Organophosphorus Chemistry

Organophosphorus Chemistry Volume 31 SPECIALIST PERIODICAL REPORTS Systematic and detailed review coverage in major ,...

Author: D.W. Allen | J.C. Tebby

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Organophosphorus Chemistry Volume 31

SPECIALIST PERIODICAL REPORTS Systematic and detailed review coverage in major ,'recisof chemical research. A unique service for the active research chemist with m n u l or biennial, in-dt pth accounts of progress in particular fields of chemistry, in print m d online.

NOW AVAILABLE ELECTRONICALLY - chapters from volumes published 1998 onwards are now available online, fully searchable by ke) Lvorti, on a pay-to-view basis. Contents pages can be viewed free of charge.

Or visit our web pages today:

www.rsc.org/spr

A Specialist Periodical Report

Organophosphorus Chemistry Volume 31 A Review of the Literature Published between July 1998 and June 1999 Senior Reporters D. W. Allen, Sheffield Hallam University, Sheffield, UK J. C. Tebby, Staffordshire University, Stoke-on-Trent, UK Reporters

N. Bricklebank, Sheffield Hallam University, Sheffield, UK C. D. Hall, King's College, London, UK N. M. Howarth, Heriot-Watt University, Edinburgh, UK R. N. Slinn, Staffordshire University, Stoke-on-Trent, UK J. C. van de Grampel, University of Groningen, The Netherlands J. S. Vyle, The Queen's University of Belfast, UK B. J. Walker, The Queen's University of Belfast, UK

RS*C ROYAL SOCIETY OF CHEMISTRY

ISBN 0-85404-329-2 ISSN 0306-07I3

43 The Royal Society of Chemistry 2001 All rights reserved Apurt from uny fuir deulingfor the purposes of research or privute study, or criticism or review us permitted under the terms of the UK Copyright, Designs und Patents Act, 1988, this publication may not be reproduced, stored or transmitted, in any form or by uny meuns without the prior permission in writing of The Royul Society of Chemistry, or in the cuse of reprogruphic reproduction only in uccordunce with the terms of the licences issued by the Copyright Licensing Agency in the UK, or in uccordunce with the terms of the licences issued by the appropriate Reproduction Rights Orgunizution outside the UK. Enquiries concerning reproduction outside the terms stuted here should be sent to The Royul Society of Chemistry ut the ucIcITL'ssprinted on this puge.

Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 OWF, UK Registered Charity Number 207890 For further information see our web site at www.rsc.org

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Introduction

After more than a century of activity, organophosphorus chemistry continues to be a lively area of wide international interest as judged by the increasing volume (and the origin) of the literature to be reviewed. However, for this Report, we have experienced some difficulties in securing coverage of all of the traditional areas, notably that of tervalent phosphorus acid derivatives and part of the physical methods chapter. We hope to redress these deficiencies in the next volume (Volume 32), by providing reviews covering two year’s literature. Within the broad area of organophosphine chemistry, increased interest is evident in the application of phosphine-borane adducts in synthesis, and in the structural characterisation of metallophosphides. The maturity of the low coordination number phosphorus area is reflected by the appearance of a book on the subject by Dillon, Mathey, and Nixon. There is a resurgence of interest in mechanistic and theoretical studies of the Wittig reaction and ylides. One notable ylide investigated structurally is the simplest that can be made, methylene(trimethy1)phosphorane. Linking of independent procedures into ‘tandem’ reactions is always of interest, and the latest development in the Wittig area is the first tandem Wittig-hydroformylation reaction. Controlled free-radical polymerisation is another topical area, and a number of organophosphorus compounds, including Wittig reagents, have been used to exert ‘control’ on the polymerisation process. As usual, the synthesis of an ever more complex array of biologically active compounds has been achieved using Wittig procedures. The number of publications in the field of nucleotides and nucleic acids has again risen sharply. Novel oligonucleotide analogues have continued to attract considerable attention and an increase in interest in oligonucleotides incorporating conformationally-locked sugars that have been shown to hybridise to complementary oligonucleotide targets with unprecedented affinity has also been apparent in the literature. Exciting new methodology has been developed for preparing oligoribonucleotides using alternatives to the protecting groups previously employed. The rapid increase in the number of novel modified nucleoside triphosphates can be attributed to the development of techniques for nucleic acid library construction and selection. Such libraries have been utilised in several roles: generating novel nucleic acid reactivity; probing protein-nucleic acid and nucleic acid-nucleic acid interactions; and determining metal ion binding sites. Several new reports of the incorporation of site-specific metal ion binding sites into DNA have been made utilising either novel post-synthetic methodology or a solid-phase Heck-type reaction. V

vi

Introduction

This year saw the 70th birthday and retirement of Professor Robert Holmes, distinguished for his outstanding contributions to hypervalent phosphorus and silicon chemistry, and it is a pleasure to acknowledge the tribute paid to him by the dedication of the July (1998) issue of Heteroatom Chemistry to his work. Another major contributor to phosphorus chemistry reached his seventieth birthday in 1999 and the seventh and eighth issues of Heteroatom Chemistry, Vol. 10 are fittingly dedicated to Professor Alfred Schmidpeter who provides an ‘Essay on Phosphorus Chemistry’ at the outset of a series of articles from friends and colleagues throughout the world. In a review dealing with donor interaction by N, 0 and S atoms at tri-, tetra- and pentacoordinate phosphorus Robert Holmes points out that such interactions give rise to higher coordination and may be highly relevant to enzyme activity. Specifically, phosphate substrates are displaced modestly towards pentacoordinate structures (equivalent to the ground state complex) whereas pentaoxyphosphoranes are displaced more strongly towards octahedral geometry (equivalent to the transition state complex) by a donor interaction, which results in P-0 bond weakening and, consequently, higher reaction rates. Similar reasoning leads to the conclusion that coordination of the tyranosyl carbonyl group with the pentacoordinate transition state in the activation of tyrosine by tyrosyl-tRNA synthetase enhances reactivity. Biological aspects of quinquevalent phosphorus acid chemistry, quite separate from nucleotide chemistry, continue to increase in importance. Tetracoordinate phosphorus compounds are a major source of transition state analogues for the generation of abzymes, etc. A wide variety of natural and unnatural phosphates, especially those of carbohydrates, and their phosphonate and phosphinate, particularly fluorinated, analogues have been synthesised, usually with some biologically-related purpose. The synthesis of extremely complex natural carbohydrate phosphates and unnatural analogues has rapidly developed, and the synthesis and biological properties of inositol phosphates, phosphatidylinositols and related compounds have again been particularly active areas. The interest in phosphorus analogues of all types of amino acids continues. The importance of enantiomeric and asymmetric synthesis is illustrated in many of the reports and the synthesis, and use of chiral phosphorus(V) amides as chiral catalysts, features in many publications. Interest in approaches to easier and safer nerve gas hydrolysis continues. Acylphosphonates have substantial potential as synthetic intermediates and investigations of their synthesis and reactions have increased. A number of thorough mechanistic studies of reactions involving a variety of tricoordinate phosphorus(V) compounds as reactive intermediates have appeared. The first example of a phosphide in a variation of the Staudinger reaction led to the formation of a phosphonium diylide. Intramolecular aza-Wittig reactions have facilitated heterocyclic ring extensions with reports on the use of a chiral ylide to prepare diastereomeric a-aminoesters as well as new reagents for electrophilic amination leading to pyridopyrimidines. The number and variety of applications for phosphazenes continues to expand in a remarkable manner. A number of uses for phosphazenes as bases are reported

Introdurt ion

vii

as well as for phosphazenium cations as catalysts. Several heterocubanes and some new dendrimers have been characterised. High yields of cyclophosphazenes bearing macrocyclic polyether substituents have been achieved and an example of self-assembling cyclophosphazenes is reported. Polymeric phosphazenes with useful surface properties and further examples of sols, electrolytes and membranes have been described. Such properties have found useful applications in medicine, for example fluoroalkoxy derivatives as coatings for blood contacting devices. Novel analysis of the ESR linewidth in TR-ESR experiments has been used for the measurement of addition constants and structural relationships of phosphinoyl radicals. The line width is not affected by spin-polarisation processes, easing determination of rate constant. The first examples of crystal structures of lithiated organophosphorus enamines have been reported

Contents

Chapter 1

Phosphines and Phosphonium Salts By D. W. Allen

1

1 Phosphines 1.1 Preparation 1.1.1 From Halogenophosphines and Organometallic Reagents 1.1.2 Preparation of Phosphines from Metallated Phosphines 1.1.3 Preparation of Phosphines by Addition of P-H to Unsaturated Compounds 1.1.4 Preparation of Phosphines by Reduction 1.1.5 Miscellaneous Methods of Preparing Phosphines 1.2 Reactions of Phosphines 1.2.1 Nucleophilic Attack at Carbon 1.2.2 Nucleophilic Attack at Halogen 1.2.3 Nucleophilic Attack at Other Atoms 1.2.4 Miscellaneous Reactions of Phosphines

1

12 17 17 18 19 22

2 Phosphine Oxides and Related Chalcogenides 2.1 Preparation 2.2 Reactions 2.3 Phosphine Chalcogenides as Ligands 2.4 Structural and Physical Aspects

23 23 25 27 28

1

1 5 10 11

3

Phosphonium Salts 3.1 Preparation 3.2 Reactions

28 28 30

4

p,-Bonded Phosphorus Compounds

31

5 Phosphirenes, Phospholes and Phosphinines

37 43

References Organophosphorus Chemistry, Volume 3 I ((3 The Royal Society of Chemistry, 2001

ix

Contents

X

Chapter 2

Pentacoordinated and Hexacoordinated Compounds By C.D. Hall

62

1 Introduction

62

2 Acyclic Phosphoranes

63

3 Monocyclic Phosphoranes

63

4 Bicyclic and Tricyclic Phosphoranes

67

5 Hexacoordinate Phosphorus Compounds

75

References Chapter 3

80

Quinquevalent Phosphorus Acids By B. J. Walker

82

1 Introduction

82

2 Phosphoric Acids and their Derivatives 2.1 Synthesis of Phosphoric Acids and their Derivatives 2.2 Reactions of Phosphoric Acids and their Derivatives 2.3 Selected Biological Aspects

82

3 Phosphonic and Phosphinic Acids 3.1 Synthesis of Phosphonic and Phosphinic Acids and their Derivatives 3.1.1 Alkyl, Cycloalkyl, Aralkyl and Related Acids 3.1.2 Alkenyl, Alkynyl, Aryl, Heteroaryl and Related Acids 3.1.3 Halogenoalkyl and Related Acids 3.1.4 Hydroxyalkyl and Epoxyalkyl Acids 3.1.5 Oxoalkyl Acids 3.1.6 Aminoalkyl and Related Acids 3.1.7 Sulfur- and Selenium-containing Compounds 3.1.8 Phosphorus-Nitrogen Bonded Compounds 3.1.9 Phosphorus-containing Ring Systems 3.2 Reactions of Phosphonic and Phosphinic Acids and their Derivatives 3.3 Selected Biological Aspects

82 93 100 03

03 03 05 108 109 111 112 115 1 15 116 117 124

xi

Contents

4

Chapter 4

Structure

126

References

127

Nucleotides and Nucle.: Acids By J.S. Vyle and N. M. Howarth

135

1 Introduction

135

2 Mononucleotides 2.1 Nucleoside Acyclic Phosphates 2.1.1 Mononucleoside Phosphate Derivatives 2.1.2 Polynucleoside Monophosphates 2.2 Nucleoside Cyclic Phosphates

135 135 135 140 142

3

Nucleoside Polyphosphates

4 Oligo- and Polynucleotides 4.1 DNA Synthesis 4.2 RNA Synthesis 4.3 The Synthesis of Modified Oligodeoxynucleotides and Modified Oligoribonucleotides 4.3.1 Oligonucleotides Containing Modified Phosphodiester Linkages 4.3.2 Oligonucleotides Containing Modified Sugars 4.3.3 Oligonucleotides Containing Modified Bases

154 154 161

5 Oligonucleotide Conjugates

191

6 Nucleic Acid Structures

204

References Chapter 5

145

161 161 170 178

208

Ylides and Related Species By N. Bricklebank

219

1 Introduction

219

2 Phosphonium Ylides 2.1 Theoretical and Mechanistic Studies of Phosphorus Ylides and the Wittig Reaction 2.2 Synthesis and Characterisation of Phosphonium Ylides 2.3 Ylides Coordinated to Metals

219 219 223 227

Conten ts

xii

2.4

Reactions of Phosphonium Ylides 2.4.1 Reactions with Carbonyl Compounds 2.4.2 Miscellaneous Reactions

3 The Synthesis and Reactions of Aza-Wittig Reagents

235

4 Structure and Reactivity of Lithiated Phosphine Oxide Anions

238

5 Structure and Reactivity of Phosphonate Anions

238

6 Selected Synthetic Applications of Wittig Reactions

24 1

References

Chapter 6

244

Phosphazenes By J. C. van de Grampel

249

1 Introduction

249

2 Linear Phosphazenes

249

3 Cyclophosphazenes

260

4

Polyphosphazenes

5 Crystal Structures of Phosphazenes and Related Compounds

Chapter 7

23 1 23 1 233

27 1

280

References

286

Physical Methods By R.N. Slim

295

1 Electron Paramagnetic (Spin) Resonance Spectroscopy

295

2 Vibrational and Rotational Spectroscopy 2.1 Vibrational Spectroscopy 2.2 Rotational Spectroscopy

297 297 298

3 Electronic Spectroscopy 3.1 Absorption Spectroscopy 3.2 Fluorescence and Chemiluminescence Spectroscopy

298 298 298

4 X-Ray Structural Studies

299

...

Contents

Xlll

4.1

X-Ray Diffraction (XRD) 4.1.1 Two-coordinate Compounds 4.1.2 Three-coordinate Compounds 4.1.3 Four-coordinate Compounds 4.1.4 Five- and Six-coordinate Compounds 4.2 X-Ray Absorbtion Near Edge Spectroscopy (XANES) 4.3 Electron Diffraction

302 303

5 Electrochemical Methods 5.1 Dipole Moments 5.2 Cyclic Voltammetry and Polarography 5.3 Potentiometric and Conductometric Methods

303 303 303 304

6 Thermochemistry and Thermal Methods

304

7 Mass Spectroscopy/Spectrometry

304

8 Chromatography and Related Techniques 8.1 Gas Chromatography and Gas Chromatography-Mass Spectroscopy (GC-MS) 8.2 Liquid Chromatography 8.2.1 High-performance Liquid Chromatography and LC-MS 8.2.2 Thin-layer Chromatography (TLC) 8.3 Capillary Electrophoresis (CE) and Micellar Electrokinetic Chromatography (MEKC)

305

References Author Index

299 299 299 300 302

305 305

305 306

306 306 310

Abbreviations

Benzamide adenine dinucleotide Cyclodiphospho D-glycerate Capillary electrophoresis Creatine kinase Controlled potential electrolysis 1-(Zchlorophenyl)-4-methoxylpiperidin-2-yl Cyclic voltammetry cv DETPA Di(2-ethyIhexy1)thiophosphoric acid DMAD Dimethylacetylene dicarboxylate Dimet h yl formamide DMF DMPC Dimyristoylphosphatidylcholine DRAMA Dipolar restoration at the magic angle Differential scanning calorimetry DSC Differential thermal analysis DTA Energy resolved mass spectrometry ERMS Electrospray ionization mass spectrometry ESI-MS Extended X-ray absorption fine structure EXAFS Fast atom bombardment FAB 1 -(2-fluorophenyl)-4-methoxylpiperidin-2-yl FPmP High-performance liquid chromatography HPLC LA-FTICR Laser iblation Fourier Transform ion cyclotron resonance Matrix assisted laser desorption ionization MALDI Micellar electrokinetic chromatography MCE Mass-analysed ion kinetic energy MIKE Polycyclic aromatic hydrocarbons PAH H ydroquinone-0, 0'-diacetic acid QDA 9-[2-(phosphonomethoxy)ethyl] adenine PMEA S-acyl-2-thioethyl SATE Secondary ion mass spectrometry SIMS Spermidinekpermine-N 1-acetyltransferase SSAT SSIMS Static secondary ion mass spectrometry Thiazole-4-carboxamide adenine dinucleotide TAD tert-Butyldimethylsilyl tBDMS TFA Trifluoroacetic acid Thermogravimetric analysis TGA Thin-layer chromatography TLC TOF Time of flight X-Ray absorption near edge spectroscopy XANES

BAD cDPG CE CK CPE CPmP

xiv

1 Phosphines and Phosphonium Salts BY D. W. ALLEN

1

Phosphines

1.1 Preparation. - 1.1.1 From Halogenophosphines and Organometallic Reagents. The use of organolithium reagents has dominated the field in the past year, with only a few examples of the use of Grignard reagents having been noted. A Grignard route has been used in the synthesis of the alkoxysilylfunctionalised arylphosphine ( l), treatment of which with lithium aluminium hydride gives the air-stable phosphine (2). The alkoxysilyl phosphine (1) undergoes acid-catalysed hydrolysis and condensation to form a phosphinofunctional gel, the prototype of a new family of hybrid 'inorganic-organic' gels containing phosphorus. The same group has also used a Grignard procedure for the synthesis of the alkoxysilylated alkylphosphine (3), but attempts to

form hydrogels from this resulted in cleavage of the carbon-silicon bond'. A benzylic Grignard reagent has been used in the synthesis of the phosphine (4), subsequently converted by in situ demethylation and electrochemical oxidation of its platinum complexes to related complexes of the phenolic and quinonoidal phosphines, (5) and (6), respectively2. Sequential treatment of phos-

phorus trichloride with aryl- or bulky alkyl-Grignard reagents (1 mole), followed by methylmagnesium halides and borane protection, has provided a route to the protected systems (7). Subsequent metallation at a methyl group using butyllithium in the presence of (-)-sparteine, followed by treatment with a dichlorophosphine, and final Grignard methylation provides a route to Organophosphorus Chemistry, Volume 3 I 6;: The Royal Society of Chemistry, 2001

2

Organophosphorus Chemistry

the chiral diphosphines (8), isolated in borane-protected form3. Both Grignard and organolithium reagents have been applied in the synthesis of a range of new, electron-rich, bulky phosphines, e.g., (9) and (lo), which have been

b"

BH3 Me R-P( Me (7) R = Ph, Pr', Cy or But

t

(8) R = Ph, Pr', Cy or But

(9) R = But or Cy

shown to fhcilitate the palladium-catalysed synthesis of diary1 ethers4? Organolithium routes to long-chain arylalkylphosphines, e.g., (1 l), have also been developed. These phosphines have been shown to undergo sulfonation at the terminal benzene ring to give surface-active water-soluble systems6. Lithiation of the diacetal (12) is the first step in a divergent synthetic approach to OMe

OMe

Br

tunable, expanded aldehyde-functional phosphine ligands from which chiral iminoarylphosphines may be prepared7. New iminophosphine ligands, e.g., (13)* and (14)9, have been prepared from lithiated aldimine and ketimine precursors. Aryllithium reagents have been used in the synthesis of the chiral functionalised phosphines (15)'O and (16)". A chiral alkyllithium reagent has found use in the synthesis of the new chiral ligand (17), in which the chiral group is attached to phosphorus by a non-stereogenic chiroptic centre12.

PriP-CH-C=NR3

I

R'

I

Ph2P

R2

(13) R',R2 = H or Me; R3 = But or Cy

(15) R = Me or Et

(14)

Me

Me

Ph+Ph PhM&Ph 3

(16) R' = H or OMe; R2 = Me, Ph or 2,6-Me&&

Me

Me

(17)

Ph,-P(C

F=CF2)n

(18) n + m = 3

I : Phosphines and Phosphonium Salts

3

Trifluorovinylphosphines, e.g., (18), have been prepared by lithiation of trifluoromethylfluoromethane, followed by treatment with the appropriate halogenophosphine' 3. Direct lithiation of heterocyclic systems followed by treatment with halogenophosphines is the method of choice for the synthesis of a range of new phosphines, e.g., the atropisomeric quinazolinone phosphine ( 19)14, the sydnone systems (20)' 5 , the diphosphinobis(pyrazo1-1-yl)methanes (2 1) and related diphosphinobis(imidazolyl)methanes16, and a range of 'widebite' diphosphines, e.g., (22)17918.Lithium-halogen exchange on 2-bromodiben-

(19) R = PPh2,SH or SMe

R (20) R = H or PPh2

7 fJ J J -

Ar2P =

I PPh2 (21) R = H or M%Si

(22)

zofuran is the key step in the synthesis of a range of dibenzofuran-based phosphines (23), which have been shown to undergo regiospecific sulfonation at the 7-position of the dibenzofuran ring system to give a series of watersoluble phosphineslg. Several groups have reported the synthesis of indenylphosphines via direct metallation of indene with butyllithium. With chlorodiphenylphosphine, the phosphine (24) is formed. Further metallation/ phosphination yields the diphosphine (25)20. The outcome of the reaction of

indenyllithium with dichlorophenylphosphine depends on the choice of solvent. When THF is used, the 1H-inden-3-yl system (26) is formed, whereas when toluene is used, the isomeric 1H-inden-1-yl system (27) results2*.Both isomers were isolated from the reaction conducted in diethyl ether2*. This work also reported the synthesis of the mixed fluorenyl-indenylphosphine(28) via sequential treatment of phenyldichlorophosphine with fluorenyllithium and indenyllithium. Each of (26)-(28), and the related difluorenylphenylphosphine,


4

P-Ph

P-Ph

P-Ph

can be deprotonated to give anionic phosphine ligands from which a range of metallocene-like complexes of zirconium and hafnium have been prepared. The past year has seen a considerable number of publications describing the synthesis of new phosphines, many of which are chiral, which involve the ferrocene system as the essential core of the molecule. Access is usually via direct lithiation of the ferrocene system, followed by reaction with a chlorophosphine. Further chiral C2-symmetric ferrocenyl diphosphines, e.g., (29), have been described23-25.The aminoalkylferrocenylphosphine (30) has both

@ wN bSR @PPh2 I

Fe PPh2 I

(31) R = Me or Ph

axial and planar chiral elements26.Routes to unsymmetrically substituted 1,l'~ - ~ stannylferroce*. ferrocene systems, e.g., (3l), have also been d e ~ e l o p e d ~ The nylphosphine (32) has been transformed into the chiral dihydrooxazolinylferrocenylphosphines (33)29. Sequential lithiation and phosphination of the

Fe I @PPh2

(32)

Fe I

R

@PPh2

(33)R = Pr', But or Ph

bis(ferroceny1)phosphine (34) has given the new phosphinoferrocene systems (35)30.Sequential treatment of 1,l'-dilithioferrocene with t-butyldichlorophosphine, methylmagnesium bromide, and borane, followed by separation of the various isomeric forms, has given the chiral diphosphine (36)3'. In a similar vein, direct lithiation of bis(tetrahydroindenyl)iron, followed by treatment

1: Phosphines and Phosphonium Salts

(34)

5

(35) X = Br or PPr’2

r””‘ -P, Me Me., P-

I But

with chlorodiphenylphosphine, gave a mixture of isomeric diphosphines (37), subsequently separated by fractional crystallisation, and resolved into optically active forms by chiral HLPC32. Chiral cymantrenylphosphines (38) have been obtained by direct lithiation of the related cymantrene, followed by phosphinat i ~ n The ~ ~ aza-allylphosphine . (39) has been obtained from the reaction of chlorodiphenylphosphine with a lithiated aza-ally1 system, and used as an ~ . organointermediate in the synthesis of new heterocyclic N , P - s ~ s t e m s ~An lithium reagent derived from a dicarbaborane has been employed in the synthesis of a bis(di~arbaborany1)phosphine~~.A phenylcopper reagent is much more effective than phenyllithium in converting the 1,5,9-tri(chlorophospha)cyclododecane (40, X = C1) into the related cyclic phosphine (40, X = Ph)36 X

But Me3Si-N=C

\

CH-SiMe3

/

Ph2P

1.1.2 Preparation of Phosphines from Metallated Phosphines. The synthesis of organophosphines from the reactions of elemental phosphorus and phosphine with electrophiles in the presence of strong bases has been reviewed37. Twophase phosphination of 2,2‘-(bishalomethy1)-1,1’-binaphthyls with phosphine under aqueous base conditions has been used in the synthesis of the atropisomeric phosphines (41) and (42)38. The dilithio diphosphide reagent (43, R = Ph) has been employed in the synthesis of a range of chiral macrocyclic binaphthyl diphosphines (44).A similar approach using lithium diphenylphosphide has given the related non-cyclic chiral diphosphine (45)39. The reactions


6

of the dilithiodiphosphide (43, R = H) with optically pure 1,3-diol cyclic sulfate esters are the basis of a synthesis of the chiral diphosphetanes (46)40. Dilithiophosphide reagents derived from 1,2-bis(phosphino)ethane have been employed in the synthesis of the chiral bisphospholanes (47)41. The new chiral

(44) R = H, Ph or 2-naphthyl

(4)

(45)

(47) R = PhCH2 or But

heterocyclic phosphines (48)42 and (49)43have been prepared via the reactions of dilithiophenylphosphide with the mesylate esters of chiral diols. Dilithioarylphosphide-cyclic sulfate combinations have also been used in the synthesis of the 'wide-bite' chiral diphosphines (50)44,and a range of chiral phosphino-

(49) Ar = Ph or 3,5-But&6H3 R=HorMe

(50) R = H or Me X = S or CMe2

phospholanes, e.g., ( 5 l)45. Side-chain elaboration of P-menthylphosphetanes, involving the use of lithium diphenylphosphide, has given the new c h i d diphosphines (52)46. In addition to the synthesis of the new heterocyclic phosphines noted above, lithiophosphide reagents have received wide application in the synthesis of acyclic phosphines, many of which are chiral and of interest as ligands in homogeneous catalyst systems. Displacement of fluoride ions from fluoroaromatic systems by lithium diarylphosphide reagents is a common approach in

7


the synthesis of chiral phosphinooxazolines, e.g., (53)47, the crowded diphosphines (54)48, and the phosphinoarylsulfoxide (55)49. The functionalised phosphine (56) is similarly accessible from the reaction of dilithiophenylphos-

0

PM-2

(53)

(54)R = F, Bu or Ph

PPh2 (55) Ar = 2-methoxynaphthyl

phide with a meta-fluoroarylphosphonamidate.Hydrolysis of the phosphonamidate group of (56) yields a water-soluble phosphinesO. Phosphide displacement of chloride from chloroheterocyclic systems has provided routes to a series of pyrimidylphosphines (57)s1, and the diphosphinopyridazinone (58y2. Further development of lithiophosphide routes to chiral phosphino-

oxazolines has occurred, centring around the phosphine (59) as the key intermediates3. This system is also encountered in protected form in the synthesis of phosphino-functionalisedamino acids54. New chiral phosphinothioether ligands (60) are accessible via ring-opening of chiral episulfides using

AR2

R’2P

(59)

SR3

(60)R’ = Cy or Ph, R2 = Me or Cy, R3 = Me or CH2Ar

lithiophosphide reagents? The new chiral camphor-based phosphine (61) has been obtained via the reaction of a cyclic sulfate ester with lithium diphenylp h ~ s p h i d eA ~ ~borane-protected . lithium diphenylphosphide reagent has been employed in the synthesis of the intermediate (62, R = H ) subsequently transformed into a range of highly functionalised phosphino-alcohols via oxidation and treatment with functionalised organozinc reagentss7. Two g r o ~ p s ~have * * ~described ~ lithiophosphide routes to phosphinoalkylcyclopen-


8

tadienide ligand systems, e.g., (63)59.Among chelating diphosphines prepared using lithiophosphide reagents are the diphosphinomethylthiophene chiral diphosphines bearing both a diphenylphosphino group and a phenylcyclohexylphosphino group, e.g., (65)61,the chiral system (66)62, a range of

and the chiral diphosphine (67)64. chiral bis(dipyridylphosphin~)methanes~~, Lithiophosphide reagents have also found use in the synthesis of calix-[4]-arene systems bearing phosphino substituents at the upper rim65, phosphinocarbaboranes66,and new p o l y p h o s p h ~ r u sand ~ ~ phosphorus-silicon68 ring and cage structures. The reactions of lithium diphenylphosphide and potassium dimethylphosphide with the mesylate ester of cholesterol have been used in the synthesis of the phosphines (68)69.

(68) R = Me or Ph

Sodium- and potassium-organophosphide reagents have also found considerable use in the synthesis of new phosphines. Sodium dimethylphosphide (generated from cleavage of tetramethyldiphosphine with sodium in liquid ammonia) has been employed in the synthesis of new phosphine-thioether ligands, e.g., (69)'O. Sodium diphenylphosphide was the reagent of choice for the synthesis of the chiral amidophosphines (70)7*and the P,S-donor (71)72. The unusual salt (72), containing the diphenylbis(cyanamido)phosphonium

(70)R' = COBu', Me or CH2Ph R2 = Me or Ph X = 0 or H2


9

diylide anion, have been obtained from the reaction of sodium diphenylphosphide with cyanogen a ~ i d e ~ Further ~. studies have appeared of electrontransfer nucleophilic substitution processes in the photo-stimulated reactions of sodium diphenylphosphide with neopentyl halides74. Displacement of fluoride from a fluoroaromatic system is the key step in the synthesis of the chiral phosphines (73)75.The reactions of potassium diphenylphosphide with chloroalkyl or tosylate precursors have been used in the synthesis of the functionalised triphosphine (74) (which can be linked to a cross-linked Merrifield resin via the phenolic the chiral phosphinoalkylphosphaferrocene (75)77, and a series of mixed donor chiral phosphines, e.g., (76), derived from chiral cr-hydroxyacid~~~. Ring-opening of 1,2-epoxybutane with potassium diphenylphosphide, followed by addition of chlorodiphenylphosphine, are the key steps in the synthesis of the large-span ligand (77)79. A convenient route to phosphines of the type (RCH2CH2)3P (R=aryl or heteroaryl) is afforded by nucleophilic addition of potassium phosphide (generated from red phosphorus, potassium and t-butanol in liquid ammonia) to aryl- and heteroaryl-etheneseO.The silylphosphine (78) has been obtained by treatment of a bromosilyl precursor with potassium diphenylphosphide. Subsequent treatment of (78) with butyllithium results in deprotonation at the central carbon to give a planar carbanionic systeme1.Sodium and potassium phosphide reagents have also found application in the synthesis of new polyphosphorus ring and cage system^^^*^^.

+

Ph2P

(73)X = F or PPh2

Once again, interest in the synthesis and structural characterisation of new metallophosphide systems has continued at a high level. Useful reviews have a p ~ e a r e d ~Sodiosilylpolyphosphide ~9~~. reagents have been prepared and structurally characterisede6. A simple route to Group 15 anionic heterocyclic systems has been developede7.Further examples of salts involving heptaphosphide anions, R2P7 - , have appearede8. Alkali metal organophosphides obtained by intramolecular coordinatione9, and a wide range of other alkali metal organophosphide ~ y s t e m s ~have ~ - ~been ~ , structurally characterised by X-ray techniques. The reactivity of calcium and barium trialkylsilylphosphides has been exploredg6.With diphenylbutadiyne, calcium (and strontium) bis(tri-


10

methylsily1)phosphidesgive rise to the phospholides (79), the reactions involving 1,3-Me$i A magnesium organosilylphosphide system has been structurally characterised9*.The chemistry of a l ~ m i n i u m ~ ~and - ' ~ gallium'** ' phosphide systems has continued to develop and zincIo3,copperl', tinlo5and uraniurn'O6 organophosphide systems have also been characterised.

(79) M = Ca or Sr

(80)

Interest in the reactions of phosphines metallated at carbon has also continued. Hydrolysis of the dianion obtained by treatment of 1,1'-bis(dipheny1phosphino)ethene with lithium yields the tetraphosphine (80)'07. The phosphinoaryldichlorophosphine (8 1) has been obtained from the reaction of o-lithiophenyldiphenylphosphinewith phosphorus trichloride'08. Treatment of o-lithiophenyldiphenylphosphinewith mercury(I1) chloride has given the organomercury diphosphine (82), of interest as a trans-spanning ligand' 09. Triorganostannylmethylphosphines have been used as reagents for the synthesis of new unsymmetrical diphosphinomethanes and related phosphinoarsinomethanes' lo. N-(o-phosphinoalkyl)pyrroles,e.g. (83), have been obtained by

the reactions of borane-protected lithiomethyldiphenylphosphine reagents with N-(a-bromobutyl)pyrrole, and subsequently polymerised to give phosphino-functional polypyrrole materials' I . Lithiomethylphosphines have been converted into related beryllium and magnesium systems, which have been structurally characterised' 12. Further examples of the formation of metallocenes from phosphines bearing cyclopentadienyl substituents have appeared' 13*1 14. 1.1.3 Preparation of Phosphines by Addition of P-H to Unsaturated Compounds. A new range of electronically unsymmetrical diphosphines has been obtained by base-catalysed addition of 'electron-rich' secondary arylphosphines to 'electron-poor' vinylphosphines, the reverse approach being unsuccessful. Thus, e.g., addition of diphenylphosphine to the vinylphosphine (84) has given the diphosphine (85)II5. A base-catalysed approach has also been used in the addition of diphenylphosphine to pyridyl- and pyrimidyl-alkynes, giving the new chiraI diphosphines (86)116, and also in the addition of primary or secondary phosphines to vinylpyridines' 17, and divinylsulfone' 1 8 . Radicalpromoted addition of primary and secondary silylphosphines, and phosphine, to alkenes and dienes has been investigated as a route to new organo(sily1)-


11

A

-P

PPh2 Ph2P PPh2 (86) R = 2- or 3-pyridyl or 2-pyrimidyl

2

(85)

phosphines, including heterocyclic systems. Thus, e.g., the reaction of trimethylsilylphosphine with trivinylphosphine yields the diphosphorinane system (87) as a mixture of isomers' 19. A range of partially fluorinated trialkylphosphines (88), with modulated electronic properties and fluorous phase affinities, has been obtained by large-scale AIBN-promoted addition of phosphine to partially fluorinated alkenes 120. The iminium salts (89) undergo addition of diphenylphosphine to form the phosphino-systems (90), capable of further elaboration via the iminium functionality, to give, e.g., (91)l2I. Further examples have

n

Pt(CHdx+2(CF&CF3]3 Me3si-pup3 (88) x = o - 2 y = 5 , 7 Or 9

(87)

Ar

flii2 NR2

2TfO-

Arflii2 NR2 '

(89)

2Tf0-

Ar'/

0 (911

(90)

appeared of the addition of secondary phosphines coordinated to transition metals to unsaturated systems, specifically dimethyl acetylenedicarboxylate'22 and ethyl d i a ~ o a c e t a t e ' ~ included ~. in a review of the reactions of 1,4- and 1,5diketones with P-H compounds is their reactions with primary phosphines which lead to phospholane and phosphorinane systems*24.A new class of very bulky diphosphines (92) is afforded by the addition of bis(phosphin0) alkanes with P-diketones. This reaction has also been applied to 1,2-bis(phosphino)benzene, which with acetylacetone yields the polycyclic system (93)125. 1.1.4 Preparation of Phosphines by Reduction. As usual, reduction of phosphine oxides using trichlorosilane continues to be the favoured approach. In the past Me

I

(92)PI = Me or CF3

(93)


12

year, it has been used in the synthesis of a series of perfluorocarbon-soluble triarylphosphines (94)126,the trans-chelating chiral diphosphine (95)127,the new atropisomeric diphosphines (96)12* and (97)129,and a series of mixed donor atropisomeric phosphines, e.g., (98)130 and (99)131-133. Phenylsilane has Me

(97)

(98)

(99)

been applied to the reduction of some high molecular weight arylene phosphine oxide polymers' 34, and to the synthesis of a calixarene bearing 'trans-chelating' diphenylphosphino substituents' 35. Reduction of dichlorophosphines to primary phosphines using lithium aluminium hydride has been used to prepare air-stable primary phosphines, e.g., (loo), bearing a dibenzobarrelene g r o ~ p ' ~ ~Lithium ? ' ~ ~ .aluminium hydride has also been used to reduce the cyclic acylphosphine systems (101) to the diphosphine (102)13*.A new route to the chiral phospholane (103) in enantiomerically pure form involves reduction of the corresponding phosphine oxide precursor using a combination of lithium aluminium hydride with cerium(II1) chloride' 39. This reagent system has also been used in the synthesis of P-hydroxyethylphosphines,from which a new route to alkenes has been developed involving the collapse of intermediate phosphiranium salts, and providing a phosphonium analogue of the Ramberg-Backlund rearrangement Alane (AlH3) has been used for the reduction of the phosphine oxide of (104)'42. A modular route to new chiral phosphine-oxazoline ligands of the type (105) involves the reduction of a phosphine sulfide precursor using Raney nickel 143. 1407141.

1.1.5 Miscellaneous Methods of Preparing Phosphines. Much information on the synthesis of phosphino-functional dendrimers of various kinds has been summarised in a series of review^'^-'^^. Other reviews have appeared which cover synthetic approaches to chiral p h ~ s p h e t a n e s ' ~the ~ , synthesis and reactivity of medium-ring diphosphines149, the application of borane-protected phosphorus reagents in the synthesis of chiral phosphines' 50, phosphinocar-


13

R

(100) R = H or Ph

(101) R=Ph3C

(102) R = Ph3C

(105) R = H, Me or Ph

boranes 51,water-soluble di- and tri-phosphine~'~~, polydentate and functionalised hydroxymethylphosphines which also offer water-~olubility'~~, the uses of phosphine (PH3) in the synthesis of organophosphines and other comp o u n d ~and ~ ~ the ~ , synthesis, structure and reactivity of phosphin~carbenes'~~. Full details of the synthesis of air-stable ferrocenylmethyl primary and secondary phosphines have appearedIs6. A route to the aminoalkyl-functionalised chiral ferrocenyldiphosphine ( 106) has been described; this compound has found use in the synthesis of dendrimers containing the chiral ferrocenyl unit at the surface157.The diphosphinoferrocene (107), accessible from the reaction of 1,1'-bis(diethy1phosphonato)ferrocene with an aryllithium reagent bearing an allylsilylalky1 group, is a key building block in the synthesis of phosphinoferrocenyldendrimers which exhibit catalytic activity in the core of the SiR3

R3Si

\

R3Si'

di (107) R = ally1

dendrirnersI5*.The reaction of secondary phosphines with benzylic halides, followed by deprotonation of the phosphonium salt, is the principal method used in the synthesis of the pincer-like diphosphines (108)159.No basepromoted deprotonation is required in the reaction of dibenzotropylidene chloride with secondary phosphines ( 109)160. A route to the phosphaazabarr-

14


(108) R = But or Ph X =OH, OMe or OEt

(112) R =

n=Oorl

elanes (1 10) has been described161. Base-promoted cyclisation of phenylbis(2mercaptoethy1)phosphine with bis(3-chloropropyl)sulfoxide has given the macrocycle (1 1 1) which, although stable in the solid state, undergoes oxygen transfer from sulfur to phosphorus in solution16*. A route to the rigid tetraphosphine ligands (1 12) has been reported163.The importance of pHcontrol in the work-up of the sulfonation of triphenylphosphine has been stressed and an improved procedure developed which gives the product free of contamination by the phosphine oxidela. A new ylide-based route to diphenylvinylphosphines (and their oxides and sulfides) has been devised165.Silylphosphine formation has been demonstrated in the titanocene-catalysed reaction between secondary phosphines and monoorganosilanes, providing the first example of heterodehydrocoupling between Si-H and P-H bonds166.The o-carboranylmethylphosphine(C2B OH ])CH2PPh2has been prepared167. The formation of arylphosphines by the palladium- (or nickel-) catalysed reactions of haloarenes or triflate esters of phenols with primary or secondary phosphines continues to be used, in particular in the synthesis of phosphines bearing other reactive functional groups. The past year has seen its application in the synthesis of arylphosphino-functional tx-cyclodextrinsl6*,water-soluble tethered polymeric p h ~ s p h i n e s ' ~the ~ , phosphonato-functional phosphines (113) (capable of hydrolysis to give water-soluble systems)'70, a range of substituted arylphosphines, e.g., ( I 14)17',and the water-soluble guanidiniumfunctionalised phosphines (1 15)' 72. The approach has also been applied to the synthesis of further chiral atropisomeric phosphines e.g., (1 16)173and (1 17)174, and the the synthesis of the vinylphosphines (1 18) from halogenoenamines and halogenoenol ethers175.A related palladium-catalysed cross-coupling reaction between haloarenes and silylphosphines has been used in the synthesis of arylphosphines bearing both donor and acceptor substituent groups 176. The formation of aminomethylphosphines in the reactions of hydroxymethylphos-

15


(115) R = H or Me X=CIorI

phines with primary or secondary amino compounds has received further study, having been applied in a parallel synthesis of a 96-member library of aminomethylphosphine l i g a n d ~ ' ~the ~ , phosphinomethylpiperazine (1 19)178, and chiral water-soluble phosphines, e.g., ( 120)179and ( 121)lS0,derived from

(121) R ' = H o r M e H

R2 = C02H or H

O

amino acids. The nickel(I1)-catalysed reaction of 2-(2-bromophenyl)benzothiazole with tris(hydroxymethy1)phosphine in ethanol results in the formation of the triarylphosphine (122) in 20% yield. An X-ray study reveals that in the phosphine, all three heterocyclic nitrogens are inyolved in a close approach to phosphorus, the average N-P distance (2.974 A) being significantly smaller than the sum of the Van der Waal's radii. Such apparent coordinative interactions are not so evident in the related phosphine oxide*81.Intramolecular coordination of this type in phosphorus compounds has been reviewed182, and new examples described relating to 8-dimethylamino-1naphthylphosphines and related compounds 83. A nickel-catalysed electrochemical cross-coupling reaction between aryl halides and chlorophosphines has been described, which affords tertiary phosphines in high yields. The reaction tolerates the presence of electron-withdrawing groups in the haloarene, and also can be applied to heteroaryl halides184.Arylation and alkylation of white


16

phosphorus has been achieved in the presence of electochemically-generated samarium(H)'*~.Arylation of trivalent phosphorus esters, using aryllithium reagents, has provided a route to phosphines incorporating 2-cyanophenyl substituents186and some new chiral ferrocenylphosphine systems (123) (viathe use of chiral, borane-protected, phosphinite esters) 88. Dipropargylic phosphines combine with dicyclopentadienylzirconium to form a bicyclic organozirconiumphospholane intermediate which on protonation gives new phospholanes, e.g., (12 4 p 9 . Routes to phosphinomethylsilacyclopentenes190 879

SiMe3

R

)"

sQ

Me3siT-r

Fe @PY R

and the phosphinoaminoarylphosphine (125)19 have also been described. New heteroarylmethylphosphine ligands, (126)192and ( 127)193,have been obtained from the reactions of halogenophosphines with heteroarylmethylsilyl precursors. Pentafluoropyridine has been shown to react with trimethylsilylphosphines with elimination of trimethylsilyl fluoride, to give the phosphines ( 128)'94.Thiadiazolylphosphines have been prepared by direct phosphination of the ring system with halogenophosphines19s.

(127) R = Ph or Pr'

(128)

R = PI" or Me

A variety of new phosphines has been obtained by elaboration of functional groups already present in precursor phosphines. Acylation of aminoalkylphosphines has provided the chiral diphosphines (129)'96 and (130)197,and Nacylation of chiral pyrrolidinylphosphines has given the new mixed donor ligands (13 1)198 and a water-soluble acrylate polymer-bound system199. Further examples of Schiff's base condensation of o-diphenylphosphinobenzaldehyde have appeared, e.g., to give (1 32) from 1S,2R-norephedrine. A Schiff's base condensation has also been used by the same group for the synthesis of ( 133) from o-aminophenyldiphenylphosphine with salicylaldehyde2'? The new polynitrogen-macrocyclic functionalised system ( 134) has been obtained by reductive amination of o-diphenylphosphino benzaldehyde201. The planar-chiral P,N-ligand system ( 135) has been prepared by treatment of the chromium tricarbonyl complex of o-diphenylphosphinobenzaldehyde with 2-pyridyllithium, followed by further development of the

17


k I

resulting A route to the chiral system (136) has been developed from o-diphenylphosphinobenzonitrile203. Side-chain elaboration of the phosphinoferrocene (137) has given the new chiral systems (138) and (139)204.

t PPh2 N

PPh2 (1 35) R = Me, PhCH2 or panisyl

OMe

1.2 Reactions of Phosphines. - 1.2.1 Nucleophilic Attack at Carbon. The generation of reactive intermediates by the addition of phosphines to unsaturated esters, and their subsequent reactions, has continued to attract interest. Full details have now appeared of the formation of nitrogen heterocycles via phosphine-catalysed reactions of 2,3-butadienoates, 2-butyneoates and dimethyl acetylenedicarboxylate, respectively, with electron-deficient irnines2O5. Yavari's group has continued to exploit the reactivity of the 1:l adducts of triphenylphosphine with dialkyl acetylenedicarboxylates in the synthesis of heterocyclic compounds206-208and new stabilised phosphonium ylides involving heterocyclic s u b s t i t u e n t ~ ~ ~This ~ - ~ approach ' has also led to new routes

'.


18

to cyclobutene derivatives2 and functionalised cr-pyrans2'3. Novel bismethanofullerenes and an ethenofullerene have been obtained from the reactions of methyl and ethyl propiolates with C a in the presence of triphenylph~sphine~~~. A route to vinyl-substituted furans is afforded by the phosphine-initiated reactions of enynes bearing a carbonyl group2 5. Tributylphosphine has been shown to promote [3 + 21 cycloaddition reactions between 2-alkynoate and 2,3allenoate esters with electron-deficient alkenes216and also the cyclisation of y6or &-unsaturated aldehydes to form hydroxy-cyclopentenes and -cyclohexanes2I7. ( 1-Alkoxyethenyl)diphenylphosphines are the main products of the reactions of diphenyltrimethylsilylphosphine with terminal alkoxyalkynes21*. P-Acetylenic alcohols are reduced to the related allylic alcohols on treatment with tertiary phosphines in the presence of water, the reaction proceeding via initial attack of the phosphine on the acetylenic bond2l9. The kinetics of the insertion reactions of aryl isocyanates into the C-C bond of the zwitterion formed in the addition of triisopropylphosphine to ethyl 2-cyanoacrylate in acetonitrile have been studied by a spectrophotometric technique, and a mechanism proposed220.Interest also continues in the reactions of phosphines with carbon disulfide and related cumulenes. Solvent effects have been studied for the tributylphosphine-carbon disulfide system221.The phosphinozirconaindene (140) undergoes [3 + 21 cycloadditions with carbon dioxide, carbon disulfide and isothiocyanates to form the cyclic zwitterions (14 1)222.The kinetics of quaternisation of triphenylphosphine by various benzylic halides have been studied in a range of two-phase organic solvendwater media223.

(141) X = 0, S or NR

(140)

1.2.2 Nucleophilic Attack at Halogen. A wide range of tertiary phosphinedibromine adducts has been studied and shown to adopt the ionic structure, R3PBr+ Br- in solution in deuteriochloroform. The only exception to this pattern is the adduct of tris(pentafluoropheny1)phosphine which exhibits a pentacovalent trigonal bipyramidal structure both in the solid state and in solution224.Diiodine adducts of a series of diphosphinoalkanes have also been characterised, these compounds showing the familiar 'molecular spoke' structure in the solid state, but ionising in solution in deuteriochloroform225~226. The reactions of the diphosphatricyclooctenes (142) with bromine or iodine R

R

(142) R = H or

I

Me

(143) X = hat


19

monochloride result in selective cleavage of the P-P bond of the diphosphirane units with formation of the related bishalogenophosphine system ( 143)227. Synthetic applications of the triphenylphosphine+xrbon tetrachloride system have continued to appear. An improved route to tertiary amines from alcohols has been developed, involving the direct reaction of the alcohol with triphenylphosphine, carbon tetrachloride, and a secondary amine in acetonitrile228.A new indoline-forming reaction has been developed by treatment of 242hydroxyethy1)aniline with the triphenylphosphine-carbon tetrachloride system229.Halogenation of carbohydrates has been achieved with the use of combinations of triphenylphosphine with carbon tetrachloride, hexachloroethane or 1,2-dibromotetrachloroethane in highly concentrated solutions in non-polar solvents, assisted by microwave irradiation230.The triphenylphosphine-carbon tetrachloride system has also been used for the dehydration of a diol to form a 1,5-diene23'. A gel-form of a cross-linked polystyryldiphenylphosphine in carbon tetrachloride has been shown to be effective for the conversion of primary alcohols into alkyl halides, and secondary and tertiary alcohols into a l k e n e ~ Attack ~ ~ ~ . of phosphine at halogen is also involved in reaction of 2,2,2-trihaloethyl esters with tributylphosphine in the presence of an alcohol or amine, which provides a useful procedure for the synthesis of esters and a m i d e ~and ~ ~ also ~ , in the reaction of perfluoroalkyl (bromomethyl) ketones with triphenylphosphine in the presence of titanium isopropoxide which forms the basis of a one-pot stereoselective synthesis of perfluoroalkylated (a-allylic alcohols234.Combination of trichloroisocyanuric acid with triphenylphosphine in anhydrous acetonitrile has been shown to convert alcohols into alkyl halides, carboxylic acids into acid chlorides, 1,3-diketones into vinyl chlorides and amides into nit rile^^^^. The triphenylphosphineiodotrimethylsilane system is an effective catalyst for the tetrahydropyranylation of aliphatic and benzylic alcohols with dihydropyran in dichloromethane at room temperature236.Combination of triphenylphosphine with dichloroselenuranes, R2SeC12,also provides a system which converts alcohols into the corresponding chloroalkanes, although the stereochemical course seems to depend on the structure of the Tertiary phosphines have been shown to react with germanium tetrachloride to give the ionic system R3 PCl+ GeC13-- 238. 1.2.3 Nucleophilic Attack at Other Atoms. Recent developments in the chemistry of phosphine-borane complexes have been reviewed239. Phosphineborane complexes have been prepared from diastereoisomerically pure monoisopinocamphenylcyanoborane, and shown to undergo SN2-displacementreactions at boron when treated with a more basic p h o ~ p h i n e A ~ ~series ~ . of ferrocenylphosphine-borane complexes has been prepared by treatment of the appropriate phosphine with calcium borohydride in the presence of copper(I) chloride in THF241. A triphenylphosphine adduct with tris(pentafluor0pheny1)borane has been ~ h a r a c t e r i s e d ~Whereas ~~. arylphosphine oxides usually undergo ortho-metallation on treatment with phenyl-lithium, it has now been shown that related arylphosphine-borane complexes undergo metal-

20


lation at the p a r a - p ~ s i t i o nFurther ~ ~ ~ . examples of adducts of phosphines with alkyl- and aryl-aluminium hydride acceptors have been d e ~ c r i b e d ~ A ~-~~~. study of the complexation of (31,2-bis(diphenylphosphino)ethene by aluminium-, gallium-, and indium-trihalides has revealed a tendency for the phosphine to undergo isomerisation to the (a-form as a result of complexation, the extent of isomerisation depending on the Lewis acid, and the solvent247. The use of triphenylphosphine instead of trimethyl phosphite as a deoxygenating agent results in much improved yields in the Sharpless synthesis of chiral sulfinate esters from arylsulfonyl chlorides and chiral alcohols248. Methyltrioxorhenium has been shown to be an effective catalyst for the air-oxidation of p h ~ s p h i n e sand ~ ~ the ~ phosphine-promoted, stereospecific desulfurisation of e p i s ~ l f i d e s The ~ ~ ~reduction . of alkyldisulfides with tributylphosphine in the presence of water provides a practical option for the preparation of gram quantities of thiols or thioesters from the corresponding d i ~ u l f i d el s. ~Triphe~ nylphosphine-promoted desulfurisation has been utilised in the synthesis of sulfur-rich dithiolene systems252,and also for the synthesis of a cyclic disulfide from the related cyclic t e t r a s ~ l f i d e ~A~ ~ solution . calorimetric study of the reaction of phosphines with cyclooctasulfur has shown that a good correlation exists between the enthalpy of protonation of the phosphine and the enthalpy change for the reaction with sulfur. It is concluded that a-donation from phosphorus to sulfur is the principal component of a strong phosphorus to sulfur bond in a phosphine sulfide. Bond strengths in phosphine chalcogenides decrease as expected from sulfur to tellurium, but the strength of the phosphorus-tellurium bond is still significant (52 kcal mol- in tributylphosphine telluride). The reactivity of phosphine tellurides is thought to be due to additive rather than dissociative mechanisms. There is a less significant decrease in bond strength in the series triphenylphosphine sulfide - triphenylarsine sulfide - triphenylstibine sulfide, but it has been established that triphenylphosphine will desulfurise the arsine and stibine sulfides in solution254. Nucleophilic attack at nitrogen appears to be involved in the reaction of triphenylphosphine with ethyl pentacyanocyclopropanecarboxylate, which results in the formation of the phosphazene (144)255.A range of new P,Nheterodifunctional ferrocene-based coordinating ligands, e.g., (149, has been

CN CN NC*CN

(144)

(145) R = 1-4

obtained by the reactions of di- and tri-phosphines with an azidoethenylferro~ e n e Cage-structure ~ ~ ~ . phosphazides, involving the R3P=N-N=N-Ar unit, have been obtained from the reactions of tris(2-azidobenzy1)amines with the tripod-like triphosphine 1,1,1-tris[(diphenylphosphino)methyl]ethane257~258,

1: Phosphines und Phosphonium Salts

21

Phosphazene intermediates are involved in a one-pot conversion of azides to Boc-protected amines with trimethylphosphine and 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile2s9. Interest in the Mitsunobu reaction and its applications in synthesis has continued. The use of 1,2-bis(diphenylphosphino)ethane instead of triphenylphosphine has been advocated for both Mitsunobu and Staudinger (aza-Wittig) procedures, the essential point being that the more polar diphosphine dioxide is more easily separated from the products than is triphenylphosphine oxide260.Various azodicarboxamides have been suggested as improvements on the familiar diethyl azodicarboxylate (DEAD) for use in Mitsunobu reactions. The same paper advocates the use of stabilised phosphonium ylides, e.g., cyanomethylenetributylphosphorane as alternatives to conventional Mitsunobu systems. These ylides are said to be much more versatile in promoting C-alkylation, particularly for secondary alcohols26l . A polymer-bound arylphosphine has been used for Mitsunobu reactions in combinatorial chemistry, aiding product separation262.The use of diphenyl(2-pyridy1)phosphine in Mitsunobu procedures also aids product separation, both unreacted phosphine and the phosphine oxide being acidextractable into the aqueous layer263.Use of the functionalised phosphine (146) (obtained by base-promoted addition of diphenylphosphine to t-butyl acrylate), and the azodicarboxamide (147) has enabled the development of a high 0 0 II II P ~ ~ P C H ~ C H ~ C O ~ B U ‘ Bub2CCH2NH-C-N=N-C-NHCH2C02But (146)

(147)

throughput product purification in Mitsunobu reactions. The t-butyl ester tagged reagents and byproducts are easily converted by exposure to acid into carboxylic acids which are easily removable by ion-exchange resins264.Picolinic acid has been shown to be a useful partner in Mitsunobu procedures. The resulting esters can be methanolysed under essentially neutral conditions using copper(I1) acetate in methanol265.N-Boc ethyl oxamate is a new nucleophile for use in Mitsunobu chemistry for the conversion of primary and secondary alcohols into Boc-protected amines after a mild deprotection step266.Mediation by imidazole has been employed in a Mitsunobu synthesis of alkyl t h i ~ e t h e r s ~ ~ ~ . An unusual pattern of reactivity in Mitsunobu chemistry has been recognised in the formation of 0-alkylated rather than N-alkylated products from s u h h y dantoins26x. Mitsunobu chemistry has been used in the synthesis of novel inhibitors of farnesyl t r a n ~ f e r a s e isocyanates ~~~, from alkyl- or hindered arylamines and carbon d i o ~ i d e l ~, 2-methylaminothiazolines ~~y~~ from N-(2-hydroxyethyl)-N’-methylthioureas272, t h i o n u ~ l e o t i d e s ~ and ~ ~ , N-arylpiperazinones274.A phthalimide-containing resin has been used in conjunction with the Ph,P-DEAD system in an efficient route to primary amines from the corresponding alcohols, via Mitsunobu coupling and subsequent hydrazine-induced cleavage27s.Fundamental work on the mechanism of the Mitsunobu reaction has also appeared. It was noted several years that the formation of the usual betaine in the Ph3P-DEAD system was accompanied by a low concentration of a radical species, initially thought to be (148). It has now been shown


22

that the initially formed betaine is far too difficult to oxidise to the radical, and that the latter is almost certainly formed by attack of phosphorus at carbonyl oxygen, followed by in situ oxidation to give ( 149)277.

1.2.4 Miscellaneous Reactions of Phosphines. Further theoretical278and experimental s t ~ d i e s ~ ~ 'of - ~ the ~ ' basicity of phosphines have been published. Reviews have appeared of the synthesis of organophosphorus compounds, usually via phosphonium salts of various kinds, which are obtained from the reactions of nucleophiles with phosphonium radical cations generated by electrochemical oxidation of p h ~ s p h i n e s ~This ~ ~ .approach ~ ~ ~ . has also been applied to synthetic problems in carbohydrate chemistry284. Treatment of tributylphosphine with methylviologen salts also results in a single electrontransfer process to form the related tributylphosphonium radical cation, which has then been shown to react with a range of nucleophiles as expected285.3,5Di-t-butyl- 1,2-benzoquinone has been shown to react with triphenylphosphine to form the cyclic phosphorane (1 50). Triphenylarsine behaves similarly to give the related arsorane, but the reaction with triphenylstibine yields the stablised ylide ( 151)286. Phosphinocarbenes, e.g., (1 52), are useful intermediates in synthesis. Treatment with butyllithium gives rise to the phosphonium ylidide (153), capable of further elaboration287. Coupling of an isocyanide with a diphosphinocarbene in the coordination sphere of a manganese complex yields the reactive diphosphine (1 54), which undergoes further combination with the isocyanide to give ( 155)288. The reaction of o-hydroxyalkylphosphines with

PhN

(154) R = Ph or But

(155)

bis(dimethy1amino)dimethylsilane is the basis of a divergent route for the synthesis of organophosphine-based d e n d r i m e r ~ ~ ~ The ' . cyclisation of diallylphosphines to 3-phospholenes in the presence of a tungsten-carbene complex has been reviewed, together with related conversion of diallyl-ethers, -thioethers, and - ~ i l a n e s ~ ~Metal-promoted '. ring-contraction reactions of 1,2,3-triphospholenes, giving complexed 1,2-diphosphetenes, have been ex-


23

p10red~~'. The vanadacyclopropenylphosphine (156) has been obtained from the reaction of a bis(a1kyny1)phosphine with dicyclopen t a d i e n y l ~ a n a d i u m ~ ~ ~ . a-Aminomethylphosphines ( 157), containing a secondary amino group, have been shown to exist in equilibrium in solution with diphenylphosphine and an imine. They are stabilised by electron-wit hdrawing substituents, and also by coordination at phosphorus to ~ o p p e r ( 1 ) ortho-Diphenylphosphinobenzal~~~. dehyde has been transformed into the mixed donor ligand (158)294. The Ph )p":cp

CP

PhCEC-P A 'r (156) Ar = 2,4,6-But3C6H2

Ph2P-CH-NHR2 R' I

K

(157) R' = Ph or pN02C6H4 R2 = Me, Ph, CHMePh or pN02CsH4

E

-

O

H

( 158)

reactivity of non-phosphorus functional groups in the neopentyl systems (1 59) has been e x p l ~ r e d ~Interest ~ ~ , ~ in ~ ~the . synthesis and reactivity of watersoluble phosphines has continued. The first evidence of molecular-recognition between sulfonated triarylphosphines and cyclodextrins has been obtained with the isolation of inclusion complexes297. The water-soluble 'large bite' diphosphine (160) has been obtained by conventional sulfonation of the parent d i p h ~ s p h i n e An ~ ~ ~alternative . approach to the aqueous solubility problem is the introduction of polyoxyethylene and related surfactant groups into the phosphine, which then has both ligand and surfactant properties, Fdcilitating its use as a micellar catalyst. This area has now been reviewed299.The chiral monodentate phosphine (161) has been resolved via a chiral amine-palladium complex, and the absolute configuration established by NMR studies300. A novel procedure for the synthesis of labelled imines and aldazines involves a tributylphosphine-catalysed decarboxylation step"O'. Combination of triphenylphosphine with scandium triflate provides a reagent system which promotes the Reformatsky reaction of a-bromocarboxylic acids with aldehydes302.

"""* S03Na

\

0

PPh2 (159) Z = PPh2 or SR

2

PPh2

(160)

Phosphine Oxides and Related Chalcogenides

2.1 Preparation. - The first metal-catalysed, highly selective and efficient procedure for the mono-oxidation of a,o-diphosphinoal kanes has been developed, involving treatment of the diphosphine with 1,2-dibromoethane and sodium hydroxide in the presence of palladium( 11) acetate303. The diphos-

24


phine-dioxide and -disulfide (162) have been prepared by direct reaction of the parent diphosphine with oxygen and sulfur, respectively304.Routes have also been developed to a series of multifunctional 1,2-bis(tritylated)diphosphine monoxides, e.g., (1 63)305 and the bifunctional atropisomeric diphosphine dioxide ( 164)306. Chiral p-aminophosphine oxides, e.g., (169, have been obtained by addition of a chiral secondary amine to vinylphosphine oxides307. The chiral phosphine oxides (166) are formed on addition of diphenylphosphine oxide to a chiral cyclic imine, catalysed by a lanthanide complex308. Similar additions of dimethylphosphine sulfide to the C=N bond of 3thiazolines309,and of secondary phosphine oxides to both and acyclic s u l f o n e I~, ~have ~ also been described. urtho-Metallation of a chiral amine, followed by treatment with phosphorus oxychloride, affords the chiral u(aminoalky1)arylphosphine oxide ( 167)312.Di-t-butylphosphinylbenzene(1 68, 0

WIAr2

X II

OH

PPh2 II X (162) X = O o r S

0 H, I,H ,P-P Ph3C 'CPh3

(163)

(165) R',R2 = Ph or R' = Bu', R2 = Ph

(1 64) Ar = Ph or pMe2NC6H4

(166)x = s or C H ~

(167)

R',R2 = alkyl or cycloalkyl

X = H) has been shown to undergo ortho-metallation, providing a route to a series of functionalised arylphosphine oxides3'3. Functionalised nitrogen-containing tertiary phosphine oxides have been prepared by alkylation of the sodium salts of o, m-,and p-aminophenols with chloromethyldimethylphosphine oxide314. Routes have also been developed for the synthesis of phosphinoylmethyl derivatives of N-hetero~ycles~'~, new a-amino-o-(diphenylphosphiny1)alkanoic acids3*6, and the phosphine oxide (1 69), subsequently employed in the synthesis of vitamin D systems317.

Bu'Me2Si0

OSiMe2Bu' Bu

0

1: Phosphines and Phosphonium Suits

25

A simple route to fullerene-phosphine oxides is provided by heating together a trialkylphosphine oxide and [60]-fullerene under reflux in toluene, a retro-ene mechanism having been proposed3'*. The synthesis of calix[4]arenes bearing phosphorus-containing functional groups, including phosphine oxides, has been reviewed319,and new examples reported, together with studies of their ability to selectively complex trivalent lanthanide, actinide, and other metal ions320,321,. The synthesis and reactivity of dendrimers based on phosphoryl groups has been described, together with their ability to undergo surfacefunctionalisation with chiral phosphine The phosphine oxide ( 170), prepared by hydrogen peroxide oxidation of the related phosphine, undergoes polymerisation to form a thermoset perfluorocyclobutane polymer bearing phosphine oxide f ~ n c t i o n a l i t y ~ Reports ~ ~ . of the synthesis of polyester-324, p ~ l y a m i d e and -~~~ systems incorporating phosphine oxide units have also appeared. 2.2 Reactions. - Tertiary phosphine-sulfides and -selenides are converted into the related phosphine oxides on treatment with potassium peroxymonosulfate. The reaction proceeds with predominant retention of configuration at phosp h o r ~Diphenylphosphinites ~ ~ ~ ~ . derived from cyclohexenols have been shown to rearrange on heating in toluene to form phosphine oxides. Thus, e.g., the diphosphinite (1 71) gives the bis(phosphine oxide) (172), the precursor of a chiral l i g a ~ ~The d ~ bis(phosphine ~~. oxides) (1 73) have been obtained by DielsAlder additions of 1,2- bis(diphenylphosphinoy1)ethyne to various cyclopentad i e n e ~The ~ ~ choice ~. of reaction conditions has a crucial effect on the synthesis

(173) R = H, Me, Pr or But

of phosphorylated ethers by the oxa-Michael reaction from diphenyl(hydroxymethy1)phosphine oxide and diphenylvinylphosphine oxide. In the presence of a catalytic amount of potassium hydroxide in dioxan at room temperature, the desired ether (174) is formed, whereas when the reaction is conducted in the presence of sodium hydride in THF at 50 "C the diphosphine dioxide (175) is formed, presumably via loss of formaldehyde to give diphenylphosphine oxide, which then adds to the vinylphosphine oxide33o.The phosphinoylacetic acid (176) undergoes Kolbe electrolytic coupling to form the chiral bis(phosphine oxide) ( 177)331.Methods of ring-arylation of phospholene oxides have been explored, treatment of 2-phospholene oxides, e.g., (1 78) with iodoarenes in the 0

0

0

II

tl

0 It

0 II

I1 Me**kCH2C02H

0

0

i?i II

Me

II

C8Hl7

Ph2pupph2 C 8 1 7 Me

Ph2pvoWpPh2 ( 174)

(1 75)

(176)

(177)

26


presence of ammonium formate and a palladium acetate catalyst resulting in the arylphospholanes (179). In contrast, treatment of the related 3-phospholene oxide under modified Heck conditions with an aryldiazonium salt, again catalysed by palladium acetate, yields the arylated 2-phospholene oxide system (1 80)332. The cyclic phosphine oxide (18 1) undergoes ring-expansion to

form (182) on treatment with chloroform under alkaline conditions and in the presence of a phase-transfer catalyst333.Heating the tetrazolylsulfinylmethylphosphine oxide (183) with secondary amines in dioxane at 70 "C results in the formation of the phosphinoylcarbothioamides (1 84), probably viu initial formation of the sulfine (185)334.Methods have been explored for the selective y-functionalisation of 1-phosphanorbornadienes (186)335, and C-alkylation of and a l l e n ~ l -phosphine ~~~ oxides using cuprate reagents. An Me

efficient conversion of oximinoalkylphosphine oxides (1 87) to the p-aminoalkylphosphine oxides (1 88) has enabled routes to azadienes and (a-allylamines to be developed338. Stereospecific hydrohalogenation reactions of 1alkynylphosphine oxides have been reviewed339.Further papers on the reactivity of side-chain functionalised phosphine oxides, and their use in asymmetric synthesis, have appeared340y341,Mechanistic aspects of the deprotonation of alkylphosphine oxides using organolithium reagents have been reviewed342.A review of the regioselectivity of the reactions of heteroatom-stabilised ally1 anions with electrophiles includes material on phosphine oxide chemistry343.Interest in the generation of phosphorus-based free radicals by photolysis of acylphosphine oxides has ~ o n t i n u e d ~Interest ~~-~~~. also continues in hydrogen-bonded adducts of phosphine This

(189) n = 3 0 r 4

(190) n = Oor 1

27


topic has also received a theoretical treatment351. Ring-chain halotropic tautomerism between o-bromoalkylphosphine sulfides ( 189) and heterocyclic thiophosphonium salts (190) has received further s t ~ d y ~ A~ related ~ - ~ ~ ~ . study of the alkylation of phosphinothioylacetonitriles with unsymmetrical a,o-dihaloalkanes has also appeared355. The first 1:1 adducts of tertiary phosphine selenides with bromine have been characterised, and shown to have structural differences to the related diiodine complexes356.A study has also appeared of the dipole movements of iodine and iodine cyanide complexes of phosphoryl compounds357.Diphenlyphosphine oxide has been suggested to be an alternative to organotin hydrides in the radical deoxygenation of alcohols358. 2.3 Phosphine Chalcogenides as Ligands. - A series of new cavitand ligands, (191), providing phosphine oxide or sulfide donor sites, has been designed and applied to the separation of lanthamide and actinide ions359.Further triphenylphosphine oxide complexes of lanthanide salts have been investigated360.The coordination of triphenylphosphine oxide to lanthanide ions has also received a theoretical The crystal struture of the tetrakis(tripheny1phosphine 0xide)lithium bromide complex has been described362.The structural chemistry of complexes of organotin moieties with chelating bis(phosphine oxides) has received and a tin(11) complex with triphenylphosphine oxide characterised by X-ray techniques364.A study of the coordination complexes of platinum(I1) with the (pyridyloxymethy1ene)dimethylphosphine oxides ( 192) has revealed that coordination to the metal is from the pyridine ring nitrogen, rather than from the phosphine Triphenylphosphine oxide complexes of iron have been explored, and shown to exhibit antimicrobial properties366. Tertiary phosphine sulfides are effective ligands in the palladium(I1)-catalysed bis(alkoxycarbony1ation) of a l k e n e ~ The ~ ~ ~bis(diphenylthiophosphory1)pyri. dine (193) has been shown to act as a terdentate ligand in its coordination complexes with rhenium carbonyl acceptors368.Silver complexes of w-diphenylphosphinoalkydiphenylphosphine sulfides have been c h a r d c t e r i ~ e d ~ ~ ~ . Mixed phosphine sulfide (or se1enide)-thioether ligands, e.g., (194), readily coordinate to palladium(I1) and platinum(I1) acceptors370.The phosphinophosphine selenide ligdnd (195) forms complexes with a range of transition metal ions371.

(191) X = O o r S

(192)

X

X

It

Ph2P-( CH&-S--(

II

CH&-PPh2

(194) X = S or Se

28


2.4 Structural and Physical Aspects. - Interest continues in the nature of the phosphorus oxygen bond in phosphine oxides and related compounds, and a further two theoretical treatments have a p ~ e a r e d ~A ~theoretical ~ , ~ ~ ~ approach . to the study of structural characteristics of trialicylphosphine oxides, sulfides, and selenides has produced results that agree reasonably well with published X-ray and electron-diffraction data374. A full X-ray structural study of bis(methoxycarbonylmethy1)phenylphosphine oxide has been reported375. Thermodynamic parameters associated with the formation of micelles from long-chain alkyldimethylphosphine oxides have been determined376.

3

Phosphonium Salts

3.1 Preparation. - A series of hexacoordinate phosphonium salts (1 96), involving intramolecular N -+ P coordination, has been prepared. The effects of coordination on reactivity have also been explored377.Routes to the functionalised arylphosphonium salts (197) and (198), bearing carboxylic acid and phenolic substituents, respectively, have been developed for use in Wittig reactions in aqueous media. These compounds are soluble without decomposition in dilute aqueous sodium hydroxide solution378. Quaternisation of benzylic bromide systems, e.g., ( 199), with triphenylphosphine, in the presence of dibenzo[24]crown-8, results in the formation of [2]rotaxane systems, in which the 'linear' diphosphonium salt, e.g., (200), is threaded through the Me,

f""

Ye,Me

(196) R' = H, Me or Ph R2 = H or CH2C02Et

(197)

(198) n = 1 or 2

centre of the macrocycle, the bulky phosphonium end-groups acting as 'stoppers' which prevent the separation of the components379. Conventional quaternisation reactions have also been applied in the synthesis of a series of chiral monophosphoniophosphine ligands, (e.g., 201)380, the phosphonioisoxazoles (202)3x1,the alkyltris[2-arylvinyl]phosphoniumiodides (203)382,and a range of polymer-supported phosphonium salts of value as phase-transfer ~ a t a l y s t s ~ *ion-exchange ~.~~~, systems, and antibacterial agents385. A new synthesis of arylphosphonium salts is afforded by the electrochemical oxidation of tripropylphosphine in the presence of toluene and water, the initially formed radical cation then being involved in electrophilic substitution on the

29


Ph2P' PPhZ I Me X-

[Ar-CH=CHkh (202) R = Me or Ar

(2011

I-

(203) Ar = Ph, 4-FC6H4,2-Fury1 or 2-Thienyl R = Bu, Pentyl or Me

arene386.A nickel(0)-catalysed route has been used for the synthesis of chiral arylphosphonium salts, e.g., (204), from the related b r o m ~ a r e n e ~ * The ~ > ~a~*. fluorovinylphosphine (205) undergoes conventional quaternisation with alkyl halides, and is converted into the related arylphosphonium salt (206) on treatment with diphenyliodonium triflate in the presence of ~ o p p e r ( 1 ) N~~~. Trichlorovinylpyridinium chloride has been shown to undergo nucleophilic attack by tributylphosphine at the 4-position of the pyridine ring, with the formation of the dihydropyridylphosphonium salt (207)390.The ylidylphosphine (208) has been converted into the zwitterionic phosphonioalkyl dithio (or seleno) phosphinates (209)39'. Betaine systems have also been obtained

A

H

A0

HN

+ P B U ~ct-

I

from the reactions of phosphines with unsaturated carboxylic acids and their derivatives392.The reactions of long-chain aliphatic aldehydes with phosphine in the presence of hydrogen chloride have given a series of tetrakis(ahydroxyalky1)phosphonium salts, in a variety of stereoisomeric forms393. Interest in the synthesis of phosphonium salts involving unusual anions has continued. A series of phosphonium cyclopentadienide salts has been obtained from the reactions of phosphonium ylides with c y ~ l o p e n t a d i e n e s ~Tetra~~. octylphosphonium triphenylmethanide has been prepared and used as a metalfree anionic initiator for the living polymerisation of met ha cry late^"^. A tetramethylphosphonium salt involving the 2,5-dimethyltetracyanoquinodi-

30


methane radical anion has also been characterised, the salt exhibiting both ferromagnetic behaviour and high electrical conductivity at room temperat ~ r e Methyltriphenylphosphonium ~ ~ ~ . tetrahydroborate has been shown to be a stable, selective, and versatile reducing agent397.Another useful reagent is found in benzyltriphenylphosphonium peroxodisulfate, an easily prepared and stable salt, useful for the efficient oxidation of organic compounds under nonaqueous and aprotic condition^^^^,^^^. A variety of phosphonium salts bearing complex anions derived from both main g r o ~ p and ~ ~transition ~ - ~ metal ~ ~ has also been characterised.

3.2 Reactions. - Iodomethyltriphenylphosphonium tetrafluoroborate combines with chlorine to form the polyhalomethylphosphonium salt (2 The dehalogenation of chlorophosphonium ions by halide ions has been investigated in a quantum-chemical study410.Treatment of the squaric acid-triphenylphosphine betaine (2 11) with oxybis(dipheny1borane) results in the formation of (212), a new type of phosphonio-borate betaine4". Ketones and

esters have been prepared efficiently from the reactions of Grignard reagents with acyltributylphosphonium salts412.Further examples of the synthesis of heteroarylphosphonium salts from the reactions of functionalised vinylphosphonium salts have been d e ~ c r i b e d ~ ' ~ -The ~ I ~electrochemical . reduction behaviour of pentafluorophenylphosphonium salts has been compared with that of other pentafluorophenyl 'onium species by cyclic ~ o l t a m m e t r y ~ ' ~ . Ylides are among the products of electroreduction of alkyl- and benzyltriphenylphosphonium salts in acetonitrile. The related arsonium salts give triphenylarsine as the main reduction product4' 7 . The equilibrium acidities of a series of substituted benzyl-phosphonium, -arsonium, and other related 'onium salts of sulfur, selenium, and tellurium have been c ~ m p a r e d ~ The '~,~~~. phosphonio-phosphonato betaine (213) is the final product of the reaction of triphenyl( phenylethyny1)phosphonium bromide with dimethyl or trimethyl p h o ~ p h i t e ~Five~ ~ . and six- coordinate hydrido-phosphorus intermediates have been identified by3'P NMR techniques in the reduction of tetraphenylphosphonium salts with lithium aluminium hydride in THF at room temperature. Under these conditions, the phosphorus-containing products are the phosphorane Ph3PH2 and triphenylphosphine. Under reflux conditions, only triphenylphosphine is obtained. Similar room temperature reduction of benzylphosphonium salts proceeds much faster, and it is difficult to detect intermedia t e ~ A~ study ~ ~ .of the reduction of benzylphosphonium salts using lithium aluminium deuteride has provided further insight into the mechanism of such reduction reactions422.An NM R technique for determining the enantiomeric purity of chiral phosphonium ions relies on the use of the trisphate anion (214)

31


as a chiral shift reagent423.Further consideration has been given to the various supramolecular ‘phenyl embraces’ that are possible in crystalline systems involving tetraphenylphosphonium ions424,425.Compared with the related quaternary ammonium dication, it is much less easy to incorporate the longchain diphosphonium cation (2 15) into a - c y c l ~ d e x t r i n s ~Clay ~ ~ . containing intercalated palladium chloride and tetraphenylphosphonium bromide has

Ph + / Ph3P-CHZC ‘pp MeO’ yo

+ + Me3P-(CH2)10-PMe3

been shown to be a useful catalyst in the cross-coupling of aryl halides with arylboronic acid, giving b i a r y l ~ and ~ ~ ~also , in the arylation of alkenes, giving unsymmetrical trans-stilbenes in high yield428. Metastable Induced Electron Spectroscopy (MIES), a surface analysis technique, has been applied to the study of the surface activity of phosphonium salts in the polar solvent f ~ r m a m i d e ~Benzyltriphenyl~~. and anthracen-9-yltriphenyl-phosphonium salts have been used as photoinitiators for the polymerisation of ethyl c y a n ~ a c r y l a t e ~(Acetylmethy1)triphenylphosphonium ~~. bromide is a useful catalyst for the protection and deprotection of alcohols as alkylvinyl ethers, a strategy that can be applied to primary, secondary and tertiary alcohols, and also to phenols43’. Phosphonium tosylates, obtained by the reaction of tertiary phosphines with alkyl tosylates in refluxing toluene, have been used as ‘clean’ ionic solvents for catalytic hydrogenation reactions. The catalyst system, and the solvent, can be recovered easily, and r e - ~ s e d The ~ ~ ~synthetic . utility of fluorinated P-ketophosphonium salts has been reviewed433.Co-polymers of vinylbenzylltriphenylphosphonium chloride with various polymers have been prepared, and used for the fabrication of moisture sensitive membranes434.

4

pn- Bonded Phosphorus Compounds

The maturity of this area of organophosphorus chemistry is doubtless reflected in the publication of a book by Dillon, Mathey and N i ~ o n Other ~ ~ ~useful . reviews have also appeared, covering homonuclear multiple bonding in the heavier elements of main Groups 13, 14 and 15,436 the chemistry of P=P and P=C and the utility of cyclobutadienes and phospha-alkynes as tools for the development of phospha-organic systems and their valence isomers439. Routes to diphosphenes (and unsymmetrical dipnictenes) have been developed in which the p,-bonded system is stabilised by 2,6-diarylphenyl gro~ps~~ . ~ (2 ~ 16), ’ , which, when electron-rich diarylamino substituents e.g., are also present, raise the interesting possibility of redox-active systemsM2. Further consideration has been given to factors affecting the 3 1 P NMR

Orgunophosphor us Chemistry

32

(216) R' = Me or Pr' R2 = H or N(C6H40Me-p)2

(217) M = (q5C5Me5)(C0)2Fe Mes* = 2,4,6-But3C&

chemical shifts of diphosphenesa3. Ab initio quantum chemical investigations have been used to compare the phenyldiazonium cation and its phosphorus analogue, PhP2+ . The latter is shown to exist preferentially as phenyl bridged structure, and the results suggest that it should be stable in the gas phase and probably be accessible from the reaction between P2 and the phenyl cationw. The triphosphorus system (217) has been obtained from a cycloaddition reaction between a diphosphene bearing a complexed metallo group at phosphorus, and a p h ~ s p h a a l k y n e The ~ ~ ~chemistry . of mixed h3-h5diphosphorus systems, e.g., (218), has also continued to d e v e l ~ p ~these ~ ? com~~~, pounds having been shown to undergo a phospha-Wittig reaction with aldehydes, to form p h ~ s p h a a l k e n e s The ~ ~ ~first . stable phosphorus-containing heterofullerenes, C59P and c69P, have been prepared and identified by mass spectrometrya8. Another first is the synthesis of the para-phosphaquinone system (219), an air-stable orange solid which can be reduced using sodium in

%

Ar-P=PR3 (218) Ar = Mes or 2,4,6-BUt3C&

R=Me

T H F to form a related radical anion in which the unpaired spin is predominantly located at phosphorusa9. Routes to the functionalised phosphaalkenes (220) have also been described450.The chemistry of phosphaalkenes bearing reactive groups at phosphorus has been exploited in the synthesis of a range of new systems. On heating in vacuo, the P-trimethylsilyl system (22 1)is converted into the oxadiphosphole (222), a new heterocyclic system, from which other heterocyclic- and cage-structures have been obtained via cycloaddition reactions with alkynes or p h ~ s p h a a l k y n eI s. ~Treatment ~ of the trimethylsilylphosphaalkene (223) with pivaloyl chloride and benzoyl chloride provides a route to the acylated systems (224). It has also been shown that carbon disulfide and phenyl isothiocyanate undergo insertion into the Si-P bond of (223) to give the functionalised phosphaalkenes (225)452.The P-chlorophosphaalkene (226) has been shown to react with dialkylphosphinotrichlorosilanes to give new P-

33


Mesyp, OSiMe3

Me3Si-P=C

0 11 R-C-P=C

NMe2

P Y O

Mes

R (220)R = CH=NPh or 2-pyridyl

Me3SiP=C/

/

(221) /NMe2

NMe2 R(X)C-P=C

NMe2

NMe2

NMe2

(225) R(X)C = Me3SiS(S)C or Ph(Me3Si)N(S)C

(224)

(223)

dialkylphosphinophosphaalkenes(227). The P=C bond in these compounds can be reversibly protected by a [2 + 41 cycloaddition with cyclopentadiene, to give the P-phosphinophosphanorbornadienes(228)453.P-Halophosphaalkenes have also been shown to react with 1-(dialkylamino)alkynes, with the initial formation of unstable 2-phospha- 1,3-butadienes via electrophilic 1,2- addition at the alkyne triple bond with preservation of the two-coordinate phosphorus atoms. The phosphabutadienes subsequently rearrange to dihydrophosp h e t e ~ The ~~~ reactivity . of the phenylthio-functionalised phosphaalkene (229) has been investigated. This metallates normally with organolithium reagents to give (230), which, on treatment with copper(I1) undergoes oxidative coupling to give the 1,4-diphospha-1,3-butadiene(23 1)455. Metallation of bis(phosphaalkene) (232), followed by oxidative coupling with iodine, has given the bis(ph0sphabutadiene) (233)456.Dehydrofluorination of the germyl-substituted phosphaalkene (234) by tertiary butyllithium in the presence of chlorotri-

(Me3Si)2C=PCI

Me3Si

(227) R = Pr' or But

(226)

Ar,

/ \

(Me3Si)2C=P-PR2

/SPh

Ar,

/SPh P=C

P=C Br

(229) Ar = 2,4,6-But3C6H2

\

(230)

Li

SiMe3

(228)

'

phsHsph

Ar-P

P-Ar

(2311

methylsilane leads to the formation of the 1,2-bis(phosphaalkenyl)-1,2-digermacyclobutane (235), probably via head to head dimerisation of an Hydrostannylation of phosintermediate 1-pho~pha-3-germabutadiene~~~. phaalkenes has also been explored458.Phosphaalkene and related systems have also received further attention from the theoretician^^^^-^^'. The first phosphasilaallene system (236) has been obtained by dechlorination of the corresponding (chlorosily1)chlorophosphaalkene with t-butyllithium at low temperatures. In the absence of trapping agents, (236) dimerises to form two types of dimer, e.g., (237), depending on which double bonds are involved462.

34


p+p P I

Ar,

,Cl P=C

Mes \ I

Ge-CHR2

I CI CI I Ar Ar (235) R = M e s

F'

(234) R2CH = fluorenyl Ar = 2,4,6-BUt3C6H2

A cyclic voltammetry study has shown that the monophosphaallene (238) undergoes irreversible reduction to form a monophosphaallylic radical, characterised by EPR In a similar vein, reduction of the diphosphaallene (239) is reported to give a radical anion. Oxidation of (239) gives a E-allylic radical cation464.The anionic 1,3-diphospha-2-silaallylic system (240) has been obtained from the reaction of a lithium arylphosphide with t r i c h l o r ~ s i l a n e s ~ ~ ~ .

Th Ph Ar-P=C=Si

' i P + ~ ~ ~ * '

I

\

Ph Ar-P=C=C

PAr

Ph

Tip (236) Ar = 2,4,6-BUt3C6H2 Tip = 2,4,6-Pr'&~H2

Ph

(238) Ar = 2,4,6-6Ut3C&

(237)

R

I

Ar-P-Si=P-Ar Li+

Ar-P=C=P-Ar

(239)Ar = 2,4,6-BUt3C&

(240) Ar = 2,4,6-But&H2 R = But, Mes or MesCp

A route to the arylphosphaalkyne (241) has been reported. This compound undergoes the expected cycloaddition reactions with 1,3-dienes and with (242), on the other hand, shows a ~ i d e s The ~ ~ ~trimethylsilylphosphaalkyne . unusual behaviour in its reactions with dienes, forming various phosphorus cage structures467. Sterically stabilised phosphaalkynes have been shown to

Me3

Me

/

Me (241)

Me3Si-C (242)

=P

Me3Si (243) R = But, 1-adamantyl or CMe2Et


35

undergo cycloaddition reactions with substituted 1,3,6-cyclooctatrienes to form phosphatricyclodecadiene systems, e.g., (243), which are then able to undergo further cycloadditions with alkynes and phosphaalkynes to form new cage structure^^^^^^^^. A route to selenophosphaalkenes is afforded by the 1,2addition reactions of phosphaalkynes with phenylselenyl halides470.Phenylphosphaethyne, PhC = P, undergoes spontaneous polymerisation in the neat state, or when in solution471. Interest in the coordination chemistry of phosphaalkynes has continued. The rare q ‘-coordination mode for ButC = P results in a shortening of the P = C triple bond relative to the uncoordinated ligand, in contrast to the more familiar q2-mode, in which the P = C bond length increases472.New aspects of the coordination chemistry of Bu‘C = P have also emerged in a study of ‘hydroosmiation’ of the p h ~ s p h a a l k y n e ~ ~ ~ . Transition metal-promoted cycloaddition and related reactions of phosphaalkynes continue to be a profitable area of s t ~ d y ~Phosphorus-aluminium ~ ~ - ~ ~ ~ . and phosphorus-gallium cage structures are formed in the reactions of phosphaalkynes with trialkyaluminium and trialkylgallium reagents478.New diphosphapolycyclic systems have been obtained from the reactions of a zirconocene-phosphaalkyne dimer The phosphaalkyne radical C H 2 C r P has been generated by a dc-glow discharge on a mixture of phosphine and acetylene, and characterised by microwave spectroscopf8*. A theoretical consideration of 1,4-diphosphabutadiyne, P = C-C = P, has concluded that it is likely to be thermodynamically stable but to have a strong tendency to polymerise. The possibility of stabilising it by coordination, e.g., to a Cr(C0)S acceptor, was also suggested481.Both the cyaphide anion, [C-PI-, and methyl isocyaphide (244), have been characterised in the coordination sphere of transition metals482.Theoretical studies of 31Pand I3C NMR chemical shifts and vibrational frequencies of phosphaalkynes have shown agreement with experimental values483.

+

+

Interest in the chemistry of phosphenium cations, R2P+, has also continued. Calculations on a series of phosphenium (and arsenium) ions support the assumed singlet ground states, and have also shed some light on bonding in their lowest triplet state, and on the course of their reactions with b ~ t a d i e n e ~ ~ ~ . Consideration has also been given to Factors affecting stabilities, electrophilicities, and carbene-like properties of phosphenium cations485. A structural comparision of the phosphenium salt (245) with the chlorophosphine (246) reveals that the former involves a 6n-delocalised aromatic phosphenium cation, whereas the latter is, as expected, covalent486.New chiral phosphenium salts involving potential coordinating groups in the vicinity of the phosphorus,


36

e.g., (247) and (248), have been prepared and shown to form complexes with borane, in effect being phosphenium borane cations. The phosphonium cations undergo the usual cycloaddition reactions with d i e n e ~ ~Other ~~. phosphenium salts (249), which are stabilised by intramolecular donoracceptor N +P interactions, have been ~ h a r a c t e r i s e d Evidence ~~~. of a transient acylphosphenium ion (250) has been provided by trapping experiments489. Similarly, evidence for the formation of the ion (251), generated in the gas phase from trimethyl phosphite, has been obtained by trapping with 2,3dimethyl-1,3-butadiene and characterisation of the adduct (252) by mass M e0, +,0Me

spectrometry490. Dimethylzirconocene, Cp2ZrMe2, acts as a source of the methyl carbanion, converting phosphenium cations to methylph~sphines~~'. The supermesitylphosphenium ion (253) has been characterised as a transition metal complex492.The activity of phosphenium ion-me,tal complexes has also received further attention, their behaviour in cycloaddition reaction^^^^?^^^, and towards protic reagents495having been explored. A theoretical study of the correlation between structure and 31PNMR shifts of phosphenium cations has been reported496. The trapping of phosphinidenes, RP:, by carbenes, and also by transition metal acceptors has been reviewed497. The electrophilic versus nucleophilic character of transition metal-phosphinidene complexes has received a theoretical treatment498. and new phosphinidene-silver cluster systems have been described499.The bis(ph0sphinidene) complex (254) has been characterised by

t %

i-) P P

% (253)

i

\


37

trapping experiments500.Terminal phosphinidene complexes have been shown to react with aldimines to form complexed 1,2,3-~zadiphosphetidines, together with other P,N-heterocyclic products501.Phosphiranes and diphosphiranes bearing the supermesityl group, e.g., (255), have been prepared as anticipated precursors to phosphinidenes, and their photolyses studied by spectroscopic techniques. Phosphinidenes were not detected in these experiments, most products isolated having arisen from reactions involving the ortho-t-butyl groups502. Interest has also continued in the search for evidence of involvement of three-coordinate, pentacovalent, (03h5)-p,bonded systems in phosphorus chemistry. The ferrocenyldithioxophosphorane (256), generated by thermal decomposition of ferrocenyldithiaphosphetane disulfide, has been identified by trapping experiments with dienes, alkenes, and thioaldehydes. Thus, e.g., with norbornadiene, the tricyclic adduct (257) is formed503.Reactions of dithioxophosphoranes with phosphonate esters have also been studied504.Harger's group has provided further evidence, usually stereochemical, for the involvement of (03h5)-systems, e.g., (258), in nucleophilic displacement reactions of

certain P(V) acid derivative^^^^-^^*. A theoretical consideraton of the species H2PCH has concluded that the ground state of the molecule is best described as a phosphinocarbene rather than a h5-pho~phaacetylene~~~.

5

Phosphirenes, Phospholes and Phosphinines

The phosphirene system continues to attract the attention of the theoreticians, the past year having seen studies of insertion reactions of phosphirenium (and phosphiranium) cations with ethene and ethyne510, exchange and insertion reactions involving borane adducts of phosphirene and phosphirane5' I , and a study of the electron affinity of substituted ph~sphirenes~'~. A new and versatile approach to 1-phenyl-and 1-chlorophosphirenes (259) is offered by the reactions of titanocene complexes of various electron-poor alkynes with phenyldichlorophosphine or phosphorus trichloride513. Alkynyl-substituted phosphirenes are formed from the addition of the phenylphosphinidenetungsten pentacarbonyl complex to various diynes. Bisphosphirenes are not formed under these conditions5I4.The reaction of [bis(disopropylamino)phosphino](trimethylsilyl)carbene with t-butylphosphaalkyne gives the 2-phosphino -2H-phosphirene (260). The latter is unstable, rearranging at room temperature to the diphosphete (261). UV irradiation of (260) again results in


38 R' Q2

P

I

R3 (259)R' = Ph, SiMe3, Bu or ferrocenyl R2 = Ph, SiM% or But R3 = Ph or CI

(260) R = NPrI2

(263)R=SiMe3

(261)

(264) R=SiMe3

the diphosphete (261) as the major product, but also gives the l-phosphino1H-phosphirene (262) in 10% yield515. A similar irradiation of the 1Hphosphirene (263) results in the formation of a 1,2-phosphasilete (264), which, on further treatment with an acid chloride, undergoes ring-expansion to form the oxaphosphasiline (265)516.New routes to 2H-azaphosphirene complexes (266) have been described,517and their reactions explored in detail. In the presence of alkynes, 1H-phosphirenes are and when heated in the presence of both an alkyne and dimethylcyanamide, 2H- 1,2-azaphospholes result520.Heating in the presence of both an alkyne and benzonitrile has given the first 7-aza- 1-phosphanorbornadiene complex (267y2I . Various diazaphosphole systems have been obtained from the reactions of 2H-azaphosphirene complexes solely with nit rile^^^*.

\ I'

Me02C

R' k (265) R = SiMe3

Cp* '[MI (266)Cp' = Me5Cp [MI = W ( W 5

Me02C' P~

(267)

The past year has again seen much activity in phosphole chemistry. A route to the 2-pyridyl-substituted phospholes (268) has been developed, and their reactivity and spectroscopic properties explored523.A series of diphospholylalkanes (269) has been prepared in a one-pot, high yield reaction by treatment of a,o-dibromoalkanes with 1-1ithi0-2,5-diphenylphosphole~~~. The dilithiophosphole (270) has been obtained by metallation of the related 2,Sdibrornophosphole, and used to prepare functionalised phosphole systems525.Further consideration has been given to the increase in aromaticity and planarisation Ph

Ph

Mw

Li I

Ph (268)

n=

Ph

Ph 1 or 2

(269)n = 2-6

Li

I Ph

(270)

39


of phospholes as a result of increasing the steric bulk of the substituent at phosphorus. A route to the phosphole (271) has been developed, this compound having the lowest ionisation energy ever reported for a phosphole, again consistent with decreasing pyramidality of phosphorus526.A theoretical treatment of phosphindolizine (272), as yet unknown, has indicated that the tricoordinated phosphorus is nearly planar, having a very low inversion barrier. Both five-and six-membered rings exhibit significant aromatic character, and the lone pair at phosphorus is d e l ~ c a l i s e d Structural ~~~. studies of three key intermediates in the synthesis of 2,2'-biphosphole have been reported528.The enophilic reactivity of simple phospholes has been exploited further for the synthesis of new chiral phosphine ligands. In the presence of palladium complexes of chiral ligands, v i n y l p h o ~ p h i n e s N-vinylimida~~~~~~~, ~ o l e ~2~- ~' i,n y l p y r i d i n eand ~ ~ ~other , unsaturated c o m p o ~ n d add s ~ to~ the ~ ~ ~ ~ ~ dienic system of 1-phenyl-3,4-dimethylphospholein a stereoselective manner, to give chiral complexes of new phosphorus ligands which can be isolated subsequently following decomplexation. Using this approach, a range of new chiral phosphine ligands, e.g., (273), and (274), has been characterised. In a similar vein, addition of coordinated allenylphosphines to 1-phenyl-3,4dimethylphosphole has given the diphosphines (275)535, and addition of alkynylstannanes results in the bicyclic system (276)536.The chemistry of

$' I

k2P = Ph2Por dibenzophospholyl

. ..

phospholide anions continues to be exploited. Treatment of the phospholes (277) with potassium t-butoxide in THF at 150-160 "C gives the phospholides (278) via a [1,5]-sigmatropic shift of the P-aryl substituent. These anions have then been used in the synthesis of new phosphaferrocenes, and other l i g d n d ~ ~Other ~ ~ . new phosphaferrocenes have been prepared, including (279)538,(280)539,and (28 1)540, and complexes of phosphaferrocenes with rhodium(1) and iridium(I) acceptors have also becn described541.The 1H- 1,3diphosphindolide system (282), a new delocalised, aromatic species, has been described542.Calcium543,gallium544,and l a n t h a r ~ i d ephospholides ~~~ have also been described. Studies of the coordination chemistry of simple phosphole and 2,2'-biphosphole systems also continue to appear, and it has been concluded


40

SiMe3

I

kj I

6 Ar

Ar (277) Ar = 1-methylpyrrolP-ylor 2-(dipheny1phosphino)phenyl

K+

(278)

SiMe3 (279)

M e j,ti

9 I

(280)

(281) X = OH, Ph2P or Cy2P

that the predominant interaction between these phosphole ligands and the metal ion is o-donation from phosphorus with little n-back donation'46. Phospholes with reduced pyramidal character (283), resulting from the effect of the bulky P-aryl substituent, have been shown to form a series of platinium(I1) complexes547.Structural data on metal carbonyl complexes of 1phenyl-3,4-dimethylphosphole sulfide show that the ligand is acting as a 6electron q4-C4,q'-S chelating ligand in an unusual coordination mode548.The aromaticity of polyphosphaphosphole systems increases as the number of twocoordinate phosphorus ring-members increases, this being reflected in a decreasing pyramidality at the trico-ordinate phosphorus549.The triphosphole (284) slowly rearranges on exposure to sunlight or to a tungsten lamp to form the bicyclic system (285), which is labile in solution, undergoing a rapid

"'eR2 +Q 2

A3

(283) R1 = R2 = R3 = Pr' or But R1 = R2 = But, R3 = Me

I R

(284) R = CH(SiMe&

sigmatropic rearrangement in which the two phosphorus atoms in the fourmembered ring are exchanged550. The triphospholide-indium complex (286) has been obtained by the co-condensation of indium vapour and t-butylphosphaethyne at 77 K . It has also been prepared by a more conventional route from the potassium triphospholide salt and indium(1) iodide55'. The 1,2-

41


diphosphole system (287) is among the products of the reaction of allylidenetriphenylphosphorane with phosphorus t r i c h l ~ r i d eThe ~ ~ ~reaction . of a diphosphastibolyl anion with selenium- or tellurium-dithiocarbamates provides a simple route to 1,2,4- selena- and tellura-diphospholes (288)553,which have been structurally characterised by X-ray ~ r y s t a l l o g r a p h y New ~ ~ ~ .routes to the benzaphosphole system (289) have been developed5? Synthetic approaches to the 2-phosphaindolizine system (290) have been revieweds56,and new synthetic approaches d e v e l ~ p e d ~The ~ ~reactivity . ~ ~ ~ . of the two-coordinate phosphorus atom in this system has also been explored5s9~s60. Further studies of the reactivity of 1,2,3-dia~aphospholes~~~-~~, e.g., (29l), and 1,2,4=diazaphosp h o l e have ~ ~ ~been ~ reported.

(288) X = Se or Te

N R

The involvement of transition metals in the synthesis and subsequent studies of the reactivity of phosphinines has been r e ~ i e w e d ~ 2-Bromophosphi~~3~~~. nines have been transformed efficiently into the diphosphinines (292) by sequential treatment with zirconocene, a nickel(I1) diphosphine complex, and finally hexa~hloroethane~~~. Treatment of the zirconium-substituted phosphinine (293) with hex-3-yne followed by phosphorus tribomide gives the 1,4diphosphaindene (294), from which the related phosphininophospholide anion

can be generated on treatment with lithium569.Phosphinines and diphosphinines continue to attract the attention of the coordination chemistry community570-571. A theoretical comparison of the three isomeric diphosphinines and their P2(C-H)4 valence isomers has concluded that the three ‘aromatic’ planar diphosphinine isomers are the most stable572. Phosphaalkynes have been shown to undergo cyclotrimerisation in the presence of t-butylimidovanadium(V) to form 1,3,5-triphosphinines (295)573.These compounds have been shown to undergo cycloaddition reactions with phosphaalkynes, giving new tetraphosphabarrelene (296) and tetraphosphasemibullvalene (297) systems, depending on the substituents present in the ph~sphaalkyne’~~. A full struc-

42


(296) R'=BU'

(297)

R~ = BU' or Pent'

tural study of (295, R = But) has also been reported, together with a related study of a 1,3-di~hosphinine~~~. The coordination chemistry of (295, R = But) has also been explored, this system acting as an q6-ligand towards transition metal carbonyl and related acceptors576.Further studies have been reported of the cycloaddition reactions of 1,2-dihydrophosphinine oxides (298), with the formation of 2-phosphabicyclo[2,2,2]octenesystems, e.g., (299), whose fragmentation on thermolysis or photolysis to form reactive 03h5-phosphorus intermediates is the key i s s ~ e ~Cycloaddition ~ ~ - ~ ~ ~of .phosphaalkynes to 1,3,2diaza- and 1,2-azaphosphinines has also been explored. Thus, e.g., the reaction of 4,6-di-t-butyl-1,3,2-diazaphosphinine (300) with t-butylphosphaethyne has given the diazadiphosphabarrelene (301)579.Interest in h5-phosphinine and related h5-azaphosphinine systems has also continued. The h5-triphosphinine (302)580has been prepared, and routes to 1,2h5-azaphosphinines (303)58' and 1-a~a-2,4-diphosphinines~~* have also been described.

R2*R'

&a (298) R' = Me or H

0 (299)R = Ph or OEt

R2 = H or Me R3 = Ph or OEt

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46 97 98 99 100 101 102 103 104 105 I06 107 108 109 110 111 112 113 114

1 I5 116 1 I7

118

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533 534 535 536

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580 58 1 582

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2 Pentacoordinated and Hexacoordinated Compounds BY C.D. HALL

Introduction

1

This year saw the 70th birthday and retirement to the position of Professor Emeritus of Professor Robert Holmes distinguished for his outstanding contributions to hypervalent phosphorus and silicon chemistry and it is a pleasure to acknowledge the tribute paid to him by the dedication of the July (1998) issue of Heteroatom Chemistry to his work. * Another major contributor to phosphorus chemistry reached his seventieth birthday in 1999 and the seventh and eighth issues of Heteroatom Chemistry, Vol. 10 are fittingly dedicated to Professor Alfred Schmidpeter who provides an ‘Essay on Phosphorus Chemistry’ at the outset of a series of articles from friends and colleagues throughout the world.* In a review dealing with donor interaction by N, 0 and S atoms at tri-, tetraand pentacoordinate phosphorus Robert Holmes points out that such interactions may be highly relevant to enzyme a ~ t i v i t yThus . ~ it is shown that donor groups (N, 0 and S) typical of enzyme residues at active sites of phosphoryl transfer enzymes give rise to higher coordination. Specifically, phosphate substrates are displaced modestly towards pentacoordinate structures (equivalent to the ground state complex) whereas pentaoxyphosphoranes are displaced more strongly towards octahedral geometry (equivalent to the transition state complex) by donor interaction which results in P-0 bond weakening and, consequently, higher reaction rates. Similar reasoning leads to the conclusion that coordination of the tyranosyl carbonyl group with the

N3:

P =O ,I t

7

H~N-C-C
99% being obtained in 85%) in (n- 1)mer content was achieved by using fully-protected trimeric phosphoramidite synthons ( 127).85

ov Hov 0

0 I

(127) B = T, CBz,GiBu,AB‘

SiMe(Ph)p

ow I

OH (128) a X = S , Y = O b X=O, Y = S

Reese and Song have reported the full experimental details for the synthesis of oligonucleotides and oligonucleotide phosphorothioates in solution using an H-phosphonate-based approach.86Bis(2-chlorophenyl)phosphorochloridate was employed as the coupling agent and either 2-(4-~hlorophenylsu1fanyl)isoindole-1,3(2H)-dione or 4-[(2-cyanoethyl)sulfanyl]morpholine-3,5-d~one as sulfur transfer reagents. 2-(Diphenylmethylsily1)ethyl (DPSE)-protected 3’phosphoramidites have been shown to be useful synthons in the preparation of DNA and oligodeoxyribonucleotide phosphorothioates. Krotz et al. have reported an improved deprotection procedure for DPSE-protected ( O,O,O)and (O,O,S)-trialkyl phosphorothioate oligomers (1 28a and b respectively)

165

4: Nucleotides and Nucleic Acids

using tetrabutylammonium fluoride in THF.87 This gave the corresponding phosphorothioates with no formation of phosphodiester linkages being detected . The utility of phenylacetyl disulfide (PADS) as a potential sulfur transfer agent in the solid-phase synthesis of oligodeoxyribonucleotide phosphorothioates has been investigated.88 A 0.2 M solution of PADS in 1:l (v/v) acetonitrile :3-picoline was reported to rapidly and efficiently sulfurise internucleotide phosphite linkages with equivalent efficiency to Beaucage reagent but with greater reproducibility. 3-Methyl-1,2,4-dithiazolin-5-0ne(MEDITH; 129), has also been applied in the synthesis of oligonucleotides phosphorothioates via solid-phase phosphoramidite chemistry.89The sulfurisation efficiency of a solution of 0.03 M MEDITH in acetonitrile was investigated; >99.5% sulfurisation was observed with this reagent using a reaction time of 1 minute and was maintained after three weeks. The stereochemistry of DBU/LiCl-assisted nucleophilic substitution at phosphorus in nucleoside-3’-O-(S-methylmethanephosphonothiolate) and 3’-0(Se-methyl methanephosphonoselenolate) derivatives has been re-evaluated by Stec and c o - w o r k e r ~Single-crystal .~~ X-ray analysis was used to demonstrate that this reaction proceeded by inversion of configuration. 2’,3’-Dideoxyribonucleoside-3’-N-(2-oxo-4,4-( spiropentamethylene-1,3,2-oxathiaphospholanes)) (130)91 and -3’-0-(2-thio-4,4-(spiropentamethylene-l,3,2-oxathiaphospholanes)) have been prepared9* and their solid-phase couplings reported. Stec and co-workers have also described the first stereocontrolled solid-phase synthesis of di-, tri- and tetra[adenosine (2’,5’) phosph~rothioate].~~

DMT*

DMTrO

-T

0 I

s=p-o-

Il?0 (129)

I H

(130)

(131) B = ABz, CBz,GiW, T

A major limitation in the solid-phase synthesis of phosphorodithioate DNA using the phosphoramidite approach has been the synthesis of the thiophosphoramidite monomers. Seeberger et al. have developed an alternative synthesis of phosphorodithioate oligonucleotides using an H-phosphonothioate r n e t h ~ d o l o g y .5’-0-DMT-protected ~~ nucleoside H-phosphonothioate monomers (1 31) were prepared from commercially available methyl-protected nucleoside phosphoramidites in two steps in almost quantitative yield. DPCP was found to be an efficient activator in the solid-phase synthesis of phosphorodithioate DNA utilising these monomers, and resulted in coupling yields consistently higher than 97.5%. 2,4-Dichlorobenzylthiosuccinimidewas employed in the sulfurisation step, performed after each coupling, to afford the corresponding phosphorodithioate triester which was stable during the course of the synthesis.

166


An improved synthesis of oligodeoxyribonucleotide N3’+ 5’ phosphoramidates and their chimerae via amine exchange of hindered 5’-0-(cis-2,6-dimethylpiperidinyl 2-cyanoethy1)phosphoramiditemonomers (132) and (133) has been reported.95 Initial studies were also performed using 5’-0-phosphoramidite monomers (134a-c). An improved oxidation reagent consisting of hydrogen peroxide, water, pyridine and THF was also introduced. Oligomers were prepared on scales up to 10 mmol using 3.6 equivalents of monomer (133). A final coupling with a standard 2’-TBDMS-protected uridine phosphoramidite

ODMTr

I

(132)

B

NHTr = ABZ, CBz,GIBu Opt, T

NHTr

(133)

MMTrHN OTBDMS (135) B = ABz, T

enabled modified sequences synthesised on a 1 mmol scale to be purified by RPHPLC. This lipophilic handle was removed following treatment with 1:1 1M sodium fluoride:concentrated aqueous ammonia. A novel solid-phase ‘reversesynthesis’ strategy of N3’+ 5’ phosphoramidate oligonucleotides has also been reported by Baraniak et al.96 Support-bound nucleoside 5’-0-( 0-P-cyanoethylin the H-phosphonates) were coupled with 3’-amino-2’,3’-dideoxynucleosides presence of iodine. Average coupling yields were in the range of 92-96% for A, C and T nucleosides and 87% for G nucleosides were reported. Gryaznov and Winter have described the application of amine exchange chemistry to the preparation of oligoribonucleotide N3’ +5’. phosphoramidates via 5‘-phosphoramidite monomers ( 135).97 Oligoribophosphoramidates were found to be resistant to enzymatic hydrolysis and formed stable duplexes with complementary natural phosphodiester DNA and RNA strands, as well as with oligodeoxyribonucleotide N3’+ 5‘ phosphoramidates. Crude H-phosphonate oligonucleotides bearing N-unmodified bases have been prepared with 6-hydroxyhexyl phosphonates at both 5’ and 3’ termini to stabilise the internucleotide linkage during n-propylamine-mediated release from the solid support.98 An effective method for the solid-phase synthesis of oligodeoxyribonucleoside boranophosphates has been reported involving Hphosphonate chain elongation followed by b ~ r o n a t i o n .The ~ ~ boronation procedure required intermediate conversion of an H-phosphonate diester into a phosphite triester by silylation and subsequent oxidation by a borane-amine complex. The efficiency of the boronation procedure was approximately equivalent to iodine oxidation in the formation of oligodeoxyribonucleotides.

167


He et al. have prepared a series of 15-mer oligodeoxyribonucleotide analogues in which one or more phosphodiester linkages have been replaced by a neutral formacetal moiety.loo The formacetal linked dimer phosphoramidites (136a-c) were all prepared using a modification of van Boom’s procedure in which a nucleoside phosphinate, 3’-O-CH2-OP(O)R2, was employed in the condensation reaction instead of a nucleoside phosphate. Dimer phosphoramidite (136d) was synthesised by condensation of the 3’4-methylthiomethyl derivative of a protected 2’-deoxyguanosine with the 5’-hydroxyl group of another protected 2’-deoxyguanosine in the presence of N-iodosuccinimide and trifluoromethanesulfonic acid. These formacetal-linked dimer units were incorporated into oligodeoxyribonucleotides using standard solid-phase chemistry and the phosphoramidite method. A pentathymidylate fully substituted with 3’-thioformacetal internucleotide linkages ( 137) has been prepared and incorporated into a 15-mer oligodeoxyribonucleotide.l o l This oligomer was prepared in solution via an iterative procedure starting with the condensation of a nucleoside sulfhydryl (138) with a phosphinate (139) to yield the dimer sulfhydryl (140) following deprotection. Chain extension to give (141) and a

vpr

DMTrO

vP

DMTrO

O\

T

‘OV2 0 , I DBUIDMFEonnamlde ii MsOHEt3SiH

DMTrS (139)

SH (140)

T


168 PivO

'r;l +

-

i DBU/DMFAmarnide ii NaOMeMeOH 111 DMTCllPy

(137)

final condensation reaction performed wit,, a 3'-O-lauroyl-protected phosphinate derivatives (142) yielded the pentamer (137). Barawkar and Bruice have reported the synthesis of mixed backbone oligodeoxynucleotides (18-mers) consisting of positively charged guanidinium linkages along with negatively charged phosphodiesters via the dimer phosphoramidite ( 143).Io2Bruice and

co-workers have also reported full experimental details for the solid-phase synthesis of an octameric thymidyl DNG oligomer and evaluated a pentameric t hymidyl methy Ithiourea. * O4 Peptide nucleic acids (PNA) and analogues have continued to enjoy considerable attention this year. Nielsen and co-workers have synthesised the protected 6-thioguanine PNA monomer (144) and incorporated it into a 10mer PNA oligomer.'05 The introduction of a single 6-thioguanine residue in the PNA oligomer resulted in a decrease in stability of the antiparallel PNA:DNA heteroduplex. A simple and efficient one-pot method for the synthesis of known and novel PNA monomers, e.g., (149), has been developed using the Ugi Four Component Condensation reaction (Scheme 5).'06 Lutz et af. have prepared a monocharged PNA primer (150) that was recognised as a Io37

169


SI

OH

-Q

T

substrate by several DNA p o l y m e r a ~ e s . This ' ~ ~ primer was synthesised using the novel phosphoramidite building block (151). Novel chirdl PNA monomers ( 152a-d) have been synthesised by reductive amination of N*-Boc-protected

H

(151)

(152) a R = (42H2CHMeZ b R = I-CH2Ph c R = wH(OCH2Ph)Me d R = I-CH2CsH4-pOH

chiral aldehydes, derived from Leu, Phe, Tyr(Bz1) and Thr( Bzl) respectively, with methyl glycinate.lo8 A novel PNA (153) has been prepared which shows all-or-none-type hybridisation with complementary DNA targets. lo9 Gangamani et al. have synthesised homothymine oligomers of 4-aminopropyl PNAs ( 154), a class of

170


'

conformationally constrained chiral PNA analogues. l o The D-trans- ( 155) and L-trans- ( 156) 4-aminoproline thymine monomers were also incorporated into standard PNA oligomers. Serinol-derived acyclic nucleoside analogues have been incorporated into oligonucleotides via the corresponding phosphoramidites (157). Triplex-forming oligonucleotides bearing these residues showed

(154) B = T

RCONH H

reduced hybridisation capabilites. von Matt and co-workers have described the introduction of 2'-deoxyribo polyamide nucleic acid monomers into fully substituted and chimeric oligonucleotide analogues using appropriate monomer synthons (158)-( 160). l 2 Binding affinities to complementary nucleic acids were similar to those observed for unmodified oligonucleotides. 4.3.2 Oligonucleotides Containing Modijied Sugars. Conformationally restricted oligonucleotide analogues containing bicyclic monomers have at-

MMTrHNv b. 0

F

'F

171


tracted considerable attention due to their potential for formation of entropically favourable duplexes. Continuing their research in this area, Wengel and co-workers have reported the synthesis of the first analogues of LNA (Locked Nucleic Acids, (161a)): 2’-Thio-LNA (161b) and phosphorothioate-LNA (161c). l 3 9-mer LNAs incorporating one, three or five LNA-2’-thiouridylate monomers, prepared via the phosphoramidite (162)’ were found to hybridise to complementary DNA and RNA targets with thermal affinities comparable to those of the parent LNAs. Workers in the same group have also prepared novel and 2’-methylamino-2’-N,4’-C-methylene bicyclic 2’-amino-2’-N,4-C-methylene ribonucleoside analogues with significantly increased thermal stability toward complementary DNA (ATm= +3.0 “C) and RNA (ATm= +6.0 to +8.0 OC).lL4 These conformationally restricted oligonucleotides were prepared via the corresponding phosphoramidite monomers ( 163a,b). Kvaerns and Wengel have prepared LNAs containing an ‘abasi’ LNA unit via the corresponding phosphoramidite (164). l5 This monomer was incorporated into oligonucleotides using automated solid-phase synthesis under normal conditions except that coupling time was extended. The conformational changes mediated via the nucleobase were demonstrated to be pivotal to the properties of LNA.

? DMTroxl x‘o

O=P-Y-

I

0-! (161) a X = Y = O , B = T b X=S, Y=O, B = U c X=O, Y=S, B = T

s‘0 I

pr12N0p\O/\/CN (162)

DMTrov/ DMTrox? N O R ‘

0‘0

Obika et al. have incorporated bicyclic pyrimidine nucleoside analogues with a fixed N-type conformation into oligonucleotides via the corresponding phosphoramidites (1 65). I I 6 This group has also prepared and evaluated 2-5‘linked oligonucleotide analogues containing 3’-0,4-C-methyleneribonucleosides (166).’I 7 These modified oligonucleotides bound to complementary RNA more strongly than 2’,5‘-RNA and demonstrated significant selectivity for RNA over single-stranded (ss) DNA. Wang et al. have examined oligodeoxyribonucleotides analogues containing 2’,4’-C-bridged 2’-deoxyribonucleosides synthesised via the corresponding phosphoramidite ( 167) using standard automated solid-phase synthesis proto-

172


cols except that more concentrated solutions and extended coupling times were employed. l8 Hybridisation studies on the modified oligonucleotides showed that incorporation of the bridged bicyclonucleosides significantly enhanced hybridisation to complementary RNA targets.

y-$ 0

DMTrov DMTrO

oMTroli7 O

P

(166) B = T, CBz

0 I

o=p-o-

I H (168) B = 5MeCBz, T

Zou and Matteucci have reported the synthesis and properties of an oligonucleotide analogue bearing 1',3'-di-O-methylene-a-~-fructose prepared from the hydrogen phosphonate monomers (1 68). l9 Hybridisation studies on this modified oligonucleotide indicated that it did not bind to complementary RNA. Enhanced T, values were observed with both complementary RNA and DNA. Phenazine (Pzn)-tethered ara-uridine and xylo-uridine oligodeoxyribonucleotide conjugates have been prepared and the thermal stabilities and fluorescence properties of their duplexes and triplexes have been investigated using automated solid-phase synthesis and the modified phosphoramidite (169a) or succinated derivatives (1 69b,c), ( 1 7 0 a - ~ ) . ' ~ ~ 2'-0-( 1-pyrenylmethyl)uridine has been incorporated into the central position of 9-mer oligonucleotides at the central position via the corresponding phosphoramidite (171). The binding affinities of the 9-mers to the complementary DNA (increased) and RNA (decreased) were measured and sequencedependent fluorescence enhancement was observed with DNA. l 2 * 2'- 0-Aminooxyethyl modified 5-methyluridine and adenosine nucleotides have been incorporated into oligonucleotides via the corresponding phosphoramidites ( 172). The 2'-O-modifications were found to significantly enhance hybridisation against RNA (1.2 "C per substitution) and exhibited specificity for RNA against DNA. Enhanced nuclease resistance of these oligonucleotides compared with unmodified DNA was o b s e r ~ e d . I ~ ~ - ~ ~ ~

173


(169) a R’

= (-P(NPt2)0CH2CH2CN, R2= Me, n = 1 R2= Me, n = 1

b R’ =$&OH, 0

R2 = Pac, n = 3,5

c,d R’ =$&OH, 0

(170) a R = M e , n = l b,c R = Pac, n = 4, 6

0

DM DMTro (?

N c * O N0 ‘ 0 \ N P B

NC*O/

O - O - N BO

p, NPr‘2

0 (171)

(172) B = ABZ, T

Electroactive oligodeoxyribonucleotides have been prepared utilising a phosphoramidite that bears a 9,lO-anthraquinone (AQ) group tethered to the 2-0 of uridine via a hexylamino linker (173).’” Nearly reversible two-electron waves characteristic of an adsorbed anthraquinonehydroquinone redox couple was observed for all of the AQ-ODN conjugates. Fully protected modified oligoribonucleot ides containing 2’- 0-cyanomethylribonucleotide residues were prepared from the corresponding phosphoramidites ( 174) using automated solid-phase synthesis.125 The 2’-O-cyanomethyloligoribonucleotides were post-synthetically converted into 2’-O-carbamoylmethyloligoribonucleotides (175) during standard deprotection conditions with aqueous ammonia. The 2’-0-carbamoylmethyloligori bonucleotides-RNA heteroduplexes were found to be substantially more stable than the corresponding RNA homoduplexes and 2’-0-carbamoylmethyloligoribonucleotides showed a high level of discrimination between complementary RNA and DNA targets. Greiner and Pfleiderer have reported the synthesis of 2’-amino-2‘-deoxyribo-

174


(173)

s-

DMTrovp ' O J . jI >

0 0-CN

NH2

I

0-I

Pt2N (174) Bp = Up", CBz,A'',

(175) B = U, C, A, G

G

nucleoside-3'-0-phosphoramidites(176a-f). 126 The aglycone and 2'-amino functions were protected using the 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) group. 2'-N-(npeoc)-3'-O-succinylnucleoside- derivatised solid supports could not be used in the solid-phase synthesis of 2'-aminooligodeoxyribonucleotides due to the tendency of the succinyl group to migrate during npehpeoc

0 I

NHnpeoc

prl*N P \ / v C N (176) a R =MMTr. B p = C " F b R = DMTr, Bp= C " p

c d e f

R R R R

= MMTr, BP = U =DMTr, B p = U = DMTr, Bp = G ; K =DMTr. BP=Anp

deprotection with DBU. Consequently, deoxynucleoside or acetyl-protected 2'aminouridine derivatives were attached to the support. The synthesis of oligonucleotides containing 2'-0-(trifluoromethy1)adenosine has been described using the phosphoramidite derivative (1 77).'27 These oligonucleotides were found to form less stable duplexes with complementary DNA but more stable duplexes with complementary RNA. 2'-O-Methylribonucleoside bicyclic oxaphospholidine phosphoramidites (178) and ( 179) have

175


DMTrowp DMTr 6 ,

O ,

OMe

OMe

been synthesised from (R)- and (5‘)-2-pyrrolidine methanol respectively and used in the stereoselective solid-phase synthesis of ( Rp)- and (Sp)-2’-0methyloligoribonucleoside phosphorothioates.128 Interestingly, higher stereoselectivity was obtained in the preparation of (Sp)-2’-0-methyloligoribonucleoside phosphorothioates (96-98%) than (Rp)-2’- 0-methyloligoribonucleoside phosphorothioates (63-76%). A series of novel 2’-0-methylribonucleoside3’0-[2-(4-nitrophenyl)ethyl]dialkyl-phosphoramidites ( 180) has been prepared

R30vp 0

OMe

I

R’Y p \ O R

R2 (180)

B = A*”, AnW,

Cnm, R = MMTr, DMTr R‘ = Me, Et, Pr‘ R2 = Et, Pr’ R3 = npe

G”,,

U

and their stabilities and reactivities have been compared in the automated solid-phase synthesis of 2’-0-methyloligoribonucleosides with the standard 2’0-methylribonucleoside 3 ‘ 4 4P-cyanoethyl)diisopropylphosphoamidites. 29 It was found that although the [2-(4-nitrophenyl)ethyl]diisopropylphosphoramidites were more stable to decomposition than the conventional P-cyanoethyl diisopropylphosphoramidites, they were less reactive. However, if the diisopropyl group was replaced by a diethylamino, isopropyl(methy1)amino or an ethyl(isopropy1) group, then reactivity was retained. Piccirilli and co-workers have described a strategy for the incorporation of 2’-C-P-methylcytidine into oligonucleotides via solid-phase synthesis using phosphoramidite derivatives (1 8 1).13* Oligonucleotides containing 2’-C-Pmethylcytidine were shown to undergo base-catalysed degradation analogous to natural RNA. Dunkel and Reither have prepared 2’-C-a-difluoromethylarauridine 3’-0-phosphoramidite (1 82) from uridine.131 This monomer was employed as a replacement for uridine at position U4 in the synthesis of a hammerhead ribozyme. It was found that substitution of this modification for uridine at U4 resulted in cleavage activities close to 2’-amino-2’-deoxyuridine or similar to 2’- C-allyl-2’-deoxyuridine,known 2’-modified uridines employed


176 NHBz

6I

OR

Pr‘2N, P , O ~ C N (181) R = THP, TBDMS

in the endonucleolytic stabilisation of hammerhead ribozymes. MatulicAdamic et al. have further refined the ‘5-ribo’ nuclease stabilised hammerhead motif by systematic incorporation of 1-(P-D-xylofurdnosyl)adenine (xA) and 1(g-D-xyl0furanosyl)guanine(xG) via the corresponding 3‘-O-phosphoramidites (183).l3* Modified ribozymes substituted with xA at conserved positions A1 5.1 and A6 demonstrated catalytic activity close to the parent stabilised ribozyme. Analogous guanine substitutions at positions G5, G8 and G12 substantially lowered catalytic rates. In contrast to the mechanism of DNA strand cleavage via 4’-radicals, the corresponding RNA cleavage mechanism has not been investigated to any significant extent. Giese and co-workers have introduced the 4’-acetyl derivative of adenosine into an oligonucleotide using H-phosphonate chemistry via the monomer (184).133Irradiation of the oligomer at 320 nm led to formation of the #-radical and subsequent strand cleavage under aerobic or anaerobic conditions proceded at reduced rates compared with those observed for the 2’deoxy analogue. Workers in the same group have also incorporated 4’pivaloyl-substituted guanosine into oligodeoxynucletides. 134 A highly efficient synthesis of oligonucleotides containing the 2’-deoxyribonolactone lesion ( 185) has been deve10ped.l~~ This lesion is a common ‘abasic’ site found in DNA and is reported to be mutagenic, resistant to repair nucleases and responsible for DNA strand scission. The key to the synthesis was irradiation of an oligonucleotide containing a 7-nitroindole nucleoside unit ( 186). This resulted in formation of (1 85) and 7-nitrosoindole with no trace of other side-products. P-D-Allofuranosyl cytosine phosphoramidites with pendant metal ionbinding sites (187) have been utilised in the preparation of oligoribonucleotide analogues containing 1-aza-18-crown-6 and triethyleneglycol. 36

177


Rlo$:q

R1oPo

OR2 (186) R1 = d(CGCAC), R2 = d(CACGC)

OR2 (185) R1 = d(CGCAC), R2 = d(CACGC)

[1’,2’,3’,4’,5’]-13C5-labelled ribonucleoside phosphoramidites (99 atom YO ( 188) have been synthesised from commercially available 3C6-~-

’3C)

glucose.’37These have then been used in the solid phase synthesis of specifically 13C-labelledstem (27A and 43G), bulge (24C) and loop (31U)regions of 29-mer HIV-1-TAR RNA hairpin. The chemical synthesis of appropriately NHR’

I

protected partially-deuterated 2’(RIS), 3’,5’(RIS)2H3-2’-deoxyribonucleoside phosphoramidites (189a,b) [- 43 atom YO2H at C5’(R); 57 atom YO2H at C5’(S); 15 atom YO2H at CZ’(R); 85 atom YO2H at CZ’(S) and >99 atom YO 2H at C3’] has also been reported. 38 These deuterium labelled building blocks have been incorporated into the Dickerson-Drew dodecamer by solid phase synthesis.

-

-

-

DMTrov 0

I

OTBDMS

0 I

R2

pr12N’p\o%CN

NC*O’p\NPr‘p (188) B = A’‘,

DMTroQ

CBz,GIB”,U

(189) a B = A ~cAc, ~ G ,‘,;: b B = ABz, CAc,G;:‘,

T; R’ = D, R2 = H T; R 1 = H, R2 = D


178

4.3.3 Oligonucleotides Containing ModiJied Bases. Potential triple-helix-stabilising 2'-deoxycytidine analogues have been prepared and incorporated into oligonucleotides via the corresponding phosphoramidites ( 190). 39 Khattab and Pedersen have reported the highest stabilisation observed to-date for an oligodeoxyribonucleotide three-way junction. 14* This was achieved by incorporating an a-cytidine conjugated to a pyrenylmethyl intercalating moiety at the junction region of an a-oligodeoxyribonucleotide.The oligonucleotide was prepared via the phosphoramidite ( 191). 2'-Deoxy-5-methyl-N4-(4-phenoxypheny1)cytidine has also been introduced at the branch point of a three-way junction using standard phosphoramidite ( 192) chemistry.141 Eritja and coworkers have described the preparation and properties of oligodeoxyribonucleotides containing mercaptoethyl groups at position N-4 of cytosine using a t-butyldisulfide-protected phosphoramidite ( 193).142 Reaction of the resulting thiol-Oligodeoxyribonucleotides with a maleimido-peptide carrying the c-myc tag-sequence yielded a conjugate specifically recognised by an anti c-myc monoclonal antibody. Oligonucleotides incorporating a p-cyano substituted 5-benzoyl-2'-deoxyuridine residue were prepared via the phosphoramidite ( 194).143Photoirradiation of these oligonucleotides at 312 nm followed by treatment with hot piperidine led to selective cleavage at the 5'-G of a GG motif downstream of the

8,

HN

0 I

no'0

HN

HN

-S-SBu'

179


site of modification. Photochemical site-specific cross-linking methods employing photoactive derivatives of nucleotides find a broad range of applications in the elucidation of nucleic acid structure and in the analysis of protein-nucleic acid complexes. Topin et al. have synthesised a novel photo-cross-linking nucleoside analogue, 5-[4-3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl]-2'-deoxyuridine, and incorporated it into the recognition site of EcoRII and MvaI restriction-modification enzymes via the phosphoramidite (195). Becker et al. have reported a novel phosphoramidite (1 96) for site-specific incorporation of 4-thiouridine into oligoribonucleotides.145 4-Thio-2'-deoxyuridine residues in oligodeoxyribonucleotides have been quantitatively regenerated from S-alkylated 4-thio-2'-deoxyuridine moieties using sodium hydrosulfide.146 This method facilitated the 'reuse' of the thiocarbonyl moieties in alkylation reactions within oligodeoxyribonucleotides containing thionucleoside derivatives.

DMTrov DMTm ""'"74 $IOTBDMS

""'"v

Hunziker has synthesised the protected 5-(2-amino-2-deoxy-fb~-glucopyranosyloxymethyl)-2'-deoxyuridine phosphoramidite ( 197) from uridine in twelve steps.147 This novel nucleotide analogue was subsequently incorporated into oligodeoxyribonucleotides using automated solid-phase synthesis. The aminoglycoside-modified oligonucleotides showed decreased binding affinities for complementary RNA and DNA targets. 5-Formyl-2'-O-methyluridinehas been incorporated into oligonucleotide sequences containing the NF-KB binding sequence or its complement via the phosphoramidite (I 98). 148 Following cleavage, deprotection and purification,


180

the resulting oligonucleotides were treated with sodium periodate to afford the desired 5-formyl-2‘-O-methyluridine derivatives. CS-substituted nucleoside phosphoramidites with pendant 2-nitr0-4,Sdimethoxybenzyl-protected carboxylic acid (199a) or amine (199b) functions

0 OMe I

P

OMe OMe

have been incorporated into oligodeoxyribonucleotides.149 The reactive functional groups were selectively unmasked upon irradiation at 365 nm to afford protected, modified oligodeoxyribonucleotides which were subsequently derivatised and deprotected to afford conjugates (200) in high yield. Khan and Grinstaff have used the Sonogashira Pd(0) cross-coupling reaction to attach alkynyl-derivatised amines, biotin and a transition metal complex to an oligonucleotide (201) during automated solid-phase synthesis immediately following incorporation of 5-iodo-2’-deoxyuridine via the corresponding phosphoramidite, to give (202).150 Ruthenium-labelled oligonucleotides have been prepared by automated solid-phase synthesis using a ruthenium-nucleoside phosphoramidite (203). 15’ Fox and co-workers have prepared triplex-forming oligonucleotides in which third strand 5 4 1-propargylamino)-2’-deoxyuridine residues were introduced via the phosphoramidite (204). 52 Enhanced triplex formation of such oligonucleotides compared with those in which thymidine was utilised was demonstrated by footprinting and melting studies. Two series of modified oligonucleotides based on the self-complementary dodecamer d(CGCTAATTAGCG) incorporating CS-propargyl derivatives of 2‘-deoxyuridine were synthesised using the phosphoramidites (205) and (206).153 Zanta et al. have synthesised a capped 3.3 kbp CMVLuciferase-NLS gene containing a single nuclear localisation signal peptide incorporated at a modified 2’-deoxyuridine residue (207).154 Transfection of cells with the tagged gene remained effective down to nanogram quantities of DNA. Asseline and co-workers have described the application of a dinucleoside H-phosphonate


181

..yX

RioG OR2

(200) a R' = 'd(TACGTACTGA), R2 = yd(GCAGCTCGT), n = 2, X

=$

b R1 = ''d(TACGTACTGA), R2 = 'd(GCAGCTCGT), t~ = 3,

0

ODNi*

HNW

N

H

R

ODN2'

AGCA CT T GCA GTT GA TACATCCTA CT GGTCTTATT(CAC)2- CT -AATAACCTCAGT T cu

(DMTr0)-

(202)a R = S-COCF3 b R = $+(O)OCMe3

(208) in which the nucleobases were linked via a semi-rigid bridge to the generation of 5'-5'-linked oligonucleotides designed for alternate strand triplex formation. 55 Oligonucleotides containing tandem base lesions


182

v

DMTrO

0

DMTrov (204) R

(206) R=$--Me,

S-Ph,

-8

0

(205) R

N-(2-deoxy-~-~-erythvo-pentofuranosyl)-formylamine/8-oxo-7,8-dihydro-2’-deoxyguanosine (209a,b) have been prepared via the corresponding phosphoramidites. 156 Carell and co-workers have prepared oligonucleotides with a formacetallinked thymidine or the cis-syn photodimer analogue via the corresponding phosphoramidites (2 10) and (2 11) respectively. 157 Photolyase-mediated repair of these single-stranded oligonucleotides or in complex with the complementary DNA was found to be considerably more efficient than when in complex with the complementary RNA. Mizukoshi et al. have prepared oligonucleotides containing the (6-4) photoproduct of thymine-cytosine using the corresponding phosphoramidite (2 1 2 b ) J 8 The key step involved irradiation of thymidyl(3’-5‘)deoxycytidine to give the (6-4) photoproduct (2 12a). Phosphoramidite (212b) was incorporated into oligonucleotides (2 13) using solid-phase synthesis in the absence of the capping step that avoided acylation of the 5amino function. Template-directed photoligation of oligonucleotides has been reported by irradiation at 366 nm of a ternary complex with adjacent thymidine and 4-thiothymidine termini (Scheme 6). 159 Circular DNA templates have also been constructed in this manner.


183 R

0

I

o=p-o-

0

ODMTr

0

I H-P=O

(208)

0-

A tricyclic pyrimidine nucleoside analogue has been incorporated into oligonucleotides via the H-phosphonate derivative (217). 160 T, analysis showed enhanced recognition of both complementary adenine and guanine within a DNA duplex. Moreau and co-workers have reported the synthesis of phosphoramidite derivatives of benzo[gj]- (218) and benzom-quinazolines (219). 16' Triplexforming oligonucleotides incorporating benzoquinazolines as substitutes for thymine were prepared using (218) and (219). Benzo[g]quinazoline revealed strong fluorescence emission properties which were used to monitor selectively the formation of triple-helical structures. Two 32-mer oligonucleotides containing the triazolo[2,3-a]purine ring system have been prepared from their phosphoramidites (220a,b) using automated solid-phase synthesis.16* Khullar et al. have developed a post-synthetic method for generating the major acrolein adduct of 2'-deoxyguanosine in DNA (221).'63 The phosphoramidite derivative (222) was incorporated into oligodeoxyribonucleotides using automated solid-phase synthesis under standard conditions. Subsequently, the purified oligomer was treated with an excess of aqueous sodium periodate. This approach facilitated the site-specific introduction of (221) into ssDNA. Cadet and co-workers have prepared a series of oligonucleotides incorpor-


184

R

hOMe

(212) a R ' = H , R ~ = $

0 NPri2 b R' = DMTr, R2 =$-PCO-CN


185

0

0

HN

+

Y- OR^

R~O-x

(213) R’ = ’CTTAAGCAA, R* = H,PO,%, R3 = 5’CGTAATC, R4 = ”TGCTTA, , R5 = 5’GATTACG, ’XY = AA, AG, AC, AT, GA, CA, TA

Scheme 6 F

v

DMTrO

DMTro

0 I

H-P=O

I 0-

(217 )

ating 5’,6-cyclopyrimidine, (223),lM and 5’,8-cyclopurine, (224) and (225),1659166 residues. The incorporation of (223) required the use of a nonstandard 5’-levulinyl protecting group in the 3’-phosphoramidite derivative (226) due to the poor reactivity of the 5‘-hydroxy group towards standard detritylation conditions. Seela and co-workers have published several papers describing the introduction of 7-deazapurine analogues into oligonucleotides. The phosphoramidite derivatives of 7-halogenated 8-aza-7-deazaguanines (227 a,b),1677-deaza-2’deoxyinosine (228)168 and pyrazolo[3,4-d]-pyrimidines(229)169 have been synthesised and incorporated into oligonucleotides. In addition, Seela and Leonard have incorporated the H-phosphonate or phosphoramidite derivatives of N7-(2’-deoxy-P-~-erythro-pentofuranosyl)-adenine (230), -hypoxanthine (23 1) and -guanine (232) into oligodeoxyribonucleotides under solid-


186

0

phase conditions. I7O Seela and Wei have reported the solid-phase synthesis of oligonucleotides containing 7-deaza-2'-deoxyisoguanosineusing appropriately protected monomers (233) and (234).1 7 ' The synthesis of phosphoramidite derivatives of 7-propynyl-, 7-iOdO- and 7-cyano-7-deaza-2-amino-2'-deoxyadenosines has been reported (235). 172 Spectroscopic melting experiments of oligodeoxyribonucleotides incorporating these analogues with complementary RNA showed increases of +3-4 "C per modification for single substitutions and smaller increases per incorporation for multiple substitutions relative to unmodified control sequences. Anti-sense sequences targeting the 34-UTR of murine C-raf mRNA incorporating three and four substitutions of the 7propyne analogue exhibited a 2-3-fold increase in potency over unmodifed controls. Weinhold and co-workers have described a novel post-synthetic protocol for the modification of the exocyclic amino function of adenosine residues within a double-stranded target sequence (236) of S-adenosyl-1-methionine-dependent methyltransferase from Thermus aquaticus to yield N6-alkylated sequences (237; Scheme 7). 173 Diastereoisomeric @-substituted deoxyadenosine-benzo[c]phenanthrene diol epoxide adducts have been incorporated into oligodeoxyribonucleotides via the corresponding phosphoramidites (238a,b).174 The preparation of oligodeoxyribonucleotides containing substituted adenine residues (240) has been reported. 175 Deprotection of phenoxyacetyl-protected oligodeoxyribonucleotides incorporating 6-chloropurine using 0.1 M sodium hydroxide followed by solution-phase reaction of the resultant oligomers (239) with amine nucleophiles yielded (240). This methodology was applied to the preparation of a double-stranded oligodeoxyribonucleotide cross-linked by a


187

4-carbon tether between N6 positions of deoxyadenosines in the two strands (240b). Saito and Kuroda have reported the preparation of base-modified nucleoside phosphoramidites (24 1) for triple helix-mediated recognition of A-T base pairs. 76 A post-synthetic modification protocol has also been applied to the preparation of DNA templates containing oestrogen quinone-derived adducts.i 7 7

188


I A' R' =H, R 2 = PH(O)O-Et$JH+ OR2

(230) a b R' = H, R2 = P(OCE)NPri2 C

R'

=: Me,

R2= PH(0)O- EtSNH'

d R' = Me, R2 = P(OCE)NH2

OR2

(232)a R' = H, R2 = PH(0)O- Et3NH+ b R' = H, R2 = P(OCE)NRi2 c R' = Me, R2 = P(OCE)NW* NHBu'

DMTrnvdloA NPh2

OR (233)R = F'H(0)O- EtSNH', P(OCE)NPr'2

die

OSTrnV

OR (234) R = PH(0)O- Et3NH+, P(OCE)NR'2

0

I

prI2&O/\/CN (235) a R' =j-Me. b R' =$-CN,

c R' =$-I,

R 2 = Bz R2 = Piv R ~ BZ =

Xu has reported an efficient one-step procedure for attaching a variety of biologically useful functional groups specifically onto thioguanine residues in DNA. 17* A carboxyrnethyl, hydroxymethyl and aminoethyl group and the fluorescent tag 1,5-AEDANS (243) have all been introduced by treating a thioguanine-containing oligodeoxyribonucleotide (242) with the appropriate

189


Taql Methyl transferase

+ cotactor R’O

R’O

R~O-T- OR^

R30-T-OR4

(238)

(237)

Me

HO

HO

OH

OH

R’ = “GCCGCTCG R2 = “TGCCG R3 = ”CGAh%GCGGC R4=”CGGCA R5 = !--Me,

jmNQA HO

OH

scheme7 NHR

I

iodo alkyl derivative. Quantitative and reversible disulfide cross-links within duplex DNA containing appropriately positioned thionucleoside bases (4-thio2’-deoxyuridineand 6-thio-2’-deoxyinosine) has been effected using iodine. 146 Rieger et al. have described the deprotection of oligodeoxyribonucleotides incorporating dimethylaminomethylene-protected 8-amino-2’-deoxyguanosine

190

Organophosphorus Chemistry CI

HNHR3

I

I

(239) a R' = CGGAC, R2 = AGAAG, R3 =HO

(240)

TPh

b R' = GC, R2 = TCCTGCACGACG, R3 = GGAN"cHh'

?9

TGCAG

residues using concentrated ammonia at 55 "C for 20 h or more in the presence of 2-mercaptoethanol. 179 The phosphoramidites of the naturally occurring P-dimethyladenosine modified nucleotides A@-methylguanosine(244) and p, (245) have been prepared and incorporated into short oligoribonucleotides. lSo The 2-(p-nitrophenyl) protecting groups were removed from RNAs containing @-methylguanosine by treatment with TBAF in THF. Beaussire and Pochet have developed a suitable synthetic route to the phosphoramidite derivative of isohypoxanthine (isoI) (246) in which the C2-exocyclic oxygen is protected

191


with a diphenylcarbamoyl group. This was required for an investigation into the hybridisation properties of 5-methyl-isocytosine (5MeisoC) and isoI. Heptadecamers containing either is01 or 5MeisoC at the central position were subsequently assembled using automated solid-phase synthesis and standard phosphoramidite chemistry. Interest in nucleoside analogues selectively enriched with stable isotopes has been growing due to their utility in heteronuclear NMR studies for deter-

NMe2

I

o I

OTBDMS

0

mining nucleic acid structures and dynamics. Ahmadian and Bergstrom have developed a convenient and efficient procedure for synthesising 3C methyllabelled thymidine. 18* The corresponding 3’-phosphoramidite derivative was subsequently prepared and incorporated into an oligodeoxyribonucleotide. LaFrancois et al. have reported the incorporation of I3C(8)-enriched adenine into an oligodeoxyribonucleotide.183

5

OligonucleotideConjugates

A diaziridinylquinone-triple helix-forming oligonucleotide (TFO) conjugate (247) has been prepared by reacting the triethylammonium salt of the 5’hexylamine modified TFO with a diaziridinylquinone derivative bearing a 2,3,5,6-tetrafluorophenyl activated ester linker. This conjugate acts as a triplex-directed interstrand D N A cross-linker with up to 38% interstrand cross-linking occurring at pH 6.2. Skibo and Xing have detailed the alkylation reactions of mononucleotides and D N A by aziridinyl quinones (248a-d).Is5 Bulk D N A was up to 35% alkylated by protonated aziridinyl quinones. Under acidic conditions, these hard electrophiles were found to alkylate the phos-

192

Organophosphorus Chemistry 0

N+50-P-O--”TF0It

I 0-

H& - $ ? ) NE

0

“OR’ R2

(247)

0 (248) a R2 =$-Me N ,

b R2 = I

Me C

d

phate backbone preferentially. The benzimidazole-based aziridinyl quinone (248d) was observed to undergo aziridine ring opening followed by hydrolytic removal of the aminoethyl group from the quinone ring to yield the aminoalkyl phosphate triester. Artificial ribonucleases involving a dinuclear zinc(11) complex as the catalytic centre have been prepared using the phosphoramidite monomer containing a N, N, N’,N’-tetrakis(2-pyridylmethyl)-3,5-bis(aminomethyl)benzene (TPBA; 249).186 This monomer was coupled to the 5’-termini of DNA oligomers and the cleavage of target RNA oligomers monitored. Sequenceselective cleavage in the presence of a twofold molar excess of zinc(I1) was observed. Negligible cleavage occurred in the presence of only zinc(I1) ions or with equimolar initial concentrations of the TPBA-DNA oligomer and the metal ion. The phosphoramidite derivative of a bifunctional ruthenium(I1) complex (250a) has been prepared from 2,2’-bipyridine4,4‘-dicarboxylicacid in four steps.187 This phosphoramidite was incorporated into self-complementary sequences with a coupling efficiency of >95% when performed ‘off-column’ in a glove box, to yield ruthenium(I1)-bridged DNA hairpins (250b-d). An alternative strategy has been developed by McLaughlin and co-workers. A non-nucleoside linker based upon the 2,2’-bipyridine ligand and ethylene glycol was inserted into the backbone of oligothymidylates via the phosphoramidite (251 ). 188 Ruthenium(I1)-containing DNA complexes (252a-d) were prepared upon reaction with cis-dichlorobis(2,2‘-bipyridyl)Ru(I1). Both duplexes and triplexes were formed with (252a-d). Such linkers might therefore have utility in incorporating metals into higher order DNA structures and in antisense technologies. Mercaptoacetyldiglycyl-modifiedaptamer RNA sequences (253a; X = H or SBu‘) have been prepared following post-synthetic modification of a 5’aminoalkylated aptamer sequence. The technicium-99m-labelled aptamer (253b) was prepared following reduction of sodium pertechnetate in the presence of (253a; X = H or SBut).189


(250) bipy-

193

0-0 / \

1\

a R’ =DMTr, # = P(OCH&H&N)NP& b R’ = 5bT4, R2 =“dA4 c R’ = 5’dG3, R2 = ‘dC3 b R‘ = R2 = 5b(GCAATTGC)

(252) a R’ = R2 = dT5 b R1=R2=dTa

c R’ = Sb(CGCACCCAT), R2 = ’d(CTCTCC) d R’ = R2 = 5’d(TG),

Paramagnetic oligodeoxyribonucleotides (254) have been prepared and utilised as contrast agents for magnetic resonance imaging. 190 Meunier and coworkers have observed the chemical transformation of a thiourea linkage to a guanidinium function during the deprotection in ammonia of a fluorescent conjugate based on a manganese cationic porphyrin carboxylate derivative linked to a 5’-amino-3’-fluorescein-labelled oligodeoxyribonucleotide. Solid-phase synthesis of several pept ide-oligonucleotide 5’-conjuga tes (255) has been accomplished on CPG using a fragment coupling approach.I9* The

1 94


ys HNio,

0

(253) a R =

NH HN

X = H , I-SBu'

A L . 0

n

' y 'i N 1

-No"

b R=

s'

0

Gd(111)

O-~ODN

H

peptide-!

%N

'r( 0

(255) peptide = Gly, Leu.Gly.lle.Gly,Glu(Arg)3(Pro)2.Glu.Gly; n = 2, 5, 11 ;

ODN = dTI2, "d(CCAGGATCTACTGGCT), 5'rUa, 'r(C*GA*A^AC*U*C*C*);N* = Y-Omethylriboside

conjugates contained either glycine, a hydrophobic tetrapeptide or a basic peptide from the HIV-1 Tat protein linked to either dT12, a mixed base Tat d 16-mer, rU9 or a 9-mer mixed ribo/2'- 0-methyloligoribonucleotide.Improved yields were obtained when the internucleotide p-cyanoethyl protecting groups were removed from the CPG-bound oligonucleotide prior to peptide fragment coupling and by use of a long alkyl spacer in the linkage between oligonucleotide and peptide. Several novel procedures for the preparation of oligodeoxyribonucleotides conjugated to peptides at the 3' position have been reported. A modified Tentage1 support (256) has been applied to the solid-phase synthesis of a 17mer oligodeoxyribonucleotide conjugated at the 3'-terminus with the tripeptide Gly-Gly-His (258).193 McMinn and Greenberg have reported the convergent solution-phase synthesis of a nucleopeptide (259) containing a modified DNAbinding helix of the helix-turn-helix protein, h repressor. 194 The nucleopeptide was obtained in a 72% yield using only five equivalents of the protected peptide relative to the protected oligodeoxyribonucleotide. The same group has also described the application of a photolabile support (260) to the preparation of protected oligodeoxyribonucleotides containing 3'-alkyl carboxylic acids (261). The protected oligodeoxyribonucleotides were efficiently conjugated (>SO%) with amines in solution to yield products (262) of high purity under mild reaction conditions. 195 Greenberg and co-workers have also reported an efficient method for preparing 5',3'-bisconjugates of oligodeoxy-


0 ODN synthesis

(2%)

OTBDMS

(257)

0-

OTBDMS

?

p“

NH

I AcNH-As”. Phe.Leu.Ala.Gly.Val.Ala.Ser.GluAO (259)

ribonucleotides (265) via 3’,5’-bisamines (263). 196 An alternative solid-phase synthesis of 3’,5’-bismodified analogues of DNA peptidyl appendages at both ~~ glycolic acid, termini (267) has been developed by Schwope et ~ 2 Z . lSerine, hydroxylauric acid, and dimethylhydroxypropionic acid were tested as 3’linker residues (266). The latter, together with a direct amide link at the 5’terminus of 5’-amino-5’-deoxythymidine, gave the highest yields of amino acid-DNA hybrids. The nuclease stability of these hybrids was significantly enhanced compared to unmodified oligomers. Covalent coupling of nuclear localisation signal (NLS) peptides incorporating a photoreactive moiety (268) to plasmid DNA following photoactivation has been reported. lg8 Torrence and co-workers have prepared 2-5A-PNA adducts (269) using solid-phase techniques. When evaluated for their ability to cause the degradation of two different RNA substrates by the 2-5A-dependent RNase L,


196

0 R'0-S

~

~

P-o * I

~

~

-

OR2 (261) a R ' = R ~ = H b R'

= DMTr. F?

i R%&, qrsOP. Ps$JEt

1

=FCN

ii Depraledbn

0

HO--"OD"-0-P-0

I 0-

H

these new 2-5A-PNA conjugates were found to be potent RNase L activators.Ig9 Sakakura and co-workers have prepared a series of allyl-protected phosphoramidites (270) that have been applied to the synthesis of oligodoeoxynucleotides bearing 3'-terminal phosphate functions including base-labile functionality.2oo Full experimental details for synthesis of a set of novel achiral linker reagents (271a-c) and modified CPG supports (272a-c) have been reported.20' These were designed to enable free amino groups, fluorescein or biotin to be incorporated into oligodeoxyribonucleotides.Apart from having to use t-butyl hydroperoxide in the oxidation step, these linker reagents and solid supports are fully compatible with standard automated DNA synthesis protocols employing phosphoramidite chemistry. Rothschild and co-workers have described the preparation of phosphoramidites (273a,b) that facilitate the preparation of oligodeoxyribonucleotides containing photocleavable 5'-terminal amino functions.202Conjugates of these oligodeoxyribonucleotides with biotin, digoxigenin, tetrarnethylrhodamine or a solid support were prepared. Guzaev and Manoharan have developed a novel method for synthesising oligodeoxyribonucleotides conjugated to a variety of primary amines and m e r ~ a p t a n s This . ~ ~ ~involves use of the Nchloroacetamidohexyl phosphoramidite reagent (274) that is coupled to the 5'terminus of the oligodeoxyribonucleotide in the last step of the solid phase


197 0

0

II

I

O-P-O-5'ODN'-O-P-0

II

H

H2Nw6

O-/CN

(283)

H

0 II

0 II

I

I

O-P-O-5'ODN'-O-P-0

R2)'(N,w6

0

O/\/CN

H

MsNKR'

/- v C N O (264)

0 H

IhV

I1

I

It ~ C O & iPyBOP, . Pr'flEt iii NHAaq)

0 II

O-P-O-5'ODN'-O-P-0

R2yNw6 0

&

0I

H

XNKR1 0

(285) ODN = "d((TACGTACTGATGCAGCTCGT), ODN' = protected ODN

0

R1=ybNo2 , R2=

Me0

o m i @ 0

0

II R1-N-5'd(TGCGCA)-O-P-O-R2 H I

0MeMe

s'sBu'

(266) R' = H, R 2 = &iAco2-, NHZ

NvCa2H

ykp,co2-,

0 yAJ&ncQ-

?$'0

0

X

0-

0

(267) a X = Y = Gly, Trp, Asp, Lys, Phe b X = Trp, Y = Library, Ala/Pro/Asp/Met/PheTryrA7p

synthesis protocol. Subsequent treatment of the support-bound modified oligodeoxyribonucleotides with the appropriate primary amine or mercaptan, followed by ammonia, yielded the respective oligodeoxyribonucleotide conjugates in good yield. A photolabile linker phosphoramidite (275) has been applied to the prepara-


198

s\

,Cys.Gly.Ala.Gly.Pro.Lys.(X).Lys.Arg.Lys.Val

R

HO-P-

I HO

N H

(269) n = 4 , 8, 12

Cl

OYJ NT H

n

O

199

4: Nucleotides and Nucleic A c i h

(271) a R = Fmoc b R = C(S)NHfluore~cein(Pv)~ c R =biotin

h - R H (272) a R = Fmoc b R = C(S)NHfluorescein(Pv)2 c R=biotin

NPe2

I

Yo’p‘o-cN (273) a R = Fmoc

tion of a new multifunctional dinucleotide analogue (276a) for application in in vitro selection experiments with linker-coupled reactants.204The molecule incorporated a 5’-pCC ligation site for recognition by T4 RNA ligase, three flexible hexaethylene glycol spacers, a photocleavable o-nitrobenzyl unit and a 3’-terminalcarboxy-function. Three model compounds (276b-d) were prepared from (276a). Seelig and Jaschke have described the enzymatic synthesis of RNA conjugates by T7 RNA polymerase using modified initiator nucleotides during transcription.*05 The solid-phase synthesis of a trinucleotide functionalised at both 3’- and 5’termini with sugar residues (277a) has been reported. Deprotection of (277a) yielded (277b).*06 Novel methodology has been reported for the synthesis of oligodeoxyribonucleotides containing 5’- and 3’-phosphorothioate monoester termini (279) following periodate-mediated removal of uridine from the corresponding phosphorothioate diester (278).*07 Application of this methodology to the preparation of 3’-phosphorothioate terminated oligoribonucleotides did not yield the expected product; a putative terminal 2’,3’-cyclic phosphate was proposed. This reaction was eliminated by incorporating a 2’-deoxynucleotide residue at the penultimate 3’-position. Several novel oligodeoxyribonucleotide conjugates (281) were prepared by reaction of terminal phosphorothioate monoesters with 2-pyridyl and 2-nitropyridyl disulfide derivatives (280) (Scheme A 2,3’-cyclic phosphate-terminated oligouridylate (286b) has been prepared under neutral conditions by iodine-mediated cyclisation of a phosphorothiolate attached to a support (285b) Scheme 9).209A novel support (287) has been prepared and utilised in the synthesis of oligodeoxyribo- and oligoribonucleotides bearing a 3’-terminal puromycin moiety.210 8).2077208

200


b"" 0 II

HO-P-

I

OH

(275)

'OW 0 OH

I

O=P-OH 1

OH

OH

1

0"'

O="

HO

(276) a R = $-OH CI

HO

6H

A phenanthrodihydrodioxin (PDHD)-based phosphoramidite (288) has been incorporated at the 5'-terminus of a 9-mer oligodeoxyribonucleotide.The conjugate hybridised to a complementary 30-nucleotide-long target and efficiently cleaved it in a sequence specific manner following irradiation at 350 nm.211Komiyama and co-workers have incorporated an azobenzene moiety into an oligodeoxyribonucleotide via the phosphoramidite (289). Cis and trans isomers (produced upon photoirradiation) could be resolved by HPLC.*'* McLaughlin and co-workers have prepared perylene- (290) and naphthalene-

4: Nucleotides and Nucleic A c i h

RR ’ 01

20 1

O--”d(N)3-O-P-O O OR’S 0 II

HO OH

H

0 I

0

I O=PI

O=P-0-ODN I

0-ODN

0-

0-

(279)

(278)

RS-S

0 II

AS-s-P-0

&-

I

ax (280)

v 0 I

O=P-0-ODN

I

0Scheme 8

(2811

derived (291) phosphoramidites and incorporated these derivatives into oligodeoxyribonucleotides. Duplexes and triplexes formed with these oligomers were found to be ~ t a b i l i s e d . ~ ~ ~ A phenazine-derived phosphoramidite (292) has been prepared and incorporated at the 5’-terminus of oligodeoxyribonucleotides.’20 Hybridisation of oligodeoxyribonucleotide conjugates containing one or two androstane units inserted into each strand by short phosphoryl linkers via the corresponding phosphoramidite (293) was shown to generate hydrophobic pockets in aqueous Cysteine-derivatised oligodeoxyribonucleotides (294) have been

202


o=p-o(286) a R 2 = H b R2 = (Up),

0

MeyMe

.N H+

FmocN

NPI'~ I ,P, wCN

0

OMe (287)

0 I


203

prepared and shown to react specifically and efficiently with maleimidederivatised synthetic peptides corresponding to regions within the glycoprotein of HIV that have been shown to have membranotropic activities.215Bannwarth and Iaiza have synthesised o-DNAs (295) containing two different linkers for use in triplex investigations with homopyrimidine ssDNA and RNA The linear 3'-phosphorylated precusors (295a) were assembled using automated solid-phase synthesis. Cyclisation was effected in solution using EDC. A sulfhydryl-terminated antisense oligodeoxyribonucleotide has been efficiently and rapidly conjugated to an HPMA-based polymer. The polymeroligodeoxyribonucleotide conjugate (296) was efficiently taken up by cultured

" " " O w B

I

H

0 OH OH

H

is, \SH

0 0

0 0 (294) f

'TCTCTC"-X

Y-'TCCTTCT3'

L 3'AGAGAG-

AGG AAG A"

3


204

R

OH

OH

OH

(296) R = Fluoresceinyl

(297)

0-

cells.*17 Umeno et al. have reported the synthesis of a ssDNA-poly(Nisopropylacrylamide) conjugate (297) for use in 'thermally-induced affinity precipitation separation' of oligodeoxyribonucleotides.2'8 Hybridisation of the conjugate with its complementary oligodeoxyribonucleotide target is performed at a temperature below the phase transition point where the conjugate is soluble in water. The conjugate is subsequently precipitated from the aqueous solution with its complementary oligodeoxyribonucleotide target on raising the temperature above the phase transition point. The conjugate is able to distinguish its target sequence from mismatch DNAs. Workers in the same group have also covalently bound poly(N-isopropylacrylamide) bearing a terminal psoralen group to plasmid pBR 322 DNA via a photochemical r e a ~ t i o nl 9. ~Temperature-responsive precipitation due to the aggregation of poly(N-isopropylacrylamide)chains when heated above 3 1 "Cwas used for the one-pot separation of restriction endonuclease EcoRI. A novel approach to the radioactive labelling of peptides and PNA oligomers based on the conjugation of a deoxynucleoside 3'-phosphate with the terminal amine of the substrate, followed by phosphorylation of the 5'hydroxyl group of the nucleotide using T4 polynucleotide kinase and [y-32P]ATPhas been described.220

6

Nucleic Acid Structures

Several crystal structures of complexes between E. coli aminoacylated tRNAs and aminoacyl tRNA-binding proteins including threonyl-tRNA synthetase,221methionyl-tRNA(f)( Met) transformylase,222and a ternary complex of Cys-tRNA(Cys) and EF-Tu-GDPNP have been reported.223Two groups have published crystal structures of the highly conserved complex between a 58-


205

nucleotide domain of large subunit rRNA and the RNA-binding domain of Other crystal structures of RNA binding proteins ribosomal protein Ll 1 in complex with their target sequences that have been described include the second dsRNA-binding domain of RNA-binding protein A complexed with dsRNA,226the ternary complex between the spliceosomal U2BW2A’ protein complex and hairpin-loop IV of U2 small nuclear RNA227 and also the complex formed between two RNA-binding domains of a Sex-lethal protein and a 12-nucleotide,single-stranded RNA.228 The structures of several RNA aptamers bound to their targets have been published. These include the solution structure of the aminoglycoside antibiotic tobramycin complexed with a stem-loop RNA a ~ t a m e r ,the * ~co-crystal ~ structures of two aptamer sequences bound to MS2 coat protein230and the cocrystal structure of reverse transcriptase in complex with a 33-nucleotide long RNA p s e ~ d o k n o t . ~ ~ ’ Doudna and co-workers have identified the first specific monovalent metal ion binding site within a catalytic RNA using x-ray crystallography; a potassium ion was shown to be coordinated immediately below AA platforms of the Tetrahymena ribozyme P4-P6 domain.232 The crystal structures of the 247-nucleotide ribozyme derived from the Tetrahymena thermophila group I intron catalytic core,233a lead-dependent r i b ~ z y m e and , ~ ~the ~ 72-nucleotide hepatitis delta virus (HDV) r i b ~ z y m e ~ ~ ~ have all been detailed. A’-form RNA has been chara5terized from the single crystal structure of a tridecaribon~cleotide.~~~ A 1.6 A crystal structure of a viral RNA pseudoknot has been described.237The crystal structure of a selfcomplementary RNA duplex with non-adjacent G.U and U.G wobble pairs has been determined to 2.5 resolution.238The crystal structure at 3.0 resolution of an 82-nucleotide RNA-DNA complex formed by the 10-23 DNA enzyme in which two strands of DNA and two strands of RNA gave rise to five double-helical domains has been described.239 The structural and dynamic features of an RNA bulge motif defined by two adjacent adenine nucleotides opposite a uridine nucleotide within a 21 nucleotide hairpin have been investigated using heteronuclear NMR spectroscopy.240 The metal ion requirement of hammerhead model ribozymes has been investigated using electron paramagnetic resonance spectroscopy in the presence of Mn2’ ions.241 Structures of several modified oligodeoxyribonucleotides have been determined. The crystal structure of a fully modified 2’-0-(2-methoxyethyl)-RNA dodecamer duplex (CGCGAAUUCGCG) was determined at 1.7 A resoluEgli and co-workers have described the crystal structures of three Aform DNA duplexes containing 2’- 0-modified ribot hymidine building The solution structure of a DNA decamer duplex containing a pyrimidine(6-4)pyrimidone photoproduct [(6-4) adduct] has been determined using NMR.244Detection of thymine [2+2] photodimer repair in DNA using the selective reaction of KMn04 with thymines has been reported.245The crystal structure of a stalled, covalently-tethered complex of HIV- 1 reverse transcriptase in complex with both the double-stranded DNA template-primer .2249225

.

A

A

206


A

and the deoxynucleoside triphosphate substrate has been solved at 3.2 resolution.246The crystal structures of a double-stranded DNA containing cisplatin i n t e r ~ t r a n dor~ ~i n~ t r a ~ t r a n dcross-links ~~~ have been described. The crystal structures of several complexes of EcoRV endonuclease and its cognate binding site incorporating base analogues have been solved.249Four crystal structures of single-stranded DNAs containing either oxygen or sulfur at a 3’bridging position bound in conjunction with various metal ions at the 3’-5’ exonucleolytic active site of the Klenow fragment (KF) of DNA polymerase I from Escherichia coli have been solved at up to 2.03 A resolution.250Workers in the same group have also provided the first functional evidence that metallophosphotransferases can mediate catalysis via metal ion coordination to both the leaving group and a nonbridging oxygen of the scissile phosphate utilising a phosphodithioate substrate in which both the 3’-oxygen and the proSp oxygen are simultaneously substituted with The co-crystal structures of restriction endonucleases complexed with DNA in the presence of Ca2+ ions (EcoRV)~’~ or Mn2+ and Ca2+ ions (BamH1)253have been solved. The crystal structure of the complex between a biologically active Ni(I1)bound diphtheria toxin gene repressor(C 102D) mutant and a 33-base-pair DNA segment containing the toxin operator has been Kielkopf et al. have determined the crystal structure of a specific polyamide dimer-DNA complex.255 Several proteins involved in transcription and its regulation have been crystallised in complex with their target DNA. A transcription bubble formed from the four base pairs closest to the catalytic active site of T7 RNA polymerase has been observed in the structure of the enzyme in complex with a 17-base-pair promoter.256 King et al. have described the structure of HAP1 bound to its cognate upstream activation sequence from the CYC7 gene and also of the same sequence bound to a mutant.257-258 The first crystal structure for a member of the AraC prokaryotic transcriptional activator family, MarA, in complex with its cognate DNA-binding site has been described.259 The structure of the 45-amino acid transcriptional repressor CopG bound to its target operator DNA in which compression of both major and minor grooves gives rise to a DNA bend of 60” has been solved.260 The crystal structures of DNA complexes with several homeodomain transcription factors have been described.26* -263 The 2.7 A-resolution crystal structure of a quaternary complex of the DNAbinding domains of NFAT, Fos and Jun with a DNA fragment containing the distal antigen-receptor response element from the interleukin-2 gene promoter, has been determined.264The low-temperature co-crystal structure of a P22 Arc repressor mutant, FVlO, and a 22 base-pair operator sequence has been solved.265STAT proteins are a family of eukaryotic transcription factors that mediate the response to a large number of cytokines and growth factors. The first crystal structure of a STAT protein bound to its DNA recognition site at 2.25 resolution has been reported.266 The 2.1 crystal structure of Zct (a DNA-binding domain of RNA adenosine deaminase) complexed to DNA has been solved.267Sac7d belongs

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to a class of small chromosomal proteins from hyperthermophilic archaea which bind to DNA without any particular sequence preference and thereby increase its melting temperature by up to 40 “C and is extremely stable to heat, acid and chemical agents. The crystal structure of Sac7d in complex with two DNA sequences has been solved.268 A novel DNA-binding motif of a Smad3 MHl domain bound to an optimal DNA sequence has been identified from the crystal structure determined at 2.8 A resolution.269 Three structures have been determined for complexes between HhaI methyltransferase (M.Hha1) and oligodeoxyribonucleotides containing a G-A, G-U or G-AP (AP = abasic or apuriniclapyrimidinic) mismatch at the target base pair. The mismatched adenine, uracil and abasic site were all flipped out of the DNA helix and located in the enzyme’s active-site pocket.270It was therefore proposed that rotation of the DNA backbone is the key to base flipping. A new zinc-bound fold and endonuclease active site have been identified in the 1.8 resolution crystal structure of the I-PpoI homing endonuclease bound to homing-site DNA.271The structures of both uncleaved substrate and cleaved product complexes were determined. Van Duyne and co-workers have published the X-ray crystal structures of three DNA Holliday junctions bound by Cre R e ~ o m b i n a s e .The ~~~ crystal ?~~~ structure of human 3-methyladenine DNA glycosylase complexed to a mechanism-based pyrrolidine inhibitor has been determined.274 Multilamellar domains with a regular spacing of 70 and 68 have been characterised in supramolecular assemblies formed by guanidinium-cholesterol reagents and DNA designed for gene transfection using cryotransmission electron microscopy studies and small-angle X-ray scattering experiments.275 Two different structures of PcrA DNA helicase complexed with the same single strand tailed DNA duplex have provided snapshots of different steps on the catalytic pathway of this enzyme.276Large and distinct conformational changes were observed upon binding DNA and a nonhydrolysable analogue of the nucleotide (ATP) cofactor (mimicking a ‘substrate’ complex) or DNA and sulfate ion (mimicking a ‘product’ complex) from which an ‘inchworm’ mechanism was proposed. The crystal structure of the two-subunit Oxytricha nova telomere end binding protein cFmplexed with single strand telomeric DNA has been determined at 2.8 A resolution.277The structure reveals four oligodeoxyribonucleotide/oligosaccharide-bindingfolds, three of which form a deep cleft that binds the ssDNA, and a fourth that forms an unusual protein-protein interaction between the alpha and beta subunits. This structure provides a molecular description of how the two subunits of OnTEBP recognize and bind ssDNA to form a sequence-specific, telomeric nucleoprotein complex that caps the very 3’ ends of chromosomes. A conformational variant of B-DNA has been characterised from crystal structures of bovine papillomavirus E2 dodecanucleotide targets.278Several groups have published NMR scalar couplings across Watson-Crick base pair hydrogen bonds in DNA.279 Opine dehydrogenases catalyse the NAD(P)H-dependent reversible reaction

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to form opines that contain two asymmetric centers exhibiting either (L,L) or (D,L) stereochemistry. The first structure of a (D,L) superfamily member, N-( 1D-carboxylethyl)-L-norvahe dehydrogenase (CENDH) from Arthrobacter sp., strain lC, has been determined at 1.8 resolution and theolocation of the bound nucleotide coenzyme has been identified.280The 2.9 A structure of a ternary complex of the human type I1 isoform of inosine monophosphate dehydrogenase with the substrate analogue 6-chloropurine riboside 5’-mOnOphosphate and the NAD analogue selenazole-4-carboxamideadenine dinucleotide has been solved.281 Four crystal structures of the catalytic domains of adenylyl cyclase (AC) in complex with two different ATP analogues (p-~-2’,3’dideoxyadenosine 5’-triphosphate or adenosine 5’-(a-thio)-triphosphate) and various divalent metal ions have been determined.282 There have been several reports of the application of techniques- that facilitate single molecule observation to understanding oligodeoxyribonucleotides. Wang et al. have described the use of an optically controlled gauge to measure transcriptional velocities and forces for single molecules of Escherichia coli RNA polymerase.283DNA shortening and bending upon binding of yeast centromeric DNA binding factor 3 to its target sequence was demonstrated by atomic force microscopy.284 The progressive denaturation of a single DNA molecule as it was unwound was shown to generate distinct, stable denaturation bubbles, beginning in A-T-rich regions.285 The same group has also proposed a structure derived from positive supercoiling in which the phosphate backbones are tightly interwound and bases are exposed in common with Pauling’s early RecA has been shown to bind strongly to stretched DNA grafted between an optical fibre, acting as a force transducer, and a latex bead manipulated with a micropipette mounted on piezoelectric transducers.287 Quake and co-workers have described the fabrication and use of a singlemolecule DNA sizing device for sizing and sorting DNA restriction digests and ladders spanning 2-200 kbp.288Restriction enzyme cleavage of DNA and the unfolding of a DNA hairpin have both been studied using single-molecule fluorescence spectroscopy.289~290 Knots have been introduced into a single DNA molecule using optical tweezers.291

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23 1 232 233 234 235 236 237 238 239 240 24 1 242 243 244 245 246 247 248 249 250 25 1 252 253 254

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276 277 278 279 280 28 1 282

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5 Ylides and Related Species BY NEIL BRICKLEBANK

1

Introduction

In this chapter we have adopted a revised approach, similar to that introduced last year, but with a greater focus on the organophosphorus reagents themselves and with less of an emphasis on their use in synthesis of specific compounds. The level of interest in Wittig chemistry remains high, primarily as a result of the diversity of application of the reagents. There has been a moderate increase in the number of theoretical and computational studies together with further mechanistic investigations into the thio-Wittig reaction. Other notable highlights include reports on the structures of the simplest phosphorane, methylene(trimethyl)phosphorane, and the first stabilised diaminophosphonium diylide. Linking of different organic reactions into ‘tandem’ processes is a topical area and the first tandem Wittig-Hydroformylation reactions have been described. All of these discoveries are discussed in greater detail in the relevant sections below. 2

Phosphonium Ylides

2.1 Theoretical, Structural and Mechanistic Studies of Phosphorus Ylides and the Wittig Reaction. - Previous mechanistic studies of the Wittig reaction have established that the principal intermediate is an oxaphosphetane which, after pseudorotation, decomposes to give phosphine oxide and alkene products. The characteristics of specific reactions are dependent on variables such as the structure of the ylide and carbonyl substrates, solvent, base etc. Current mechanistic interest is focused towards stereochemical variation of the oxaphosphetane intermediates, i.e. their cisltrans selectivity, and hence that of the alkene products. A computational study by Yamataka and Nagase, using a higher level of calculation than previous work (HF/3-21 G* and B3LYP/631G* levels), compares the reactivities and selectivities of a range of nonstabilised and semi-stabilised ylides with benzaldehyde and acetaldehyde. The reactions between alkylidenetriphenylphosphoranes (non-stabilised ylides) or benzylidenetriphenylphosphoranes (semi-stabilised ylides) and benzaldehyde both displayed two transition states, one with an almost planar structure, Organophosphorus Chemistry, Volume 3 1 q:) The Royal Society of Chemistry, 2001

219

220


which gave a trans-oxaphosphetane intermediate, the other with a puckered structure, which gave a cis-oxaphosphetane. In contrast to previous semiempirical calculations, these results indicated that the planar transition state is more stable for semi-stabilised ylides whereas the puckered transition state is more stable for the non-stabilised ylide. These calculated selectivities agree with experimental observations. The carbonyl-carbon kinetic isotope effects (KIE) were also calculated for the two reactions;' KIEs are a useful tool for investigating the nature of transition states at the rate-determining steps of chemical reactions. The calculated value for the semi-stabilised ylide (1.05 1 at OOC) was in qualitative agreement with the experimental value. However, the calculated KIE for the non-stabilised ylide (1.039 at OOC) did not agree with the experimentally determined value of unity, suggesting that the calculated cis-oxaphosphetane process may not actually represent what occurs experimentally. The differences in the calculated and observed KIE for the nonstabilised ylide implies that, although the product selectivity is determined by the planar and puckered transition states, the puckered transition state is not the rate-determining transition state for reactions involving non-stabilised ylides. The authors go on to conclude that a full description of the Wittig reaction of non-stabilised ylides by theoretical calculations remains a challenge for the future.' Intermediates, transition states and complexes in a hypothetical aza-Wittig reaction (Scheme 1) have been optimised using a6 initio calculations at the H3P=NH

+

H&O

-

H3P=0

+

H2CNH

Scheme 1

MP2/6-3 1G** level.2 The electronic structure of phosphonium ylide-betaines of the pyrimidine series (1)-(3) have been determined using SCF MO LCAO

Me

(3)

calculations at the CND012 spd level3 The study indicates that the ylide centre is better stabilised by the thiocarbonyl compared with a carbonyl group. The poor reactivity of these compounds in the Wittig reaction is explained in terms of coupling between the carbanion and the pyrimidine 7c system. A quantum mechanical study of the thermolysis of P-oxoethylidenephosphorane, at the AM1 MO level using restricted Hartree-Fock calculations, has been rep~rted.~ In a very detailed study, the pseudorotation, conformations and decomposition kinetics of two unstabilised, unconstrained, Wittig intermediates, ( 3RS,4SR)- and (3RS,4RS)-4-cyclohex y l-2-ethyl-3,4-dimethyl-2,2-diphenyl1,2h5-oxaphosphetane, (4) and ( 5 ) respectively, have been measured by dynamic 3'P NMR spectro~copy.~ For both diastereomers, the two rotamers

5: Ylides und Related Species

22 1

which have the ethyl group in an equatorial position dominate in pseudorotation. Oxaphosphetanes (4) and ( 5 ) stereoselectively decompose to (2)-and 2-cyclohexylbut-2-ene, respectively. At - 30 "C, pseudorotation is faster than decomposition by a factor of ca. 10' and, at -20 "C, the half-life of (5) in alkene formation is ca. 8 times longer than that of (4).

(a-

Although it is now relatively clear that oxaphosphetanes are the primary intermediates in Wittig olefinations, and that betaine intermediates are not involved in Wittig reactions of non-stabilised ylides under salt free conditions, thermodynamic factors make the thio-Wittig reaction somewhat different. In particular, the weaker nature of a phosphorus-sulfur bond compared to a phosphorus-oxygen bond should make thiophosphetane formation less favourable than oxaphosphetane formation. In support of this, Erker and coworkers provide further structural and spectroscopic evidence for the formation of gauche-betaine intermediates in the thio-Wittig reaction.6 These workers describe the structure of betaine (6), isolated from the reaction of phosphorane (7) with Michler's thioketone (8) in deuterated pyridine (Scheme 2). Within (6), the central S-C-C-P atom core is non-planar with a dihedral

Me2N

s(6)

(eP=CH*

+ S=C(CsH,+NMe&

C5ND5 300 k

( e P = S

+ H2C=C(C6H4NMe&

(7)

angle of 52.9(3)", and the separation between the sulfur and phosphorus atoms is large [3.312(2)A]. In a series of comparative reactions, the ylides methylene(triphenyl)phosphorane, methylene(diphenylmethy1)phosphorane and methylene(phenyldimethy1)phosphorane were treated with bisb-methoxyphenyl)ket one or bis(p-methoxyp henyl)t hioket one; the character istic 1 Jpci,,,(aryl) coupling constant was used to elucidate the structural nature of the intermediates. The reactions with the ketone all showed evidence of oxaphosphetane intermediates whereas those involving the thioketone gave signals characteristic of phosphonium species, indicative of betaine formation. Several purely structural investigations of phosphonium ylides have been reported. Mitzel and co-workers have reported the single crystal X-ray crystal-


222

lographic determination of the simplest isolable phosphonium ylide, methylene(trimethyl)phosphorane, Me3P=CH2. The solid-state structure is compared with that determined in the gas phase, by electron diffraction, and theoretically by ab initio calculations. The theoretical and gas phase structures compare quite favourably, with the P=CH2 moiety having a pyramidal geometry in which the plane of the CH2 group is at an angle of 27.4(58) to the P=C bond (this compares well with a similar angle of 26 in Ph3P=CH2, which serves as a reference structure for phosphonium ylides). However, in the crystal, the geometry of Me3P=CH2 is strikingly different showing marked deviation from that e ~ p e c t e d .The ~ ylide (2,4-cyclopentadien- 1-ylidenehydrazono)triphenylphosphorane (9) can be represented by several canonical forms. The crystal structure of (9) has been determined in order to establish which canonical form predominates. The results show a clear bond alternation in the cyclopentadiene ring, which continues into the azo substructure, indicating that the resonance form containing the non-aromatic neutral cyclopentadienylidene moiety best describes the actual hybrid form.* The preference for an s-transoid ( E ) geometry for the P-N-N-C fragment of (9) was also confirmed. 3-Carboethoxy-3-triphenylphosphoranylidene-2-oxopropane triphenylphosphonium bromide ( 10) contains triphenylphosphonium ylide and triphenylphosphonium salt moieties, both of which have the expected distorted tetrahedral geometries, linked by a carboethoxy-2-oxopropane group.9 The latter adopts an anticonformation, presumably to relieve electrostatic repulsions. Spirobicyclic phosphorane (11) has previously been used in Wittig reactions and in the O

O

0 \,-OR

formation of metal complexes. l o The structure consists of two independent molecules each displaying a distorted trigonal bipyramidal geometry; the distortion follows closely the Berry pseudorotation coordinate. The reaction of stabilised ylides and unsymetrically substituted phthalic anhydrides proceeds at temperatures below 5 "C to yield acyclic adducts. However, if the reactions are allowed to proceed above 5 "C then enol lactones are formed. In an attempt to gain an insight into the mechanism of these reactions the structures of the acyclic intermediates methyl(tripheny1phosphorany1idene)acetate ( 12), methyl( 3-methoxy-2-methoxycarbony1benzoy1)triphenylphosphoranylideneacetate (1 3 ) and methyl(2-methoxycarbonyl-6nitrobenzoy1)triphenylphosphoranylideneacetate ( 14) have been determined. Phosphorus-31 NMR has been used to study the kinetics of the reaction between phthalic anhydride and stabilised ylides. I 2 In a very comprehensive study, Cheng et al. have determined the equilibrium

5: Ylides and Related Species

223

acidities (pK,s) of a number phosphonium salts (15), together with those of their Group 15 and 16 congeners, in dimethyl sulfoxide solution. The results have been used to create a scale of thermodynamic stability for the species.13 The acid-base properties of ylides bearing a hydroxyl functionality, such as (16), have been determined. The results indicate that ylides with the hydroxyl

(15) R = Ph, BU X = H, CF3, C02Me, CN, NO2, OMe

group in the onium fragment of the molecule are less basic than those with the hydroxyl group on the carbanionic fragment.I4 The solution structures of P,ydioxoalkyl(tripheny1)phosphonium salts have been determined for the first time, by NMR spectroscopy, in deuterated chloroform solution. Compounds (17a,b) were found to exist predominantly as a mixture of cis- and trans-enol forms. In contrast, compound (1 8) was found to exist as a mixture of the ketoand one-en01 form. Similarly, bisphosphonium salt (19) has one of the phosphorus centres in the keto form and the other in the enol form. Treatment of salt (19) with base generates ylide (20), which is resistant to further deprotonation and which exists only in the enol form.15

(17) a R = O M e b R=OEt

OH (19)

2.2 Synthesis and Characterisation of Phosphonium Ylides. - Lithium phosphonium diylides were first discovered by George Wittig in 1949. As part of their studies into the reactivity of these species, Taillefer et al. have prepared the first stabilised diaminophosphonium diazaylide; sodium diphenylbis(cyanamido)phosphonium diylide (21) was synthesised by a new variation of the

224 Ph2PCI


2Na, THF

Ph2PNa

-NaCI

12hP5 O

2NaN3

2BrCN, MeCN -2NaBr

C

NCN

* 2N3CN

(21)

scheme 3

Staudinger reaction (Scheme 3).16 Diylide (21) reacts with metal ions; the crystal structure of its copper complex was reported. The synthesis and crystal structure of an a-(1ithiomethylene)phosphorane (22) has been reported. Compound (22) reacts with water or electrophiles to produce ylides (Scheme 4).

'

SiMe3

SiMe3

SiMe3

Several new chiral stabilised ylides (23), based on the binaphthyl molecule, have been prepared, together with their palladium, rhodium and ruthenium complexes. Environmental concerns continue to stimulate research into synthetic organic chemistry using water as solvent. With the aim of performing Wittig reactions in aqueous media, Russell and Warren have reported the synthesis of a range of new phosphonium salts, (24) and (25), which are soluble and stable in basic aqueous solution.19 The Wittig reactions of these salts with benzaldehyde derivatives in aqueous sodium hydroxide are also discussed. The preparation and synthetic applications of phosphonium ylides bearing

(23) R' = p M e C 6 H 4 ; R2 = C02Et. C0&Me3, CN

(24) R = 4-C02H, 4-OH, 3-OH

(25) R = 4-OH, 3-OH

225


perfluorinated substituents is the subject of several recent publications. Treatment of (a-furoy1)methy It riphenylp hosp honium bromide or (a-thienacy1)methyltriphenylphosphonium with methyl 2-perfluoroalkylnoates, in the presence of potassium carbonate, yields 4-(ac-furoyl)-2-triphenylphosphoranylidene-3-perfluoroalkyl-3-butenoates or 4-(a-thienacyl)-2-triphenylphosphoranylidene-3-perfluoroalkyl-3-butenoates(26) respectively.2092' Hydrolysis of phosphoranes (26) with hot aqueous methanol produces a-furoyl or a-thienacyl pyranones and butenoates. The first a-fluorovinylphosphonium salts, (27a,b) (Scheme 5), have been prepared from fluorovinyldiphenylphosphine.22 C02Me

ph3p=c R

0

(26) E = 0 ,S ; R = CF3, C2F5, R C ~ F ~

i cat CuCI, 140 "C 1,1,2,2-tetrachloroethane

The ylides generated from compounds (27a,b) are useful reagents for introducing a monofluoroethylene moiety into carbonyl compounds although the reactivity of phosphonium salt (27a) was generally lower than that of (27b); for example, sequential treatment of (27b) with ethoxide ion, in ethanol at room temperature, followed by benzaldehyde, yields 1-benzylidene-1-fluoro-2-ethoxyethaneas a 4357 mixture of the E and 2 isomers in 75% yield, whereas salt (27a) provides only a 52% yield of product, with E:Z of 53:47. Aitken and co-workers continue to study the synthesis of new ylides and their decomposition induced by flash vacuum pyrolysis. Compounds prepared include seven new stabilised ylides, (28)-30) (Scheme 6), which are designed to undergo thermal tandem c y c l i ~ a t i o nUpon . ~ ~ flash vacuum pyrolysis at 850 "C the ylides undergo tandem cyclisation and/or abstraction-rearrangementextrusion processes leading to tri- and tetra-cyclic aromatic heterocycles. In a second paper, Aitken reports the synthesis of six new examples of the little known a-sulfinyl phosphorus ylides (31) (Scheme 7).24 Upon flash vacuum pyrolysis at 500°C ylides (31) are found to undergo predominantly extrusion of triphenylphosphine to give thioesters, although it was observed that the ccarylsulfinyl ylides also lose triphenylphosphine oxide to give additional side products. Mikolajczyk et al. have also prepared a family of a-sulfinyl phosphorus ylides (32), although their methodology was based on the reaction of

226


2BuLi

6Ph3 Hal-

I\

PhCH=CHCOCI

I\

CHz=CHCH&H&OCI

(28)

YMe = = X=Y=S x=o, Y = S x = s , Y=O

PPh3

Ph

(30)x = o , s

(29)

Scheme 6

0 RSH

II

2Ph3P=CHPh

RNS\CI

PhMe. 0°C. NZ, Bu'Li

2S0&12

Ph3pYPh

R = Et, 'Pr, CH2Ph, Ph, 4-MeC6H4,4-CIC6H4

(311

scheme 7

ylides with sulfinic acid esters. These workers utilised the ylides (32) in the stereoselective synthesis of racemic and optically active E-vinyl and E-dienyl sulfoxides.25 Two unusual phosphoranes have been obtained from the reaction of sulfurcontaining heterocycles with organophosphorus reagents. Compound (33), the first azacyclopentadienylphosphorane, was obtained by treating dicyano-

""Y" (32) R = Me, Et, Pr", Me2CH, Me&, Ph

(34) R = H, Me

methylenedithiazole with excess triphenylphosphine.26 Ylides such as (34) were among the products isolated from the reactions between 2-thioxo-4-thiazolidinones and formylmethylenetriphenylphosphorane.27Similarly, the apparently very complex reactions between substituted benzothiazoles and ylides yields a variety of products including benzothiazole-substituted ylides.** In a series of papers, Schmidpeter and co-workers have explored the frequently complex reactions between phosphonium ylides and phosphorus trihalides and related The reaction of allylidenetriphenylphosphorane with phosphorus trichloride has been shown to follow a complicated substitutioddisproportionation pathway yielding diphospholes (35a,b) to-


227

(35)a R = PC12 b R=H

gether with 1,4,7,1O-tetraphosphaphenalene (36).29 Condensation of phosphorus trichloride or phosphorus tribromide with bis(trimethylsily1)ylideyields ylidediylphosphine tetramers (37a) and (37b) (Scheme S), the cations of which have a tetraphosp habicyclo[2.2,2]octane (tetraphospha-barrelane) skeleton. Upon treatment with Lewis acids, (37a) undergoes skeletal rearrangements as illustrated in Scheme Se30The structure of bis(chloropheny1)phosphinylmethy'PPh3

Ph3P=C(SiMe3)2

+

- 3

x\PAP/x

PX3

Ph3P Ph3P

PP '

h3

(37) a X = C I b X=Br

M = Al, Ga

Scheme8

lide (38a) has been determined crystallographically; the structure is analogous to related bis(phosphiny1)ylides (38b) and (38c). Reduction of (38a) results in the formation of diphosphine (39) and 1,2,4,5-tetrapheny1-3,6-bis(triphenylphosphoni0)- 1,2,4,5-tetraphosphinane(40).31 PhP-PPh PhP+ PhsPrCR2

(38)a R = PPhCl b R = PPh2 c R = PC12

)=PPh

Ph/? ?\Ph CI CI (39)

PhP-PPh Ph3P=(

)==PPh3 PhP-PPh

2.3 Ylides Coordinated to Metals. - Niobium complexes (41) and (42) are the products of the reactions bet ween (2-thiazolylcarbony1)met hylenetriphenylphosphorane and [ (NbCl3(dme)}, I and [NbC13(dme)(RC= CR')], respect i ~ e l y Treatment .~~ of alkyne complex (42) (R'= Ph, R2 = Me) with methyl-


228

(42) R' = R2 = Ph, Me, Et R' = Ph, R2 = Me, Et, Pr, SiMe3

(43)

lithium produces, through deprotonation of a phenyl ring, ortho-metallated complex (43). Furthermore, complex (42) (R'= Ph, R2 = Me) undergoes loss of the alkyne ligand when treated with silver or gold triflate species, yielding heterometallic complexes. In a very comprehensive study, Doherty and co-workers have investigated the nucleophilic, regioselective, addition of tris(dialky1amino)phosphines to the binuclear iron allenyl complex (44) (Scheme 9).33On the basis of NMR

Scheme 9

and crystallographic evidence, these authors conclude that the zwitterionic dimetallacyclopentane complexes (45) do not display any significant ylidic character but vinylidene-bridged complex (46) and dimetallacyclobutane complex (47), which co-crystallise in a 2: 1 ratio, are delocalised with contributions from the ylidic resonance forms. The dimetallacyclopentane complexes (45) undergo thermally induced decarbonylation producing vinylenecarbene


229

complexes or a-phosphonium alkoxide-functionalised alkenyl complexes, neither of which show any phosphorus ylide character. A series of bimetallic complexes, such as (48), containing gold and the ferrocene system, has been prepared from the reaction of ferrocenyl ylides with a variety of gold species.34 Treatment of carbodiphosphorane (49) with nickel tetracarbonyl in toluene gives the yellow-orange coloured tricarbonyl complex (50) (Scheme 10). If the

@ 1.PPh3

(C0)3Ni-C\,,

(48)

THF

/ , F 3

(CO)2Ni-C

PPh3 (50)

\’.

PPh3

(51)

scheme 10

same reaction is repeated in tetrahydrofuran then the red dicarbonyl complex (51) is obtained. Complex (50) converts smoothly into (51) when dissolved in tetrahydrofuran; both complexes have been characterised crystallographially.^^ Several model complexes (with hydrogen atoms replacing the phenyl groups of the phosphorane) were subjected to quantum chemical calculations at the DFT level of theory (B3LYP). Analysis of the nickel-phosphorane bonding in (50) and (51) indicated that metal to ligand donation was more significant than ligand to metal back-donation. The coordination chemistry of ylides towards platinum and palladium continues to attract a great deal of attention; Navarro and co-workers are highlighted as making many significant new reports in this field. The chemistry of bis(y1ide) (52) is the subject of two paper^.^^.^^ Ylide (52) is obtained from phosphonium salt (53) when the latter is treated with palladium acetate, the ylide thus generated coordinating to the palladium, yielding complex (54) (Scheme 1 1 ) . Treatment of (54)with a molar equivalent of thallium perchlorate yields dinuclear complex (55), which forms (56) when treated with a further two equivalents of thallium p e r ~ h l o r a t eThe . ~ ~ reactivity of complexes (55) and (56) towards a variety of different species, including pyridine, tertiary phosphines, ylides and thallium acetylacetonate has been explored.36 When coordinated to palladium, as in complex (55), ylide (52) undergoes either thermally-induced or ligand-induced orthometallation, generating the C,Cchelating ligand illustrated in complexes (57) and (58).37The orthometallation proceeds through an electrophilic substitution pathway with the proton generated by the metallation being captured by an ylide group via an

230


2c1- Pd(0Ac)z

1

o=cvA P d : " ' CI

1

0 (53)

r

r

M

2+

c 2+

2TIC104

MeCN. r.t.

I

L

+PPh3

(57)

(58)L = Py, 3,5Lutidine, PPh3, PPhMe2 scheme11

intramolecular acid-base rea~tion.~' The reactivity of complexes (57) and (58) towards various deprotonating agents is discussed in a third p ~ b l i c a t i o nFor .~~ example, treatment of (57) with mercury acetate yields the interesting trinuclear complex (59) in which the ylide acts as a C,C,C-tridentate chelating ligand. The coordination chemistry of several iminophosphoranes (60), (61) and (62), towards a variety of platinum and palladium subtrates has been ~ t u d i e d .Ylide ~ ~ , ~(60) ~ displays a high selectivity for coordination through the terminal nitrogen.39 Compound (6 I), which has a poor coordination ability, only bonds through the iminic-nitr~gen.~~ In contrast, (62) displays a variety of coordination modes, including monodentate bonding through the pyridylnitrogen, N,N-chelation and N, 0-chelation; this was proven in complex (63) which was characterised by X-ray cry~tallography.~~ Several platinum(I1) complexes of ketenylidenetriphenylphosphorane have been prepared (Scheme 12). All contain the phosphorane bonded in an q ' mode though the ylidic-carbon atom. The bis(y1ide) complex (64) is stable in solution only at low temperature^.^'


23 1

L

/

/

Ph3P

Ph3P

scheme12

(64)

2.4 Reactions of Phosphonium Ylides. - 2.4.1 Reactions with Carbonyl Compounds. Bolli and Ley have developed polymer-bound Wittig reagents for use in automated combinatorial synthesis.42The ylides generated from phosphonium salts (65) were reacted with aldehydes as a step in the overall conversion of alcohols to P-hydroxyamines. Polymer-bound 4-benzylsulfonyl-1 -triphenylphosphoranylidene-2-butanone(66) has been used in Wittig reactions with aldehydes in the preparation of piperidin-4-one derivative^.^^

Lactones and amides do not usually undergo Wittig olefination under normal conditions because their carbonyl groups are not sufficiently reactive towards phosphoranes. However, Sabitha et al. have found that microwave irradiation can promote these difficult reactions; for example, upon irradiation at 90°C for ninety seconds, diphenyl pyrazolone is converted into a 90:lO mixture of 2- and E-pyrazolylidenacetate in 86% yield.44 Electroreduction of phosphonium salts in acetonitrile, in the presence of substituted benzaldehydes and a supporting electrolyte, led to the formation of olefins via Wittig reactions.45 Kinetic studies of two Wittig reactions performed under phase-transfer

232


conditions have been reported; in the first, the conversion of aldehydes into allylic dioxolanes by 1,3-dioxolan-2-yl-methyltriphenylphosphoniurn bromide was i n ~ e s t i g a t e dthe ; ~ ~second studied the reaction between substituted benzaldehydes and benzyltriphenylphosphonium bromide.47 Wang and Verkade have reported the synthesis and Wittig reactions of (67), a novel semi-stabilised Compound (67) readily reacts with aldehydes forming alkenes in high yield and with high E-stereoselectivity. The utility of phosphonium salt substituents in the synthesis of functionalised porphyrins is the subject of a short review.50 Wittig reaction of the aldehyde-functionalised porphyrin chlorin led to the unexpected formation of an unusual chlorin-spirochlorin dimer.51 Treatment of aldehyde (68) with iodo-substituted ylide (69) results in moderate yields of the cis epoxides (70) in addition to the expected 2-iodo I

Ph3P=C,

Me&OSiMe2CMe3

/

774

7

Me

OSiMe2CMe3

(69) Me

Me .'""'

OCH&H40Me-p R'R3 = 0, R2 = R4 = H R' = R3 = H, R2R4= 0

~ l e f i n . Wittig ~* reactions have been utilised in the stereoselective synthesis of a number of species including enantiopure a-alkyl, a-formyl and a-hydroxyl ketones and esters,53a-bromo-a$-unsaturated esters (Scheme 13).54 Phospho0 k O E t

Br I

\

*V0

Br

Scheme 13

nium salts (71) have been prepared and the related ylides utilised in the enantiospecific synthesis of a-amino acids through their reactions with Lglutamic and L-aspartic acid semialdehydes.55 Similarly, treatment of a-amino aldehydes, such as (72), with a-substituted alkoxycarbonyl phosphoranes (73) yields a-substituted a$-unsaturated y-amino acids (74) without racemisati~n.*~ Galactosylmethylene phosphorane (79, generated in situ from the corresponding phosphonium iodide, has been used to prepare oligogalactosides

233

5: Ylides and Related Species RCH26Ph31(71) R

=

X

v

'

7

-

-

4 '

fl 4 7 '

-

-

4

using an iterative Wittig olefination process.57 Partially protected sugar lactones have been shown to react with stabilised ylides at elevated temperatures producing activated ole fin^.^* Standard Wittig reactions have been used to prepare a variety of cyclic and heterocyclic compounds including c ~ u m a r i n s ,quinolines,60 ~~ dio~epanes,~~ substituted cyclohe~enones~~ and tetraepoxyann~lenes.~~ The latter compounds were prepared by a cyclising two-fold Wittig reaction of E,E,E5,5(hexa-1,3,5-triene-l,6-diyl)bisphosphoniumiodide (76) with the corresponding bis-aldehyde. Although not strictly a Wittig reaction in the conventional sense, phosphoranylidenephosphines (77), so called phospha-Wittig reagents, have been shown to react with aldehydes producing phosphaalkenes in high yield.64

H+PPh3Br- 2

-n B BnO OBn (75)

y

o /

'PPh3

y

7H2

RP=PMe2

2.4.2 Miscellaneous Reactions. Lawrence and Muhammad have detailed the preparation of alkenes from phosphinyl alcohols (Scheme 14). This reaction, OH

PPh2 OH PC13,NEt3

*

CHPCb,r.t., 2 h

R

'

d

R

2

PPh2 R' = PhCH2,Me, R2 = Ph

Scheme 14

an anti-Wittig elimination, proceeds via an epi-phosphonium (phosphiranium) species (78) and has been used to prepare cis-combretastatin A-4 (SO), a potent antimitotic stilbene, from phosphinyl alcohol (79).65 In order to probe the involvement of epi-phosphonium salts (78) in the conversion of phosphinyl

234

Organophosphorus Chemistry Ph,+,Ph R’ (78) R‘ = PhCH2, Me, R2 = Ph

alcohols into alkenes further, the same workers have prepared a series of dibenzyldiphenyl phosphonium salts (8 1) which, upon treatment with base, are converted into stilbenes (82) (Scheme 15). Again, the reactions were shown to proceed via species such as (78). 66

(811 (82) fl’ = Ph, R2 = Ph, 4-MeOC6H4, 2-MeC&4,4-N*CeH4, 4-MCeH4; fl’ = R2 = 2-MeC&4. TM P = 2,2,6,6-tetramethylpiperidine NBS = N-brornosuccinimide Scheme15

In an effort to develop more efficient synthetic transformations, Breit and Khan have reported the first domino hydroformylation-Wittig and hydroformylation-Wittig-hydrogenations.These new sequences employ methallyl and homomethallyl alcohols as alkenic substrates and utilise stabilised ylides as the active Wittig c ~ m p o n e n t . ~ ~ A number of stabilised ylides have been treated with excess nitrogen dioxide, in dichloromethane, at room temperature.68 The products of the reactions were shown to be dependent upon the structure of the ylide (Scheme 16). Stabilised ylides have been shown to react with fluorinated amides producing a tautomeric mixture of enamines and imines via a putative oxaphosphetane intermediate.69 Pentafluorophenyl or chlorotetrafluorophenyl allenes have

R’ = R2 = EtO&

Scheme 16


235

been prepared from the reaction of phosphoranes (83) with hexanoyl chloride and t riethylamine.70 The synthesis of heterocycles and heterocyclic-fused ring systems mediated by vinylphosphonium salt species, produced in situ from acetylene carboxylates and phosphines or phosphites, continues to provide a fruitful avenue of A typical procedure is illustrated in Scheme 17.74 Similarly, R Ph3P=C

\

c6F4x

(83)R = H, Me, Et, Pr, Bu, Pen X = CI, F

0

nitrogen heterocycles have been prepared by phosphine-catalysed reactions of butanedienoates or butynoates and dimethyl acetylenedicarboxylate with amines; the proposed mechanism involves the formation of vinyl phosphonium salt intermediates.77 The controlled 'living' radical polymerisation of vinylic monomers is an important industrial goal. Many compounds have been screened as potential initiatorskatalysts for such processes including several phosphorus y l i d e ~ . ~ * , ~ ~ Polymerisations of methyl methacrylate using ylides showed 'living' characteristics and produced polymers with narrow molecular weight distribution^.^^ 3

The Synthesis and Reactions of Aza-Wittig Reagents

Buono and co-workers have reported the synthesis of the first chiral iminophosphoranes (iminodiazaphospholidines)(84), (85), which contain a stereogenic phosphorus centre. The compounds have been used for the asymmetric

(85) R = NMe2, Ph

(86) R = m, p B r ; m-, pCI; 5 - .pMeO; m, p F ; m, p M e ; 5


236

copper-catalysed cycloproponation of olefins.80A series of substituted benzylaminotriphenylphosphoranes (86) has been prepared by deprotonating the corresponding phosphonium bromides with sodium amide in liquid ammonia.8' Other iminophosphoranes which have been made for the first time include 2-[(triphenylphosphoranylidene)amino]tropene (87), which was used to prepare cyclohepta-annulated heterocycles,82 and 2-[(arylsulfonyl)methyl]-Ntriphenylphosphorany1idene)anilines (88)' which have been used to prepare indoles.

(88) R1 = H, R2 = Me R' = CI, R2 = H, Me

Molina and co-workers have prepared a number of impressive multifunctional iminophosphoranes which contain ferrocene moieties (89)-(92).84 The compounds were made by selective functionalisation of polyphosphines by the Staudinger reaction. CO2Et

@

@

CO2Et

(89)n = 1 4

&PPh2 (91)

Aza-Wittig reactions have been used in the synthesis of a number of carbodimides which have been used to prepare a variety of species including 86 and i m i d a z o l e ~ Another .~~ aza-Wittig 'first' to be d i a ~ e p i n e s quinolines, ,~~ reported this year is the aza-Wittig reaction of a p-lactam carbonyl group,88 which was used to prepare quinazolines or quinazolones. Other nitrogenheterocycles obtained as a result of aza-Wittig methods include pyrimidine^^^ and p t e r i d i n ~ n e ~derivatives, ~?~' obtained from iminophosphoranes (93) and (94) respectively. A series of new eight-membered heterocycles that contain ylide moieties


237

0

0

(93) R = CH2=CHC12, "Pr, 'Pr, PhCH2, 'Bu,'Bu, CH2C02Me,1-Methylprop-2-enyl, 1-Methylbut-3-enyl

(94) R = CH&02Me, 'Bu, CHMeEt

CHMeCH&H=CH2, CH2=CHCH2, Pr, CHMe2

have been reported by Yamamoto and c o - ~ o r k e r s The . ~ ~ new heterocycles were obtained from the cycloaddition and ring-expansion reactions of cyclic aza-ylides (95a,b) (Scheme 18). Treatment of (95a) with DMAD yields hetero-

P ib h c104-

(95) a n=O

b n=l

(97)

cycle (96) in 58% yield. Treatment of six-membered ylide (95b) with trichloroacetonitrile results in a [2 + 21 cycloaddition, producing four-membered bicyclic intermediate (97), which then undergoes a ring-expansion giving heterocycle (98). In contrast, under similar conditions, five-membered ylide (95a) yields an amidine (99). Aza-Wittig mediated annulation provides an efficient strategy for the synthesis of quinazolin-4-ones on a solid support.93 Treatment of a,p-unsaturated esters with lithiated phosphorane (100) provides a route to new N-(a,Punsaturated acyl)phosphinimines, e.g. (101), which, upon heating to 65- 100 "C, undergo intramolecular aza-Wittig reactions producing the corresponding nit rile^.^^

The reaction between 1,2-dihydro-1,3,2-diazaphosphinine and acetylenic carboxylates proceeds chemoselectively , depending on the react ion conditions (Scheme 19), to give ylidic-adducts (102) and ( 103).95

238


scheme19

4

(103) R = C02Me, C02Et

Structure and Reactivity of Lithiated Phosphine Oxide Anions

Phosphine oxides have been used to control stereochemistry in the asymmetric synthesis of 4-alkenyloxazolidin-2-ones.96 A mechanistic study of the stereoselective reactions of lithium derivatives of chiral phosphine oxides has been reported.97 The stereochemistry of the reaction of lithiated 1-diphenylphosphinoyl-2-phenylpropane ( 104) with cyclohexanone was elucidated by ringopening the epoxide product, producing the phosphine oxide syn,syn,anti(105), the structure of which was determined crystallographically.97

5

Structure and Reactivity of Phosphonate Anions

Continuing the theme of the previous section, the first crystal structure of a geminal dilithiated phosphonate, (106), has been reported.98 The solid state structure consists of a hexameric aggregate containing six molecules of the dilithiated phosphonate (106) and two molecules of dimethylamine. In addition, two lithium ions, coordinated by four TMEDA ligands, are present, which balance the remaining negative charge. Treatment of a mixture of phosphonate ( 107) and carbonyl compounds with lithium diisopropylamide has led to the synthesis of a new family of alkenyl phosphonates (108) (Scheme 20).99 Treatment of P-hetero-substituted vinylphosphonates, such as (109), with lithium diisopropylamide or LTMP results in lithiation at the a-position; the resulting a-lithiovinylphosphonates can be trapped by a variety of electro-


239

R' H H H Me Me Me Me Ph Ph Ph Ph

R2

R3

'BU H Et Me 4-t-butylcydohexanone BU H Ph H PhCH2CH2 H 4-t-butylcydohexanone H 'Bu Ph H H PhCH2CH2 Et Me scheme20

philes affording a-functionalised vinylphosphonates, e.g, (1 10) (Scheme 21). loo These a-functionalised phosphonates were then used to prepare related phosphonates bearing p-oxy- or P-thio-substituents. 0

0

(110)

E = SiM%, SiPh3, GeMe3, SnPh3, SMe; X = I, Br Scheme 21

A number of new phosphonates have been prepared, all for their use in the synthesis of specific compounds via Horner-Wadsworth-Emmons procedures. For example, chiral phosphonate (1 11) has been utilised in a new approach for the asymmetric synthesis of a-amino acids; l o l Chiral phosphonates which contain (1R,2S,SR)-S-phenylmentholas a chiral auxillary (1 12) have found application in asymmetric Horner-Wadsworth-Emmons reactions with mesoaldehydes;Io2tetrakis(2,2,2,-trifluoroethyl)methylenediphosphonate (1 13) has

(1 12) R = Me, Et, Pr', CF3CH2

been used to prepare 2-vinylphosphonates and 2-olefins; Io3 (a-fluoropropargy1)phosphonates (1 14) have been used in the synthesis of conjugated fluoroenynes;lo4 both E- and Z-isomers of fluoroisoprenoidal phosphonate (1 15) have been prepared and used to make fluorinated analogues of retinoids;Io5 a-chlorophosphonates (1 16) have been used to synthesise vinyl ch1orides;lo6


240 I

(114) R = Ph, n-C5HI1,c-hex

CI

(116) R = H, Me, M e 0

P-ketophosphonates (1 17) are useful starting materials for the preparation of a,o-diaminocarboxylates and azabicyclo[X.Y .O]alkane amino acids. '07 Chromium tricarbonyl-complexed benzylphosphonates ( 1 18) provide a convenient route to redox-active alkenyl-bridged bi- and tri-nuclear arene complexes by Horner-Wadsworth-Emmons reactions with organometallic aldehydes. Solid-phase Homer-Wadsworth-Emmons reactions between three resin-

(117) n z 1 - 3

(118) X = H , R = M e X = (Et0)2P(O)CHz, R = Et

bound phosphonates and sixteen aldehydes have been used to synthesise a library of olefins. In order to demonstrate the usefulness of the procedure in library synthesis, the process was semi-automated, with robots performing laborious weighing, concentrating and resin-cleavage procedures. lo9 A study of the regioselectivity of the Horner-Wadsworth-Emmons reaction between 3,4-enuloses and the lithium, sodium and potassium enolates of dimethyl(methoxycarbony1)methyl phosp honate and diethyl(et hoxycarbony1)methyl phosphonate, has been reported;"' no reaction took place in the presence of lithium salts; when sodium enolates were employed, together with chelating solvents, 1,2-addition was the main reaction whereas in the less polar, non-chelating solvent toluene, 1,4-addition is favoured; only the 1,2adducts were formed by the potassium enolates. Synthesis of a,P-unsaturated esters by Horner-Wadsworth-Emmons procedures usually results in the formation of the E-isomers. In an effort to expand our knowledge of 2-selective olefinations, a series of a-substituted ethyl(diary1phosphono)acetates (1 19) has been prepared which react with a variety of aldehydes, with high selectivity, yielding 2-esters.' I Olefination of aldehydes and ketones under so-called Bonadies-Scettri conditions (Scheme 22) afforded the expected E,E-dienoates in high yield (86%) and high selectivity. I 2 Standard Horner-Wadsworth-Emmons olefinations, using known phosphonates, have been utilised in the preparation of a variety of substrates including glycoamino acids, I 3 a-fluoro-a,p-unsaturated esters' l4 and sulfoxide-substituted fused-furan systems.'15 Iorga el af. have reviewed the preparation of phosphorylated aldehydes and their use in Horner-Wadsworth-Emmons reactions, with an emphasis on the synthesis of biologically active compounds. l 6

'


6

24 1

Selected Synthetic Applications of Wittig Reactions

In this section we review some of the more significant or unusual compounds that have been made using Wittig or related methodologies. Two reviews which include substantial sections concerning the use of ylides in the synthesis of carbon-carbon double bonds’ l 7 and nitrogen- oxygen- and sulfur-containing heterocycles’ * have been published. Brevetoxins are a family of extraordinary natural products by virtue of their structural and biological properties. In a series of papers,’ 19- 122 the culmination of ten years work, Nicolaou and co-workers discuss their strategies for the first total synthesis of a brevetoxin, brevetoxin A . Wittig and related reactions have been employed widely in these explorations and examples of ylide precursors which have been developed/studied include phosphonium salts (120) and (121), and phosphonate (122). Ylide coupling and protection methods have been employed in the synthesis of macrocyclic tricarbonyl depsipeptide elastase inhibitors YM-47141 and

’

6Pha I-

Ph- -

- .OPiv TrO

Ph- -

242


YM-47142. An important molecule in this synthesis is ylide (123), which contains the unnatural 2,3-dioxo-4-amino-6-methylheptanoic acid amino acid residue together with the beginnings of the vicinal tricarbonyl moiety; the central carbonyl group is protected in ylide form.123Similar ylide coupling methodology, involving cyano-ylide (124), has been used to prepare marine metabolites verongamine, hemibastan-2 and aerothionin. 124 OMe

Wittig reaction of 2-deoxy-galactopyranosylphosphoniumsalt (125) has been used in the diastereoselective synthesis of B-( 3,4,6-tri-O-benzyl-2-deoxyP-D-galactopyranosyl)-N-tert-butoxycarbonyl-D-alanine. 25 Phosphonium salt (126) is a key intermediate in the stereoselective synthesis of epothilone B.126 Cyclisation of the phosphorane derived from (127) provides a new route to Me

\ I

Br-

Me+[PC16] applied as catalysts in the polysiloxane Due to their strong deprotonation capacity, phosphazene bases are useful reagents in synthetic chemistry. EtN=P(NMe2)2N=P(NMe2)3 (Et-P2) has been used for the synthesis of arylcyclopropane carboxylates.88 B u ' N = P [ N = P ( N M ~ ~ )(But-P4) ~]~ has been applied to the Ullmann biaryl ether synthesis,89 for the preparation of azolidene carbenes,%for the anionic polymerization of butyl acrylateg' and for the synthesis of [poly(butadiene)-poly(ethy1ene oxide)] and [poly(isoprene)poly(ethy1ene oxide)] block copolymer^.^^ The strong base But-P4 and phosphazenium cations have been proven to be useful catalysts for anionic ring opening polymerization of cyclosiloxanes.93-96Various patents have been issued dealing with ring opening polymerization of organic ring systems in presence of phosphazenium cations.97-lo6 X-Ray structure determinations of some miscellaneous linear compounds containing a N=P entity are summarized in Section 5.107-1153132

3

Cyclophosphazenes

Reviews on cyclophosphazenes have appeared covering several subjects: dendrimers, cyclophosphazenes and cyclophosphazanes, l 6 boratophosphazenes,' l 7 polymer precursors' * and atomic transfer radical polymerization.' l 9 Various calculation methods have been applied to study the bonding in cyclophosphazenes. A spin-coupled valence bond approach has been used to study the molecular structure of (NPF2)3, (NPF2)4and (NPF&. For all ring systems highly polarized N--P+ bonds are found with minor d-orbital participation.120Ab initio calculations at MP2/6-3lG* level of theory for the cyclic compounds (NPC12)3, (NCCl)(NPC12)2, (NSOX)(NPC12)2 (X = F, Cl) and (NSOF)(NPF2)2 also point to highly polar ring skeletons with negative charge concentrated on the nitrogen atoms. I2l For the thionylphosphazenes and the carbophosphazene, heterolytic ligand-ring bond cleavage and ring opening has been calculated to occur probably close to the sulfur heteroatom. This observation is in line with experimental results. 1 2 1 A recently developed condensed-phase optimized ab initio force field (COMPASS) has been used for the description of phosphazenes. Physical and structural data obtained by molecular mechanics calculations and molecular dynamics simulations for a number of cyclophosphazenes are in line with the experimental data, the only exception being the fluorine substituted cyclophosphazenes.122 A study of Langmuir-Blodgettmonolayers of N3P3[0(CH2)2(CF2)&F3]bon water surface strongly points to an arrangement in which the phosphazene ring lies on the

26 1

6: Phosphazenes

water surface with perfluorinated aliphatic chains protruding into the air. 123 2H NMR measurements on inclusion compounds of tris( 1,2 dioxypheny1)cyclotriphosphazene with deuterated 1,3- and 1,4 dioxane and 1,3,5-trioxane show the guest molecules to be very mobile and to be subject to conformational motions and orientation processes.124High mobility has also been found for benzene guest molecules in channels of the host lattice of tris(2,3naphthalenedioxy)cyclotriphosphazene, even resulting in a less rigid host system in comparison to the guest-free structure. Smaller mobility for the guest molecules has been observed for the analogous xylene inclusion compound with xylene positioned in cage cavities.125 Weak second harmonic generation effects have been found for [NP(SC6H5)2]3 and [NP(NHC6H5)2]3.126 Liquid crystallinity of a number of cyclophosphazenes with mesogenic substituents has been investigated. The compounds hexakis[4-(4’-octyloxy)biphenyloxy]cyclotriphosphazene N3P3{ OC6H4[C6H4(OC8H7+4]}6 and hexakis[4-{ N(4‘-alkyloxypheny1)-iminomethyl)phenoxy]cyclotriphosphazene N3P3 { OC6H4[CH=NC6H4(OCnH2,+1-4’)-4]}6 (n = 3- 12) exhibit smectic phases. On the contrary, the corresponding tetrameric analogues do not show mesomorphic phase transitions, which can be explained by the random orientation of the mesogenic A smectic C* phase has been found for a cyclotriphosphazene with optically active ligands, viz. hexakis[4-(4’-(6-methyl)octyloxy) biphenyloxyl-cyclotriphosphazene N3P3{ OC6H4[C6H4[O(CH2)5CHMeCH2Me4/1-41}(,.I2’ A kinetic study of the phenolysis of (NPC12)3under phase-transfer conditions clearly reveals the influence of NaOH concentration on the reaction parameters of phenoly~is.’~~ Both (NPC12)3 and C13P=NSiMe3 are well-known precursors for the preparation of phosphazene polymers. A new method for the preparation of (NPC12)3 has been developed. Very slow addition at reflux temperature of a solution of PC15 in CH2C12to a solution of N(SiMe3)3 in the same solvent followed by a reflux period of 8 h provides the trimer in a yield of about 75% together with some higher cyclic systems and oligomeric linear species. A scheme has been put forward (see Scheme 2) to explain the ring closure by a reaction of N(SiMe3)3 with the linear cation [C13PNPC12NPC13]+. By changing the reaction conditions (fast addition of the N(SiMe3)3 solution to the PC15 solution at 0°C followed by addition of hexane) the linear compound C13P=NSiMe3can be obtained in a 40% yield.130The preparation

+ .PCI. -.

N(SiMe&

- 2 CISiMe3

C13P=NSiM%

+ 2Pclr;

CI3P=NSiMe3

[C13P=N-PC13]’pCl&

- ClSiMe3

Scheme 2

262


of high purity (NPC12)3by the reaction of PC15 and NH4Cl in presence of ZnO has been r e ~ 0 r t e d . I ~ ~ The synthesis of a tris(hydrido)cyclotriphosphazene has been achieved by with treatment of the linear phosphazene [(~yclo-Hex)~N]~P(H)=N-Zr(Cl)Cp2 Et3N.HCl at room temperature. The reaction product that is characterized by NMR and mass spectroscopy can be formulated as [NP(H)N(~yclo-Hex)2]~.'~~ Four reactions products have been reported for the reaction of (NPC12)2NPCl(NH2) and S02C1, viz. (NPC12)2NPCl(NSO), (NPCl&NPCl(NSC12), (NPC12)2NP(C1)NSNP(Cl)(NPC12)2 and (NPCl2)2NP(C1)OP(Cl)N(NPC12)2. In the last two compounds the phosphazene rings are coupled by a NSN bridge and an 0 bridge, respectively. Structures have been assigned based on spectroscopic and diffraction methods. 1 3 3 The reaction of (NPC12)3 with 4-chloropyridine-N-oxideleads to a salt-like product with composition (NPC12)3.6(CSNH4ClO). 34 The reactivity of (NPC12)3 and (NPC12)4 towards cycloalkylamines has been investigated. The major reaction product of the trimer with cyclopropylamine, cyclopentylamine and cyclohexylamine appear to be the gem-tetrakis(amin0) derivative in all cases. The more flexible, and thus more reactive, tetramer (NPC12)4 reacts with the cycloalkylamines to give the fully amino-substituted products. 135 The reactivity of (NPCh), towards the cycloalkylamines seems to be intermediate between that of the trimer and tetramer. Aminolysis yields poly(aminophosphazenes) with a small amount of residual chlorine. Surprisingly, these polymers are completely insoluble in water.13sThe macrocyclic polyether derivative (49) has been obtained in an excellent yield from the reaction of { NP[N(Me)NH2)]2}3 with 4'-formylbenzo15-crown-5. Addition of Na+ ions to compound (49) leads to profound shifts in the 13CNMR spectra, due to the complexation of the cations. Shifts remain constant after the addition of about six equivalents. In the case of K+ ions saturation has been reached after the addition of three equivalents, which can be ascribed to the formation of 2: 1 sandwich complexes.136

$jHO co

H2N(Me)N, ,N(Me)NH2

6

0'O

O>0

+

H2N(Me)N-,P, H2N(Me)N

"P"' I1

I N5P,-N(Me)NH2 N(Me)NH

I

Me

h

263

6: Phosphazenes

The complexation of amino and pyrazolyl substituted cyclotriphosphazenes with metal halides has been shown to give a number of interesting metallophosphazene complexes. Non-geminal coordination through one endocyclic nitrogen and two exocyclic nitrogen atoms of different Dmpz groups (Dmpz = 3,5-dimethylpyrazolyl) takes place for the 1: 1 complexes of NP(NH2)2[NP(Dmpz)2]2 with CuC12, CuBr2, NiC12, NiBr2 and CoC12 (5Oa) and the 1 :1 complexes of NP(S~~~O-HNCH~CH~CH~NH)[NP(D~~ with CuC12, CuBr2 and CoC12 (50b). This has been confirmed by an X-ray structure determination of (50a).137

I

(51) Me groups omitted for clarity

A completely different coordination between metal and cyclophosphazene has been found for the complex [NP(Dmpz)2]3.SmC13 (51). Apart from one ring nitrogen, four nitrogen atoms belonging to two sets of geminal Dmpz groups contribute to the coordination to SmC13. The coordination polyhedron formed around Sm can be described as a distorted hendecahedron. From a comparison of their IR spectra, similar coordination can be assumed for the complexes [NP(Dmpz)2]3.MC13 with M = La, Ce and Nd.138 Preparation and structure analysis of dimeric complexes [NP(OPh)2]2NP(OPh)[NHCH2(C,H,N-3)].HgI2, [NP(OP~)~]~NP(OP~)[NHCH~(CSH~N 4)].HgI2 (52) and [NP(OPh)2]2NP(OPh)[OCH2(C5H4N-4)].Hg12 (53) have been described. In all compounds complex formation between the phosphazene derivative and mercury occurs through the pyridyl nitrogen atoms. Dimerization takes place via asymmetric I-bridges. Van der Waals interaction between the dimers via the remaining iodine atoms leads for (52) to the formation of an infinite [HgI2] chain with phosphazenic ligands in a syndiotactic arrangement. Complex formation has not been observed for HgI2 and the o-substituted pyridyl derivative [NP(OPh)2]2NP(OPh)[NHCH2(C5H4N-2)], which probably


264

can be ascribed to steric h i n d r a n ~ e . ’On ~ ~ the other hand Cu(N03)2 shows complex formation with the ortho, meta and para isomers of [NP(OPh)2]2NP(OPh)[OCH2(CsH4N)]giving complexes with composition { INP(OPh)212NP(OPh)[OCH2(C5H4N-2)])2.CU(N03)2 (54) { “P(OPh)212NP(OPh)[OCH2(C5H4N-3)]}2.Cu(N03)2(55) and { [NP(OPh)2]2NP(OPh) [OCH~(CSH~N-~)]} ~ . C U ( N O ~Again ) ~ . complexation of the metal takes place through the pyridyl nitrogens. In (54) the copper atom is four-coordinated by two pyridine nitrogens and two nitrate oxygen atoms in a square planar geometry, whereas in (55) coordination around copper can be described a distorted octahedron, formed by four oxygen and two nitrogen atoms.140 (Ph0)zP’ II Nef70Ph)2 N,p5N

FHAH’

trans-NP(OPh)2{ NP(OPh)[NHCH,(C5H4N-2)]) reacts with CuI and oxygen to give a salt-like metal-phosphazene complex. Four phosphazene units, being deprotonated at one of the amino groups, surround a [ C U I I ~ ~ O cluster, ~I] thus forming a three-valent cation. Each phosphazene unit can be considered as a hexadentate ligand, involving pyridyl, amino, amido and phosphazene

265

6: Phosphazenes

nitrogen atoms. The counter ion is formed by the new iodocuprate [CU&]~- .212 Complexes of divalent 3d-metal salts with [NP(NHEt)&, 141 [NP(N H CH2Ph)2]3, [NP(OEt)2]3 and [NP( Morph)C1I2NPMorph2 (Morph = -fiCH2CH20CH&H2) 142 have been investigated for their antifungal activity. In all cases smaller activities are found in comparison to current industrial products. Some azido (N3) derivatives of (NPC12)3 have been prepared with trifluoroalkoxy, phenoxy, dimethylamino or diethylamino groups as cosubstituents. In their reaction with PIrrcompounds to form the corresponding iminophosphoranes, the amino-azido cyclophosphazenes appear to be less reactive than the trifluoro and phenoxy derivative^.'^^ Investigations in the thermal behavior of hexakis(pyridinoxy)cyclotriphosphazenes N ~ P S ( O C ~ Hshow ~ N ) the ~ 4-pyridinoxy and the 2-pyridinoxy derivatives to undergo ring opening polymerization of the phosphazene ring at temperatures above 150 "C and 200 "C, respectively. This is in contrast with the meta isomer that polymerizes neither in bulk nor in solution. Based on conductivity data the first step in the polymerization process is assumed to be the formation of a pyridinoxy anion. The lower resonance energy of the 3pyridinoxy anion in comparison to other isomers may explain the failure of [NP(3-OC5H4N)2I3to polymerize. Compounds (56)-(60) have been used as starting materials in sol-gel hydrolysis processes. In particular the hydrolysis products derived from (58), (59) and (60) show a remarkable high thermal stability with decomposition temperatures varying from 320 "C-430 "C. 145 Condensation of the silicon cyclophosphazenes (56) and (57) with (methacryl(Et0)3Si(CH2)3HN R R_'pMNCP NH(CH2)3Si(OEt)s II I N, p/"

1

I \

(EtOhSi(CH&HN R (56)R = NH(CH2)3Si(OEt)3 (57) R = NH(CH2)3Me

-0- 'OPh

(Et0)3Si(CH2)3HN

A/

(58) R

(Me0)3SiH2C

I ,CHfii(OMe)3

R&=p

\ N " ,R NNP\ N, p+ CHfii(OMe)3

N.

(Me0)3SiH2C- p' R/

+

/ \

(MeO)&iH& R (59) R = CH$3i(OMe)3 (60) R = M e


266

oxypropyl)trimethoxysilane, CH2=C(Me)C(0)O(CH2)3Si(OMe)3, leads to UV-sensitive sols, which produces coatings with a high degree of hardness after UV curing. 145 Phosphazene-phosphazane rearrangement is an interfering factor with respect to the stability of alkoxy substituted cyclophosphazenes, in particular, when the arising carbocation in a-position to the P-O bond can be stabilized. Methacryloyl derivatives, which are not capable of undergoing this rearrangement, have been prepared by linking the methacryloyl group to a five or sixmembered spiro derivative of (NPC12)3.This is exemplified by the compounds (61) and (62). Simulation of the NMR spectra of these structures shows a close correlation between observed and simulated spectra. 146 Ferrocenyl-2-propanol reacts with (NPC12)3 to produce the monosubstituted product (63) in moderate yields. Although the carbocation-stabilizing ferrocenyl group in (63) is situated on a p position relative to the oxygen atom, the secondary alcohol environment enhances carbocation stability, thus lowering the stability of (63).’47 0 Me II

*0c-

I .C=CH2

0 Me tI

I

0°C-c=CH2

I

H CH2 H2C-C’ I

\

ct-P, CI’

N5P\-cI CI

Reaction of (NPC12)3 with CpFeC5H&h2NHMe gives a series of stable compounds with formula N3P3C16-n[N(Me)CH2C5H4FeCp],(n = 1-3). The aminolysis follows the normal non-geminal substitution pattern for secondary amines. On the contrary, chlorine substitution of the methacrylate containing cyclophosphazene N 3P3Cl5[O(CH2)40C(O)C(Me) =CH2] leads exclusively to the formation of the geminal disubstituted product (NPC12)2NP[O(CH2)40C(O)C(Me)=CH2J[N(Me)CH2C5H4FeCp].147 An interesting example of self-assembly of two cyclophosphazene derivatives in one crystal lattice has been found for a 1: 1 mixture of [NP(OC6H&02H4)2]3 and (NP[4-(OCH2)C5H4NI2} 3. Interaction between the two molecules takes place on both sides of the phosphazene rings via hydrogen bridges -COOH.. . .NC5H4-,thus forming a cylindrical structure (64).14* In order to get information about synthetic conditions at macromolecular level, reactions have been carried out at the level of small cyclic molecules, viz. (NPC12)3 with C6H4[0CH2CH20CH2CH20Na1](CgHl7-4);14’ (NPCl2)3, N3P3(OCH2CF3)5C1 and N3P3(0Ph)&1 with NaOCH2CH2NMe2, NaOCH2CH20CH2CH2NMe2 or NH2CH2CH2NMe2;I5O(NPC12)3 and N3P3(0Ph)&l with NaOCH2CH2SMe,l5I and subsequent oxidation reactions of the SMe to S(0)Me and S(02)Me moieties.15’ As already described in Section 2, dendrimers with internal -P(Ph+N-P( S)-

267

6: Phosphazenes H

linkages offer the possibility for grafting reactions within the dendrimeric architecture. In addition to PPh2(CH2)6PPh2 as a linear bifunctional core, N3P3C16 has been used as a hexafunctional cyclic core for the preparation of dendrimers. Consecutive reactions of N3P3C16 with NaOC6H4CH0-4, H2NNHMe, Ph2PCHZOH, N3P(S)(OC6H4CHO-4)2 and H2NNMeP(S)C12, consecutively, lead to compound (65). Extension of the dendrimer can be achieved by reactions of (65) with NaOC6H4CHO-4 and H2NNMeP(S)C12. This yields a dendrimer (66) with six -P(Ph+N-P(S)- linkages at the level of the first generation and 48 chlorine atoms on the surface.* By replacing these chlorine atoms by a phenoxy group the dendrimer (67) has been obtained suitable for reactions at the internal -P(Ph+N-P(S)Organic backbone polymers with pendant cyclophosphazene groups and their precursors are still the subject of investigation. Compounds N3P3(0Prn)n [O(CH,),OC(O)C(Me)=CH,l,_, polymerize to flame retardant polymers when cured by UV light in presence of a radical initiator. The pencil hardness of

268


coatings of these polymers decreases with increasing propoxy content. 52 Copolymers of vinylbenzyl chloride and 2-allylphenoxy derivatives of (NPC12)3 show a large increase in thermal stability when compared to the homopolymer poly(vinylbenzy1 chloride). Is3 The combination of an unsaturated organic group and 3,5-dimethylpyrazolyl groups, as realized in compound (68), offers the possibility to prepare hybrid inorganic-organic polymers (69) with the ability for complexation to metal ions. Copolymerization of (68) with small amounts of divinylbenzene offers a cross-linked analogue of (69) that is not soluble in organic solvents.'54

Dmpz-P, / Dmpz

P .-,

(W

Dmpz Dmpz

Dmpz-P, / Dmpz

N/,P,-Dmpz Dmpz (69)

Another example of a cyclophosphazene with two organofunctional side groups has been illustrated by [4-(a-methylethenyl)phenyl]-[2-phenylethynylltetrafluorocyclotriphosphazene.This compound exists in three isomeric forms, gem (70), cis and trans (71) and can undergo radical copolymerization with styrene leading to the copolymers (72) and (73). It has been shown that complexation of Co*(C0)6 to the ethynyl group in (73) yields a redox active copolymer, 55 Research on phosphazenic ring systems in which phosphorus centers are replaced by non-carbon atoms is reflected by a small number of papers. Oxidation of the chair form of the eight-membered ring

269

6: Phosphazenes

II

I

F-P, F

,P-F \F (70)

AIBN

F-P, F

II

'

I ,P-F N \F (72)

MeC=CH2 1

F-P,

F/

,P-F 'C=CPh (71)

AIBN

F-P, F

5P-F 'C=CPh (73)

S(R)NP(Ph2)NS(R)NP(Ph2)fi (R = Ph, Me) or the boat form of S(Me)NP(Ph2)NS(Me)NP(Ph2)N with an excess of rn-chloroperbenzoic acid gives the thiazylphosphazenes trans- $(O)R-NP(Ph2)NS(O)R-NP(Ph2)h (74, R = Me; 75, R = Ph) and cis-S(O)Me-NP(Ph2)NS(O)Me-NP(Ph& (76), respectively. All eight-membered rings (74-76) adopt a twisted-boat conformation in the solid state. Their high stability renders these compounds unsuitable as precursors in a ring opening polymerization procedure.

'

trans

cis

(74) R = M e (75) R = Ph

(76)

In addition to the reaction with GaC13, investigations of the reactivity of the well-known boratophosphazene k(C12)N(Me)P(C12)NP(C12)h(Me) towards halogen acceptors have been extended to AlC13 and BC13. Crystal structure determinations reveal formation of compounds [k(Cl)N(Me)P(C12)NP(C12)N (Me)]+(MC14)- (77, M=Al, B). NMR data of (77, M = B ) in CDC13 solution point to a coordination of the BCL- anion towards the ring boron atom. All cations show a significant shortening of the BN bond lengths of 0.9- 1.O pm in comparison to compound k(C12)N(Me)P(C12)NP(Cl2)N(Me). Substitution reactions at boron with Ag(OS02CF3) and Ag(BF4) lead to the boratophosphazenes (78) and (79), respectively.'57 Cyclostannaphosphazenes (80)-( 82) have been prepared by transamination and cyclocondensation of the linear phosphazenes HN=P(Ph2)N=P(Ph2)NH2

270

Organophosphorus Chemistry + MCI-

and Bu',P(NH+NH with diaminostannanes. Compounds (8 1) and (82) are dimers arising from donor (N)-acceptor (Sn) coupling. s8

An important application of cyclophosphazenes forms their use as additives in perfluoropolyether lubricants for magnetic recording media. Two series of cyclophosphazenes can be discerned, those with fluoro or fluoroalkyl substituted phenoxy groups as P-bonded substituents [XI-P, (83)], and those with fluoroalkoxy substituents [X-100, (84)]. Also eight-membered phenoxy substituted cyclophosphazenes, in which at least one OC6H4CF3 or OC6H4F group is present, have been claimed as lubricant^.'^^ H(CF2)4CH20, /OCH2(CF2)4H N"+N II

H(CF2)4CH20-P\ H(CF2)&H2d

XI-P

(83)

I

,P-OCH2(CF2)4H N \ OCH2(CF2)4H

major compound in a mixture of fluoroalkoxy cyclophosphazenes (X-1 00)

(84)

27 1

6: Phosphazenes

The application of X1-P as a lubricant additive has been reported to improve the tribological performance of the head in hard disk perform a n ~ e . ' ~ ' - The ' ~ ~ coverage of the hard disk by mixtures of peduoropolyalkylethers PFPAE and X1-P has been investigated by means of a special X-ray technique.166A comparison of the phase separation phenomena of XI-P and X-100 in PFPAE lubricants showed the latter additive to exhibit a smaller effect. Moreover, it has been found that proper choice of hard disk properties and additive can reduce the phase separation to a m i n i m ~ m . ' Another ~~~'~~ application of organo-substituted cyclophosphazenes (and polyphosphazenes) concerns their use in processing of silver halide photographic materials. 169-174 Flame retardant properties have been reported for N3P3(OPh)4(NH&, 75-177 N3P3(OPh)6,'78"79N 3P3(OPrn)6179 and N3P3(0Me)50Ph.180Cross-linked phenoxycyclotriphosphazenes have been prepared by reacting (NPC12)3 with the dilithium salt of hydroquinone, followed by treatment with NaOPh. The compound thus obtained has been used as flame retardant in polymer blends. 1 8 1 The reaction of a polyester with 2,4-toluenediisocyanate in presence of small amounts of [NP(OC6H4CH20H4)2]3has been reported to yield a modified polyurethane with a flame retardant capacity comparable to that of blends of polyurethane and (NPC12)3.182 Other examples of the applications of (Im ~ )=] imidazolyl) Z cyclophosphazenes are: N P I ~ ~ [ N P I ~ ( N H C H ~ C H = C H as degradable cross-linker for the preparation poly(N-isopropylacrylamide)gel particles; 83 (NPC12)3as modifier of small pore molecular sieve catalysts;184 perfluoroalkoxy-substituted cyclotriphosphazenes as calibrants in mass spectroscopy; 85 CH2=C(Me)C(O)OCH2CH*OH (HEMA) derivatives of (NPC12)4 as starting material for the preparation of dental resins. X-Ray structure determinations of some miscellaneous cyclic compounds containing a N=P entity are summarized in Section

'

1867187

5.1559188

4

Polyphosphazenes

A general review has appeared of the preparation, properties and applications of polyphosphazenes and polyheterophosphazenes, including cyclomatrix, linear matrix and cyclolinear phosphazene polymers. 89 Another general review has focused on synthesis and properties of linear polyphosphazenes only. 190 Special reviews cover synthesis of functional polyphosphazenes,19* biodegradable p o l y p h o s p h a ~ e n e s ~and ~ ~ application 3~~~ of polyphosphazenes for solid electrolytes.195 Polyphosphazenes form part of a general review of inorganic and organometallic polymers. 96 Application of the ab initio force field COMPASS (see Section 3) in case of the polymers [NP(OBun)2]n,[NP(OBuS)2]nand [NP(OBut)2]nhas shown a good agreement between calculated and experimental values for polymer density and glass transition temperature. 122 The structure and geometry of (NPX2), ( X = F , Cl, Br, pyrrolidyl) have been calculated with the use of the standard MNDO method.197 Studies of solid polymer electrolytes still attract considerable attention. The

'

272


addition of 20 weight percent of dispersed y-LiA102 as ceramic filler to the polymer blend of poly(ethy1ene oxide) (PEO) and poly[(octafluoropentoxy)(trifluoroethoxy)phosphazene] (PPz) with LiS03CF3 as electrolyte has been shown to change the morphology of the polymer-salt complex. Addition of propylene carbonate only results in a decrease of the crystallinity, but has no effect on the morphology of the crystalline regions.lg8 With respect to the ionic conductivity it has been found that low level incorporation of y-LiA102 causes a decrease in conductivity, whereas higher concentrations show the opposite effect.199 The impedance of plasticized and unplasticized polymer blends of polyethers and PPz has been investigated.2mA series of linear (85), (86) and triarmed polyphosphazenes (87) with methoxyethoxyethoxy (MEE) side groups and controlled molecular weight and polydispersity have been prepared by cationic-induced polymerization of the phosphoranimine C13P=NSiMe3 with an appropriate cationic initiator, followed by treatment with an excess of NaOCH2CH20CH2CH20Me.201 Their ionic conductivities in the presence of LiS03CF3, LiC104 and LiAsF6 increase with increasing salt concentration to a maximum value. Highest maximum values have been observed for (85; x = 180) and (87; x = 60), which can be compared to that for (88). The latter highly branched polymer, however, is considerably more dimensionally stable than the others.201

CI3P=NSiMe3

I PC15

OR

+N={k

ii NaOR

OR (85) x = 20,60,180

OR

t 't

OR' I

OR' I

N=P N=P-HNCH$H2NH-P=N I 540 I I OR' OR OR' (86)

t

OR

OR

i [ X H f l HP(0R)F NPC1312"[ PCI&*II NaOR

I {N[CH&HzNHP(OR')FN PCi3]#+[PCls]3s il NaOR

OR

OR' I

I

\

tN=~~p=~-HNCH2CH2--N OR

OR'

OR'

OR

OR' OR'

OR OR

CH2CH2NH--t=Nf('=N*

OR' (87) x = 20,60, 180 R = CH2CH20CH2CH20Me R' = CH2CF3

OR

A method to improve the mechanical properties of [NP(OCH2CH20CH2CH20Me)2], (MEEP) consists of sol-gel processing of a mixture of MEEP and tetraethyl orthosilicate (TEOS). It has been found that apart from the salt concentration the ionic conductivity of a MEEP/TEOS/ LiS03CF3 system

273

6: Phosphazenes RO\ ,OR

N”+N II

I

ROyP, CH&HflCH&H@CH&H20

,P-OR \OR

0’ +=f+Oo

O\

CH&H@CH&H20CH&H20\ RO-P”+oR II

OR

I

Kp,N / \

RO OR (88) R = CH&H20CH&H20Me R’ = CH&F3

depends on the MEEP/TEOS ratio, and decreases with increasing TEOS content but remains about constant for TEOS concentrations of more than 30 weight percent.202Addition of dimethylformamide to salt complexes of MEEP and its sulfur analogue [NP(OCH2CH20CH2CH2SMe)21nwith LiS03CF3 or AgS03CF3 does increase the ionic conductivity by 1-2 orders of magnitude when compared to the solvent-free complexes.203It has been found that addition of MEEP to ionic glass LiCF3S02N(CH2)30Me.[2.2.2.]cryptand results in an enhancement of the ionic conductivity and an improvement of viscoelastic properties.204The presence of strongly polar sulfoxide or sulfone moieties lowers the conductivity of polymer systems {NP[OCH2CH2JLiS03CF3 when comS(O)MeI2}JLiS03CF3 and { NP[OCH2CH2S(O2)MeI2} pared to {NP[OCH2CH20Me]2}n/ LiS03CF3. A similar observation has been made for the corresponding gel-electrolyte systems with propylene carbonate as solvent/plasticizer. 5 1 Phenoxy substituted polyphosphazenes have proven to be attractive materials for the preparation of membranes. Membranes with poly[(phenoxy)(4carboxylatophenoxy)phosphazene], [NP(OPh),.*(OC6H4CO*H-4)o.2]n,as active component have been used to separate tritiated water from light water.205A study has been made of the pervaporation for mixtures of benzene and cyclohexane through poly[(bis(phenoxy)phosphazene] (PPOP) mernbranesa2O6 Sulfonation of [NP(OC6H4Me-3)2]nby SO3 has been reported to take place both at the phenoxy group and the nitrogen of the polymer chain, when the molar ratio S03/polyphosphazene is larger than 0.64.It could be concluded from solid state 13C NMR data that introduction of SO3 to the phenyl group occurs initially at the para-position (C-4). At higher degrees of sulfonation carbon atoms C-2, C-5 and C-6 are attacked as well.207The sulfonated polymers represent promising materials for proton-exchange membranes in fuel cells, when cross-linked by UV radiation in presence of benzophenone as iniator.208Small angle X-ray scattering has shown the formation of cluster domains in sulfonated [NP(OC6H4Me-3)2], at sufficiently high ion-exchange capacity.2o9Strong interaction between the polyelectrolyte and cationic dye has been observed for the the systems [NP(OC6H4C02Na)2]n- methylene blue

274


and [ NP (OC6H4C02Na)2], - (1-dimethylaminonaphthalene-5-sulfonamidoethy1)trimethylammonium perchlorate210 NLO active polyphosphazenes with Disperse Red 1 (DR-1) as chromophore have been synthesized by side-group chemistry at carboxylic acid or hydroxyl functionalized polymers. Examples are the multi-step preparation of compounds (89) and (90). The former polymer also contains the 6-iodo-2naphthoxy group to generate a high refractive index.

CI

+N=kh CI

-

R'

R'

0

0

OR

0

I OR

OR

I NaOR

il NaOCsH4R'-4

'H NMR data indicate that in both examples approximately one DR-1 group is present per repeating unit. Efforts to increase the loading of DR-1 for polymer (90) to the maximum value of two failed, the highest value obtained being 1.2.21' The complexing capacity towards Cu2+, Ni2+ and Co2+ ions of polyphosphazenes bearing 2-, 3- or 4-pyridylmethylamino and phenoxy side groups has been investigated. 2-Pyridylamino substituted polyphosphazenes show an increasing uptake of Cu2+ ions with increasing content of the amino group, whereas for 3-pyridylmethylamino substituted polymers a maximum Cu2+ uptake is reached at 50% amino substitution. Polymers bearing 4-pyridyl-

6: Phosphazenes

275

CI

OR”

OR”

I I -+N=y-N=P-N=P I 0 0

OR”

OH

-

0

OH

:h

i LiN(SiMe& ii ROTS

0

0

OH

OH

(90)

methylamino groups show a decreasing Cu2+ affinity with increasing aminosubstitution. Selectivity of the pyridylamino substituted polyphosphazenes for Cu2+is higher than that for Ni2+and Co2+.212 Triethoxysilane has appeared to be a versatile coupling reagent for grafting allylphenoxy-substituted polyphosphazene ( N P ( O P ~ ) O . ~ ~ ( O C ~1.20H~E~-~) [OC6H3(0Me-2)(CH2CH=cH2-4)]o.03} onto poly(viny1 alcohol) (PVA) or poly-(ethylene-co-vinylalcohol) (PE-co-PVA). The bifunctional character of HSi(OEt)3 allows for two separate grafting routes, viz. reaction of polyphosphazene with HSi(OEt)3 followed by grafting onto PVA or PE-co-PVA or reaction of PVA or PE-co-PVA with HSi(OEt), followed by reaction with polyphosphazene as shown in Scheme 3. Apart from these routes a third procedure has been described that consists of a simultaneous reaction of PVA, polyphosphazene and HSi(OEt),. It has been observed that the thickness of the polyphosphazene layer depends on the p r ~ c e d u r e* . ~Thermally induced grafting of an oxaline containing maleate (9 1) onto a number of 4-alkylphenoxy substituted polyphosphazenes in presence of dicumyl peroxide under various reaction conditions has been described. Oxaline moieties grafted in this way onto [NP(OC6H4Me-4)2],(92)


276

qoMe CH&H=CHz

iI

HSi(0Et)j

-

N

=

P

w

+I

I

0

HSi(OEt)3

H I

+OM‘

/ !

\\ /-N&-L

i

PVA or PE-c@PVA

N

I I

CHSH CH2

=

P

w

i scheme3

have been used to react with poly(methy1 methacrylate) (PMMA), yielding chemical blends (93) between the inorganic polyphosphazene and an organic p01ymer.~l4 Reactions of [NPPhMe], and [(NPMe2)(NPMePh)4], with BunLi and Si(OMe)3Cl have been shown to yield { NPPh[CH2Si(OMe)J]), and { (NPMe2)1.4[NPCH2Si(OMe)3]o.6(NPMePh)4} ”, respectively. From their gas permeability values for N2, 0 2 , CH4 and C 0 2 these polymers may be considered as attractive materials for membranes.2’ Preparation, characterization and light-induced cross-linking (via the benzophenone group) of the photosensitive polymer [NPR’2][NPR’t2][NPR’R’’]with R’= OCH2CH20CH2CH20Me and R” = OC6H4[C(0)C6HS-4] have been reported. Cross-linking enhances the dimensional stability of this MEEP copolymer, which might be of

6: Phosphazenes

277

+ I

Hex"

+ CHC0$HCti$H=CH(CH2)7-&!-TH2 I

It

CHC02Me

I

H-C-H I H

-LN-

0-CH2

(91)

dicumylperoxkte

I

0 0

Hex" I

CH2C02CHCH2CH=CH(CH2)7-C, H-6 -6HCO2Me 0-CH2 I

H

-p=N-

I

(92)

1

PMMA

I

i0;l

Hex" I CH2C02CHCH2CH=CH(CH2)7 H-C-CHC02Me I

H

H2

0 I1

I

H

(93)

interest for an application as conductive material when doped with an electrolyte.21 The synthesis of two cyclolinear phosphazene polymers have been reported. Reaction of the bis-spiro substituted cyclophosphazene (94) with a diisocyanate leads to formation of the phosphazene polyurethane (95). The presence of the phosphazene unit has a favorable effect on thermal stability.217 In another approach the phosphazene ring of NP(OPh)2[NP(0Ph)(OCbH4C02H-4)]2 (96) is incorporated in the polymer backbone of a poly(ether ketone), as exemplified by the preparation of polymer (97). It is worthy of note that the presence of phosphazene residues in polymers (97) enhances the solubility in polar organic solvents.218 7-4) has The reaction of (NPClZ), with NaOCH2CH20CH2CH20C6H4(CgH been reported to yield an amorphous polymer with all chlorines substituted by the lipophilic organic substituent. Lithium salt complexes of this polymer exhibit poor ionic conductance. 149 A number of polyphosphazenes bearing tertiary trial kylamino containing groups have been synthesized. Polymers in which the trialkylamino containing groups are attached to the P-N backbone

278


f

QQ

QQ

1

6: Phosphazenes

279

by a P-O(a1iphatic) bond (98), (99) are moisture sensitive, even when hydrophobic cosubstituents, e.g. OPh, are present. Stable polymers have been obtained when bonding to phosphorus occurs through a P-N(alky1) bond, (100)-(102). These polymers can be used in

I OCH2CH$CH2CH2NMe2

(99) NHCH$H2NMe2

NHCH2CH2NMe2 & -N-

-6=NI

I

NHCH$H2NMe2 ( 100)

membrane and surface studies. 50 Ketone derivatives of poly(methylpheny1phosphazene) ( 103) have been synthesized from (NPMePh),(NPPhCH2Li),, by two methods, viz. treatment of the Li salt with CuLi and acid chlorides, or with ethyl esters followed by hydrolysis.219 Ph +{=NfT(

Bu"Li

Ph Ph t t = N ~ = N j y

Me

Me

Ph I

CH2Li

cur, ii RCOCl

f

b

or i EtOCR, ii H+

Ph

ti=N#=N+y

Me

YH2

RC=O (103)

Novel biodegradable thermosensitive polyphosphazenes with methoxypoly(ethy1ene glycol) [O(CH2CH20),Me] and amino esters as substituents (104) have been prepared and fully characterized by spectroscopic and analytical methods.220

With respect to medical applications, polyphosphazenes can be roughly divided into three main groups, viz. polyelectrolytes, perfluoro systems and biodegradable systems. Within the group of polyelectrolytes, [NP(OC6H4C02H-4)2],(PCPP), and polymers derived thereof, are the most important representatives, which is reflected by numerous papers and patents. Improved methods for the preparation of PCPP starting from (NPC12)n have been reported.22' Hydrolysis of the reaction intermediate [NP(OC6H4C02Prn-4)2]n223 and purification224and c h a r a c t e r i z a t i ~ nof~PCPP ~ ~ have been T~~~

280


described separately. An in vitro study has revealed that the combination of Burtonella henselue antigen with PCPP provides a full protection against that infection.226The immunoadjuvant property of PCPP has also been found for a wide variety of other antigens. This underlines the general application of PCPP as an adjuvant.227 Coacervation of aqueous solutions of PCPP by NaCl solutions in water, followed by treatment with aqueous CaC12 solutions, has been shown to be a reproducible process to prepare cross-linked hydrogel microspheres of PCPP. This method of cationic cross-linking also allows for microencapsulation of proteins.228 Polymers (NP(OCbH&02H-4),[(CH2CH20),Me)2-x]}n(m = 1, 2, 16) have been prepared and fully characterized. Among these [NP(OC6H&02H-4) 1.1 6(OCH2CH20Me)0.84]n and [NP(OC6H4C02H-4)1 .62(OCH2CH20CH2CH20Me)o.381n exhibit immunoadjuvant properties, even larger than that of PCPP.229*230Copolymers with composition [NP(OC6H4C02Na-4)x(OCH2CH20Me)2-x]n cross-linked by 60Co y radiation also form hydrogels in aqueous medium, which can be used for medical application^.^^ It has been shown that surfaces of [NP(OCF2CF&ln exhibit a high biocompatibility and a low thrombogenicity due to specific protein absorption.232-234These properties enable the application of [NP(OCF2CF3)2]n as coating for blood contacting devices.235 The use of 32P labelled [NP(OCF*CF3)2]n has been described.236 Polymers (N=P(OMe)[O(CH2)5C02HI)n have been used as precursors for the synthesis of biodegradable drug carriers. Introduction of the antitumor (diaminocyclohexane)platinum(II) group could be achieved via L-glutamate or aspartate spacers, coupled by peptide bonds to the 5-carboxyl- 1-pentoxy substituents. These pentoxy groups also serve as points of attachment for saccharide moieties.237In another study, doxorubicin, known as cytostatic for solid tumors, has been coupled to the phosphazene backbone through a combination of carboxylpentoxy and Lglutamato groups or more directly by a carboxylpentoxy group only.238 Biodegradable polymers { NP(Im)o.4[NHCH(Me)CO&t]~.6}n (Im = imidazolyl) and { NP[NHCH(CH2C6HS)CO2Etl2},,have been utilized in the treatment of bone defects.239 Other applications of organo-substituted polyphosphazenes refer to flame r e t a r d a n ~ yand ~ ~ the ~ processing of silver halide photographic light-sensitive material,’69*171-173-241-246 while (NPC12), has been used as an additive to a metal hydride blend in alkali metal batteries.247

5

Crystal Structures of Phosphazenes and Related Compounds

The following compounds have been examined by diffraction methods. Distances are given in picometers and angles in degrees. Standard deviations are given in parentheses.

28 1

6: Phosphazenes

Compound

Comments

(5), n = 4 (12). MeCN, R = C02Me (13), R=CONH2 (15), Ar = C6H4Me-4 (19).6CH2C12, R = Me

NP 156.6(2) NP 157.9(2), N(Rh)P 160.6(2) NP 160.3(2) NP 160.7(2) 7 NP in unit PNP 152(l), 160(1) mean NP(S) 164(2) LPNP 152.1(7) NP in unit PNP 153(6), 159(6) mean NP(C12S) 165(5) LPNP 148(5) NP in unit PNP 154.2(5) 158.6(5) mean NP(C12S) 165.2(4) LPNP 148.3(4) NP in unit PNP 156.1(4), 159.2(4) NP(C12S) 163,6(5), 165.5(5 ) LPNP 138.5(3) mean NP 159.9(2) LNPN 117.9(2), 118.9(2) NP 156.0(2)- 157.3(2) NP 155.7(5) 41 mean NP 159.6(4) mean NP 159.5(6) mean NP 159.3(3) NP 159.3(4) NP 157.4(4) mean NP 153.5(4) NP 160.9 (3) NP 162.4(4)

( 19).2CH2C12.4MeOH,

R = CH=C=CH2 ( 19).1.5CH~Cl2,R = CH2CHzCH2

(20).4CH2C12

(27) (28).CD2C12 (27).R h(cod)BF4 (27).CoCl2.3CH2C12 (27).PdC12.0.5CH2C12.0.5CHC13 (30) (31) (32) trans- [PdC12(NCNPPh&] { Pd(dmba)[Ph3PNC(O)-2NC5H41) +[c1041dmba = dimethylbenzylamine (33).5thf (34).3thf, M = Ce (34).3thf, M = Sm (Ph3PN)3M ON [MnBr(NPEt3)]4 [FeCl(NPEt3)]4 [CoBr(NPMe3)]4.MeCN [CoBr (NPEt 3)]4 [Co(C=CMe3)(NPMe3)]4 [Co(C = CSiMe3)(NPEt3)]4 [NiBr(NPMe3)I4.MeCN [NiBr(NPEt3)]4.2PhMe [NiI(NPEt 3)14.PhMe [ZnCl(N PMe &. Ph Me

mean NP mean NP mean NP mean NP mean NP mean NP mean NP mean NP mean NP mean NP mean NP mean NP mean NP mean NP

153.7(3) 155.2(3) 154.3(8) 157.4(2) 159.4(6) 158.9(2) 158.8(4) 159.2(6) 157.4(3) 159.7(4) 158(1) 160.1(4) 160(1) 157.3(4)

Ref: 5 6 6 8

8 9 10 12 41 41 41 42 43 43 43 44 45

52 52 52 53 54 54 55 55 55 55

56 56

56 57

282


[Zn(C = CSiMe3)(NPMe3)]4 [Zn(C = C-C = CSiMe3) (NPEt3)14.4PhMe [ZnH(NPMe3)4].4thf (39, M = Ag (39, M = Cu (36).CH2C12 (37).2CH2C12 (38) mean (39) mean

mean NP 156(1) mean NP 156.5(8)

mean NP 155.5(7) mean NP 159.1(6) mean NP 161.7(6) NP 160.0(4) NP 157.3(7)-163.2(7) NP 159.3(4) NP 159.8(3) [ C U ( H N P E ~ ~ ) ] ~ [ C F ~ S ~ ~NP ] ~165.4(4) .~CH~C~~ Pt2Me6(P-I)~( pHNPMe3) .CH2C12 NP 160(2) (40) mean NP 167.9(5) (41) mean NP 165.7(9) (42) mean NP 165.5(9) NP 158-165 (43) mean NP 159.4(4) Pd(C9H 2N)[Ph2P(Se)NP(Se)Phz-Se,Se’] PNP 124.9(4) mean NP 159.2(8) Pt(C8Hl20Me)[Ph,P(S)NP(S)Phz-S,S‘] LPNP 126.7(6) Pd((3-C3H5)[Ph2P(S)NP(S)Ph2-S,S’] mean NP 159.1(3) mean LPNP 129.3(5) { Pd(q3-C3H5)[Ph2P(0)NP(Se)mean NP 158.0(4) LPNP 136.8(6) Ph2-Se112 NP 157.4(6), 160.4(6) Pd(C12H12N)[Ph2P(0)NP(Se)Ph2-0, Se]2 LPNP 126.4(4) Pd[Cl(PMe,Ph][Ph,P(O)NP( Se)mean NP 158.7(7) Ph2-0, Se]2 LPNP 131.6(3) { Pd(A2)[Ph2P(O)NP(Se)Ph2-0,Se]2> mean NP 159( 1) A = PPh3 LPNP 125.8(7) { Pd(A)[Ph2P(0)NP(Se)Ph2-0,Se],} NP 157.4(5), 159.8(5) A = Ph2P(CH&PPh2 LPNP 123.0(3) { Pd(A)[Ph2P(O)NP(Se)Ph2-O,Se],} NP 156(2), 165(2) A = c ~ s - P ~ ~ P ( C H ) ~ P P ~ ~ LPNP 125(2) mean NP 158.5(7) (44) LPNP 124.8(6), 129.3(6) NP 157.1(7), 159.7(2) (45) LPNP 134.4(4) NP 155.1(3), 157.9(3) Zn[(EtO),P(O)NP(S)Ph2-0,q2 LPNP 134.1(2) NP 156.6(3), 159.4(3) Pd [(Et 0)2P(S)NP(S)Ph 2- S,S’]2 LPNP 125.1(2) NP 149(2)- 160( 1) Pt[(Et0)2P(S)NP(S)Ph2-S,S’32 LPNP 125.1(7), 127.8(9) [Pt(PMe3)2(Et0)2P(S)NP(S)Ph2-S,S]+NP 152(l), 161(1) LPNP 132.0(6) +

+

+

57 57 58 60 60 61 61 62 62 63 63 65 65 65 66 68

68 68 68 71 71 71

71 71 72 72 75 76 76 76

6: Phosphazenes

Te[PhZP(Se)NP(Se)Phz-Se,Sell2

mean NP 158.8(3) LPNP 137.2(2), 140.8(2) (47).3CH2C12 NP 155.7(8), 162.4(9) LPNP 132.1(6) (48) mean NP 158.3(7) LPNP 136.5(4) Ph3PN-&CHC(O)N(Me)C(OMe)=fi N P 159.2(2) Ph3PN-&CHC(O)N(Me)C(SMe)=h N P 158.8(2) Ph(DCA)( Me2N)PNS3N3 N(S3N3)P 160.7(3) DCA = dicyclohexylamino Ph(DCA)(PriNH)PNS3N3 N(S3N3)P 160.1(5) N(S3N3)P 160.2(2) Ph2(PriNH)PNS3N3 [Et3PNAsPh3]Cl NP 159.9(3) [Et3PNAsPh3]Br NP 159.5(2) Pri2NP(C12)NP(O)C12 NP 153.7(3), 156.4(3) LPNP 134.0(2), LNPN 112.2(1) two independent molecules in the unit cell mean NP 155.9(2) LPNP 133.3(2), 135.8(2) { MeN[CH2C6H4NP(OEt)3-2]3} +BF4 NP 153.8(7) [Me3PNHPMe3I2+ mean NP 165.6(8) mean LPNP 133.5(7) [Rb( 18-crown-6)]+[Ph2PNPPh2] mean NP 165.7(2) LPNP 112.8(2) [Cs(18-crown-6)]+[Ph2PNPPh2] NP 163.2(4), 165.3(4) LPNP 113.4(3) [Cs(1~ - C ~ O W ~ - ~ ) I ~ ~ + [ P ~ ~ P(H ) N153.5(5) ]~~mean NP [(cyclo-Hex)2NI2P(H)=N-Zr(Cl)Cp2 NP(Zr) 156.0(3) mean NP(cyc10-Hex)~165.9(2) LNPN 110.3(1)-114.7(1) mean NP(C12) 158.5(2) NP(C1,N) 159.2(5) exocycl. NP 168.1(7) mean endocycl. LNPN 118.7(3) mean endocycl. LPNP 120.9(2) (NPC12)2NP(Cl)OP(CI)N(NPC12)2 NP 156.8(4)-159.8(4) mean LNP(C12)N 118.5( 1) mean LNP(C1,O)N 117.5(3) LPNP 119.6(2)-122.9(2) LPOP 122.9(2) gem-NPCI2{ NP[NH(cyclo-He~)]~)~in segment P(C12)NP(N2) mean NP(C12) 155.7(4) mean NP(N2) 162.2(4) in segment P(Nz)NP( N2) mean NP(N2) 158.5(4)

283

78 78 79 107 107 108 109 109 110 110 111 112

113 114 115 115 115 132 133

133

135

284

{ NP[NH(cyclo-Pr)]2}4

(5Oa)

[NP(OPh)2]2NP(OPh)[NHCH2(C5H4N-3)JmHg12

(52)

(53) [NP(OPh)2]2NP(OPh)[OCH2(CsH4N-2)J (54)


LNP(C12)N 121.3(3) mean LNP(N2)N (endo) 114.0(3) mean LP(C12)NP(N2) 121.0(2) LP(N2)NP(N2) 127.3(3) exocycl. NP 161.9(5)-164.1(5) 135 two indept. mols. in the unit cell NP(endo) 156.9(3)-159.1(3) endocycl. LNPN 118.7(2)- 122.0(2) LPNP 129.2(2)- 136.9(2) exocycl. NP 164.3(3)- 167.8(3) in segment P(NH2)2NP(Dmpz)2 137 mean NP(NH2)2 161.5(4) mean NP(Dmpz);! 155.9(4) in segment P(Dmp~)zNP(Dmpz)~ mean NP( D m p ~ 1)6~1.7(8) LNP(NH&N 112.9(3) mean LNP(Dmpz)2N 116.9(6) LP(Dmpz)2NP(Dmpz)2 114.0(3) mean LP(NH&NP(Dmpz)2 122.1(8) mean exocycl. N(H2)P 162.0(8) mean exocycl. N(Dmpz)P 168.2(3) in segment PN(Sm)P 138 mean N P 159.3(6) in segment P(Dmpz)2NP(Dmpz)2 mean N P 157.3(5) mean LNPN 118.4(3) mean LP(Dmpz)2NP(Dmpz)2 120.8(4) mean exocycl. NP 168.4(5) endocycl. NP 149 (1)- 156(1) 139 LNP(0,N)N 110.7(5) mean LNP(0,O)N 120.0(4) LP(O,O)NP(O,O) 117.1(7) mean LP(N,O)NP(O,O) 125.9(4) exocycl. NP 162(1) endocycl. NP 149(2)-162(2) 139 mean LNPN 115.8(5) LPNP 120( 1)-127(2) mean exocycl. NP 156(2) mean NP 156.3(6) 139 mean LNPN 117.4(4) mean LPNP 121.4(4) NP 156.1(4)-158.7(4) 140 mean LNPN 117.3(2) mean LPNP 122.3(2) mean NP 157.8(3) 140 mean LNPN 117.4(2)

285

mean LPNP 121.5(2) mean NP 157.1(2) 140 LNPN 115.9(3)119.0(3) LPNP 120.8(4)124.2(3) mean NP 157.0(2) mean LNPN 117.3(1) mean LPNP 122.2(2) NP 155.6(5)159.8(5) mean LNPN 117.9(4) mean LPNP 121.3(2) NP 160.8(5)-162.5(5) 156 NS 155.2(5)-157.4(5) mean LNPN 119.1(2) mean LNSN 113.6(3) LPNS 123.3(3)-128.7(4) NP 160.4(4)-161.8(4) (75) NS 155.5(4)- 157.2(4) mean LNPN 118.7(2) LNSN 112.6(2), 113.5(2) LPNS 122.1(3)-127.4(2) NP 160.9(4)- 162.1(4) NS 155.5(4)- 157.7(3) mean LNPN 118.6(2) mean LNSN 112.6(1) LPNS 122.5(2)-123.8(2) $(NMe2)NP(Ph2)NS(NMe2)NP(Ph2)$Jmean N P 160.7(3) NS 159.5(2), 162.2(2) LNPN 116.6(1) LNSN 109.6(1) LPNS 123.3(l), 125.2( 1) $(NMe2)NP(Et2)NS(NMe2)NP(Et2)N mean NP 161.9(2) mean NS 160.3(4) LNPN 117.6(2) LNSN 107.9(2) LPNS 117.1(2), 125.7(2) mean N(Me)P 162.7(1) (77) M = A1 mean N P 155.8(2) mean BN 144.5(3) mean LNPN 112.3(1) LPNP 125.3(2) (77) M = B mean N(Me)P 162.3(5) NP 154.8(6), 157.9(6) BN 143.4(7), 146.2(6) mean LNPN 112.8(2) LPNP 125.8(3) two indept. mols. in the unit cell

144

146

56

156

156

156

157

157

157

286


mean N(Me)P 159.0(3) mean N P 154.8(4) mean BN 150.9(5) mean LNPN 113.4(2) mean LPNP 126.3(2) mean N(Me)P 158.4(2) (79) mean N P 155.6(2) mean BN 155.2(3) mean LNPN 114.5(1) LPNP 124.5(2) (81) R = Me NP 158.7(4)-160.6(4) LNPN 112.1(2), 117.3(2) LPNP 120.5(2) (82) mean NP 160.3(5) LNPN 101.4(2) trans-(NPMorph2)2[NPMorph(NHEt)12 mean endocycl. N P 158.3(2) Morph = morpholino LNPN 117.4(2), 121.5(2) LPNP 127.3(2), 134.4(2)

157

158

158 188

References

2

3 4 5

6 7

8 9

10 11 12

13

14

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51 52

53 54 55

56 57

58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74

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75 76 77

78 79

80 81 82 83 84 85 86 87

88 89 90 91 92 93 94 95 96 97 98 99

100

101 102 103

289

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250


104

M. Isobe, K. Ohkubo, S. Sakai, U. Takaki, T. Nobori, T. Izukawa and S. Yamasaki, Eur. Pat. Appl., EP 0897940 A2. S. Yamazaki, Y. Hara, T. Nobori, U. Takagi and T. Izukawa, fpn. Kokai Tokkyo Koho, JP 1 1035673 (Chem. Abstr., 1999,130, 169100). M. Aoki, T. Osada and U. Takagi, fpn. Kokai Tokkyo Koho, JP 11060669 (Chem. Abstr., 1999, 130, 238293). J. N. Low, G. Ferguson, J. Cobo, M. Nogueras, A. Sanchez and A. Marchal, Acta Crystallogr., 1998, C54, 1355. J. Gopalakrishnan, J. Srinivas, G. S. Murthy and M. N. S. Rao, Proc. Indian Acad. Sci., 1998, 110, 89. J. Gopalakrishnan, J. Srinivas, G . S. Murthy and M. N. S. Rao, Indian J. Chem., 1998,37A, 1052. S. Chitsaz, B. Neumiiller, K. Harms and K. Dehnicke, Z. Anorg. Allg. Chem., 1998,624, 1341. T. Hokelek, Z. KiliC and H. Dal, Acta Crystallogr., 1998, C54, 523. F. Belaj, Acta Crystallogr., 1998, C54,1735. C. Foces-Foces, A. L. Llamas-Saiz, M. Alajarin, A. Lopez-Lazaro and P. Molina, Acta Crystallogr., 1999, C55, 373. T. Grob, F. Weller and K. Dehnicke, 2. Naturforsch., 1998,53b, 552. J. Ellermann, W. Bauer, M. Schiitz, F. W. Heinemann and M. Moll, Monatsh. Chem., 1998, 129,547. S. S. Krishnamurthy, MGCN, 1997,5, 12. D. P. Gates, P. Nguyen, A. L. Rheingold and I. Manners, Phosphorus Sulfur Silicon Relat. Elem., 1997, 124 & 125, 355. J. C. van de Grampel and G. Bosscher, Main Group Chem. News, 1998,6,42. K. Matyjaszewski, P. J. Miller, E. Fossum and Y. Nakagawa, Appl. Organomet. Chem., 1998,12,667. M. Raimondi, M. Sironi, J. Gerratt, D. L. Cooper and P. B. Karadakov, f . Chem. SOC.,Faraday Trans., 1998,94,1541 . R. Jaeger, M. Debowski, I. Manners and G . J. Vancso, Inorg. Chem., 1999, 38, 1153. H. Sun, P. Ren and J. R. Fried, Comput. Theor. Polym. Sci., 1998,8,229. Y. Tian, Q. E. Ng and J. H. Fendler, Langmuir, 1998,14, 3067. A. Liebelt and K. Miiller, Mol. Cryst. Liq. Cryst. Sci. Technol., 1998, 313, 145; A. Liebelt, J. Schumacher and K. Miiller, in Mol. Recognit. Inclusion, Proc. 9th Int. Symp., 407, ed. A. W. Coleman, Kluwer Academic Publishers, Dordrecht, The Netherlands, 1998, pp. 407-410. A. Comotti, M. C. Gallazzi, R. Simonutti and P. Sozzani, Chem. Mater., 1998, 10, 3589. Y. Xia, C. Zhan, J. Qin, D. Liu, B. Wu and C. Chen, Proc. SPIE-Int. Sac. Opt. Eng., 1998,3556, 97. K. Moriya, T. Masuda, T. Suzuki, S. Yano and M. Kajiwara, Mol. Cryst. Liq. Cryst., 1998,318,267. K. Moriya, T. Suzuki, Y. Kawanishi, T. Masuda, H. Mizusaki, S. Nakagawa, H. Ikematsu, K. Mizuno, S. Yano and M. Kajiwara, Appl. Organomet. Chem., 1998, 12,77 1 . H.-S. Wu and S.-S. Meng, Chem. Eng. S c i , 1998, 53, 4073; H.-S. Wu, D. Y. Ke and C. Y. Yeh, J. Chin. Inst. Chem. Eng., 1999, 30, 41 (Chem. Abstr., 1999, 130, 338 170).

105 106 107 108 109 110 111 112 113

114 115 116 117 118 119

120 121 122 123 124

125 126 127 128

129

6: Phosphazenes 130

29 1

H. R. Allcock, C. A. Crane, C. T. Morrissey and M. A. Olshavsky, Inorg. Chem., 1999, 38,280.

A. E. Shumeiko, L. P. Kurchenko and A. A. Afon’kin, Khim. Prom-st., 1998, 64 (Chem. Abstr., 1998, 129, 162635). 132 G. Schick, M. Raab, D. Gudat, M. Nieger and E. Niecke, Angew. Chem. Int. Ed., 131

1998,37,2390. 133 134

J . Bfinek, M. Alberti, J. Marek, Zak and J. Touiin, Polyhedron, 1998, 17, 3235. V. V. Vapirov, 0. V. Sergeeva and N. V. Khobotova, Russ. J. Gen. Chem., 1998, 68,24.

V. Chandrasekhar, K. Vivekanandan, S. Nagendran, G. T. S. Andavan, N. R. Weathers, J. C. Yarbrough and A. W. Cordes, Inorg. Chem., 1998,37,6192. 136 F. Hochart, C. Mouveaux, J. Levalois-Mitjaville and R. De Jaeger, Tetrahedron Lett., 1998,39, 6171. 137 K. R. J. Thomas, V. Chandrasekhar, K. Vivekanandan, G. T. S. Andavan, S. Nagendran, S. Kingsley and E. R. T. Tiekink, Inorg. Chim. Acta, 1999, 286, 135

138 139 140 141 142 143 144 145 146 147

148 149 150 151 152 153 154 155 156 157 158 159 160

127. B. H. Koo, Y. Byun, E. Hong, Y. Kim and Y. Do, Chem. Commun., 1998, 1227. U. Diefenbach, P. Adamaszek, M. Bloy, M. Kretschmann and S. Scholz, 2. Anorg. Allg. Chem., 1998,624, 1679. U. Diefenbach, P. Adamaszek and M. Bloy, Heteroatom Chem., 1999,10,9. B. P. Baranwal, S. S. Das and P. Singh, 2. Naturforsch. B, 1998,53, 1039. C. Guran, M. Barboiu, P. Diaconescu, V. Iluc, M. Bojin, A. Scozzafava and C. T. Supuran, Met. -Based Drugs, 1998,5,287. M. B. McIntosh, T. J. Hartle and H. R. Allcock, J. Am. Chem. SOC.,1999, 121, 884 Y. Cho, H. Baek and Y. S. Sohn, Macromolecules, 1999,32,2167. A. Schneider, S. Kairies and K. Rose, Monatsh. Chem., 1999, 130, 89. R. F. Hayes and C. W. Allen, Heteroat. Chem., 1998,9, 669. C. W. Allen and C. N. Myer, Phosphorus Su@r Silicon Relat. Elem., 1997, 124 & 125,43 1. K. Inoue, T. Itaya and N. Azuma, Supramol. Sci., 1998,5, 163. I. I. Selvaraj, S. Chaklanobis and V, Chandrasekhar, Polym. Int., 1998,46, 1 1 1. H. R. Allcock, M. B. McIntosh, E. H. Klingenberg and M. E. Napierala, Macromolecules, 1998,31, 5255. H. R.Alicock and D. L. Olmeijer, Macromolecules, 1998,31,8036. Y. W . Chen-Yang, J. R. Chuang, Y. C. Yang, C. Y. Li and Y. S. Chiu, J. Appl. Polym. Sci., 1998,69, 1 15. H.-S. Wu and D.-Y. Ke, J. Polym. Res., 1998,5,95. V. Chandrasekhar, A. P. Athimoolam, K. Vivekanandan and S. Nagendran, Tetrahedron Lett., 1999, 40, I 185. C. W. Allen and M. Bahadur, J. Inorg. Organomet. Polym., 1998,8,23. M. Brock, T. Chivers and M. Parvez, Inorg. Chem., 1998,37, 3263. D. P. Gates, A. R. McWilliams, R. Ziembinski, L. M. Liable-Sands, I. A. Guzei, G. P. A. Yap, A. L. Rheingold and I. Manners, Chem. Eur. J., 1998,4, 1489. U. Doering, D. Hanssgen, M. Jansen, M. Nieger and A. Tellenbach, 2. Anorg. Allg. Chem., 1998,624, 965. T. A. Morgan, C. E. Pawloski and K.Kar, PCT Int. Appl., WO 9818804 Al. C. M. Mate, P. H. Kasai, G. W. Tyndall, C. H. Lee, V. Raman, D. J. Pocker and R. J. Waltman, IEEE Trans. Magn., 1998,34, 1744.

292


161

D. J. Perettie, T. A. Morgan, Q. Zhao, H.-J. Kang and F. E. Talke, J. Magn. Magn. Mater., 1999,193, 318. Z . Jiang, M. M. Yang, M. Sullivan, J. L. Chao, M. Russak, D. S. Chhabra, Y. Fu and C. H. Yang, J. Appl. Phys., 1999,85,5624. T . Matsuo and K. Sawada, Jpn. Kokai Tokkyo Koho, JP 10143836 A2 (Chem. Abstr., 1998,129, 75407). I . Nishiguchi, H. Hara, S. Tsuboi, S. Sugi and K. Higuchi, Jpn. Kokai Tokkyo Koho, JP 11049716 (Chem. Abstr., 1999,130,238517). H. Hara, S. Sugi, T. Akita and K. Yokota, Tribol. Lett., 1998,5,275. L. Rodriguez-FernPndez, W.N. Lennard, G. R. Massoumi, H. Xia, L. J. Huang, Y. Hung and S. Chang, Nucl. Instrum. Methods Phys. Res. B, 1998, 136-138,

162 163 164 165 166

1191. 167 168 169 I70

171 172 173

H. J. Kang, Q. Zhao, F. E. Talke, D. J. Perettie, B. M. Dekoven, T. A. Morgan, D. A. Fischer, S. M. Hsu and S. Bhatia, Lubr. Eng., 1999,55,22. D. J. Perettie, T. A. Morgan and K. J. Van Heel, US., US 5908817. Y. Yamashita and N. Fukuwatari, Jpn. Kokai Tokkyo Koho, JP 10339938 A2 (Chem. Abstr., 1999,130, 117282). T. Marui and N. Fukuwatari, Jpn. Kokai Tokkyo Koho, J P 11015103 A2 (Chem. Abstr., 1999, 130, 160610). H. Adachi and N. Fukuwatari, Jpn. Kokai Tokkyo Koho, J P 11024197 (Chem. Abstr., 1999,130, 175235). N . Fukuwatari and E. Ueda, Jpn. Kokai Tokkyo Koho, J P 11065040 (Chem. Abstr., 1999,130,229939). J. Fukawa, Jpn. Kokai Tokkyo Koho, J P 11084561 (Chem. Abstr., 1999, 130,

274039). W. Ishikawa and N. Fukuwatari, Jpn. Kokai Tokkyo Koho, JP 11 109544 (Chem. Abstr., 1999,130, 330529). 175 M. Fujimoto, T. Sugino and M. Ikeyama, Jpn. Kokai Tokkyo Koho, JP 10266054 A2 (Chem. Abstr., 1998,129, 304387). 176 M. Fujimoto, T. Sugino and M. Ikeyama, Jpn. Kokai Tokkyo Koho, JP 10276866 A2 (Chem. Abstr., 1998, 129, 332077). 177 M. Fujimoto, T. Sugino and M. Ikeyama, Jpn. Kokai Tokkyo Koho, JP 10276871 A2 (Chem. Abstr., 1998, 129, 317559). 178 S. Hagiwara, H. Saito and H. Sue, Jpn. Kokai Tokkyo Koho, JP 10259292 A2 (Chem. Abstr., 1998, 129, 303445). 179 G. Kumar, J. C. Prindle, Jr. and C. J. Nalepa, U.S., US 581 1470 A. 180 K. Ikehata, K. Midori, S. Uchida, T. Nakanaga and Y. Tada, Jpn. Kokai Tokkyo Koho, JP 10298188 A2 (Chem. Abstr., 1999,130,39748). 181 Y . Nakacho, T. Yabuhara, Y. Tada and Y. Nishioka, PCT Int. Appl., WO 9919383 A l . 182 Y. Hu, W. Fan, Q. Wang, T. Kawamora, N. Koseki, Y. Akutsu and M. Tamura, Prog. Nat. Sci., 1999, 9, 103. 183 J. S. Oh, J. M. Kim, K. J. Lee and Y. C. Bae, Eur. Polym. J., 1999,35,621. 184 H . Sun, PCT Int. Appl., W O 9829189 A 1. 185 J. M. Flanagan, U.S., US 5872357 A. 186 H. Kobayashi, Shika Zairyo, 1998,17, 145 (Chem. Abstr., 1998, 129, 235616). 187 S . Higashi, T. Ohsumi, K. Kuroki, K. Ozumi, H. Inoue, E. Sagara and S. Yuta, Kyushu Shika Gakkai Zasshi, 1998, 52,429 (Chem. Abstr., 19989,130,7 1465). 188 T. Hokelek, E. Kiliq and Z. KiliC, A c f a Crystallogr., 1998, C54, 1295. 189 R. De Jaeger and M. Gleria, Prog. Polym. Sci., 1998,23, 179. 174

6: Phosphazenes

293

190 S. V. Vinogradova, D. R. Tur and V. A. Vasnev, Usp. Khim., 1998, 67, 573 (Chem. Abstr., 1998, 129,245502). 191 H. R. Allcock, Appl. Organomet. Chem., 1998,12,659. 192 H. R. Allcock, in ACS Symp. Ser., 704, eds. A. 0. Patil, D. N. Schulz and B. M. Novak, ACS, Washington, 1998, p. 261. 193 C. Elvira, A. Gallardo, J. San Roman and B. Lopez, Rev. Pfast. Mod., 1999, 77, 49 (Chem. Abstr., 1999,130,342823). 194 J. Vandorpe, E. Schacht, S. Dejardin and Y. Lemmouchi, in Handbook of Biodegradable Polymers, Vol. 7 (Drug Targeting and Delivery), eds. A. J. Domb and J. Kost, Harwood Academic Publishers, 1997, p. 161. 195 H. R. Allcock, M. E. Napierala, D. L. Olmeijer, C. G. Cameron, S. E. Kuharcik, C. S. Reed and S. J. M. O’Connor, Electrochim. Acta, 1998,43, 1145. 196 I. Manners, Annu. Rep. Prog. Chem., Sect. A, Inorg. Chem., 1998,94,603. 197 M. Breza, Eur. Polym. J., 1999,35,581. 198 E. Morales and J. L. Acosta, J. Appl. Polym. Sci., 1998,69,2435. 199 E. Morales and J. L. Acosta, Solid State Ionics, 1998, 111, 109. 200 C. Del Rio, P. J. Martin-Alvarez and J. L. Acosta, J. Appl. Pofym. Sci., 1998,70, 2181. 20 1 H. R. Allcock, N. J. Sunderland, R. Ravikiran and J. M. Nelson, Macromolecules, 1998,31, 8026. 202 C. Kim, J. S. Kim and M.-H. Lee, Synth. Met., 1998,98, 153. 203 H. R. Allcock, M. E. Napierala, D. L. Olmeijer, S. A, Best and K. M. Merz, Jr., Macromolecules, 1999,32, 732. 204 R. E. Dillon and D. F. Shriver, Muter. Res. SOC. Symp. Proc., 1998,496,505. 205 J. B. Duncan and D. A. Nelson, J. Membr. Sci., 1999,157,211. 206 Y.-M. Sun, Y.-K. Chen, C.-H. Wu and A. Lin, AIChE J., 1999,45,523. 207 H. Tang, P. N. Pintauro, Q. Guo and S. O’Connor, J. Appl. Polym. Sci.,1999, 71, 387. 208 Q. Guo, P. N. Pintauro, H. Tang and S. O’Connor, J. Membr. Sci., 1999,154, 175. 209 H. Tang and P. N. Pintauro, Pofym. Muter. Sci. Eng., 1999,80,333. 210 G. Masci, A. Barbetta, M. Dentini and V. Crescenzi, Macromol. Chem. Phys., 1999,200, 1 157. 21 1 H. R. Allcock, R. Ravikiran and M. A. Olshavsky, Macromolecules, 1998, 31, 5206. 212 U. Diefenbach, M. Kretschmann and B. Stromburg, Phosphorus Sulfur Silicon Relat. Elem., 1997,124 & 125, 143. 213 L. Pemberton, R. De Jaeger and L. Gengembre, J. Appl. Polym. Sci., 1998, 69, 1965. 214 M. Gleria, F. Minto, R. Po, N. Cardi, L. Fiocca and S. Spera, Macromol. Chem. Phys., 1998, 199,2477. 215 M. C. Gallazzi and E. Montoneri, J. Inorg. Organomet. Polym., 1997,7,251. 216 F. Minto, M. Gleria, R.Bertani, V. Di Noto and M. Vidali, J. Inorg. Organomet. Polym., 1998,8,67. 217 I. Dez and R. De Jaeger, Phosphorus Sulfur Silicon Relat. Elem., 1997, 130, 1. 218 U. Tunca and G. Hizal, J. Polym. Sci. A , 1998,36, 1227. 219 P. Wisian-Neilson and C. Zhang, Macromolecules, 1998,31,9084. 220 S.-C. Song, S. B. Lee, J.-I. Jin and Y. S. Sohn, Macromolecules, 1999,32,2188. 22 1 A. K. Andrianov and J. R. Sargent, U S . , US 5760271 A. 222 A. K. Andrianov, M. P. LeGolvan, Y. Svirkin and S. S. Sule, PCT Znt. Appl., WO 9858014 Al.

294 223 224


A. K. Andrianov, J. R. Sargent and S. S. Sule, PCT Int. Appl., WO 9839386 A l . A. K. Andrianov, M. P. LeGolvan, Y. Svirkin and S. S. Sule, PCT Int. Appl., WO 9851740 A2. 225 A. K. Andrianov, M. P. LeGolvan, Y. Y. Svirkin and S. S. Sule, Polym. Prepr. (Am. Chem. SOC.), 1998,39(2), 220. 226 R. L. Regnery, J. A. Rooney and S. A. Jenkins, PCT Int. Appl., WO 991 1285 Al. 227 L. G. Payne, G. Van Nest, G. L. Barchfeld, G. R. Siber, R. K. Gupta and S. A. Jenkins, Dev. Biol. Stand., 1998,92, 79. 228 A. K. Andrianov, J. Chen and L. G. Payne, Biomaterials, 1998,19, 109. 229 A. K. Andrianov, J. R. Sargent, S. S. Sule, M. P. LeGolvan, A. L. Woods, S. A. Jenkins and L. G. Payne, Polym. Prepr. (Am. Chem. SOC.), 1998,39(2), 262. 230 A. K. Andrianov, J. R. Sargent, S. S. Sule, M. P. Le Golvan, A. L. Woods, S. A. Jenkins and L. G. Payne, J. Bioact. Compat. Polym., 1998,13,243. 23 1 A. M. A. Ambrosio and H. R. Allcock, U.S., US 5898062. 232 M. Grunze, A. Welle and D. Tur, 56th Annu. Tech. Cinf - SOC. Plast. Eng., 1998, Vol. 3, 271 3. 233 A. Welle, M. Grunze and D. Tur, Mater. Res. SOC.Symp. Proc., 1998,489, 139. 234 I. Verweire, E. Schacht, 1. Scheerder, C. Klein and M. Davies, Polym. Prepr. (Am. Chem. Soc.), 1998,39(2), 880. 235 L. A. Pavlova, D. R. Tur, V. A. Davankov and M. P. Tsyurupa, U.S., US 5773384 A. 236 M. Grunze and A. Welle, PCT Int. Appl., WO 99 16477 A2. 237 S.-C. Song and Y. S. Sohn, J. Controlled Release, 1998,55, 161. 238 S.-C. Song, C. 0. Lee and Y. S. Sohn, Bull. Korean Chem. Sac., 1999,20,250. 239 F. M. Veronese, F. Marsilio, S. Lora, P. Caliceti, P. Passi and P. Orsolino, Biomaterials, 1999, 20,9 1 . 240 M. Uchida, M. Nomichi and R. Ogiwara, Jpn. Kokai Tokkyo Koho, J P 11043495 (Chem. Abstr., 1999,130, 197401). 24 1 S. Morita and H. Okada, Jpn. Kokai Tokkyo Koho, JP 10307356 A2 (Chem. Abstr., 1999, 130, 59004). 242 K. Tsukada and N. Fukuwatari, Jpn. Kokai Tokkyo Koho, J P 11030842 (Chem. Abstr., 1999, 130, 189352). 243 W. Ishikawa and N. Fukuwatari, Jpn. Kokai Tokkyo Koho, JP 11038548 (Chem. Abstr., 1999, 130, 202864). 244 T. Mitsuhashi and N. Fukuwatari, Jpn. Kokai Tokkyo Koho, JP 11044926 (Chem. Abstr., 1999, 130, 202868). 245 K. Yamashita, Jpn. Kokai Tokkyo Koho, JP 11065010 (Chem. Abstr., 1999, 130, 229930). 246 N. Kubo, E. Ueda and I. Kurachi, Jpn. Kokai Tokkyo Koho, JP 11084607 (Chem. Abstr., 1999, 130, 274050). 247 M. Maly-Schreiber, Ger. Oflen., DE 197078 17 A 1 .

7 Physical Methods BY R. N. SLINN

Compounds in each subsection are usually dealt with in the order of increasing coordination number of phosphorus. In the formulae, the letter R normally represents hydrogen, alkyl or aryl, while X represents an electronegative substituent, Ch represents a chalcogenide (usually oxygen or ‘sulfur) and Y and Z are used to represent groups of a more varied nature. There are no sections on theoretical methods, nuclear magnetic resonance spectroscopy or kinetics, but it is planned to include this year’s literature on these topics in Volume 32.

1

Electron Paramagnetic (Spin) Resonance Spectroscopy

EPR spectra and structures of radicals and radical ions generated from the parent two-coordinate P(II1) compounds have been discussed in the light of ab initio calculations. The 1,3-diphosphaallyl radical (1, Ar = 2,4,6-tri-tert-butylphenyl) has been identified by EPR supported by DFT calculations: and both the radical cation and anion have been studied using EPR spectroscopy, cyclic voltammetry, and pulse radi~lysis.~ Bis(2,4,6-tri-tert-butylphenyl)-1,3-diphosphaallene does not absorb significantly above 300 nm, but the spectrum of the radical cation is characterised by bands centred at 320 and 410 nm. The spectra are far more complex than in recent reports and significant differences are observed upon chemical or electrochemical reduction. A higher spin density on the P atoms in the radical anion than in the cation is seen, in agreement with the different nature of the singly-occupied molecular orbital (SOMO) in the two species as predicted by ab initio calculations for the model diphenyl-1,3-diphosphaallene. In both radical ions the unpaired electron is mainly localised in the PCP moiety, in a n-allylic type MO in the cation and in a o-MO in the anion, and pictures of the SOMO are opposite to those recently reported following ab initio calculations on the unsubstituted diphosphaallene. The radical anion of the first stable 1,4-phosphaquinone (2) has also been ~haracterised.~ Stable phosphaverdazyl free radicals (3), obtained by oxidation of tetraazaphosphorine 6-oxides (4), have been characterised in solution by EPR spectroscopy.’ Time-resolved (TR-ESR) experiments have been used for structurereactivity relationships of phosphinoyl radicals. The variation in reactivity of Organophosphorus Chemistry, Volume 3 1 0The Royal Society of Chemistry, 2001

295

296


bis(acy1)phosphinoylradicals (5) has been correlated with the degree of radical localisation and s-character on the P atom from the 31P hyperfine coupling constant measured by TR-ESR.6 Since high 31Phyperfine splitting is observed for a high degree of spin localisation in a o-orbital, typical radical addition and atom abstraction reactions correlate well with the 31Phyperfine coupling whereas an inverse correlation was observed for electron-transfer reactions, where a higher p-character of a localised orbital enhances the reaction. Novel analysis of the ESR line width in TR-ESR experiments has been used for the measurement of addition constants and structural relationships of phosphinoyl radical^.^ The line width is not affected by spin-polarisation processes, easing determination of rate constant. But,

H I

/. .\ C

Ar-P ' ' ' P-Ar (1) Ar = 2,4,6-tri-tert-bulylphenyi

I

I

4

ph

(3)

(5)

R' = 2,4,6-tri-Me or 2,edi-OMe R2 = Ph or C8H17

I

I

"YNbH ph

(4)

(6)(dtsq = dithiosquarato)

An EPR study of the mechanism of oxidation of nickel(0) phosphine complexes with boron trifluoride etherate has been reported.8 The reaction of Ni(PPh3)4 with BF3.OEt2 results in initial formation of Ni(I1) which reacts with the Ni(0) complex to form the Ni(1) compounds (containing valence Ni-F and Ni-B bonds. Reaction with BF3.OEt2 transforms Ni(1) borides into Ni(1) fluorides which are then converted, in the presence of excess etherate, into the cationic monomeric paramagnetic Ni(I) complexes. In the case of Ni(PPh3)3(~C2H4) the reaction of Ni(I1) with Ni(0) slows down and the Ni(I1) complexes accumulate in the system. Ternary complexes of Cu(I1) with L-methionine (and L-tryptophan) and nucleotides (S'AMP, S'GMP, SIMP) have been studied by EPR spectroscopy and cyclic ~oltammety.~ The influence of fluorinated alcohols on spin adducts of phosphoryl radicals and c60 and C70 fullerenes has been reported.1° Complex formation of C60P(0)(OPri)2 or three isomers of C 7 0 fullerenes with fluorinated alcohols results in an increase of 3-4 G in the 31Phyperfine splitting constants and only

297

7: Physical Methods

monoadducts are formed with the Cm fullerene. The g and hyperfine coupling tensors from the EPR spectra of the tetraphenylphosphonium complex with vanadium (6) have been used in its characterisation,' and a new photochromic charge-transfer complex between tungstophosphoric acid and quinoline has been characterised using IR, UV, and EPR spectroscopy.

'

'*

2

Vibrational and Rotational Spectroscopy

2.1 Vibrational Spectroscopy.- The use of IR spectroscopy (as a complementary technique) in the characterisation of organophosphorus compounds is abundant in the literature. For example, in the synthesis of the phosphine borane adduct (7) the structure has been confirmed using IR and NMR spectroscopy and X-ray structure analysis. The conformational behaviour of 1,3,2,6-dioxaphosphazocineshave been studied by FT-IR spectroscopy and molecular mechanic^,'^ with at least five conformers detected under various experimental conditions. IR and Raman spectroscopy, normal coordinate analysis, and molecular mechanics have been used to study the conformations of alkoxy-chlorophosphines (8).15In the case of R = Et, the molecules prefer to exist in more or less extended conformations with R and PC12 groups spatially far apart, whereas when R = OMe convoluted conformations are preferred. The energetic preference for the convoluted conformation is explained in terms of intramolecular interactions. The vibrational spectra (Raman and IR), conformational stability, and structure of fluoromethyldichlorophosphine (9) have been studied in gas, liquid, and solid phases, with data confirmed by ab initio calculations.I6 Two conformers are present in the liquid state where the gauche conformer is the predominant species whereas only the trans rotamer remains in the crystalline solid. FT-IR spectroscopy has been used in a study of the reversible equilibria in Rh(I)(triphos) aryloxycarbonyl complexes (10). I7

Rh(l)(triphos)(CO)(OAr) (10) {triphos = bis(2-diphenylphosphinoethyl)phenyl phosphine}

(1, ~ - H O C G H ~ N H ~ ) ~ P . + O ~ ~ . ~ H ~ O (1 1)

Formation constants for the H-bonded complexes between phenol (donor) and selected phosphoryl compounds (acceptors) have been determined from IR Av shifts.I8 Compared with the C=O group, the P=O group is two orders of magnitude stronger as an acceptor. The IR absorption (vpo) band showed weak response to involvement in H-bonding and the AvOH shifts of the donor provided a better measure of the formation constants. Hydrogen bonding of dialkyl-substituted diphosphonic acids in non-polar (toluene and CC14) and polar ( 1-decanol) solutions has been investigated using IR and molecular mechanics calculations, and association found in non-polar solvents. IR spectroscopy has also been used, with X-ray and thermal analysis methods, to


298

characterise a new organic-cation cyclotetraphosphate ( 11),20 and to investigate pressure-induced phase transition (rhombohedra1 to monoclinic) in the compounds K3LuI-,Yb,(P04)2, Rb3Dy(P04)2, and KzRbH0(P04)2.~~ 2.2 Rotational Spectroscopy. - The submillimetre-wave rotational spectrum of the PS radical in the electronic and vibrational ground state has been recorded in the frequency region between 54 GHz and 1.07 THz, covering rotational quantum numbers from J = 30.5 to J = 60.5.22The PS radical was generated by discharging PSC13 buffered with Ar. Analysis of the complete rotational data set of PS allows the derivation of a full set of molecular parameters, including the rotational constants (B, D, H), the fine-structure constants (A, y, Dy), the parameters for the A-doubling (p, D,, q), and the magnetic hyperfine constants (a, b, c, d, CI), and a, c, and C1 have been obtained for the first time.

3

Electronic Spectroscopy

3.1 Absorption Spectroscopy. - UV spectroscopy has been used mainly as a complementary technique in structure elucidation, for example with IR and EPR spectroscopy in the characterisation of a new photochromic chargetransfer complex. A photochromic reversible substitution reaction of tridentate Schiff s base-Ru(I1) complexes (12a) has been reported.23 In acetonitrile, the Cl ligands are substituted with MeCN molecules giving an equilibrium mixture in the dark of (12b) and (12c), accompanied by a colour change from orange to yellow. On irradiation with UV-visible light, the colour reverts to orange with the products converted back to (12a). This process can be repeated and a reversible photochromic reaction system constructed. A study on the UV-visible spectra of Fe(11) diphosphine carbonyl compounds has assigned the main absorption peaks.24 [RuCl2(ppb-etol)(PPh3)] (12a) (ppbetol) = N(2diphenylphosphinobenzilidene)-Bhydroxyethylamine

(RuCI(MeCN)(ppb-etol)(PPhs)]CI (12b)

+

(Ru(MeCN)2(ppb-etol)(PPh3)]CI2

(12c)

3.2 Fluorescence, Luminescence, and Chemiluminescence Spectroscopy. Fluorescent dansylated nucleoside triphosphates have been synthesised and used to investigate sequencing of DNA via a scheme that does not involve electroph~resis.~~ A novel high-nuclearity luminescent Au(I)-sulfido complex

7: Physical Methods

299

(13) has been prepared and investigated.26The complex exhibits long-lived, orange-red and green luminescence in the solid state and solution, respectively. The emission is assigned as derived from triplet states of a ligand-to-metal charge-transfer character that mix with metal-centred states which are modified by Au' . . . .Au' interactions. 10-Hydroxy- and 10-amino-pyridazino-quinolinediones (14) have been synthesised and discovered to be efficiently chemiluminescent in similarity to luminol in the presence of H202 and horseradish peroxidase in a solution of phosphate buffer (pH 8).27 Arylacetate enol phosphates (15) have been prepared as chemiluminescent agents for industrial use.28 x

(13) (dppm = Ph2PCH2PPh2)

4

o

(14) R = H. MeO, di-OMe, Et2N X = OH, NH2

X-Ray Structural Studies

4.1 X-Ray Diffraction (XRD). - 4.1.I Two-coordinate compounds. A phosphavinylidene carbenoid DME-solvate (16) has been characterised by multinuclear NMR spectroscopy and low-temperature XRD,29 revealing discrete monomeric molecules with donor-solvated metal atoms both in solution and in the solid state. The chemistry of diazaphospholephosphines (17) has been extended by study of reactions at the exo-phosphine ( X = F , NMe2, OCH2CF3),30with the crystal (and molecular) structures of two diazaphospholephosphine imines, derived from (17, X = F), determined. The synthesis and single-crystal X-ray structures of silacalix[n]-phosphinines (1 8), (19) have been r e p ~ r t e d . ~The ' macrocycle (18) is fluxional in solution and adopts a partial-cone conformation in the solid state, whereas it adopts an opened-out partial-cone conformation when n = 4. X-ray analysis of mixed macrocycles (19) reveal that these also adopt an opened-out partial-cone conformation in the solid state. 4.1.2 Three-coordinate compounds. The molecular and X-ray crystal structure of bis(trichloromethy1)chlorophosphine reveals that the P atom has a pyramidal configuration of bonds with the sum of the bond angles = 302.7°.32The first neutral spiro Se(I1) complex containing a true square-planar Se(Se4) core has been prepared and characterised by XRD.33 In bis([N-(diphenylphosphin ylselenoy1)-P, P-diphenylphosphinylselenoic amidato-Se,Se']selenium(II), two selenide ligands are coordinated symmetrically to the central atom forming a spiro complex. The crystal structures of the novel Eetrameric itrido Re(V) complexes (20) and (21) have also been determined.34

300

Organophosphorus Chemistry Me-NrxMe p

(Z)-Mesa-P=C(Cl)(Li(DME)}2

PXp

(17) X = F, NMe2,OCH&F3

(16)

M I ,?he

Me Me,\ si

Si I

(19)

x = 0,s

[{C~C~O-R~N}~ Et2)4.C14( ( S ~ C NPM+Ph)4] .2acetone (211

4.1.3 Four-coordinate compounds. Two upper-rim functionalised calix[4]arenes,

with P-containing groups tethered at the upper rim, have been prepared and characterised by NMR spectroscopy and X-ray crystal analysis.35 XRD analysis of 2,2'-biphosphirene-W2(CO)lo complexes (22) shows that some delocalisation takes place within the diene subunit^.^^ The X-ray crystal structure of a 2-substituted phosphono- 1,3,2-dioxaphosphorinane 2-sulfide reveals a cis configuration and a preferred chair conformation for the molecule,37 and 1,4-diphosphaindenes (23) have also been examined by XRD.38 The crystal structures of phosphinimines Ph3PNCl and [Ph,PNPEt$l have been determined,39 and whereas Ph3PNCl has a monomeric molecular structure (without perceptible intermolecular contacts) with respective P-N and N-Cl distances of 161.0 and 175.9 pm and a P-N-Cl bond-angle of 1 10.31', [Ph3PNPEt3]Cl has an almost symmetric P-N-P bridge with P-N distances of 158.6 and 157.0 pm with a bond-angle of 145.9'.

7: Physical Methods

301

(22) R = SiMe3, But

(23) R = M e

x= s

The X-ray structures of mixed sulfur/oxygen diethoxy diphenylimidodiphosphinates (24, 25) reveal P=O.. . .H-N H-bonded structures with distinct differences in packing and c o n f ~ r m a t i o nThe . ~ ~former exists with the P=S and P=O groups in a gauche or cisoid orientation whereas the latter is a transoid dimer. The crystal and molecular structure of 2-aminoethylphosphonic acid have been redetermined at 153 K4' In the crystal structure the adjacent molecules are bonded by intermolecular H-bonds. Ethylenebis(phosphonic acid) has been isolated and its structure ~haracterised.~~ In the crystal structure, characterised by strong intermolecular 0-H-0 sp2 H-bonds, only the R*,S* diastereomer is found. Multiple introductions of phosphonate groups, around the quinone 0 in p-benzoquinone, creates a novel, highly-bent substituted p-benzoquinone (26) through steric and electronic repulsion.43The repulsion produces a chair conformation with a bent angle as large as 17.8", in contrast to the hydrogenated dihydroxybenzene product (27). The crystal structure of bis(2-chloroethyl)(1-hydroxy-2-nitroethy1)phosphonate has also been determined, revealing the molecules in infinitely-long chains formed by intermolecular H-bonds between the hydroxyl H and the phosphoryl 0 atoms.44

The first crystal structures of lithiated phosphinamides (28) have been reported.45 Ph,P(0)CH=C(But)N(H)Li and its TMEDA hemisolvate exist as tetrameric and dinuclear arrangements respectively, and the lithiated phosphane oxide starting-material is shown to contain Li-C contacts of two distinct types. The crystal and molecular structures of related phosphorylated phosphinamides (29)-(31) and their K salts have also been reported.46 Interesting, amino-substituted phosphonium salts have been prepared and characterised by X-ray analysis, including colourless 4-bromobenzyl phosphonium bromide (32) to yellow-red for the corresponding tribromide (33),47and orange-red for the benzylphosphonium bromide (34),48 the cationic three N atoms being

302

Organophosphorus Chemistry Ph2P(0)CH=C(But)N(H)Li

(SPPh2)[OP(OEt)2]NH

(28)

K[(SPPh&OP(OEt)p}NI.H20

(29)

(30)

(OPPh2)[0P(OEt)2NH.1RHCl.1/4H20

[(Pr2N)pCHSeH4-4-Br]+Br-

(31)

(32)

[(R2N)3PCH2Ph]+Br-

[(P I ~ N ) ~ P C H ~ C ~ H ~ - ~ - B ~ ] + B ~ :

(33)

((H2NhPI'Br-

(34)R = Me, Et, Pr, Bu

(35)

(36)

planar. Novel tetraaminophosphonium salts (35) and (36) have been prepared by anion exchange in liquid NH3,49 with (35) forming a tetragonally-distorted, variant CsCl structure and (36) consisting of [(HZN)4P]+ cations, "031anions, and OP(NH2)3 molecules interconnected by a complex system of Hbonds. AS crystal supramolecular motifs, two- and three-dimensional networks of Ph4P+cations engaged in six-fold phenyl embraces have been reported.50 4. I . 4 Five- and six-coordinate compounds. Structural changes, from ideal tetrahedral to ideal trigonal bipyramidal geometry, have been observed on the conversion of the 1,2h5-azaphosphole (37) to the cycloadducts (38) and (39).5* The crystal structures of the cyclen phosphine oxide (40),52 and of the metathesis reaction products of cyclenphosphoranes (41),53 have also been reported, hydrogen-bonding and transannular NP interaction being observed in (40). The first isolation and crystal structure of the stable dioxaphosphirane species, 12-P-6 phosphate (42), has also been d e ~ c r i b e d . ~ ~

C02Me

Me02C

P h F , M e Ph

NI"'

(37)

Me

Me ph Ph Ph

(38)

Ph Ph

(39)

4.2 X-Ray Absorption Near Edge Spectroscopy (XANES). - XANES measurements at the phosphorus K-edge of the tri-substituted phosphine chalcogenides Ch=PR3 (R = OPh, Et, Ph), and the influence of the environment on the spectra, have been reported.55 The electronic structures of [LFeMFeL]"+ (M = Cr, Co, Fe; n = 13) linear thiophenolate-bridged heterotrinuclear complexes (43), including PF6 salts, have been studied using a combination of Fe

7: Physical Methods

303 [LFeMFeL]"+

[Mo($-arene)(TRI)]

(43) M = Cr, Co, Fe; n = 1-3

(44) TRI = PhP(CHgH2PPhd2

and M K-edge XANES, magnetic susceptibility measurements, and UV, EPR and Mossbauer spectro~copy.~~

4.3 Electron Diffraction. - Electron diffraction and ab initio calculations have been used to determine the molecular structure of di-tert-butyl(trich1orosily1)phosphinein the gas phase.57 5

ElectrochemicalMethods

5.1 Dipole Moments. - Dipole moment and Kerr effect evidence for the steric structure of substituted 1,3,6,2-dioxaphosphocineshas been reported?* The conformational composition varies with substituents in the 2- and 6-positions but the conformational mixtures always contain the chair-chair form with an axial P=S bond. 5.2 Cyclic Voltammetry and Polarography. - The 1,3-diphosphaallyl (1, Ar = 2,4,6-tri-tert-butylphenyl)radical ions have been studied using EPR spectroscopy, cyclic voltammetry, and pulse radi~lysis,~ with cyclic voltammetry indicating an oxidation potential of 2.0 V (against SCE) and a reduction potential in the range - 1.97 to - 2.10 V, depending on solvent. Molybdenum complexes (44), containing the tridentate ligand PhP(CH2CH2PPh2)2, have been characterised using cyclic voltammetry and 'H NMR s p e c t r o s ~ o p y . ~ ~ Each complex showed a reversible, one-electron oxidation in the cyclic voltammogram at - 1.O V (against the ferroceniudferrocene couple at 0.0 V) for Mo(0) to Mo( 1+), and a second pseudo-reversible oxidation. Tris[6(dimethylamino)-1-azulenyl]methyl(and analogous) cations (45), with high (spectrophotometrically-determined)pKR+ values, have been shown to be extremely stable and their electrochemical reduction and oxidation has been followed by cyclic voltammetry.60The redox reactions of Cp*FeP5 (46) in nonR3

P=p

A

I'

Pi. I;, P P

I

Fe

I

I

R2 R2 (45) R' = H, R2 = R3 = NMe2

Me (46)

304

OrganophosphorusChemistry

aqueous solvents have been characterised by cyclic voltammetry and bulk electrolysis as reversible, one-electron processes, with evidence of dimerisation.61The electrochemical reduction of pentafluorophenyl phosphonium (and other) salts has also been studied by cyclic voltammetry.62

5.3 Potentiometric and Conductometric Methods. - A study of the complex formation in acetonitrile between copper(1) perchlorate and organic hgdnds, including triethyl phosphite, has beeen carried out by conductometric titration at 298 K.63In the case of triethyl phosphite, a 1 :4 complex is formed. 6

Thermochemistry and Thermal Methods

The heat capacity and thermal decomposition of 1,6-bis(diphenylphosphino)hexane has been studied by adiabatic calorimetry, DSC and TGA.@ The lowtemperature heat capacity was determined by automated adiabatic calorimetry at 80-350 K, with no indication of phase transition or thermal anomaly in this range, and the high-temperature heat capacity determined by DSC at 310730 K. From the DSC curve, a solid-liquid transition was found at 399.4 K and the enthalpy and entropy of transition evaluated as 66.8 kJ mol-' and 167.2 J K - ' mol-' respectively. An endothermic change was observed between 690 and 730 K, with an enthalpy of reaction of 81.6 kJ mol-'. Thermogravimetric analysis, carried out at 300-800 K, shows that the compound starts to decompose at 690 K and decomposition is complete at 710 K, in a single step. A thermochemical investigation of the phosphine ligandsubstitution reactions involving trans-tert-phosphine-Ru-carbenecomplexes has been carried out based on their enthalpies of reaction.65 The thermal degradation of phosphorus-containing polyimides,66 and of poly(viny1 phosphonic acid),67have been followed by TGA and a combination of TGA and FTIR spectroscopy, respectively.

7

Mass Spectroscopy/Spectrometry

There are numerous publications using mass spectroscopy as a complementary analytical technique for structure elucidation, but the applications that follow use mass spectrometry as the sole or main technique. Electrospray ionisation (ESI) mass spectrometry has been used in an investigation of the relative ligand properties of YPh3 ligands (Y = P, As, Sb, and Bi) towards Ag+ and Cu' ions.68 An increase in coordination number from two, for PPh3 in [Ag(PPh&]+, to four, for SbPh3in [Ag(SbPh3)$, is found, consistent with the decreasing donor ligand ability and increasing metal-Y bond-length going down the series. ESI mass spectrometry has also been used to characterise Pd(I1) diphosphine c ~ m p l e x e sThe . ~ ~ electron impact (EI) and high-resolution mass spectra of 3substituted 7,8-dimethyl-2,4,3-benzodioxaphosphepin3-oxides have been studied to understand fragmentation processes and establish their stru~ture.'~

7: Physical Methods

305

The vaporisation of boron phosphate BP04 has been studied by Knudsen effusion mass spectrometry and the vapour shown to consist of B2O3, P4OlO, PO2 and PO, BP04 and BPo3.71 EI mass spectrometry studies, on several structurally-related series of 8, 9, and 10-membered cyclic phosphate^,^^ have found that their fragmentation mode is similar and governed by both ring-size and substituent present. The EI mass spectra of some new thiophosphorus compounds have also been reported.73 Of biological interest, peptides containing phosphorylated tyrosine have been characterised by ESI and MALDI-TOF mass ~pectrometry,~~ and dinucleoside and nucleoside glucopyranosides lipophilic phosphotriesters have been examined by FAB-tandem mass spectrometry (FAB-MS/MS).7S The mass-analysed ioh kinetic energy spectra (MIKES) of the [M-HI- ions of nucleoside and dinucleoside glucopyranoside phosphotriesters aid to establish the fragmentation mechanism. The reactions of the dichlorophosphenium ion (Cl-P+-Cl) with cyclic organic ethers in the gas phase in a FT-ICR mass spectrometer have been studied.76A variety of reactions occur, depending on the exact structure of the ether, and these and their mechanisms are reported.

8

Chromatography and Related Techniques

Gas Chromatography and Gas ChromatographyMassSpectroscopy (GCMS). - The composition of, and 'impurities in, trialkylphosphine oxides (used as extractants) have been determined by GC-FID analysis on FFAP capillary columns with N2 carrier gas.77A GC procedure is also described for the assay and impurities in 0-isobutyl S-2-(N,N-diethylamino)ethylmethyl thiophosphonate.78 The photo-assisted decomposition products of dimethyl methylphosphonate (over amorphous manganese oxide catalysts) have been identified by GC, together with analysis (of the spent catalyst) by ion chromatography (IC) and FTIR s p e c t r o ~ c o p y . ~ ~ 8.1

Liquid Chromatography. - 8.2.I High Performance Liquid Chromatography and LC-MS. Quantitative structure-retention relationship equations for predicting the retention (k) values of 0-alkyl-0-( 1-methylthioethylideneaminophosphoramidates on reversed-phase HPLC (RP-HPLC) columns have been reported,s0 and good agreement with predicted and experimental values was found. The enantiomers of thirty-nine 0-ethyl-0-phenyl N-isopropylphosphoramidates have been separated on a chiral column by HPLC,81 and the enantiomeric purity of synthetic phosphonic analogues of L-amino acids has also been determined by HPLC analysis on a chiral column.82 An ion chromatography study of the alkaline hydrolysis of phosphoruscontaining esters, e.g., triethyl phosphate,83 has shown that hydrolysis occurs during IC determination due to the counter ions in the anion-exchange resin. Two diastereomers of 1-phosphonopropane- 1,2,3-tricarboxylic acid have been separated by ion chromatography using two columns connected in series.84 8.2

306


The method achieved baseline separation and a 69 :3 1 ratio of stereoisomers, in agreement with preliminary NMR measurements. Six quaternary ammonium salts of alkylphosphonothiolates have been characterised by LC-MS/MS.85 The daughter ion spectra measured after collision-induced dissociation (CID) of the characteristic M+ cation provides important structural information. Two papers report the separation of phosphonic acids,86 and or-aminophosphonic and a-aminophosphinic acids,87by LC and capillary electrophoresis (CE), and are described under CE. 8.2.2 Thin Layer Chromatography. There are several references using TLC for clean-up of samples but no specific applications have been noted.

8.3 Capillary Electrophoresis (CE) and Micellar Electrokinetic Chromatography (MEKC). - The separation and identification of phosphonic acids (in a spiked water sample) by a combination of LC-MS and CE-MS analysis has been reported.86 MS/MS analysis allows an accurate identification of these compounds. Enantiomeric resolution of or-aminophosphonic and a-aminophosphinic acid or esters by HPLC and CE has also been reported.87 HPLC separation of the esters (on a chiral cellulose or amylase stationary phase) and CE separation of the racemic acids (using different P-cyclodextrin derivatives) depends on individual structure and conditions.

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7: Physical Methods

69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87

309

C. C. H. Chin, J. S. L. Yeo, Z. H. Loh, J. J. Vittal, W. Henderson, and T. S. A. Hor, J. Chem. SOC.,Dalton Trans., 1998, 3777. N. C. Raju and M. V. S. Prasad, Asian J. Chem., 1999,11,651. S . I. Lopatin and A. K. Sikder, Rapid Commun. Mass Spectrom., 1999, 13, 1398. N. Sikder and J-P. Morizur, Asian J. Chem., 1999, 11, 850. M. Culea, N . Palibroda, Z. Moldovan, S. Nicoara, I. Fenesan, R. Popescu, V. Muresan, E. Postoiu, and V. Znamirovschi, Rapid Commun. Mass Spectrom., 1998,12, 1808. L. F. Bonewald, L. Bibbs, S. A. Kates, A. Khatri, J. S. McMurray, K. F. Medzihradszky, and S. T. Weintraub, J. Pept. Res., 1999,53, 161. A. Liguori, L. Maiuolo, A. De Nino, A. Procopio, and G. Sindona, J. Am. SOC. Mass. Spectrom., 1999, 10, 379. L. E. Ramirez-Arizmendi, Y. Q. Yu, and H. I. Kenttamaa, J. Am. SOC. Mass. Spectrom., 1999, 10,975. R-X. Zin, J-Y. Chen, J-F. Lang, and C-L. Song, Guangpu Shiyanshi, 1999, 16, 233 (Chem. Abstr., 1999,131, 153 226). I . N . Stan’kov, V. S. Polyakov, A. A. Sergeeva, and S. N. Lanin, J. Anal. Chem., 1999,54, 194. S. R. Segal, S. -L. Suib, X. Tang, and S. Satyapal, Chem. Mater., 1999, 11, 1687. Q. S. Wang, L. Zhang, M. Zhang, X. D. Xing, and G. Z. Tang, Chromatographia, 1999,49,444. R-Y. Gao, J-M. Huang, G-S. Yang, H-2. Yang, and Q-S. Wang, Chin. J. Chem., 1999, 17,92. F. Hammerschmidt and F. Wuggenig, Tetrahedron: Asymmetry, 1999,10, 1709. G. G. Ivanova, A. A. Ivanov, and 0. A. Shpigun, Vestn. Mosk. Univ., Ser. 2: Khim., 1998,39,400 (Chem. Abstr., 1999,130, 296 738). G. Hagele and J. Weiss, Spureyanal. Bestimm. Ionen: Ionenchromatogr. Kapilla!arelektrophor., Proc. Fachtag. Olonenanal. Chromatogr. Kapillararelektrophor.0, 1996, 31 (Chem. Abstr., 1999, 131, 96614). H. Bjork, H. Kiljunen, and P. Vanninen, Adv. Mass. Spectrom., 1998, 14, DO371 70/1. J-P. Mercier, P. Morin, and M. Dreux, Chiniia, 1999, 53, 51 1 . C. Fischer, U . Schmidt, T. Dwars, and G. Oehme, J. Chromatogr., A, 1999, 845, 273.

Author Index

In this index the number in parenthesis is the Chapter number of the citation and this is followed by (he reference number or numbers of the relevant citations within chat Chapter. Abboud, K.A. (1) 405 Abd-El Baky, C.(1) 493 Abd-Ell&, I.M. (2) 13 Abdou, W.M. (1) 286; (5) 28,59, 115

Abe, I. (1) 198 Abid, M. (1) 397 Abram, U. (7) 34 Abu-Yousef, I.A. (1) 253 Acebo, P. (4) 260 Acevedo, O.L. (4) 172 Achiwa, K. (1) 128 Ackermann, H. (6) 62 AGO-, J.L. (6) 198-200 Adachi, H. (6) 171 Adamiak, R.W.(4) 137 Adams, C.J. (4) 230 Adams, H. (3) 132; (6) 47 Adams, J.J. (1) 20, 113; (3) 181 Adamszek, P. (6) 139, 140 Adelt, S.(3) 36 Adinolfi, M. (4) 206 Afiuinkia, K. (1) 336 Afon'kin, A.A. (6) 13 1 Agbossou, F. (1) 307 Agganval, A.K. (4) 253 Agrawal, S. (4) 128 Agrawal, V.K. (4) 162; (5) 101 Agrios, K.A. (5) 119-122 Aguerre, 0. (4) 275 Agustyns, K. (3) 202 Ahlmark, M. (3) 196 Ahmad, I.K. (1) 480

Ahmadian, M.R(4) 54, 153, 182 Ahn, S.H.(1) 24 Airiau, M. (4) 275 Aitken, R.A. (5) 15,23,24,68 Akashi, K. (4) 291 Akhavan-Tafti, H. (7) 28 Akibas, K.-y. (7) 54 Akita, T. (6) 165 Akutsu, Y. (6) 182 Aladzheva, I.M. (1) 352-354,369 Alajarin, M. (1) 257,258; (5) 85, 88; (6) 1,2, 19,34, 113 Alam, T.M.(1) 471 Albaouy, D. (3) 154 Albers, T. (1) 36 Albert, S.(3) 186 Alberti, A. (1) 464; (7) 2,3 Alberti, M. (6) 133 Albinati, A. (1) 130 Albouy, D. (1) 393; (3) 136 Alcaraz, G. (1) 160 Alcudia, A. (3) 180 Alcudia, F. (3) 180 Alder, R.W. (1) 149 Aldcrfcr, J.L.(5) 5 1 Alefelder, S.(4) 207 Alcgria, L.A.(2) 9 Alexander, R. (5) 101 Alexandrov, K. (3) 101 Alfonsov, V.A. (7) 15 Ali, O.M.(4) 141 Aliev, A.E. (1) 368 Alkorta, 1. (1) 35 1 3 10

Allcock, H.R. (6) 46, 130, 143, 150, 151, 191, 192, 195,201, 203,211,231 Allemand, J.F. (4) 286 Allen, C.W.(6) 146, 147, 155 Allen, D.W.(1) 181 Allspach, T. (1) 466 Almena Perea, J.J. (1) 23,25,204 Almstead, N.G. (3) 162 Alonso, C.A.M. (3) 84 Al'pert, M.L. (1) 382 Al-Shaibi, Y.(2) 13 Alt, H.G. (1) 22 Al-Taweel, S.M. (1) 538 Altenbach, H.-J. (3) 36 Altmann, K.H. (4) 112,243 Alvarez-Sarandks, R. (6) 24 Alvey, L.J. (1) 120 Ambrosio, A.M.A. (6) 23 1 Amelia, M. (1) 472 Ammar, G.M. (4) 190 Anastasio, M.V. (3) 162 Andavan, G.T.S. (6) 135, 137 Andcrs, E. (1) 343, 390 Anderscn, J.-A. (1) 432 Anderson, P.G.(1) 142 Andcrson, S.R(1) 251 Anderson, C. (1) 199 Ando, F. (1) 417; (5) 45 Ando, J. (3) 173 Ando, K. (5) 111 Ando, T. (5) 114 Andoh, J. (4) 116

311

Author Index Andrade, M. (4) 84 Andrei, G. (4) 19 Andrimov, A.K. (6) 221-225, 228-230

Andrieu, J. (1) 293 Anfang, S. (6) 52 Angelici, R.J. (1) 482 Anslyn, E.V. (3) 91; (6) 35 Ansorge, M. (1) 337 Antinolo, A. (1) 16; (5) 32 Antipin, M.Yu. (1) 255,352,354, 355 Aoki, M. (6) 99, 101, 106 Aoki, Y. (1) 129; (3) 204 Aparicio, D. (1) 338; (3) 161 Aqvist, J. (3) 68 Arai, Y. (4) 291 Aranyas, A. (1) 4 Araya-Maturana, R.(5) 9 Arbuzova, S.N.(1) 37, 80, 117, 118, 154 Arca, M. (6) 79 Arcas, A. (6) 7 Aresta, M. (3) 193 Arghavani, Z. (7) 28 Arimitsu, M. (4) 109 Arimoto, H. (5) 52 Arisha, A.H.I. (3) 88 Ariza, 2.(1) 259 Armspach, D. (1) 167 Armstrong, D.R. (1) 342 Armstrong, RW.(5) 129 Amaud-Neu, F.(1) 320,321 Aronov, A.M. (1) 275 Arques, A. (1) 256; (5) 84; (6) 5 Arsanious, M.H.N. (5) 27 Arshinova, R.P. (7) 14,58 Arsu, N. (1) 430 Artyushin, 0.1. (1) 355 Arumugam, S. (2) 26 Arya, D.P.(4) 103, 104 Asakura, T. (4) 148 Asano, Y. (4) 280 Asao, T. (7) 60 Asensio, A. (6) 36 Asghari, S. (1) 206,211; (5) 75 Ashford, L. (1) 197 Ashley, J.A. (3) 206 Askin, D. (1) 274 Asseline, U. (4) 155 Astleford, B.A. (3) 15 Athimoolam, A.P. (6) 154 Atwood, J.D. (1) 164 Aubertin, A.-M. (4) 4 Aucott, S.M. (1) 191 Augustin, J. (1) 366 Aurniiller, A. (6) 49,50 Aurby, A. (5) 58

Avarvari, N. (1) 513,567,579; (7) 31

Avendaiio, C. (6) 16-18 Avent, A.G. (1) 81 Averin, A.D. (1) 454 Awakumova, A.E. (7) 15 Ayers, J.T.(1) 251 Aiancheev, N.M. (2) 18 Azhayev, A.V. (4) 67 Azuma, N. (6) 148

Barluenga, J. (5) 95 Barnes, C.L. (1) 180; (6) 6 Barone, G. (4) 206 Barr, RK. (1) 235 Barragan,V. (3) 117 Barranco, E.M. (5) 34 Barrans, RE., Jr. (7) 19 Barrell, J.K.(5) 101 Barsegyan, S.K.(1) 219 Bartel, D.P. (4) 61

Barth,D. (1) Baba,,N. (3) 56 Babb, D.A. (1) 323 Baceiredo, A. (1) 287,489; (5) 17 Bacher, A. (3) 103, 108, 109,203 Bae, Y.C. (6) 183 Biickvall, J.E. (3) 73 Baek, H. (6) 144 Bagatin, LA. (1) 65; (7) 35 Bahadur, M.(6) 155 Bai, J. (7) 24 Baird, E.E.(4) 255 Ba-Issa, A.A. (2) 13 Baker, D.C.(4) 124 Bakhtiyarova, Yu.V. (1) 220,392 Balavoine, G. (1) 528 Balm, G. (7) 46 Balema, V.P. (1) 35, 151 Balitskii, Yu.V. (1) 488 Ballatore, C. (4) 1 Ballcrcau, S. (3) 39 Balow, G. (4) 172 Balzarini, J. (3) 144; (4) 1, 19,33, 34

Banejee, P. (1) 395 Banez, J.M. (1) 38 1 Bangcr, K.K. (1) 13 Bangerter, F. (5) 5 Banham, R.P. (1) 13 Bankaitis-Davis, D. (4) 94 Bannwarth, W.(4) 216 B a n d , R.K. (1) 555-560 Banton, N.J. (1) 426 Bar, N. (3) 128 Barahona, P. (5) 9 Baranetskaya,N.K.(1) 24 1 Baraniak, J. (4) 91, 96 Baranwal, B.P. (6) 141 Barascut, J.-L. (4) 5 Barbas, C.F.(4) 52 Barber, A.M. (1) 269 Barbetta, A. (6) 210 Barboiu, M. (6) 142 Barbosa, J. (3) 13 Barchfield, G.L.(6) 227 Barco, A. (5) 43 Barloy, L. (1) 44

110

Barthen, P. (1) 416 Barton, D.H.R. (1) 301; (3) 112 Bashilov, V.V. (7) 10 Basset, J.-M. (1) 290 Basu, S.(4) 232 Batchelor, A.H. (4) 263 Batt, RV. (1) 348 Baucby-Barbier, D. (1) 545 Bauer, A. (1) 254 Bauer, G. (1) 365 Bauer, W. (6) 115 Bautista, D. (6) 7 Bayler, A. (1) 79 Bayly, S.F.(4) 199 Bazhcnova, I.A. (7) 44 Beabealashvilli, RS.(4) 43 Beaschlin, D.K. (3) 49 Beaton, G. (4) 94 Beaton, M.W. (3) 27,29 Beauchamp, A.L. (1) 190 Bcaulieu, P.L. (3) 98 Bcaussire, J.-J. (4) 181 Becher, G. (4) 167 Becker, C.(4) 41 Becker, H.F. (4) 145 Becker, S. (4) 266 Beer, P.D. (1) 197 Behr, J.P. (4) 154 Behrens, C. (4) 201 Beier, M. (4) 72, 73 Beigelman, L. (4) 132 Beijer, B. (4) 125 Bcijersbergen van Henegouwen,

W.G.(5) 130 Beilstcin, A.E. (4) 151 Beissel, T. (7) 56 Bekiaris, G. (2) 24 Belaj, F. (6) 112 Bclanger-Gariepy, F. (1) 190 Beletskaya, 1.P. (1) 8, 175, 176, 194,218,454; (3) 123

Belguise-Valladier, P. (4) 154 Bellan, J. (2) 15 Belogorlova, N.A. (1) 117, 118, 310,311,382

Beltran, T. (4) 4 Belyaev, A. (3) 202

3 12

Benabra, A. (3) 180 Benaglia, M. (1) 464; (7) 2,3 Benarafi, L.(7) 21 Benayoud, F. (5) 104 Ben-David, Y. (1) 159 Bender, B.R (4) 38 Bender, H. (1) 465 Bendinskas, K.G. (4) 21 1 Benedetti, E. (4) 193 Benetti, S. (5) 43 Benhida, R. (4) 111 Benner, S.A. (4) 107 Bennet, B. (3) 201 Bennett, M.A. (1) 109 Bensch, W. (1) 403,404 Bensimon, D. (4) 285,286 Benter, M. (1) 102 Berclaz, T. (1) 137 Berestovitskaya, V.M. (7) 44 Bergbreiter, D.E. (1) 169 Berger, J.M. (4) 237 Bergqvist, S.(4) 152 Bergstriisser, U.(1) 227,439,451,

Bibbs, L. (7) 74 Bickelhaupt, F. (1) 450,481 Bickelhaupt, F.M. (1) 481 Bieger, K. (5) 95 Bielawska, H.(3) 77 Bihovsky, R. (3) 146 Bijanzadeh, H.R. (1) 209 Bijapur, J. (4) 152 Bill, E.(7) 56 Binch, H.M.(1) 336 Binder, H. (1) 82, 105 Binger, P. (1) 476,478,574-576 Birdsall, D.J.(6) 74 Birrell, G.B. (3) 28 Bischofbergcr, N. (4) 100 Bischoff, R.(6) 95,96 Bischoff, S. (1) 50 Bishop, O.A. (6) 35 Bishop, P.A. (6) 35 Bitterer, F.(1) 38 Bjork, H. (7) 85 Blackburn, G.M. (3) 132, 197; (4)

458,466-469,479,5 16,527 Bergstrom, D.E. (4) 153, 182 Berkassel, A. (3) 63 Berke, H. (1) 242; (7) 13 Berkmann, C.E.(3) 11 Berkowitz, D.B. (3) 114 Bern4 J. (1) 257,258; (6) 1,2 Bernal, F. (3) 72 Bernard, M.A. (6) 90 Bernardinelli, G. (1) 136, 137 Berning, D.E. (1) 153, 180 Bemy, F. (1) 361 Be&, F. (1) 266 Berry, D.E. (1) 20 Bertani, R. (5) 41; (6) 216 Bcrthen, P. (7) 62 Bertilsson, S.K. (1) 142 Bertounesque, E. (3) 13 Bertrand, G. (1) 155,287,489, 5 15; (5) 17; (6) 43 Besson, T. (1) 229 Best, S.A. (6) 203 Beste, A. (4) 41 Beswick, M.A. (1) 84,87,91 Beuttenmiiller, E.W. (1) 32, 115 Bevers, S. (4) 213 Bevetwijk, V. (1) 450 Bevilacqua, J.M. (4) 277 Bewberry, K.J. (4) 252 Bharatiya, N. (1) 557, 560 Bhatia, G.S.(5) 53 Bhatia, S. (6) 167 Bhattacharyya, P. (1) 200; (6) 68 Bhuniya, D. (3) 114 Bibart, R.T.(4) 63

Blades, K. (3) 134 Blagg, B.S.J. (3) 25 Blanc, D.(1) 40 Blanche, F. (4) 198 Blandy, C.(1) 292 Blanquet, S. (4) 222 Blaschette, A. (1) 363 Blaser, D. (1) 101 Blasko, A. (3) 59 Blaszczyk, J. (4) 92 Blatnak, J.M. (7) 17 Blauruck, S. (1) 35 Bleczinski, C.F.(4) 197 Block, S.M. (4) 283 Bloy, M. (6) 139, 140 Bo, C. (1) 18 Bocskei, 2 . (1) 578 Boczkowska, M. (4) 92 Boden, N. (3) 58 Boegge, H. (1) 452 Bochlow, T.P. (2) 9 Bohmcr, V.(1) 320 Boele, M.D.K. (1) 18 Borner, H.G. (6) 91 Boemgter, H. (1) 359 Boese, R. (1) 101 Boggs, C.M.(3) 3 Bolmen, F.M. (1) 10 Bohres, E. (6) 41 Boi, Y. (2) 29 Boivin, J. (4) 10 Bojin, M. (6) 142 Bolmd, W.(5) 131 Boldeskul, I.E. (1) 279 Bolli, M.H. (5) 42

65

Organophosphorus Chemistry Bologna, J.C.(4) 83 Bolte, J. (3) 92 Bonafoux, D. (1) 81 Bonaplata,E.(1) 134 Bonewald, L.F. (7) 74 Bongert, D. (1) 105 Bonnington, L.S. (7) 68 Bookham, J.L. (1) 116 Boonc, H.W. (1) 323 Borisenko, A.A. (1) 8,454 Borncr, A. (1) 25,41, 150 Borodkin, S.A. (5) 14 Borozov, M.V. (1) 58 Borrman, H. (1) 580 Bosscher, G.(6) 118 Botschwina, P. (1) 480 Boukherroub, R. (1) 189 Boulard, S. (5) 69 Boullanger, P. (6) 3 Boulle, C.(5) 136 Boulmaaz, S.(1) 160 Boulos, L.S. (5) 27 Bourdat, A . 4 . (4) 135, 156 Bourdieu, L. (4) 287 Bourghida, M.(1) 26 Bourissou, D. (1) 513 Bourne, S.A. (3) 83 Bousquet, S.(1) 524 Bowden, A.A. (1) 164 Boyd, R.J.(1) 484 Boyd, V. (4) 95 Brain, P.T. (5) 7 Brands, K.M.J. (3) 10 Brandsch, R.(4) 80 Brandsma, L. (1) 80 Brandt, P.F. (1) 119 Brassat, L. (1) 540 Braun, N.A. (5) 54 Braunstein, P. (1) 192 Brautigam, C.A. (4) 250 Bravo, P. (6) 36,37 Bravo, R.D. (5) 125 Bredikhin, A.A. (2) 17 Bredikhina, Z.A. (2) 17 Breipohl, G. (4) 107 Breit, B. (5) 67 Breitsameter, F. (1) 391,552; (5) 29,31

Brenner, C.(4) 65 Breslow, R. (3) 5 Bressollcs, D. (3) 6; (6) 8 Breuer, E.(3) 141 Brevnov, M.G. (4) 144 Breia, M. (6) 80, 197 Bricklebank, N. (1) 225 Briley, J.D. (4) 40 Bfinek, J. (6) 133 Brisdon. A.K. (1) . , 13

Aulhor Index Britton, K.L. (4) 280 Brock, M.(6) 156 Broom, A.D. (4) 162 Brosette, T. (4) 45 Brovarets, V.S. (1) 413,414 Brown, D.H.(5) 7 Brown, D.M. (4) 58 Brown, F.,Jr. (3) 15 Brown, J.M. (1) 45 Brown, T. (4) 152 Browne, J.K. (1) 321 Browning, J. (1) 20 Bruckmann, J. (1) 476,574,575; (7) 42

Bruice, T.C. (3) 59; (4) 102-104 Brun, A. (1) 393; (3) 136 Brunel, J.-M. (1) 487; (3) 82, 189, 192; (5) 80 Brunet, J.-J. (1) 380,524 Brunner, H. (1) 7 Bruno, J. (1) 409 Bruzik, K.S. (3) 99 Brynda, M. (1) 136, 137 Bubb, W.A. (3) 198 Bubnov, N.N. (7) 10 Bucci, E. (4) 193 Buchwald, S.L. (1) 4,5 Buckheit, R.W., Jr. (4) 162 Budihardjo, I. (4) 59 Budnikova, Yu.G. (1) 184,185 Biitkle, U. (5) 54 Bujard, H. (3) 164 Bullivant, D.P. (1) 348 Bunnage, M.E. (5) 119-121 Buono, G. (1) 487; (2) 25; (3) 82, 189, 192; (5) 80 Burford, N. (1) 484 Burgard, M. (1) 319 Burgdorf, L.T. (4) 157 Burgemeister, T. (5) 63 Burger, K. (3) 149 Burgess, D.J. (3) 61 Burgess, K. (1) 11,53,54; (4) 47, 48; (7) 25 Burke, S.D.(1) 233 Burke, T.R.,Jr. (3) 200 Burlina, F.(4) 192 Burnaeva, L.M.(2) 16 Burns, G. (5) 23

Burrell, A.K. (5) 50 Burth, D.(1) 20 Burton, D.J. (3) 133 Burton, N.A. (3) 95,96 Busca, P. (3) 17 Bushby, R.J. (3) 58 Buss, J. (4) 190 Butenandt, J. (4) 157 Butler, 1.R (1) 30

B w d , D.J. (1) 171 B u h , F.-X. (1) 148 Byk, G. (4) 198 Bykhov~kaya,O.V.(1) 352-354, 369

Byriel, K.A. (1) 347 Byme, D.(1) 321 Byun, Y.(6) 138 Caballero, E. (6) 17 Caballero, M.C. (3) 9 Cabrita, E.J. (3) 84 cadet,J. (4) 156, 164-166 Cadiemo, V. (1) 222 Cagle, E.N. (4) 95 Cahard, D.(4) 1 Cahiil, J.P. (1) 10 Cai, B. (2) 8 Caillet, J. (4) 221 Caldwell, W.B. (4) 289 Calias, P.(3) 35 Caliceti, P.(6) 239 Caliman, V.(1) 550 Callaghan, C. (1) 55 1 Callies, J.A. (1) 409 C w a ~ aM.4. , (3) 144 Cameron, C.G. (6) 195 Cameron, D.R (3) 98 Caminade, A.-M. (1) 144-147, 322; (3) 6; (6)8-11 Camp, D. (1) 276 Candeias, S.X.(3) 84 Canseco-Melchior, G.(6)77; (7) 33

Cantrill, S.J. (1) 379 Cao, P. (1) 42 Cao, T. (3) 200 Cao, W. (5) 20,21 Capaldi, D.C. (4) 85 Capdevielle, V.(1) 190 Capobianco, M.L. (4) 81 Capozzi, M.A.M. (3) 191 Capps, K.B. (1) 254 Carbon, J. (4) 284 Carboni, B. (I) 239 Cardcllicchio, C. (3) 190, 191 Cardi, N. (6) 214 Care, F. (1) 377 Carell, T. (4) 157 Cariou, M. (5) 136 Carloni, P. (3) 210 Carmichael, D. (1) 45, 544 Camera, C.J. (4) 59 Carrillo-Hermosilla, F. (1) 16; (5) 32

Carson, D.A. (4) 59 Carter, RG. (5) 126

3 13 Canithers, M.H. (4) 77,94 Case, B.L. (1) 169 Casey, C.P.(1) 115 Casper, M.D. (4) 122, 123 Cassels, B.K. (5) 127 Castaneda, F. (5) 9 Cate, J.H. (4) 232 Catrina, I.E. (3) 64 Cauzzi, D.(1) 371 Cavell, R.G. (1) 56 1,562; (7) 30 Cazaux, L. (2) 15 Cea-Olivares, R.(6) 77; (7) 33 Cech, T.R. (4) 233 Cendrowski-Guillaume,S.M.(1) 106

Cermak, D.M. (3) 137 Cha, K.H.(1) 236 Cha, M.-H. (1) 272 Chadnaya, 1.A. (1) 8 Chaklanobis, S.(6) 149 Chambers, J.Q. (4) 124 Chan, A.S.C. (1) 63 Chan, S.-H. (1) 530,533 Chandrasekaran, A. (2) 34-38 Chandrasekhar, V.(6) 135,137, 149, 154

Chang C.-K. (1) 27 Chang, C.P. (4) 263 Chang, C.-W.T. (1) 143 Chang, S.(6) 166 Chang, T.C. (7) 66 Chao,J.L. (6) 162 Chao, Q. (4) 59 Chaouch, A. (5) 58 Chapell, B.J. (1) 3 13 Chaperon, A.R (3) 49 Chapleur, Y.(5) 58 Chaquin, P. (1) 512 charbonneau, v. (3) 49 Charrier, C. (1) 537,542 Chassignol, M.(4) 208 Chatenay, D. (4) 287 Chattpadhyaya, J. (4) 120, 137, 138

Chaturvedi, S.(4) 214 Chaudhry, A. (3) 187 Chaudret. B. (1) 147 Chauhan, M. (1) 183,377 Chauvin, R (1) 380 Chavet, E. (3) 5 Cheetham, G.M.T. (4) 256 Chemla, D.S. (4) 289, 290 Chen, B.I. (1) 15 Chen, B.-L. (1) 60 Chcn, C. (6) 126 Chen, C.C. (1) 63 Chen, C.4. (3) 46 Chen, G.S.(1) 461

3 14

Chen, J. (3) 41; (6) 228 Chen, J.-H. (5) 123 Chen, J.-Y. (7) 12, 77 Chen, L.(3) 162; (4) 32,264; (5) 104; (6) 4

Chen, L.Q. (4) 237 Chen, R.(3) 2, 141 Chen, Y.-K. (6) 206 Chen, 2. (1) 42 Chen, Z.-K. (5) 137 Cheng, C.-H. (1) 214 Cheng, C.S. (4) 180 Cheng, E.C.-C. (7) 26 Cheng, J.-P. (1) 418,419; (5) 13 Cheng, X.D. (4) 270 Chentit, M. (1) 463 Chen-Yang, Y.W. (6) 152 Cheo, H.S. (1) 15 Cherkasov, R.A. (1) 220,392, 563; (2) 12

Chemega, A.N. (1) 488; (7) 32 Chemysheva, N.A. (1) 117,118 Cheruvallath, Z.S. (4) 84, 87, 88 Chesnut, D.B. (1) 372,373 Cheung, K.-K. (7) 26 Cheung, W. (3) 66 Chhabra, D.S. (6) 162 Chiarizia, R. (7) 19 Chidambareswaren, S.K. (1) 2 14 Chin, C.C.H. (7) 69 Chin, J. (3) 65,66 Ching, C.B. (6) 4 C ~ ~ OC.-M. U , (3) 46 Chirkov, E.A. (1) 175 Chitsaz, S.(6) 110 Chittur, S.V.(4) 13 Chiu, Y.S. (6) 152; (7) 66 Cluvers, T. (6) 156 Chmutova, G.A. (1) 52 Cho, C.G. (1) 317 Cho, D.H. (1) 358 Cho, S.-D. (1) 267 Cho, Y. (6) 144 Choi, B.S. (4) 244 Choi, J.S.(1) 24 Choi, J.Y. (3) 8 Choi, N.-H. (1) 87,236 Chopra, R. (4) 246 Chou, H.P. (4) 288 Choukroun, R.(1) 292 Chow, C.P. (3) 11 Christensen, L. (4) 105 Christian, E.L. (4) 11 Christopherson, R.I. (3) 198 Chrostowska, A. (1) 444 Chu, X.-J. (5) 119 Chuang, J.R. (6) 152 Chuburu, F. (7) 52

Chucholowsky, A. (5) 93; (6) 27 Chuit, C. (1) 1, 182, 183,377 Chun, M.W. (1) 273 Chunechom, V.(6) 47 Chung, B.Y. (1) 75 Chung, Y.K.(1) 202 Cicrpicki, T.(3) 208 Cieslak, J. (4) 7 Ciolina, C. (4) 198 Cirelli, A.F. (5) 110 Civade, E. (3) 157 Clade, J. (7) 55 Clardy, D.R (4) 24 1 Clarson, S.J. (6) 93 Clayden, J. (1) 340; (5) 96 Clayton, M.T.(3) 15 Cleary, M.L.(4) 263 Cledcra, P. (6) 16 Clegg, W. (1) 89, 107; (5) 33; (7) 45

Clement, F. (5) 112 Clentsmith, G.K.B. (1) 55 1 Cleophax, J. (1) 230;(3) 30, 3 1 Cloke, F.G.N. (1) 475,55 1 Coates, R.M.(3) 4 Cobo, J. (6) 107 Cockerill, G.S.(3) 135 Cody, W.L. (3) 199 Coe, D.M. (3) 8 Coidan, G.N. (7) 32 Colbran. S.B.(1) 2,201 Colby, T.D. (4) 281 Cole, D.L.(4) 76,84, 85, 87,88 Coleman, R.S.(4) 146 Colinas, P.A. (5) 125 Coll, M. (4) 260 Coll, R.K. (7) 68 Collet, A. (6) 38 Collignon, N. (3) 120 Colombet, L. (1) 5 12,572 Colonna, F.P. (4) 81 Colvin, M.E.(3) 87 Colvin, O.M.(3) 87 Comotti, A. (6) 125 Conn, G.L.(4) 224 Connolly, J. (1) 370 Conrad, 0. (1) 445 Contcl, M. (1) 109 Convery, M.A. (4) 230 Cook, P.D. (4) 122-124,242 Cooper, D.L. (6) 120 Corby, B.W. (3) 79 Cordes, A.W. (6) 135 Corriu, R.J.P. (1) 1,377 Cosstick, R. (4) 26, 29 Coste, F. (4) 247 Cottam, H.B. (4) 59 Couctoux, B. (1) 46

OrganophosphorusChemistry Coumt, T. (1) 524 Coutrh, S.(4) 100 Coveney, P.V. (3) 159 Cowden, C.J. (5) 133 Cowley, A.H. (1) 497 Cox, C.D. (1) 505; (3) 174 CAg, D.C. (1) 2,20 1 Cramer, H. (4) 129 Crane, C.A. (6) 130 Creminon, C. (4) 45 Crescenzi, V.(6) 210 Crestia, D. (3) 186 Crich, D. (3) 78 Cristau, H.J. (1) 73, 165,330; (5) 16.25.94; (6) 12,51

Cristoffers, J. (1) 78 Croquette, V. (4) 285,286 Cross, W.I. (1) 13 Croteau, R (3) 104 C r o w J. (4) 275 Crucianelli, M.(6) 36, 37 Csok, Z. (1) 547 Cucullu, M.E.(7) 65 Culea, M.(7) 73 Cupertino, D.C. (6) 74-76; (7) 40 Curini, M. (3) 194 Cumow, O.J.(1) 20, 113 Cumo, A. (1) 160 Cume, J. (6) 96 Curtis, M. (1) 134 Cushman, M.(3) 203 Czada, W. (1) 362,401 Dabbagh, A.-H. (1) 232 Dabkowski, W.(3) 160 Da Costa, C.P. (3) 2 10 Daeyacrt, F.F.D. (7) 16

Dahan,M.(4) 290 Dahl, 0. (3) 116; (4) 105,201 Dahring, T.K.(3) 199 Dai, X. (1) 14 Dal, H. (6) 111 d'Alarcao, M.(3) 35 Damant, G. (1) 13 Damme, E. (6) 85,86 Dance, I. (1) 424,425; (7) 50 Dmg, Q. (4) 18 DAngelantonio, M. (1) 464; (7) 3 Daniher, A.T. (4) 132 D m , J.-C. (1) 528 &Arbeloff,S.E. (1) 474 Darcel, C. (1) 111 Darnbrough, S. (5) 109 Dartiguenave, M. (1) 190 Dartiguenave, Y. (1) 190 Das, S.S.(6) 141 Dasaradhi, L. (4) 177

Author Index Dasgupta, M. (1) 289 Datsenko, S.(1) 416; (7) 62 Daubresse, N. (5) 46 Daugulis, 0. (1) 43 Davankov, V.A. (6) 235 Davey, R.J. (3) 159 Davies, D.R. (4) 259 Davies, M. (6) 234 Davies, R P . (1) 342; (7) 45 Davis, A.A. (5) 103 Davis, F.A. (3) 153 Davis, J.J., Jr. (6) 90 Davis, J.T. (5) 113 Davis, R.J. (3) 39 Davisson, V.J.(4) 13 Dawson, M.J. (5) 128 Day, R O . (2) 34-38 De, B. (3) 162 Dean, A.B. (3) 90 Debart, F. (4) 82 Deborde, V.(1) 523 Debowski, M. (6) 121 De Buyck, L.(3) 185 De Buyl, F. (6) 86 de Cian, A. (1) 44, 135 de Clercq, E. (4) 1, 19,33,34 Declerq, J.-P.(1) 457,462 Decouzon, M. (1) 278,280 Dedieu, A. (1) 361 DeDionisio, L.A. (4) 95 Defranq, E. (4) 135 Dehnicke, K.(1) 402; (6) 52-66, 110, 114;

(7)39

Deiko, L.I.(7) 44 Deiters, J.A. (2) 1 De Jaeger, R.(6) 136, 189,213, 217

Dejardin, S.(6) 194 de Kimpe, N. (3) 152,185 Dekoven, B.M. (6) 167 de la Cruz, A. (3) 7 DCh g , R.-J. (1) 80 Dclgado, S.(6) 29 D~lgado-C~tro, T. (5) 9 Delmau, L.H.(1) 320 de 10s Santos, J.M. (3) 131 Del Rio, C. (6) 200 del Solar, G. (4) 260 Demay, S. (1) 328 De Meester, I. (3) 202 De Mesmaeker, A. (4) 112 Demuth, R.(1) 5 1 Dem'yanovich, V.M.(1) 312 Dcmynck, C. (3) 92 De Napoli, L.(4) 193,206 Dcng, Y. (3) 55 De Nino, A. (7) 75 Deniz, A.A. (4) 289,290

315

Denk, M.K.(1) 486 Denmark, S.E. (3) 8,80,81 Dent, B.R. (3) 26 Dentini, M. (6) 210 Deplano, P. ( I ) 225 Deras, M.L.(4) 13 De Risi, C.(5) 43 DeRose, V.J. (4) 241 Dervan, P.B. (4) 255 Deschamps, B. (1) 548 Deschamps, E.(1) 525 Desilva, R. (7) 28 Desmars,0.(5) 136 Desmazeau, P. (1) 332 Desmurs, P. (1) 545 Desponds, 0. (1) 243 De Valette, F. (4) 5 Devillanova, F.A. (6) 79 Devivar, R.V.(4) 66 Devys, M. (4) 111 Dewynter, G. (I) 268 Dez, I. (6) 217 Diaconescu, P. (6) 142 Dibble, A. (3) 106 Dibenedetto, A. (3) 193 Didierjean, C. (5) 58 Dieckbreder, U. (2) 11 Diedenhofen, M.(6) 65 Diefenbach, U. (6) 139, 140,212 Diep-Vihuulc, A. (6) 88 Dierkes, P.(1) 44 Dietliker, K.(7) 7 Dietrich, A. (6) 53,61 Dietz, J. (1) 293 Diez-Barra, E. (I) 16; (5) 32 Digeser, M.H. (1) 96, 97,543 Dillingham, M.S. (4) 276 Dillon, K.B. (1) 435 Dillon, R.E.(6) 204 Dilworth, J.R. (1) 72; (7) 34 Dimov, D.K. (5) 78,79 Ding, H. (1) 6 Ding, K.(1) 13 1 Ding, M.-W. (5) 87; (6) 3 1,32 Ding, W.(5) 20,21 Ding, X.C.(4) 254 Dinon, F. ( I ) 216 Di Noto, V. (6) 216 Dinya, Z. (4) 138 Dipple, A. (4) 174 Distefano, M.D. (3) 105 Djahaniani, H. (1) 207,2 10 Do, Y.(6) 138 Dobbcrt, E. (1) 445

Dock-Bregeon, A.C. (4) 221 Doering, S.(1) 242; (7) 13 Docring, U. (6) 158 Doherty, A.M. (3) 199

Doherty, S. (1) 89; (5) 33 Dohno, C.(4) 143 Dohno, R. (3) 69 Doi, G.C. (1) 163 Doi, T. (4) 116 Dolling, U.-H. (3) 10 Dondoni, A. ( 5 ) 57 Dong, M. (5) 12 Dong, T.-Y. (1) 27 Donnadieu, B.(1) 222,292,380; (3) 6; (6) 8-10,42

Donnerstag, A. (3) 2 1 Donoghue, N. (1) 421,422 Doris, E.(1) 30 1 Dou, D. (1) 67 Doucet, H. (1) 45 Doudaa, J.A. (4) 232,235 Dougherty, T.J.(5) 51 Dovgopoly, S.I.(1) 564 Downey, K.M.(4) 177 DOZO~, J.-F. (1) 320 Drabowicq J. (1) 237 Drach, B.S.(1) 415; (5) 3 Drake, J.E. (7) 46 Dransfield, A. (1) 549 Draper, D.E. (4) 224 Draths, K.M.(3) 90 Drauz, K.(3) 150 Drcux, M.(7) 86

Drew, M.G.B. (1) 197; (4) 30 Dness, M.(1) 68,90, 101, 104 Driss, A, (7) 20 Driver, R.W. (1) 233 Dros, A.C. (3) 209 Drueckhammer, D.G. (4) 63 Drysdale, M.J. (5) 24 Du, Y.(3) 137 DUW J.J.-W. (3) 13 Dubey, 1. (4) 191 Dubourg, A. (1) 457,462 Dubreuil, D. (3) 30,3 1 Ducca, J.S. (1) 74 Duesler, E.N. (1) 67,495 Dufour, P.(1) 190 Dujols, F. (3) 186 du Mont, W.-W. (1) 453; (7) 57 Du Mortier, C.M.(5) 110 Dunaway, C.M.(3) 162 Dunbar, L.(1) 342; (7) 45 Duncan, J.B. (6) 205 Dunham, K.L.M. (3) 162 Dunina, V.V. (1) 300 Dunkel, M.(4) 13 1 Dunlop, S.E. (3) 15 Dumd, J.-0. (1) 56 Dung, J.R (7) 16 Dussy, A. (4) 133 Dutasta, J.-P. (7) 58

3 16

Dutta, D. (1) 262 Dvorakova, H.(4) 19 Dwars, T. (3) 150; (7) 87 Dyatkina, N.B. (4) 43 Dybowski, P. (3) 74 Eaborn, C. (1) 81 Eager, M.D. (1) 249 Easterfield, H.J. (3) 135 Eaton, S.R. (3) 199 Ebata, Y. (4) 17 Eberson, L. (1) 273 Ebert, B. (3) 116 Eckstein, F. (4) 207 Edelstein, RL. (3) 105 Edmondson, S.P.(4) 268 Edwards, P.G. (1) 36 Efimova, I.V. (1) 175,218 Efiem, D.I. (2) 5 Efremov, Y.Y. (1) 504 Egli, M. (4) 237,242,243 Eguchi, S.(5) 89-91; (6) 13, 15, 20,21,33,39

Ehresmann, B. (4) 221 Ehresmann, C. (4) 221 Ehrl, R. (5) 63 Eichhofer, A. (1) 499 Eichhorn, B.W. (1) 88 Einolf, H.J.(4) 56 Eisenreich, W. (3) 108 Eisenstein, 0. (1) 571 El-Abadla, N. (3) 20 Eleuteri, A. (4) 85 Elguero, J. (1) 351 El-Hammadi, M.S. (2) 13 Elkhoshneih, Y.O. (1) 286 Elkington, K.E. (1) 348 Ellenberger, E. (4) 274 E I I c ~ MJ., (6) 115 Ellinger, Y. (1) 463 Ellington, A.D. (4) 230 Elliott, M.E.(1) 186 Elmes, P.S. (1) 270,271 Elschenbroich, C. (1) 570 Elsegood, M.R.J. (5) 33 Elvira, C. (6) 193 Elzbieta, B. (3) 171 Embse, R.A.V. (3) 112 Emmi, S.S.(1) 464; (7) 3 Endo, S.(1) 396 Engel, R. (1) 385 Engemann, C. (7) 55 Englich, U. (1) 95 Ephritikhine, M. (1) 106 Epifano, F. (3) 194 Erickson, B.W.(3) 121 Erion, M.D. (4) 18

Eritja, R.(4) 142,260 Erker, G. (1) 242; (5) 6; (7) 13 Escudie, J. (1) 457,462 Esmaili, A.A. (1) 211; (5) 74 Espartero, J.L. (3) 180 Espenson, J.H. (1) 249,250 Espinosa, M.(4) 260 Espinoza-PCrez, G.(6) 77 Etemad-Moghadaq G. (1) 393; (3) 136,154

Evans, S.A., Jr. (2) 6 Evans, S.D.(3) 58 Evens, P.R. (4) 227 Eymard, S.(1) 320 Eymery, F. (3) 110; (5) 116 Fabricant, J.D. (4) 66 Fagan, P.J. (1) 55 Faghihi, K.(1) 232 Falck, J.R (1) 267 Fakiewicz, B. (4) 108 Falvello, L.R. (5) 36-40; (6) 44, 45

Fan, M. (2) 33 Fan, W. (6) 182 Farquhar, D. (4) 2 Faulhaber, A.E. (4) 290 Faulhaber, M.(1) 104 Faulmann, C. (1) 405 Faure, J.-L. (1) 489 Fawcett, J. (1) 156,360 Faza, N. (6) 54,60 Fearon, K.L. (4) 95 Feasson, C.(3) 120 Fe de la Tom, M. (3) 9 Fci, X.-S. (2) 28,30 Fclding, J. (1) 313 Fellcrmeier, M. (3) 103 Fender, J.H. (6) 123 Fenesan, I. (7) 73 Feng, L. (3) 41 Fenske, D. (1) 499; (6) 65 Ferguson, G. (6) 107 Ferguson, M.A.J. (3) 23,24 Ferland, J.M. (3) 98 Fernandez, C. (4) 279 Fernandez, I. (3) 180 Femandez, S. (5) 36-39; (6) 44 Fernandez-Baeza, J. (1) 16; (5) 32 Fernandez-Lopez, A. (1) 16 Ferraro, J.R (7) 19 Ferrc-D'Amare, A.R. (4) 232,235 Femeres, V. (3) 47 Ferse, F.-T.(3) 19 Fethe, M.E.(5) 54 Fettinger, J.C. (1) 88 Fiaud,J.-C. (1) 139,332; (3) 165

Organophosphorus Chemistiy Fiedler, W. (1) 467 Fields, S.C.(3) 118 Fieseler, R.M.(5) 130 Filippov, D. (4) 15 Findeisen, M. (3) 19,20 Finke, R.G. (4) 38 Fiocca, L. (6) 214 Firouzabadi, H. (1) 397 Fischer, C.(3) 150; (7) 87 Fischer, D.A. (6) 167 Fischer, J. (1) 44 Flaherty, T. (3) 106 Flanagan, J.M. (6) 185 Flett, J.1. (7) 68 Flick, K.E.(4) 27 1 Floeder, K.(3) 19 Florih, J. (3) 68,207 Fluck, E. (1) 580,582; (3) 167 Flynn, D.L. (1) 264 FOCCS-FOCCS, M.C. (5) 85; (6) 34, 113

Fdldesi, A. (4) 137, 138 Fdrster, S. (6) 92 Fontani, M. (1) 30 Foos, E.E. (1) 245 Foreman, M.RSt. J. (1) 503 Foss, V.L. (1) 176 Fossum, E. (6) 119 Fourmentin, S.(1) 297 Fourrey, J.L. (4) 111, 145 Fox, K.R.(4) 152 Foy, M.F.(4) 95 Fraanje, J. (1) 18 Fracchiolla, G. (3) 190, 191 Fraenkel, E. (4) 261 Francesch, C.(5) 46 Franch, T. (4) 141 Francis, M.D.(1) 470,553,554 Francotte, E. (5) 56 Frank, S.A. (3) I5 Frankc, R. (7) 55 Frediani, J.E. (4) 95 Frenking, G. (5) 35; (6) 65 Frenzel, C. (1) 92 Fresneda, P.M. (6) 29,30 Fried, A. (1) 493,494 Fried, J.R. (6) 122 Fries, G.(1) 110 Friestad, G.K. (3) 13 Frison, G. (1) 498 Fritz, G.(1) 446 Frochlich, R.(1) 242; (3) 150; (5) 6; (7) 13

Frohn, H.-J. (1) 416; (7) 62 Frolow, F. (4) 278 Frost, J.W. (3) 32,90 Froyen, P. (1) 228 Fruchier, A. (1) 183

Author Index Fryzuk, M.D.(1) 192 Fu, G.C. (1) 77 Fu, H. (2) 39; (3) 71 Fu, X.(3) 14 Fu,Y. (6) 162 Fuji, K.(1) 174 Fujie, N. (1) 128 Fujii, S.(4) 236 Fujii, T. (1) 334; (5) 18 Fujii, Y. (3) 168 Fujimaki, N. (3) 173 Fujimoto, J. (4) 183 Fujimoto, M. (6) 175-177 Fujimoto, T. (5) 92 Fujinami, S.(1) 193 Fujisawa, K.(4) 143 Fukawa, J. (6) 173 Fukui, Y. (3) 45,94 Fukuwatari, N. (6) 169-172, 174, 242-244

Furneaux, R.H. (3) 26 Furukawa, I. (5) 18 Furutani, S. (4) 121 Furyk, S. (1) 169 Fustero, S. (6) 36 Gabaidullin, A.E. (7) 44 Gabor, B. (1) 576 G h e r s , S.(1) 163 Gagnk, M.R.(3) 115 Gainsford, G.J.(1) 21; (3) 26 Gait, M.J. (4) 192 Gal, J.-F. (1) 278,280 Gali, H. (1) 153 Galkin, V.I. (1) 220,392 Gallagher, M.J. (1) 421,422 Gallant, M. (3) 152 Gallardo, A. (6) 193 Gallazzi, M.C.(6) 125,215 Gallego, M.H. (1) 74 Gallegos, A. (3) 44 Gamble, M.P.(3) 126 Ganesh, K.N. (4) 110 Gangamani, B.P. (4) 110 Gani, D. (3) 27,29 Ganoub, N.A. (5) 28, 115 Gankr, B. (1) 539,540 Ganter, C.(1) 539,540 Gao, R.-Y. (7) 8 1 Gao, X.(4) 75 Gao, X . 4 . (7) 64 Gao, Y.G. (4) 268 Gamu, A. (6) 79 Garbesi, A. (4) 81 Garcia, A. (1) 256; (5) 84; (6) 5 Garcia, J. (1) 338; (3) 131, 161 Garcia., M. (3) 117

Garcia, M.M. (5) 39,40; (6) 44, 45

Garcia-Granada,S.(5) 95 Garcia Montalvo, V. (6) 77; (7) 33 Garcia y Garcia, P. (6) 77 Garegg, P.J. (3) 16 Gamer, P. (5) 120-122 G a s p ~ ~ t tD. o ,(4) 156, 164-166 Gasparyan, G.T. (1) 219 Gastaldi, S.(3) 78 Gates, D.P.(6) 117, 157 Gatlik, A. (7) 7 Gauthier, J. (3) 98 Gautier, N. (5) 136 Gaytan, P. (4) 74 Gee, V. (1) 125 Geiger, W.E. (7) 61 Geiseler, G. (1) 402; (6) 52; (7) 39 Gclb, M.H.(1) 275 Gelles, J. (4) 283 Gelpke, A.E.S.(1) 19 Gendin, D.V.(1) 117 Genet, J.P. (1) 40 Genge, A.R (1) 370 Gengembre, L. (6) 213 Gcnini, D.(4) 59 Geoffroy, M. (1) 136, 137,463; (7) 1

Georg, G.I.(1) 262 George, T.A.(7) 59 Georgiev, 1.0.(1) 179 Georgieva, I. (1) 365 Gerdes, K. (4) 141 Gero, S.D.(3) 30,31 Gerratt, J. (6) 120 Gcrus, 1.1. (2) 10 Gescheidt, G. (7) 7 Gcuguen, C.(1) 341 Gevrey, S,(1) 490 Ghassemi, H. (1) 134 Ghiro, E. (3) 98 Ghosh, K. (3) 169 Gibbons, W.A. (5) 55 Gibbs, RA. (4) 47 Gicse, B.(4) 133,134 Gil, J.M. (3) 125, 172 Gilbert, I.H. (3) 42 Gilbertson, S.R (1) 143 Gill, D.S.(7) 63 Gillerd, J. (3) 98 Gilles, T. (1) 114 Gilman, A.G. (4) 282 Gilson, J,-M. (6) 85 Gimeno, M.C.(5) 34 Ginglinger, C.(1) 423 Girardet, J.L. (4) 6, 118 Gittus, A.G. (4) 224 Gladysz, J.A. (1) 120

3 17 Glaser, T. (7) 56 Gleiter, R (1) 575 Gleria, M.(6) 189,214,216 Glinsboeckel, C. (1) 539 Glocklc, A. (1) 66 Glover, J.N.M. (4) 264 Glover, N.R.(3) 97 Goaning, M.D.(3) 138 Goddard, R (1) 10,32,5 1,478; (6) 41

Godde, F. (4) 161 Godfrey, S.M.(1) 224,225,238, 356

Godovikov, N.N.(1) 151 Godovikova, T.S.(4) 53 Goedheijt, M.S.(1) 19, 152,298 Giirg, M.(2) 11 Goerlich, J.R. (1) 138,309; (2) 4, 14

Goerls, H.(1) 390 GO=, E. (3) 108 Golden, B.L. (4) 233 Goldstein, B.M.(4) 281 Gololobov, Yu.G. (1) 220 Golubin, A.I. (1) 410 Gomcz-Bcngoa, E.(6) 89 Gomis-Ruth, F.X.(4) 260 Gong, H. (2) 39 Gong, M.-S. (1) 434

Gonikberg, E. (4) 179 Gonzalet, A. (4) 260 Gonzalez, C. (4) 132 Gooding, A.R. (4) 233 Goodwin, N.J. (1) 156 Goody, R.S.(3) 101; (4) 41,54 Gopalakrishnan,J. (6) 108, 109 Gopaul, D.N.(4) 272,273 Gorbunova, M.G. (2) 10 Gordillo, B. (3) 89 Gordon, P. (5) 69 Gorgucs, A. (5) 136 Gornitzka, H. (1) 287; (5) 17; (6) 43

Gorsuch, S. (4) 30 Gorys, V. (3) 98 Goryunova, L.E. (4) 43 Gospodova-Ivanova, T. (2) 20 Gosselin, F. (5) 107 Gosselin, G. (3) 12; (4) 4,6, 282 Gottschalk, A. (6) 49,50 Gottschiing, D. (4) 142 Goujon, L. (4) 45 Gould, J.H.M. (4) 30 Gould, RO. (6) 56,57 Goumain, S.(3) 120 Goumri-Magnet, S.(1) 287; (5) 17

Gouvereur, V.(3) I64

3 18 Gouygou, M. (1) 528 Graf, C.-D. (1) 12,57 Graiff, C. (1) 371 Gramlich, V.(1) 160 Gramstad, T. (1) 357 Grande, M. (6) 18 Grasby, J.A. (4) 209 Grassert, I. (3) 150 Grassi, J. (4) 45 Gray, E.J. (7) 68 Gray, M.(1) 3 13 Grebe, J. (1) 402; (7) 39 Green, L.G. (3) 49 Greenberg, M.M. (4) 149, 194196

G r e g a F.(3) 210 Greiner, B. (4) 126; (6) 59 Grembecka, J. (3) 208 Grenier, S. (4) 62 Griesbach, U. (1) 30 Griesser, H. (5) 125 Griffin, J.L.W. (3) 159 Griffith, O.H. (3) 28 Griffiths, D.V. (1) 72; (7) 34 Grigera, R.J. (5) 125 Grinstaff, M.W. (4) 150, 151 Grishin, Yu.K. (1) 300 Gritsenko, O.M. (4) 144 Grobe, J. (1) 445,574 Grochovsky, S.L. (4) 53 Grob, T. (6) 114 Groger, H. (1) 309 Grornova, E.S.(4) 144 Groner, B. (4) 266 Grosjean, H. (4) 145 Gross, D.C. (6) 81 Grnli, M. (4) 125 Grove, S.J.A. (3) 42 Grover, G. (1) 459 Grubbs, R.H. (7) 65 Gruber, H. (1) 400 Gruen, K. (1) 492-494 Griin, M. (4) 41 Griitunacher, H. (1) 160,461 Grunefeld, J. (1) 4 11 Grunwell, J . R (4) 290 Grunze, M. (6) 232,233,236 Grushin, V.V. (1) 303 Grutsch, T.L. (3) 15 Gruttner, C. (1) 320 Gryanov, P.I. (2) 16 Gryaznov, S.M. (4) 97 Gryaznova, T.V. (2) 16 Gu, F. (3) 162 Gu, Q.M.(4) 37 Guarente, L. (4) 257, 258 Guariniello, L. (4) 206 Guasch, A. (4) 260

Organophosphorus Chemistry Guchhait, S.K.(3) 169 Gudat, D. (1) 485; (6) 132; (7) 29 Gucckcl, C.(1) 543 Guegen, C. (5) 97 Guengerich, F.P.(4) 56 Guenter, J. (4) 19 Giinther, K.(1) 476 Guerard, C. (3) 92 Guerra, M. (1) 464; (7) 2,3 Guerret, 0. (1) 155,489 Guga, P. (4) 92 Guha, A.K. (3) 70 Guilemette, V. (1) 289 Guillaumet, G. (1) 229 Guillemin, J.-C. (1) 278,280 Guillen, F.(1) 139; (3) 165 Guillory, T.A. (4) 66 Guiry, P.J. (1) 10, 173 Guise, S. (1) 432 Gull, A.M. (7) 17 Gunersel, E.D.(1) 346 Gunic, E. (4) 118 Gunzelmann, N. (1) 123 Gunzner, J.L. (5) 119-122 Guo, F. (4) 272,273 Guo, M.J. (4) 128 Guo, Q. (6) 207,208 Guo, Z.Q. (4) 68 Gupta, G. (1) 560 Gupta, N. (1) 555-560 Gupta, O.D. (7) 53 Gupta, R.K. (6) 227 Gupta, S. (1) 81,486 Guran, C. (6) 142 Gumowski, A. (4) 65 Gusarova, N.K.(1) 37,80,117, 118, 154,310,311,382

Guymon, R. (4) 225 Guzaev, A.P. (4) 24 Guzei, LA. (1) 94; (6) 157 Gurnaev, A. (4) 203 Guuo-Pernell, N. (4) 139

Hamilton, C.J. (4) 43,44 Hammami, A. (5) 94; (6) 5 1 Hammcrschmidt, F. (7) 82 Hammond, G.B.(5) 104 Hammud, H.H. (7) 59 Han, J.W. (1) 202 Han, Y.X. (4) 89 Hanaki, E. (1) 215 Hanamoto, T. (1) 389; (5) 22 Hanaya, T. (3) 168 Handa, N. (4) 228 Handel, H. (7) 52 Hang, J.4. (3) 21 1 Hangge, A.C. (3) 60 Hanna, M.M. (4) 5 1 Hannachi, J.-C. (6) 38 Hans,J.J. (1) 233 Hansen, C.A. (3) 90 Hansen,H.F. (4) 105 Hansma, H. (4) 284 Hanson, B.E. (1) 6 Hanson, G.R (1) 276 Hanson, K.J. (1) 409 Hanson, P.R. (3) 163, 188 Hansson, J. (3) 16 Hanus, V.(1) 132 Hao, L. (1) 166 Hap, M. (1) 114 Hara, H. (6) 164, 165 Hara, Y. (6) 98-100, 105 Harada, H. (4) 200 Harada, Y. (4) 29 1 Hamlambidis, J. (4) 139,215 Hardcastle, I.R. (1) 269 Hardcr, S. (1) 394 Harger, M.J.P. (1) 505-508; (3) 174-178, 187

Hari, Y.(4) 116, 117 Harins, K. (7) 39

Haflprasad, v. (3) 75

Harkness, B. (6) 94 Ham, K.(1) 328,402,570; (6) 52, 54,55,57,63, 65, 110

Ha, T.J.(4) 289,290 Haber, S. (1) 516 Hackenbracht, G. (1) 560 Hackney, M.L. (1) 119 Haddadi, R. (1) 399 Haemers, A. (3) 202 Hacnssgen, D. (6) 158 Hagele, G. (7) 84 Hagiwara, S. (6) 178 Hahn, J. (I) 38 Haiduc, I. (7) 46 Hajipour, A.R. (1) 398,399 Hamashima, Y. (1) 306 Hrundaoui, B. (3) 117

Harpp, D.N. (1) 253 Harris, C.M. (4) 175 Hams, M.E. (4) 11 Harris, RK. (1) 349 Hams, T.M. (4) 175 Harrison, S.C. (4) 246,264 Harrod, J.F. (1) 166 Harrowfield, J.M. (1) 319 Harsch, A. (4) 21 1 Hart,J.C. (3) 95,96 Hartle, T.J. (6) 143 Hartley, R.C. (5) 128 Hartmann, E.(7) 55 Harwood, S.J. (1) 308 Hasan, A. (4) 39,40

Author Index Hashimoto, Y.(1) 302,367; (3) 45,94

Hassler, K. (1) 83,95 Hauchecorne, M.(4) 275 Hauptman, E.(1) 55 Hausch, F. (4) 204 Hawkins, P.T. (3) 42 Hay, C. (1) 523 Hayakam Y.(4) 7 1,200 Hayashi, M. (1) 367 Hayashi, T. (6) 97 Hayes, R F . (6) 146 Hazeri, N. (1) 207,210 He, G.(1) 532 He, G.-X. (4) 100 He, K.Z.(4) 20,39,40 He, Q. (4) 248 He, Z. (3) 83 Heard, P.J. (1) 368 Heckmann, G. (1) 105,580,582; (3) 167

Hedstrom, L. (4) 12 Hegde, R.S.(4) 278 Hehl, R.(1) 406 Heinemann, F.W. (1) 291; (6) 115 Heinicke, J. (1) 555, 557,559 Heinze, K. (1) 295 Heise, H. (1) 94 Heitz, W. (6) 91 Helleand, A . 4 . (3) 16 Heller, D. (1) 4 1 Hellrung, B. (7) 7 Helmchen, G. (1) 33,47 Helvoigt, S.A. (4) 187 Henagge, A.C. (3) 64 Henderson, W. (1) 156; (7) 68,69 Hendrych, J. (7)41 Hennig, L.(3) 19-21 Hepuzer, Y. (1) 346 Hbrault, D.A. (3) 63 Herbert, A. (4) 267 Herd, 0. (1) 38, 172 Herlinger, A.W. (7) 19 Hedndez, J. (3) 89 Hedndez, S. (6) 77 Hernandez-Ortega, S.(7) 33 Herron, W.(6) 96 Hessler, A. (1) 172 Heydari, A. (3) 148 Hey-Hawkins, E.(1) 35,92 Hibbs, D.E.(1) 30, 181,216,554 Hiberty, P.C. (1) 572 Hicks, R.G. (7) 5

Hida, S. (1) 164 Hiegel, G.A. (1) 235 Hiemstra, H. (1) 19; (5) 130 Hietikko, M. (1) 163 Higashi, S.(6) 187

3 19

Higson, A.P. (3) 23 Higuchi, K.(6) 164 Hilger, C.S.(4) 189 Hill, A.F. (1) 473 Hill, M.L.(3) 42 Hill, S.E. (1) 348 Hillier, I.H. (3) 95,96 Hilton, J. (1) 348 Hincs, J.V. (4) 190 Hingst, M.(1) 172 H i m , I. (4) 230 Hiroaki, H. (4) 236 Hiroi, K. (1) 9,49, 198 Hirokazu, K.(5) 52 Hirose, M. (4) 200 Hirose, T. (1) 129 Hirschbein, B.L. (4) 95 Hirth, U.-A.(1) 492 Hitchcock, P.B. (1) 34,81,472, 474,475,550.55 1,554 Hitomi, K.(4) 158 Hitota, T. (7) 27 Hizal, G.(6) 218 Hochart, F. (6) 136 Hockless, D.C.R (1) 109 Hoff, C.D. (1) 254 Hoff, R.H. (3) 60 Hoff~nan,J. (1) 5 16 Hoffinann, A. (1) 478 Hofmann, M.A. (1) 468 Hogan, P.G. (4) 264 Hogen-Esch, T.E.(5) 78,79 Hokelek, T. (6) 111, 188 Holand, S. (1) 537 Holland, D.R (3) 199 Hollingswoth, RI. (3) 54 Holmes, A.B. (3) 42 Holmes, C.F.B. (3) 14 Holmes, RR. (2) 3,34-38 Holy, A. (4) 19 Holz, J. (1) 41, 150 Holz, R.C. (3) 20 1 Hon, Y.-S. (1) 43 1 Honda, F. (4) 98 Hondal, R.J. (3) 99 Honeycutt, T.R (7) 16 Hong, C.I. (1) 236 Hong, E.(6) 138 Hong, S. (5) 4 Hong-Gen, W. (7) 37 Hooper, R (7) 5 Hope, E.G.(1) 126 Hopkins, A.D. (1) 87,91 Hor, T.S.A. (7) 69 Homes, J. (7) 55 Horstmann, S. (7) 49 Horton, J.R. (4) 270 Horton, N.C.(4) 252

Horton, T.E. (4) 241 Horvath, M.J.(1) 270,27 1 Horvath, M.P. (4) 277 Houalla, D. (2) 20 Houghton, T.J. (1) 348 Hourdin, G. (6) 38 Hovell, M. (1) 348 Howc, D.L. (3) 107 Hsiao, T.-Y. (1) 214 Hsieh, W.(4) 284 Hsiue, G.H. (1) 350 HSU,A.-L. (3) 46 Hsu, S.M.(6) 167 Hu, W.H. (1) 63 Hu, Y.(6) 182 Huang, D.T.C. (3) 198 Huang, H. (4) 246; (5) 21 Huang, 3.-M. (7) 81 Huang, L.J. (6) 166 Huang, T. (3) 139; (5) 20,21 Huang, W. (5) 137 Hudecova, D. (1) 366 Hudhomme, P. (5) 136 Hudson, A. (1) 464; (7) 2, 3 Hiibler, K.(1) 483 Hug, G. (7) 7 Huggman, J.C. (1) 186 Hull, K.G. (3) 13 Hung,Y. (6) 166 Hunziker, J. (4) 147 Hursthouse, M.B.(1) 30, 181, 216,554 Huscbyc, S.(6) 78 Hutchins, M.K. (3) 181 Hutchins, R O . (3) 181 Hutchinson, J. (5) 121 Huttner, G.(1) 76, 113,295,296, 494 Huy, N.H.T. (1) 500,50 1; (7) 36 Huynh, C.(1) 243 Hwang, C.K. (5) 121 Hwang, G.S.(4) 244 Hwang, J.-J. (1) 223; (5) 47 Hynes, R.C. (3) 65

Iacobucci, S. (3) 35 Iadonisi, A. (4) 206 laiza, P. (4) 2 16 Ichikawa, J. (3) 170; (5) 100 Ide, H. (4) 57 Iden, C.R (4) 179

Idrissi, M.S.(7) 21 Igau, A. (1) 222,292,49 1 Ignat'ev, N. (1) 416; (7) 62 Iijirna, T. (2) 22 Ikeda, I. (1) 29 Ikcda, s. (4) 210

320 Ikehata, K. (6) 180 Ikematsu, H. (6) 128 Ikeyama, M. (6) 175-177 Iluc, V. (6) 142 Imamoto, T. (1) 3 1,64 Imanishi, T.(3) 119; (4) 116, 117 Imbach, J.-L. (3) 12; (4) 4 4 8 3 Imhof, W. (1) 390 Inamati, G.B. (4) 124,242 Indzhikyan, M.G.(1) 2 19,420 Inguimbert, N. (1) 73; (5) 16; (6) 12

Inoue, H. (6) 187 Inoue, J.4. (4) 148 Inoue, K. (6) 148 Inoue, Y. (3) 86; (7) 43 Invidiata, F.P. (3) 113 Iorge, B. (3) 110; (5) 116 Ipaktchi, J. (3) 148 Ireland, T.(1) 204 Isaia, F. (6) 79 Isamo, T. (6) 88 Ishibashi, S.(1) 294; (7) 23 Ishikawa, W. (6) 174,243 Ishikubo, A. (4) 186 Ishizuka, I. (3) 52 Ishmaeva, E.A. (1) 374, 375,504; (2) 18

Islami, M.R. (1) 209 Isobe, M. (6) 104 Issartel, J.P.(4) 46 Itami, K. (3) 73 Itaya, T. (6) 148 Ito, K. (4) 148 Ito, S.(1) 261,455; (7) 60 Ito, Y.(1) 127 Itoh, H. (4) 291 Ivanov, A.A. (7) 83 Ivanova, G.G. (7) 83 Ivanova, I.A. (3) 24 Ivanova, N.I. (1) 310 Ivanova, T.M.(4) 53 Ivkova, G.A. (2) 16 Ivory, A.J. (3) 197 Iwai, S.(4) 158 Iwase, R. (4) 121 Iwashima, M.(3) 13 Iyer, R.P.(4) 128 Izad, K. (1) 89, 107 Izukawa, T. (6) 98-105 Jaber, M.R.(5) 112 Jackson, S.L.(1) 356 Jackson, W.R. (1) 270,271 Jacob, J. (1) 250 Jacobi, A. (1) 76 Jacobs, J.S.(1) 265

OrganophosphorusChemistry Jacobsen, H. (1) 242; (7) 13 Jaeger, J. (4) 23 1 Jager, L. (1) 73; (5) 16; (6) 12 Jaeger, R.(6) 121 Jaf€res, P.A. (3) 128 Jain, C.B.(1) 557,559 Jakeman, D.L.(3) 197 Jalil, M.A. (1) 193 Jamison, G.M.(1) 47 1 Jan& K.D. (3) 206 Jan& D.O.(1) 358 J a g , H.-Y. (I) 202 Janik, J.F. (1) 99, 100 Jankowska, J. (4) 7 Jansen, M.(1) 448; (6) 158; (7) 55 Janura, M. (1) 7 Jarman, M.(1) 269 Jarvinen, T. (3) 196 Jaschke, A. (4) 204,205 Jaworck, C.H. (3) 35 Jayamman, L. (4) 269 Jeannerat, D.(1) 423 Jehle, H. (1) 122 Jeng, R.-J. (1) 350 Jenkins, A.T.A. (3) 58 Jenkins, I.D.(1) 276 Jenkins, S.A. (6) 226,227,229, 230

Jeong, L.S. (1) 273 Jerina, D.M.(4) 174 Jeruzalmi, D. (4) 256 Jeske, J. (1) 517 Jess, I. (1) 404 Jia, Z. (7) 37 Jiang, D.J. (7) 67 Jiang, L.C.(4) 229 Jiang, Q. (1) 42 Jiang, 2.(6) 162 Jimcno, C. (3) 182 Jimeno, M.-L. (3) 144 Jh, J.4. (6) 220 Jin, Y. (4) 22,23 Jo, J.-J. (I) 223 Jockusch, S.(1) 345; (7) 6 Jorchcl, P. (1) 92 Johansson, F. (1) 142 Johnson, B.F.G.(1) 477 Johnson, F. (4) 163 Johnson, R.A. (4) 282 Johnston, F. (4) 179 Johnston, J.F. (4) 172 Jones, C. (1) 470,473,553,554 Jones, D.J. (1) 36 Jones, D.K. (1) 506; (3) 175 Joncs, E. (1) 582 Jones, P.G. (1) 65,363,453,517522,557,559; (2) 4, 14; (7) 35

Jones, R.A. (4) 78 Jones, W.D. (1) 110 Jsrgensen, K.A. (6) 40 Jouini, T. (7) 20 Joyce, G.F. (4) 239 Jubault, P. (3) 120 Juengling, S. (5) 79 Jug&,S.(1) 111,423 Juliette, 1.1.J. (1) 120 J u g , K.-Y. (2) 7 Jung, M. (1) 22 Junk, P.C.(1) 470 Jurica, M.S.(4) 271 Jus, S.(1) 40 Just, G.(4) 22-24 Jwo, J.J. (5) 47 Kabachnik, M.I. (1) 352-354,369 Kabachnik, M.M.(1) 8 Kaczmarek, R (4) 91,96 Kadyrov, A.A. (2) 11 Kafkrski, P. (3) 208 Kagerer, H. (1) 89 Kagoshima, H.(1) 302 Kahl, J.D. (4) 149, 195, 196 Kainosho, M. (4) 279 Kairies, S. (6) 145 Kajihara, Y. (4) 17 Kajiwara, M. (6) 127, 128 Kakehi, A. (5) 89,91,92; (6) 15, 33,39

Kakinuma, K. (3) 108 Kakkar, A.K. (1) 289 Kalindjian, S.B.(1) 260; (6) 22 Kamel, A.A. (1) 286 Kamer, P.C.J. (1) 17-19.44, 152, 158, 163,187,298

Kamil, K. (5) 60 Kamiya, H.(4) 55 KaMi, M. (1) 71,306,308 Kanaori, K. (4) 57 Kang, H.-J. (6) 161, 167 Kang,J. (1) 24 Kang, S.O.(1) 167 Kang, T.W.(1) 236 Kann, N. (5) 102 Kanomata, N. (6) 23 Kant, M. (1) 50 Kar, K. (6) 159 Karadakov, P.B. (6) 120 Karaghiosoff, K. (1) 86,560 Karakasa, T. (6) 26 Karasik, A.A. (1) 179 Kargin, Yu.M. (1) 184, 185 Kariman, A. (3) 148 Karlstedt, N.B.(1) 176 Karlstrom, A.S.E. (3) 73

Author Index Karodia, N. (1) 432; (5) 15,68 Karpi M. ($1 5 Karsch, H.H. (1) 112 Karthikeyan, S. (6) 48 Karwowski, B.(4) 92 Karzai, A.W. (4) 265 Kasai, H. (4) 55 Kasai, P.H. (6) 160 Kashiwabara, K. (1) 70 Kasparek, F. (7) 41 Kataev, A.V. (1) 374,375 Kataev, V.E. (1) 374,375 Katalenic, D. (4) 31 Kataoka, M. (4) 71 Kataoka, S. (7) 27 Kates, S.A. (7) 74

Kato, K. (5) 134 Katritzky, A.R. (1) 343 Katsyuba, S.A. (7) 15 Katti, K.V. (1) 153, 180; (6) 6 Katzenellenbogen, J.A. (5) 8 Kaufman, M.D. (5) 52 Kaur, D. (1) 459 Kawabata, T. (1) 174 Kawagishi, R. (1) 49 Kawaguchi, H.(1) 474 Kawakami, M.(1) 215 Kawamora, T. (6) 182 Kawanishi, Y.(6) 128 Kawasaki, A.M. (4) 122,123 Kawasaki, M.(4) 219 Kawase, M. (5) 90,91; (6) 21,33 Kawashima, T. (2) 22 Kaya, K. (3) 212 Kayser, M. (5) 11 Kazakova, E.I. (1) 300 Kazankova, M.A. (1) 175,218, 454; (3) 123

Ke, D.Y. (6) 129, 153 Kana, J.F.W. (3) 28 Keen, S.P.(3) 147 Keglevich, G. (1) 333,526,547, 577,578

Kehler, J. (3) 116 Kehr, G.(1) 66,242; (7) 13 Kelley, J. (3) 200 Kellogg, R.M.(3) 209 Kelly-Borges, M. (3) 14 Kempe, R. (3) 150 Kenawy, E.-R (1) 383,384 Kennard, C.H.L. (1) 347 Kenttamaa, H.I. (7) 76 Keppler, M.D.(4) 152 Kerr, L.C.(1) 91 Kers, A. (4) 25 Keseru, G.M. (1) 578 Keyte, R.W.(6) 75,76; (7) 40 Khachatryan, R A . (1) 420

321

Khajuria, R (7) 63 Khan, S.J. (4) 150, 151 Khan, S.R (4) 2 Khatri, A. (7) 74

Khattab, A.F. (4) 140 Khdankin, V.V. (1) 409 Kheradmandan, S. (1) 93 Khiar, N.(3) 180 Khil'ko, M.Ya. (1) 118 Khobotova, N.V. (6) 134 Khoruzhaya, I.A. (5) 14 Khrustalev, V.N.(1) 255 Khullar, S.(4) 163 Khusainova, N.G. (1) 563; (2) 12 Kibardin, A.M. (2) 16 Kida, T. (1) 29 Kiddle, J.J. (5) 103 Kielkopf, C.L. (4) 255 Kiesow, T.J. (5) 109 Kiguchi, Y. (1) 389; (5) 22 Kikinuma, K. (3) 204 Kikuchi, H.(2) 22 Kikuchi, S. (7) 60 Kilian, P. (6) 77 Kilic, E.(6) 188 Kilic, 2.(6) 111, 188 Kiljunen, H.(7) 85 Kim, C.(6) 202 Kim, E.-N. (1) 236 Kim, H. (1) 272; (4) 175 Kim, I. (4) 228 Kim, J. (1) 358 Kim, J.M. (6) 183 Kim, J.S. (6) 202 Kim, J.-W. (1) 236 Kim, 0. (1) 434 Kim, S.(1) 167; (5) 81 Kim, Y.(1) 273; (6) 138 Kimmerling, T.S. (1) 186 King, C.-R. (3) 200 King, D.A. (4) 257,258 Kingsley, S. (6) 137 Kingson, J.E. (1) 197 Kinoshita, T. (1) 174 Kinosita, K.(4) 29 1 Kirchmeier, R.L. (7) 53 Kis, K. (3) 103, 108,203 Kisanga, P.B. (2) 32 Kishi, Y. (4) 27 Kissling, R.M. (3) 115 Kittaka, A. (4) 148 Kiu, X.(2) 31 Kiyomori, A. (1) 4 Kiyono, S. (6) 97 Kjeldgaard, M. (4) 223 Klasek, A. (5) 60 Kleban, M. (5) 57 Klein, C.(6) 234

Klein, E.(1) 465 Klein, H. (7) 22 Klein, I. (5) 54 Kliegel, W.(1) 41 1 Klingenberg, E.H.(6) 150 Klinkhammer, K.W.(1) 82 Klisch, E. (7) 22 Klochkov, V.V. (1) 392 Knaggs, A.R. (5) 128 Knidiri, M. (7) 21 Knight, D.A. (1) 108 Knispel, T. (4) 33,34 Knizek, J. (1) 96,543; (5) 3 1 Knochel, P. (1) 12,23, 25, 57, 204,328 Knowlcs, P.F.(3) 58 KO, J. (1) 167 Kobayashi, H.(6) 186 Kobayashi, K. (3) 52; (5) 52 Kobayashi, M.(4) 57 Kobayashi, T. (1) 5 81 Kobiro, K. (7) 43 Kobychev, V.B.(1) 4 10 Koch, A. (6) 49,50 Koch, T. (4) 245; (5) 131 Kochetkov, A.N. (1) 175,218 Kocovsky, P. (1) 132, 133 Kodana, H.(4) 17 Koeig, M. (1) 189 Koeller, K.J. (3) 7 Kiillner, C.(1) 157 Koening, M. (3) 154 Kiister, H.(4) 69,70 Kogan, V.A. (5) 14 Kohama, M. (1) 396 Kohlpaintner, C.W. (1) 6 Koide, T. (1) 284 Kojima, M. (1) 294; (7) 23 Kojima, T. (1) 546 Koketsu, J. (1) 4 17; (5) 45 Kokotos, G.(5) 55 Kollar, L. (1) 547 Kolodziejczyk, A S . (4) 108 Kolpashchikov, D.M. (4) 53 Komarov, I.V. (1) 564 Komiyama, M. (4) 186 Kondo, M. (1) 389; (5) 22 Kondo, S.4. (3) 67 Konovalova, A.I. (2) 17 Konovalova, I.V. (2) 16 Konze, W.V. (1) 482 Koo, B.H.(6) 138 Koohang, A. (3) 4 Kooijman, H.(1) 450; (3) 209 Kool, E.T. (4) 60 Koontz, S.L. (4) 66 Korba, B.E.(4) 6 Korczynski, D. (4) 91, 96

322

Korschunova, G.A. (4) 144 Koseki, N. (6) 182 Koshkin, A.A. (4) 113 Kosmrlj, J. (5) 60 Kostyuk, A.N. (1) 564 Kotera, M. (4) 135 Koubitz, K. (1) 18 Kouno, R.(3) 170; (5) 100 Koutentis, P.A. (5) 26 Kowalska, K. (4) 108 KO&, C.M. (1) 304 Kozikowski, A.P. (3) 44,57 Koziolkiewicz, M. (4) 92 Kozlov, E.S.(2) 5 KOZIOV, LA. (4) 220 Kozlova, G.V. (1) 382 Kozyreva, O.B.(1) 310 =er, E. (6) 92 Kraikivskii, P.B. (7) 8 h e r , B. (5) 125 Kraszewski, A. (4) 7 Krautscheid, H. (1) 446; (6) 65 Krawiwcka, B. (3) 142 Krayevsky, A. (4) 43 Krebs, B.(1) 445 Kreimeyer, A. (4) 3 Kreitmeier, P.(5) 63 Kresheck, G.C. (1) 376 Kretschrnann, M. (6) 139,212 Krieger, M.(6) 56-59,63,64 Krifta, M. (1) 98 Krishnamurthy, S.S.(6) 116 Kristensen, J. (4) 217 Krofta, M. (1) 96 Krogsgaard-hen, P.(3) 116 Kronman, M. (4) 49 Krotz, A.H. (4) 76,87 Kruck, T. (1) 114 Kriiger, C. (1) 10,476,493,574, 575; (7) 42

Kruger, V. (1) 46, 148 Krumlacher, W. (1) 83 Krutlco, D.P. (1) 58 Krylova, A.I. (1) 241 Krzymanska-Olejnik, E. (4) 202 Krzyzanowska, B.K. (4) 39 Ku, Z.-J. (7) 12 Kuang, S.-M. (1) 178 Kubiak, C.P. (7) 17 Kubiak, R.J. (3) 99 Kubo, N. (6) 246 Kuboki, H. (6) 26 Kudis, S.(1) 33 Kiihnau, D. (6) 40 Kiihnel, M. (1) 38 Kuharcik, S.E.(6) 195 Kukhar, V.P.(2) 10 Kumar, G.(6) 179

Kumar, P.(5) 106 Kumar, R (4) 113, 114 Kumar, S. (4) 174 Kumar, V.A. (4) 110 Kumaraswamy, S. (5) 106 Kummer, S.(1) 291,575 Kunihiro, T. (6) 103 Kunkel, M. (3) 44 Kunz, M. (7) 7 Kurachi, I. (6) 246 Kurahashi, N. (5) 18 Kurchenko, L.P. (6) 13 1 Kurirnoto, K. (4) 228 Kurk, D.N. (7) 59 Kuroda, H. (1) 215 Kuroda, R (4) 176 Kuroki, K. (6) 187 Kuwahara, M. (4) 109 Kuwano, R.(1) 127 Kuwata, K. (1) 344 Kuze, T. (4) 148 Kumina, L.G. (1) 300 Kuznctsova, E.E.(1) 382 Kuzuya, A. (4) 186 Kumyama, T. (3) 102 Kvm~w,L. (4) 115 Kyogoku, Y. (4) 236 Labaudiniere, R. (5) 109 Lacour, J. (1) 423 Lafont, D. (6) 3 La Francois, C.J. (4) 183 Lagier, C.M. (1) 349 LaGrandeur, L.M. (3) 15 Laguna, A. (5) 34 Lai, J.-Y. (1) 267 Lai, Y.-H. (5) 137 Lake, C.M. (6) 90 Lakhrissi, M.(5) 58 Lamande, L. (2) 15 Lamazzi, C.(1) 229 Lambeir, A.M. (3) 202 Lamm,E.A. (1) 563 Lammertsma, K. (1) 5 14 Lampilas, M. (3) 20 Lampronti, 1. (3) 113 Landgrafc, C. (1) 170 Landick, R.(4) 283 Landskron, K.(7) 49 Landy, D. (1) 297 Lanfranchi, M. (1) 288,371 h y , H. (1) 343,53 1,534 L a g , J.-F. (7) 77 Lange, D. (1) 465 Lange, H. (1) 575 Lanin, S.N. (7) 78 Lankiewicz, L. (4) 108

Orgaiiophosphorus Chemistry Lao,X.-F. (1) 3 18 LaPointe, A.M. (1) 177 Lappert, M.F. (1) 34 Lara-Sanchez, A. (1) 16; (5) 32 Larazev, P.G. (7) 8 h 1 5 , C. (3) 6; (6) 8-10 Lartigue, M.-L. (1) 322 Laspths, M. (3) 154 Lattman, E.E. (4) 224 Lattman, M. (2) 33 Lau, A.Y. (4) 274 Laurent, R (1) 145, 147 Lauterbach, C. (7) 55 Lavety, R.(4) 286 Law, V.S. (4) 100 Lawlor, J.M. (4) 139 Lawrence, A.J. (4) 26 Lawrence, N.J.(1) 140, 141; (5) 65.66

Layh, M. (1) 34 h o , I. (5) 40; (6) 45 Lebeau, L. (4) 45,62 Lcbecq, F. (6) 85 Lebuis, A.-M. (3) 66 Lecher, J. (4) 284 Le Corre, M. (1) 266 Lecubin, F. (4) 111 Lee, C.-F. (1) 43 1 Lce, C.-H. (1) 167; (6) 160 h e , C.O. (6) 238 Lee, H.-W. (1) 236; (3) 70 Lee, I. (1) 202; (3) 70 Lee, J.H. (1) 24; (4) 244 Lee, K.H. (5) 81 Lee, K.J. (6) 183 Lee, M.-H. (6) 202 Lee, M.-Y. (2) 7 Lee, N. (4) 32 Lee, R.-H.(1) 350 Lee, S.(1) 75 Lee, S.B.(6) 220 Lee, S.H.(1) 75 Lee, Y.H. (1) 167 Leempoel, P. (6) 85,86 Lefebvre, F. (1) 290 Lefebvre, I. (4) 4 Le Flwh, P. (1) 513,541,566569,571,579; (7) 31,38

Le Gall, T. (1) 240 Leger, J.F. (4) 287 Leglaye, P. (1) 380 Le Golvan, M.P. (6) 222,224, 225,229,230

Legrand, 0. (3) 82, 189, 192; (5) 80

Legros, J.-Y. (1) 332 Le Guen, V.(1) 240 Lehmann, C.W. (7) 42

A urhor Index Lehn, J.M. (4) 275 Lehn, P. (4) 275 Leininger, S.(1) 227,458,573 Leitner, W. (7) 42 Lemmouchi, Y.(6) 194 le Moigne, F.(3) 155 Lemonovskii, D.A. (1) 58 Lemos,N.D.A. (1) 472 Leng, M. (4) 247 Lennard, W.N. (6) 166 Lennon, P.J. (3) 157 Lensink, C. (1) 21 Leonard, P.(4) 170 Leoni, L.M. (4) 59 Leont'eva, I.V.(1) 353 LeProust, E.(4) 75 Lerner, H.-W. (1) 86 Lesnik, E.A. (4) 172 Letsinger, R.L. (4) 187,214 Leumann, C. (3) 62 Leung, P.-H. (1) 162,529-534 Levalois-Mitjaville, J. (6) 136 Le Van,D. (1) 445,574 Le Vilain, D. (1) 52'3 Lewandowska, E. (4) 28 Lewis, F.D. (4) 187 Lewis, S.(1) 274 Ley, S.V.(3) 49; (5) 42 Lhomme, J. (4) 135 Li, C.(7)65 Li, C.Y. (6) 152 . Li, J.-L. (1) 329 Li, L. (7) 64 Li, S.(7) 24 Li, W.-H. (3) 40 Li, 2.(2) 39 Li, Z.-L. (3) 71 Liable-Sands, L.M. (1) 94,245; (6) 157

Liang, J. (4) 289 Liao, X.M.(4) 130 Liao, Y. (3) 145 Liddle, S.T. (7) 45 Liebelt, A. (6) 124 Lieberknecht, A. (5) 125 Liedtke, J. (1) 160 Liesen, P.J. (1) 428 Liguori, A. (7)75 Lima-Monaiio, L. (6) 77 Limousin, C. (1) 230 Lin, A. (6) 206 Lin, C. (3) 39 Lin, C.-H. (3) 206 Lin, K.Y. (4) 160 Lin, R.-L.(1) 223; (5) 47 Lin, S.T.(1) 15 Lindeman, S.V. (6) 78 Lindemann, U.(4) 134

3 23

Linkletter, B.A. (4) 102 Linscheid, M.(4) 173 Liou, S.-Y. (1) 159 Lippard, S.J. (4) 248 Lippolis, V. (6) 79 Lipshutz, B.H. (1) 171 Litvinov, LA. (7) 44 Liu, A. (1) 162,529 Liu, B. (1) 418,419; (5) 13,81 Liu, C.B. (6) 14 Liu, D. (6) 126 Liu, G.(5) 4 Liu, H.-L. (1) 405 Liu, H.-W. (3) 50 Liu, J. (1) 131; (5) 12 Liu, J.Q. (4) 159 Liu, Q. (3) 58 Liu, R.(5) 20, 21 Liu, S.-2. (7) 12 Liu, X. (2) 29; (3) 132 Liu, X.H.(4) 65 Liu, Y. (4) 18 Liu, Y.4. (1) 169 Liu, 2.-J. (6) 32 Llama~-SaiZ,A.L. (6) 113 Liinas-Bmet, M.(3) 98 Loakes, D. (4) 58 Lobanov, D.I. (1) 352-354,369 Liibcr, 0. (1) 467,469,579 Loffler, J. (5) 118 Loh, S.-K. (1) 532 Loh, Z.H. (7) 69 Long, N.L. (1) 28 Longmire, J.M. (1) 62 Lopatin, S.I.(7) 71 Lopcz, B. (6) 193 Lopez, C. (2) 20 Lopez, J.A. (1) 381 Lopez, L. (2) 15 Lbpez, R. (6)89 Upez-Cardozo, M. (6) 77 Upez-Laizaro, A. (1) 258; (6) 1, 113

Lbpez-Leonardo, C. (1) 257; (6) 2 Lopusiriski, A. (3) 179 Lora, S.(6) 239 Loss, s. (1) 160 Lotz, M. (1) 23 Lough, A.J. (1) 486 Loupy, A. (1) 230 Lovel, C.G. (1) 270,271 Low,J.N. (6) 107 Lowe, R.(1) 263; (5) 53 Lowenhaupt, K. (4) 267 Loy, D.A.(1) 471 Lu, G.H. (3) 199 Lu, w. (5) 2 Lu, W.C. (6) 14

Lu, X.(1) 205; (5) 77 Lu, x.-Y. (1) 339 Lu, Y.(1) 419; (5) 2, 13 Lubell, W.D. (5) 107 Luczak, J. (1) 237 Luczak, L. (3) 179 Ludanyi, K.(1) 577 Ludeman, S.M.(3) 87 Liicking, u. (3) 49 Lukacs, G.(1) 230 Lukashev, N.V.(1) 454 Lukin, P.M. (1) 255 Luther, A. (4) 80 Lutsenko, S.V.(3) 123 Lutz, c. (1) 57 Lu@ M. (1) 187; (4) 107 Ly, T.Q.(6) 67,72, 73 Lynch, D.E. (1) 347 Lynch, G.P. (3) 26 Lyon, A.P. (1) 426 Lysenko, K.A. (1) 352-355 Ma, S.-M. (1) 339 Maack, A. (1) 456 Mabbs, F.E.(6) 72,73 McAlister, D.R (7) 19 McAllister, G.(5) 128 Macartney, D.H. (1) 426 McAuliffe, C.A. (1) 224-226,356 McCarthy, J.R (1) 263 McCarthy, M. (1) 173 McCaskill, D.(3) 104 Macciantelli, D.(1) 464; (7) 2,3 McClain, M.D. (1) 471 McClcod, D.(2) 26 M c C I U ~C.K. , (2) 7-9 McCoull, W.(3) 153 McCrary, B.S.(4) 268 McCready, T.L. (3) 14 McCurdy, S.N. (4) 95 McCutcheon, J.P. (4) 225 Macdonald, C.L.B. (1) 484 McDonald, M.A. (1) 5 10 McDonald, R.(1) 562; (7) 30 McEwen, W.E.(2) 1,2 McFarlane, W.(1) 107 McGarry, D.G. (5) 119 McGarth, J.E. (1) 134 McGlinchey, M.J. (1) 304 McGuigan, C. (4) 1 Machnitzki, P. (1) 170, 172 Maciagiewicz, I. (3) 74 McInnes, E.J.C. (6) 72,73 McIntosh, M.B. (6) 143, 150 Mack, A. (1) 45 1,466,478,479 McKay, D.B. (4) 234 McKervey, M.A. (1) 32 1


324

Mackewitz, T. (1) 554 Mackie, A.G. (1) 226 Mackie, H. (4) 74 McKinney, M.A. (7) 67 McLaughlin, L.W.(4) 188,213 McMinn, D.L.(4) 194, 196 McMurray, J.S. (7) 74 Macoratti, E. (5) 56 McPartlin, M. (1) 87 McPhail, S.J. (3) 162 McPheeters, D.S.(4) 11 McWilliams, A.R. (6) 157 Madrigal, A. (6) 18 Madsen, T.A. (2) 9 Maeda, H.(1) 282-284,412; (3) 184

Maeda, M. (4) 218,219; (6) 26 Maerkl, G. (1) 565; (5) 63 Maestro, A. (1) 381 MaBni, M. (4) 81 Maghsoodlou, M.T. (1) 207,210 Magnusson, G. (3) 51 Mahnke, J. (1) 453 Maienza, F. (1) 188 Maier, U. (3) 103 Maigrot, N. (1) 537,542; (7) 3 1 Maison, W. (4) 106 Maitra, K. (1) 535 Maitre, P.(1) 572 Maiuolo, L.(7) 75 Maj, A.M. (1) 307 Majima, T. (3) 69 Majoral, J.-P. (1) 144-147,222, 292,322,491; (3) 6; (6) 8-11 Majner, W.(4) 90 MA, T.C.W. (1) 178 Makhaev, V.D. (1) 241 Makino, K. (4) 57 Makita, K. (1) 417; (5) 45 Makitra, RG.(1) 221 Malaq c. (1) 12 Malik, K.M.A. (1) 30, 181,217, 494

Malinge, J.M. (4) 247 Malisch, W. (1) 122, 123,492, 493

Mallakpour, S.E.(1) 232 Mallamo, J.P. (3) 146 Malmstrom, T. (1) 199 Maltseva, T.V. (4) 137, 138 Maly-Schreiber, M. (6) 247 Malysheva, S.F.(1) 37, 117, 118, 310,311,382 Mamoto, T.I.(1) 3 Manabe, K. (1) 387,388 Manalili, S.(4) 122, 123 Manferdini, M. (3) 113 Manger, M. (1) 110

Mann, J. (4) 30 Manners, I. (6) 117,121, 157,196 Manoharan, M.(4) 24, 122-124, 203,242

Manriquez, V. (5) 9 Manthey, M.K. (3) 198 Manuel, G. (1) 189 Mao, C.T. (4) 100 Marchal, A. (6) 107 Marchenko, A.P. (7) 32 Marchetti, P.(5) 43 Marchi, C. (2) 25 Marciacq, F. (4) 46 Marcitullio, M.C. (3) 194 Marcos, C.F.(1) 252 Marek, 1. (6) 78, 133; (7) 41

Maria, P . 4 . (1) 278,280 Marinetti, A. (1) 40,46, 148 Markham, G.D.(4) 28 1 Markidis, T. (5) 55 Marko, J.F.(4) 287 Markus, A. (3) 20 Marlitre, P. (4) 3 Marmorstein, R (4) 257,258 Marosi, G. (1) 578 Marquez, V.E.(4) 34 Marra, A. (5) 57 Marriott, J.H. (1) 269 Mars, D.J. (1) 321 Marsden, C.J. (1) 5 15 Marshall, W,(1) 55 Marsilio, F. (6) 239 Martens, J. (1) 309; (4) 106 Martcns, R. (7) 57 Martin, A.M. (4) 249 Martin, J. (1) 28 Martin, J.C. (2) 2 1 Martin, N. (5) 135 Martin, 0.R (3) 17 Martin, P.(4) 243 Martin, R. (4) 16 Martin, R.G. (4) 259 Martin, T. (5) 55 Martin, V.S. (5) 55 Martin-Alvmz, P.J. (6) 200 Martinez, C.I.(4) 47 Martinez de Martinez, E.(3) 172 Marui, T. (6) 170 Masci, G. (6) 210 Mase, N.(1) 248 Masojidkova, M. (4) 19 Massa, W. (6) 52,54,60,64 Massague, J. (4) 269 Massoumi, G.R (6) 166 Mast, C. (6) 59 Mi~tryukova,T.A. (1) 352-355, 369

Masuda, T.(6) 127, 128

Mate, C.M. (6) 160 Matem, E.(1) 446 Matevosyan, G.L.(I) 315 Mathk, C. (3) 12 Mathey, F. (1) 335,435,498,500, 501, 513,525,536,537,541, 542,544,548,566,567,569, 57 1,579; (7) 3 1,36,38 Matray, T.J. (4) 60 Matrosov, E.I. (1) 369 Matsuda, A. (3) 37,38; (4) 36, 127 Matsuda, K. (3) 52 Matsuda, S. (4) 186 Matsuda, T. (4) 50 Matsuda, Y.(1) 546 Matsufuji, M. (6) 99 Matsui, M. (1) 128 Matsui, S. (4) 50 Matsumoto, S. (1) 284; (6) 99 Matsumoto, T.(1) 129 Matsumoto, Y. (4) 50 Matsumura, K.(5) 134 Matsuo, T.(6) 163 Matsuoka, M. (1) 389; (5) 22 Matsushita, H.(3) 204 Matt, D. (1) 65,69, 135, 167,319; (7) 35 Ma#amana, S.P.(1) 88 Matter, B.A. (1) 115 Matteucci, M.D. (4) 8, 101, 119, 160 Matulic-Adamic, J. (4) 132 Matyjaszewski, K.(6) 119 Mayer, T.G. (3) 48 Mayes, A.M. (1) 395 Mechulam, Y. (4) 222 Medelec, J.-Y. (1) 184 Medzihradszky, K.F. (7) 74 Meetsma, A. (3) 156 Meggers, E.(4) 134 Meidine, M.F. (1) 472 Meicr, C. (4) 33,34 Meicr, L.A. (5) 5 Meisel, M. (7) 47, 48 Melanson, R. (5) 11 Meldgaard, M. (4) 113 Meliet, C. (I) 297 Melnicky, C.(7) 15 Melnik, M. (1) 366 Meneghetti, F. (5) 41 Mcnkndez, J.C. (6) 16, 17 Meng, H. (5) 137 Mcng, J.-€3. (1) 329 Meng, S.-H. (7) 64 Meng, S.-S. (6) 129 Mercier, A, (3) 155 Mercier, F. (1) 335,536

Aulhor Index Mercier, J.-P. (7)86 Mercuri, M.L. (1) 225 Mereiter, K.(1) 26 Merkulov, A.S. (1) 195 Men, K.(1) 104 Men, K.M., Jr. (6)203 Merzweiler, K.(1) 73;(5) 16;(6) 12 Messere, A. (4) 193 Mestre, B. (4)192 Metzger, A. (3) 91 Meunier, B. (4)191 Meyer, A. (4)82 Meyer, 0.(1) 242;(7) 13 Meyer, R.B. (4) 184 Meyer, T.J. (3) 121 Meyer-Klaucke, W.(7)56 Mezailles, N. (1) 5 13,541,568 Mezzetti, A. (1) I88 Miankarirni, M,(1) 263 Michalska, M.(3) 77 Michalski, J. (3) 142,179 Michel-Beyerle, M.E.(4)134 Michelot, G.(1) 266 Midden, W.R.(4)211 Midori, K.(6) 180 Mieling, G.E.(3) 162 Migaud, M.E. (3) 32 Mihalic, J.T. (3) 203 Mikami, K.(1) I31 Mikolajczyk, M. (1) 237;(5) 25 Mikoluk, M.B. (1) 561,562 Mikoluk, M.D.(7)30 Milecki, J. (4) 137 Miles, R.E.(3) 58 Miller, D.J. (3) 29 Miller, P.J. (6)119 Milne, G.W.A. (3)200 Milstein, D. (1) 159 Minami, T.(3) 170;(5) 100 Minasov, G. (4)242 Minowa, T. (3) 151 Minto, F. (6)214,216 Minuutolo, F. (5) 8 Mioskowski, C.(1) 240;(3) 164, 205;(4)45,62 Miquel, Y.(1) 292 Mironov, V.F.(2)16-18 Mirza-Aghayan, M. ( I ) 189 Misawa, M.(1) 196 Mishchenko, N.I.(1) 415 Misiura, K.(4)93 Mitchell, H.(4)32 Mitrofanov, S.V.(1) 244 Mitsuhashi, T. (6)244 Mittelbach, C.(4)168 Mitzel, N.W.(5) 7 Miura, T. (1) 64

Miurh Y.(3) 56 Miyasaka, T. (4)148 Miyashita, A. (1) 129 Miyata, H.(4)291 Mizukoshi, T. (4)158 Mizuma, M. (3)93 Mizuno, K.(6) 128 Mizusaki, H.(6)128 Mizuta, Y.(1) 344 Mo, 0.(I) 278 Mochizuki, A. (3) 1 Modammadi, H.(1) 398 Modi, C.(1) 336 Modro, A.M. (7) 18 Modro, T.A. (3) 83;(7)18 MGhlen, M.(6)65,66 Moers, 0.(1) 363 MGschel, C.(1) 448 Mohammadpoor-Baltork, I. (1) 398,399 Mohan, V.(4)172 Mok, K.-F. (1160,162,529,530, 532 Moldovan, 2. (7) 73 Molina, P. (1) 256;(5) 84,85,88; (6) 5, 19,29,30,34,113 Molitor, E.J. (3)50 Molko, D.(4)46, 165 Moll, M. (6)115 Monflier, E.(1) 297 Monia, B.P.(4)172 Moniz, G.A. (5) 104 M o w < RJ. (4)271 Monnier, L. (1) 239 Monse, C.(1) 101 Montahaei, A.R (5) 73 Montero, J.-L. (3) 117 Montesarchio, D.(4) 193 Montgomery, C.D. (5) 10 Montoneri, E.(6)215 Moody, K. (1) 270,271 Moon, H.R.(1) 273 Moore, P.B. (4)180 Moorhoff, C.M. (5) 62 Moradei, O.M.(5) 110 Modes, E. (6)198,199 M o J.-R. ~ (3) 9 Mom, D.(4)221 Moreau, S.(4) 161 Morcly, C.P. (1) 553 Moreno, A. (1) 16 Morcno, B.(7)9 Morkre, A. (3) 117 Morgan, T.A. (6)159,161,167, 168 Mori, T. (4)218 Morigaki, E. (3) 56 Moriguchi, Y.(3) 1 19

3 25 Morimoto, T. (1) 196 Morin, P.(7) 86 Mario, K.4. (4)116, 117 Morisaki, N. (3) 45,94 Morishita, N.(1) 344 Morita, H (1) 334 Morita, K. (3) 45,94 Morita, S.(6)241 Moriya, K.(6) 127, 128 Morizur, J.-P. (1) 490;(7)72 Morr,M. (4)35 Momsey, C.T.(6) 130 Morrison, J. J. (5) 23 Mortreux, A. (1) 297,307 Moman, F. (4)83 Mosquera, M.E.G. (1) 84,87,91 Mosslemin, M.H.(1) 208;(5) 71, 73 Motevalli, M.(3) 124 Motita, N.(7)60 Mountford, P. (1) 475 Mouret, J.F. (4)46 MouriPS, V. (1) 536;(3) 110;(5) 116 Mouveaux, C.(6) 136 Moyano, A. (3) 182 Mucke, M. (7)48 Muelle, A. (1) 452 Miiller, D.(3) 19,20 Miiller, J.F.K. (1) 203;(5) 98 Miiller, K.(6) 124 Miiller, T.J.J. (1) 337;(5) 108 Miiller, U.(1) 362,400,401,408 Muhammad, F.(1) 140,141;(5) 65,66 Mukhaiimana, P. (1) 454 Mulatier, J . 4 . (6)38 Mullah, N.(3) 106 Mullenix, A.N.(4)124 Muller, C.W.(4)266 Muller, L.(7)57 Mulliez, M. (3) 186 Mulvey, RE.(7)45 Munakata, M. (1) 396 Munoq A. (1) 393;(3) 136 Muragavel, R (3) 1 1 1 Murakami, F. (1) 449;(7)4 Murakami, K.(3) 50 Mumkami, S.(6)87 Mudidhar, J. (1) 407 Murano, T.(3) 151 Muresan, V.(7)73 Murphy, J.R (4)254 Murphy, P.J.(1) 216 Murray, C.L.(1) 260;(6)22 Murthy, G.S. (6) 108, 109 Mushtaq, I. (1) 224,238 Musigmann, C.(1) 320

OrganophosphorusChemistty

326 Mush, R.Z.(2) 16 Mussons, M.L. (3) 9 Mutch, A. (1) 290 Muthiah, C. (5) 106 Muto, Y. (4) 228 Mu&, N. (1) 361 Myer, C.N. (6) 147 Mynott, R. (1) 476,576 Myshakin, E.N. (1) 58 Nachbauer, A. (1) 227,468,573 Naether, C. (1) 403 Nagai, K. (4) 227 Nagao, Y. (5) 114 Nagaoka, Y.(1) 71; (5) 99 Nagasawa, T. (1) 474 Nagase, S. (5) 1 Nagel, S. (1) 38 Nagendran, S.(6) 135, 137, 154 Nahorski, S.R.(3) 39 Naicker, K.P. (1) 427,428 Nair, V. (4) 14

Nakacho, Y.(6) 181 Nalcagawa, S.(6) 128 Nakagawa, Y.(1) 71; (6) 119 Nakajima, K. (1) 70,294; (7) 23 Nakajima, S.(3) 56 Nakamoto, M. (7) 54 Nakamura, M. (3) 69, 170; (5) 100

Nakamura, T. (4) 143 Nakamga, T. (6) 180 Nakano, H. (4) 212 Nakata, T. (6) 23 Nakatani, K. (4) 143 Nakatsu, N. (3) 45,94 Nakatsuji, Y. (1) 29 Nakhle, B.M. (3) 121 Nalepa, C.J. (6) 179 Namoto, K.(3) 72 Nan, F. (3) 44 Nanbu, D. (4) 116 Napierala, M.E. (6) 150, 195,203 Nasakin, O.E.(1) 255 Nasedkina, T.V.(4) 53 Naso, F. (3) 190, 191 Natchus, M.G. (3) 162 Nather, C.(1) 404 Natt, F. (4) 243 Naud, F. (1) 192 Navarro, A. (6) 36 Navarro, R (5) 36-40; (6) 44.45 Ndifon, P.T. (1) 226 Neamati, N. (4) 14 Nechev, L. (4) 175 Neganova, E.G. (1) 194 Neibecker. D. (1) . , 524

Neilson, RH. (6) 48 Nejat, F.S.(1) 213; (5) 76 Neijar, R (7)21 Nelson, D.A. (6) 205 Nelson, J.H. (1) 535 Nelson, J.M.(6) 46,201 Nelson, J.S. (4) 95 Nesterov, V.N. (1) 255 Nettekoven, U. (1) 187 Neubauer, P.(7) 47 Neuburger, M.(1) 203; (5) 98 Neumann, B. (1) 452 Neumiiller, B. (1) 582; (6) 53-55, 57,58,61,62,65,66,

110

Newlands, C.(1) 432 Ng, Q.E.(6) 123 Ng, S.-C. (1) 60; (6) 4 Nguyen, K.A. (1) 5 14 Nguyen, M.Q.(4) 95 Nguyen, P. (6) 117 Nguyen, S.T.(7) 65 Nguyen-Ba, P. (4) 32 Niccolai, D. (4) 81 Nichols, A. (4) 89 Nicholson, B.K. (1) 156 Nickcl, T.(I) 170 Nicoara, S.(7) 73 Nicolaou, K.C.(3) 72; (5) 119122

Niecke, E.(1) 465; (6) 132; (7) 29 Nief, F.(1) 545 Nieger, M. (1) 465; (6) 132, 158; (7) 29

Nielsen, P.E. (4) 105,220 Niemi, R. (3) 196 Niewiarowski, W.(4) 93 Niihata, S. (3) 204 Niikura, K. (3) 91 Nikolaev, A.V. (3) 23,24 Nikonov, G.N. (1) 555 Nikonowicz, E.P. (4) 240 Ninomiya, Y. (1) 417; (5) 45 Nishi, Y. (3) 204 Nishida, Y. (3) 52 Nishigaichi, Y. (3) 8 Nishiguchi, I. (6) 164 Nishikawa, A. (3) 45,94; (6) 99 Nishikawa, H. (1) 193 Nishimura, K.(1) 396 Nishioka, Y.(6) 181 Nishizono, N. (4) 127 Nissen, F. (4) 223 Nitta, M. (1) 58 1; (5) 82 Nixon, J.F. (1) 435,472,474,475, 477,550,551,554

Nobori, T. (6) 97-105 N o h , R (4) 2 12 Noh, H.(1) 86,96,97, 543; (5)

30,31

Nogueras, M.(6) 107 Nohira, H. (1) 129,331 Nolan, S.P.(7) 65 Nolte, J. (7) 47 Nolte, R.J. (1) 163 Nomichi, M.(6) 240 Norman, A.D. (1) 119 Norrby, P.O. (5) 102 Novikova, V.G.(2) 17 Novikova, Z.S. (1) 8 Novosad, J. (6) 77,78; (7) 33 Nowakowski, J. (4) 239 Nowotny, M. (1) 477 Noyori, R. (4) 200; (5) 134 Nurcki, 0. (4) 228 Nutley, B.P. (1) 269 Nyborg, J. (4) 223 Nyulaszi, L. (1) 509,526,527, 549,554

Oba, G. (1) 189

Oberbrodhage, J. (1) 429 Obika, S.(4) 116, 117 Obrecht, D. (5) 93; (6) 27 OBrien, P. (1) 34 1; (5) 97 Ochoa de Retana, A.M. (3) 130, 166

O'Connor, S.J.M. (6) 195,207, 208

O'Dea, T.P. (4) 213 Odinets, I.L.(1) 355 Oehme, G. (1) 61; (3) 150; (7) 87 Officer, D.L. (5) 50 O ' G q M. (4) 270 Ogata, y.(1) 9 Ogawa, A.K. (5) 129 Oget, N. (7) 52 Ogilvie, W.W. (5) 121 Ogiwara, R.(6) 240

Oh,D.Y.(3) 125 Oh, J.S. (6) 183 OHagan, P.(1) 321 O m ,M. (1) 150 Ohkubo, T.(6) 26 Ohlsson, J. (3) 5 1 Ohmori, H. (1) 282-284,412; (3) 184 Ohndorf, U.M. (4) 248 Ohno, A. (1) 285 Ohnuma, M. (5) 82 Ohrui, H. (3) 52 Ohshima, S.(1) 129 Ohsumi, T. (6) 187 Ohta, T. (5) 18 Oiarbide, M. (6) 89 Okada, H.(6) 24 1

Author Index Okamoto, Y.(6) 15 Okano, T. (3) 212; (6) 13 Okauchi, T. (3) 170; (5) 100 Okawa, T. (5) 89-91; (6) 13, 15, 20,21,33,39

Okazaki, R. (2) 22 Okruszek, A. (4) 95

Okubo,Y. (1) 131 Okuma, K.(5) 61 Old, D.W. (1) 4,5 Olejnik, J. (4) 202 Olesker, A. (1) 230 Olive, G. (3) 155 Olivieri, A.C. (1) 349 Olmeijer, D.L. (6) 151, 195,203 Olmstead, M.M. (1) 44 1 Olshavsky, M.A. (6) 130,211 Omelanczuk, J. (5) 25 Ondrejkovicova, I. (1) 366 Oneil, I.A. (4) 26,29; (6) 22 O'Neill, A. (1) 260 Onen, A. (1) 430 Ono, A. (4) 279 Ono, K. (1) 546 Ono, S.(1) 334 Onoa, B. (7) 9 Onys'ko, P.P. (2) 19 Oosterom, G.E.(1) 158 Opitz, A. (1) 390 Opromolla, G.(1) 28 Orgel, L.E.(4) 220 Orlova, T.N. (4) 53 Omelas, M.A. (1) 23 1 Orpen, A.G. (1) 125 Orsolino, P. (6) 239 Orti, E.(5) 135 Ortoleva-Donnelly, L. (4) 49 O m , H.(4) 245 Osada,T. (6) 101, 106 Osbom, J.A. (1) 44 Oscarson, S.(3) 16 O'Shaughnessy, P. (1) 89, 107 Oshovskii, G.V.(1) 195 Osorio-Olivares, M. (5) 127 Ostemm, N. (4) 54 Otero, A. (1) 16; (5) 32 Oudrhiri, N. (4) 275 Ouellette, M. (5) 120, 121 Ovakimyan, M.Z.(1) 219,420 Owen, D.J. (3) 4,101 Own, Z.Y. (1) 15 Oyarzabal, J. (3) 130, 131, 166 Ozeki, H. (1) 480 Ozurni, K. (6) 187

Pabo, C.O.(4) 248,261 Padron, J.M.(5) 5 5

327 Pagano, S.(1) 290 Pai, C.C.(1) 63 Pailhous, I. (1) 457 Paine, R.T. (1) 67,495 Painter, G.F.(3) 42 Palacios, F.(1) 338; (3) 130, 131, 161,166, 172

Palibroda, N. (7) 73 Palmer, J.S. (1) 91 Palomo, C.(6) 89 Palyutin, F.M.(1) 386 Pan, Y.(7) 24 Panchanathewsar;in, K.(1) 364 Panchishin, S.Y.(1) 4 15 Pandey, R.K.(5) 5 1 Pandolfo, L. (5) 41 Pandurangi, RS.(6) 6 Panek, R.L. (3) 199 Panvert, M.(4) 222 Paolucci, F. (1) 464; (7) 3 Papadogiankis, G.(1) 299 Papathomas, P.M. (7) 57 Park, J. (1) 167 Parker, D. (3) 158 Parlow, J.J. (1) 264 Parr, J. (1) 200 Parraga, A. (4) 260 Parrott, S.J.(7) 34 Parsons, S.(1) 13,477; (5) 7 Parthasarathi, v. (1) 364 Parvez, M.(6) 156 Passi, P. (6) 239 Pasto, M. (I) 32 Patel, B.K.(4) 207 Patel, D.J. (4) 229 Pater, C. (1) 508; (3) 178 Paterson, I. (5) 132,133 Patnaik, U. (1) 407 Patsanovskii, 1.1. (1) 374,375, 504; (2) 18 Paulsen, E.L. (1) 115 Pavey, J.B.J. (4) 26,29 Pavlctich, N.P. (4) 269 Pavlova, L.A. (6) 235 Pawloski, C.E. (6) 159 Paync, L.G.(6) 227-230 Peabody, D.S.(4) 230 Pearson, J.E.(4) 66 Pcbler, J. (6) 56 Pedersen, E.B.(4) 140, 141 Peinador, C.(6) 24 Pekari, K.(3) 47 Pellois, J.P.(4) 75 Pcltier, W.J. (4) 66 Pemberton, L. (6)2 13 Percy, J.M. (3) 134, 135 Perea, J.J.A. (1) 23,25,204 Percgudov, A.S. (1) 241

Perettie, D.J. (6) 161, 167, 168 P k e ~ - P & r eM.-J. ~ , (3) 144 Pergament, I. (3) 122 Pericas, M.A. (3) 182 Perichon, J. (1) 184 Pkrigaud, C. (3) 12; (4) 4,6 Pens, G. (3) 114 Perlikowska, W.(5) 25 Perona, J.J. (4) 249,252 Perozzi, E.F.(2) 21 Pemud-Darcy, A. (5) 25 Persson, 0. (1) 277 Pervushin, K.(4) 279 Peters, C. (1) 573 Petit, A. (1) 230 Petocz, G. (1) 547 Petreus, 0. (1) 324 Petrovskii, P.V.(1) 352-355 Petrucci-Samija, M.(1) 289 Petrusiewicz, K.M.(1) 307,375 Petz, w.(5) 35 Peyrottes, S.(4) 192 Pfister, H.(1) 494 Pfister-Guillouzo, G.(1) 444 Pfitmer, A. (1) 98 Pfleiderer, W.(4) 72,73, 126, 129 Phetmung, H.(1) 125 Phillips, P. (1) 476 Phillips, S.E.V.(4) 230 Philosof-Oppenheimer, R (3) 5 Phkubo, K.(6) 104 Piccialli, G. (4) 193,206 Piccirilli, J.A. (4) 130,250,251 Pieken, W.A.(4) 189 Pielcs, U.(4) 112 Pierini, A.B. (1) 74 Pierron, E.(1) 466 Pietrasanta, L.I.(4) 284 Pietrowska, D.G. (3) 140 Pietschnig, R.(1) 465 Piffl, M.(1) 343 Pignot, M. (4) 173 Pikies, J. (1) 446 Pikul, S.(3) 162 Pilato, R.S.(3) 3 Pilcher, A.S.(4) 174 Pina, B. (6) 36 Pinchuk, A.M. (1) 195,564 Pintauro, P.N. (6) 207-209 Pipelier, M.(3) 30, 3 1 Piper, D.E. (4) 263 Pipko, S.E.(1) 488 Pires, R.M. (4) 146 Ping, Y.N.(1) 221 Pimd, B. (4) 275 Pitsch, S.(4) 136 Piulats, J. (4) 142 Plack, V. (1) 138,305; (2) 4, 14

Organophqhorus Chemistry

328 Plamer, M.J. (3) 183 Plank, S.(1) 580; (3) 167 Plante, O.J. (3) 18 Platt, A.W.G. (1) 360 Player, M.R

Organophosphorus Chemistry

Organophosphorus Chemistry

Organophosphorus Chemistry