Some Aspects of the Chemistry and Toxic Action of Organic Compounds Containing Phosphorous and Fluorine

245 Pages·3.405 MB·English

by  Saunders B.C.

(a)
Hot* *
(*>)
Pupil sizes. Left eye exposed to di-/wpropyl phosphorofluoi idate (0-008 mg./l.
2 min. exposure): (a) 3 hr. after exposure; (b) '24 hr. after exj)osure.
SOME ASPECTS OF THE
CHEMISTRY AND TOXIC ACTION
OF ORGANIC COMPOUNDS
CONTAINING PHOSPHORUS
AND FLUORINE
BY
BERNARD CHARLES SAUNDERS
M.A., PH.D., Sc.D., D.Sc., F.R.I.C.
Fellow and Charles Kingsley Lecturer in
Natural Sciences, Magdalene College,
University Lecturer in Chemistry,
Cambridge
WITH A FOREWORD BY
PROFESSOR SIR ALEXANDER TODD
M.A., D.Sc., LL.D., F.R.S.
Professor of Organic Chemistry,
Cambridge
CAMBRIDGE
AT THE UNIVERSITY PRESS
1957
63092
PUBLISHED BY
THE SYNDICS OF THE CAMBRIDGE UNIVERSITY PRESS
Bentley House, 200 Euston Road, London, N.W. I
American Branch: 32 East 57th Street, New York 22, N.Y.
By the same author
NOTES ON QUALITATIVE ANALYSIS
Printed in Great Britain at the University Press, Cambridge
(Brooke Crutchley, University Printer)
CONTENTS
FOBEWORD page xiii
PREFACE xv
CHAPTER I. INTRODUCTION AND GENERAL SURVEY 1
Phosphorofluoridates 1
Production on a technical scale 6
Phosphorodiamidic fluorides 7
Fluoroacetates 10
2-Fluoroethyl fluoroacetate 12
Other compounds 15
Fluoro-aspirin, £>. 15. Di-2-nuoroethylphosphoronuorid-
ate, p. 15. Triethyl-lead fluoroacetate, p. 16. 'Sesqui-
fluoro-H', p. 16. Fluorine-containing ammonium salts,
p. M
Particular applications 18
CHAPTER II. NOMENCLATURE OF ESTERS CON-
TAINING PHOSPHORUS 21
Early nomenclature 21
Notes 23
Accepted nomenclature 25
Notes on the agreed system for compounds con-
taining only one phosphorus atom 27
CHAPTER III. NOTES ON THE MAMMALIAN NER-
VOUS SYSTEM 28
The transmission of nervous effects 28
The autonomic nervous system 31
The sympathetic nervous system, p. 31. The para-
sympathetic nervous system, p. 33. The physiology of
the autonomic nervous system, p. 33. Diagrammatic
representation of acetylcholine action, p. 36
CONTENTS
The eye page 37
Accommodation, p. 38. Intraocular pressure, p. 39
Autonomic inhibitor drugs 40
Spasmolytics, p. 40. Sympatholytics, p. 41.
CHAPTER IV. THE PHOSPHOROFLUORIDATES 42
Synthetic methods 43
Preparation of di-isopropyl phosphorofluoridate
(D.F.P.) 46
Some properties of D.F.P. 47
Hydrolysis of D.F.P. by alkali, p. 48. Hydrolysis by
N/2 sodium hydroxide at room temperature, p. 48.
Hydrolysis of D.F.P. by water, p. 49. D.F.P. and
mustard gas, p. 49
Preparation of esters of phosphorofluoridic acid by
means of phosphorus oxydichlorofluoride 50
Phosphorus oxydichlorofluoride 54
Apparatus, p. 54. Procedure, p. 55. Diethyl phos-
phorofluoridate, p. 55. Di-^sopropyl phosphorofluorid-
ate, p. 55. Diq/cZohexyl phosphorofluoridate, p. 56
Alternative 'one-stage' process for the preparation of
esters of phosphorofluoridic acid 56
Di-^sopropyl phosphorochloridate, p. 57. Esters of
phosphorofluoridic acid, p. 57. (i) General procedure,
p. 58. (ii) Dici/cfohexyl phosphorofluoridate, p. 58
Anticholinesterases 59
Inhibition of cholinesterase by D.F.P. 61
Results, p. 62
Inhibition of cholinesterase by D.F.P.: alternative
technique 62
Poisons, p. 63. Results, p. 63. Reversibility, p. 64.
Effect of substrate concentration, p. 64. True and
pseudo-cholinesterase, p. 66. Assessment of inhibitory
power, p. 66
vi
CONTENTS
Toxic effects of D.F.P. page 68
Detailed pharmacological studies 70
Effect on the eye, p. 72. Further observations, p. 73
Enzymic destruction of D.F.P. 74
Radioactive D.F.P. 75
Apparatus, p. 76. Preparation of phosphorus tri-
chloride, p. 76. Di-^sopropyl phosphorofluoridate,
p. 77. Results, p. 77
Reaction of esterases with radioactive di-isopropyl
phosphorofluoridate 78
Structural requirements for high toxicity and myotic
action of esters of phosphorofluoridic acid 79
Discussion, p. 81
Other compounds related to the phosphorofluoridates 82
Dialkyl phosphorofluoridites 85
CHAPTER V. I. PHOSPHORODIAMIC FLUORIDES.
II. TABUN AND SARIN 87
I. Phosphorodiamic fluorides 87
Alkyl phosphoramidofluoridates 90
II. Tabun 91
Sarin 92
CHAPTER VI. SELECTED REACTIONS or ESTERS
CONTAINING PHOSPHORUS 95
The Arbusov reaction 95
Formation of esters of phosphorous and phosphoric
acids 98
Anhydrides 100
Alkylation by means of phosphorus-containing esters 100
Some further reactions of phosphorus trichloride 101
The interaction of phosphorus pentachloride and
alcohols 102
vii
CONTENTS
Esters of metaphosphoric acid page 103
Esters of pyrophosphoric acid 103
Methods of phosphorylation 106
Dialkyl phosphoroiodidates 108
Dialkyl phosphorobromidates 108
Preparation of alkyl- and acylphosphonic acids 108
Carbon-phosphorus bonds 109
Polyphosphorus compounds 111
CHAPTER VII. THE FLUOROACETATES 114
Methyl fluoroacetate (M.F.A.) and related compounds 114
2-Fluoroethanol (F.E.A.) and its derivatives 122
Fluoroacetamide and related compounds 125
2-Fluoroethyl fluoroacetate and related compounds 129
2:2'-Difluorodiethyl ethylene dithioglycol 130
Fluorine-containing ammonium salts 131
Relationship between physiological action and chemi-
cal constitution in the fluoroacetate series 133
More detailed consideration of toxic action of f fluoro-
acetates3 136
Action of sodium fluoroacetate on enzymes 139
Cause of fluoroacetate poisoning 140
Naturally occurring potassium fluoroacetate 145
Stability of the C—F link 146
Enzymic rupture of a C—F bond 148
CHAPTER VIII. OTHER COMPOUNDS CONTAINING
THE C—F LINK 149
w-Fluorocarboxylic acids and derivatives 149
Synthetic methods employed in this series of
compounds 155
viii
CONTENTS
Further evidence for the /?-oxidation of w-fluoro-
carboxylic acids in vivo page 157
Synthetic methods, p. 158
w-Fluorocarboxylic acids and derivatives containing
an oxygen atom as a chain member 160
Pharmacological examination 162
Other examples of alternating toxicities 163
Antagonisms of 6>-fluorocarboxylic acids 165
Fluorocarbons 168
Fluorochlorocarbons, p. 169
CHAPTER IX. INSECTICIDES 170
Systemic insecticides 170
Octamethylpyrophosphoramide (O.M.P.A.) 172
Oxidation of O.M.P.A. 173
Radioactive O.M.P.A. 175
Tetramethylphosphorodiamidic fluoride 177
Diethyl ^-nitrophenyl phosphate (paroxan) 177
OO'-Diethyl 0"-p-nitrophenyl phosphorothionate
(parathion) 178
Systox 179
00'-Diethyl-$-/?-diethylaminoethyl phosphorothiolate 180
Tetraethyl pyrophosphate (T.E.P.P.) 181
Sodium fluoroacetate 182
Comparison of the action of organo-phosphorus com-
pounds on mammals and insects 183
Organo-phosphorus compounds and fly control, p. 185
CHAPTER X. ESTERASE ACTIVITY AND MEDICAL
ASPECTS 186
Further consideration of esterase activity 186
Structural requirements for anticholinesterase
activity 187
ix
CONTENTS
Theoretical considerations page 188
Active centre in chymotrypsin 193
An irreversible cholinesterase inhibitor in white
clover 193
Anticholinesterases containing quaternary N groups 194
Medical aspects of D.F.P. and related compounds 195
The use of D.F.P. in post-operative paralytic ileus 196
D.F.P. and my asthenia gravis 197
Protection in vitro of cholinesterase against organo-
phosphorus compounds 198
Protection against benzoylcholine by the injection of
pseudo-cholinesterase 199
Demyelination of nerve fibres 199
Permeability of nerve fibres 200
D.F.P. and cell growth 200
Cholinesterase in the retina 201
Organic phosphates as radiosensitizers in the radio-
therapy of malignant tumours 202
EPILOGUE 203
APPENDICES
A. DETERMINATION or FLUORINE IN ORGANIC
COMPOUNDS 205
Determination of fluorine in phosphorofluoridates 206
Breakdown of the phosphorofluoridate 206
The lead chlorofluoride method 207
Specimen determination of fluorine in di-^sopropyl
phosphorofluoridate 207
Determination of fluorine in fluoroacetates 208
Fluoroacetamide standard 208
Specimen determination of fluorine in methyl fluoro-
acetate by fusion with sodium 209
Standardization of the 'sodium peroxide bomb'
method with pure fluoroacetamide 210
CONTENTS
Fluorine determination of radioactive D.F.P. by
thorium nitrate page 210
Reagents 210
Method 211
Standardization of thorium nitrate solution using
A.R. sodium fluoride 211
Standardization, p. 211. Results, p. 211
Determination of fluorine in D.F.P. 211
Method, p. 211. Results with a sample of radioactive
D.F.P., p. 215
B. TABLE OF PROPERTIES OF TYPICAL FLUORO
COMPOUNDS 212-13
C. FIRST-AID TREATMENT FOR NERVE-GAS
POISONING 215
GENERAL BIBLIOGRAPHY 216
INDEX 219
XI