Synthesis and characterisation of hindered organophosphorus compounds by T. E. Netshiozwi Submitted in fulfillment of the requirements for the degree PHILOSOPHIAE DOCTOR in Chemistry in the Faculty of Science of the Johannesburg University Supervisor: Prof. D. B. G. Williams 2009 ii DECLARATION I declare that this research is my own work and that it was conducted under the supervision of Prof D. B. G. Williams. No part of this research has been submitted in the past, or is being submitted, for degree at another university. Takalani. E Netshiozwi iii ACKNOWLEDGEMENTS I would like to express my sincere appreciation to my promotor, Prof. D. B. G. Williams, for his continued guidance, invaluable advice and for the knowledge I gained during the course of this study. I would also want to express my appreciation to Dr Cornelius Marthinus Erasmus, Dr Andre´ Pienaar and Mr Don Smith for persuading the Armscor Reseach and Development Management board to approve and financially support this project. I would want to thank my former colleagues Ms Talitha Hildebrand and Mr Francois van Straten for offering me an opportunity to use the GC•MS in their department. The unlimited love goes to my brothers Thivha, Maanda, Thizwi, Shumi, Thina, Mom and especially to my late father Mr J. M. H. Netshiozwi and grandmother Mrs Phophi Anna Netshiozwi. This thesis is dedicated to Khudi and Daki Phophi Netshiozwi. Finally, I want to thank Tina,Tlou and all my colleagues for their encouragement and support during the course of this study. iv Abstract The main objective of the research described in this dissertation was the preparation and characterisation of hindered organophosphorus compounds. For this purpose, ionic and free radical mechanisms were applied in the synthesis of selected hindered organophosphorus compounds, some with interesting spectral properties. A brief background of the element phosphorus and the early development of organophosphorus chemistry is provided. The early development of the chemical nerve agents derived from phosphorus, their toxicity and illicit manufacture by terrorist groups is discussed. The vital role played by the organisation for the prohibition of chemical weapons in enforcing the prohibition of the development, production, acquisition, stockpiling and the use of chemical nerve agents and their destruction by the state party is highlighted. The methodologies such as Michaelis • Arbuzov, Michaelis • Becker, Perkow Pudovik, Abramov and radical protocol reactions used to synthesise phosphorus containing compounds, are reviewed. In the present research project, diphenylphosphonous chloride and phenylphosphonous dichloride reagents were used in nucleophilic substitution reactions with bulky alcohols. This resulted in the synthesis and characterisation by1H, 13C, 31P NMR and GC•MS spectroscopy of the compounds shown in Scheme 0.1, where R’ was derived from 2,2•dimethylpropanol, 3• methylbutanol, 1,2•dimethylpropanol, 3,3•dimethyl•2•butanol, 1,1•dimethylethanol and 2•methyl•2• butanol. Y H2O2 R'OH or (R)xPCl(3•x) (R)xP(OR')(3•x) (R)xP(OR)(3•x) Et3N S8 R=Aryl, and Y=O, S Scheme 0.1 v The importance of using activated alcohols in the form of metal alkoxides in the cases of 1,1• dimethylethanol and 2•methyl•2•butanol for successful reactions was demonstrated. The influence of steric hindrance on the reactivity of these ionic reactions was studied by substituting diphenylphosphonous chloride, or phenylphosphosphonous dichloride, withtert• butylphosphonous dichloride or di•tert•butylphosphonous chloride. This resulted in no nucleophilic substitution reaction taking place betweentert•butylphosphonous dichloride and hindered alcohols in the presence of triethylamine. For successful reactions, the use of excess activated hindered alcohols in the form of either the lithium or potassium alkoxide was required. It was found that replacing both of the chlorine atoms intert•butylphosphonous dichloride with hindered alcohols like 1,1•dimethylethanol and 2•methyl•2•butanol was sluggish, and in the present study this could not be realised. It was demonstrated that di•tert butylphosphonous chloride is resistant to react with activated hindered alcohols due to enhanced steric hindrance in the organophosphorus reagent. The use of free•radical mechanisms in the phosphorus•carbon (P•C) bond forming reaction is briefly reviewed. The importance of finding a non•toxic replacement of organotin reagents in radical protocols is also highlighted. The scope of the present work was limited to the reaction of phosphonyl•centered radicals generated by the triethylborane•oxygen system with various alkenes ranging from less electron rich to more electron rich alkenes, including those containing a free hydroxy moiety. The reaction of diphenyl thiophosphite or diphenyl phosphite (Scheme 0.2) in the presence of triethylborane under aerobic conditions with enol ether alkenes afforded the expected anti• Markovnikov products. On the other hand, the reactions of diphenyl phosphite with the same set vi of enol ether alkenes under the same reaction conditions afforded, most unusually, the Markovnikov products (Scheme 0.2). S S OR + PhO P H a OR PhO P OPh OPh (anti•Markovnikov products) O O a OR OR + PhO P H PhO P (Markovnikov products) OPh OPh a: Et3B•O2, toluene, rt Scheme 0.2 Furthermore, it was noted that no reaction took place between diphenyl phosphite with less electron rich alkenes such as cyclohexene or 1•dodecene under these reaction conditions. There were no addition products formed under the same reaction conditions with the same set of enol ether alkenes with diethyl phosphite (EtO)2P(O)H or di•iso•propyl phosphite i•(PrO)2P(O)H. However, all of the above phosphite reagents, with the exception of diphenylphosphine oxide (reaction not pursued), reacted with cyclic or acyclic enamines to afford Markovnikov products (Į• aminophosphonates) in good yields. vii List of abbreviations AIBN 2,2’•azo•bis•iso•butyronitrile ATP adenosine triphosphonate n•BuLi n•butyllithium CW chemical weapon CWC chemical weapon convention CI chemical ionisation d doublet dd double of doublets DEPT distortionless enhancement by polarisation transfer DMF N,N•dimethylformamide DMSO dimethyl sulfoxide DNA deoxyribonucleic acid EA2192 O•hydrogen•S•(2•diisopropylaminoethyl) methylphosphonothioate EI electron ionisation Et ethyl ESI electron spray ionisation esr electron spin resonance epr electron paramagnetic resonance GA Tabun GB Sarin GC gas chromatography GD Soman viii GF Cyclosarin HOMO highest occupied molecular orbital IR Infrared i•Pr iso•propyl LD50 the amount of material that it takes to kill 50% of the organism tested LUMO lowest unoccupied molecular orbital MHz megahertz MS mass spectrum NMR nuclear magnetic resonance OPCW Organisation for the Prohibition of Chemical Weapons 2•PAM 2(E)•2•(Nitromethylidene)•1H•pyridine q quartet RNA ribonucleic acid rt room temperature SOMO single occupied molecular orbital t triplet tert tertiary THF tetrahydrofuran UK United Kingdom US United States U.S.S.R Union of Soviet Socialist Republics VX O•ethyl•S•(2•di•iso•propylaminoethyl) methylphosphonothioate Vx O•iso•propyl•S•(2•diethylaminoethyl) methylphosphonothioate ix TABLE OF CONTENTS CHAPTER 1 LITERATURE OVERVIEW AND MOTIVATION 1.1 THE HISTORY OF PHOSPHORUS ELEMENT 1 1.2 EARLY DEVELOPMENT OF ORGANOPHOSPHORUS CHEMISTRY 1 1.3 HISTORY OF ORGANOPHOSPHORUS NERVE AGENTS 3 1.3.1 Background 3 1.3.2 Hydrolysis products of V•agents 6 1.3.3 Hydrolysis products of Sarin and Soman 8 1.3.4 Hydrolysis products of Tabun 9 1.4 BIOLOGICAL ACTION OF NERVE AGENTS 9 1.5 MISUSE OF ORGANOPHOSHORUS COMPOUNDS 11 1.6 THE ORGANISATION OF PROHIBITION OF CHEMICAL WEAPONS 12 1.7 LITERATURE REVIEW ON PREPARATION OF DIALKYL AKYLPHOSPHONATES AND ALKYL HYDROGEN ALKYLPHOSPHONATES 13 1.7.1 Michaelis•Arbuzov and Perkow Reaction 14 1.7.2 Michaelis•Becker Reaction 16 1.7.3 Phosphonylation by Abramov Reaction 16 1.7.4 Transesterification of trimethyl phosphite 18 1.7.5 Phosphonates from alkylphosphonic halides 19 1.7.6 Phosphonates from nucleophillic substitution at phosphorus 21 1.7.7 Preparation of dialkyl alkylphosphonates fromH•phosphonates using a free•radical mechanism 22 x 1.8 MOTIVATION AND AIMS 24 1.9 REFERENCES 29 CHAPTER 2 SYNTHESIS OF HINDERED P•OR SYSTEMS 2.1 INTRODUCTION 37 2.2 SYNTHESIS OF ALKYL DIPHENYLPHOSPHINITES AND THEIR ELABORATION TO THEIR TO THE PHOSPHORYL AND THIOPHOSPHORYL FORMS 44 2.3 THE USE OF NMR SPECTROSCOPY IN IDENTIFYING THE SYNTHESISED PRODUCTS 45 2.4 SYNTHESIS OF DI•ALKYLPHOSPHONITES AND THEIR ELABORATION INTO THE PHOSPHORYL AND THIOPHOSPHORYL FORMS 54 2.5 SYNTHESIS OF ALKYL PHENYLCHLOROPHOSPHONITES AND THEIR ELABORATION INTO THE PHOSPHORYL AND THIOPHOSPHORYL FORMS 57 2.6 SYNTHESIS OF S•ETHYL DIPHENYLPHOSPHINOTHIOATE, DI•(S•ETHYL) PHENYLPHOSPHONOTHIOITE ESTER AND THE HALF ESTER 58 2.7 SYNTHESIS OF TERT•BUTYL DIPHENYLPHOSPHINITES AND THEIR ELABORATION INTO THE PHOSPHORYL FORMS 61 2.8 SYNTHESIS OF DI•(TERT•ALKYL) PHENYLPHOSPHONITES AND TERT•ALKYLPHENYLCHLOROPHOSPHONITES 65 2.9 SYNTHESIS OF ALKYL DI•TERT•BUTYLPHOSPHIONITES AND THEIR ELABORATION TO THE PHOSPHORYL AND THIOPHOSPHORYL FORMS 67 2.10 ATTEMPETD SYNTHESIS OF O•TERT•BUTYL DI•TERT•BUTYLPHOSPHINITE 69 2.11 ATTEMPTED SYNTHESIS OF DIALKYL•TERT•BUTYLPHOSPHONITES 69 2.12 DISCUSSION 71 2.12.1 Alkyl diphenylphosphinites(94) and their analogues 71 2.12.2 Dialkyl phenylphosphonites (98) and their analogues 75 xi 2.13 CONCLUSION 79 2.14 REFERENCES 81 CHAPTER 3 ADDITION OF DIFFERENT PHOSPHORUS•CENTRED RADICALS TO VARIOUS ALKENES 3.1 INRODUCTION