also relatively selective. Thus, C1- reacts with a wide range of phosphate esters to give (M +C1)- ions l 1 but will not, for example, react with hydrocarbons. The direct analysis of a lubricating oil that contains a zinc dithiophosphate ester by this method produces a chloride-attachment spectrum of the phosphate ester, with virtually no interference from the hydrocarbons and no need for prior purification of the sample.'* Field Desorption and Ionization by Energetic Particles.-A field-desorption (FD) source contains an emitter - a tungsten wire of diameter 1 0 p m , on which microscopic carbonaceous dendrites have been grown - which is held at a high positive potential with respect t o an adjacent counter-electrode. The sample is deposited on this emitter from solution. Positive sample ions, formed on the surface of the emitter in the intense electric field, are drawn towards the counter-electrode and analysed. The emitter wire is heated during analysis, to promote diffusion and volatilization of the sample. These processes are also assisted by the structure of the dendrites, which allows the sample to be distributed over a very large surface area. No evaporation (to achieve a given vapour pressure of the sample) prior t o ionization is required, unlike the introduction of sample from a probe or from a gas chromatograph prior to EI or CI. Despite being a relatively difficult technique experimentally, field desorption has been widely and successfully used in the analysis of involatile and labile materials.13 Field desorption is a very mild ionization process, so that the spectra show intense M+ and/or (M+H)+ ions, with the possibility of increasingly abundant fragment ions as the temperature of the emitter is raised. In the field of phosphorus compounds, the technique has particularly been applied to the analysis of nucleotides and phospholipids, which is discussed in more detail below. Ionization by energetic particles embraces a range of ionization techniques which have come to prominence more recently. Essentially, the sample is lo

I'

''

H. Y. Tannenbaum, J. D. Roberts, and R. C. Dougherty, Anal. Chem., 1975,47,49. A. K. Ganguly, N . F. Cappuccino, H. Fujiwara, and A. K. Bose, J . Chem. SOC.,Chem. Commun., 1979, 148. R. C. Dougherty and J. D. Wander, Biomed. Mass Spectrom., 1980, 7 , 401. K. P. Morgan, C. A. Gilchrist, K. R. Jennings, and 1. K. Gregor, Int. J. Mass Spectrom. Ion Phys., 1983,46,309. H.-R. Schulten, Int. J . MassSpectrom. ion Phys., 1979, 32, 97.

28 2

Organophosphorus Chemistry

Table 2 Methods o f ionization by energetic particles Method

Typical particle t y p e and energy

Reference

".'Cf fission fragment ionization Caesium ion bombardment Fast- atom bombardment Secondary ion mass spectrometry Laser desorption

100 MeV Tc' 8-28 keV Cs' 5 keV ArO 5 keV Ar' 256 nm photon

16 17 15 14 18

placed o n a target, which is then bombarded, using a beam of neutral atoms, ions, or photons, t o produce sample ions by a sputtering process. The different methods are mainly distinguished by the type and energy of the bombarding particles (Table 2). The most popular method at the time of writing is fast-atom bombardment (FAB), which uses a beam of energetic neutral atoms. This technique, which employs a matrix material, such as glycerol, to dissolve the sample and to promote the diffusion of the sample t o the surface layers, has the advantages of experimental simplicity and ready compatibility with magneticsector mass spectrometers which permit the analysis of ions of high mass. The most obvious advantage of energetic-particle-bombardment techniques is their ability in many cases to provide information on molecular and fragment ions from molecules of extreme polarity and high molecular weight, well beyond the practical limits of field desorption ( c f . p. 286). Additionally, a technique such as FAB, when compared with FD, is simpler, operates with equal facility in the negative- and positive-ion modes, is more sensitive, and is less affected by the presence of impurities. Against this, FD produces far fewer background ions, particularly since it employs no matrix material, and can be a better method for the analysis of mixtures, particularly for the detection of minor components in mixures (cf. p. 288). Identification of Metastable Ions.-Although the electron-impact spectrum of a phospholipid usually shows no molecular ion, it was demonstrated quite early on that intact molecular ions are formed in the source under EI conditions but that these fragment before reaching the d e t e ~ t o r . These '~ so-called 'metastable' ions may be identified, using a variety of experimental techniques that are available on double-focusing magnetic-sector instruments. If a metastable ion of mass m l fragments as shown in reaction (3), then techniques which make use of the energy-analysing properties of doublefocusing instruments may be used t o elucidate the initial mass m l ,even l4

A. Eicke, W. Sichtetmann, and A. Benninghoven, Org. Mass Spectrom., 1980, 15, 289.

l5

M. Barber, R. S. Bordoli, R . D. Sedgwick, and A. N. Tylor, Nature (London), 1981, 293, 270.

R. D. MacFarlane and D. F. Torgerson, Science, 1976, 191, 920. W.Ens, K. G. Standing, B. T. Chait, and F. H. Field, Anal. Chem., 1981, 5 3 , 1241. l RM. A. Posthumus, P. G. Kistemaker, H. L. C. Meuzelaar, and M. C. Ten Noever de Brauw, Anal. Chem., 1978, 5 0 , 985. l 9 R. A. Klein, J. Lipid Res., 1971, 12, 6 2 8 . l6

l7

Mass Spectrometry of Organophosphorus Compounds

283

though the recorded ions have mass r n 2 . * O Thus, molecular weights may be elucidated in certain cases, even though the molecular ion is absent from the normal spectra.lg, ml*+

+

m 2 * ++ m 3

(3)

Another technique for metastable ions, known as ‘linked scanning’,22 may be used to record selectively only those ions that are produced by subsequent collision-induced dissociation of a chosen molecular ion that has been formed by a soft ionization technique such as field desorption23 ( c f . p. 285). This method provides an alternative to thermolysis as a method of increasing the amount of information on fragment ions that is available from soft ionization techniques. Liquid Chromatography.-Combined gas chromatography-mass spectrometry (g.c.-m.s.) is a well-established technique. However, since gas chromatography is limited in its ability t o handle polar and labile materials, there is an obvious interest in combined liquid chromatography-mass spectrometry (1.c.-ms.) in the field of phosphorus chemistry, as in many others. The 1.c.-m.s. interfacing methods that are currently available are the moving belt, in which a mechanical transport system is used to convey the sample from the column t o the ion source,24 and the direct liquid-introduction (DLI) system, in which the liquid eluent itself is used as the transport medium.25 Although a preference for the DLI system seems to be emerging, 1.c.-m.s. interfacing is still an evolving technique, and not yet at the stage where definitive comparisons of the available systems may be made. It is more practicable at this stage merely to draw the reader’s attention t o published applications in the field of phosphorus chemistry, viz. analysis of nucleotides by thermospray (DLI) 1.c.-m.s. ,26 analysis of phospholipids (DLI),27 and analysis of organophosphorus pesticides (DLI).28 3 Natural Products Nuc1eotides.-The principal mass-spectrometric techniques that have been applied to the analysis of nucleotides are electron-impact ionization, field desorption, and (more recently) ionization by energetic particles. Electron-impact ionization has been used in the analysis of oligonucleotides despite its known inability to offer information on molecular weights by direct analysis of the nucleotides. The application of this technique has been 2o

21

22

23 24 25

*‘

21

2R

R. G. Cooks, J. H. Beynon, R. M . Caprioli, and G . R. Lester, ‘Metastable Ions’, Elsevier, Amsterdam, 1973. S. G. Batrakov, V. L. Sadovskaya, V. N. Galyashin, B. V. Rosynov, and L. D. Bergel’son, Bioorg. Khim., 1978, 4, 1390. A. P. Bruins, K. R. Jennings, and S. Evans, Znt. J. Mass Spectrom. Ion Phys., 1978, 26, 395. K. M. Straub and A. L. Burlingame, Adw. Spectrom., 1980, 8 , 1127. W. H. McFadden, J. Chromatogr. Sci.,1979, 17, 2. P. J. Arpino and G. Guiochon, Anal. Chem., 1979, 51, 682A. C. R. Blakley, J . J. Carmody, and M . L. Vestal, J. Am. Chem. SOC., 1980, 102, 5931. F. R. Sugnaux and C. Djerassi, J. Chromatogr., 1982, 2 5 1 , 189. C. E. Parker, C. A. Haney, and J . R . Hass, J. Chromatogr., 1982, 2 3 7 , 233.

284

Organophosphorus Chemistry

mainly due t o t h e efforts of W i e b e r ~ , who ~ ~ - has ~ ~ developed methods for the interpretation of information from fragment ions in the spectra of oligonucleotides. These spectra, which are produced partly by electron-impact-induced processes and partly by thermolysis, offer information o n the bases that are present and (in smaller oligonucleotides) their sequence 3 2 , 33 as well as o n the location and identity of protecting groups that have been introduced during synthetic procedure^.^^ This technique is a particularly sensitive method for confirming that all blocking groups have been removed following synthesis. Another application that has successfully been examined by Wiebers is the detection and identification of abnormal nucleotide residues in DNA.M For example, this method has been used t o establish the occurrence of 5-methyland 5-hydroxymethyl-cytidine. Wiebers’ original work o n the identification of bases has been continued and developed by other author^.^' A more recent report by Ulrich and co-workers also discusses the pyrolysis-electron-impact mass spectrometry of protected phosphotriester oligodeoxyribonucleotides.36 The recorded spectra give ions that are characteristic of the bases and the protecting groups. An alternative approach t o the analysis of nucleotides, using electronimpact ionization, has been via the formation o f derivatives. Both Baker 37 and, more recently, Pettit 38 have used trimethylanilinium hydroxide t o permethylate nucleoside monophosphates, for subsequent analysis by g.c.m.s. Both authors used electrons of lower energy ( 1 1-20 eV), and Pettit reported characteristic molecular and fragment ions from a number of samples. The 2’-, 3’-, and 5‘-monophosphates of adenosine all gave distinct spectra as their hexamethyl derivatives, although the method was not completely satisfactory for the unequivocal location of the phosphate Thymidine and uridine phosphates were also analysed, the latter also by field ionization, when only a molecular ion was observed.38 Ribonucleosides that are liberated by hydrolysis with a phosphatase can be permethylated prior t o g.c.-m.s., using sodium methoxide o r methyl iodide in DMSO. In this case the concentration of the quasi-molecular ion that is formed by chemical ionization (using isobutane) was monitored, as the basis of a quantitative method.39 Trimethylsilylation of halogenated nucleotides and nucleosides has been used by Gelpi t o permit their analysis by g.c.-m.s. techniques. Finn 41 has M . A. Armbruster and J. L . Wiebers, Anal. Biochem., 1977, 83, 570. J. L. Wiebers,Anal. Biochem., 1973, 5 1 , 542. 3 ’ D. K . Burgard, S. P. Perone, and J . L. Wiebers, Anal. Chem., 1977, 4 9 , 1444. 3 2 J . L. Wiebers and J . A. Shapiro, Biochemistry, 1977, 16, 1044. 33 D. K . Burgard, S . P. Perone, and J. L. Wiebers, Biochemistry, 1977, 16, 1051. 34 J. L. Wiebers, Nucleic Acids Res., 1976, 3, 2959. 35 N. Turkkan, F. Soler, and K. Janowski, Biomed. Mass Spectrom., 1982, 9 , 9 1. 36 J. Ulrich and M . J . Bobenrieth, Z . Naturforsch., Tril. B, 1980, 35, 2 1 2 . 37 K. M . Baker, Adv. Mass Spectrom. Biochem. Med.. 1976, 1, 231. 38 G. R. Pettit, J. J. Einck, and P. Brown, Biomed. Mass Spectrom., 1978, 5 , 153. 3 9 I . Jardine and M. M. Weidner, J . Chromatogr., 1980, 182, 395. 4 0 E. Gelpi, J . Pares, and C. Cuchillo, Adv. Mass Spectrom. Biochem. Med., 1976, 1, 215. 4 1 C. Finn, H. J. Schwandt, and W. Sadee, Biomed. Mass Spectrom., 1979, 6, 194. 29

30

Mass Spectrometry o f Organophosphorus Compounds

28 5

trimethylsilylated the free bases that are produced by hydrolysis of a nucleotide, subsequently monitoring the M+ and (M - CH3)’ ions during analysis by g.c.-m.s., t o provide a method for the quantitative determination of uracil and thymine at the picomole level. Unlike electron-impact ionization, field desorption produces spectra from nucleotides that contain peaks which give information on molecular weights. Fragment ions are also present which identify the base. Ions with a low mass in the spectrum of 5’-AMP suggest the presence of ribose rather than d e o x y r i b o ~ e .In ~ ~ the original paper, measurement of mass was used t o confirm the composition of each peak.42 Extension of this work to dinucleotide monophosphates produced spectra that again gave information about the molecular weights of the compounds and the separate units from which they were made up.43 Pyrolysis-field desorption of deoxyribonucleic acid gave complex spectra which nevertheless contained information related to the constituent bases.44 In his most recent paper, Schulten4’ has used FD t o identify protected synthetic deoxyribonucleotides after their separation by high-performance liquid chromatography (h.p.1.c.). The spectra contained intense cationized molecular ions and a small number of structurally significant fragment ions, as well as information on organic and inorganic impurities. H.p.1.c. can offer a valuable method of cleaning up samples prior t o F D ( c f . p. 282), since the performance of a field desorption source is very much dependent on the presence or absence of impurities. This problem, and that of deterioration of the emitter in the analysis of nucleotides, has been discussed by Budzikiewicz and co-workers.& These same authors used FD to study the course of the reaction of several dinucleoside phosphates with diazomethane.47 In a particularly elegant study, Burlingame 2 3 has applied field desorptioncollision-induced dissociation (FD-CID) mass spectrometry t o the sequencing of polynucleotides that have been modified by interaction with intermediates derived from the potent carcinogen benzo [alpyrene. In this technique, collision with inert gas molecules is used to enhance the fragmentation o f field-desorbed molecular ions, These collision-induced fragment ions are then selectively recorded, using the linked-scan technique mentioned on p. 283. By this means, the direct analysis of a modified deoxyadenosine-deoxythymidine dinucleoside was achieved. The FD spectra of cyclic nucleotides have also been reported.48 Cyclic AMP has also proved amenable to DCI analysis, giving information on

42 43 44

45

46 47

48

H.-R. Schulten and H. D. Beckey, Org. MassSpectrom., 1972, 7, 861. H.-R. Schulten and H. M. Schiebel, Fresenius’ 2. Anal. Chem., 1976, 280, 861. H.-R.Schulten, H. D. Beckey, A. J . H . Boerboom, and H. L. C. Meuzelaar, Anal. Chem., 1 9 7 3 , 4 5 , 2358. H. M . Schiebel and H.-R.Schulten, Z . Naturforsch., Teil. B, 1981, 36, 967. H. Budzikiewicz and M. Linscheid, Biomed. Mass Spectrom., 1977, 4. 103. M . Linscheid, G. Feistner, and H. Budzikiewicz, Zsr. J . Chem., 1978, 17, 163. C.-H. Wang, Y.-X. Wang, K.-X. Cao, L.-H. Chang, L.-T. Ma and X. Wang, Huah Hsueh Tung Pao, 1981, No. 1, p. 11.

286

Organophosphorus Chemistry

’”

molecular and fragment ions, using methane 49 o r ammonia as the reagent gas. F D cannot be used t o distinguish isomeric nucleoside 3’- and 5’-monophosphates whereas the EI spectra of the per- trimethylsilyl derivatives o f these compounds d o allow a distinction t o be made.” The analysis and sequencing of protected oligonucleotides, using an energetic-particle-ionization method, was first reported by McNeal and coworkers in 1980,52 using the method involving a 252Cf source (see Table 2) that had been developed by McFarlane and Torgerson.I6 This technique, although very simple in practice, has been used by few investigators because of problems in handling the source material and because of the specialized nature of the mass spectrometer used. It has, however, provided results which remain a target for other more accessible energetic-particle techniques. In a series of papers, McNeal and co-workers have recorded molecular and dimer ions from a protected synthetic deoxydodecanucleotide of molecular weight 6275 53 and have demonstrated the use of the technique in sequencing protected ribo-oligonucleotides that contain up t o seven nucleoside units. 54-56 Information giving the molecular weight is available in the positive-ion mode whilst the negative-ion spectra contain two nested series of fragment ions which resemble the summed products of two parallel enzymatic digests, utilizing a 5’- and a 3’-exonuclease. The information o n base sequence from one set of fragment ions is thus mirrored in the complementary set. Ionization of fully protected di- and tri-ribonucleoside phosphates with Cs+ ions (of energy 8-28 kV) has produced similar data.57 The positive- and negative-ion spectra again contain information enabling the determination of the molecular weight, the identification of the protecting groups and bases present, and the determination of the base sequence (the last, again, particularly from the negative-ion spectrum). Ionization using sources of less energetic particles has so far been restricted t o unprotected nucleotides. Thus, mass spectra from mono- and di-nucleotides have been produced by the impact of low-energy ions l 4 and of low-energy neutral atoms l 5 (molecular SIMS and fast-atom bombardment, respectively) and an (M - H)- ion from a tetranucleoside triphosphate has been observed at m / z 1172, using the FAB technique.” Spectra obtained by using these tech49

52

53 54

55

56

57

58

D. F. Hunt, J . Shabanowitz, F. K. B o t z , and D. A. Brent, Anal. Chem., 1977, 49, 1160. E. J . Esmans, E. J . Freyne, J . H. Vanbroeckhoven, and E’. C. Aldenveireldt, Biomed. Mass Spectrom., 1980, 7 , 377. H. Budzikiewicz and G . E‘eistner, Biomed. Mass Spectrom., 1978, 5 , 5 12. C. J. McNeal, S. A. Narang, R . D. Macfarlane, H. M . Hsiung, and R. Brousseau, Proc. Natl. Acad. Sci. USA, 1980, 7 7 , 7 3 5 . C. J. McNeal and R . D. Macfarlane,J. Am. Chem. SOC., 1981, 103, 1609. C. J . McNeal, K. K. Ogilvir, N . Y . Theriault, and M . J . Nemer, J . A m . Chem. SOC., 1982, 104, 972. C. J . McNeal, K. K. Ogilvie, N. Y . Theriault, and M. J . Nemer, J. A m . Chem. SOC., 1982,104,976. C. J. McNeal, K. K. Ogilvie, N . Y . Theriault, and M. J . Nemer, J. A m . Chem. SOC., 1982, 1 0 4 , 9 8 1 . W . Ens. K. G. Standing, J . B. Westmore, K. K. Ogilvie, and M. J . Nemer, Anal. Chem., 1982, 54, 960. D. H. Williams, C. Bradley, G. Bojesen, S. Santikarn, and L. 2 . E. Taylor, J. A m . Chem. SOC.,1981, 103, 5700.

Mass Spectrometry of Organophosphorus Compounds

287

niques are very similar to those observed when using the sources of more energetic particles, and it is therefore expected that techniques such as FAB should also be applicable t o the analysis of protected nucleotides. Somewhat similar spectra to those obtained by using less energetic particles have been recorded for unprotected mono- and di-nucleotides by workers who used laser-desorption ionization techniques.I8 Nucleotides have recently become amenable to analysis by 1.c.-m.s., using a technique for direct introduction of a liquid that has been developed by Vestal and co-workers.26 In this method, ions that have been pre-formed in solution can be evaporated from the surface of tiny droplets, these being formed when the flow from the liquid chromatograph is sprayed into the vacuum system of the mass spectrometer. Spectra with intense quasimolecular ions and excellent signal- to-noise characteristics have been obtained for adenosine monophosphate and two dinucleoside monophosphates by using this mode of operation. Phospholipids.-Phospholipids are another class of polar compounds that present difficulties in analysis. Many routine analytical methods rely on hydrolytic procedures, after which the component fatty acids may be determined by chromatographic techniques. A more direct method of analysis is, however, provided by the use of field desorption. In an early paper," Wood and co-workers reported on the problems caused by organic and inorganic contaminants in the FD analysis of phospholipids. In particular, inorganic ions such as Na" result in low ion intensities, increased fragmentation, and the formation of cluster ions or even complete masking of the spectra of the lipids. More recently, this same school reported on the successful use of a modified extraction technique t o clean up phospholipid samples prior to FD analysis, giving much improved spectra.60 The FD spectrum of dipalmitoylphosphatidic acid that is published in this later paper gives information on the molecular weight and consistuent fatty acids. The (M + H)" ion is the base peak whilst the (M + Na)+ ion has been reduced to the level of 1% of that intensity. Published data from field-desorption studies are now available for the following classes of phospholipids: phosphatidylcholines,5g~ phosphatidy let ha no la mine^,^^ phosphat idic acids,59, glycerophosphoryl lipids,59 and the aldehydogenic phospholipids (1).@ These spectra always show intense quasi-molecular ions, but structurally informative fragment ions are less common. In a very recent study, silicon emitters were used for fielddesorption studies of phospholipids and related derivative^.^' 59

6o 61

62

63 64 65

G. W. Wood, P. Y. Lau, G. Morrow, G. N. S. Rao, D. E. Schmidt, Jr., and J . Tuebner, Chem. Phys. Lipids, 1977, 18, 316. G. W. Wood and S . E. Perkins, Anal. Biochem., 1982, 122, 368. G. W. Wood, P.-Y. Lau, G. N . Rao, and G. N. S. Rao, Biomed. M a s s Spectrom., 1976, 3 , 172. G. W. Wood, P. A. Tremblay, and M. Kates, Biomed. Mass Spectrom., 1980, 7 , 11. G. W. Wood and P. Y. Lau, Biomed. Mass Spectrom., 1974, 1, 154. A. V. Chebyshev, S. P. Kabanov, A. A. Perov, G. A. Serebrennikova, S. E. Kupriyanov, and R. P. Evstigneeva, Bioorg. Khim., 1977, 3, 1370. J . Sugatani, M . Kino, K. Saito, T. Matsuo, H. Matsuda, and I. Katakuse, Biomed. Mass Spectrom., 1982, 9, 293.

Organophosphorus Chemistry

288 CH~OCH=CHR'

CH20CH2(CH2)14Me

CHOCOR~

CHOH

II

I

An interesting study of the practical use of FD in the analysis of phospholipid mixtures has been presented by Catlow,66 who points o u t that whereas conventional FD gives moiecular, fragment, and adduct ions, e.g. (M + CH3)+ and (M + Na)', from phospholipids, the addition of a strong acid such as toluene-p-sulphonic acid changes the spectrum so that it comprises only a ( M + H ) + ion.67 This simplicity and the absence of interfering background which make the method ideal for the analysis of mixtures may be contrasted with FAB results also obtained by Catlow on these mixtures. In this case, molecular species are also seen, but the intense background that is characteristic of FAB spectra means that minor components of mixtures are usually not recognized. Chemical ionization may also be used t o provide spectra of intact phospholipids. For example, the 1-O-alkylglyceryl-3-phosphorylcholine ( 2 ) ( 0 deacetyl platelet-activating factor) that is released from leucocytes was identified by CI mass spectrometry, using isobutane as the reagent gas6* The CI spectrum gave information o n molecular weights and o n fragment ions that resulted mainly from cleavages at phosphate bonds. Sugnaux and Djerassi 27 have compared the methane and ammonia DCI spectra of dimyristoylphosphatidylcholine with the spectrum, run in the presence of ammonia, of the same sample when introduced from a liquid chromatograph via a DLI interface. Since the quality of DCI spectra varies considerably with time, these authors concluded that the 1.c.-DLI technique is better for quantitative determination of this material. The quasi-molecular ion is less intense in the DLI spectrum than in the ammonia DCI spectrum, but is still more intense than that observed in the methane DCI spectrum. Fragmentation in all three spectra results mainly from cleavage of phosphate ester bonds. Workers at Strasbourg have demonstrated that phospholipids that are evaporated close t o the electron beam from an inert gold support give spectra with information on the molecular ion even under electron-impact condit i o n s 6 A stable beam, allowing scanning o r mass-measurement experiments, is obtained by using this technique. Under EI conditions, fragment ions (allowing identification of t h e constitutent fatty acids) are also seen. Sugnaux and Djerassi 27 have also recorded the EI spectrum of dimyristoylphosphatidylcholine when it was being rapidly evaporated. 66 67 68

D. A. Catlow, Int. J. Mass Spectrom. Ion Phys., 1 9 8 3 , 4 6 , 387. T. Keough and A. J . DeStefano, Anal. Chem., 1981, 53, 2 5 . J. Polonsky, M . Tence, P. Varenne, B. C. Das, J . Lunel, and J . Benveniske, Proc. Natl. Acad. Sci. USA, 1980, 7 7 , 7019.

Mass Spectrometry o f Organophosphorus Compounds

289

Under more normal conditions of introduction of the sample, when the molecular ion is not seen, information on the molecular weight has been obtained for phosphatidylglycerols, lecithins, and phosphatidylethanolamines by using one of the techniques for metastable ions that was described above (p. 283).21 G.c.-m.s. techniques can be used for the structural analysis of phospholipids, following their enzymatic hydrolysis. Monohydroxy-compounds that are formed o n hydolysis are analysed as trimethylsilyl 69 or t-butyldimethylsilyl 7o derivatives whereas 1,2-diols and 1,3-diols are conveniently analysed as cyclic boronate derivatives, using EI 69 or CI 71 conditions. An alternative method is based on the analysis of the monoacetyl diglycerides that are formed by acetolysis of the phospholipid^.^^ The identification of 9- and 10-trichloromethyl-stearic acids as esterifying acids in phospholipids that were isolated during studies of the metabolism of carbon tetrachloride was accomplished by mass-spectrometric examination of transmethylation products." G.c.-m.s. studies of compounds ( 3 ) and (4), as their bis-trimethylsilyl derivatives, have been reported as the basis of a method for the identification of the polar moiety of phospholipids, foliowing their enzymic hydrolysis and N- demethylation. 74 0

(3)

(4)

Miscellaneous Natural Phosphates.-Bombardment with fast atoms has been used t o identify ecdysone 22-phosphate and 2-deoxyecdysone 22-phosphate, isolated from eggs of the desert Fast-atom bombardment, used in the negative-ion mode, gave molecular ions at m / z 543 and 527 respectively, whereas field desorption and chemical ionization were unable to provide information on the molecular weight. The ions of highest mass that were seen when using chemical ionization by isobutane were reported at m / z 447 and 431. Bombardment with fast atoms has also provided mass spectra of intact vitamin BI2 and vitamin B12 coenzyme, the molecular weights being 1354 and 1578 respectively. l5 ,76 Previously, the spectrum of vitamin B 12 that was obtained by laser-assisted field desorption had been regarded as an extreme achievement in this field.77 69

70 71

I2 73

S. J. Gaskell and C. J. W. Brooks, J. Chromatogr., 1977, 142, 469. K. Satouchi and K. Saito, Biomed. MQSSSpectrom., 1979, 6 , 396. S. J . Gaskell and C. J . W. Brooks, Org. MQSSSpectrom., 1977, 1 2 , 651. Y. Ohno, I . Yauo, and M . Masui, Adv. MassSpectrom. Biochem. Med., 1977, 2, 559. J . T. Trudell, B. Boesterling, and A. J . Trevor, Roc. Natl. Acad. Sci. USA, 1982, 79, 2678.

14

S. G. Karlander, K. A. Karlsson, and I. Pascher, Biochim. Biophys. Acta, 1973, 3 2 6 ,

I5

R. E. Isaac, M. E. Rose, H. H. Rees, and T. W. Goodwin, J. Chem. SOC., Chem. Commun., 1 9 8 2 , 2 4 9 . M . Barber, R. S. Bordoli, R. D. Sedgwick, and A. N . Tyler, Biomed. MassSpectrom., 1981, 8 , 492. H.-R. Schulten, W. D. Lehmann, and D. Haaks, Org. MassSpectrom., 1978, 1 3 , 361.

174. 16

77

Organophosphorus Chemistry

290

Monosaccharide phosphates have been analysed successfully as their disodium salts, using field d e ~ o r p t i o n ,although ~~ these samples form tarry residues o n the emitter, making their analysis d i f f i ~ u 1 t . l ~Dimethyl phosphates of monosaccharides have been analysed under electron-impact conditions, as their cyclic butaneboronate esters.79 The relatively intense (M-C4Hg)+ ion that is seen in these spectra may be used as the basis of a method for the isotopic analysis of these compounds. The field-desorption spectra of pyridoxal 5'-phosphate and pyridoxamine 5'-phosphate have also been recorded." Natural phosphates have been used as test materials for other ionization techniques that are intended for labile materials. For example, intact oestriol 3-phosphate disodium salt has been analysed by laser desorption. l 8 4 Synthetic Compounds

In this section, organophosphorus ester pesticides form a distinct sub- section because of their economic importance and the consequently large body o f published work devoted t o their analysis. For many of the compound classes that are dealt with in t h e following sub-sections, the basic rules of electronimpact fragmentation have been described in three early reviews3' "' 82 Detailed discussion in this Report is therefore reserved for compounds of novel structure, reported subsequently (post 1973). Organophosphorus Ester Pesticides.-Whereas the development o f mass spectrometry in the fields of nucleotides and phospholipids has been directed mainly towards the goal of structural analysis, mass spectrometry in pesticide analysis has the further aim of detection of traces of the compounds. Thus, in addition t o spectra giving structural information, there is a requirement for spectra that consist only of one or two diagnostic ions, of high intensity, that are produced under circumstances giving the best possible signal- to-noise ratio. A survey of mass spectrometry in the field of organophosphorus pesticides provides some interesting observations on the tailoring of chemicalionization techniques t o meet requirements through the choice o f the reagent gas. A thorough review of the mass spectrometry o f orgaiiophosphorus esters and their alteration products, covering the literature up t o the end of 1973, and including extensive spectral data and references, was provided by D e ~ m a r c h e l i e r . ~Some applications of g.c.-m.s. techniques in pesticide analysis have been discussed by VanderVelde and Ryan.83 A first comparison of the electron-impact and positive-ion chemicalionization spectra of fifteen organophosphorus pesticides and fourteen of their major metabolites was provided by Holmstead et aZ. in 1974.2 Samples H.-R. Schulten, H. D. Beckey, E. M. Bessel, A. B. Foster, M. Jarman, and J . H . Westwood, J. Chem. Soc., Chem. Commun., 1973,416. l9 J. Wiecko and W. R. Sherman, Org. MassSpectrom., 1975, 10, 1007. M. C. Sammons, M. M. Bursey, and D. A. Brent, Biomed. Mass Spectrom., 1974, 1, 169. " I. Granoth, Top. Phosphorus Chem., 1976,8 , 41. 8 2 R. G. Gillis and J . L. Occolowitz, Anal. Chem. Phosphonts Compounds, 1972,295. 8 3 G. Vaiider Velde and J. F . Ryan, J. Chrornatogr. Sci., 1975, 13, 322.

7R

291

Mass Spectrometry o f Organophosphorus Compounds

were introduced via the direct-insertion probe. Most of the spectra were recorded while using methane as the reagent gas, so that some fragmentation was evident, although the spectra were generally simpler than those obtained by using EI ionization. The fragmentation that arose when CI was used often differed from that observed on electron-impact ionization, so that EI and CI were regarded as complementary techniques. Ammonia was used as a reagent gas t o provide quasi-molecular ions in two cases where methane failed t o do so. Stan has published a number of papers dealing with the g.c.-m.s. analysis of organophosphorus pesticides, using both CI and EI technique^.^-^^ A survey using three different positive-ion reagent gases, with 23 pesticides, showed that the transition from methane t o isobutane to methanol as the reagent gas produced successively simpler spectra, with only (M + H)+ ions being formed when methanol was used. Isobutane, which always produced (M + H)' ions together with some fragmentation, was recommended for routine work." All but two of these 23 compounds could be separated on a capillary column, with detection at the 0.45 p.p.m. level by scanning and down to 40 p.p.b. in a number of cases by monitoring selected ions.87 Monitoring selected ions in the CI mode gave better detection limits than the EI mode.87 Nevertheless, electron-impact ionization formed the basis of a comprehensive classification scheme, based on a repetitive-scanning g.c.-m.s. analysis. Forty-nine compounds could be classified as dimethyl or diethyl phosphorodithioates (5), phosphorothionates (6), phosphorothiolates (7), or phosphates (8) on the basis of the ion intensity at only five values of mass. Typical ions, allowing the separate identification of each compound, are also listed in this paper.s4 S

( R'O)

0

II

( R'o),P-s-R~

0

(R'o),P-o-R~ U

ti ,P-o-R~

I 1

(EtO),P-S-CH,jS-C,H,Cl

(7)

A comparison of five ionization methods, using sixteen organophosphorus pesticides, was carried out by Hass and co-workers in 1978.88 The ionization methods that were used were electron-impact, positive-ion chemical ionization (using methane), and negative- ion chemical ionization [using methane H. J . Stan, B. Abraham, J. Jung, M. Kellert, and K. Steinland, Fresenius' 2. Anal. Chem., 1977,287,271. " H. J. Stan, Fresenius'Z. Anal. Chem., 1977,287, 104. 86 H. J. Stan, Chromatographia, 1977, 10, 233. a 7 H. J. Stan, Z. Lebensm.-Unters. Forsch., 1977, 164, 153. K. L. Busch, M . M . Bursey, J . R . Hass, and G. W. Sovocool, Appl. Spectrosc., 1978, 3 2 , 388. R4

292

Organophosphorus Chemistry

(electron-capture spectra), a methane-oxygen mixture, and oxygen as the reagent gases]. The negative-ion spectra, which were characterized by intense phosphate [e.g. ( S a ) ] or aromatic anions [e.g. (9a), when the latter were suitably substituted] , afforded much higher sensitivity than EI or positive-ion CI. Thus, methane or methane-oxygen negative-ion CI allowed the detection of as little as 75 femtomoles of some compounds by monitoring selected ions. The use of C1- as the reagent ion with seventeen phosphorodithioate ester pesticides and a single phosphorothiolate ester (demeton) gave simple, characteristic spectra in every case." The spectra again generally showed the anion (R0)2PS2- [(R0)2POS- for demeton] as the base peak, and a chlorideattachment ion (M + Cl)-, giving the molecular weight, was invariably present. Other intense ions were formed when potentially stable anions, e.g. ( 9 a ) ,were present in the molecule. The chloride-attachment ion allows unequivocal identification in a simple screening method. The temperature dependence of these spectra was also studied. Field desorption has recently been introduced as a method for the quantitative determination of all four groups (5)-(8) of organophosphorus ester pesticides in waste water.89 The FD spectra show abundant molecular ions and characteristic fragment ions, formed by cleavage a! [for groups (6) and (8)] or p [for groups (5) and ( 7 ) ] to the phosphorus atom. Organophosphorus ester pesticides can be identified in waste water at the nanogram level, without prior purification, by the use of high-resolution field deso rp t ion. Hass and co-workers have recently also reported a preliminary examination of methods of analysis of organophosphorus pesticides, using on-line 1.c.m.s. techniques2' A system for directly introducing liquids was used for samples that had been separated on a reversed-phase column, using 60/40 acetonitrile/water as the mobile phase. The spectra were reported to be simple and similar to these recorded for methane negative-ion CIYg8although molecular anions were generally not observed. The method was proposed as being suitable for residue analysis. Phosphates.-The fragmentation of phosphate esters under electron-impact conditions has been reviewed by Granoth8' and by Gillis and Qccolowitz.82 Alkyl and aryl phosphates show both simple bond cleavages and rearrangement processes, the latter being more common in the aryl series. Parallel to their greater thermal stability, aryl phosphates are more stable under electron impact, giving much more intense molecular ions. Fragment ions that contain phosphorus are relatively rare in the spectra of aryl phosphates. Chemical-ionization studies of trialkyl and triaryl phosphates and related phosphoramidates (10) and (1 1) used ammonia as the reagent gas.g0 Unlike 0

.

( Pr10)2

R9 90

II

~

~

~

2

H.-R. Schulten and S. E. Sun, Int. J. Environ. Anal. Chem., 1981, 10, 247. P. A. Cload and D. W. Hutchinson, Org. Mass Spectrom., 1983, 18, 5 7 .

Mass Spec t ro m etry of Organ op h osp h orus Co m po u n ds

293

the EI spectra, which often showed very weak molecular ions, these CI spectra all showed intense (M +H)+ ions. Fragment ions which gave information as to the nature and number of groups bonded t o phosphorus were usually present in the CI spectra, although trimethyl phosphate and triphenyl phosphate showed very little fragmentation. Capillary gas chromatographyammonia chemical ionization was used t o identify tri-p-cresyl phosphate (amongst other additives) in ester oils.” Negative-ion chemical-ionization screening techniques were used by Dougherty 92 to detect tris-( 1,3-dichlor0-2-propyl) phosphate, a flame retardant that has mutagenic properties, in human seminal plasma. Although the screening technique gives only a molecular ion cluster, the elemental composition of the molecular ion could be established (by accurate measurement of its mass and a consideration of the pattern of chlorine isotopes) as C4HI504PCl6.Negative-ion spectra of phosphate esters and sulphur analogues that were recorded under electron-impact conditions (i.e. low pressure in the ion source) show characteristic fragment ions, but no molecular ion, unless an additional electron-capturing group is present.93 A number of authors have discussed the electron-impact spectra of the cyclic phosphate esters ( 12; X = 0)-( 16; X = 0) and their sulphur [ ( 12; X = S ) and (14; X = S ) ] and selenium analogues (14; X=Se),94-97 in addition t o X

( 1 2 ) Y = O M e , O P h , OH, 4 - M e 0 - C 6 H 4 0 ,

( 1 3 ) R = H or Meg7

SMe, Me, or Phg7

(14) Y

=

O H , O M e , SMe,

C1, or SHg4 ”

Me (15 ig6

A. Zernan, Fresenius’ 2. Anal. Chem., 1982, 310, 2 4 3 .

’’ T. Hudec, J. Thean, D. Kuehl, and R . C. Dougherty, Science, 1981, 211, 951. 93

94 95

’‘

H. J. Meyer, F. C. V. Larsson, S. D. Lawesson, and J . H. Bowie, Bull. SOC. Chim. Belg., 1978, 8 7 , 517. H. Keck, W. Kuchen, and H. F. Mahler, Org. Mass Spectrom., 1980, 15, 59 1. K. J . Voorhees, F. D. Hileman, and D. L. Smith, Org. MassSpectrom., 1979, 14, 459. A. Murai and M. Kainosho, Org. Mass Spectrom., 1976, 11, 175. N. Fukuhara and M. Eto, Nippon Noyaku Gakkaishi, 1980, 5 , 6 3 .

Organop h osph or us Che m istry

294

X

bo R

( 1 7 ) X = 0 , S , o r S e ; Y = NR1R2

x

( 1 6 ) R = H , M e , E t , o r CH20Hg5

=

R1,

NR~R'; Y = 0 , S, or Se R2= H , M e , P h , e t c .

detailed studies of the spectra of diastereoisomeric pairs of the dioxaphosphorinans (1 7).98-'00 In both monocyclic esters (1 3) and (1 5), migration of hydrogen t o oxygen is a first step in the formation of many ions. Thus compound (15), for example, gives an intense ion with the composition [(H0)3P(OC6H5)]'. Rearrangement also takes place with compounds of structure (14). Observation of the direct formation of ions with the composition (C6H4)2X from the parent ion indicates migration of X from phosphorus t o carbon o n electronimpact ionization. Migration of other groups, such as methyl, phenyl, and halogen, is n o t uncommon in the field of phosphorus compounds, making the interpretation of spectra in structural terms difficult in some cases. Simple cleavage of the P-Y bond is not observed in (14) whereas it is a common mode of fragmentation in many similar compounds. Thus compound (1 2; X = 0, Y = SMe) fragments t o give a ( h l - SMe)' ion. The bicyclic esters ( 16) fragment by loss of e t h ~ l e n e , ' ~ unlike the corresponding phosphites, which lose the elements of formaldehyde (see p. 298). The EI spectra of enolic phosphate esters (18) show fragmentation patterns that depend o n the substitution of the double bond."" lo2 Thus, if R 3 = H , loss of a n olefin is the major pathway, but when R3= Me, rearrangeX

0

II ( Et0)2POC=C, I R3

,R

1

0

COMe

R1O lI, / R 2 O /poc\H

R

M e (19)

0,

ii

MeLI Me

( 2 0 ) X = 0 or S

H

/

' O A r

H

98

99 loo lo'

lo*

W. J . Stec, B. Zielinska, and B. van de Graaf, Org. MassSpectrom., 1980, 1 5 , 105. Z. J. Lesnikowski, W. J . Stec, and B. Zielinska, Org. Mass Spectrom., 1980, 15, 454. B. Zielinska and W. J . Stec, Org. Mass Spectrom., 1978, 13, 6 5 . E. M. Gaydou and G. Peiffer, Org. Mass Spectrom., 1974,9, 514. E. M. Gaydou, G. Peiffer, and M . Etienne, Org. Mass Spectrom., 1974,9, 157.

Mass Spectrometry of Organophosphorus Compounds

295

Cl

ment processes involving the enolic chain occur. Phosphoacetoin and its methyl esters (1 9) show mass spectra that are complex mixtures of thermal and electron-impact-induced p r o c e s ~ e s . ' ~ ~ The spectra of some nitrogen-containing analogues of cyclic phosphate esters (20)-(23) have been r e p ~ r t e d . ' ~ - ' ~The ' stable benzodiazaphosphole unit forms the basis of abundant ions in the spectra of compounds (21). Corresponding fragments are found in the spectrum of compound (22). Both of these structures also fragment by cleavage of both P-N bond^."^' lo6 The chlorine-containing compounds of structure (23) fragment initially by a retro-Diels-Alder reaction to give ( M - P02C1)+ ions, which then undergo further fragmentation.lW The presence of amino-substituents o n the phosphorus atom of compounds of structure (20) results in preferential cleavage in this substituent and cleavage of the P-N bond.'07 Thus ions at m / z 167 (C5H12P02S)+ and 133 (C5H10P02)+ are characteristic of the sulphides (20; X = S). Cyclophosphamide (24) and a number of its metabolites which are not amenable to electron-impact analysis may be identified by field desorption.lo8 Field desorption has also been used for the quantitative determination of cyclophosphamide and its metabolites. ' 0 9 , Another report describes electron-impact ionization (following methylation) for the same analysis."' The activated intermediates that are derived from cyclophosphamide are hydroperoxides. Even under field-desorption conditions, a molecular ion is difficult to detect for these compounds, and (M - H2O)' is the most significant ion in this region. The quantitative analysis of these intermediates may be accomplished by allowing them t o react with benzyl mercaptan, which provides benzyl thioethers; these give excellent EI spectra. '12 The products arising from thermal decomposition of the 00 '-diethy1

Io4

lo'

lo6 Io7

Io8 log

'lo

112

S. Meyerson, E. S. Kuhn, F. Ramirez, J . F. Marecek, and H. Okazaki, J. Am. Chem. SOC.,1980, 102, 2398. V. N . Gogte, P. S. Kulkarni, A. S. Modak, and B. D. Tilak, Org. Mass Spectrom., 1981, 16, 5 1 5 . M. S. R. Naidu and C. D. Reddy, Indian J. Chem., Sect. B, 1977, 15, 706. M. S. R. Naidu, C. D. Reddy, and P. S. Reddy, Indian J . Chem., Sect. B, 1979, 17, 458. R. S. Edmundson, Phosphorus Sulfur, 1981, 9, 3 0 7 . H.- R. Schulten, Biomed. Mass Spectrom., 1974, 1, 22 3. H. D. Lehmann and H.-R. Schulten, 2. Anal. Chem., 1978, 290, 121. U . Bahr, and H.-R. Schulten, Biomed. MassSpectrom., 1981, 8 , 5 5 3 . R. F. Struck, M. C. Kirk, M . H. Witt, and W. R. Laster, Jr., Biomed. Mass Spectrom., 1975, 2 , 4 6 . M. Przybylski, H. Ringsdorf, U. Lenssen, G. Peter, G. Voelcker, T. Wagner, and H. J . Hohorst, Biomed. Mass Spectrom., 1 9 7 7 , 4, 209.

296

Organophosphorus Chemistry

S-butyl ester of dithiophosphoric acid and of 00 '-diethy1 phosphorothionyl disulphide have been studied, using g.c.-m.s. techniques. '13 Phosphonates.-A detailed study, based on the EI spectra of 24 alkyl and six aryl phosphonates, has been described by Occolowitz and Swan114 and the spectra of phosphonate esters have subsequently been r e ~ i e w e d . ~',22 Many saturated dialkyl phosphonates (25) show the same base peak [i.e. HP(OH)3+] as trialkyl phosphites whereas the ion R'P(OH)3' is usually the base peak in the EI spectra of dialkyl alkylphosphonates (26), which are isomeric with the corresponding trialkyl phosphites. 0

II

RIP(

OR^ ) ( 2 7 ) X = CH2, CHC1, C H B r , or CBr2

(26)

0

II

(Et0)2PCHRX

0

( 2 8 ) R = H; X = C O O E t , C N , CH=CH2,

R

=

o r COOH

0

II ll (Et0)2P-COCH2Ph

M e ; X = COOEt

Whilst the molecular ion in the EI spectra of phosphonates is frequently weak, the CI spectra that were obtained by using both ammonia and hydrocarbon as the reagent gas '15 gave intense (M+H)' ions. Useful structural data could also be obtained from the ammonia CI spectra, which included those of a number of bisphosphonate esters (27) and of variously substituted phosphonate esters (28) and (29).'* 0

0

II

Me-P-OR

I

F

~e

II

-P -sR~ I

0

I1

Me2N-P-OEt

OR2

I

CN

A comparison of chemical ionization and electron-impact ionization of a range of alkyl phosphonates, phosphonofluoridates (30), phosphonothiolates ( 3 l), and an amidophosphorocyanidate (32) favoured chemical ionization as an identification t e ~ h n i q u e . " ~Methane reagent gas gave spectra with quasimolecular and fragment ions whereas ethylene and isobutane gave simpler spectra, with more intense quasi-molecular ions. The best sensitivity was achieved by using ethylene both as the carrier gas in the gas chromatograph and as the reagent gas. Negative-ion spectra of phosphonate esters and of sulphur analogues, recorded under electron-impact conditions, show V. Trdlicka, J. Mitera, and J. Mostecky, BrdoeIKohIe, Erdgas, Petrochem., 1977, 30, 332. 'I4

'I5

J. L. Occolowitz and J . M. Swan, Aust. J. Chem., 1966, 19, 1187. S. Sass and T. L. Fisher, Ox. Mass Spectrom., 1979, 14, 2 5 7 .

297

Mass Spectrometry o f Organophosphorus Compounds

characteristic fragment ions, but no molecular ion unless an additional electron-capturing group is p r e ~ e n t . ' ~ A number of trichloromethyl-substituted cyclic esters and nitrogen analogues (33)-(35), containing five- and six-membered rings, have been prepared and their EI spectra examined.l16 These authors compared the fragmentation of the dioxaphospholans (33) (which produce four-membered cyclic ions by ring-contraction) and of the dioxaphosphorinans (34) with that of compounds that contain P-N [e.g. (35)] and P-S bonds, which mostly undergo cleavage of the P-C bond t o give the base peak. In another recent study,"' the electron-impact spectra of a series of linear phosphonoacetals (36) were compared with those of the cyclic compounds (37). Spectra have been reported for the aromatic system (38) ' 1 8 and for acetylenic dialkyl- and y6 -ethylenic 0-keto-phosphonates.'19

(36) n = 1 or 3 0

/O\CHCHZP(

II

OEt ) 2

/-\

I

S

( H2C ) n J O

(38) Y

=

Y

OH, OEt, or C1

( 3 7 ) n = 0 or 1

The fragmentation (under electron impact) of the acid chloride (39; R = Cl), which is used in the synthesis of compounds (33)-(35) and of other acid chlorides with the general formula (39), had also been documented in an earlier paper.'20 The compounds (39) give carbonyl fragment ions (RCO)' by C1-0 exchange. The EI spectra of the acid halides (40) and (41) have been recorded by Miller and co-workers.121 0

I1

RCCl 2PC 1 (39) 'I'

"*

"'

S

II

C6F5P(Hal)2 (40)

0

II C6F5PF2 (41)

B. M. Kwon and D. Y. Oh, PhosphomsSulfur, 1981, 11, 177. S. Yanai, PhosphorusSulfur, 1982, 12, 369. M. S. Bhatia and Pawanjit, Org. M ~ s s S p e c t r o m . ,1977, 12, 1. G. Peiffer and E. M. Gaydou, Org. MQSSSpectrom., 1975, 10, 122. G.Schmidtberg, G.Haegele, and G. Bauer, Org. MQSSSpectrom., 1974, 9, 844. T. R. B. Jones, J . M. Miller, and M. Fild, Org. Mass Spectrom., 1977, 1 2 , 317.

Organ op h 0 sp h orus Che m is try

298

Phosphonoacetic acid has been determined quantitatively as its tristrimethylsilyl ether, using methane chemical ionization t o give a spectrum comprising only (M + H)+ and (M - CH3)+ ions.'22 Trimethylsilyl derivatives of alkyl- and aminoalkyl- phosphonic acids 123 and N - trifluoroacetyl n-butyl esters of (aminoalky1)phosphonic acids 124 have also been prepared for g.c.m.s. analysis. Field desorption has been used t o determine the molecular weights of a series of phosphonate- and phosphate-ester-based macrocyclic compounds.'25 P1iosphites.-The EI spectra of aryl and alkyl esters have been reviewed.'" 82 Alkyl phosphites generally give very weak molecular ions and a base peak which contains phosphorus, oxygen, and hydrogen only, e.g. HP(OH)3+. The base peak in the spectrum of triphenyl phosphite ( m / z 94) has the composition of phenol.

R

( 4 2 ) R = H , Me, E t , o r C H 2 0 H

Several authors 957 126912' have studied the EI mass spectra of bicyclic esters of formula (42), particularly since some compounds of this structure are extremely toxic for mammals. A specific loss of formaldehyde is sufficient t o distinguish these compounds from the corresponding phosp h a t e ~ .126 ~ ~ ,Mass spectrometry has been used for the identification of phosphite and thiophosphite esters. 12' Ammonia chemical-ionization studies o f trialkyl and triphenyl phosphites show ( M + H ) + ions, carrying at least 10% o f the total ion current.g0 Some fragmentation is observed. For example, the major fragmentation for triphenyl phosphite was the loss of phenol from (M + H)+. Negative-ion spectra of phosphite esters that were recorded at low electron energy ( G 8 eV) showed mainly (M - R)- ions, formed by a dissociative electron-capture process. 129 Phosphinates.-A substantial body o f work on the electron-impact spectra of phosphinic acids and phosphinate esters has been reviewed by Granoth and D e ~ m a r c h e l i e r and , ~ particularly thoroughly by Gillis and Occolowitz.'* Since then, t h e electron-impact spectra of steroid esters of dimethylphosphinic acid

''

124 125

'27

J. R o b o z , R. Suzuki, G. Bekesi, and R. Hunt, Biomed. Mass Spectrom., 1977, 4 , 29 1 . D. J. Harvey and M . G. Homing, Org. Mass Spectrom., 1979, 9, 1 1 1 . M. L. Rueppel, L. A. Suba, and J. T. Marvel, Biomed. MassSpectrom., 1976, 3 , 2 8 . V. G. Golovatyi and E. N. Korol, Teor. Eksp. Khim., 1981, 17, 849. H. Kenttamaa and J . Enquist, Org. Mass Spectrom., 1980, 1 5 , 5 2 0 . D. G. Hendricker, J . Heterocycl. Chem., 1967, 4 , 385. F. Bartonicek, J . Hrusovsky, and L. Hanus, Vet. Med. (Prague), 1977, 22, 7 1 3 . I. I . Furlei, U. M . Dzhemilev, V. I . Khvostenko, and G. A. Tolstikov, Izu. Akad. Nauk SSSR, Ser. Khim., 1976, 2 127.

299

Mass Spectrometry o f Organophosphorus Compounds

and of dimethylthiophosphinic acid (43),130perfluoroalkylphosphinate esters (44; R1= p e r f l u ~ r o a l k y l ) , ' ~ and ~ two substituted cyclic acids (45) 13* have appeared in the literature. The spectra of phosphinic acid halides with the general formula (46) 1 2 1 9 1 3 3 and of the azides (47) 133 have also been published.

0

X

II Me 2P-O-

II

E t ( R1 )POR2

s t e roi d

(43) X = 0 or S

Y

(44) (45) X

=

Br, Y = H

X = H , Y = Br X 1211 R R PHal ( 4 6 ) X = 0 , S , or Se

(47) X = 0, S , or Se

Phosphines.-A number of detailed studies of electron-impact spectra of phosphines have been described, following earlier reviews of this subject.81' 82 These studies covered triphenyl-, tritolyl-, and tri-(2,6-dimethylphenyl)-,lX d i ~ h e n y l - , 'and ~ ~ mixed aryl(alky1)- p h o ~ p h i n e s , ' 137 ~ ~ ' aminomethyl-,1373 h y d r ~ x y m e t h y l - , 'cyano~~ (48),'39 and acyl-substituted phosphines (49),'37 tri-( p -alkylphenyl)phosphines,lm and neopentyl- substituted phosphines. 14' When a comparison was made of the ease of cleavage of phosphorus-aryl R2P( CH=CH)n CN (48) n

= 0

or 1

X C O P R ~R~ ( 4 9 ) X = a l k y l , OMe,

Me2N, or NHPh

R 1 2 P ( CH2)n PR2R3 ( 5 0 ) R1=

a l k y l or a r y l

R2= a l k y l o r H

R3= alkyl or a r y l I3O

K. Jacob, W. Vogt. M. Knedel, and W. Schaefer, Biomed. Mass Spectrom., 1976, 3 , 64.

A. V. Garabadzhiu, A. A. Kodin, A. N. Lavrent'ev, and E. G. Sochilin, Zh. Obshch. Khim., 1981, 51, 41. K. Moedritzer a n d R. E. Miller, PhosphorusSulfur, 1981, 10, 279. 1 3 3 H. F. Schroeder a n d J. Mueller, 2. Anorg. Allg. Chem., 1979, 451, 158. 134 T. R. Spalding, Org. Mass Spectrom., 1976, 11, 1019. 13' K. Henrick, M. Mickiewicz, a n d S. B. Wild, Aust. J . Chem., 1975, 28, 1455. 136 K. Henrick, M. Mickiewicz, N . Roberts, E. Shewchuk, a n d S . B. Wild, Aust. J. Chem.,

131

1 9 7 5 , 2 8 , 1473. 137

13' 13'

14'

R. G. Kostyanovsky, A. P. Pleshkova, V. N . Voznesensky, and Yu. I. El'Natanov, Org. Mass Spectrom., 1976, 11, 237. R. G. Kostyanovsky, V. N. Voznesensky, G. K. K a d o r k h a , and Yu. I. El'Natanov, 0%.Mass Spectrom., 1980, 15. 412. R. G. Kostyanovsky, A. P. Pleshkova, V. N. Voznesensky, a n d Yu. 1. EI'Natanov, Org. MassSpectrom., 1980, 15, 397. G. Marshall, S. Franks, and F. R. Hartley, Org. MassSpectrom., 1981, 16, 272. R. B. King, J. C. Cloyd, Jr., a n d R. H. Reimann, Org. MassSpectrom., 1976, 11, 148.

300

Organophosphorus Chemistry

bonds in mixed aryl-phosphines, phenyl was found t o be more readily lost than p-anisyl, which in turn was more readily lost than p-dimethylaminophenyl. 142 Dissociative electron-capture spectra of phosphines R3P, which comprise mainly (M - R)- ions, were recorded in another publication.128The spectra of phosphines (50) that contain more than one phosphorus atom have also been reported in two papers. 14' , 143

R

Ar

Ph2 PCH= CHEPh2

7 fJ J -

aPPh2 (55) E = P or A s

\

/

I

R

EPh2

( 5 3 )146

( 5 4 ) E = P , A s , or Sb

Ph2P( CH2 ) 2 A s P h 2 (56)

A number of heterocyclic phosphines ( 5 1)- - (53) have been subjected to analysis under electron-impact conditions 144-146 and the spectra of phosphine-related o -phenylene chelating agents (54) that contain phosphorus, arsenic, or antimony donor atoms have been discussed by Sedgwick and cow o r k e r ~ . ~The ~ ' EI spectra of other diphosphine and phosphine-arsine ligands (55) and (56) have also been p ~ b 1 i s h e d . l149 ~~' A review of the spectra of phosphine oxides and sulphides" has been supplemented by EI data on tri-( p-alkylpheny1)phosphine oxides,'40 diphenylphosphine s ~ l p h i d e s , neopentylphosphine '~~ sulphides and and the cyclic phosphine oxides (57; X = O ) and sulphides (57; X = S ) and

(58).15' L. Horner and U. M. Duda, Phosphorus, 1975, 5 , 135. J. C. Briggs, C. A. McAuliffe, W. E. Hill, D. M. A. Minahan, and G. Dyer, J. Chem. SOC.,Perkin Trans. 2, 1982, 321. 144 W. D. Weringa a n d I. Granoth, Org. Mass Spectrom., 1973, 7 , 459. 145 T. R. B. Jones, J. M. Miller, S. A. Gardner, a n d M. D. Rausch, Can. J. Chem., 1979, 5 7 , 335. 146 V. N. Bochkarev, A. N. Polivanov, V. I. Aksenov, E. F. Bugarenko, a n d E. A. Chernyshev, Zh. Obshch. Khim., 1974, 44, 1273. 1 4 7 W. J. Kevason, C. A. McAuliffe, and R. D. Sedgwick, J. Organomet. Chem., 1975, 84, 239. 14' K. K. Chow a n d C. A. McAuliffe, J. Organomet. Chem., 1973, 5 9 , 2 4 7 . 149 G. Cauquis, B. Divisia, and J. Ulrich, Org. MassSpectrom., 1975, 10, 1021. G. Cauquis, B. Divisia, a n d J. Ulrich, Org. Mass Spectrom., 1975, 10, 770. l S 1 M . G, Voronkov, V. Yu. Vitkovskii, N . W. Kudyakav, and R . K. Valetdinov, Zh. Obshch. Khim., 1981, 5 1 , 2176.

14'

143

301

Mass Spectrometry of Organophosphorus Compounds

/\

X

R ( 5 9 ) X = 0 or S

( 5 7 ) 146

A comparison of t h e spectra of a number of cyclic phosphine oxides and sulphides with the general formula (59) showed that there are more intense molecular ions when X = S and that there is a reduction in the effect of the ~~ keto-group on fragmentation in the spectra of the ~ u l p h i d e s . 'Positive-ion chemical ionization, using methane o r isobutane, afforded intense (M + H)' ions from a number of alkyldiphenylphosphine oxides which only gave weak M+ and (M + H)' ions under electron-impact condition^.'^^

s s

s s I1 II

I1 II

R2P-PR2

R( M e )P-P(

M e )R

i i

P

Ph2P-X-PPh2

Ph2PR

( 6 3 ) X = C H 2 , C H = C H , o r CN2

(64)

A study of the spectra of a number of diphosphine disulphides (60) and (61) showed that, unlike t h e case of the sulphides of trisubstituted phosphines,81 a direct loss of sulphur from the molecular ion is not common.154 A rearrangement t o a four-membered ring (62), prior t o fragmentation, was suggested for these compounds. Disulphides with the general formula (63) gave very complex spectra, with evidence for migration of phenyl groups from one phosphorus atom to another, or to sulphur, or to electrophilic carbon atoms.'49 Migration of sulphur atoms was also observed. Migration of phenyl or methyl groups occurs in the related monosulphides (64).'"

+ Ph3RP+

Hal-

+

Ph3P(CH2)nPPh3

Hal-

Phosphonium Salts.-The direct analysis of phosphonium salts only became possible with the introduction of field-desorption techniques. Field-desorption analysis of six monophosphonium halides (65) showed the cation as the base peak, although the anion was normally difficult t o determine by this

'" Is3

A. E. Lyuts, V. V. Zamkova, A. P. Logunov, Z. A . Abrarnova, B. M. Butin, and Yu. G . Bosyakov, I z v . Akad. N a u k K a z . SSR, Ser. Khim., 1979,No. 2, p. 20. S. D. Goff, B. L. Jelus, and E. E. Schweizer, Org. Mass Spectrom., 1977, 12, 3 3 . H. Keck and W. Kuchen, Org. Mass Spectrom., 1979, 14, 149.

302

Organophosphorus Chemistry

t e c h n i q ~ e . ' ~ 'In the spectra of a number of bisphosphonium halides (66), the base peak represented two cations, associated with an anion."' Phosphonium salts with the general formula (67) underwent cleavage of the P-aryl bond on field ionization t o give phosphine cation radi~a1s.l~' The thermolysis of (1 -methoxycarbonylalkyl)triphenylphosphonium bromides has been studied, using electron-impact i o n i ~ a t i o n . ' ~ ~ Ph3P=C /R1 P h a A r l b A r 2 P+

Br-

( 6 7 ) a+b+c = 4

\R2

(68)

(69)

Stabilized phosphonium salts with the general formula ( 6 8 ) , which were originally extensively studied by Cooks et were also the subject of a later paper.lS8 In this case,158the phosphinyl-stabilized compounds (69) gave strong M+ and (M - H)+ions, together with fragment ions that are representative of the phosphonate and phosphonium moieties under electron impact.

Phosphazenes.-Hexakis(polyfluoroalkoxy)cyclotriphosphazenes (70) have been synthesized and thoroughly investigated as reference compounds, of high molecular weight, for mass s p e ~ t r o m e t r y . ' ' ~These compounds, which are relatively volatile and easily synthesized, are particularly suitable for work with soft ionization techniques, in the mass range 1000-2000. Phosphonitrile chlorides (PNC12), have been suggested as reference compounds for negativeion chemical-ionization operation. 160 Me X/ N \ \N/PF2Y

R ( 7 1 ) X = C=O o r P F Y 2

(70)

(72) lSs 156

Is7

G. W. Wood, J. M. Mclntosh, and P.-Y.Lau, J. Org. Chem., 1975, 40, 636. F. Sanchez-Ferrando and A. Virgili, An. Quim., 1977, 73, 1059. R. G. Cooks, R. S. Ward, D. H. Williams, M. A . Shaw, a n d J. C. Tebby, Tetrahedron, 1 9 6 8 , 2 4 , 3289.

159

L. Toekes and G. H. Jones, Org. M~ssSpectrom.,1975, 10, 241. K. L. Olsen, K. L. Rinehart, Jr., a n d J. Carter Cook, Jr., Horned. Muss Spectrom.,

I6O

Y. Hirata, K. Matsurnoto, a n d T. Takeuchi, Org. Muss Spectrom., 1978, 13, 1 1 1.

ls8

1977, 4, 284.

303

Mass Spectrometry of Organophosphorus Compounds

The spectra of the phosphadiazetidines (7 1) have been discussed in two publications.'61y The disphosphadiazetidines (71; X = PF2Y) show an electron-impact-induced fragmentation t o give M / 2 + 1 , M/2, and M/2 - 1 as the most abundant ions.'61 The spectrum of the cyclophosphazene (72), which shows anti-tumour activity, has recently been p ~ b 1 i s h e d . l ~ ~ Miscellaneous.-Whilst the present Report in no way claims t o be exhaustive, some other organophosphorus compounds that are not classified within the preceding sections have been noted in the literature of mass spectrometry, viz. a cubane-like P-N compound (73),'@ tin-containing phosphate esters (74),16' (75),'66 phosphorus-containing hydrazides (76) and (77),'67 a series of phosphorus-containing carbamates (78),16' (79),'69 di- and tri-peptide organic analogues that contain aminomethylphosphonic acid groups (80),' hypophosphates and their mono- and dithio-derivatives,"' some simple phosphor in^,'^' and closo-phosphorimide and closo - t h i o p h o ~ p h o r i m i d e s . ' ~ ~ 0

0

I II

[ MeN-PF2 ]

II

( MeNCNMe )

(73)

0

II Ph2PNHNH2

II

R3SnOP( O P h ) 2 (75) X = 0 or S

(74) 0

(ArO)2PNHNH2 II

0 R 1211 R PNPhCOR'

The thermal depolymerization of polymers with the general formula (8 1) has been studied by heating them whilst they are o n the sample probe of the mass ~ p e c t r o m e t e r . ' Polymer ~~ (8 la) decomposed t o form cyclic oligomers, lbl 16'

163

167

16' 169

17' 17'

17'

0. Schlak, R. Schmutzler, a n d I . K. Gregor, Org. MassSpectrom., 1974, 9, 5 8 2 . M . A. Baldwin, A. G. L o u d o n , R. E. Dummer, R. Schmutzler, and I . K. Gregor, Org. Mass Spectrom., 1977, 1 2 , 2 7 5 . B. Monsarrat, J.-C. Prome, J.-F. Labarre, F. Sournies, a n d J. C. Van d e Grampel, Biomed. Mass Spectrom., 1 9 8 0 , 7 , 4 0 5 . K. Utvary, M . Kubjacek, a n d K. Varmuza, 2. Anorg. Allg. Chem., 1979, 4 5 8 , 2 8 1 . K. G. Molloy, F. A . K. Nasser, a n d J. J. Zuckerman, Inorg. Chem., 1 9 8 2 , 2 1 , 1 7 1 1 . S. W. Ng a n d J. J. Zuckerman, Organometallics, 1 9 8 2 , 1, 7 1 4 . M. E l - D e e k , J . Chem. Eng. Data, 1 9 8 0 , 2 5 , 1 7 1 . V. A. Kolesova a n d Yu. A. Strepikheev, Zh. Obshch. Khim., 1 9 7 9 , 4 9 , 2 2 1 3 . V. A. Kolesova, Yu. A. Strepikheev, a n d V. A. Valavoi, Tr.-Mosk. Khim: Tekhnol. Inst. im. D. I. Mendeleeva, 1 9 7 7 , 9 4 , 38. K. Yamauchi, Y. Mitsuda, a n d M. Kinoshita, Org. MassSpectrom., 1977, 12, 119. W. J. S t e c , B. Zielinska, a n d J. R. Van Wazer, Org. MassSpectrom., 1 9 7 5 , 1 0 , 4 8 5 . C. Jongsma a n d F. Bickelhaupt, Org. Mass Spectrom., 1 9 7 5 , 10, 5 1 5 . A . Wolff, A. C a m b o n , a n d J. Riess, Org. Mass Spectrom., 1 9 7 4 , 9, 5 9 4 . A. Ballistreri, S. Foti, G. Montaudo, S. Lora and G. Pezzin, Makromol. Chem., 1 9 8 1 , 182. 1 3 1 9 .

Organophosphorus Chemistry

304

(81) a ; R = Onaphthyl

b ; R = NHAr

c; R

= 1-piperidyl

whereas polymers of the type (81b) decomposed with the evolution of amines. Polymer (8 1c) decomposed completely, t o give ammonia and elemental phosphorus. The isotopic analysis of organophosphorus compounds has been described in t w o papers.'75' 176

W. Reimschussel and P. Paneth, Org. Mass Spectrom., 1980, 1 5 , 302. V. I . Mosichev and 8. B. Alipov, K h i m . Tekhnol. Irot. Mechenykh Soedin., 1977, N o . 1, p. 19.

11 Physical Methods BY J. C. TEBBY

The abbreviations n’, n 3 , n4, n 5 ,and n6 refer t o the co-ordination number of phosphorus, and the compounds in each subsection are usually dealt with in order of increasing co-ordination number of the phosphorus atom. In t h e formulae, the letter R represents hydrogen or organic groups, X represents an electronegative substituent such as halogen, alkoxy-group, etc., Ch represents chalcogenides (usually oxygen and sulphur), whilst Y and Z are used when the substituents have a more varied nature. The terminology apical and radial has been retained for the stereochemical description of substituents of n 5 atoms that possess trigonal-bipyramidal geometry, so that the terms axial and equatorial can be reserved t o describe the conformational preferences of substituents o n n4 atoms in six-membered rings and related cyclic systems. The nomenclature ‘phosphane’ is used for n 3 phosphorus compounds in general, reserving the term ‘phosphine’ for phosphanes which possess three carbon or hydrogen substituents o n phosphorus and the term ‘phosphite’ for phosphanes which possess three alkoxy or aryloxy substituents. Some relevant theoretical and inorganic studies are included in this chapter. 1 Nuclear Magnetic Resonance Spectroscopy

Biological, Analytical, and Instrumental Aspects.-The applications of n.m.r. spectroscopy t o the study of biological systems that contain organophosphorus compounds are t o o numerous t o review properly. However, several reviews are noted,”’ one of which concerns the study of whole animals and humans.’ The monitoring of pH can be achieved by using 31P n ~ n . r .and ~ the temperature of samples under study by 31P n.m.r. can be measured by using a capillary insert, containing a 0.1 molar solution of triphenylphosphine and its oxide.4 The analytical determination of phosphorus in complexes by using F.T. 31P n.m.r. spectroscopy has also been d e ~ c r i b e d . ~ Chemical Shifts and Shielding Effects.-Phosphorus-31. Positive shifts are downfield of 85% phosphoric acid, and are usually given without the appellation p.p.m.

’ D. G. Gadian, Biosci. R e p . , 1981, 1, 449. C. S. H u and L. P. Kao, Chem. Abstr., 1 9 8 1 , 9 4 , 7 9 474; G. K. Radda, Biochem. Soc. Trans, 1981, 9, 213. J. P. Yesinowski, R. J . Sunbury, and J . J . Benedict, J. Magn. Reson., 1982, 47, 85. F. L. Dickert and S. W. Hellmann, JEOL News, ( S e r . ] Anal. Instrum., 1982, 18A,51; Anal. Chem., 1980, 52, 996. F. Kasler and M. Tierney, Mikrochim. Acta, 1981, 2, 301.

305

306

Organophosphorus Chemistry

6 p of n' compounds. 3,3-Dimethyl-l-phosphabut-l-yne ( 1 ) is a stable compound which has a shielded phosphorus atom ( 6 p = - 69.2).6 6 p of n 2 compounds. The chemical shifts of a variety of phosphide anions which have varying degrees of delocalization have been recorded.778 The shifts range from 245 t o -193.' A study of ( E ) - and (Z)-isomers of the phosphaethene (2) showed no regular dependence of stereochemistry. Phosphaethenes of the type HP=CXR resonate upfield (9.2 t o 54) l o of most trisubstituted phosphaethanes of the type R'P=CXR'. The electronic structure of the related 32P-labelled phosphaethene, H3*P=CH2, has been the subject of CND0/2 calculations." Whilst the P-amino-iminophosphines (3; Y = R2N) .have values of 6 p of 293 t o 306,'' the CP=N group in (3; Y = B u t ) has a highly deshielded phosphorus atom ( 6 p = 4 7 2 ) l 3 and the cation (4) sets a new record with 6 p =513.4.14 The novel compound ( 5 ; R=C6H2But3)has 6 p =203." ButCW (1)

Ph-PrC/

NR2 'PR2

YP=NBut

w2GsPBu

RP=PR

(3)

(4)

(5)

(2)

8 p of n3 compounds. Steric compression that is caused by the methyl groups in the phospholans (6; R =Me) causes pronounced deshieldirig of the phosphorus atom compared t o the less crowded compounds (6; K=H).16 The inclusion of a phosphino-group in a nine-membered ring causes 6 p t o move downfield relative t o that of the six-membered heterocycle." This effect has been attributed t o an increase in CPC bond angle, due t o conformational changes. It has also been found that the replacement of methyl groups in acyclic phosphines by cyclopropyl groups causes downfield shifts. l8 The unusual cyclic thiadiphosphiran ( 7 ) resonates well upfield, at 8 p = - 9 1 .5.19 A series of hypophosphorous acid derivatives (8; X = O , S , or NR) and their C-methyl analogues have been prepared. Again the sulphur compounds are furthest upfield ( 6 p = - 1.5 to - 45)." The change in the value of 6 p of G. Becker, G. Gresser, a n d W. Uhl, Z. Naturforsch., Teil. 5, 1981, 36, 16. M. K. Deng and K. B. D i l l o n , J . Chem. SOC., Chem. Commun., 1981, 1170; R. Batchelor a n d T. Birchall, J. A m . Chem. Soc., 1982, 104, 674. E. Fluck, T o p . Phosphorus Chem., 1 9 8 0 , 10, 266. R. Appel, V. Barth, H. Kunze, a n d B. Laubach, ACS S y m p . Ser., 1981, 171, 395. G. Becker, M. Roessler, and W. Uhl, Z. Anorg. Allg. Chem., 1981, 473, 7. N. I . Gabov, V. V. Pen'kovskii, and V. P. Sergeev, Teor. Eksp. K h i m . , 1980, 16, 8 2 1 . 0. J. Scherer and H. Conrad, Z. Naturforsch., Teil. B, 1981, 36, 5 1 5 ; E. Niecke, M. Engelmann, H. Zorn, B. Krebs, and G. Henkel, Angew Chem., Int. Ed. Engl., 1980,

' R. lo I' I'

19, 7 1 0 . l3

E. Niecke, R. Rager, and W. W. Scheller, A n g e w Chem., Znt. Ed. Engl., 1981, 20, 1034.

l4

A . H. Cowley, M. L a t t m a n , a n d J . C. Wilburn, Inorg. Chem., 1981, 20, 2916. M. Yoshifuji, I . Shima, N. I n a m o t o , and K. Hirotsu, J. A m . Chem. S O C . ,1981, 103, 4587.

L. D. Quin, K. A. Mesch, a n d W. L. O r t o n , PhosphorusSulfur, 1982, 12, 161. L. D. Quin, E. D. Middlemas, and N. S . Rao, J . Org. Chem., 1982, 47, 9 0 5 . I n H. Schmidbaur and A. Schier, Chem. Ber., 1981, 114, 3385. l 9 M. Baudler, H. Suchomel, G. Furstenberg, and U. Schings, Angew Chem., Int. Ed. E n g l , 1 9 8 1 , 20, 1044. " E. E. Nifantiev, S . F. Sorokina, A. A. Borisenko, A. Zavalishina, and L. A. Vorobjeva, Tetrahedron, 1981, 37, 3183. l6 I'

307

Physical M e t h o d s

d

S

B U p/-\PB

\

(7)

Ut

n

X

X

P ‘’

H

R2N--P

4y \z

(9)

(6)

(8)

diphosphipes upon the formation of metal chelates correlates with the size of the chelate ring.21 Some unusual n 3 carbon and nitrogen ylides ( 9 ) resonate well downfield, i.e. 182’15for [9;Y=Z=C(SiMe3)7,]a n d ( 9 ; Y = S , Z = C H R ) , b u t a t 5 3 + 3 for (9;Y = z = N R ) . ~ ~ 8 p of n4 compounds. The substitution of cyclopropyl groups for methyl groups in phosphonium salts and ylides causes 8 p t o move downfield.18 The (E)-isomers of a series of vinylphosphine oxides have 8 p t o high field of the ( Z ) - i s ~ m e r sThe . ~ ~ anisotropies of various phosphine chalcogenides have been determined;24 the screening is largest along the P-Ch bonds. This conclusion is supported by C N D 0 / 2 calculations on trimethylphosphine oxide.” A review of the phosphinimines (10) includes a section o n spectroscopic properties.26 The chemical shifts of a variety of phosphinimines correlate with inductive substituent constants;” on the other hand, CNDO/? calculations have indicated that the steric effect of the group R that is bound t o nitrogen is important, and that the magnitude of the positive charge o n p h o s p h o a s is not controlled by the electronic properties of R.” A study of

0

II I OH

HOOCCH2NHCH2PCH2COOH (13) 21 22

23 24

P. E . Garron, Chem. Rev., 1981, 81, 2 2 9 . R . Appel, J. Peters, a n d A. Westerhaus, A n g e w Chem., I n t . Ed. Engl., 1982, 21, 80; E. Niecke and H.-G. Schafer, Chem. Eer., 1 9 8 2 , 115, 185; E. Niecke a n d D.-A. Wildbredt, J. Chem. Soc., Chem. Commun., 1981, 72. M. Duncan and M . J. Gallagher, Org. Magn. Reson., 1981, 15, 37. J . B. Robert and L. Wiesenfeld, Moi. Phys., 1 9 8 1 , 44, 319; R. Radeglia and A . R . Grimmer, Z. Phys. Chem. (Leiprig), 1982, 263, 204. R. Radeglia and R. Wolf, 2. Naturforsch., Teil. A , 1981, 36, 1177. E. W. Abel a n d S. A. Mucklejohn, PhosphorusSulfur, 1981, 9, 2 3 5 . Yu. P. Egorov, A. A. Kudryavtsev, A. M . Pinchuk, A. P. Marchenko, a n d V. A . Kovenya, Teor. Eksp. Khim., 1982, 18, 58. A. S. Taresevich a n d A. M. Nesterenko, Teor. Eksp. Khim., 1981, 17, 750.

*’ ’’ 26

28

11

308

Organophosphorus Chemistry

the influence of d,-p, bonding o n 6 p of N-aryl-phosphinimines showed that the nature of the substituent o n phosphorus determined whether increased d, bonding caused shielding or deshielding. The direction of the effect appears to be related t o the rr-bonding power of the substituents o n phosphorus. Increased crowding about the phosphorus atom increased the shielding influence of d,-p, bonding.2g The chemical shifts of the phosphonates (1 1) correlate with uox. As expected, the influence of Y was considerably less than that of X.30 The chemical shifts of the dichlorides (1 2) also correlate with uo, indicating the absence of a direct resonance interaction of the aryl ring with the phosphorus The value of 6 p for the phosphonic acid (1 3) showed a strong dependence (k 13 p.p.m.) on P H , ~ ’a property characteristic of acid phosphate^.^^ The 31P n.m.r. spectra of eight- and sixteen-membered heterocycles (14) have been discussed in relation t o their s t e r e o ~ h e m i s t r y . ~ ~ 6 p of n5 compounds, Cross-polarization and magic-angle-spinning techniques have shown that oxyphosphoranes have similar structures in solid and liquid states. Plots of 6 p against the percentage distortion from t.b.p. geometry for dioxytriorganylphosphoranes gave separate lines for diapical P - 0 and apical-radial P-0 series.35 Hydrogen-1, - 2 , and -3. The ‘H chemical shift of the ortho-proton Ho in the phosphoranes ( 1 5 ) moves downfield with increasing polarity of the phosphorus-halogen bond. An equation which includes stereochemical relationships was developed.36 The ‘H n.m.r. spectra of the phosphorane (16) showed enhanced separation of the multiplet for the radial phenyl group when the n 5 molecule was stable in ~ o l u t i o n . ~The ’ difference in 31P sub-spectra for each polarization of the phosphorus nucleus was used t o detect two-dimensional H spectra of cellular phosphate^.^^ Resolution-enhanced 3 H n.m.r. spectra of various tritiated methyl compounds have been r e p ~ r t e d . ~ ’

P. Murphy and J. C. Tebby, A C S S y m p . Ser., 1981, 171, 573. P. A. Manninen, A c f a Chem. Scand., Ser. B, 1981, 35, 13. 3 1 R. C. Grabiak, J. A . Miles, and G. M. Schwenzer, Phosphorus Sulfur, 1980, 9 , 197. ” L. Maier, PhosphomsSulfur, 1 9 8 1 , 11, 1 4 9 . 3 3 V . I. Gorbach, V . V. Isakov, Yu. G. Kulesh, P. A. Luk’yanov, T . F. Solov’eva, and Yu. S. Ovodov, Bioorg. Khim, 1 9 8 0 , 6 , 81. 34 J. Martin and J. B. Robert, Org. Magn. Reson., 1 9 8 1 , 15, 87. 3 5 L. W. Dennis, V . J. Bartuska, and G. E. Maciel, J. A m . Chem. SOC., 1982, 104, 2 3 0 . 3 6 I . Granoth and J. C. Martin, J . A m . Chem. Soc., 1981, 103, 2 7 1 1. 3 7 A. C. Sau and R. R. Holmes, J. Organomef. Chem., 1981, 217, 157. 3 R P. H. Bolton, J. Magn. Reson., 1981, 45, 239. 3 9 J. P. Bloxsidge, J. A. Elvidge, J. R. Jones, E. A. Evans, J. P. Kitcher, and D. C. Warrell, 0%.Magn. Reson., 1981, 15, 2 1 4 .

” 30

309

Physical Methods

Carbon-13. The differences in the 13C chemical shifts of the meta- and paracarbon atoms of the phenyl ring of t h e arylphosphines (17) are linearly related t o the position of the conformational equilibrium, as determined by U.V. spectroscopyw (see also Section 4). The 13C chemical shifts of t h e atoms C-1 and C-4 of cyclophosphazenes appear t o be governed mainly b y inductive effects.41 Oxygen-I 7. The chemical shifts of oxygen in phosphate esters have been measured and related t o c o n f i g ~ r a t i o n . Improved ~~ spectra, for aqueous solutions were obtained by depleting the 1 7 0 content of the water.43 In phosphorus acid esters, the magnetic shielding of the 170atoms decreased as the electron-donor capacity of the substituents increased.@ Fluorine-I 9. The (substituted 2-pyrroly1)tetrafluorophosphorane ( 18) is the first P-C- bonded tetrafluorophosphorane t o exhibit different "F chemical shifts for the apical and radial fluorine atoms.45 R

\II

O

RO/p-p\oR (19)

H /OR

RZN-P-NHR

=

I I

R2N-P=NR

bR

OR

(20)

(21)

A R2P\3

P 2

J

c 1/Ge\

c1

Studies of Equilibria, Hydrogen- Bonding, and Shift Reagents.-Phosphorus31 n.m.r. studies have shown that the reversible isomerization of monooxidized diphosphines (1 9) occur via a P-0-P intermediate.& There have been studies of a number of novel tautomeric equilibria, such as that between the arninophosphane (20) and the iminophosphorane (21),47 and that 40 41

42

G. V. Ratovskii, A. M. Panov, V. I . Glukhikh, G. A. Kalabin, V. I. Dmitriev, and I . A. Aliev, Zh. Obshch. Khim., 1 9 8 1 , 51, 1504. B. De Ruiter and J . C. Van de Grampel, Org. Magn. Reson., 1 9 8 1 , 1 5 , 1 4 3 ; S. S. Krishnamurthy, P. Ramabrahmam, and M. Woods, ibid., 1 9 8 1 , 1 5 , 2 0 5 . J . A. Gerlt, P. C. Demou, and S . Mehdi, J. A m . Chem. Soc., 1 9 8 2 , 104, 2 8 4 8 ; J . A. Coderre, S. Mehdi, P. C. Demou, R. Weber, D. D. Traficante, and J. A . Gerlt, ibid., 1981, 103, 1870.

43 44

I . P. Gerothanassis and N. Sheppard, J. Magn. Reson., 1 9 8 2 , 4 6 , 4 2 3 . V. V. Vasil'ev, V. E. Dmitriev. B. I. Ionin. and V. Mets. Zh. Obshch. Khim., 1 9 8 1 , 5 1 . 2134.

M . J . C. Hewson and R. Schmutzler, PhosphorusSulfur, 1 9 8 0 , 8, 9 . V. L. Foss, V. V. Kudinova, and I . F. Kutsenko, Zh. Obshch. Khim., 1 9 8 0 , 5 0 , 2 8 0 3 . 41 V. D . Romanenko, A . V. Ruban, N. N. Kalibabchuk, S. V . Iksanova, and L. N . Markovskii, Zh. Obshch. Khim., 1 9 8 1 , 5 1 , 1 7 2 6 . 11* 4s 46

Organophosphorus Chemistry

310

between the keto-phc’sphine (22) and the phospha-enol (23).48 Isomerism of carbodiphosphorane 49 and phosphotropic rearrangement of n s oxaphospholens have also been studied. The fluxional character of the germanium ylide (24) that was observed in the 31Pn.m.r. spectrum froze at - 80 ‘C.” The structural and dynamic aspects of the co-ordination chemistry of phosphane, as studied by 31Pn.m.r. spectroscopy, have been reviewed.” Chemists who are studying hydrogen-bonding are finding n.m.r. spectroscopy a useful technique for systems involving phosphoryl corn pound^.^^ Lanthanide shift reagents have been used t o assist in stereochemical studies of bicyclic oxides,54 p h o ~ p h o l a n s and , ~ ~ various butadienylphosphonates ( 2 5 ) . 5 6 r

1

Pri2P-C-Y

II

0

Variable-Temperature Studies: Inversion.-There has been a theoretical study of the inversion of p h ~ s p h i n e . ’A ~ comprehensive study of a series of acyl-phosphines (26) showed a correlation between the barrier t o inversion and the value of 6p.’’ The influence of bonds t o silicon, tin, and germanium o n inversion at phosphorus has also been reported.” Restricted Rotation and Conformation,-An iterative analysis of the exchange-broadened ”F spectra of the fluorinated triarylphosphine (27) and its oxide was used to investigate restricted rotation.60 Similar effects in

‘‘ G . Becker, Z. Anorg. Allg. Chem., 1981,480, 38.

H. Schmidbaur a n d U. Deschler, Chem. Ber., 1981, 114,2491. N . A. Polezhaeva, A. V. Aganov, A. I. Khayarov, a n d B. A. Arbuzov, Dokl. Akad. N a u k S S S R , 1981,261, 376. W. W. D u Mont, G. Rudolph, a n d N. Bruncks, A n g e w Chem., Int. Ed. Engl., 1981, 20, 475. 5 2 D. W. Meek and T. J . Mazanec, Ace. Chem. Res., 1981, 14,266. 5 3 N. S . Golubec, G. S. Denisov, E. I. Matrosov, and M. I. Kabachnik, Dokl. Akad. Nauk S S S R , 1981, 260, 907; K. Poblocka, W. Waclawek, C. Puchala, a n d A. Domagala, Muter. Semin. Nauk Wydz. Mat.-Przyr., Wyrsza S z k . Pedagog. Czestochowie, 1979,2, 94;N. Futsaeter a n d T. Gramstad, Spectrochim. Acta, Part A , 1980, 36, 1083. Mazhar-ul-Haque, W. Horne, S. E. Cremer, and J. T. Most, J. Chem. Soc., Perkin Trans. 2, 1981, 1000. j 5 V. M . Berestovitskaya, D. A. Efremov, G . A. Berkova, V. V. Perekalin, and V. I. Zakharov, Zh. Obshch. Khim., 1980,50, 2680. j6 G. A. Berkova, G. S . Vafina, V. I. Zakharov, L. N . Mashlyakovskii, a n d B. I. Ionin, Zh. Obshch. Khim., 1981, 51, 745;A. D. Lykov, L. N. Mashlyakovskii, G. S . Vafina, and B. I. Ionin, ibid., p. 1703. s7 D. S . Marynick and D. A. Dixon, J . Phys. Chem., 1982,86, 914. 5 8 I. I. Chervin, M . D. Isobaev, Yu. I. El’natanov, Sh. M. Shikhaliev, L. V . Bystrov, a n d R. G. Kostyanovskii, Izv. Akad. Nauk S S S R , Ser. Khim., 1981, 1769. s 9 T. H. Newman, J . C. Calabrese, R. T. Oakley, D. A. Stanislawski, and R. West, J. Organomet. Chem., 1982, 225, 211; C. Couret, J . EscudiB, B. Saint-Roch, J. D. Andriamizaka, and J. Sat& J. Organomet. Chem., 1982,224,247. E. E. Wille, D. S. Stephenson, P. Capriel, and G. Binsch, J. A m . Chem. Soc., 1982, 104,405.

49

’’

‘”

Physical Methods

31 1

mesitylphosphonium salts have been studied by 'H n.m.r.61 (cf. the ab initio calculations on a mesitylphosphinic chloride 62). The barriers t o rotation about the CN bond in dimethylaminotriazaphosphorines have been measured 63 and the rotational isomerism in phosphorus analogues of aspartic acid has been studied.@ The conformational analyses of various five-, six-, seven-, and ninemembered cyclic compounds are reported:' in the case of phenyl phosphorodichloridate, a nematic phase was utilized.66 Pseudorotation.-The barriers to pseudorotation of a series of cyclic oxyphosphoranes (28) correlated better with the Hammett inductive substituent constant (01) than with the electronegativity of Y.67 There have been a number of studies of fluorophosphoranes,68 apicophilicity is discussed for alkoxyfluorophosphoranes, and detailed analyses of the spectra of fluorodiazadiphosphetidines such as (29) have been ~ n d e r t a k e n . ~ ' R

Spin-Spin Couplings.-J(PM) and J(PP). One- bond P-Hg couplings are in the spectacular range 2600-5900 Hz7' Strong donor properties of a phosphino-group towards Sn" are confirmed by large P-Sn coupling^,'^ and a study of P-Se couplings in phosphole selenides has led t o an explanation for the superior donor properties of phosphole ligands towards metal acceptors.'* The relationship of one-bond P-P couplings in tetraphosphines 61

A. J. Bellamy, R. 0. Gould, and M. D. Walkinshaw, J. Chem. SOC.,Perkin Trans. 2,

62

M. Yoshifuji, I. Shima, N . I n a m o t o , a n d T. A o y a m a , Tetrahedron L e t t . , 1981, 2 2 ,

1981, 1099. 3057.

E. Fischer, H. Weber, M. Michalik, and B. Thomas, Z . Chem., 1981, 2 1 , 143. Z. Siatecki and H. Kozlowski, Org. Mugn. Reson., 1981, 17, 172. 6 5 L. D. Quin, E. D. Middlemas, N . S . Rao, R. W. Miller, and A. T . McPhail, J . A m . Chem. SOC.,1982, 104, 1893; Yu. Yu. Samitov, F. Karataeva, a n d V. V. Ovchinnikov, Zh. Obshch. Khim., 1981, 51, 7 1 1 ; B. E. Maryanoff, A. T . McPhail, a n d R. D. Hutchins, J. A m . Chem. Soc., 1981, 103, 4 4 3 2 ; V. N. Nabiullin, A. A . Musina, P. P. Chernov, and E. T. Mukmenov, I z v . Akad. N a u k S S S R , Ser. K h i m . , 1981, 1036. 6 6 J. Hansen a n d J. P. Jacobsen, Org. Magn. Reson., 1981, 15, 29. 6 1 G. Buono a n d J. R. Llinas, J. A m . Chem. SOC., 1981, 103, 4532. 6 8 D. Roberts, C. Demay, and J. G. Riess, Inorg. Chem., 1982, 21, 1805; I. R u p p e r t , Z . Anorg. Allg. Chem., 1981, 411, 59. 6 9 R. K. Harris, M. I. M. Wazeer, 0. Schlak, a n d R. Schmutzler, Phosphorus Sulfur, 1981, 11, 2 2 1 ; 0. Schlak, R. Schmutzler, R. K. Harris, E. M. McVicker, and M. I . M. Wazeer, ibid., 1981, 10, 87. '' H. B. Buergi, E. Fischer, R. W. Kunz, a n d M . Parvez, Inorg. Chem., 1982, 21, 1246. l 1 A. Tzschach a n d W. Uhlig, Z. Anorg. Allg. Chem., 1981, 415, 251. 72 D. W. Allen and B. F. Taylor, J. Chem. Res. (S)., 1981, 220.

63 64

Organophosphorus Chemistry

312

and diphosphine dioxides t o conformation has been discussed.73 A novel phosphorylphosphorane bond possessed a P-P coupling of 709 Values of ’J(PNP) for acyclic diphosphinoamines can vary from - 34 t o 732 H z . ~ ’ An exceptionally large P-0-P coupling (37.9 Hz) was recorded for an oxop h o ~ p h a z a n e .Whilst ~~ vicinal P-P couplings in compounds of the type (30) ~ related fluoro-compounds ( 3 1) have are in the region 52-58 H z , ~the couplings of twice this magnitude.= A long-range five-bond coupling between n 3 phosphorus atoms has also been observed.79 Ch

II PhPCH

I

H

Ch

II CH PPh 2 H1

0

II

F2PCH2CH2PF4

JIPF). The magnitudes of ‘J(PF) in 1-fluorophosphorins are largest when the fluorine is axial in phosphoryl compounds, but smallest in thiophosphoryl and phosphonium salts.80 In fluorophosphonium salts this coupling can be as large as 1032 Hz.” A very interesting study of a series of tricyclic monofluorophosphoranes showed that ‘J(PF) was suddenly reduced t o zero when the strain that was induced by the tricyclic system reached a critical point, thus inducing dissociation.82 Geminal P-F couplings of 104 and 19 1 Hz have been recorded for the n 2 compounds (32).83 The couplings are of a similar magnitude in (fluorinated methyl)phosphines.84 The large difference in the PPCF couplings of 4 Hz and 17.3 Hz for the diphosphine (33) is attributed t o a through-space contribution for one of the group^.^' Spin-tickling and -decoupling experiments showed that the cis and the trans vicinal couplings for the vinylphosphonate (34) are opposite in sign (-12.6 and 19.5 Hz, respectively).86 J(PN). A number of direct P-”N

coupling constants have been measured.

M. Baudler, G. Reuschenbach, and J. Hahn, Z . Anorg. Allg. Chem., 1981, 482, 27; H. Quast, M. Heuschmann, W. Von der Saal, W. Buchner, K. Peters, and H. G. von Schnering, Chem. Ber., 1982, 115, 1154. l4 H. W. Roesky and H. Djarrah, Inorg. Chem., 1982, 21, 844. ” R. Keat, L. Manojlovic-Muir, K. W. Muir, and D. S . Rycroft, J . Chem. SOC.,Dalton Trans., 1981, 2 1 9 2 . 76 R. Keat, D. S. Rycroft, V . R. Miller, C. D. Schmulbach, and R. A . Shaw, Phosphorus Sulfur, 1981, 10, 121. 17 G. Grossmann, B. Walther, and U. Gastrock-Mey, PhosphorusSulfur, 1981, 11, 259. l 8 W. Althoff, M. Fild, and R. Schmutzler, Chem. Ber., 1981, 114, 1082. 7 9 A . B. Burg, Inorg. Chem., 1981, 20, 3734. 80 D. S. Milbrath, J . P. Springer, J. C. Clardy, and J. G. Verkade, Phosphorus Sulfur, l3

1981, 11, 19. ” ” R3

R. Bartsch, 0. Stelzer, and R. Schmutzler, 2. Naturforsch., Teil. 5, 1981, 36, 1349. J. E. R i c h m a n a n d R. B. Flay, J. A m . Chem. SOC.,1981, 103, 5265. H. Eshtiagh-Hosseini, H. W. Kroto, J. F. Nixon, and 0. Ohashi, J. Organomet. Chem., 1979, 171, C1.

84

86

A. B. Burg, Inorg. Chem., 1981, 20, 2739. A. B. Burg, Inorg. Chem., 1981, 20, 3731. R. Dittrich and G. Haegele, PhosphorusSulfur, 1981, 10, 127.

Physical Methods

(32)

313

(33)

(34)

Their signs can be positive or negative, depending on the nature of the s ~ b s t i t u e n t s .88 ~~'

J(PC). The large values (175 Hz) of 'J(PC) of n4 phosphorins have been used as strong evidence for a phosphonium ylide structure.89 Whilst the direct P-C coupling constants of phosphonates increase steadily as the hybridization of the a-carbon atom changes in the order s p 3 , s p ' , s p , the geminal P-C coupling varies markedly ( 2 3 o r 8 Hz), depending o n the cis-trans geometry of the molecule, and jumps t o 92.3 Hz for an s p carbon.g0 The geminal P-C coupling can also vary considerably in certain phospholans, i.e. it is exceptionally large (28 Hz) when t h e a- and 0-carbon atoms bear bromine atoms.g1 Geminal P-N-C couplings also vary ~ o n s i d e r a b l y . The ~ ~ P-0-C and P-0-C-C couplings in oxyphosphoranes are reduced, but not lost, as the ionic character of the P-0 bond increasesg3 This contrasts with P-F couplings.82

J(PD). Deuteriation of a phosphoranide has produced a deuteriophosphorane which exhibits a P-D coupling of 113 H z . ' ~ 'J(PCH). Several groups of workers have studied the relationship between the HCP=O dihedral angle and 'J(PCH). Whilst one group of workers found the coupling to be near zero at a dihedral angle of 90°,95 others have found 'J(guuche) > ' J ( ~ n t i ) . ' ~Nevertheless, the coupling has been used t o determine the positions of conformational equilibria for (halogenated methyl)phosphine oxides.97 J(PCC, H ) and J(POCn H). The Karplus relationship for J(PCCH) is a well.~~ established tool for t h e conformational analysis of acyclic p h o ~ p h o n a t e s Its R7

RR

R9 90 91

'* 93 94 95

96

97

9R

B. Thomas, G. Grossman, and H. Meyer, Phosphorus Sulfur, 1981, 10, 375; B. Thomas, W. Bieger, and G. Grossmann, Z . Chem., 1981, 21, 292. N. Burford, T. Chivers, A. W. Cordes, W. G. Laidlaw, M. L. Noble, R. T. Oakley, and P. N. Swepston, J. A m , Chem. Soc., 1982, 104, 1282. K. Dimroth, S. Berger, and H. Kaletsch, PhosphorusSulfur, 1981, 10, 305. T. V. Zykova, V. V. Moskva, T. Sh. Sitdikova, and R. A. Salakhutdinov, Zh. Obshch. Khim., 1981, 5 1 , 2141. K. Moedritzer and R. E. Miller, PhosphorusSulfur, 1981, 10, 279. K. Bergesen, B. Pederscn, and J. Songstad, Acta Chem. Scand., Ser. A , 1981, 35, 147. D. B. Denney and D. Z. Denney, J. A m . Chem. SOC., 1981, 103, 2054. B. Garrigues and A. Munoz, C. R . Hebd. Seances Acad. Sci,, Ser. 2, 1981, 293, 617. T. A . Zyablikova, A. V. Il'yasov, 0. A. Erastov, S. Sh. Khetagurova, and S . N. Ignat'eva, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 10, 2289. H. Yamamoto, K. Yamamoto, H. Kawamoto, S. Inokawa, M. A. Armour, a n d T . T. Nakashima, J. Org. Chem., 1982, 47, 191. 0 . A . Raevskii and N. G. Mumzhieva, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 1822. Z. Siatecki and H. Kozlowski, Org. Magn. Reson., 1980, 14, 431; G. A. Berkova, G. M. Baranov, L. A. Zhidkova, and V. V. Perekalin, Zh. Obshch. Khim., 1981, 51, 757.

Organophosphorus Chemistry

314

dependence o n cis-trans geometries in olefinic n 5 compounds has also been studied.99 The cis coupling fell within the range 2 2 - 2 6 Hz whilst the trans coupling fell within the range 45-51 Hz. Studies of the influence of the orientation of a lone-pair on the phosphorus atom on the value of J ( P 0 C H ) support earlier work. loo Some long-range couplings have also been reported.'" Relaxation, CIDNP, and N.Q.R.-Relaxation. The mechanism of spin-lattice relaxation ( T1) of phosphines differs from that of the chalcogenides.lo2 Measurements of low-field dynamic nuclear polarization and of T1 were used to study the interaction of nitroxide radicals with deuteriated dimethyl p h ~ s p h i t e . " ~A study of longitudinal relaxation times of 1,3,2-dioxaphosphorinans indicates that the technique may be useful for the determination of absolute configuration of phosphorus.'w There have been similar studies of phosphate o r i e n t a t i ~ n s . ' ' ~ CIDNP. A review of phosphoranyl radicals includes a discussion of CIDNP spectra.lo6 The radical-induced inter- and intra-molecular addition of primary phosphines t o olefins was followed by n.m.r. s p e c t r o s ~ o p y . ' ~ ~ N. Q.R. A review of the conformations adopted by diheterophosphorinans includes a discussion of the n.q.r. spectra of P-chloro-derivatives such as (35).'08 The 35Cl n.q.r. frequencies of chloro(trichloromethy1)phosphoranes are used, in combination with 31P n.m.r., t o study their co-ordination state.'" N.q.r. spectroscopy has been applied t o the study of resonance transmihion in chlorodiazaphosphorines,"' and t o the reorientation of crystalline phosphazo-compounds,' "

\ (35) 99 loo

'"I

lo'

Io3 Io4

lo'

'06 lo'

lo9

'lo

(38)

Me

(36)

R. Burgada and A. Mohri, Phosphorus Sulfur, 1 9 8 1 , 9 , 285. B. M. Dahl, 0 , Dahl, and S. Trippett, J . Chem. Soc., Perkin Trans. 1, 1981, 2 2 3 9 ; 0 . Dahl, Tetrahedron Lett., 1 9 8 1 , 2 2 , 3281. P. W. Clark a n d B. K. Mulraney, J. Organomet. Chem., 1 9 8 1 , 217, 5 1 ; A . Munoz, L. Lamande, M. Koenig, R. Wolf, a n d J . Brossas, PhosphorusSulfur, 1 9 8 1 , 11, 71. K. Ramarajan, M. D. Herd, a n d K. D. Berlin,PhosphorusSulfur, 1981, 11, 199. G. J. G e r a r d i a n d J. A. Potenza, J . Phys. Chem., 1 9 8 1 , 85,2034. A. Ejchart, A. Okruszek, W. J. Stec, K. Wroblewski, and P. Oleski, Muter Ogolnopol. Semin. 'Mugn. Rezon. Jad. Jego Zastosow', 13th, 1980181, 2 1 6 (Chem. Abstr., 1982, 9 6 , 162 814). C. A. Boicelli, F. Conti, M. Giomini, and A. M. Giuliani, Spectrochim. Acta, Purt A , 1 9 8 2 , 38, 299. W. G. Bentrude, Acc. Chem. R e x , 1 9 8 2 , 1 5 , 117. B. N. Die1 a n d A. D. Norman, Phosphorus Sulfur, 1982, 1 2 , 227. R. P. Arshinova, Zh. Obshch. Khim., 1 9 8 1 , 51, 1007. V. I. Dmitriev, E. S. Kozlov, V. B. Timokhin, L. G. Dubenko, a n d A. B. Kalabina, Zh. Obshch. Khim., 1 9 8 0 , 50,2230. E. A. Romanenko, Teor. Eksp. Khim., 1 9 8 1 , 1 7 , 549. N. E. Ainbinder, G. A. Volgina, G. E. Kibrik, I . A . Kyuntsel, V. A. Mokeeva, A . N. Osipenko, Yu. I. Rozenberg, and G . B. Soifer, Radiospektroskopiya. Muterialy Vses. Simpoz. P O Magnitn. Rezonansu, Perm,, 1 9 7 9 , Perm, 1 9 8 0 , 5 8 (Chem. Abstr., 1 9 8 1 , 9 5 , 6348).

Physical Methods

315

2 Electron Spin Resonance Spectroscopy The n 3 phosphorimidoyl radicals (36) have a low a(P) value, indicating a trigonal phosphorus atom as shown.'12 The n 3 bromothio radical (37) is believed to have a tetrahedral c ~ n f i g u r a t i o n . " ~Coupling t o phosphorus differs very considerably in the diphosphine (38) l4 compared t o its dichalcogenide,'" whereas the radicals obtained by the oxidation of n 2 and n 4 phosphorins differ only slightly in their small a ( P ) values."6 There has been published an interesting series of papers o n cyclic phosphoranyl radicals. The incorporation of two phosphorus-oxygen bonds into a small ring allows the odd electron to occupy the preferred radial position ' 1 7 whereas the incorporation of three P - 0 bonds into a 0-D-ribopyranoside system, together with the presence of a sulphide anion, encourages the odd electron t o occupy a radial site.'18 Whilst diarylphosphoranyl radicals are usually tetrahedral about phosphorus, the incorporation of the aryl rings into a small ring tips the balance back in favour of a t.b.p. g e ~ m e t r y . "The ~ e(P) values of some diazadioxyphosphoranyl radicals do not appear t o depend o n the orientation of the odd electron.12' Studies of tetra-azaphosphoranyl radicals (39) indicated that exchange occurs by a Berry mechanism, with the unpaired electron acting as pivot.12' The e.s.r. spectrum of the tetrazenyl radical (40) was interesting in that, at 205 K , pseudorotation was slowed sufficiently that separate splittings from the radial and apical nitrogen atoms could be observed.'22 Studies of cyclic thio-oxyphosphoranyl radicals indicate that the E.s.r. spectroscopy RS group is more apicophilic than the RO showed that a tetra-alkoxyphosphoranyl radical is formed in the oxidation of phosphites by peroxide^.'^^ Other reports o n e.s.r. spectroscopy concern a sulphonophosphonoethylene radical,'25 an aryloxyiminophosphorane,'26 a carbaboranylphosphoranyl radical,'27 and the radical (4 l ) , which is stable for several days.'" The effect of diastereoisomeric anisochronism o n the e.s.r.

'

'I2 'I3

'14

'" 'Id I"

"* 'I9

B. P. Roberts and K. Singh, J . Chem. SOC.,Perkin Trans. 2, 1981, 866. J. C. Evans and S. P. Mishra, J. Inorg. Nucl. Chem., 1981, 43, 481. W. Kaim and H. Bock, Chem. Eer., 1981, 114, 1576. W. Kaim, 2. Naturforsch., Teil. B, 1 9 8 1 , 36, 150. K. Dimroth and W. Heide, Chem. Ber., 1981, 114, 3019, 3004. B. L. Tumanskii, A. A. Khodak, S. P. Solodovnikov, N . N . Bubnov, V. A . Gilyarov, and M. I. Kabachnik, Izv. Akad. N a u k S S S R , Ser. Khim., 1 9 8 1 , 1014. J . H. H. Hamerlinck, P. Schipper, and H. M. Buck, J . Chem. Phys., 1982, 76, 2 1 6 1 . H. M. Buck,Recl. Trav. Chim. Pays-Bas, 1 9 8 1 , 100, 2 1 7 . J . H. H. Hamerlinck, P. Schipper, and H. M. Buck, J. Chem. Soc., Chem. Commun., 1981, 1 0 4 , 1148.

12'

'" 123 124

lZ5 126 127

12*

J . H. H. Hamerlinck, P. H. H. Hermkens, P. Schipper, and H . M. Buck, J . Chem. Soc., Chem. Commun., 1 9 8 1 , 3 5 8 . J . C. Brand and B. P. Roberts, J. Chem. Soc., Chem. Commun., 1981, 1107. J . R. M. Giles and B. P. Roberts, J. Chem. Soc., Perkin Trans. 2, 1981, 1211. A . G. Davies and R . Sutcliffe, J. Chem. SOC.,Perkin Trans. 2, 1 9 8 1 , 1 5 1 2 . E. A. Berdnikov, A. A. Vafina, F. R. Tantasheva, R. M. Zaripova, F. K. Muknitova, and A . V. Il'yasov, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 1008. H. B. Stegmann, H. V. Duman, A. Burmester, a n d K. Scheffler, Phosphonrs Sulfur, 1 9 8 0 , 8, 59. B. L. Tumanskii, A. N. Degtyarev, and N . N. Bubnov, Izv. Akad. Nauk S S S R , Ser. Khim., 1 9 8 0 , 2 6 2 7 . M. Negareche, M. Boyer, and P. Tordo, Tetrahedron Lett., 1 9 8 1 , 2 2 , 2 8 7 9 .

Organophosphorus Chemistry

316

(39)

spectra of a chiral phosphonate that contains a phenoxyl radical has been described.12g

3 Vibrational and Rotational Spectroscopy Band Assignments and Absorptivity.-The fundamental bands of PD3 have been rotationally analysed I3O and the spectra of tris(cyanomethy1)phosphine,I3' of various d i h y d r o p h o ~ p h o r i n s , ' ~ and ~ of bis(dipheny1phosphino)amines 133 have been assigned. The Raman v(PP) band for tetraphenyldiphosphine dichalcogenides has been identified and the vibrational spectra of some dithiocyclophosphazenes have been a ~ s i g n e d . ' ~The ' spectra of the pyridinium salt (42) have been compared with calculated f r e q ~ e n c i e s . ' ~Infrared ~ optical densities have been used t o follow the reactions of isocyanates with p h o ~ p h i t e s . ' ~ '

@
Bonding.-There have been several analyses, based on theoretical and experimental work, of the spectra of various primary and secondary phosp h i n e ~ . ' 13' ~ ~ 'The studies have centred mainly around the PH stretching N. A. Kardanov, A. 1. P r o k o f e v , N. P. Provotorova, N. N. Bubnov, S. P. Solodovnikov, N. N. Godovikov, a n d M. I. Kabachnik, Dokl. Akad. Nauk S S S R , 1981,261, 412. I 3 O K. Kijima a n d T. Tanaka, J . Mol. Spectrosc., 1981,89, 62. I ) ' G . Borsch, 0. Dahl, P. Klaeboe, and P. N. Nielsen, Actn Chem. Scand., Ser. A , 1981, 35, 497. G. Maerkl, H. Baier, R. Liebl, and D. S . Stephenson, Liebigs Ann. Chem., 1981,870. 1 3 3 J . Ellermann a n d L. Mader, Spectrochim. Acta, Part A , 1981, 37, 449. 1 3 ' A. J. Blake, G. P. McQuillan, I . A. O x t o n , a n d D. Troy, J. Mol. Struct., 1982, 78, 265. P. J. Argent, D. Parker, R. A. Shaw, a n d M . Woods, Inorg. Nucl. Chem. L e t t . , 1981, 17, 11. I. K. Korobeinicheva a n d T. V. Mal'tseva, Izw. Akad. Nauk S S S R , Ser. Khim., 1981, 308. 137

M. I. Bakhitov, V. V. Zharkov, E. V. Kuznetsov, a n d 0. L. Klugman, Zh. Obshch. Khim., 1981, 51, 1035; M. I. Bakhitov, V . V. Zharkov, E. V . Kuznetsov, and Z. Kh. Khazeeva, ibid., p. 552. S. Pradna-Bergrova, Collect, Czech. Chem. Commun., 1981, 46, 2289;E. Niecke, A . Nickloweit-Lueke, and R. Rueger, Phosphorus Sulfur, 1982, 12, 213; D. McKean, I. Torto, and A. R. Morrisson, J. Phys. Chem., 1982, 86, 307; H. P. Figey, D. Berckmans, a n d P. Geerlings, J. Chem. Soc., Faraday Trans. 2, 1981,77, 2091. J. R. Durig, S. D. Hudson, M. R. Jalilian, and Y. S. Li,J. Chem. Phys., 1981, 74, 772.

Physical Methods

317

frequency. For a 3-phospholen, vibrations of large amplitude (using one-, two-, and three-dimensional models of the inversion of PH) have been used in calculations of vibrational H a m i l t ~ n i a n s . 'The ~ ~ role of d-orbital functions in affecting the stretching and bending modes of ylides has been estimated, using STO calculation^.'^^ CND0/2 calculations on thiophosphoryl compounds have indicated that the inclusion of d-orbitals was necessary in order t o correlate P-S bond orders with ratios of force constant^.'^^ Normalco-ordinate analysis of the spectra of trimethylphosphine tellurides gave force constants for P-Te which have been compared with those of other chalcogenide-containing groups. 143 The values of v ( P 0 ) of 1-phenoxyphospholen oxides agreed with calculated values, based on inductive constants.14 Studies of hydrogen-bonding, using i.r. spectroscopy, have concerned a l k y l - p h ~ s p h i n e s , ' ~phosphine ~ oxides,'46 and p h o ~ p h i n i m i n e s . ' ~In~ the latter study, v(CD) of CDC13 gave a linear correlation with Za*. Infrared and Raman studies of various chlorides (43) indicated the presence of molecular as so cia ti or^.'^^ The relationship of v ( P 0 ) t o the bond energies of phosphine oxide-uranyl nitrate c o m p l e x e ~ , the ' ~ ~ effect of metallation of prop-l-ynylphosphonates upon various stretching f r e q ~ e n c i e s , ' ~ 'and the spectroscopic acidities of phosphorohydrazides 15' are also reported.

Stereochemistry.-Vibrational spectroscopy is finding an expanding role in conformational analysis. The growth stems from the increasing number of bands which can be assigned to specific conformations. Dimethyl(acety1)phosphine has been shown to prefer one conformation in liquid and solid states.'52 Stereochemical studies of a variety of n4 compounds have centred on (halogenomethy1)phosphine oxides,'53 silyl p h o s p h o n a t e ~ , ' dimethyl ~~ methylphosphonate and its deuterio- and '3C-analogues,'55 some cyclic thio-

M. A. Harthcock and J. Laane, J. Mol. Spectrosc., 1982, 91, 300. D. J. Mitchell, S . Wolfe, and H. B. Schlegel, Can. J. Chem., 1981, 59, 3280. 14* I. Silaghi-Dumitrescu and I. Haiduc, Phosphonrs Sulfur, 1982, 1 2 , 205. F. Watari, Inorg. Chem., 1981, 20, 1776. K. Moedritzer and R. E. Miller, PhosphorusSulfur, 1981, 9, 293. 14' E. V. Ryl'tsev and A. K. Shurubura, Zh. Khim., 1981, Abstr. 20B1517 (Chem. Abstr., 1982, 96, 19 575). S. Dietz, H. Hobert, and H. Winde, Z. Chem., 1981, 21, 374. 147 I. F. Tsymbal, E. V. Ryl'tsev. Yu. P. Egorov, A. A. Kudryavtsev, and G. N. Koidan, Teor. Eksp. Khim., 1981, 17, 44. R. Kh. Musyakaeva and R. R. Shagidullin, Deposited Document 1980, VINITI 4983, (Chem. Abstr., 1982, 96, 68 174). 1 4 9 V. V. Yakshin, A. V. Romanov, and B. N. Laskorin, Dokl. Akad. NaukSSSR, 1981, 257, 173. M. Kirilov, G. Petrov, and A. Sidjimov, Monatsh. Chem., 1980, 111, 135 1. R. Mathis, A. M. Pellizzari, T. Bouissou, M. Revel, and M. Chihaoui, Spectrochim. Acta, P a r t A , 1981, 37, 677. G. M. Kuramshina, A. K. Petrov, L. S . Khaikin, 0. D. Ul'yanova, and Yu. A. Pentin, Zh. Fir. Khim., 1981, 55, 2981. l S 3 0. A. Raevskii, N. G. Mumzhieva, T. E. Kron, and E. N. Tsvetkov, I z v . Akad. Nauk SSSR, Ser. Khim., 1981, 1292. Yu. V. Kolodyazhnyi, I. A. Lapin, A. P. Sadimenko, and 0. A. Osipov, Zh. Obshch. Khim,, 1981, 51, 794. B. J. Van Der Veken and M. A. Herman, Phosphorus Sulfur, 1981, 10, 357.

Organophosphorus Chemistry

318 n

and s e l e n o - p h ~ s p h o n a t e s , ~a~ ~seIeno-l,3,2-dio~aphosphorinan,'~~ S-silyl t h i o p h o s p h a t e ~ , ' ~0-silyl ~ phosphate^,'^' and some 2-chloro-1,3,2-dioxaphosphepans.I6' Rotational Data.-Structural and dipole-moment parameters have been determined from the microwave spectra of a series of phosphaethynes (44).16' Further data on phosphaethene (45; Y = H ) and its ' H and13C In addition, the structural paraisotopic analogues have been reported. meters for P-chlorophosphaethene (45; Y = C1) have been determined.'63 The rotation-inversion line parameters from the i.r. spectra of phosphine have been measured and a new approach for the treatment of the rotational spectra has been r e ~ 0 r t e d . lThe ~ ~ rotational constants for deuteriated methyl- and dimethyl-phosphines have been calculated from their microwave spectra.'39 There have been several reports of theoretical studies of phosphines. MIND0/3 and MNDO approaches were used t o estimate rotational barriers and structural parameters for a wide range of methyl- and ethyl-phosphines'" and also for tris(dimethylamino)ph~sphhe.'~~ Calculztions of pseudopotentials have been used t o estimate the barriers t o rotation about P-N of aminophosphines.16' The microwave spectra of vinyldifluorophosphine 169 and of methylphosphonic difluoride I 7 O have been recorded and structural and conformational data calculated.

'"

R . R. Shagidullin, I. Kh. Shakirov, R. Kh. Musyakaeva, a n d I . A. Nuretdinov, Izv. A k a d . N a u k S S S R , Ser. K h i m . , 1981, 1890; R. R. Shagidullin, I . Kh. Shakirov, R . Kh. Musyakaeva, I. I. V a n d y u k o v a , a n d I. A. Nuretdinov, ibid., p. 1156. I s ' R . R . Shagidullin, I. Kh. Shakirov, R . Kh. Musyakaeva, I. I. Vandyukova, a n d I . A. Nuretdinov, I z v . A k a d . N a u k S S S R , Ser. K h i m . , 1981, 1535. I s ' R. R. Shagidullin, I. I. Patsanovskii, I. Kh. Shakirov, E. A . Ishmaeva, and G . A. Kutrev, Zh. Obshch. K h i m . , 1981,51, 19. Is' Yu. V. Kolodyazhnyi, I. A . Lapin, E. F. Bugerenko, a n d 0. A. Osipov, Zh. Obshch. K h i m . , 1981,5 1 , 806. I6O R. R. Shagidullin, D. F. Fazliev, R . Kh. Musyakaeva, A. Kh. Plyamovatyi, 0. N . Nuretdinova, a n d I. I. V a n d y u k o v a , I z v . A k a d . N a u k S S S R , Ser. K h i m . , 1981,561. 16' K. O h n o , H. W. K r o t o , a n d J. F. N i x o n , J. Mol. Spectrosc., 1981, 90, 507; H.W. K r o t o , J. F. N i x o n , a n d K. O h n o , ibid., p. 512; H. O b e r h a m m e r , G. Becker, a n d G. Gresser, J . Mol. S t r u c t . , 1981, 75, 2 8 3 ; J. C. T . R . B u r k e t t - S t . L a u r e n t , H. W. K r o t o , J . F. N i x o n , a n d K. O h n o , J . Mol. Spectrosc., 1982, 92, 158. 1 6 2 R . D. B r o w n , P. D. G o d f r e y , a n d D. McNaughton, A u s t . J . C h e m . , 1981, 34,465;H. W. K r o t o , J . F. N i x o n , a n d K. O h n o , J. Mol. Spectrosc., 1981,90, 367. 1 6 3 B. Bak, N. A. Kristiansen, a n d H. Svanhold, A c t a C h e m . Scand., Ser. A , 1982, 36, 1. 1 6 4 N. Hussan, A. G o l d m a n , a n d G. O r t o n , J . Quant. Spectrosc. Radiat. Transfer, 1982, 27, 505. S. P. Belov, A. V. Burenin, 0. L. Polyanskii, a n d S. M . S h a p i n , J . Mol. Spectrosc., 1981,90, 579. 1 6 6 J . A. Mosbo, R. K. A t k i n s , P. L. Bock, and B. N. S t o r h o f f , PhosphorusSulfur, 1981, 11,ll. 16'S. D. Worley, J . H. Hargis, L. Chang, and W. B. Jennings, Inorg. Chem., 1981, 20, 2339. M. Barthelat, R. Mathis, a n d F. Mathis, Thermochemisiry, 1981,2, 351. G . D. F o n g a n d R. L. Kuczkowski, Inorg. C h e m . , 1981,20, 2342. J. R. Durig; A. E. Stanley, a n d Y . S. Li, J . Mol. Struct., 1982,78, 247.

Physical Methods

319

4 Electronic Spectroscopy

Absorption Spectroscopy.-Using a combination of U.V. spectroscopy and 13C n.m.r. spectroscopy, it has been estimated that dialkylphosphino-groups have electron-donor properties up to 48% of those of the corresponding amino-groups. The U.V. molar absorptivities were used t o estimate the position of equilibria between planar and non-planar forms of dialkyl(phenyl)phosphines, on the basis that di-t-butyl(pheny1)phosphine is entirely in the non-planar form and that dimethyl(pheny1)phosphine is 50% nonplanar and 50% planar. The latter conclusion was partly based on variabletemperature 13C n.m.r. s p e c t r o s ~ o p y These . ~ ~ conclusions contrast with those drawn from measurements of the values of p K a measurements of dialkylphosphinobenzoic acids (see Section 7 of this Chapter). The bathochromic shift which accompanies the photochemical cis-trans isomerization of the phosphine chalcogenides (46; C h = O o r S) has Seen attributed t o changes

(46)

R

(47)

(50)

in the electronic interaction between the phosphorus and the styrene groups.'71 In another stereochemical study of phenylphosphine oxides, U.V. spectroscopy was used in combination with liquid-crystal circular dichroism and 13C n.m.r. spectroscopy.172 4,4'-Electronic transmission effects between a diphenylphosphoryl group and donor substituents across a stilbene moiety have been r e ~ 0 r t e d . IThe ~ ~ U.V. spectra of n 2 phosphorins 174 and of cyclophosphadithiatriazines 88 have been analysed and the technique has been used t o study the state of dissociation of chloro(trichloromethy1)phosphoranes 17' and the reactions of butoxyphosphoranyl r a d i ~ a 1 s . l ~ ~ Photoelectron Spectroscopy.-The role of d-orbitals of phosphorus in the bonding of trimethylphosphine and tris(trifluoromethy1)phosphine has been the subject of an ab initio SCF MO The photoelectron spectra of the phosphanes (47; C h = S o r Se) gave ionization potentials which have D. Gloyna a n d K.G . Berndt, Acra Phys. Chem., 1980, 2 6 , 155. J . B. Rampal, N . Satyamurthy, J . M. Brown, N . Purdie, and K. D. Berlin, J. A m . Chem. Soc., 1 9 8 1 , 103, 7 6 0 2 . 1 7 3 G . P. Schiemenz and M. Finzenhagen, Liebigs Ann. Chem., 1981, 1476. ' ' + G. Maerkl, H. Baier, and R . Liebl, Liebigs A n n . Chem., 1981, 9 1 9 . 17' L. M. Sergienko, G . V. Ratovskii, E. S. Kozlov, and V. I . Dmitriev, Zh. Obshch. K h i m . , 1981, 5 1 , 4 9 4 . B. P. Roberts and J . C. Scaiano, J. Chem. Soc., Perkin Trans. 2, 1981, 905. M. H . Whangbo and K. R. Stewart, Inorg. Chem., 1982, 2 1 , 1720. 17'

12

Organophosphorus Chemistry

320

been compared with calculated orbital energie~.'~'Photoelectron spectroscopy has been used in the conformational analysis of various n 3 compounds such as the cyclic aminophosphanes (48),17' cyclic phosphites,"" 18' and related phosphanes."' In the latter study, the ionization potential (I.P.) of the lone-pairs o n phosphorus was also examined, as a quantitative measure of basicity.'" The spectra of various cyclic aminoalkoxy-phosphanes have been recorded and the binding energies of the inner shells of nitrogen, oxygen, and phosphorus have been compared with the hydrogen-bonding abilities of the compounds.'82 The spectra of chloromethyldichlorophosphane (49; Z =lone pair), its oxide, and its sulphide gave values for the I.P. of the chlorine atoms which are linearly related t o n.q.r. f r e q ~ e n c i e s . " ~ A wide variety of vinyl, allyl, and butenyl n 3 and n 4 compounds have been studied, e.g. (50), and the photoelectron spectra analysed with the aid of C N D 0 / 2 calculations. Stabilized phosphonium ylides have been examined and discussions of photoelectron spectra are included in reviews of phosphinimines 26 and of n4-phosphorins.'86

'"

Optical Rotation.-From a study of optically active spirophosphoranes, the molecular rotation was separated into several independent components, thus giving the rotational contributions of the ligands and the helical ~ t r u c t u r e . ' ' ~ The analysis allows the prediction of the absolute configurations.

5 Diffraction

X -Ray Diffraction.-The structural parameters of a variety of n 3 compounds have been established. In addition t o tris(cyanoethyl)phosphine,'" a dibenzothere have been p h o ~ p h o n i n , ' ' ~and a novel l-phosphanorb~rnadiene,~~~ studies of a diphosphacyclo-~ctane,'~'the cage diphosphine ( 5 l),'" 'triphos' ( 5 2),Ig3 a triphospha[ 14]monocycle,'" and a tetraphosphadisilahexane M. C. B o e h m , M. Eckert-Maksic, R. Gleiter, J. G r o b e , and D. Levan, Chem. Ber., 1981, 114, 2 3 0 0 . IRn

D. G o n b e a u , M. S a n c h e z , a n d G . Pfister-Guillouzo, Inorg. Chem., 1 9 8 1 , 20, 1966. V. V. Zverev, J. Villem, and R . P. Arshinova, Dokl Akad. Nauk S S S R , 1981, 256,

''I

R. P. Arshinova, V. V . Zverev, Ya. Ya. Villem, a n d N . V. Villem, Zh. Obshch. Khim.,

1412. 1 9 8 1 , 51, 1757.

E. V. Borisov, N . L. Ivanova, a n d E. E. Nifant'ev, Zh. Fiz. Khim., 1981, 55, 1786. V. V. Zverev, L. V. Ermolaeva, a n d J. Villem, Zh. Obshch. Khijn., 1980, 50, 2 6 9 0 . V. V. Zverev, J. Villem, N . V. Villem, B. G. Liorber, a n d Y u , P. Kitaev, Zh. Obshch. Khim., 1 9 8 1 , 51, 303. S. Huang, Y . S h e n , W. Ding, a n d Y. Huang, Y o u j i H u a x u e , 1981, 6, 426. K. D i m r o t h , Acc. Chem. R e x , 1 9 8 2 , 15, 5 8 . I n ' A. Klaebe, J. F. Brazier, B. Garrigues, R. Wolf, a n d Y. Stefanovsky, Phosphorus Sulfur, 1 9 8 1 , 10, 53. IR'F. A. C o t t o n , D. J . Darenshurg, M. F. Fredrich, W. H. Ilsley, a n d J . M. T r o u p , Inorg. Chem., 1981, 2 0 , 1869. I R 9 D. Hellwinkel, W. Krapp, a n d W. S. Sheldrick, Chem. Ber., 1981, 114, 1786. '91 F. Mathey, F. Mercier, a n d C. Charrier, J . A m . Chern. Soc., 1981, 103, 4 5 9 5 . I 9 l B. A. Arhuzov, 0. A. Erastov, G. N. Nikonov, I . A. Lutvinov, D. S . Yufit, a n d Yu. T. S t r u c h k o v , Dokl. Akad. N a u k S S S R , 1981, 257, 127. D. S c h o m b u r g a n d Y. Kobayashi, Phosphovus Sulfur, 1981, 10, 17. 1 9 3 C. Mealli, A c f a Crystallogr., Sect. B, 1982, 38, 1040. 1 9 4 E. P. Kyba, R . E. Davis, C. W. H u d s o n , A. M . J o h n , S . B. B r o w n , M. J. McPhaul, L . K. L i u , a n d A. R. Glover, J. A m . Chem. Soc., 1981, 103, 3868.

321

Physical Methods

( Ph2CHZ ) 3CMe

(52)

which occupies a boat c o n f o r m a t i ~ n . The ’ ~ ~ stereochemistries of some threemembered,’96 four-membered,19’ and eight-membered cyclic aminophosphanes have been determined, as well as those of a new bicyclic hexaphosphine 199 and an octaphosphine.’” Four compounds that have been examined possess both n 3 and n 4 phosphorus groups, viz. a phosphinophosphonium ylide,’” a phosphinophosphoryl heterocycle that contains a P-P bond,”’ a germanium complex of a d i p h o ~ p h i n e , ” and ~ a diazadiphosphetidine.’w The X-ray diffraction studies of n 4 compounds which follow are dealt with in the order of decreasing number of P-C bonds. In addition t o a tetraphenylphosphonium salt,20s the structures of 2 5 triphenylbenzylphosphonium salts have been compared.206The latter study showed that the anion always occupies a face (apical) orientation with respect to the tetrahedral phosphonium centre. There was also evidence of an interaction of the anions with the acidic @-hydrogens, so that the structure corresponds to an early stage of removal of a proton. The molecular structures of the bis(triethy1phosphonium) salt (5 3),’07 a bis(phosphino1inium) salt,20s a phosphetanium + +

’’’

Et3PCHZSSCHZPEt3 (53) R . Frohlich a n d K. F. Tebbe, A c t Q Crystallogr., Sect. B, 1982, 38, 115. 1 9 6 E. Niecke, K. SchwichtenhBvel, H.-G. Schafer, and B. Krebs, Angew. Chem., Int. Ed. Engl., 1 9 8 1 , 20, 9 6 3 ; E. Niecke, A. Nickloweit-Lueke, R . Ruger, B. Krebs, and H. Grewe, Z . Naturforsch., Teil. B, 1981, 36, 1566. 19’ M. L. T h o m p s o n , A. Tarassoli, R . C . Haltiwanger, and A. D. Norman, J. A m . Chem. Soc., 1 9 8 1 , 103, 6770. 1 9 * W. Zeiss, T. Kuhn, D. Lux, W. Schwarz, and H. Hess, Z.Naturforsch., Teil. B, 1 9 8 1 ,

19’

36, 561. 199 200

*02

203 204 205

’06 207 2oFi

M. Baudler, Y. Aktalay, K. F. Tebbe, and T. Heinlein, Angew. Chcm., Int. Ed. Engl., 1 9 8 1 , 2 0 , 967. M . Baudler, J. Hellmann, P. Bachmann, K. F. Tebbe, R. Frohlich, and M. E‘erer, Angew. Chem., Int, Ed. Engl., 1981, 2 0 , 406. H. J . Bestmann, G. Schmid, W. E. Bohmer, E. Wilhelm, and H. Burzlaff, Chem. Ber., 1980, 113, 3937. W. S . Sheldrick, S . Pohl, H. Zamankhan, M. Banek, D. Amirzadeh-Asl, and H. W. R o e s k y , C h e m . Ber., 1 9 8 1 , 114, 2 1 3 2 . N. Bruncks, W. W. D u Mont, J . Pickardt, and G. Rudolph, Chem. Ber., 1981, 114, 3572. S . Kleeman, E. Fluck, and W. Schwarz, PhosphorusSulfur, 1981, 1 2 , 19. H. W. Roesky, W. Schmieder, and W. S . Sheldrick, J . Chem. Soc., Chem. C o m m u n . , 1981, 1013. S. J . Archer, T. A. Modro, and L. R. Nassimbeni, PhosphorusSulfur, 1 9 8 1 , 11, 101. C . Bianchini, A. Meli, a n d A. Orlandini, PhosphorusSulfur, 1981, 11, 335. N . Gurusamy, K. D. Berlin, D. Van der Helm, a n d M. B. Hossain, ACS S y m p . Ser., 1981, 171, 561.

Organophosphorus Chemistry

322

bromide,20g a boradioxaphosphorinan,210 and a phosphaferrocene 211 have also been reported. A number of phosphonium ylides have been studied. These include two cyano-stabilized an iron a ~ y l - y l i d e , ~a ' ~ b e n ~ y l i d e , ~two ' ~ c a r b o d i p h o ~ p h o r a n e s ,and ~ ~ ~a cadmium benzodiphosphepinide .* l 6 Several ylides that contain only three P-C bonds have been examined. ' ~ an ylidic There were triphenylphosphinimines - one c y a n o - ~ t a b i l i z e d , ~one 2nd one a cyclic phosphazene d e r i ~ a t i v e ; ~two ' ~ others that incorporated a triphospholenyl cation,220 and a trisilaphosphazine.2*1 Apart from the hydrobromide of diphenyl(2-hydroxypheny1)phosphine 222 and a diazaphosphorinane derivative,223 the remaining compounds in the group that include three P-C bonds were phosphine oxides, i.e. 2-(dimethylphosphoryl)benzoic acid.224 a derivative of pentenoic and two derivatives of The molecular structure of (-)-menthy1 t-butylphenylphosphinate in the crystal was compared to that determined for a solution, using n.m.r.227 Fiveand eight-membered phosphinates have been studied,228 as have the phosphinimides (54; R = H or Me) 229 and the unusual heterocycle (55).230

*I4

Mazhar-ul-Haque, W. Horne, S. E. Cremer, P. W. Kremer, and P. K. Kafarski, J. Chem. Soc., Perkin Trans. 2, 198 1, 1 138. B. A. Arbuzov, 0. A. Erastov, G. N. Nikonov, A. A. Espenbetov, A. I. Yanovskii, a n d Yu. I. Struchkov, I z v . Akad. N a u k S S S R , Ser. Khim., 1981, 1545. B. Deschamps, J. Fischer, F. Mathey, A. Mitschler, and L. Ricard, Organometallics (Washingfon,D.C.), 1982, 1, 3 1 2 . H. J. Hecht a n d G. Ruban, Cryst. Strucf. C o m m u n . , 1 9 8 1 , 10, 4 9 5 ; G. Ruban and V. Zabel, ibid., p. 4 9 9 . H. Blau, W. Malisch, S. Voran, K. Blank, and C. Kruger, J. Organome?. Chem., 1980, 202, c33. H. Schmidbaur, U. Deschler, B. Milewski-Mahrla, and B. Zimmer-Gasse, Chem. Ber.,

'Is

U. Schubert, C. Kappenstein, B. Milewski-Mahrla, and H. Schmidbaur, Chem. Ber.,

*Ib

H. Schmidbaur, T. Costa, and B. Milewski-Mahrla, Chem. Ber., 1981, 114, 1428. M. Yu. Antipin, A. P. Polishchuk, Yu. T. Struchkov, Yu. P. Egorov, V. M. Yurchenko, V. E. Didkovskii, and A. A. Yatsishin, Zh. Strukt. Khim., 1981, 22, 117. C. Glidewell a n d H. D. H o l d e n , J . Organomet. Chem., 1982, 226, 171. M. Krishnaiah. L. Ramamurthv. .. P. Ramabrahman. a n d H. Manohar. 2. Narurforsch.. Teil. B, 1 9 8 1 , 3 6 , 1 6 5 . A. SchmidDeter. S. Lochschmidt. and W. S . Sheldrick. Anaew. Chem.. I n t . Ed. Enal..

209

'lo

'I1 'I'

'I3

1981, 114, 6 0 8 . 1 9 8 1 , 114, 3070. 'I' 'I8

'I9 ""

~~

1982, 2 1 , 63.

'

G. Fritz, U. Braun, W. Schick, W. Honle, and G. H. von Schnering, 2. Anorg. Allg. Chem., 1 9 8 1 , 4 7 2 , 4 5 . "* J. Heinze-Sauer, Chem. Abstr., 1 9 8 2 , 96, 162 837. 2 2 3 B. A. Arbuzov, 0. A. Erastov, G . N. Nikonov, T. A. Zyablikova, D. S. Yufit, and Yu. T. Struchkov, Izv. Akad. N a u k S S S R , Ser. Khim., 1981, 1539. 2 2 4 M . Yu. Antipin, Y u . T. Struchkov, E. A. Matrosov, N . A. Bondarenko, E. N . Tsvetkov, and M. I. Kabachnik, Zh. S f r u k t . Khim., 1981, 22, 100. 2 2 5 M . L. Glowka, Acta Crysfallogr.,Sect. B, 1 9 8 1 , 37, 1780. '*'V. V. Tkachev, N . A. Bondarenko, E. I. Matrosov, E. N . Tsvetkov, L. 0. Atovmyan, and M. I. Kabachnik, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 2 0 9 ; M. L. Glowka a n d Z. Galdecki, Acta Crysfallogr.,Sect. B, 1 9 8 1 , 37, 1183. W. S. Sheldrick, G. Haegele, and W. Kueckelhaus, J. Mol. S f r u c f . , 1 9 8 1 , 74, 331. *" G . Maas, M. Regitz, K. Urgast, M. Hufnagel, and H. Eckes, Chem. Ber., 1982, 115, 221

'"

669. 229 230

A . F. Cameron a n d F. D. Duncanson, Acta Crystallogr., S e c t B, 1981, 37, 1604. N. Burford, T. Chivers, P. W. Codding, and R. T. Oakley, Inorg. Chem., 1982, 2 1 , 982.

323

Physical Methods

The structures of three quasi-phosphonium salts (56) have also been Studies of the X-ray diffraction of menthyl methyl phenylphosphonate and its thio-analogue have been reported,232 as has work o n the thioglycolyl compound ( 5 7 ) 233 and the phenyl ester (58).234 The stereochemistries of a dithiazaphosphorinone 235 and an oxazaphospholidine (5 9) have also been established.236 In the latter study, the relationship of the length of the P=N bond t o the angle of the P=N-Y bond was discussed.

(58)

A wide variety of n4 compounds that d o not have any P-C bonds have been covered. The group includes several cyclic and acyclic phosphate^,^^' a series of cyclic t h i o p h o ~ p h a t e s , and ~ ~ ~ the tricyclic phosphatrane (60).239 Most of the compounds in this group possessed PN bonds. They include two multi-ringed heterocycles - one an oxazaphosphole tetramer 240 and the other

235

D. Mootz, W. Poll, H. Wunderlich, and H. G. Wussow, Chem. Ber., 1981, 114, 3499. J. D o n o h u e a n d N. Mandel, J. Cryst. Mol. Struct., 1981, 11, 189. V. G. Andrianov, A. E. Kalinin, Yu. T. Struchkov, T. A . Mastryukova, A. E. Shipov, M. S. Vaizberg, a n d M. I. Kabachnik, Zh. Strukt. Khim., 1981, 2 2 , 6 8 . M. D. Crenshaw, S . J. Schmolka, H. Zimmer, R. Whittle, a n d R. C. Elder, J. Org. Chem., 1 9 8 2 , 4 7 , 101. S. Scheibye, S. 0. Lawesson, a n d C. Roemming, A c t a Chem. Scand., Ser. B , 1981,

236

M. Yu. Antipin, Yu. T. Struchkov, and N. A. Tikhonina, Zh. Strukt. Khim., 1981,

131

232 233 234

35, 239. 22,93. 237

238 239

H. Nomura, H. Nakamachi, a n d Y. Wada, Chem. Pharm. Bull., 1982, 30, 1024; P. F. Fewster and R. H. Fenn, A c t a Crystallogr., Sect. B, 1982, 38, 2 8 2 ; R. Van Nuffel, A. T. H. Lentra, a n d H. J. Geise, Bull. Soc. Chim. Belg., 1982, 91, 4 3 ; L. N. Mazalov, G. N. Dolenko, and V. D. Yumatov, Zh. Strukt. K h i m . , 1981, 2 2 , 18. M . W. Wieczorek, Phosphorus Sulfur, 1980, 9, 137. D. Van A k e n , I. I. Merkelbach, J. H. H. Hamerlinck, P. Schipper, a n d H. M. Buck, A C S S y m p . Ser., 1981, 1?1, 439. M. Yu. Antipin, Yu. T. Struchkov, a n d Yu. V. Balitskii, Zh. Strukt. Khim., 1981, 2 2 , 98.

324

Organophosphorus Chemistry

cig 0-P

"'1

a bis-amidothionophosphate 241 - some analogues of c y c l o p h ~ s p h a m i d e , ~ ~ ~ and a glucopyranose derivative.243 Studies of t w o diazadiphosphetidines have been reported a n d a review of this class of compounds contains a section o n their molecular structures.245 Other structures that have been established are those of a p e n t a c h l o r o p h ~ s p h a z e n e a, ~p~e~r c h l o r o p h ~ s p h i n i r n i n e ,a~ ~ ~ tris(dimethy1amino)phosphane oxide a d d u ~ t , ' ~ ' and a tripiperidyl compound. 249 Amongst cyclic n 5 compounds that have been examined there is a bicyclic dioxyphosphorane which has a radial P-H bond and a monocyclic oxyphosphorane which has an apical P-H bond.250 Spiro-trioxy- 251 and -tetraoxyphosphoranes as well as bis-benzoxazaphosphole 253 have been investigated. F o u r phosphoranes that possess P-P bonds have been described;2541255 two of t h e compounds have both phosphorus atoms in t h e n 5 state.255The use of X-ray structural data for modelling pseudorotation has been briefly reviewed.256 24'

242

243

24q

245

*" *4p

I. A. Litvinov, Y u . T. S t r u c h k o v , B. A. A r b u z o v , V. N . Nabiullin, and E. T. Mukmenev, PhosphorusSulfur, 1 9 8 1 , 12, 1 . L. E. Carpenter, 11, D. Powell, R. A. Jacobson, and J. G . Verkade, PhosphorusSulfur, 1 9 8 2 , 1 2 , 2 8 7 ; S. D. C u t b u s h , S. Neidle, G . N . T a y l o r , a n d J . L. G o s t a n , J . Chem. Soc., Perkin Trans. 2, 1981, 9 8 0 . I. A. Litvinov, Y u . T. S t r u c h k o v , B. A . Arbuzov, L. S. Liakisheva, L. I. Gurariy, and E. T. Mukmenev, PhosphontsSulfur, 1981, 12, 5 . J. S. Jessup, R. T. Paine, a n d C. F. C a m p a n a , Phosphorus Sulfur, 1 9 8 1 , 9, 2 7 9 ; D. E. C o o n s , V. S. Allured, M . D. N o i r o t , K. C. Haltiwanger, and A. D. N o r m a n , Inorg. Chem., 1 9 8 2 , 2 1 , 1947. A . F. G r a p o v , L. V. Kazvodovskaya, a n d N . N . Mel'nikov, R i m . Chem. R e v . (Engl. Transl.), 1 9 8 1 , 50, 324. G . I. Bullen, J. Crysrallogr. Spectrosc. Res., 1982, 12, 1 1 . M . Yu. Antipin, Yu. T. S t r u c h k o v , V. M . Y u r c h e n k o , a n d E. S. Kozlov, Zh. Strukt. Khint., 1982, 2 3 , 7 2 . D. H. Brown, A . F. C a m e r o n , K. J. Cross, a n d M. McLaren, J. C h e m Soc., Dalron Trans., 1 9 8 1 , 1459. V. B. R y b a k o v , V. M . l o n o v , A. V. Mironov, a n d L. A. Aslanov, Zh. Strttkr. Khim.,

'"'

1981, 2 2 , 178. 250

*'I 252

M. K. Ross a n d J. C. Martin, ACS S y m p . Ser., 1981, 1 7 1 , 4 2 9 . M. R. Marre, J. F. Brazier, K . Wolf, a n d A . Klaebe, Phosphorus Sulfur, 1981, 1 1 , 8 7 . D. S c h o m b u r g , N. Weferling, a n d R. S c h m u t z l e r , J. Chem. Soc., Chem. Cotnmun., 1981,810.

''' M. Wieber, 0. Mulfinger, a n d H. Wunderlich, Z . Anorg. A&. 254

255

*"

Chem., 1 9 8 1 , 4 7 7 , 108. D. S c h o m b u r g , N . Weferling, a n d R . S c h m u t z l e r , J. Chem. SOC.,Chem. Commun., 1 9 8 1 , 6 0 9 ; N. Weferling, R. S c h m u t z l e r , a n d W. S. Sheldrick, Liebigs A n n . Chem., 1 9 8 2 , 167. H. W. Koesky, D. A m i r z a d e h - A d , a n d W. S. Sheldrick, J. A m . Chem. Sor., 1982, 1 0 4 , 2 9 1 9 ; J. E. Kichman, R. 0 . D a y , a n d K. R. Holmes, Inorg. Chem., 1981, 2 0 , 3378. R. R. H o l m e s a n d J . C. Gallucci, A C S Symp. Ser., 1981, 1 7 1 , 537.

325

Physical Methods

One very novel n6 compound that has been studied is a tris(trif1uoromethy1)phosphorane that contains a NN-dimethyl~arbamato-group.~~~ Flectron Diffraction,-The technique has been used t o show that bis(dimethy1phosphino)methane has a staggered conformation, with one of the P-C bonds of the PMe2 group anti t o the P-CH2 bond.258 The structure of trimethylphosphine-boron tribromide in the gas phase 259 and those of three fluorophosphoranes 260 have also been determined.

6 Dipole Moments and Kerr Effects The dipole moment of phosphine has been estimated from its Stark effect and its inversion dependence, studied using an ab initio SCF scheme.261The dipole moments of a variety of arylphosphines have been determined and the bond moments shown t o be non-additive when the phosphorus atom is unsymmetrically substituted.262 The dipole moment of vinyldifluorophosphane 169 has been calculated from its microwave data. The P-N bond moments in the phosphane (61) and its chalcogenides appear to be in the opposite direction to those in the corresponding acyclic compounds.263 MINDO/3 calculations of dipole moments have been compared with those obtained by using the MNDO method.264 Dipole moments have been used in the conformational analysis of the dioxaphosphepans (62; X = C1, EtO, or PhO) 265 and of some dialkyl phosphites.266 R

\ R

The conformational analyses of a variety of n 4 compounds have utilized dipole moments, frequently in combination with Kerr constants. In addition to the presentation of new data on mono- and di-arylphosphine

'" K . G. Cavell, K. I. The, and L. Van d e Griend, Inorg. Chem.,

1981, 20, 3 8 1 3 .

D. W. H. Rankin, H . E . Robertson, s n d H. H. Karsch, J. Mol. Strucr., 1981, 7 7 , 121. K. Iijima, E. Koshimizu, and S . Shibata, Bull. Chem. Soc. Jpn., 1981, 5 4 , 2 2 5 5 . 260 H . Oberhammer, J . Grobe, and D . Le Van, Inorg. Chem., 1982, 21, 2 7 5 . 261 . Scappini and R . Schwarz, C'hem. f h y s . Lett., 1981, 80. 3 5 0 ; V. Spirko and P. C a r s k y , J. Mol. Spectrosc., 1981, 87, 584. 2 6 2 F'. G. Khalitov and A . N . Vereshchagin, Zh. Ohshch. Khirn., 1981, 5 1 , 7 9 . 2 6 3 B. A . Arbuzov, R . P. Arshinova, D. W. White, and J. G. Verkade, Phosphorus Sulfur, 1 9 8 1 , 10,2 7 . "' G . Frenking, F. Marschner, and H . Goetz, Phosphorus Sulfur, 1 9 8 0 , 8 , 343. 2 6 s B. A . Arbuzov, K. A. Kadyrov, R. P. Arshinova, and N. A . Mukmeneva, Izv. A k a d . N a u k S S S R , Ser. Khim., 1 9 8 1,184. 2 b 6 V . V. Levin, V. L. Kadin, and K. M . Dzhamalov, Izv. A k a d . N a u k Uzb. S S R . Ser. Fiz.. Mat. Nauk, 1 9 8 1 , No. 2 , p. 9 0 . 2 6 7 S . B. Bulgarevich, L. V. Goncharova, P. N . Kozachenko, A . A. Shvets, and 0. A . O s i p o v , Z h . S t r u k t . Khim., 1 9 8 1 , 2 2 , 157.

25R

326

Organophosphorus Chemistry

the conformational analysis of the cyclohexane [63; Y = P h 2 P ( 0 ) ] , bearing two diphenylphosphoryl groups, has been reported.268Other conformational ~~~ vinylstudies concerned fluoroand s e l e n o - p h o ~ p h o r i n a n s , various phosphonyl compounds,270 methylphosphonyl d i f l ~ o r i d e , ’ ~butadienyl~ phosphonic acid,56 and an a z i r i d i n y l p h o s p h ~ n a t e .The ~ ~ ~conformations of a variety of silyl phosphates and t h i o p h ~ s p h a t e s , ’1581 ~ ~ ’159 together with those of some N-substituted d i o x a z a p h o ~ p h o c i n e s , have ~ ~ ~ been studied, using dipole moments in combination with vibrational spectra.

7 Values of pKa and Thermochemical and Kinetic Studies values have been calculated from measurements of Hammett UI and values o f p K a for the dialkylphosphinobenzoic acids (64). It has been suggested that the arylphosphines have the lone-pair of electrons in the plane

(64)

o f the benzene ring, i.e. negligible ,vn-pH conjugation.z73 This conclusion contrasts with that drawn from U.V.and I3C n.m.r. studies (see Section 4 of this chapter). It is reported that the proton affinities of phosphine, as calculated by the ab initio MQ method, agree with the experimental values.274 Measurements o f p Ka by voltammetry showed a cyanomethyltriphenylphosphonium salt to be a stronger acid than acetic The values o f p K a for some arylazophenacyltriphenylphosphonium bromides have also been reported.276N.m.r. studies of a Schiff base from fluorinated amino-acids and pyridoxal phosphate showed it to be very Avariety of phosphonic acids 278 have been studied and some fluoromethylene derivatives were found to have values of p K a in the region of those of phosphoric acids.279 26R

269

271

272

273

*” 2’6

’” 27R

A. P. Baranov, V. G. Dashevskii, T. Ya. Medved, G . Petov, E. I. Matrosov, a n d M. I. Kabachnik, Teor. Eksp. Khim., 1981, 17, 833. I. I . Patsanovskii, E. A. Ishmaeva, I. A . Nuretdinov, a n d A . N . Pudovik, I z v . Akad. N a u k S S S R , Ser. Khim., 1981, 230. I. A. Lapin, Yu. V. Kolodyazhnyi, E. F. Bugerenko, a n d 0. A . Osipov, Zh. Obshch. Khim., 1981, 51, 7 9 9 ; I . I. Patsanovskii, E. A . Ishmaeva, Ya. A . Levin, M . M. Gilyazov, a n d A. N . Pudovik, ibid., p. 985. N. G. Khusainova, 2 . A. Bredikhina, E. A . Ishmaeva, A. A . Musina, and A . N . Pudovik, Zh. Obshch. Khim., 1981, 51, 526. 1. I. Patsanovskii, E. A . Ishmaeva, V. M . D’yakov, A . B. Remizov, G. A. Kuznetsova, 1. M . Lazarev, M. G. Voronkov, a n d A. N. Pudovik, Zh. Obshch. Khim., 1981, 51, 980. E . N. Tsvetkov, I . G. Malakhova, a n d M . I. Kabachnik, Zh. Obshch. Khim., 1981, 51, 734. D. S. Marynick, J. Phys. Chem., 1981, 85, 3364. A . J . Bellamy a n d I. S. Mackirdy, J. Chem. Soc., Perkin Trans. 2, 1981, 1093. A . S. Shawali, A. 0. Abdelhamid, H. M. Hassaneen, a n d C . Parkanyi, Phosphorus Sulfur, 1982, 1 2 , 377. C. Beguin a n d S. H a m m a n , Org. Magn. Reson., 1981, 16, 129.

T. Ya. Medved, I. B. G o r y u n o v a , F. I. Bel’skii, a n d M. I . Kabachnik, Izv. Akad. Nauk S S S R , Ser. Khim.. 1981, 6 4 6 ; V. P. Vasil’ev, L. A . Kochergina, N . V. Morozova, a n d M. V. K u d o m i n o , Zh. Obshch. Khim., 1981, 51, 286; L. Maier, Phosphorus Sulfur, 1981, 11, 139; I. A. Kozanov, E. N. Beresnev, a n d M. A. Mop’eva, Zh. Neorg. K h i m . , 1981, 26,2424.

’’’ G. M . Blackburn a n d D. A. England, J. Chem. Soc., Chem. Commun.,

1981, 930.

321

Physical Methods

The heats of formation of a range of primary, secondary, and tertiary phosphines have been estimated, using hIIND0/3 and MNDO programs.'66 The redistribution equilibria of mixed phosphanes (65)-(67) or of analogous phosphoryl compounds can be predicted with the aid of a scheme for the decomposition of bond energies.280 Other studies have concerned the heats of neutralization of glycine bis(methy1enephosphonic acid),281 the heats of solution of cyclic and acyclic phosphonates,282 and the thermolysis of phosphonium halides 283 and phosphonous

The kinetics of exchange of protons between dithiophosphoric acids and acetic and thioacetic acids indicate that exchange proceeds through cyclic hydrogen-bonded complexes, in two steps.285The nucleophilicities of tertiary phosphines 286 and phosphites 287 have been studied and found t o relate t o the inductive effects of the phosphane, with steric influence varying according t o the nature of the electrophile.288 The rates of alkylation of anions of phosphorus acids with onium keten acetals have been determined and the rates shown t o be strongly dependent o n the nucleophilicity of the anion.289 The kinetics of a wide range of reactions have been recorded, many of which are reviewed in the earlier Chapters of this Report.

8 Chromatography and Surface Properties The intermolecular interactions of a wide variety of organophosphorus compounds with proton donors and proton acceptors have been studied with regard t o their applicability t o c h r o m a t ~ g r a p h y . ~ ~ ~ Gas-Liquid Chromatography.-The separation of trialkyl phosphates and dialkyl phosphonates has been d e ~ c r i b e d , ' ~ 'as has a method for the determination o f organophosphorus pesticides in onions.292

'" J. C. Elkaim and J . G. Riess, Tetrahedron, ''I

ZR2

1981, 37, 3203.

V. P. Vasil'ev, L. A . Kochergina, N. V. Morozova, M. V. Rudomino, and E. K. Kolova, Zh. Obshch. K h i m . , 1 9 8 1 , 51, 1557. V. V. Ovchinnikov, R. A . Cherkasov, and A. N. Pudovik, Dokl. Akad. Nauk S S S R , 1980, 255, 1169.

2R3

ZR4

R. Ferrillo and A. Granzou, Thermochim. Acta, 1 9 8 1 , 45, 177. N. A. Andreev and 0. N. Grishina, Zh. Obshch. Khim., 1981, 51, 1743.

'*'V. K. Pogorelyi and V. V. Turov, Teor. Eksp. Khim., 1981, 17, 6 2 8 . '*' Yu. G. Gololobov, L. Kasukhin, M. Ponomarchuk, T. Klepa, and R.

I . Yurchenko, PhosphomsSulfur, 1 9 8 1 , 10, 339. *" I. G. Maslennikov, A. N. Lavrent'ev, N. Yu. Kuz'mina, and L. N. Kirichenko, Zh. Obshch. Khim., 1 9 8 1 , 51, 1567. "* J . Koketsu and K. Kitaura, Chubu K o g y o Daigaku K i y o , A , 1 9 8 1 , 17, 7 3 (Chem. Abstr., 1 9 8 2 , 9 6 , 142 991). Z R 9 A. T. Zaslona and C. D. Hall, J . Chem. Soc., Perkin Trans. 1, 1 9 8 1 , 3059. 2 9 0 V. F. Novikov, S. Kh. Nurtdinov, and M. S . Vigdergauz, Zh. Obshch. K h i m . , 1 9 8 1 , 51, 5 7 9 . 291

292

B. R. Gandhe, P. Panday, R. K. Sharma, R. Vardyanathaswamy, and S . K. Shinde, J. Chromatogr., 1981, 219, 2 9 7 . Y. Iwata, A. Sugitani, and F. Yamada, Shokuhin Eiseigaku Zasshi, 1981, 22, 484 (Chem. Abstr., 1982, 9 6 , 1 2 0 995).

Organophosphorus Chemistry

328

Thin- Layer, Paper, and Gel C1iromatographies.-An improved developing agent for stable phosphate esters has additives of ascorbic acid and anthranilic acid.293 An extensive series of phosphoramidates and phosphorodiamidates has been separated by t . l . ~ . ’Paper ~ ~ chromatography 295 and gel chromahave also been recommended for the analysis of phosphate tography esters.

’’’

High-Performance Liquid Chromatography.-Monoand bis-phosphonium salts have been purified by preparative h.p.l.c., using a reversed-phase column.297 An off-line graphite furnace atomic absorption detector has been used in the analysis of phosphorus compounds.298 Phosphates can be handled by using an inductively coupled argon plasma atomic emission detector.299 Thiamine phosphates have been detected by fluorescence spectroscopy after their conversion into a thiochrome derivative by alkaline oxidation with cyanogen bromide.300 H.p.1.c. has also conveniently monitored the alkylation of a t h i o p h ~ s p h o n a t e . ~ ’ ~ Column Chromatography.-The separations of sugar phosphates,”’ nucleoside 5’- t r i p h ~ s p h a t e s , ~thiamine ’~ phosphate^,^^ and a dichloromethylenediphosphonate 30s have been described. Surface Properties.-The surface activities and micelle-forming properties of oxovinyltriethylammonium triphenylphosphonium dichlorides have been studied. ’06

293 294 295 296

297

B. R. Bochner, 1). M. Maron, and B. N. Ames,Anal. Eiochem., 1981, 117, 81. I. P. Titarenko, V. M. Ovrutskii, I. I. Kuz’menko, and L. D. Protsenko, Farm. Zh. (Kiev), 1981, 39. M. J.-U.-R. Umar, M. H. Khan, and M. Alam, J. Pharm. (Lahore), 1980, 2, 5; S. N . Ali,J. Chromatogr., 1 9 8 1 , 214, 111. K. Hirayanagi, S. Aoyagi, and T. Ishikawa, Kogakubu Kenkyu Hokoku (Chiba Daigaku), 1 9 8 1 , 33, 109. P. Jandik, U . Deschler, a n d H. Schmidbaur, Fresenius’ 2. Anal. Chem., 1981, 305, 347.

29R 299 300

P. Tittarelli and A. Mascherpa, Anal. Chem., 1 9 8 1 , 53, 1466. M. Morita and T. Uehiro, Anal. Chem., 1981, 53, 1997. K. Ishii, Hiroshima Daigaku Igaku Zasshi, 1981, 2, 7 7 7 (Chem. Abstr., 1982, 9 6 , 4 8 479).

301

T. Sjaus, S. Zupanc, and M. Cosic, Naucno-Teh. Pregl., 1980, 30, 7 7 (Chem. Abstr.,

301

A. Gascon. T. Wood. a n d L. Chitemerere. Anal. Biochem.. 1981. 118. 4. I. Kleinminn, V. SvAboda, a n d K. Mudra; Radioisotopy, 1980, 21, 7 9 7 . T. Matsuda a n d J. R. Cooper, Anal. Eiochem., 1 9 8 1 , 117, 203. T. L. Chester, E. C. Lewis, J . J . Benedict, R. J . Sunberg, a n d W. C. Tettenhorst, J. Chromatogr., 1981, 2 2 5 , 17. M. I. Shevchuk, V. P. Rudi, I. V. Megera, and F. A. Nadtochii, Zk. Obshch. Khim.,

1981, 9 5 , 9 6 501). ’03 304 ’05

’06

1981, 51, 1024.

Author Index

Aaron, H. S., 1 2 2 Abdelhamid, A. O., 23, 326 Abdel-Rassoul, A. A , , 9 4 Abdurashidova, G. G., 2 0 0 A b e , Y., 1 4 3 Abel, E. W., 307 Abicht, H.-P., 4 A b o , M., 1 9 1 Abraham, B., 2 9 1 Abramova, Z. A,, 3 0 1 Achakzi, D., 1 4 , 7 5 Adair, W. L. jun., 165 Adamiak. R. W.. 2 0 6 Adams, B. L., 2 2 2 Adams, D. L., 1 0 4 Addison, W. R., 2 2 0 Adler, L., 8 4 Adler, S., 1 8 7 Afanas'ev. M. M.. 1 4 6 Agafonov; S. V., ~ 1 2 3 Aganov, A. V., 310 Agawa, T., 1 0 7 , 1 2 9 Ainbinder, N. E., 3 1 4 Airoldi, C., 9 3 Akaiwa. H.. 9 3 A k h t a r , M., 2 6 0 Akiha, K.-Y., 9 8 , 9 9 , 130. 250.254 Aksenov, V. I., 3 0 0 Aksnes, G., 88, 1 5 3 Aktalay, Y., 5 , 7 0 , 321 Alam, M., 3 2 8 Alcarez, J.-M., 3 6 Alderfer, J . L., 2 2 8 Alderweireldt, F. C., 1 7 4 , 286 Alemagna, A,, 2 3 6 Aliev, 1. A., 309 Alikin, A. Yu., 1 5 0 , 1 5 1 Alipov, B. B., 3 0 4 Al-Jibori,S. 1 7 , 1 8 Al- Jumaliy, 197 Alkabets, R 4 7 , 72, 8 8 Alkema, D. ' 5 2 1 A l - K h a i d a r ' K h . Ya., 1 4 9 Allen, D. G:, 5 Allen, D. W., 8 4 , 31 1 Allen, F. S . , 2 3 0 Allman, T., 17 Allured, V . S . , 3 2 4 Alt, R., 2 4 7 Altenbach, H. J . , 1 5 0 , 2 5 0 Althoff, W., 312 Altona, C., 2 0 4 Alvarado- Urbina, ti., 2 0 9 Aly, H. F., 9 4 Ames, B. N . , 1 7 1 , 3 2 8 Amirzadeh-Ad, D., 52, 127, 321, 324 Amitai, G., 1 6 8 A m m a , J. P., 5 Anderson, R. L., 1 5 8

h'.,

Anderson, S., 2 19 Anderson, V., 1 6 0 Andreev, N. A., 327 Andreevskaya, 0. I., 1 Andriamizaka, J. D., 6, 310 Andrianov, V. G., 3 2 3 Andrutskii, L. G., 9 4 Angelov, Kh., 1 5 0 Angenault, J., 8 A n n a n , N . D., 2 1 8 Ansari, A. A , , 1 8 3 Antczak, K., 1 3 5 Antipin, M. Y u . , 3 2 2 , 3; !3, 324 Anufrieva, T. V., 1 3 2 Aoki, T., 9 4 Aoyagi, S., 3 2 8 Aovama. T.. 31 1 Apbel, R . , i 4 , 2 8 , 2 9 , 30, 31, 62, 63, 71, 75, 107, 112, 118, 233, 306, 707

Araki,'S., 1 4 3 Arbuzov, B. A., 35, 1 1 4 , 1 2 6 , 310, 3 2 0 , 3 2 2 , 324, 325 Archer, S. J., 321 Arduengo, A. J . tert., 5 2 , 66, 102 Argent, P. J., 3 1 6 Arigoni, D., 161 Armbruster, M. A., 2 8 4 Armour, M. A., 31 3 Arpino, P. J., 2 8 3 Arrieta, A , , 1 4 3 Arshinova, R. P., 3 1 4 , 320, 32 5 Artas. M.. 7 5 Asato, A.'E., 2 6 0 Ash. D. E.. 192. 1 9 3 Ashhni, Y., 1 6 8 Ashe, A. J. tert., 3 6 Aslanov, L. A , , 3 2 4 Assaf, Y., 1 5 Asseline, U., 2 0 4 Atkins, R. K., 3 1 8 Atkinson, T. C., 2 0 9 Atovmyan, L. O., 322 A t t o n , J. G., 12 Augustyniak, J., 2 2 7 Aultman, K. S., 2 2 1 Avaeva, S. M., 1 7 0 Avigad, G., 1 5 8 Axelrad, G., 9 8 Ayed, N . , 35 Azuhata, T., 131

~.

Baackr, M., 7 Baboulene, M., 1 4 6 Baccolini, G., 1 5 Baceiredo, A , , 8 1 Bachmann, P., 321

3 29

Badanyan, Sh. O., 1 5 0 Badel, B., 1 2 4 Badesha, S. S., 1 4 3 Baalioni. C.. 2 1 9 Bahr, U.; 2 9 5 Baier, H., 6 5 , 3 1 6 , 319 Bailar, J . C., 5 Baird, M. C., 18 Bak, B., 6 1 , 3 1 8 Baker, G. L., 5 Baker, K. M., 2 8 4 Baker, R., 2 4 9 Baker, S. R., 2 5 0 Bakhitov, M. I., 1 3 7 , 3 1 6 Bakos, J., 5 , 122 Balasubramanian, K., 1 5 9 Baldwin, M. A,, 3 0 3 Balgobin, N., 2 0 6 , 2 0 8 Balitskii, Y u . V., 3 2 3 Ballistreri, A , , 3 0 3 Baltzinger, M., 1 9 7 Banek, M., 1 2 7 , 32 1 Banks, B. E. C., 1 9 3 Bantick, J. R., 2 6 3 Baraldi, P. G., 2 6 9 Baraniak, J., 1 8 1 , 1 8 2 Baranov, A. P., 8 4 , 326 Baranov, G. M., 1 4 9 , 3 1 3 Baranskii, V . A , , 1 2 3 Barber, J . J . , 1 5 8 Barber, M . , 2 8 2 , 2 8 9 Barco. A,. 2 6 9 Bardos, T: J., 1 7 5 Barieux, J.-J., 1 6 Barker, R., 162 Barr, P. J., 179 Barrau, J., 1 6 Barrett, A. G. M . , 2 4 0 Barrett, M., 1 7 Barry, C. N., 13, 7 6 Barth, V., 2 9 , 3 0 6 Barthelat, M., 3 1 8 Bartoli, G., 15 Barton. D. H. R.. 1 5 . 271 Bartonicek, F., 2'98 ' Bartsch, R . , 7, 2 3 , 4 1 , 7 2 , 7 5 . 312 Bartuska, V . J., 3 0 8 BBrzu, O., 1 9 5 Basha, F'. Z., 2 7 6 Batchelor, R., 3 0 6 Batrakov, S. G., 2 8 3 Batyeva, E. S., 1 4 6 Baudler, M., 5 , 6 , 9 , 1 0 , 1 2 , 60, 7 0 , 7 1 , 306, 3 1 2 , 321 Bauer, G., 2 9 7 Baumstark, A. L., 1 7 , 4 4 Baxtrr, S. G., 32 Baykov, A. A,, 1 7 0 Bayley, P. M., 196 Bazhenov, B. N . , 1 5 3 Beauliru, P. L., 145

330

Author Index

Beavo, J . A., 1 8 4 Bechtolsheirner, H.-H., 2 7 Becker, G., 30, 7 1 , 306, 310, 3 1 8 Beckey, H. D. 2 8 5 , 2 9 0 Beechey, R. B:, 1 9 6 Beeny, M . T., 1 3 3 Beer, P. D., 1 1 Begley M. J., 2 5 4 Beguin: C., 3 2 6 Begunov, A. V., 1 5 3 Behmooras, T., 2 2 6 Beigelman, L. N., 2 1 1 Bekasi, G., 2 9 8 Belgacem, B., 3 5 Bellarnv. A. 1.. 26. 311. 326 ’ Bellville, D. J., 3 6 Belov, S. P., 3 1 8 Bel’skii, F. I., 3 2 6 Belyalov, R. U., 6 8 , 8 8 , 153 Bender, R., 2 0 9 Benedict, J. J., 305, 3 2 8 Benetti, S., 2 6 9 Benhammou, M., 1 2 9 Benkovic, S. J., 1 6 7 , 1 8 7 , 193,219 Benn, R., 3 6 Benner, S. A , , 1 5 5 Benninghoven, A , , 2 8 2 Bentrude, W. G., 1 1 9 , 1 8 0 , 314 Benveniske, J., 2 8 8 Berckmans, D., 3 1 6 Berdnikov, E. A,, 1 9 , 3 15 Beres, J., 1 8 2 Beresnev, E. N., 3 2 6 Beresten, S. F., 222 Berestovitskaya, V. M., 1 5 1 , 301 Bergel’son, L. D., 2 8 3 Berger, S., 3 6 , 3 1 3 Bergeson, K., 3 1 3 Bergstein, W., 5 Berkova, G. A , , 1 5 1 , 3 1 0 , 313 Berkovec, A. B., 1 4 7 Berkowitz, G. A , , 1 7 5 Berkowitz, W. F., 2 6 9 Berlin, K. D., 1 9 , 81, 314, 319, 321 Berrnan, S. T., 2 3 Berndt, K. G., 8 4 , 3 1 9 Berson, J. A , , 2 5 1 Bertozzi, S., 4 Bertrand, G., 8 1 Bertz, S. H., 7 7 , 1 0 0 Bespal’ko, G. K., 6 0 Bessel, E. M., 2 9 0 Bessman, M. J . , 2 1 8 Bestmann, H. J., 2 3 8 , 2 4 0 , 2 4 7 . 2 6 6 . 2 6 8 . 321 Beth, A,,1 5 9 ’ Beynon, J. H., 2 8 3 Bhatia, M. S.. 2 9 7 Bhatt, R., 2 0 7 Bhatt, R. S., 179 Bhattacharya, A. K., 9 5 Bianchini, C., 21, 321 Biciunas, K. P., 2 4 8 Bickelhaupt, F., 28, 2 9 , 236, 3 0 3 I

,

Bieger, W., 3 1 3 Biellmann, J. F., 1 5 8 , 1 5 9 Biernat, J., 2 2 0 Bigge, C. F., 2 2 1 Binsch, G., 2 , 3 1 0 Biosca, J. A., 1 8 2 Birchall. T.. 3 0 6 Bittner,’S., ‘1 5 Black, A. Y., 2 7 2 Blackburn. G. M.. 130. 166, 185, 326 Blackmore, P. F., 1 5 8 Blake, A. J., 8 3 , 8 4 , 3 1 6 Blakley, C. R., 2 8 3 Bland, J. L., 2 2 9 Blank, K., 3 2 2 Blanquet, S., 1 9 0 Blau, H., 322 Blizzard, T. A., 2 7 6 Blonski, C., 1 4 8 Bloxsidae. J. P.. 3 0 8 Blum, l%,’136 ’ Bobenrieth, M. J . , 2 8 4 Bobrova. 0. B.. 9 5 Bobst, A. M., 2 1 6 Bochkarev, V. N., 3 0 0 Bochkarev. Yu. A.. 1 6 Bochner, B. R., 17’1, 3 2 8 Bock, H., 8 9 , 315 Bock, P. L., 3 1 8 Bodalski, R., 1 5 4 Boehrn, M. C., 3 2 0 Boerboorn, A. J . H., 2 8 5 Boesterlinn. B.. 289 Boettcher,-B., 1 9 7 Bogdanov, A. A,, 2 2 1 , 2 2 2 Bogdanovic. B.. 2 3 5 Bodel’fer, L. Ya., 1 4 2 , 1 4 8 Bohlmann, F., 2 7 2 Bohmer, W. E., 32 1 Boicelli, C. A., 3 1 4 Boisdon. M. T.. 35. 11 5 Bojesen,’G., 2 8 6 Bokadia, M. M., 1 4 , 2 4 5 Bokanov. A. I., 8 3 Boland W., 2 7 4 B o l d e s h , I. E., 7 0 Boleslawska, T., 1 5 Bolton P. H., 3 0 8 Bonda; V . A , , 7 0 Bondarknko, N . A., 3 2 2 Bonnard, H., 33. 3 4 Boos, K. S., 1 9 5 Bordoli R. S., 2 8 2 , 2 8 9 Borisenko, A. A., 30, 1 1 8 , 306 Borisov, E. V., 3 2 0 Borisov G., 1 1 1 Borisov;, E. E 4 8 Bornemann, S:: 1 9 0 Bornstein, P., 1 6 8 Borsch, G., 3 1 6 Boschetti, E., 2 2 9 Bose, A. K., 2 8 1 Bosyakov, Yu. G., 3 0 1 Botha, C., 2 2 Botz, F. K., 2 8 6 Bouissou, T., 3 1 7 Boulangar, Y., 1 9 7 Boutevin, B., 9 5 Bowen J . M., 8 1 Bowie,’J. H., 2 9 3 Boyd, V. L., 1 6 3 I

I

Boyer, M., 315 Bradburv. R. H.. 2 4 4 Bradley,-C., 286’ Brand, J. C., 4 5 , 315 Brand. W. W.. 1 2 5 Brandks, S. J.’, 9 0 Brandi, A., 3 5 , 1 1 4 Brandstetter, H. H., I S Brandt, C. A., 2 5 3 Brandwein, H. J., 1 9 4 Brauer, M., 2 2 8 Braun, U., 3 2 2 Brautigan, D. L., 1 6 8 Brazier, J. F., 52, 110, 320, 324 Bredikhina, Z. A., 149. 326 Brems, D. N., 1 6 9 Brennan. C. A.. 2 1 6 Brent, D: A., 2 8 6 , 2 9 0 Breque, A,, 3 3 , 3 6 , 6 3 Breuer. E.. 1 5 4 . 2 5 4 Brevet,’A.; 1 9 7 ’ Bridger, W. A , , 2 2 7 Bridson. P. K.. 2 1 3 Briggs, J. C., 8 , 3 0 0 Brimacornbe, R., 1 9 9 Brion, F., 2 5 6 Britelli, D. R., 9 5 , 2 4 3 Brody R. S. 1 8 7 Broekhof, N’. L. J. M., 9 1 , 252 Brooks, C. J . W., 2 8 9 Brossas, J., 3 1 4 Brousseau, R., 2 8 6 Brown, D. H., 8 3 , 3 2 4 Brown, J. M., 4 , 3 1 9 Brown, P., 2 8 4 Brown, R. D., 31 8 Brown, S. B., 4 , 3 2 0 Bruce, A. G., 2 2 4 Brugidon, J., 2 7 0 Bruins, A. P., 2 8 3 Bruist, M. F., 1 9 7 Bruncks, N., 16, 310, 321 Brunden, M. J., 2 1 1 Bruneger, E., 1 6 9 Brunner, H., 9 , 7 1 Bruzik, K., 4 1 , 1 6 4 Bryant, D. R., 1 7 Bryant, F. R., 1 8 7 Bubnov, N . N., 3 1 5 , 3 1 6 Buchholz, E., 9 7 Buchner, W., 6 5 , 8 0 , 312 Buchwald, S. L., 1 4 4 , 1 4 5 , 167 Buck, H. M., 3 1 5 , 3 2 3 Buckingham, D. A., 1 4 4 Bucknel, W., 161 Budowsky, E. I., 2 0 0 Budzikiewicz, H., 2 8 5 , ~

286

Biichi,-G., 2 0 9 Biildt, G., 1 6 5 Buergi, H. B., 3 1 1 Buaarenko. E. F.. 300. -318, 3 2 6 Bulgarevich, S. B., 325 Bullen. G. J.. 3 2 4 Buneva, V . N., 1 9 9 Bunton, C. A,, 1 4 4 , 1 6 9 Buono, G., 31 1 Burashkina, N . I., 1 3 7

Author Index Burckett-St Laurent, J. C. T. R.. 29. 3 1 8 Burenin’A. V., 3 1 8 Burford: N., 3 13, 322 Burg, A. B., 2 9 , 312 Burgada, R., 4 8 , 5 6 , 9 9 , 314 Burgard, D. R., 2 8 4 Burilov, A. R., 1 4 7 Burke, M., 1 8 4 Burkhard, A., 1 9 8 Burlingame, A. L., 2 8 3 Burmester, A., 315 Burnaeva, L. A., 4 5 , 128, 132,138 Burnett, R. M., 1 6 0 Burrow, P. D., 36 Bursey, M. M., 2 9 0 , 291 Burt, C. T., 227 Burton, D. J., 2 5 , 1 3 0 Burzlaff, H., 32 1 Busch, K. L., 291 Butin, B. M., 301 Butorin, A. S., 221 Butsugan, Y., 1 4 3 Buttars, T., 8 0 Buttero, P. D., 2 3 6 Butters, T., 1 1 Bystrov, L. V., 3 1 0 Cabr&Castellvi, J., 1 4 3 Cadogan, J. I. G., 54, 8 7 Calabrese, J. C., 6 , 310 Calas, R., 8 Cambon, A , , 3 0 3 Cameron, A. F., 8 3 , 322, 324 Cameron, A. G., 2 6 , 2 7 0 Campana, C. F., 3 2 4 Canevet, J. C., 2 5 3 Cao, K.-X.,285 Cappuccino, N. F., 2 8 1 Capriel, P., 2 , 310 Caprioli, R. M., 2 8 3 Capuano, L.,2 4 6 Caras, I. W., 2 0 0 Carlson, G . M., 197 Carmody, J. J., 2 8 3 Carpenter, L. E. sec., 324 Carr, M. C., 1 2 5 Carr S. A , , 2 8 0 C a r r k , R., 3 5 , 1 1 4 Carsky, P., 325 Carter, J. B., 2 7 6 Carter Cook, I . jun., 302 Carty, A. J., 1 8 Caruthers, M. H., 204, 209 Carver, D. R., 2 5 Casida, 5 . E., 1 4 5 , 279 Caskey, C. T., 1 8 4 Castell, J. V., 1 9 0 Catlow, D. A., 2 8 8 Cauquis, G., 300 Cava, M. P., 1 5 5 Cavell, R. G., 5 8 , 325 Cayley, P. J., 2 1 9 Celewicz, L., 2 12 Cerny, M., 3 Cetinkaya, B., 2 8 , 1 1 8 Chabaud, B., 2 2 Chabrier, P., 2 0 4 Chagas, A. P., 9 3 Chait, B. T., 2 8 2

331 Chakhmakhcheva, 0. G., 208 Chakraburtty, K., 2 0 0 Champoux, J. J., 168 Chan, L., 1 8 4 Chandrakumar, N. S., 1 6 3 Chang, C.-D., 191 Chang C. T.-C. 179 Chang: G.-G., 1$7 Chang, L., 3 1 8 Chang, L.-H., 2 8 5 Chang, S. H., 221 Chang, T. C. T., 5 6 Chanon, M., 1 0 Charlier, J., 1 9 5 Charrier, C., 34, 8 7 , 3 2 0 Cha;ybala, R., 1 7 2 , 203, L11

Chassignol, M., 2 0 4 Chattopadhyaya, J. B., 179,206,208 Chauvin, Y., 3 Chauzov, V. A., 18, 8 4 , 123 Chawla, R. R., 191 Chayet, L., 1 6 9 Chebyshev, A. V., 2 8 7 Chen, C. H., 2 0 Chene, A., 2 2 Cheng, D. M., 2 2 8 Cheng, Y.-C., 1 9 5 Cherkasov, R. A., 1d.0, 3 2 7 Cherkasova, 0. A., 129 Cherkina, M. V., 4 5 , 1 2 8 , 138

Chernokal’skii, B. D., 5 6 Chernov, P. P., 31 1 Chernukho, N. P., 7 0 Chernyshev, E. A , , 300 Chernyuk, I. N., 2 6 Chervin, I. I., 310 Chester, T. L., 3 2 8 Chichkova, N . V., 221 Chihaoui, M., 3 1 7 Chimitova T. A , , 199 Chin, N . Y’., 167 Chitemerere, L., 1 6 1 , 328 Chivers T 3 1 3 322 C h l a d e i S : , 2 1; Chmutoba, M. K., 7 8 , 84, 94 Choi, H. S., 12 Clioudry S. C., 269 Chow F’ 2 0 9 Chow’ K‘.’K. 300 Chrisdpe, D.’R., 4 4 Christensen, A., 2 2 1 Christenson, J. R., 2 Christol H. 2 2 , 2 6 Chuang.’D. ?.. 1 6 0 Chu-Chi Tang, 1 2 6 Chudakova, T. I . , 1 4 8 Ciabatti, R., 269 Ciampi, M. S., 2 1 9 Ciampolini, M., 4 Ciesiolka, J., 2 2 0 Clardy, J. C., 312 Clark, C. R., 1 4 4 Clark, P. W., 4 , 314 Clark T 2 1 Claus’ T:’H., 1 5 8 Claytbn, D. A., 2 3 0 Cleaver, J. E., 2 2 6

Clegg, R. M., 1 9 0 Clegg, W., 10 Clennan, E. L., 17 Clertant, P., 197 Clive, D. L. J., 1 4 5 Cload, P. A , , 292 Clothier, B., 1 6 8 Clough, J. M., 9 1 , 2 5 8 Clough, W., 1 6 6 , 2 1 8 Cloyd, J. C. jun., 299 Codding, P. W., 322 Coderre, J. A , , 309 Coffman, D. S., 1 9 7 Cohen, S., 1 6 8 C o h n , M., 1 9 3 Coleman, J. E., 229 Coleman, P. S., 1 9 7 Colle, K. S., 2 7 , 9 7 Collignon, N., 1 3 5 Collins, D. J., 1 3 8 Collins, P. M., 2 5 6 Colton, F. A., 320 Colvin, E. W., 251 Colvin, 0. M., 1 7 9 Comasseto, J . V., 2 5 3 Comisso, G., 3 Commereuc, D., 3 Conner, B. N., 227 Connor, J. A., 9 8 , 1 2 9 Connolly, B. A., 1 8 6 , 1 8 8 , 192 Conrad, H., 306 Constantin, E., 2 8 0 Conti, F., 314 Cc,itreras, R., 4 1 Cooke, M. jun., 2 4 8 Cooks, R. G., 2 8 3 , 302 Cooney, C. L., 1 5 8 Cooney, J. V., 2 6 , 2 4 5 Coons, D. E., 324 Cooper, J. R., 3 2 8 Cooper, K., 2 5 4 Cooperman, B. S., 167 Cordes, A. W., 31 3 Corey, E. J., 1 0 5 , 2 6 2 , 2 6 6 Cori, O., 169 Corkins, H. G., 1 4 5 Cornforth, J. W., 1 6 1 Cornish- Bowden, A., 189 Corriu, R. J. P., 145 Cortese, R., 2 19 Cosic, M., 3 2 8 Costa, T., 2 , 2 2 , 2 3 1 , 232, 322 Costisella, B., 6 9 , 1 3 7 C o t t o n , F. A., 8 3 Couret, C., 6 , 1 6 , 310 Couturier, J.-C., 8 Cowley, A. H., 3 2 , 6 2 , 1 1 2 , 1 1 7 , 306 C o x , M. M., 1 8 5 COX, R. A., 217 Cramer, F. 1 9 5 Crathorn, R., 2 2 4 Cremer, S. E., 1 9 , 83, 310, 322 Crenshaw, M. D., 3 2 3 Cristau, H. J., 2 2 , 2 6 Cristol, H., 2 7 0 Cross, D. J., 9 5 Cross R. J. 8 3 324 Croudh, R. k.,i 6 0 Crow, F. W., 2 8 0

A.

332 C r o w t h e r , J . B., 2 2 9 Cuchillo, C., 2 8 4 Cuchillo, C. M., 1 8 2 Cullis, P. M., 1 2 5 , 1 6 7 , 188, 189 C u m m i n g , D. A , , 1 5 8 C u m m i n s , C., 1 3 2 Curran, D. P., 2 4 3 C u t b u s h , S. D., 3 2 4 Cuzin, F., 1 9 7 C z a r n i k , A . W., 1 9 1 Dabbagh, G., 7 7 , 1 0 0 Dahl, B. M., 5 2 , 1 2 1 , 3 1 4 Dahl. 0.. 3 1 . 5 2 . 1 1 7 . 1 2 0 . 121, 314,’316 Dahlquist, F. W., 2 6 0 Dalziel, J. R., 7 D a m e , J . B., 1 6 8 Damrauer. R.. 2 7 Danenberg, K:, 1 7 9 Danenberg, P. V., 1 7 9 Dangyan, Y u . M., 1 5 0 Daniels, L., 1 5 8 Danilov, L. L., 1 6 2 Danilyuk N . K., 2 2 2 Dankowski, M., 9 D a n n a , K. J., 2 2 9 D a p p o r t o , P., 4 Darensbourg, D. J., 8 3 , 320 Darling, G . D., 1 6 0 Darling, S. D., 2 , 6 4 , 7 7 , 90 Das, B. C., 2 8 8 Dashevskii, V. G., 8 4 , 3 2 6 Daskalov, H. P., 2 0 5 Daves, G . D. jun., 2 8 0 David, S., 1 3 , 7 6 , 1 7 4 Davies, A. G., 3 1 5 Davies, D. R . , 1 5 8 Davis, R. E., 4 , 3 2 0 Day, R. O., 3 9 , 4 1 , 3 2 4 Deaciuc, I. V . , 1 9 5 Dean, P. A. W., 9 3 De Bernardini, S., 2 0 3 Declerc, J. P., 1 4 8 De Clercq, E., I 6 6 , 2 1 6 De G o o y e r , W. J., 1 6 0 Degtyarev, A. N., 31 5 d e Haas. G. H.. 1 6 5 Dei, A.,’4 Deiters, J. A., 3 9 de l o n g , E. W. P., 1 9 0 Dekker, C. A , , 1 7 8 De Kruijff, B., 1 6 5 d e L a u z o n , G., 3 4 Deleris, G., 8 d e Maine, M. M., 1 6 7 De March, P., 2 1 , 2 4 0 DBmarcq, M. C., 1 6 , 12 1 D e m a y , C., 31 1 D e m b e k , P., 2 1 9 Demidova, N . I., 8 3 D e m o u , P. C., 2 2 8 , 3 0 9 Deng, G., 2 1 7 Deng, R . M . K., 3 0 6 den Hartog, J . A . J., 1 4 2 , 173, 1 9 0 , 2 0 6 , 2 2 7 Denis0v.A. Yu.. 1 9 1 Denisov; G. S., 3 1 0 D e n n e y , D. B., 4 2 , 4 3 , 107, 313

Author Index D e n n e y , D. Z., 4 2 , 4 3 , 1 0 7 , 31 3 Dennis, E. A., 1 6 5 Dennis, L. W . , 3 0 8 D e n n v . M.. 2 6 0 Depn;;, J.,’ 2 6 9 De-Queiroz, J. C., 9 3 Derse, D., 1 9 5 De R u i t e r , B., 3 0 9 De Sarlo, F., 3 5 , 1 1 4 Deschamps, B., 3 5 , 3 2 2 Deschler, U., 2 2 , 2 3 3 , 2 3 4 , 236, 310, 322, 328 Descotes, G., 3 d e S e n n y e y , G., 1 3 , 7 6 , 174 Desmarchelier, J . M., 2 7 9 De S t e f a n o , A. H., 2 7 9 , 288 Devanesan, P. D., 2 1 6 Devillers, J. R., 3 9 de Wit, R. J. W., 1 8 2 Dianova, E. N., 3 5 , 1 1 4 Dickert, F. L., 3 0 5 Di Cosimo, R., 1 5 8 Didkovskii, V. E., 3 2 2 Diel, B. N., 6 , 3 1 4 Dietz, S., 317 Dillon, K. B., 9 2 , 3 0 6 D i m k e , B., 1 9 5 D i m r o t h . K.. 36. 3 1 3 . 3 1 5 . 320 Ding, C., 1 7 8 Ding, W., 3 2 0 Disselnkotter, H . , 2 6 9 Dittrich, R., 1 3 0 , 3 1 2 Di Verdi, J. A , , 2 2 9 Divisia, B., 3 0 0 D i x o n , D. A , , 3 1 0 Djarrah, H., 5 2 , 3 1 2 Djerassi, C., 2 8 3 Dmitriev, V . E., 3 0 9 Dmitriev, V. I., 3 9 , 3 0 9 , 314, 319 Dmitriev, V . K., 39 Dmitrieva, N . V., 1 2 9 Dobrikova, E. Y u . , 199 Dobrowolski, J., 1 2 4 Dodin. G.. 1 8 4 Dobler, C . , 5 Doi, T , , 2 0 9 D o l e n k o , G . N., 1, 1 3 9 , ,

I

,

Drygala, P. F., 1 3 8 D u b c h e n k o , T. N., 1 4 9 D u b e n k o , L. G . , 3 1 4 Dubowski, D., 9 8 , 1 2 9 D u c k , P. D., 2 0 9 Duda, U. M., 3 0 0 Durr, H., 1 1 D u f f a u t . N.. 8 Duffy, T. H:, 1 6 0 Duhl-Eniswiler, B. A., 2 3 8 Uuker. N.. 2 2 6 D u m a n , H’. V., 31 5 D u m m e r , R. E., 3 0 3 d u Mont. W.-W.., 1 6 ., 310.. 32 1 Dunaway-Mariano, D., 1 6 7 Duncan. M.. 3 0 7 Duncanson, F. D., 3 2 2 Dunogues, J., 8 Duri, J. Z., 1 3 , 7 5 Durig, J. R., 3 1 6 , 3 1 8 Dutasta, J. P., 1 1 1 Duthell, J. P., 1 4 5 Dvoinnikova, T. A , , 1 3 9 Dworskv. A , . 1 9 8 D’yako;,’V. M., 3 2 6 Dyer, G., 8 , 3 0 0 Dylla, M. E., 9 , 7 1 Dzhamalov, R . M., 3 2 5 Dzhemilev, U. M., 2 9 8

,

32 3

D o l i i n a y a , N . G., 2 1 3 Domagala, A , , 3 1 0 D o m d e v . H.. 2 1 7 D o n n e l i y , M: I., 1 6 9 D o n o h u e , J., 3 2 3 D o n s k i k h , V . I., 3 9 , 7 4 , 129. Doroshkina, G . M., 6 5 D o u g h e r t y , R. C., 2 8 1 , 2 9 3 Dougherty, T. M . , 1 6 0 Dousse, G., 1 6 D o u t h w a i t e , S., 2 2 1 D o z y , A. M., 2 1 9 Dickerman, H. W., 1 8 5 Dickerson. R. E.. 2 2 7 Drager, M.’, 9 ’ Drake, A. F.,1 7 9 Drew, H. R., 2 2 7 Drozdova, L. I., 2 0 7 Drutsa, V . L., 2 1 3

Ebel, J.-P., 1 9 9 , 2 2 1 Ebel, R. E., 1 5 9 Eberspach, W., 9 7 E b r e y , T. G., 2 6 0 Eccleston, J . F., 1 8 9 . 1 9 2 . 2 30 Eckert. J.. 1 4 2 . 1 7 3 Eckert:Maksic,’M., 3 2 0 Eckes, H., 8 7 , 3 2 2 Eckstein, E . , 1 8 6 , 1 87 , 188, 1 9 2 , 2 1 8 , 2 1 9 E d e l m a n n , K., 1 9 5 Edge, M. D., 2 0 9 E d m o n d s , M., 185 E d m o n d s o n , D. E., 1 6 0 E d m u n d s o n , R. S., 2 9 5 Efimov, V. A , , 2 0 8 Efremov, D. A., 1 5 1 , 3 1 0 Eeeerer. H.. 1 6 1 Egry, J.:M.,’ 2 2 9 Egorov, Y u . P., 3 0 7 , 31 7 , *-.. JLL

E h r e s m a n n , B., 1 9 9 Eicke, A , , 2 8 2 Eigel, A , , 2 2 9 Eiki, T., 1 5 3 Einck, J . I., 2 8 4 Ejchart, A., 3 1 4 E k b o r g , G., 1 7 8 El-Deek, M., 3 0 3 Elder. R . C.. 2 5 2 . 3 2 3 Elion; G. B.; 1 9 5 ’ Eliseeva, G. I . , 1 6 2 Elkaim, J.-C.. 6 9 . 1 3 9 , 327 El Khatib, F., 1 0 7 El Khoshnieh, Y. 0 . , 4 8 , 9 9 Ellermann, J., 3 1 6 El-Maghrabi, M. K., 1 5 8 Elmblad, A,, 2 0 9 EI’Natanov, Yu., 2 9 9 , 3 1 0 Elvidge, J. A , , 3 0 8 Engel, R., 9 8

Author Index Engelmann, M., 3 0 6 Engels, J., 1 7 3 , 2 0 8 England, D. A , , 130, 1 6 6 , 32 6 Enoki, Y., 1 7 9 Enquist, J., 2 9 8 Ens, W., 2 8 2 , 2 8 6 Erastov, 0. A., 313, 3 2 0 , 322 Eriksson, B., 1 6 6 Eriksson, S., 2 0 0 Ermolaeva, L. V., 3 2 0 Ernst, B., 2 3 9 Ernst, I., 2 6 3 Ernst, L., 1 8 0 , 2 6 0 Ertas, M., 1 4 EscudiB, J., 6 , 3 1 0 Eshtiagh-Hosseini, H., 3 12 Esmans, E. L., 1 7 4 , 2 8 6 Espenbetov, A. A., 322 Essigmann, J . M., 2 0 9 Etienne, M., 2 9 4 E t o , M., 2 9 3 Ettlinger, M., 2 3 8 Evans, E. A , , 3 0 8 Evans, J. C., 31 5 Evans, S., 2 8 3 Evans, S. A., 1 3 , 7 6 Evstigneeva, R. P., 2 8 7 E x t o n , J . H., 1 5 8 Fabre, G., 1 3 5 Fakhrai, H., 2 1 2 Fankhauser, H., 1 7 5 Fasiolo, F., 1 9 7 Fatti, G., 4 Favara, D., 2 6 9 Favilla, R., 1 9 6 Fazliev, D. F., 3 1 8 Fedorova, G. K., 1 3 4 Feigon, J., 2 2 8 Feist, P. L., 2 2 9 Feistner, G., 2 8 5 , 2 8 6 Felix, R., 1 6 6 Fenn, R. H., 3 2 3 Fenselau, C. C., 1 7 9 Ferer, M., 3 2 1 Ferreira, S. A., 2 3 0 Ferrillo, R., 327 Ferrillo, R. G., 2 7 Feshchenko, N. G., 4 2 , 7 0 , 134 Fewster, P. F., 3 2 3 Field, F. H., 2 7 9 , 2 8 2 Figey H. P., 316 Fild, M., 2 9 7 , 312 Filipowicz, W., 2 17 Filippova, A. Kh., 1 2 9 Finch, A., 3 9 , 7 3 Finn, C., 2 8 4 Finzenhagen, M., 9 2 , 319 Fischer, E., 31 1 Fischer, J., 3 4 , 3 5 , 8 7 , 322 Fisher, T. L., 2 9 6 Fitts, S. W., 1 6 7 Flay, R. B., 2 4 , 5 2 , 312 Fleisch, H., 1 6 6 Flitsch, W., 2 4 7 Flockerzi, D., 2 0 3 Floyd, D. M., 2 7 6 Fluck, E., 9 , 2 8 , 1 1 2 , 306, 32 1 Fluharty, A. L., 1 6 3

333 Flynn, R. M., 2 5 , 1 3 0 Farster, H., 29 Fong, G. D., 6 1 , 3 1 8 Font, J.,21,240 F o n t Friede, J. J. H. M., 59 Ford, W. T., 27 Foss, V. L., 309 Fossel, E. T., 1 6 8 Foster, A. B., 2 9 0 Foti, S., 3 0 3 Foucaud, A., 12, 1 0 1 , 107 Foucaud, B., 1 5 9 Fowler, K. W., 2 0 9 Fraga, B. M., 1 3 , 7 5 Fraij, B., 1 6 9 Frank, A. W., 2 6 Frank, R., 2 2 0 Frank, R. W., 2 4 1 Franks, S., 8 4 , 2 9 9 Franzen, D., 1 8 0 , 2 1 4 Franzus, B., 13, 7 6 Fraser-Reid, B., 2 5 6 Fratini, A. V., 2 2 7 Fredrich, M. F., 8 3 , 3 2 0 Freedman, L. D., 1 Freeman, H. S., 1 Freeman, J. P., 1 0 4 Freist, W., 195 Frenking, G., 325 Frew, A. A , , 2 8 Frey, P. A., 1 2 3 , 1 6 7 , 1 8 6 , 187, 188 Freyne, E. J., 1 7 4 , 2 8 6 Fridland, S. V., 1 2 9 Friebe, S., 9 Friedman, S. L., 1 7 9 Friedrich, K., 1 0 4 Fritz, A. W., 2 7 6 Fritz, G., 322 Fritz, H., 2 4 3 Fritschel, S. J., 5 Fritszsche, T. M., 1 5 9 , 191 Frohlich, R., 3 2 1 Fuldner, H. H., 1 8 8 , 2 2 9 Furstenburg, G., 1 0 Fujimoto, M., 1 7 2 Fujiwa, T., 1 4 3 Fujiwara, H., 2 8 1 Fukuhara, N., 2 9 3 Fukui, T., 1 6 2 , 2 1 4 F u k u m o t o , R., 209 F u k u t o , T. R., 2 7 9 F u n k , G., 5 Furin, G. G., 1 Furlei, I. I., 2 9 8 F u r m a n , P. A , , 1 9 5 Furatenberg, G., 7 0 , 3 0 6 Furuichi, Y., 1 9 0 Furukawa, I., 19 Futsaetrr, N., 3 1 0 Gabov, N. I . , 3 0 6 Gadian, D. G., 2 2 9 , 305 Gaffnav. B. L.. 205 Gafni, A.,1 6 8 ' Gait, M. J., 2 11 Gajda, T. M., 1 1 9 , 1 8 0 Galdecki, Z., 8 3 , 322 Galka, R., 7 Gallagher, M. J., 307 Galley, R. A., 17 Gallis, B., 1 6 8 Gallmeirr, H. J . , 1 0 4

Gallucci, J . C., 3 2 4 Galpin, I. J., 16 Galyashin, V. N., 2 8 3 Gamayurova, V. S., 5 6 Gandhe, B. R., 327 Ganguly, A. K., 2 6 1 , 281 Ganoza, M . C., 2 2 1 Garabadzhiu, A. V., 2 9 9 Garbers, D. L., 1 6 8 Gardner, S. A., 3 0 0 Gareev, R. D., 4 8 , 1 3 2 Garegg, P. J., 1 4 , 1 7 8 Gar'kin, V. P., 15 Garrett. R. A,. 221 Garrigues, B.,'313, 320 Garrison, P. J., 131 Garron. P. E.. 307 Gartner, W., 2 6 0 Gasc, M. B., 1 4 8 Gascon,A., 161, 328 Gaskell, S. J., 2 8 9 Gasteiger, J., 9 6 , 131 Gastrock-Mey, U., 312 Gates, P. N., 3 9 , 7 3 Gavrilovic, D. M., 4 3 , 1 0 7 Gaydou, E. M., 2 9 4 , 2 9 7 Gazizov, T. Kh., 6 8 , 8 8 153 Gee, R. D., 8 7 Geerlings, P., 3 16 Geffrotin. G.. 1 9 7 Gehring, R., 1 3 9 , 1 4 2 Geise. H. J.. 3 2 3 Gelpi; E., 2 8 4 Gerardi, G . J., 3 1 4 Gerdau, T., 2 Gerlo, E., 195 Gerlt, J. A , , 1 7 6 , 1 7 7 , 2 2 8 , ?na

Germ"&, G., 1 4 8 Gerothanassis. 1. P.. 309 Gesing, E. R. F., 2 4 7 Gieg6, R., 2 2 1 Gilbert. C. S.. 1 9 7 Gilbert; J. C.,'251 Gilbert, W., 2 1 9 , 2 2 0 Gilchrist. C. A.. 2 8 1 Gilchrist; T. L.,' 2 4 4 Giles, J . R. M., 315 Gilham, P. T., 2 1 1 Gillam, I. C., 2 2 0 Gillam, S., 2 1 7 Gillen, M. F., 2 0 9 Gillis, R . G., 2 9 0 Giloni, L., 2 2 4 Gilpin, M . L., 2 6 1 Gilyarov, V . A,, 315 Gilyazov, M. M., 3 2 6 Gioeli, C., 179, 2 0 6 Giomini, M., 3 1 4 Girijavallabhan, V. M., 261 Girot, P., 2 2 9 Giuliani, A. M., 3 1 4 Gleiter, R., 3 2 0 Glick, J. A , , 1 6 3 Glidewell, C., 322 Gloede. J.. 46. 51. 6 9 . 75. l08;109 ' ' ' Gloggler, K. G., 1 5 9 , 19 1 Glotter, E., 2 7 2 Glover, A. C., 4 Glover. A. R.. 320 Glowka, M. L ~ . 8 , 3 , 322

Author Index

334 Gloyna, D., 8 4 , 319 Glukhikh, V . I., 7 4 , 129, 309 Godfrey, P. D., 3 1 8 Godovikov. N.A , . 3 1 6 Goel, R. G.’, 17 ’ Gortz, H.-H., 2 0 7 Goetz, H., 325 Goff, S. D., 3 0 1 Gogte, V. N.,2 9 5 Goia, I., 195 Goldberg, I. H., 225 Goldfield, E. M.,2 2 8 Goldman, A . , 3 1 8 Goldman, D., 1 7 9 Goldwhite, H., 2 8 , 1 1 8 Golob. J.. 9 4 Gololobov, Y u . G., 1 4 8 , 1 4 9 . 327 GolovaiyilV. G . , 2 9 8 Golubec, N. S.,3 1 0 Gonbeau, D., 3 2 0 Goncharova, L. V.,325 Goodwin, T. W., 170, 289 G o o d y , R.S., 1 9 2 Gorbach, V. I., 3 0 8 G o r d o n , J., 1 5 8 Gorelic, L . , 2 0 0 Gorenstein, D. G., 2 2 8 Gornicki, P., 2 0 0 Goryunova, I. B., 3 2 6 Gosney, I., 8 7 Gossauer, A . , 2 4 5 Gosselin. G.. 2 12 Gostan, J . L:, 3 2 4 Gottikh, M. B.,1 9 9 Gough, G. R.,2 1 1 Gould, R.O., 31 1 Govindan, C . K., 4 4 Govindan, M . , 75 Govindjee, R.,2 6 0 Grabiak, R. C., 132, 1 3 3 , 308 Grabley, F. F., 2 4 8 Grachev, M.A , , 1 9 6 , 1 9 7 Graifer, D.M.,1 9 9 Gramstad, T.,3 1 0 Granot, J., 2 2 8 Granoth, I., 1 , 4 7 , 6 8 , 7 2 , 80, 88, 9 7 , 2 9 0 , 3 0 0 , 308 Granzow, A . , 2 7 , 327 Grapov, A. F., 1 0 9 , 1 2 3 , 137, 324 Gray, D.M.,2 3 0 Gray, G. M.,4 Green, A. R.,2 0 9 Green. D. E..1 9 4 Greengrass, C. W., 2 6 1 Greenlee, W.J., 1 6 6 Gregor, I. K., 2 8 1 , 3 0 3 Grenshaw, M.D., 252 Gresser, G., 3 0 6 , 3 1 8 Gresser, M.J., 1 9 4 Grewe, H., 1 0 , 1 1 3 , 321 Griend, L. V.,5 8 Griffiths, D. V.,9 9 , 104 Grilc, V . , 9 4 Grimmer, A. R.,307 Grishina, 0. N.,327 Grobe, J., 7 2 , 3 2 0 , 325 Grochowski, E.,1 5 Grollman, A . P., 2 2 4

Gross, D.S.,2 2 7 Gross, H., 4 6 , 5 1 , 108, 1 0 9 , 127 a ” ,

Gross, H. J., 2 17 Gross, S.C., 185 Grossberger, D., 1 6 6 , 2 1 8 Grossmann, G., 3 1 2 , 3 1 3 Gruner, C., 6 Gruszecka, E., 6 7 , 1 0 1 , 135 Grzejszczak, S., 1 3 1 , 2 5 0 Guan, Q., 1 7 8 Gubaidullin, M.G., 1 3 9 Guggolz, E., 3 1 , 117 Guidon, Y.,2 6 3 Guiochon, G . , 2 8 3 Gui-Ping Wu., 1 2 6 Gulewicz, K.,2 2 0 Guliev, A. N.,1 4 9 Gulliver, D. J., 4 Gullo, J. M.,125 Gulyaev, N.N.,1 8 0 G u m p o r t , R. I . , 2 1 6 G U O ,L.-H., 2 1 9 Gupta, R. C., 2 2 4 G u p t a , S. C., 1 7 9 Gurariy, L. I . , 324 Gurevich, P. A , , 7 8 Gurria, G. M.,1 6 9 Gurusamy, N.,1 9 , 321 Guschlbauer, W., 227 Gusev, A. I., 8 3 Guthrie. R. D..15 Gutschow, C.,’161 Guzzi, U . , 2 6 9 Haaks, D., 2 8 9 Haas, B.,2 1 7 Haase, M.,1 0 Haddadin, M.J., 1 0 4 Hader, P. A , , 2 2 1 Haegele, G., 1 3 0 , 2 9 7 , 3 1 2 , 322 Haenel P., 8 9 HaertlL, T . , 227 Haga, M.,3 Haga, N.,105 Hahn,J.,6,71,312 Hai, T. T . , 1 9 1 Haiduc, I., 317 Hajdu, J., 1 6 3 Hakimelahi, G. H., 261 Haley, B. E.,1 9 7 Hall, C. D.,1 1 , 1 7 , 2 0 , 4 4 , 1 4 0 , 327 Hall, C. R.,1 4 1 , 1 4 2 , 1 4 5 , 161 Hall, J . , 1 7 2 Hall, R.G., 9 7 Haller- Pauls, I., 1 1 , 8 0 Halstenberg, M.,29 Hata, T., 1 0 2 , 1 0 3 , 1 2 0 , 1 2 5 , 1 3 1 , 152, 2 0 1 , 202, 203,205 Haltiwanger, R. C . , 1 1 4 , 321, 324 Hamanaka, N.,2 6 9 Hamaoki, H., 2 0 2 Hamaoki, K., 125 Hamashima, Y.,1 0 5 Hamerlinck, J . H. H., 3 1 5 , 32 3

Hamill, B. J . , 251 Hamm, D.J., 1 6 7 H a m m a n , S.,3 2 6 Hammes, G. G., 197 H a m m o n d , P. J., 1 1 , 17, 44 Hampton, A., 1 9 0 , 191 Hanes, C. S.,1 7 1 Haney, C. A , , 2 8 3 Hansen, D. E.,1 8 9 Hansen, J., 1 9 7 , 3 1 1 Hansen, S. W., 25 Hanson, J. R.,1 3 , 7 5 Hanus, L . , 2 9 8 Harbridge, J . B.,2 6 1 Harger, M.J. P., 1 5 6 Hargis, J. H., 3 1 8 Harper, S. D., 5 2 , 6 6 , 102 Harris, B. A , , 1 9 5 Harris, E.E., 1 6 6 Harris, R. K.,4 5 , 31 1 Harrison, C. A , , 1 9 9 Harrison, R.,1 6 1 Hart, D.M.,2 2 6 Harthcock, M.A . , 317 Hartley, F.R.,8 4 , 2 9 9 Hartman. F. E..1 6 9 Hartwick, R. A:, 2 2 9 Harusawa, S.,1 4 3 Harvey, D.J., 2 9 8 Hasegawa, Y ., 9 3 Hashimoto, S.,1 9 Hashimoto, Y.,2 2 6 Hashizume, A , , 1 0 2 , 1 5 2 Haslinger, E . , 1 4 9 Hass, J . R.,2 8 3 , 2 9 1 Hassaneen, H. M.,2 3 , 326 Hauk, G., 11 Hauser, H., 1 6 5 Hawley, D. M.,1 7 8 Hayashi, M.,269 Hayashi,T., 1 4 3 , 1 4 9 Haynes, R. K.,1 4 , 7 5 Haynie, S. L.,9 Hazel, G. L . , 2 2 8 Heah. P.C.. 17 Heathcliffel G. R.,2 0 9 Hecht, G. A. M., 9 , 7 1 Hecht, H. J., 322 Hecht, S.M.,1 8 3 , 222 Heide, W., 3 6 , 3 15 Heidelberger, C., 1 7 9 Heideman, W., 187 Heinlein, T . , 5 , 7 0 , 321 Heinonen, J. K.,1 7 0 Heinze-Sauer, J . , 322 Heitman. P.. 1 6 7 HBlGne, 226 Helfman, D.M.,1 8 2 , 1 8 4 Hellingwerf, K. J., 2 2 9 Hellmann, J., 1 2 , 6 0 , 3 2 1 Hellmann. S.W..305 Hellwinkel, D., 320 Hemmings, M.A , , 2 16 Hendricker, D.G., 2 9 8 Henkel, G., 3 0 6 Henning, H. G., 8 4 Henning, R., 2 5 2 Henrick, K.,2 9 9 Hercouet, A , , 2 4 6 Herd, M.D., 314 Herman, M.A . , 317 Hermkens, P. H. H., 315

c.,

Author Index Hers, H.-G., 1 5 8 Herscovics, A., 1 6 2 Hershberger, J., 9 7 Hervaud, Y., 9 5 Herzig, C., 9 6 , 1 3 1 Hesbain- Frisaue. A: M. 158 Hess, H., 3 2 1 Hesse, M., 1 0 Heuschmann, M., 65, 8 0 , 8 5 , 1 1 8 , 312 Hewson, A. T., 2 6 , 2 7 0 Hewson, M. J. C., 3 0 9 H e y d t , D., 2 3 Hiester, E., 1 4 Hietkamp, S., 1 , 7 , 6 0 Higuchi, T., 1 4 3 Hileman, F. D., 2 9 3 Hilhorst, H. W. M., 2 1 6 Hill, W. E., 3 0 0 Hillen, W., 2 3 0 Hinke, A , , 61 Hinkle. D. C.. 1 9 9 Hino, q., 1 8 4 Hinton, D. M., 2 1 6 Hinz, H.-J., 1 9 4 Hirao, T., 1 0 7 , 1 2 9 Hirata, Y., 302 Hirayanagi, K., 3 2 8 Hirobe, M., 1 4 3 Hirosaki, H., 2 0 3 Hirotsu, K., 3 0 6 Hirwe, S. N., 2 4 2 Hishikura, H., 9 3 Hitchcock, P. B., 2 8 , 2 9 , 118 Hobbs, C. F., 3 Hobbs, J. B., 1 8 7 Hobert, H., 317 Hocking, M. B., 3 4 Hodes, M. E., 1 7 8 Hoehne, S., 5 , 9 , 7 1 H b n l e , W., 322 Hoffmann, H. M. R., 2 5 2 H o f m a n , W., 1 9 2 H o h n e , W. E., 1 6 7 Hohorst, H. J., 2 9 5 Holand, S., 3 3 , 8 7 , 1 2 2 Holden. H. D.. 322 Holden: M., 1 4 , 7 5 Holmes, J. M., 39 Holmes. R. R.., 39., 4 1 .,3 0 8 . 324’ Holmstead, R. L., 2 7 9 Holy, N., 2 2 , 2 3 6 H o n d a , S., 2 0 3 Hong, Y. S., 1 4 4 Honjo, M., 6 7 , 1 7 4 Honkasalo, S. H., 1 7 1 Hoople, D. W. T., 2 6 1 Hopf, H., 2 6 0 Hopkins, P. B., 1 0 5 H o p p e , J., 1 8 2 Hopper, D. J., 1 6 0 Horiguchi, T., 1 5 3 H o r n e , W., 1 9 , 8 3 , 3110, 322 Horner, L., 2 , 1 3 9 , 1 4 0 , 142. 300 H o m i n g , M. G., 2 9 8 H o r t o n , D., 1 6 3 Hossain, M. B., 1 9 , 3 2 1 H o u , X. L., 8 9

335 Houalla. D.. 4 1 Howard; C.; 2 6 9 Howarth, T. T., 2 6 1 Howie, R. A., 8 3 , 8 4 Hrabie, J. A , , 2 6 9 Hruska, F. E., 2 0 9 Hrusovsky, J., 2 9 8 Hsiao, L. Y., 1 7 5 Hsieh, T. C.-Y., 1 6 6 Hsiung, H. M . , 2 8 6 H u , C. S., 305 Huang, N. Z., 8 9 Huang, S., 3 2 0 Huang, S. L., 2 2 8 Huang, T. T.-S., 1 3 , 7 6 Huang, Y., 3 2 0 Huber, F., 8 3 Hudec, T., 2 9 3 H u d s o n , A., 2 8 Hudson, C. W., 4 , 3 2 0 Hudson, S. D., 3 1 6 Hue, L., 1 5 8 Hueber, R., 2 8 0 Hufnagel, M., 8 7 , 322 Hugel, R. P., 9 3 Hui, C. F., 2 1 4 Hullen, A., 2 3 5 Hung, M.-H., 1 7 9 Hunt. D. F.. 280. 2 8 6 H u n t ; R., 2 9 8 ’ Hunter, D., 7 0 , 8 4 Huong, C.-T. B., 2 7 0 Husband, J . B., 5 4 Hussan. N.. 31 8 Hutchins, R . O., 1 1 9 , 31 1 Hutchings, G. J., 1 9 3 Hutchinson, D. W., 1 6 6 , 214,292 H u t h , H., 1 9 1 H u t t n e r , G., 2 0 8 I d e n , C., 2 2 4 Ignat’eva, S. N., 3 1 3 Ihara, H., 1 4 4 Iijima, K., 3 2 5 Ikariya, T., 1 0 Ike Y . , 2 1 1 Ikehara, M., 1 7 9 , 2 0 3 , 2 0 8 , 209,211,214,226 Ikeura, Y.,1 2 4 Iksanova, S. V., 309 I k u t a , S., 2 1 1 Ilsley, W. H., 8 3 , 3 2 0 Il’yasov, A. V., 1 9 , 4 8 , 3 1 3 , 315 Imai, I . , 2 1 2 I m a m o t o , T., 1 8 I m b a c h , J.-L., 2 1 2 Imura, J., 1 7 9 Imuta; J.-I., 1 9 5 I n a m o t o , N., 2 8 , 6 2 , 8 1 , 99, 118, 155, 250, 306, 31 1 I n c h , T . D., 1 4 1 , 1 4 5 , 1 6 1 Indzhikyan, M. G., 8 , 2 1 , 26 Ing, K. Y. W., 1 0 4 Inokawa, S., 5 , 3 1 3 Inoue, T., 2 1 2 Ionin, B. I., 1 5 0 , 3 0 9 , 3 1 0 Ionov, V. M., 3 2 4 Ireland, R. E., 2 3 9 Isaac, R. E., 1 7 0 , 2 8 9

Isakov, V. V., 3 0 8 Isherwood, F. A., 1 7 1 Ishihara, T., 1 3 0 Ishii, K., 3 2 8 Ishikawa, S., 2 0 4 Ishikawa, T., 3 2 8 Islamov, R. G., 1 4 0 Ishmaeva, E. A , , 1 4 9 , 3 1 8 , 32 6 Ismagilova, N. M., 6 5 , 1 3 8 Ismailov, V. M., 1 4 9 Isobaev. M. D.. 3 1 0 Issleib, K.,4 , 30, 3 5 , 1 1 6 Istomin, B. I., 3 9 , 1 2 3 , 1 5 3 Itakura. K.. 2 0 7 . 211. 2 1 9 ItO, E.,255 ’ I t o , H., 2 0 7 , 2 1 1 Ivanova. E. M.. 2 0 8 Ivanova; N . L.,’ 320 Ivanovskaya, M. G., 1 9 9 Iwata, Y., 3 2 7 Jacob, K., 2 9 9 Jacobsen, J . P., 31 1 Jacobson, R. A., 1 1 9 , 3 2 4 Jaenicke. L.. 2 7 4 Jahngen,’J.,’ZJO Jalilian, M. R., 3 1 6 Jallo. L.. 2 6 0 Jamali, H.A. R., 1 0 4 James, T. C., 1 9 7 Jandik, P., 3 2 8 Janes, A. B., 1 2 Jansen, A. F., 7 Janowski, K., 2 8 4 Janulaitis, A. A , , 1 8 5 Janzen, A. F., 6 1 Jardine, I., 2 8 4 Jarman. M.. 2 9 0 jar vest,^ R.’ L., 125:, 1 6 7 , 176, 181, 189 Jastorff. B.. 1 8 2 Jeanloz,’ R.’W., 1 6 2 Jeck, R., 1 9 8 Jeffrey, P. D., 2 6 1 Jelus, B. L., 3 0 1 Jenkins, I. D., 1 5 Jennings, K. R., 2 8 1 , 2 8 3 Jennings, W. B., 3 1 8 Jeremic, D., 140 Jerina, D. M., 1 7 9 Jerris. P. J.. 2 7 7 Jessup, J. S . , 3 2 4 J e t t , M. F., 1 5 8 Jin, G. Y., 36, 6 3 Joergensen, K. A., 1 2 8 Johansson, R., 1 4 J o h n , A. M., 4 , 3 2 0 J o h n s o n , A. H., 2 6 0 J o h n s o n , B. J . B., 2 2 9 J o h n s o n , F., 2 2 4 , 2 6 9 J o h n s o n , K. D., 2 2 1 J o h n s o n , M. J . , 2 1 9 J o h n s o n , M. K., 1 6 8 Johnson, M. P., 4 0 J o h n s t o n , M. I., 2 1 2 Jones, A. C., 9 8 , 1 2 9 Jones, G. H., 302 Jones, J . R., 3 0 8 Jones, P. G., 2 2 7 Jones, R., 2 2 9 Jones, R. A , , 1 4 3 , 205 Jones, R . L., 2 2 9

Author Index

336 Jones, S. S., 205 Jones, T. R. B., 2 9 7 , 3 0 0 Jonrsma. C.. 3 0 3 Jod; F., 9 ’ Jordan, K. D., 3 6 Jorgensen, W. L., 2 4 4 Josephson, S., 2 0 6 , 2 0 8 , 209 Julia, M., 1 2 4 Jung, J . , 2 9 1 J u o d k a , B., 175 Jurkschat, K., 10, 111 Jurovcik, M., 2 1 2 Just, G., 2 6 6 Kabachnik, M . I., 7 8 , 8 4 , 1 4 0 , 310, 3 1 5 , 316, 322, 323, 326 Kabanov, S. P., 2 8 7 Kadin, V. L., 3 2 5 Kadorkina, G . K., 2 9 9 Kadyrov, R. A., 325 Kafarski, P., 6 7 , 1 3 5 , 1 6 6 , A,.-

JLL

Kagan, H. B., 3 Kaim. W.. 89. 315 Kainosho; M.; 2 9 3 Kakiuchi, N . , 2 1 4 Kalabin. G. A , . 309 Kalabina, A. B:, 3 1 4 Kalabina, A. V., 7 4 Kalbitzer, H. R., 1 9 2 Kal’chenko, V. I., 1 2 7 , 1 4 2 , 1 AS

Kaletsch, H., 3 6 , 3 1 3 Kalibabchuk, N. N., 309 Kalinin, A. E., 3 2 3 Kalinov, S. M., 7 7 Kallenbach, N . R., 2 2 9 Kalman, T. I., 1 7 9 Kamaike, K., 2 0 1 , 2 0 6 Kamata, S., 105 Kamentani, S., 1 3 4 Kan, L.-S., 2 2 8 Kan, Y. W., 2 1 9 Kanehira, K., 1 4 9 Kane-Maguire, L. A. P., 1 2 Kang, J., 2 6 6 Kang, J . B., 1 9 1 Kao, L. P., 3 0 5 Kansal, N. M., 1 4 , 2 4 5 Kapoor, P. N., 6 Kapoor, R. N., 6 Kappa, H. W., 1 3 9 Kappen, L. S., 225 Kappenstein, C., 2 3 2 , 322 Kappler, F., 1 9 0 , 191 Kaptein, R., 2 2 9 Karaghiosoff, K., 3 5 , 115 Karakasa, T., 1 3 4 Karataeva, F., 31 1 Karcher, B. A., 1 1 9 Kardanov, N. A., 3 1 6 Karlander, S . G., 2 8 9 Karlsson, K. A , , 2 8 9 Karlstedt, N . B., 6 8 Karpeisky, M. Yu., 2 1 1 Karpenko, A. N., 1 3 1 Karpova, G. G., 199 Karsch, H. H., 4 , 2 3 3 , 2 4 8 , 325 Karsch, J. H., 1 0 Kasai, T., 9 9 , 1 3 0 , 2 5 4

Kashemirov, B. A., 15 1 Kashman, Y., 6 3 , 8 3 , 1 3 2 Kasler. F.. 305 Kaspruk, B. I., 131 Kasuga, K., 2 0 1 Kasukhin. L.. 327 Katagiri, N., 2 4 0 Katakuse, I . , 2 8 7 Kates, M., 2 8 7 Kato, M., 9 6 , 1 3 0 , 2 0 4 Kato, T., 2 4 0 Katsuro, Y., 1 4 3 Kattan, A. M., 1 0 4 Kaufmann. G.. 9 6 Kaur, S., 9 3 Kaushik, M. P., 134 Kawabe. H.. 1 6 8 K a w a m o t o , ~ H . ,9 3 , 3 1 3 Kawashima, T., 8 1 , 1 5 5 Kay, S. N., 7 Kazymov, A. V., 2 3 Kearns, D. R., 2 2 8 Keat, R., 312 Keck, H., 2 9 3 , 3 0 1 Kedrova, 0. S., 1 2 8 Keel, R. A., 2 2 9 Keitel, I., 1 3 7 Keller, K., 8 Keller, R. K., 1 6 5 Keller, S . J., 2 1 6 Kellermann, O., 1 9 7 Keller-Schierlein., W... 2 7 6 Kellert, M., 2 9 1 Kellner, H. A , , 1 4 2 , 1 7 3 Kelly. J . M.. 2 1 7 Kemp, R. A.,3 2 , 6 2 , 1 1 2 Kempe, T., 2 0 9 Kendall. D. S.. 1 6 0 Kende, A. S., 2 7 2 Kennard, O., 2 2 7 Kenner, G. W., 1 6 Kent, D. E., 1 8 5 Kenttamaa, H., 2 9 8 Keough, T., 2 7 9 , 2 8 8 Kern, K. M., 9 5 Kerr, I. M., 1 9 7 , 2 1 9 Kesling, H. S., 2 5 Kessler, R. M., 2 5 Ketari, R., 1 2 , 1 0 7 Kevason, W. J., 300 Kezar, H. S . tert., 2 7 6 Kezdi, M . , 195 Khachatryan, R. A., 8 Khaikin, L. S., 3 1 7 Khairullin, V . K., 6 8 , 1 3 4 Khalifa, S . M., 9 4 Khalimskaya, L. M., 207 Khalitov, F. G., 325 Khan, M. H., 3 2 8 Khazeeva, Z. K., 3 1 6 Khayarov, A. I., 3 1 0 Khdanovich, E. L., 1 5 3 Khetagurova, S. Sh., 3 1 3 Khodak, A. A , , 315 Khokhlov, P. S., 1 5 1 Khristov, V., 1 5 0 Khusainova, N. G., 1 4 9 , 326 Khvostenko, V. I., 2 9 8 Kibardin, A. M., 68, 8 8 , 153 Kibrik, G. E., 3 1 4 Kice, J. L., 1 6 I

.

Kierzek, R., 207 Kiester, E., 1 0 7 Kigoshi, H., 275 Kihara, H., 1 6 3 Kijima, K., 31 6 Kim. J.-J. P.. 1 9 6 Kim; S.-H., 1 7 8 Kime. I.. 15 Kimu;a,’Y., 4 8 , 105 King, M. M., 197 King, R. B., 6 , 2 9 9 King, R. W., 2 6 9 King, T. J., 2 6 1 Kino, M., 2 8 7 Kinoshita, M., 3 0 3 Kinsella, M. A., 27 Kirichenko, L. N., 327 Kirilov, M., 3 17 Kirk, M. C., 2 9 5 Kirsanov, A. V., 1 2 4 Kirson, I., 2 7 2 Kirveliene, V., 175 Kishi. Y.. 2 3 8 Kisseiev,’L. L., 222 Kistemaker, P. G., 2 8 2 Kitagawa, Y., 185 Kitaev, Y u . P., 320 Kitaura, K., 1 0 , 327 Kitcher, J. P., 3 0 8 Kjell, D. P., 27 Klaebe, A,, 5 2 , 1 1 0 , 148, 320, 324 Klaevoe, P., 316 Klaui, W., 9 7 Kleeman, A., 5 Kleeman, S., 3 2 1 Klein, R. A., 282 Kleinmann, I., 3 2 8 Klepa, T. I., 9 5 , 327 Klepel, M., 8 , 9 Kligman, F. L., 137 Klingebiel, U., 1 0 Klose, W., 2 7 2 Kluba, M., 1 5 6 Klugman, F. L., 1 3 7 Klugman, 0. L., 3 1 6 Klysik, K., 2 3 0 Knapczyk, J . W., 1 2 Knedel, M., 2 9 9 Knight, D. W., 2 6 0 Knight. W. B.. 1 6 7 Moil, k., 28,’29, 1 1 2 Knorre, D. G., 1 9 9 , 2 0 8 Knowles. J . R.. 144. 145. 167, i s 9 Knowles. W. S.. 3 Knunyants, I. L., 1 6 KO, S . S., 2 3 8 K 0 . Y . Y . C . Y . L.. 114 Kobayashi, S., 5 6 Kobayashi, Y., 3 2 0 Kobuke, Y., 1 9 5 Kochergina, L. A , , 3 2 6 , 327 Kochetkov, N. K., 1 6 2 Kochetkova, N . E., 7 8 , 8 4 , 94 Kocsis, B., 1 6 3 Koenen, M., 2 19 Koenig, M., 4 0 , 1 0 7 , 3 1 4 K o p f , H., 6 Kdster, H., 207 Kofoid, E. C., 221

Author Index Kohler, P., 1 7 4 Koidan, G. N., 317 Koiro, 0. E., 7 8 , 9 4 Koizumi, T., 9 3 Kojima, T., 9 3 Koketsu, J . , 1 0 , 327 Kolbina, V . E., 7 4 , 1 2 9 Kolesnik, M. P., 4 3 Kolesnikova, G. G., 1 5 1 Kolesova, V. A , , 3 0 3 Kolkmann, F., 1 3 0 , 166! 185 Kolodii, Ya. I., 1 2 5 Kolodyazhnyi, 0. I., 1 2 , 30, 8 8 , 2 4 8 Kolodyazhnyi, Y u . V., 3‘ 17 , 318, 326 Kolova, E. K., 327 Komina, T. V., 7 8 Konarska, M., 2 1 7 Kondo, K., 1 3 0 , 255 Konieczny, M., 1 2 3 Konings, W. N., 229 Konoplya, M. M., 9 3 Konovalova, I. V., 4 5 , 1 ! 8 , 132, 138 Konrad, M., 1 9 2 Konrad, R., 3 1 , 117 Konstantinov, V. V., 2 0 Konstantinovic. S.. 2 3 5 Kontrohr, T., 1 6 3 ’ Kopka, M. L., 2 2 7 Koplitz, R. M., 2 1 8 Kopylov, A. M., 2 2 1 Korbacz, K., 131 2 5 0 Korff, R., 150, 2 1 0 Kormachev, V. V., 2 3 , 7 3 , 129 Kormer, 2 . S., 1 9 5 Korobeincheva, I. K., 3 1 6 Korol, E. N., 2 9 8 Korswagen, R., 2 4 7 Koschatzky, K.-H., 2 4 0 , 266 Koshimizu, E., 325 Kosinskaya, I. M., 2 0 Kostina, T. K., 1 4 9 Kostina, V . G., 42 Kostyanovsky, R. G., 2 9 9 , 310 Kovenya, V. A., 307 Kowada, S., 1 5 3 Kozachenko P. N., 325 Koziara, A , , ’104 K O Z ~ O E. V , S., 6 0 , 3 1 4 , 319, 324 Kozlov, I. A , , 1 9 5 Kozlov, V. A , , 1 3 7 Kozlowski, H 3 1 1, 3 1 3 Kozlowski, S.”A., 2 2 8 Kraevskaya, M. A., 1 6 2 Krahmer, U., 1 7 3 , 2 0 8 Kraihanzel, C. S., 4 Kral, K. M., 17 Kramolowsky, R., 2 KraPP, W., 3 2 0 Krawiecka, B. 2 3 5 Krayev, A. S.,’220 Krebs, B., 1 0 , 1 1 3 , 306, 32 1 Kremer, P. W., 322 Kreuzfeld, H.-J., 5 Krishima, K., 9 3

331 Krishnaiah, M., 322 Krishnamurthy, S. S., 3 0 9 Krishtal’, V. S., 1 2 7 , 1 4 8 Kristiansen, N. A , , 6 1 , 3 1 8 Kron, T. E., 84, 317 Kroto, H. W., 2 8 , 2 9 , 3 1 2 , 318 Krowicki, K., 1 6 Krudy, G. A , , 1 5 3 Kriiger, C., 36, 1 1 7 , 322 Krug, M., 2 1 7 Krupoder, S. A., 1 Krzyzanowska, B., 1 5 6 Krzyzosiak, W. J., 2 2 0 Kubjacek, M., 3 0 3 Kuchen, W., 6 1 , 2 9 3 , 3 0 1 Kuczkowski, R. L., 6 1 , 31 8 Kudelska, W., 1 4 5 Kudinova, V. V., 3 0 9 Kudryavtsev, A. A , , 3 0 7 , 317 Kudryavtseva, T. N., 5 0 , 68 Kudyakav, N . W., 3 0 0 Kudzin, 2. H., 1 3 5 Kueckelhaus, W., 322 Kuehl, D., 2 9 3 Kundgen, U., 3 0 , 6 3 , 1 1 8 Kuhn, E. S., 295 Kuhn, T., 3 2 1 Kukhar, V. P., 3 0 Kukhtin, V. A., 2 3 , 7 3 , 129 Kukko, E. I., 1 7 1 Kul’disheva, 0. V., 1 6 Kulesh, Yu. G., 3 0 8 Kulkarni, P. S., 295 Kumada, M., 1 4 9 Kume, A., 1 0 2 , 1 5 2 Kumada, M., 1 4 3 Kumar, A , , 221 Kumar, G., 2 1 2 Kumar, S. A , , 1 8 5 Kumitake, T., 1 4 4 Kundu, N . G . , 1 7 9 Kunieda, T., 1 4 3 Kunimaya, K., 9 9 Kunkel, T. A , , 2 1 8 Kunz, H., 2 7 Kunz, R. W., 3 11 Kunze, H., 3 0 6 Kunze, U., 2 7 , 2 4 7 Kuo, J . F., 1 8 2 , 1 8 4 Kupprat, G., 9 Kupriyanov, S. E., 2 8 7 Kuramshina, G. M., 317 Kurauchi, M., 1 8 Kurihara, T., 1 5 Kurskii, Yu. A., 7 3 , 1 2 9 Kurumaya, K., 2 5 0 Kusakabe, S., 9 3 Kutrev, G. A , , 3 1 8 Kutsrnko, 1. F., 309 Kutter, J., 61 Kutuev, A. A , , 1 3 1 Kutumova, F. Kh., 7 8 Kutyrev, A. A , , 1 4 0 Kutyrev, G. A., 1 4 0 Kutzelnigg, W., 37 Kuz’menko, I. I., 3 2 8 Kuz’min, V. K., 5 6 Kuz’mina, N . Yu., 327

Kuznetsov, E. V., 1 3 7 , 3 1 6 Kuznetsov, S. G., 1 5 3 Kuznetsova, G. A., 3 2 6 Kwiatkowski, M., 1 7 9 Kwon. B. M.. 2 9 7 Kyba,’E. P., 4 , 3 2 0 Kyllingstad, V. L., 12 Kyuntsel, I. A., 3 1 4 Laane. J.. 317 Labarre, J.-F., 3 0 3 La Belle, B. E., 4 Labotka, R. J., 2 2 7 Lafont, D., 3 Laguzza, B. C., 2 6 2 Lai, K., 2 2 8 Laidlaw, W. G., 31 3 Laine, R. A., 1 6 6 LamandB, L., 4 0 , 3 1 4 Langemeier, P. W., 2 1 6 Langer, P. R., 2 1 5 Lanneau, G., 1 4 5 Laosooksathit. S..9 8 Lapin, A. A., 1 6 ’ Lapin, I. A., 317, 3 1 8 , 3 2 6 L a m e r t . M. F... 28., 1 1 8 Laidu, I:, 1 9 5 Larsen, R. O., 8 8 , 1 5 3 Larson. H. 0.. 1 0 4 Larsson, F. C.’V. 2 9 3 Laskorin, B. N., 17 Laster, W. R. jun., 295 L a t t m a n , M., 3 2 , 6 2 , 1 1 7 306 Lau, C.-K., 2 6 3 Lau, P. Y., 2 8 7 , 302 Laubach. B.. 29. 306 Laurenco, c:, 9 8 Laval, J., 2 2 6 Lavayssiere, H., 1 6 Lavrent’ev, A. N., 2 9 9 , 3 2 7 Lawson, A. J., 2 Lawson, J. P., 2 5 Lawson, M. P., 1 9 0 Lawesson, S. O., 1 2 6 , 1 2 8 , 293, 323 L a y t o n , W. J . , 7 5 Lazarev, I. M., 3 2 6 Lazzaroni, R., 4 Le, A. T., 1 6 9 Leach, C. A , , 2 0 8 Lebedev, I. A., 8 4 Lebedev, L. B., 25 Lebedeva, N. Y u 1 8 Lechner-Knoblai’ch, U., 8 9 Le Corre, M., 2 4 6 le Goffic, F., 1 9 9 Lehmann, H. D., 295 Lehmann, I . R., 1 8 5 Lehmann, W. D., 2 8 9 Lehmkuhl, H., 3 6 Leichtling, B. H., 1 9 7 Leiden, T. M., 2 7 1 Leissring, E., 3 5 Leitner, M . , 1 9 8 Lejczak, B., 135 Lemire, A , , 61 Lentra, A. T. H 3 2 3 Leonard, N . J . , ’ i 8 6 1 9 1 Lepoivre, J. A., 1 7 4 Le Quesne, M. E., 1 6 0 Leroux, Y., 4 8 , 9 9

5

Author Index

338 Lesnikowski, Z. J . , 187, L u n d , P. A., 2 3 0 Lunel, J., 2 8 8 294 Lester, G. R., 2 8 3 Luthe, C., 2 6 6 Lester. R. L.. 1 6 6 Lutsenko. I. F.. 30. 50. 6 0 Letsinger, R.’L., 2 0 9 68, 151 ’ ’ Leutzinger, E. E., 2 2 8 Lutvinov, I. A , , 3 2 0 Lux. D.. 321 le Van. D.. 72. 320. 325 L u x o n , B. A,, 2 2 8 Levason, W., 4‘ Lever 0. W 9 1 , 255 Lyashenko, G. S., 1 2 9 Levin: V. V:,’325 Lykov, A. D., 3 1 0 Lyuts, A. E., 3 0 1 Levin, Ya. A , , 3 2 6 t y z w a , P., 2 5 0 Levinson, M. I., 155 Levitt, L. M., 2 1 8 Ma, L.-T., 2 8 5 Lewicki, J. A., 1 9 4 Ma, R.-I., 2 2 9 Lewis, E. C., 3 2 8 Maas, G., 8 7 , 1 2 3 , 322 Lewis, E. S., 27, 9 7 McAuliffe, C. A., 3 0 0 Lewis, J. C., 1 6 4 Maccarone, E., 1 0 Lewis, J. J., 2 5 McCloskey, C. J ., 4 4 Ley, S. V., 1 5 McCombie, S. W., 2 6 1 Levh. T. S.. 1 9 3 McCullough, K. J., 2 4 4 Li,‘J.; 2 6 8 ’ McDonald, W. S., 1 8 Li, Y.S., 3 1 6 , 3 1 8 McEntee, K., 185 Liakisheva. L. S.. 3 2 4 McEwen, W. E., 1 2 , 2 6 , Liakumovich, A.’G., 1 2 9 245 Licandro, E., 2 3 6 McFadden, W. H., 2 8 3 Lieb, F., 2 6 9 MacFarlane. R. D.. !82, Liebl, R., 6 5 , 3 1 6 , 3 1 9 286 Liesch. J. M.. 2 2 5 McGrane, M. M., 1 5 8 Lin,S.; 2 6 1 ’ Machida, Y.,2 2 6 Lindel, H., 1 4 0 , 1 4 2 Lindner. E.. 5. 9 . 68 , 7 1 , Maciel, G. E., 3 0 8 McIntire. W. M.. 1 6 0 7 8 , 80, 1’21 ’ McIntosh, J. M.; 302 Lin’kova, M . G., 16 McKean, D., 3 1 6 Linscheid, M., 2 8 5 Liorber, B. G., 1 5 0 , 1 5 1 , McKechnie, J., 7 0 McKee, M. L., 62 320 Lippard, S. J., 2 2 7 McKenna, C. E., 1 3 0 , 1 6 6 Litvinov, I. A,, 324 Mackirdy, I. S., 26, 3 2 6 Liu, J.-J., 2 3 0 McLaren, M., 8 3 , 3 2 4 Liu. L.-K.. 4. 3 2 0 McLaughlin, D., 2 4 4 Liu; L . - T . , ’ 4 2 McLaughlin, G. M., 5 Liu, R. S. H., 2 6 0 Maclaughlin, S. A., 1 8 Liu. W.-C.. 2 0 9 McNab, H., 5 4 Lizotte, K: E., 221 McNaughton, D., 3 1 8 McNeal, C. J., 2 8 6 Llinas, J. R., 31 1 Macomber, R. S., 1 5 3 Lloyd, J. R., 17 Lo, A. C.. 2 2 1 McParland, K. B., 2 1 8 McPhail, A. T., 8 0 , 1 1 9 , Lobana, T. s., 9 3 Lochschmidt, S., 3 2 , 322 31 1 McPhaul, M. J., 4 , 3 2 0 Lockard. R. E.. 22 1 L o e b , L.’A., 2 i 8 , 2 1 9 McQuillan, G. P., 8 3 , 8 4 , Loewen, P. C., 2 0 9 316 Logemann, E., 2 4 3 McVicker, E. M., 31 1 Loginova, G. M., 4 8 Mader, L., 316 Maeda, M., 1 9 1 Logunov, A. P., 3 0 1 Lohrmann, R., 2 1 3 Markl, G., 8 , 36, 6 3 , 65, Lopusinski, A . , 7 2 , 8 9 , 1 0 6 , 9 0 , 1 4 9 , 3 1 6 , 319 Magdeeva, R. K., 1 3 4 109, 1 2 3 , 1 2 4 , 140 Lora, S., 3 0 3 Maggiora, L., 1 7 9 Mahler, H. F., 2 9 3 Los’, M. G., 8 3 L o u d o n , A. G., 3 0 3 Maier, G. P., 6 4 , 7 8 Lowe, G., 1 2 5 , 1 6 7 , 1 7 6 , Maier, L., 9 5 , 1 3 6 , 3 0 8 , 181, 188, 189 326 Lowe, P. N., 1 9 6 Maimets, T., 1 8 4 Lowery, S., 145 Main, A. J., 2 6 3 Lrzybylski, M., 2 9 5 Maiorano, S., 2 3 6 Luczak, L., 1 0 6 , 1 4 0 Lajewski, P., 1 0 4 Ludwig, J., 175 Majoral, 1.-P., 8 1 , 1 2 4 , 1 2 9 Ludwig, M. L., 1 6 0 Malakhova, I. G., 3 2 6 Liickoff, M., 3 6 Maleki, M., 9 1 , 2 5 5 Liithey, J., 1 6 1 Malisch, W., 322 Mallamo, J. P., 2 7 2 Luk’yanov, P. A,, 3 0 8 Lulukyan, R. K., 2 1 , 2 6 Malovik, V . V., 7 0 ~

Maltman, K. L., 1 7 0 Mal’tseva, T. V., 316 Mandal, S. B., 1 6 3 Mandel, N., 3 2 3 Mander, L. N., 2 3 8 Mankin, A. S., 2 2 1 Manninen, P. A , , 3 0 8 Manning, R. G., 25 Manohar, H., 322 Manojlovic-Muir, L., 3 12 Manouni, D. E., 9 9 Marat, K., 6 1 Marcelis, A. T. M., 2 2 7 Marchal- Rosenheimer, N., 159 Marchall, H., 2 5 0 Marchenko, A. P., 6 0 , 307 Marecek. J. F.., 140.. 163., 295 Marfat, A., 2 6 2 Mariam, Y. H., 2 2 9 Marinetti, A., 35 Markert, M., 1 9 5 Markham, A. F., 2 0 9 Mark6, L., 5 , 122 Markowska, A,, 1 4 3 Markovitz, P. J., 1 6 0 Markovskii, L. N., 4 3 , 5 8 , 7 2 , 1 2 7 , 1 4 2 , 1 4 8 , 309 Marlier, J. F., 1 9 3 Marner, F.-J., 2 7 4 Maron, D. M., 1 7 1 , 3 2 8 Maroney, P. A., 2 1 9 Marre, M. R., 3 5 , 5 2 , 1 1 0 , 115, 324 Marriott, D. P., 2 6 3 Marschner, F., 325 Marshall, G., 8 4 , 2 9 9 Marston, A , , 1 6 Martens, J., 5 Martin, D. W., j u n , , 2 0 0 Martin, J. C., 6 8 , 8 0 , 308, 324 Martin, S. F., 1 3 1 M a r t h a , D., 2 5 6 Martins, T. J., 1 8 4 Marumoto.. R... 67.. 174. 203 Maruyama, T., 6 7 , 1 7 4 Marvel, J. T., 2 9 8 Mary, Y.,8 Maryanoff, B. E., 1 1 9 , 2 3 8 , 31 1 Marynick, D. S . , 310, 326 Masden, N. B., 1 6 2 Mascherpa, A., 328 Mash, E. A , , 1 6 9 Mashkova, T . D., 2 2 2 Maslennikov, I. G., 327 Mashlyakovskii, L. N., 310 Mastalerz, H., 2 , 6 4 , 7 8 Mastalerz, P., 6 7 , 1 3 5 Mastryukovd, T. A., 134, 140, 323 Masui, M., 2 8 9 Masunaga, T., 1 0 7 , 129 Matevosyan, G. L., 135 Mathey, F., 8, 3 2 , 33, 34, 3 5 , 36, 6 3 , 8 7 , 122, 3 2 0 , 322 Mathiasch, B., 9 Mathis, F., 3 5 , 3 1 8 Mathis, R., 35, 317, 3 1 8

Author Index

3 39

Matrosov, E. I., 8 4 , 310, 322, 326 Matsuda, A., I 8 2 Matsuda. H.. 2 8 7 328 Matsuda; T.,’ Matsui, K., 2 5 5 Matsui, M., 9 4 Matsumoto, H., 2 6 0 Matsumoto, K., 302 Matsumura, T., 9 7 , 1 3 6 Matsuo, T., 2 8 7 Matsuoka, H 9 8 2 5 4 Matsuzaki, J.‘,’205 Matsuzaki, J.-I., 2 0 5 Matteucci, M. D., 2 0 9 Matthes, H. W. D., 2 11 Matthews, P. M., 2 2 9 Mattocks, K. L., 151 Matyusha, A. G., 1 3 4 Matyushicheva, R. M., 135 Maugh, T . H. jun., 2 1 0 Maurer. B.. 2 7 6 Maxam; A.’M., 2 2 0 May, C. J., 10, 1 2 0 Mavaux. J.-F.. 1 9 0 Mayhew’, S . G ; , 1 6 0 Mazalov, L. N., 1 3 9 , 3 2 3 Mazanec, T. J . , 310 Mazerolles, P., 8 1 Mazhar-ubHaaue. . 19.~83. 310,322 Mazitova, F. N., 1 3 4 Mazo. A. M.. 2 2 2 Mazurova, L: A., 1 8 0 Meacock. P. A.. 2 0 9 Mealli, $, 320 ’ M e d v e d , T. Ya., 7 8 , 84, 32 6 Meek, D. W., 3 1 0 Meerholz, C. A., 1 5 Megera, 1. V., 2 1 , 2 5 , 3 2 8 Mehdi, S., 1 7 6 , 1 7 7 , 2 2 8 , 309 Mehler, A. H., 1 9 6 Mehrotra, S. K., 32 Meier, G. P., 2 Meiken, M., 199 Meister, A , , 1 9 7 Meli, A., 2 1 , 321 Mellema, J. R., 2 0 4 Melnik, M., 9 3 Mel’nik, Ya. I., 1 2 5 Mel’nikov, N. N., 1 0 9 , 1 2 3 , 1 3 7 , 324 Melnikova, N. P., 2 1 3 Melton, D. A 2 1 9 Melvin, L. s.,”l29 Menasse, R., 2 6 3 Mengel, R., 1 8 0 Mercier, F . , 8 , 3 4 , 8 7 , 320 Merkel, R., 2 7 , 2 4 7 Merkelbach I. I., 3 2 3 Merkl, B., 9: 9 0 , 1 4 9 Merkler, I., 1 6 1 Merrem. H. J.. 1 2 4 Mertens’, W., f 9 6 ’ Mertes, M. P., P 1 7 9 221 A:’ 32, 5 0 6 Mesch K. A,. Mesch, Mestre‘s. R.. i43 Mestres. Mets, V:, 309 Meuzelaar, H. L. C., 2 8 2 , 285 Meyer, H., 3 5 , 3 1 3 ~

~

~

Meyer, H. J., 2 9 3 Meyer, R. B. jun., 1 8 0 Meyers, A. I., 2 5 Meyerson, S., 2 9 5 Michalik, M., 31 1 Michalski, J., 4 6 , 5 1 , 7 2 , 89, 106, 108, 109, 123, 124, 140 Michalska, M., 1 4 5 Michie, J. K., 6 8 , 7 0 , 8 4 Mickiewicz, M., 2 9 9 Middlemas, E. D., 8, 80, 81, 3 0 6 , 311 Miecke, E., 112 Mikhailov, S. N., 2 1 1 Mikhailov, Yu. B., 1 0 Mikhailova, N. V., 1 3 2 Mikolajczyk, M., 1 3 1 , 1 4 5 , 250 Mikroyannidis, J. A., 1 0 1 Milbrath, D. S., 312 Mildvan, A. S., 2 1 8 Miles, J. A., 1 3 2 , 1 3 3 , 3 0 8 Milewski-Mahrla, B., 2 2 , 2 3 1 , 2 3 2 , 234, 322 Milgrom, Y. M., 1 9 5 Miller, C. H., 1 6 4 Miller, J . A., 6 8 , 7 0 , 8 4 , 91,255 Miller, J. M., 297, 3 0 0 , Miller, P. S., 2 1 8 , 2 2 8 Miller, R. E., 6 6 , 131, 2 9 9 , 313, 317 Miller, R. W., 8 0 , 31 1 Miller, V. R., 312 Millon, R., 199 Mills, 0. S., 1 6 Mills,S., 1 4 , 121 Minahan, D. M. A., 300 Minakami, S., 1 8 4 Minami N 2 3 8 Minkin,’V.’i., 1 5 Minta, A., 192 Mironov, A. V., 1 4 6 , 324 Misharin, A. Yu., 2 0 7 Mishra, R. S., 1 4 , 2 4 5 Mishra, S. P., 315 Mislankar, D. G., 2 , 6 4 , 7 7 Mitchell, D. J., 317 Mitchell, R. S., 1 3 6 Mitera, J . , 2 9 6 Mitrasov, Yu. N., 7 3 , 1 2 9 Mitschler, A., 3 4 , 3 5 , 8 7 , 322 Mitsuda, Y., 3 0 3 Mitsunobu, O.,1 5 Miura, K., 2 2 1 Miyake, T., 209, 2 2 6 Miyamoto, M., 4 8 , 1 0 5 Mkrtchyan, G. A., 8 Mlotkowska, B., 104, 1 4 3 Mochalova, L. V., 2 2 2 Modak, A. S., 2 9 5 Modrich, P., 1 8 7 Modro, T. A., 321 Moedritzer, K., 6 6 , 299, 313, 317 Moedritzer, M., 131 Moller, A,, 222 Morte, A., 2 3 4 Mohammed Tawfik, A. E.-R. 2 3 Mohri, A:, 5 6 , 9 9 , 3 1 4

Mokeeva, V . A., 3 1 4 Mokovetskii, Yu. P., 7 0 Molloy, K. G., 3 0 3 Monkiewicz, J., 1 5 4 Monsarrat, B., 3 0 3 Montag, R. A., 1 1 9 Montaudo, G., 3 0 3 Moonen, C. T . W., 1 6 0 Moore, J. P., 1 8 4 Moore, S. S . , 2 Mootz, D., 3 2 3 Mop’eva, M. A., 326 Moravcsik, E., 1 8 2 M., 1 8 , Moreno-Mafias, 243 Morgan, R. P., 2 8 1 Morisawa, H., 2 0 9 Morita, M., 3 2 8 Moroder, F., 2 6 9 Morozova, N. V., 326, 327 Morr, M., 1 7 4 , 1 8 0 Morrisson, A. R., 3 1 6 Morrow. G.. 2 8 7 Morton,’D. W., 1 8 , 2 3 Morton, S., 7 Mosbach, K., 1 8 3 Mosbo, J. A., 3 1 8 Mosher, H. S., 6 8 Mosichev, V. I., 304 Moskva, V. V., 3 1 3 Moss, J . R., 2 2 Moss, L. G., 1 8 4 Most, J . T., 1 9 , 8 3 , 310 Mostecky, J., 2 9 6 Mo S u n , K., 2 5 6 Motherwell, W. B., 2 7 1 Motoki, S., 1 3 4 Motozato, Y., 3 Mrozinski, J., 9 3 Mruzek, M., 1 9 3 Muchowski. J. M.. 2 0 Mucklejohn, S. A.’, 3 0 7 Mudra, K., 3 2 8 Miigge, C., 10, 11 1 Muller, D., 2 2 0 Miiller, F., 1 6 0 Mueller, J., 299 Mueller, R. A., 2 0 Miiller, W., 2 2 9 Miiller-Hill, B., 2 1 9 Mugrage, B., 2 , 6 4 , 77 Muir, A. S., 3 9 , 7 3 Muir, K. W., 312 Mukmenov. E. T.. 311 324 Mukmeneva. N. A.. 129. 32 5 Muknitova, F. K., 315 Mulfinger, O., 1 1 0 Muller, G., 3 3 Milraney, B. J., 4 , 314 Mumby, M. C., 1 8 4 Mumzhieva, N. G., 8 4 , 313, 317 Munoz, A., 4 0 , 1 0 7 , 313, 314 Munroe, J . E., 2 6 6 Munson, M. S. B., 2 7 9 Murad, F., 1 9 4 Murai, A., 2 9 3 Murakami, A., 1 9 , 110, 213 Murofushi, Y., 2 2 6

Author Index

340 7 0 , 109, 113, 114, 121, Murphy, P., 3 0 8 3 0 6 , 307, 3 1 6 , 321 Murrell, L. L., 7 Nielsen, 0. F., 230 Murrer, B. A., 4 Nielsen, P. E., 221 Musina, A. A., 1 4 9 , 3 1 1 , Nielsen, P. N . , 316 326 Nifantiev, E. E., 1 1 6 , 134, Muslinkin, A. A., 1 3 1 306,320 Mustaev, A. A., 1 9 6 G. N., 3 2 0 , 3 2 2 Musyakaeva, R. Kh., 3 1 7 , Nikonov, Nilsen, T. W., 2 1 9 318 Myasoedov, B. F., 7 8 , 8 4 , Nilsson, K., 163 Nisbet, M . P., 9 2 94 Nishikawa, K . , 222 M y n o t t , R., 2 3 5 Nishikawa, S . , 2 0 9 Niwa, H . , 215 Nixon, J. F., 2 6 , 2 9 , 3 1 2 , Nabiullin. V . N . . 3 1 1 . 3 2 4 318 Naddaka,’V. I., 1 5 Nobbs, M. S., 2 6 1 Nadtochii, F. A , , 2 1 , 3 2 8 Noble, M . L . , 313 Naeasawa. H.. 1 5 Noirot, M . D . , 3 2 4 Nagase, R:, 1 5 5 Nolan, P. A., 179 Nagata, W., 1 0 5 Nomoto, T., 201 Naidu, M. S. R., 2 9 5 Nomura, H . , 323 Nakagawa, E., 2 0 9 Nordheim, A . , 2 2 2 , 2 2 8 Nakai, S., 11 A. D . , 6, 1 1 4 , Nakajirna, M., 1 0 2 , 1 0 3 , Norman, 314, 321, 3 2 4 152 Novak, T . , 160 Nakamachi, H., 3 2 3 Novikov, V . F., 327 Nakarnichi, K., 1 9 , 1 1 0 . Novikova, 1. Y . , 195 213 Novikova, N . K., 128 Nakashima, T . T., 3 1 3 Novikova, Z . S., 3 0 , 6 0 , Nakatini. Y.. 2 8 0 151 Nakayama, C., 1 7 9 Nuir, K. W., 2 8 Narang, S. A , , 2 8 6 Nunez. H. A , . 1 6 2 Narayana, L. V., 1 4 3 Nuretdinov, I. A . , 3 1 8 , 3 2 6 Nardi, N., 4 Nuretdinova, 0. N., 1 2 6 , Nasser, F. A. K., 3 0 3 318 Nassirnbeni, L. R., 321 Nurse, K., 2 0 0 Nasybullin, S h . A., 1 3 9 Nurtdinov, S. Kh ., 6 5 , 6 8 , Navech. J.. 1 2 4 . 1 2 9 138, 327 Nazar, R. N., 2 2 1 Nurtdinova, S. S., 6 5 Nazarov, Y u . V., 1 3 1 Nussbaurn. A. L.. 2 0 2 Nealy, K. A., 1 9 1 Nussbaurn; R. L.; 1 8 4 Negareche, M., 315 Nuzzo, R . G., 9 Negishi, Y., 9 9 , 2 5 0 Negrebetskii, V. V., 1 4 2 , Oakley, R. T., 6 , 3 1 0 , 3 1 3 , 14R 322 Neidle; S., 3 2 4 O b a y a n , K. V., 15 Neilson, R. H., 1 8 , 2 3 , 3 0 Obayashi, M., 1 3 0 , 2 5 5 Neilson. T.. 2 2 1 Oberharnmer, H., 7 2 , 3 1 8 , Nelson,’S. E., 1 4 4 32 5 Nerner. M. J.. 2 1 1. 2 8 6 Occolowitz, J. L., 2 9 0 , 2 9 6 Nesmeyanov,’N. A., 2 3 O’Connor, J . V., 1 6 2 Nesterenko, A. M., 3 0 7 O’Connor, T. P., 2 2 9 Nesterova, N. P., 7 8 , 9 4 Oberg, B., 1 6 6 , 1 7 9 Neugebauer, D., 2 3 3 Oediger, H., 2 6 9 Neuhard, J., 1 7 0 Ohler, E., 1 4 9 Neukorn, C., 2 5 9 Qesterhelt, D., 2 6 0 Nevinskii, G. A , , 1 9 1 Otviis, L., 2 18 Newcomb, M., 1 9 Ofengand, J., 1 9 9 , 2 0 0 N e w m a n , T. H., 6 , 3 1 0 Ofitserov, E. N . , 1 4 6 N e w t o n , C. R., 2 0 9 O’Flaherty, J . T., 1 6 4 , 1 6 5 Newton. R. F.. 2 6 9 Ogata, K., 1 9 7 Ng, S. W., 303’ Ogata, N., 1 4 Nguyen, N. V., 9 5 Ogilvir, K. K., 2 0 9 , 21 1 , Nguyen, Thanh T h u o n g , 704 286 Ogura, F., 1 5 , 1 2 4 Nichols, S. R., 222 O h , D. Y . , 2 9 7 Nickisch, K., 2 7 2 O’Hara, D. S., 1 6 8 Nickloweit-Luke, A , , 1 0 , Ohashi, O., 312 113, 121, 316, 321 Ohashi, S., 172 Nicolaou, K. C., 2 6 6 O h k u b o . K.. 3 Nicolav. K.. 2 2 9 Nicotra,’ F.,’95, 1 6 2 O h n o , K’., 3 1 8 Niecke, E., 8 , 10, 2 8 , 3 1 , O h n o , M., 2 1 3

O h n o , Y., 2 8 9 Ohshiro, Y., 1 0 7 , 1 2 9 Ohtsuka. E.. 2 0 3 . 2 0 8 . 2 0 9 . 21 1 , 2 2 6 Ohuchida. S.. 2 6 9 Oishi, T., 2 0 s Ojhara, B., 2 6 0 Okahata. Y.. 144 O k a m o t o , Y., 1 3 0 , 1 3 1 , 143. 226 OkawaralM., 146 Okazaki, H., 2 9 5 Okazaki. T.. 2 2 6 Okruszek, A , , 3 1 4 O k u h a r a , E., 1 8 5 O k u p n i a k , J., 2 0 6 O’Leary, M. H., 1 6 0 Olejniczak, K., 2 4 1 Olejnik, I . , 1 4 3 Oleksvszvn. J.. 6 6 . 67. 78. 101, i 3 5 ’ Oleski, P., 3 1 4 Olsen, A. A., 1 9 6 Olsen, G. J., 22 1 Olsen, K. L., 302 Oltvoort. J. J.. 1 6 3 O n a k , T., 1 4 O n o , M., 1 5 3 Opella, S. J., 2 2 9 Orgel, L. E., 2 1 2 , 2 1 3 Orlandini, A , , 2 1 , 32 1 Orlov, M., 1 4 0 O r m e - J o h n s o n , W. H., 1 5 8 Ortega, C., 1 4 O r t o n , G., 3 1 8 O r t o n , W. L., 3 2 , 3 0 6 Osakada, K., 1 0 Osgood, E., 1 4 5 Osipenko, A. N.. 3 1 4 Osipov, 0. A., 3 1 7 , 318, 325, 326 Oswald, A. A., 7 O t s u b o , T., 1 5 , 1 2 4 Otsuki. T.. 1 3 0 O t t , J.,~2 1 4 O t t , N., 2 4 2 O t t o . H.. 9 7 O t t o ; K.; 2 1 9 Ourisson, G., 2 8 0 Ovakimyan, M. Zh., 2 1 , 2 6 Ovchinnikov, V. V., 1 2 9 , 311, 327 Overend, W. G., 2 5 6 Ovodov, Y u . S., 3 0 8 Ovrutskii, V. M., 3 2 8 O x t o n , I. A , , 8 4 , 3 1 6 Ozinskas, A. J., 2 1 6 I

,

Pabon, H. J. J., 2 6 6 Pace, N . R., 221 Pacha, I . O., 1 9 9 Padyukova, N. Sh., 21 1 l‘aine. R. T.. 3 2 4 Pakulski. M.. 4 6 , 5 1 , 1 0 8 , 109 Palm, ti., 2 0 9 Palomo, C., 1 4 3 Palomo-Coll, A., 1 4 3 Palorno-Coll, A. L., 1 4 3 Pan. F.. 1 9 7 Pan; L.; 1 7 8 Panackal, A , , 167

34 1

Author Index Pandav. P.. 3 2 7 Panek. I . S . . 221 Paneth P - 3 0 4 Panosy)an”G. A . , 2 1 , 1 5 0 Panov, A.’M., 3 0 9 Pardini, V . t.,2 7 , 2 3 6 Pares, J . , 2 8 4 Park, J . H.,1 5 9 Parkanyi C., 2 3 , 3 2 6 Parker, d. E . , 2 8 3 Parker, D . , 3 1 6 Parry, R . J . , 1 9 2 Parvez, M . , 3 1 1 Pascher, I . , 2 8 9 Pashinnik, V. E., 4 3 Pastukhova, I. V . , 84 Patchett, A. A . , 1 6 6 Patel, A. D . , 1 9 1 Patel D . J 2 2 8 Patsinovskji, I . I., 3 1 8 , 3 2 6 Pattenden, G., 2 5 4 , 2 5 8 Pattenden, G. M . , 9 1 Patzelt-Wenczler, R . , 1 9 6 Paul, K. G., 2 6 9 Paul, R . , 3 6 Paulen, W., 7 1 Pavlov, G . P., 2 3 Pawaniit. 2 9 7 Payne,-D~.S . , 7 0 Payne, N. C., 4 Pearson, D . E . , 1 5 9 165 Pearson, R. H., Pedersen, B., 3 1 3 Peiffer, G., 2 9 4 , 2 9 7 Pelka, H.,1 9 9 Pelling, S . , 2 2 Pellizzari. A. M . . 3 1 7 Pelter, A.’, 1 4 , 1 2 1 Pen’kovskii, V . V . , 9 3 , 3 0 6 Penninger, I . , 2 5 0 Pensionerova, G. A , , 7 4 Penssen, U . , 2 9 5 Pentin, Yu. A . , 3 1 7 Penz, G., 1 5 Pprekilin

V

V

1AQ

1Z1

Pbrez, i.M., 1 6 9 . Perie, J. J., 1 4 8 Perkins. S. E.. 2 8 7 Perone ,’S. P., ’2 8 4 Perov, A. A., 287 Perrini, G., 1 0 Petasis, N . A., 2 6 6 Peter, G., 2 9 5 Peters, J., 29. 31, 6 2 , 6 3 , 307 Peters, K., 6 5 , 8 0 , 312 Peters, M. A , , 221 Petersen, S. B., 2 3 0 Peterson, E. R., 1 6 6 Petov, G.M., 8 4 , 326 Petrenko, V. A., 2 2 2 Petrescu, I., 1 9 5 Petrov, A. A , , 84, 326 Petrov. A. K.. 317 Petrov; G., 317 Petrov, K. A., 1 8 , 8 4 , 1 2 3 Petrovskii. P. V.. 2 3 Pettit, G . R,,2 8 4 Petushkova. E. V.. 1 7 5 Pezzin, G.,303 ’ Pfeiffer, M., 1 9 8 Pfister-Guillouzo, G., 320

Pfleiderer. W.. 172. 2 0 3 . 204,2’11 ’ Piantadosi, C., 1 6 4 , 1 6 5 Pickardt, J., 1 6 , 321 Picker, D., 1 9 0 , 191 Pieronczyk, W., 9 , 7 1 Pierrard, J. C., 9 3 Pierre, J., 2 2 6 Pietrasanta, Y., 9 5 Pietrusiewicz. K. M.. 1 5 4 Pilkis, J., 1 5 8 Pilkis, S. J., 1 5 8 Pinchuk, A. M., 1 3 , 20, 6 0 , 95. 124. 307 Pini, D., 4 Pinkett, O., 197 Pinnick, H. W., 7 5 Pinto, P., 2 6 1 Pinto, R., 261 Pirozhenko, V. V., 5 8 Plateau, P., 1 9 0 Pl6nat. F.. 21. 2 4 4 Plench’ette, A:, 2 4 0 Pleshkova, A. P., 2 9 9 Pless, R. C., 2 1 8 Pliura, D. H., 1 4 5 PIUckthun, A., 1 6 5 Plunkett, W., 1 9 5 Plyamovatyi, A. Kh., 3 1 8 Poblocka, K., 310 Pogorelyi, V. K., 327 Pohl, S., 1 2 7 , 3 2 1 Pohl, T. M., 1 7 9 Polezhaeva, N . A., 310 Polishchuk, A. P., 322 Polivanov, A. N., 3 0 0 Poll, W., 3 2 3 Pollard-Knight, D., 1 8 9 Pollini, G. P., 2 6 9 Pollwein, P., 1 9 4 Polonsky, J., 2 8 8 Polushina, V . L., 19 Polyanskii, 0. L., 3 1 8 Pomerantz, M., 1 5 Poncet, J., 2 7 0 Ponomarchuk. M.. 327 Porchev, I., 1 6 5 ’ Portilla, G., 1 6 9 Posner, G. H., 272 Post, R. L., 1 6 8 Posthumus. M. A , . 282 Postma, U.’D., 2 I 6 Potenza, J. A., 3 1 4 Potrzebowski, M., 1 2 4 Pottage, C., 145 Potter, B. V . L., 125. 167. 176, 189 Potvin, P., 2 6 6 Poulter. C. D.. 169 Powell,’D., 32’4 Powell, D. W., 2 , 6 4 , 78, 254 Powell, J., 1 0 , 1 2 0 Pozdnyakov, P. I., 222 Pradna-Bergrova, S., 3 1 6 Praefcke, K., 9 Pravdin, V. G., 1 6 Preston, R. K., 1 9 1 Price, R., 9 8 , 1 2 9 Prince, J . B., 199 Prishchenko, A. A., 3 0 , 6 0 , 151 Prokof’ev, A. I., 316

Prome, J.-C., 3 0 3 Proskurnina, M. V., 50, 6 8 Protsenko, L. D., 3 2 8 Provotorova, N. P., 316 Pryor, W. A., 4 4 Pucci. S.. 4 Puchala,’C., 310 Pudovik, A. N., 1 0 , 1 6 , 1 8 , 45, 48, 68, 71, 88, 128, 129, 132, 138, 140, 146. 147. 149. 153. 326;327 Pulford, s. M.9 2 1 8 Pulleyblank. D. E.. 2 2 0 Pundak, S., ’198 ’ Purdie, N., 8 1 , 319 Purmal, A. A., 2 1 3 Putney, S. D., 2 1 9 Qazi, T. U., 1 3 Quan, C., 1 4 4 Quast, H., 6 5 , 80, 8 5 , 1 1 8 , 312 Quin, L. D., 8, 2 5 , 32, 8 0 , 8 1 , 2 3 6 , 3 0 6 , 311 Rach6n. J.. 135. 2 4 9 . 2 5 0 Rackwitz, H.-R:, 217’ Radda, G. K., 2 2 9 , 305 Radeglia, R., 307 Radics, L., 1 8 2 Raevsky, 0. A., 8 4 , 313, 1 1 7

Ra&;,’R., 306 Raculin. V. V.. 40. 52 RaTfaelG, A., 4 Ram, B., 1 4 3 Ramabrahman, L., 322 Ramabrahmam, P., 309 Ramamurthy, L.,322 Ramarajan, K., 3 1 4 Ramirez, F., 1 4 0 , 1 6 3 , 2 9 5 Ramos, S., 1 3 Rampal. J . B.. 81. 3 1 9 Randerath, K:, 2 2 4 Rankin, D. W. H., 325 Rao. G. N.. 2 8 7 Rao, G. N.’S., 2 8 7 Rao, N. S., 8 , 8 0 , 8 1 , 3 0 6 ,

-.. 511

Rapoport, S. J., 1 6 7 Rapoport, T. A., 1 6 7 Rasmussen, J . B., 1 2 6 Ratliff, R. L., 2 3 0 Ratovskii, G. V., 3 0 9 , 3 1 9 Rauchfuss, T. B., 9 Rausch, M. D., 300 Razumov, A. I., 7 8 , 150, 151 Razumova. N. A.. 40. 5 2 Razvodovikaya, L. V:, 1 0 9 , 1 2 3 , 324 Reddv. C. D.. 2 9 5 Reddy; M. V.’, 2 2 4 Reddy, P. S., 2 9 5 Redmond. J . W.. 1 6 1 Reed, G. H., 1 9 2 , 1 9 3 Reedijk, J . , 2 2 7 Rees, B., 35 Rees, C. W., 2 4 4 Rees, H. H., 1 7 0 , 2 8 9 Reese, C. B., 2 0 5

Author Index

342 Regitz, M., 2 3 , 8 7 , 23, 322 R e i m a n n , R. H., 2 9 9 Reimschuessel, W., 45 3 304 Reiner, E., 1 6 8 Reinhold, V. H., 2 8 0 Remizov, A. B., 3 2 6 Rempeters, G., 1 9 7 R e m y , P., 1 9 7 , 2 2 1 R e n a u d . M.. 1 9 7 Ressner; J. M., 4 RBtey, J., 1 6 1 Reuschenbach, G., 6 , 71. 312 Reutov, 0. A , , 2 3 Revel, M., 317 Reverdatto, S. V., 2 0 8 Rewicki, D., 2 4 2 Reynolds, D. P., 2 6 9 Revnolds. G . A , . 2 0 Ridard, L:, 3 5 , 322 Rich, A , , 2 0 4 , 2 2 2 , 2 2 8 Richard, J . P., 1 8 7 Richman, J. E., 2 4 , 4 1 , 5 2 , 312,324 Richter, W. J., 1 , 4 8 , 6 5 Rickenberg, H. V., 1 9 7 Ridd, J. H., 1 9 3 Riess, J., 3 0 3 Riess, J. G., 6 9 , 1 3 9 , 3 1 1 , 327 Riley, D. A., 1 6 3 Riley, D. P., 3 Rilling, H. C., 1 6 9 Rimbault, J., 9 3 Rinehart, K. L. j u n . , 302 Ringsdorf, H., 2 9 5 Risnik, V. M., 1 7 5 Rissler. K.. 2 4 3 Rizvi, R.,2 6 1 Roach, D. J. W., 1 6 1 Robert. J. B.., 8 4 ., 1 1 1., 3 0 7 . 308’ Roberts, B. P., 4 5 , 315, 319 Roberts, D., 31 1 Roberts, J. D., 2 8 1 Roberts, N., 2 9 9 Roberts, S. M., 2 6 9 Robertson, G. B., 5 Robertson, H. E., 3 2 5 Robins, M. J . , 1 7 9 R o b o z , J., 2 9 8 Rodin, A. A., 2 9 9 Roder, T., 2 4 7 Roemming, C., 1 2 8 , 3 2 3 Roesch, P., 1 9 2 Rosch, R., 1 9 2 Roesky, H. W., 5 2 , 1 2 7 , 312, 3 2 1 , 3 2 4 Roessler, M., 3 0 6 R o h d e , W., 2 1 7 Rojas, C., 1 6 9 Rokach, J., 2 6 3 Rolando, C., 1 2 4 R o m a n e n k o , E. A., 3 1 4 R o m a n e n k o , V . U.,3 0 9 Romaniuk. P. J.. 1 8 6 . 1 8 7 . 192 R o m a n o v , A. V., 3 1 7 R o m a n o v , G . V., 1 6 , 1 8 , 7 1 Romsted, L. S., 1 4 4 I

I

1

I

R o n c h e t t i , F., 9 5 , 1 6 2 Roaues. R.. 1 4 8 R o i , F.,’97’ Roschenthaler, G.-V., 5 1 Rose. M. E.. 170. 2 8 9 Rosehe, M.,’ 197 Rosen, W., 1 3 Rosenberger, M., 2 5 9 Rosenblum, M., 5 6 Rosendahl, M. S., 1 8 6 Rosenthal, A. F., 1 6 4 . 2 7 7 Rosevear, P. R., 1 6 2 Rosowsky, A., 1 7 8 Ross. J.. 1 7 8 Ross; M: R., 3 2 4 Rosser, R., 1 4 , 1 2 1 Rossmann, M. G., 1 5 9 Rossomando, E. F., 2 3 0 Rosynov, B. V., 2 8 3 R o t h , B., 2 7 2 R o t h , K., 2 3 8 R o t t m a n , F. M., 2 1 7 Roullier, L., 2 7 , 2 3 6 Roush. W. R.. 2 7 6 R O Y , K. L., 2 i 9 Rozanov, I. A., 3 2 6 Rozen, A. M., 9 4 Rozenburg, Y . I., 3 1 4 Rozinov, V. G., 7 4 , 1 2 9 R u b a n , A. V., 3 0 9 R u b a n , G., 322 Rudi, A,, 63, 83, 132 Rudi, V. P., 2 1 , 3 2 8 Rudolph, G., 1 6 , 310, 321 R u d o m i n o , M. V., 326, 327 Riiger, R., 8 , 1 0 , 3 1 , 7 0 , 1 0 9 , 1 1 3 , 121, 3 1 6 , 32 1 Rueooel. M. L.. 2 9 8 RiitLer, U., 2 1 9 Rugevics, C. U., 1 6 8 , 1 7 8 R u p p e r t , I., 2 8 , 2 9 , 4 2 , 7 2 , 1 1 2 , 311 R u p p r e c h t , K. M., 1 8 3 Russell. G. A.. 9 7 Russell; J . W.,’280 Russell, S. W., 2 6 6 Russo, G., 9 5 , 1 6 2 Rutkovskii, G . V., 1 5 3 R y a n , J. F., 2 9 0 Rybakov, V. B., 3 2 4 Rybkina, V. V., 7 4 , 1 2 9 Rycroft, D. S., 312 Rykov, S. V., 1 3 6 Ryl’tsev, E. V., 3 1 7 Saalfrank, R. W., 2 4 7 Saba, D., 1 7 8 Sabularse, D. C., 1 5 8 Saburi, M., 1 0 Sadana, K. L., 2 0 9 Sadanani, N. D., 6 Sadee, W., 2 8 4 S a d i m e n k o , A. P., 3 1 7 Sadovskaya, V. L., 2 8 3 Saegusa, T., 4 8 , 5 6 , 1 0 5 Sanger, H. L., 2 17 Saffhill, R., 1 7 2 Shgi, J., 2 1 8 Saini, M. S., 1 6 7 S t . Clair, M. H., 1 9 5 S a i n t - R o c h , B., 310

Saito, J., 2 8 7 , 2 8 9 Saito, T., 1 3 4 Sakata, R. T., 2 0 4 Sakurai, H., 1 3 0 , 1 3 1 Salakhutdinov, R. A , , 6 5 , 139, 313 Salatin. T. D.. 2 4 4 Salbeck, G., 1 2 7 Salem, G., 5 Salinaro, R. F., 2 5 1 Salisbury, S. A., 2 2 7 Salvadori, P., 4 Salzer, W. L., 1 6 5 Samaan, G. F., 1 6 3 S a m a m a , J . P., 1 5 8 , 1 5 9 Samitov, Yu. Yu., 311 S a m m o n s , D., 1 8 7 S a m m o n s , M . C., 2 9 0 S a m m o n s , R. D., 1 8 8 S a m s o n , L., 2 2 6 Samuelsson, B., 1 4 Sanchez, M., 3 5 , 1 1 5 , 3 2 0 Sanchez-Ferrando, F., 302 S a n d h u , G. K., 9 3 S a n d h u , S. S., 9 3 Saneyoshi, M., 1 7 9 Sanger, F., 2 1 9 Santi, D. V., 1 7 9 Santikarn, S., 2 8 6 Santini, C. C., 3 4 Sanui, K., 1 4 Sasavage, N. L., 2 17 Sasayama, K., 9 4 Sasnauskiene, S., 1 7 5 Sass, S., 2 9 6 S a t h e , G. M., 2 0 9 Satgb, J., 6 , 1 6 , 3 1 0 S a t o , H., 2 0 3 S a t o u c h i , K., 2 8 9 S a t o , S., 6 7 , 1 7 4 , 2 2 1 S a t o , T., 1 4 3 S a t o , Y., 2 0 3 S a t o h , M., 2 0 5 S a t y a m u r t h y , N., 8 1 , 3 1 9 Sau, A. C., 3 9 , 3 0 8 Savignac, P., 33, 6 3 , 1 3 5 Savran, V. I., 1 3 8 Sawai, H., 2 1 3 Savadyan. S. V.. 8 Saykowski, F., 5 Scaiano, J. C., 319 Scanlon, D. B., 2 0 9 Scappini, F., 3 2 5 Scarborough, G. A., 1 6 8 S c h a f e r , H . - G . , 1 0 , 3 1 , 113, 114, 307, 321 Schaefer, T., 6 1 Schaefeer, W., 2 9 9 S c h i t z k e , W., 2 6 6 Schaurnann, E., 2 4 8 S c h a u m a n n , J., 2 6 9 Scheffler, K., 3 15 Scheibye, S., 1 2 6 , 1 2 8 , 323 Scheinbaum, M. L., 1 0 4 Scheinker, V. S . , 2 2 2 Scheir, A,, 2 3 1 Scheit, K.-H., 1 9 0 Scheller, W. W., 3 0 6 Scherer, 0. J., 3 1 , 1 1 7 , 306 Schick, H., 2 6 9 Schick, W., 3 2 2

343

Author Index Schiff, J. A., 1 7 5 Schiebel, H. M., 2 8 5 Schiemenz. G. P.. 9 2 . 319 Schier, A.,’23, 3 0 6 ’ Schill, G., 2 4 3 Schimmel. P. R.. 2 1 9 Schindler,’P. W.; 9 3 Schings, U., 1 0 , 7 0 , 306 Schipper, P., 3 1 5 , 3 2 3 Schlak, O., 4 5 , 3 0 3 , 31 1 Schlegel, H. B., 317 Schlimme, E., 1 9 0 , 1 9 5 Schliselfeld, L. H., 2 2 7 Schmid, G., 321 Schmidbaur, H., 2 , 2 2 , 23, 231, 232, 233, 234, 2 3 6 , 306, 310, 322, 328 Schmidpeter, A., 32, 35, 1 1 5 , 322 Schmidt, D. E. jun., 2 8 7 Schmidt, F. H., 1 9 5 Schmidt, H., 3 0 Schmidt, R., 1 9 4 Schmidtberg, G 297 Schmieder, W., 3 2 1 Schmitt, J. D., 1 6 4 Schmolka, S. J 2 5 2 , 3 2 3 Schmulbach, C:’D 312 Schmutzler, P., 45” Schmutzler, R., 2 3 , 38, 4 1 , 7 2 , 7 5 , 303, 309, 311, 3 1 2 , 324 Schneiderwind, R. G. K., 142, 1 7 3 , 2 0 7 Schnolzer M. 2 17 Schollkop’f, d., 1 3 5 , 249, ?en

Schoeller, W. W., 2 8 , 31, 112, 113 Schold. M.. 2 1 9 Schomberg, D., 38, 320, 324 Schoner, W., 1 9 7 Schore, N . E., 4 S c h o t t , H., 1 8 5 Schroeder, H. F., 2 9 9 Schubert, U., 2 1 , 2 3 1 , 2 3 2 , 322 Schuch, W., 2 0 9 Schulman, L. H., 1 9 9 Schulten, H.-R., 2 8 1 , 2 8 5 , 289,290,292,295 Schulz, G., 1 5 S c h w a n d t , H. J., 2 8 4 Schwarz, R., 125, 3 2 5 Schwarz, S., 2 6 9 Schwarz, W., 32 1 Schweizer, E. E., 2 4 2 , 3 0 1 Schwenzer, G. M., 3 0 8 SchwichtenhGvel, K., 1 0 , 113,321 Scopes, R. K., 1 8 5 S c o t t , G., 1 7 , 4 4 S c o t t , R. J., 8 7 Sedgwick, R. D., 2 8 2 , 2 8 9 , 300 S e d m a n , J., 1 8 4 Seeback, D., 1 4 6 Seed, B., 1 8 4 Seela, F., 1 8 0 , 2 1 4 Seeman, N. C., 2 2 9 Sega, A., 3

Segall, Y., 7 2 , 88, 1 4 5 Segel’man, I. R., 8 3 Seitz, S. P., 2 6 6 Sekine, M., 1 0 2 , 1 0 3 , 1 2 0 , 1 2 5 , 131, 1 5 2 , 2 0 2 , 203.205 Sekine,’T., 9 3 Seliger, H., 2 0 7 , 2 1 7 Semenii. V. Ya.. 7 0 Serebrennikova,’G. A., 2 8 7 Seredkina, S. G., 7 4 , 1 2 9 Sergeev, V. P., 3 0 6 Sergienko, L. M., 3 1 9 Serguchev, Yu. A,, 1 4 2 Serizawa. K.. 5 Severin, E. S:, 1 8 0 Seyer, A., 31, 1 1 4 Shabana, R., 1 2 6 , 1 2 8 Shabanowitz, J . , 2 8 6 Shabarova, Z. A., 1 7 5 , 199, 213 Shagidullin, R. R., 3 1 7 , 318 Shain, S. A,, 200 Shaked. 2.. 1 5 8 Shakirov, I. Kh., 3 1 8 Shakked, Z., 2 2 7 Shapin, S. M., 3 1 8 Shapiro, J . A., 2 8 4 Sharipova, S. M., 3 5 , 1 1 4 Sharma, R. K., 1 4 4 , 327 Sharrard, F., 2 5 3 Shatkin, A. J., 1 8 3 Shatskii, I. N., 2 2 2 Shaw, B. L., 1 7 Shaw, M. A , , 302 Shaw, R. A., 3 1 2 , 3 1 6 Shawali, A. S., 2 3 , 3 2 6 Shchepet’eva, N. P., 1 3 4 Sheldrick, G. M., 1 0 , 2 2 7 Sheldrick. W. S.. 32. 52. 1 2 7 , ’ 3 2 0 , 321, ’322; 32 4 S h e n , P. D., 1 3 0 , 1 6 6 Shen, Y., 320 Sheuuard. N.. 309 She;man,~W.R . , 2 9 0 Shermergorn, I. M., 4 8 Shermolovich. Yu. G.. 43. 58,72 Shestakova, T. G., 6 8 S h e t h , H. G., 2 4 0 Shevchuk, M. I., 2 1 , 2 5 , 26, 328 Shewchuk. E.. 2 9 9 Shiau, W.-I., i 2 Shibata, M., 5 Shibata, S., 3 2 5 Shibaev, V. N., 162 Shichida, Y., 2 6 0 Shigetomi, Y., 9 3 Shikhaliev, Sh. M., 310 Shima, I., 2 8 , 6 2 , 118, 3 0 6 , 31 1 Shimamura. M.. 81 Sfiimidzu, T., 1 ’ 9 , l 10, 2 1 3 Shimizu, H., 1 9 4 Shimomura, S., 162 Shinde, S. K., 3 2 7 Shing, T. S., 2 5 6 Shin-Ya, S., 2 5 Shiori, T . , 1 4 3 Shipov, A. E., 3 2 3 j

I

Shirin, E., 4 7 , 88 Shishkin, G . V., 2 0 8 Shizuri, Y., 275 Shoji, M., 1 8 4 S h o n o , T., 9 7 , 1 3 6 S h o o t e r , K. V., 2 2 4 Shore, S., 12 Shorokhov. N. A.. 2 3 S h o r t t , A. B., 68 Shridhar, D. R., 1 4 3 Shriver, J. W., 2 2 8 Shtepanek, A. S., 1 2 4 Shubina, T. N., 2 2 2 S h u d o , K., 2 2 6 Shurubura, A. K., 3 1 7 Shvets, A. A , , 325 Siatecki, Z., 3 1 1 , 3 1 3 Sibanda, S., 2 0 5 Sichtermann, W., 282 Sidjimov, A , , 3 17 Silaghi-Dumitrescu, I., 317 Silber, G., 2 0 3 Silbereisen, E., 3 6 , 6 3 Silman, I., 1 6 8 Silverman, R. H., 1 9 7 Simashkevich, P. M., 1 8 4 Simoncsits, A., 1 7 5 Simoni, D., 2 6 9 Simons, G., 2 Simpkins, H., 2 2 7 Sims, R. J., 2 4 9 Singer, B., 2 1 4 Singer, T. P., 1 6 0 Singh, H., 9 3 Singh, K., 3 1 5 Singh, M., 2 1 1 Sinha, N . D., 2 0 7 Sinitsa, A. D., 1 2 7 , 1 4 2 , 148 Sinitsyna, N. I., 1 3 9 Sinou, D., 3 Sinyashin, 0. G., 1 4 6 Sitdikova, T. Sh., 3 1 3 Sivaramakrishnan, M., 1 8 4 Sivolobova. G. F.. 2 2 2 Siwapinyoyos, G.; 1 4 Sjaus, T., 3 2 8 Skelton. B. W.. 15 Skibo, E. B., 1 8 0 Skotnikov, A. S., 9 4 Skowronska. A.. 46. 51. 109 Skowrbnska, S., 1 0 8 , 1 0 9 Skripkin, E. A., 2 2 1 Slagle, J. D., 1 3 , 7 6 Slebocka-Tilk, H., 1 4 5 Sledzinski, B., 1 0 4 Slepneva, I. A., 2 2 9 Slopianka, M., 2 4 5 Smagowicz, W. J., 1 9 0 S m i t h , A. B. tert., 2 7 7 S m i t h , D. L., 2 9 3 S m i t h , J . A., 1 6 4 S m i t h , J . H., 12 S m i t h , L. T., 1 9 3 Smith, M., 2 1 7 S m i t h , M. G., 1 9 S m i t h , R. E., 1 9 0 S m i t h , R. T., 1 8 S m i t h , S. L., 7 5 S m i t h , T. W., 1 6 8 S m i t h , W. W., 1 6 0 S m r t , J., 2 1 1 , 2 1 2 ’

I

I

I

I

Author Index

344 S m y t h , T. A., 3 4 S n o w d e n , R., 2 3 Sobanska, M., 1 4 3 Sochilin, E. G., 2 9 9 Socol, S. M., 1 1 9 Soifer, G. B., 3 1 4 Sokolov, M. P., 1 5 0 , 1 5 1 Sokolova, N. I., 1 7 5 Soler, F., 2 8 4 Solodovnikov, S. P., 3 1 5 , 316 Solov'ev, A. V., 5 8 , 72 Solov'eva, T. F., 3 0 8 S o m m e r , H., 1 , 6 0 Sondheimer, F., 2 7 1 Sonenberg, N., 1 8 3 Songstad, J., 3 1 3 S o p c h i k , A. E., 1 1 9 , 1 8 0 S o r o k a , M., 1 3 5 , 1 6 6 Sorokina, S. F., 1 1 8 , 3 0 6 Sosnovsky, G., 1 2 3 Sournies, F., 3 0 3 Sovocool, G. W., 2 9 1 Spalding, T. R . , 2 9 9 Spangler, C. W., 2 7 Spence, S. C., 2 5 , 2 3 6 Spengler, S., 2 1 4 S p e t h , D., 2 4 7 Spirko, V., 3 2 5 Springer, J. P., 312 Springs, B., 1 6 7 S p r o a t , B. S., 1 8 9 Srivastava, S. C., 2 0 2 , 2 0 7 Stabinsky, Y ., 2 0 4 Stadler, H., 2 2 9 S t a f f o r d , G. C. jun., 2 8 0 Stam, C. H., 2 9 S t a n , H. J., 2 9 1 Standing, K. G., 2 8 2 , 2 8 6 Stanislawski, D. A , . 6. 3 1 0 Stanley, A. E . , 3 I 8 Staub. A , . 2 2 9 Stec, W., 4 1 Stec, W. J., 1 5 6 , 1 8 1 , 1 8 2 , 187. 294, 303, 314 Stefanovsky, Y., 3 2 0 Steffen, W. L., s Stegmann, H. B., 3 15 Steinland, K., 2 9 1 Steinwand, M . . 9 , 7 1 , 8 0 Stelzer, O., I , 7 , 2 3 , 4 1 , 6 0 , 7 2 , 7 5 , 312 Stepanov, B. I . , 8 3 Stepanov, T. Ya., 1 8 Stepanova, T . Ya., 7 1 S t e p h a n , D. W., 4 S t e p h e n s o n , D. S.. 2 , 6 5 , 310, 316 Stern, R., 3 Sternbach. H.. 1 9 5 Stewart, C'. A , , 32 Stewart, K. R., 3 1 9 Stewart, W., 7 0 , 8 4 Stille, J . K., 5 S t o c k , L. M . , 1 7 9 Stokes. J . B.. 1 4 7 Storace, L., 1 4 5 S t o r h o f f , B. N., 3 1 8 S t o r m , D. R . , 1 8 7 Storzer, W., 51 Stover, F. S., 1 3 6 S t r a n d , M. R . , 2 6 6 S t r a u b , K. M., 2 8 3

Strepikheev, Yu. A , , 1 5 1 , 30 3 S t r o t m a n n , H., 1 9 5 Struchkov, Yu. T., 3 2 0 , 322,323, 324 S t r u c k , R. F., 2 9 5 S t u r t z , G., 1 4 6 Suba, L. A., 2 9 8 Suchomel. H.. 1 0 . 7 0 . 3 0 6 Sudarev, Y u . I., 8 5 , 1 5 3 Siihs, K., 2 4 7 Suss. J.. 2 3 8 . 2 4 0 . 2 6 6 Suga, H'., 1 9 4 Sugatani, J., 2 8 7 Sugitani, A., 3 2 7 Sugiura, Y., 1 6 8 Sugizaki, M., 1 5 Sugnaux, F. R., 2 8 3 Suleimanova, 1. N., 1 5 1 Sultanova, R. B., 6 5 Sun. S . E.. 2 9 2 Sunberg, R. J., 3 0 5 , 3 2 8 Sundell, S . , 165 Sung W. L., 2 0 4 SunjiL, v., 3 Surles, J. R., 1 6 4 , 1 6 5 Sushitskaya, T. M., 1 3 6 Sutcliffe, R., 31 5 Suvatova, E. A., 1 4 8 S u z u k i , K., 9 3 Suzuki, N., 5 Suzuki, R., 2 9 8 Svanholt, H., 6 1 , 3 1 8 Svoboda, V., 3 2 8 S w a n , J. M., 1 3 8 . 2 9 6 Swarup, G., 1 6 8 Sweigart, D. A., 1 2 S w e p s t o n , P. N., 3 1 3 S y , J., 1 9 7 Sykes, B. D., 1 6 2 , 2 2 8 Szabolcs, A., 2 1 8 Szafraniec. L. L.. 1 2 2 S z e m z o , A,, 2 18' Szewczyk, J . , 1 3 5

Tabushi. I.. 195 Tagaki, W.,' 1 5 3 Takagi, K., 2 2 1 Takagi, M., 162 T a k a k u , H., 1 7 9 , 2 0 1 , 2 0 4 , 205, 206, 208 Takashima, K., 2 4 0 T a k e m o t o , D. J., 1 9 7 T a k e m o t o , L. J., 1 9 7 Takeshita, M . , 2 2 4 Taketatsu, T., 9 3 Takeuchi, T., 302 T a n i , C . C., 151 T a m k u n , J. W., 165 T a m m , C., 1 7 4 , 2 0 3 , 2 0 8 T a n a k a , H., 1 4 , 1 5 , 1 6 8 Tanaka, S., 2 0 9 'ranaka, T . , 2 0 9 , 3 1 6 Tanivama. Y.. 2 0 3 . 2 0 9 T a n n e n b a u m , H. P., 2 8 1 Tansley, G., 1 8 8 Tantasheva, F . R . , 1 9 , 315 Tapper, D. P., 2 3 0 Tarasevich, A. S., 3 0 7 Tarasova, R . I., 1 3 9 Tarassoli, A , , 1 1 4 , 32 1

Tasher, E., 1 1 1 Tashtoush, H., 9 7 Taylor, B. F., 8 4 , 3 1 1 Taylor, B. H., 1 9 9 Taylor, G. N., 3 2 4 Taylor, J. S., 1 9 4 Taylor, L. C. E., 2 8 6 Taylor, M. J., 2 8 Taylor, N . J . , 1 8 Taylor, R. J. K., 2 7 1 Taylor, W. G., 1 4 T e b b e , K.-F., 5 , 7 0 , 321 T e b b y , J . C., 9 9 , 1 0 4 , 3 308 Teller, G., 280 Temkina, V. Ya., 1 3 6 Temple, G. F., 2 1 9 Tence, M., 2 8 8 Tener, G. M., 2 2 0 Ten Noever de Brauw, C., 2 8 2 Terada, K., 2 0 3 Terao, K., 1 9 7 Teterin, E. G . , 9 4 T e t t e n h o r s t , W. C., 3 2 8 Texier-Boullet. F.. 1 0 1 T h a m m , R., 9 T h e , K. I., 5 8 , 3 2 5 Thean. J.. 2 9 3 Theriault; N. Y., 2 8 6 Thierbach, D., 8 3 T h o m a s , B., 3 1 1 , 3 1 3 T h o m a s , G. H., 2 2 6 Thomas, G. J . jun., 2 3 0 T h o m u s o n . M. L.. 1 1 4 , 32 i T h o r n e , A. J., 2 8 , I 1 8 T h o r s e t t , E. L>., 1 6 6 Thyagarajan, G., 9 5 Tierney, M., 305 Tikhonina, N . A , , 3 2 3 Tilak. B. D.. 2 9 5 Tilichenko,". M., 7 7 Tilk, S.. 145 T i m o k h i n , B. V . , 39. 3 1 4 Tishler, M., 1 5 I Titarenko, I. P., 3 2 8 Titmas. R . C.. 2 0 5 . 2 1 1 Tittarelli, P., 3 2 8 Tkachev, V. V., 322 T o b e , M. L., 1 0 Todesco, P. E . , I 5 Toekes, L., 3 0 2 Tohyania, J.. 2 2 1 Tokunaga, T., 2 0 9 Tolstikov, G . A , , 2 9 8 Toniasz, J., 1 7 5 T o m o i , M., 2 7 T o r d o , P., 3 1 5 Torgerson, D. b'., 282 T o r r e , M., 1 0 T o r r r n c e . P. F,,1 7 9 , 2 1 2 , 216 T o r t o , I., 3 1 6 T b t h , I., 5 , 122 Toulrnb, J.- J., 2 2 6 T o w n e r , P,, 2 6 0 Tozuka, Z., 2 0 8 Traficante, D. D . , 309 Tran-Thi. 0 . - H . . 1 8 0 Travers, i.'.;182' Trdlicka, V., 2 9 6 Tremblay, P. A., 2 8 7

Author Index T r e n t h a m . D. K.., 1 6 7 . 1 8 8 . 193, 1 9 4 Tret’yakova, S . S., 1 7 5 Trevor. A. J.. 2 8 9 Trippett, S., 4 0 , 5 2 , 5 9 , 97, 121, 314 Trius, A., 1 8 , 2 4 3 Trbcsanyl, E., 9 Troev, K., 1 1 1 T r o m m e r , W. E., 1 5 9 , 1 9 1 Trost, B. M., 2 4 3 T r o u p , 1. M . , 83, 3 2 0 T r o y , D., 8 4 , 3 1 6 Trudell, J. T., 2 8 9 Tsai, M. D., 1 6 4 , 2 2 8 Tsang, R., 2 5 6 Tsay, Y.-H., 3 6 , 117 Tschabunin, H., 6 Tsirul’nikova, N. V., 1 3 6 Tsivunin, V. S., 6 5 , 1 3 8 , 139 Tsivunina, I . V . , 6 8 , 138 T’so, P. 0. P., 2 2 8 T s o u , K. C., 178 Tsubata, K., 9 7 , 1 3 6 T s u h a k o , M., 1 7 2 Tsvetkov, !2. N . , 84, 3 1 7 , 322, 326 Tsymbal, I. F., 317 Tuebner, J., 2 8 7 Tullius, T. D., 2 2 7 Tulshian, D. B., 2 5 6 Tumanskii, B. L., 315 T u p c h i e n k o , S. K., 149 Turchinskv. M F 2 0 0 T u r n e r , D. H., 1 9 9 T u r n e r . J. V.. 2 3 8 Turov,’V. v.,’3 2 7 T y l o r , A. N., 2 8 2 , 2 8 9 Tzschach, A., 8, 9 , 1 0 , 1 1 1, 31 1 Ubasawa, A , , 2 0 5 Uchiumi, T . , 1 9 7 Ueda, T., 1 7 9 , 1 8 2 , 2 2 1 Uehiro, T., 3 2 8 Uemura, H., 2 0 9 U e n o , Y., 1 4 6 Ueyama, N . , 9 9 , 2 5 0 Ugi, I. K., 1 2 5 , 1 4 2 , 1 7 3 , 207 Ueolini. A , . 2 6 1 Uhl, W.; 3 0 , 3 0 6 Uhlenbeck, 0. C., 2 1 7 , 2 2 4 Uhlig,W., 10, 1 1 1 , 3 1 1 U h l m a n n , E., 2 0 3 , 2 0 4 , 211

Uhn,-E. H., 1 6 6 Uijttewaal, A . , 2 3 Ulrich, J., 2 8 4 , 300 Ul’yanova, 0. D., 3 1 7 U m a r , M. J.-U.-R., 3 2 8 U m e t a n i , S., 9 4 Urgast, K., 8 7 , 3 2 2 U n r u h , J. D., 2 U r y u p i n , A. B., 1 4 0 Ushay, H. M., 2 2 7 Ustav, M., 1 8 4 U t k i n a , N. S., 1 6 2 Utley, J . H. P., 2 7 , 2 3 6 Utvary, K., 303 Utter, M. F., 1 6 0

345 Vafina, A . A., 1 9 , 3 1 5 Vafina, G. S., 3 1 0 Vaidyanathaswamy, R., 134, 1 4 4 Vaitkevitchius, D. P., 1 8 5 Vaizbere. M. S.. 3 2 3 Valavoi;V. A., 3 0 3 Valente, L., 2 0 5 Valenzuela, D., 1 9 9 Valetdinov, R. K., 3 0 0 Van A k e n , D., 3 2 3 van Boeckel. C. A. A... 1 6 3 . 200,201’ van B o o m , J. H., 1 4 2 , 1 6 3 , 173, 190, 200, 201, 204,206 Vanbroeckhoven. J. H.. 2 8 6 van d e Graaf, B . , 2 9 4 ’ Van d e Grampel, J. C., 3 0 3 , 309 Vande G r i e n d , L. J., 1 1 9 , 32 5 V a n der G e n , A., 9 1 , 2 5 2 van der Helm, U., 1 9 , 3 2 1 van der Knaap, Th. A., 2 8 , 29,236 van d e r Marel, G. A , , 1 6 3 , 200,201,204 van d e r Poel, H., 2 9 Van Der V e k e n , B. J., 3 1 7 Vander Velde, G.. 2 9 0 V a n d e Zande, H., 1 9 4 V a n d y u k o v a , I. I., 3 1 8 V a n E t t e n , R. L., 1 6 7 van G e m e r d e n , H., 2 2 9 van Koten, G., 2 9 Van Nuffel, R., 3 2 3 van R o o d e , J. H. G., 2 1 2 Van Schaftingen, E., 1 5 8 von Schnering, G. H., 3 2 2 Von-Schnering, H. G., 6 5 , 80, 3 1 2 Van Tamelen, E. E., 2 7 1 Van Wazer, J . R., 3 0 3 Vardyanathaswamy, R., 327 Vargas, L. A., 1 6 4 , 2 7 7 Varenne, P., 2 8 8 V a r m a , R. S., 2 0 3 V a r m u z a , K., 303 Vasilenko, I., 1 6 5 Vasil’ev, V. P., 3 2 6 , 3 2 7 Vasil’ev, V. V., 4 3 , 3 0 9 Vassil, T. C., 1 6 6 Vassilenko, S. K., 2 2 1 Vedejs, E., 2 , 6 4 , 7 8 , 2 5 4 Vegeais, D., 2 2 8 V e i k o , V. P., 1 9 9 V e n k a t a m u , S . D., 1 5 9 Venuti. M. C.. 2 0 Vereshchagin,’A. N., 3 2 5 V e r k a d e , J. G., 1 9 9 , 3 1 2 , 324, 325 Verkleij, A. J., 1 6 5 Verma. S.. 14. 2 4 5 V e r n o n , C’. A,; 1 9 3 Vestal, M. L., 2 8 3 Vial. M. V.. 1 6 9 Viala, J., 2 6 Vigdergauz, M. S., 3 2 7 Villem, J., 3 2 0 Villem, N. V., 3 2 0 Villem, Ya. Ya., 3 2 0

Villems, R., 1 8 4 Villien, L., 9 6 Vinson, S. B., 2 6 6 Virgili, A , , 3 0 2 Viswamitra, M. A., 2 2 7 Vitkovskii, V. Yu., 3 0 0 Vladimirov, S. N., 1 9 9 Vlassov, V. V.,2 2 1 Vodovatova, S. N., 1 3 5 Voelcker, G., 2 9 5 Vogel, H. J., 2 2 7 Vogt, W., 2 9 9 Voigtlxnder, R., 6 Volante, R. P., 1 5 Volgina, G . A., 3 1 4 Vollmer, R., 3 5 , 1 1 6 V a n - d e r - S a a l , W., 6 5 , 80, 312 Voorhees, K. J., 2 9 3 Volynskaya, E. M., 2 6 V o r a n , S., 3 2 2 Vorbriiggen, H . , 2 0 8 Vorobjeva, L. A , , 1 1 8 , 3 0 6 V o r o n k o v , M. G., 1 5 3 , 3 0 0 , 326 Vosberg, H.- P., 2 1 9 V o s k a n y a n , M. G., 1 5 0 Vostrowsky, O., 2 4 0 , 2 6 6 Voznesensky, V. N., 2 9 9 V u , V. T., 1 7 9 Vysotskii, V. I., 7 7 Wachtl, M., 1 7 4 Waclawek, W., 3 1 0 Wada, M., 1 5 , 1 8 , 9 8 , 9 9 , 130,254 Wada, Y., 3 2 3 Waddington, T . C., 9 2 Wadsworth, A. H., 2 6 , 2 6 9 , ? in L I ”

Wadsworth, W. S. jun., 1 4 4 Wagenknecht, J. K., 1 3 6 Wagner, T., 2 9 5 Wagner, W. G., 1 3 6 Wahren, B., 1 6 6 Waid, K., 2 3 3 Wakabayashi, T., 2 0 9 Waldman, S. A., 1 9 4 Waldmeier, F., 2 0 3 , 2 0 8 Waldrop, A. A., 2 1 5 Walewski, M., 1 2 4 Walia, A , , 6 Walker, B. J . , 9 6 Walker, T . A., 2 2 1 Walkinshaw, M. D., 3 1 1 Wallace, R. B., 2 1 9 Walther, B., 3 1 2 Wamhoff, H., 1 4 , 7 5 Wander, J. D., 2 8 1 Wanderlich, H., 3 2 3 Wane. A. H.-J.. 2 0 4 W a n i ; C. c., I 84 Wane. C.-H.. 2 8 5 Wan:; C.-L.’J., 2 7 0 Wang, H. L., 1 8 4 Wane. S.-C.. 1 9 7 Wani; X., 2 8 5 Wang, Y.-X., 285 Ward. D. C.. 2 1 5 Ward; R. S.,’ 3 0 2 Warrell, D. C., 3 0 8 Warren, C. D., 1 6 2 Warren, R. A. J . , 1 7 0

346

Author Index

Wartell, R. M., 2 3 0 Wasielewski, C., 1 3 5 Wasilewski, J., 37 Watari, F., 84, 3 1 7 Wataya, J., 1 7 9 Watzlawick, H., 1 8 5 Wazeer, M. 1. M., 4 5 , 3 1 1 W e b b , M. R., 1 6 7 , 1 8 8 , 189, 1 9 2 , 193, 1 9 4 W e b b , R. L., 2 5 Webber, A., 2 7 , 2 3 6 Weber, G., 2 6 9 Weber, H., 311 Weber, R., 3 0 9 Weerazooriya, U., 2 5 1 Weferling, N., 3 8 , 3 2 4 Weidner, M. M., 2 8 4 Weinberger, D., 1 4 5 Weiner, L. M., 2 2 9 Weiss, R., 2 1 Wellander, L. L., 2 7 Wells, R. D., 2 3 0 Welsh, K. M., 1 6 7 Welzel, H. P., 2 6 9 Wendisch, D . , 2 6 9 Weringa, W. D., 300 Wessely, H.-J., 3 0 West, R., 6 , 3 1 0 Westerduin, P., 1 6 3 Westerhaus, A , , 2 9 , 3 1 ., 6 2 , 63, 307 Westerink, H., 2 0 4 Westheimer, F. H., 1 5 7 Westmore, J. B., 2 8 6 Westwood, J . H., 2 9 0 Weyerstahl, P., 2 5 0 Whangbo, M. H., 3 1 9 Whelan. D. L.. 1 7 9 White, A. H., i 5 White, D. W., 3 2 5 White, J. D., 2 7 6 Whitesides, G. M., 2 , 9 , 158

W h s i l e , R., 2 5 2 , 3 2 3 Wick, M. M., 1 7 8 Widmer. J.. 2 7 6 Wieber,’M.; 1 1 0 Wiebers, J. L., 2 8 4 Wiecko, J., 2 9 0 Wieczorek, M. W., 3 2 3 Wiedner. H.. 1 9 5 Wiesenfeld, L., 8 4 , 3 0 7 Wiest, R., 3 5 Wiewiorowski, M., 2 0 6 , 220 Wiggins, P. L., 1 6 9 Wilburn. J. C., 3 2 , 1 1 7 , 306 Wild, S. B., 5 , 2 9 9 Wildbredt, D . - A , , 3 1 , 1 1 4 , 307 Wilchek, M., 1 9 8 Wilhelm, E., 32 1 Wilkinson, S. G., 1 6 3 Wille, E. E., 2 , 3 1 0 Wille, G., 2 0 0 , 2 0 1 , 2 0 4 , 206 Willetts, S. E., 9 9 Williams, D. H., 2 8 6 , 3 0 2 Williams. H. J.. 2 6 6 Williams; N., 1 9 7 Williams, N . E., 1 4 1 , 1 4 2 Williams, T. E., 4 4

Willmes, A., 2 4 6 Wilson, M. E., 9 Wilson, S. R., 9 Wilson, W. D . , 2 2 9 Winde, H . , 3 1 7 Wing, R. M., 2 2 7 Winter, W., 1 1 , 2 7 , 80 , 2 4 7 Wirkner, C., 30 Withers, S. G., 1 6 2 Witt, M. H., 2 9 5 Wittinghofer, A , , 1 9 2 Witzel, H . , 1 6 8 , 1 7 8 Woenckhaus, C., 1 9 8 Wolf, H., 2 1 Wolf, R., 4 0 , 4 1 , 5 2 , 1 0 7 , 110, 307, 314, 320, 324 Wolfe, S., 3 1 7 Wolff, A , , 303 Wolff, c., 2 2 0 Wong, C. H., 1 5 8 W o o d , D. L., 2 1 9 W o o d , G . W., 1 8 5 , 2 8 7 . 302 W o o d , T., 1 6 1 , 3 2 8 Woods, C. W., 1 4 7 Woods, M., 3 0 9 , 3 1 6 Worley, S. D . , 3 1 8 Worms, K.-H., 1 3 6 Wower, I., 1 9 9 Wower. J.. 1 9 9 Woychik, R . P., 2 1 7 Wreschner, D. H., 1 9 7 Wrixon, A . D . , 1 5 8 Wrobleski, D. A., 9 Wroblewski, K., 3 1 4 Wu, R., 2 1 7 , 2 1 9 W u h r m a n n , J. C., 6 8 , 7 8 , 121 Wunderlich, H., 1 1 0 Wussow, H . G., 3 2 3 Wustner, D. A , , 2 7 9 Wuts, P. G. M., 2 3 9 Wykle, R. L., 1 6 4 , 1 6 5 Xing, Y. D., 8 9 Yadav. L. D. S.. 1 4 6 Yaeger, E. S., 1 9 7 Yufit, D. S., 3 2 0 Yagi. H.. 1 7 9 Yagodinkts, P. I., 2 6 Y a k o b s o n , G. G., 1 Yakovleva, T. M., 7 3 , 1 2 9 Yakshin, V. V., 3 1 7 Y a m a b e , M., 9 6 , 1 3 0 Yamada, F., 3 2 7 Yamada, K.,275 Y a m a d a , M., 5 Y a m a d a , N., 1 2 9 Y a m a d a , T., 1 9 4 Yamagata, H., 1 2 0 , 1 3 1 Yamaguchi, H., 15, 1 2 4 , 134 Y a m a m o t o , H., 3 1 3 Y a m a m o t o , K., 3 1 3 Y a m a m o t o , S., 1 0 5 Y a m a n a , K., 1 9 , 1 1 0 , 2 1 3 Y a m a n e , A., 2 1 1 Yamasaki, R., 1 5 Yamashita, M., 5

Yamauchi, K., 303 Yamazaki, T., 1 6 2 Yanaai. T.. 9 3 Yanovskii, A . I . . 3 2 2 Yarkova, E. G., Yarmolinskaya, E. V., 2 0 7 Yasuda, S., 1 4 Yatsishin, A. A., 3 2 2 Yauo, I., 289 Yavarova, R. L., 7 8 Y e m u l , S., 3 Yemul, S. S., 1 4 0 Yesinowski, J. P., 3 0 5 Yeung Lam KO, Y. Y. C., 35 Y o k a y a m a , M., 18 Yoshida. M.. 2 0 1 . 2 0 8 Yoshifuji, M.,28; 6 2 , 1 1 8 , 146, 1 5 5 , 3 0 6 , 311 Yoshikawa. S.. 1 0 Yoshikuni,’T.,’S Yoshinaga, K., 3 Yoshizawa, T., 2 6 0 Y o u - X i n Chai, 1 2 6 Y u f i t , D. S., 322 Y u m a t o v , V. D., 1 3 9 , 3 2 3 Y u r c h e n k o , A . G., 9 5 Y u r c h e n k o , R. I., 9 5 , 3 2 7 Y u r c h e n k o , V. G., 1 3 Y u r c h e n k o , V. M., 322, 324

Zabel, V., 3 2 2 Zadmik, B., 9 4 Zakharov, V. I., 5 2 , 3 1 0 Zakour, R. A., 2 1 9 Zakreia, N., 9 4 Z a m a n k h a n , H., 1 2 7 , 3 2 1 Z a m b o n i , R., 2 6 3 Zamir, A , , 1 9 8 Zamkova, V . V., 3 0 1 Zanobini, F., 4 Zard. L.. 2 0 5 Zard; S . Z., 2 7 1 Zaripov, I. N., 1 3 9 Zaripova, R. M , 1 9 , 3 1 5 Zaripova, V. G., 6 8 , 1 3 9 Zarytova, V. F., 2 0 7 Zaslona, A. T., 2 0 , 1 4 0 , 327 Zasorina, V. A . , 1 2 4 Zavalishina, A. I., 1 1 8 , 3 0 6 Zavlin, P. M., 1 3 5 Zaychikov, E. F., 1 9 7 Zbaida, S., 1 5 4 , 2 5 4 Zbiral, E., IS, 1 4 9 Zeiss, W., 3 2 1 Zeman, A., 2 9 3 Zhakarov, V . I., 4 0 Zhang, S. Y., 3 Zharkov, V. V., 1 3 7 , 3 1 6 Zhidkova, L. A . , 3 1 3 Zhmurova, I . N., 1 3 , 2 0 Ziegler, M. L., 3 1 , 1 1 7 , 247 Zielinska, B., 2 9 4 , 303 Zimin, M. G., 1 4 6 , 1 4 7 Zimmer, H., 2 5 2 , 3 2 3 Zimmer-Gasser, B., 2 3 4 , 322

Author Index Zimmermann, F., 194 Zimmermann, H., 192 Zimmermann, R . A., 199 Zon, J., 100, 135 Zorn, H . , 306 Zriely, M., 272

347 Zschunke, A , , 1 0 , 1 1 1 Zsolnai, L.,2 0 8 Zuckerman, J. J . , 303 Zupanc, S., 328 Zverev, V . V . , 320 Zwierzak, A . , 104, 156

Zyablikova, T. A . , 313, 322 Zybill, C. E., 2 3 , 2 3 3 , 2 3 6 Zykova, T. V., 6 5 , 138, 139, 150, 151, 313 Zykova, V. V., 1 S O , 15 1