Synthetic Pyrethroids Michael Elliott, EDITOR Rothamsted Experimental Station
A symposium sponsored by the Division of Pesticide Chemistry at the 172nd Meeting of the American Chemical Society, San Francisco, Calif., Aug 3 0 - 3 1 ,
1976.
ACS SYMPOSIUM SERIES 42
AMERICAN
CHEMICAL
SOCIETY
WASHINGTON, D. C. 1977
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
Library of Congress CIP Data Synthetic pyrethroids. (ACS symposium series; 42 ISSN 0097-6156) Bibliography: p. Includes index. 1. Pyrethroids—Congresses. 2. Insecticides—Congresses. 3. Chemistry, Organic—Synthesis—Congresses. I. Elliott, Michael, 1924II. Series: American Chemical Society. ACS symposium series; 42. SB952.P88S96 ISBN 0-8412-0368-7
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632'.951
77-1810
1977
American Chemical Society All Rights Reserved. N o part of this book may be reproduced or transmitted in any form or by any means—graphic, electronic, including photocopying, recording, taping, or information storage and retrieval systems—without written permission from the American Chemical Society. PRINTED IN THE UNITED STATES OF AMERICA
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
ACS Symposium Series R o b e r t F . G o u l d , Editor
Advisory Board D o n a l d G . Crosby Jeremiah P. Freeman E. Desmond Goddard Robert A . Hofstader J o h n L . Margrave N i n a I. M c C l e l l a n d J o h n B . Pfeiffer Joseph V . Rodricks Alan C. Sartorelli Raymond B . Seymour Roy L. Whistler Aaron W o l d
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
FOREWORD The A C S S Y M P O S I U
a medium for publishing symposia quickly in book form. The format of the SERIES parallels that of the continuing ADVANCES I N C H E M I S T R Y SERIES except that i n order to save time the papers are not typeset but are reproduced as they are submitted by the authors in camera-ready form. As a further means of saving time, the papers are not edited or reviewed except by the symposium chairman, who becomes editor of the book. Papers published in the A C S S Y M P O S I U M SERIES are original contributions not published elsewhere in whole or major part and include reports of research as well as reviews since symposia may embrace both types of presentation.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
PREFACE The
valuable insecticidal properties of pyrethrum were recognized i n the 19th century and stimulated detailed examination of the chemical constitution of the active esters i n the first quarter of the 20th century. Although the acidic components of the esters were correctly identified at an early stage i n these studies, only i n 1947 were the structures of the alcohols settled. The first synthetic pyrethroid, allethrin—still important today—was developed soon afterwards. B y 1968, tetramethrin, a good knockdown agent, and resmethrin and bioresmethrin, the first synthetic compounds with greate toxicity than the natural esters, had been discovered. These compounds did not greatly extend the range of application of pyrethroids for, like the natural compounds, they were unstable. Investigation of structureactivity relationships continued, and by 1973 compounds had been developed which were more photostable yet retained many of the favorable characteristics of the natural esters and earlier synthetic compounds. The new materials are now being critically assessed to establish those applications where their special combination of properties may be especially advantageous; in some instances, they may replace existing insecticides which have properties no longer considered acceptable. The structures of pyrethroids are more complex than those of other major classes of insecticides, and they are relatively expensive to manufacture; however, their greater insecticidal activity, permitting fewer applications of lower doses, may give an advantage over present compounds, especially when persistent residues i n the environment must be avoided. Further, industrial processes have been developed by which the most active optical and geometrical isomers of some pyrethroids could be prepared on a multi-ton scale—an outstanding achievement of modern chemical technology. The introductory paper on "Synthetic Pyrethroids" reviews the compounds now available from an historical viewpoint and traces development of our understanding of relationships between chemical structure and insecticidal activity, photostability and mammalian toxicity. The general implications of the discovery of more stable compounds, which may be considered to constitute a new group of insecticides, are important themes of this collection of papers. Pyrethroids are flexible molecules and their conformations probably greatly influence their insecticidal activity. In the first paper, preferred vii
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
conformations are calculated solely on the basis of non-bonded interactions and considered i n relation to the conformations i n the solid state and to biological results. The next papers consider the effects of modifying the acidic and alcoholic components of pyrethroids; nearly a l l the new compounds are less active than the parent esters on which they are based. These results and other work reviewed i n the book show the difficulty of discovering new acidic and alcoholic components of synthetic pyrethroids with the combination of properties necessary to justify commercial development. The most promising examples so far are 3-phenoxybenzyl and a-cyano-3-phenoxybenzyl alcohols and the optical and geometrical isomers of 3-(2,2-dihalovinyl)-2,2-dimethylcyclopropanecarboxylic acids and a-(4-chlorophenyl) isovaleric acid. M u c h of the volume therefore describes syntheses, the biological properties, metabolism, and analysis of esters formed from combination of these components. Although recognized which pyrethroids act remains obscure; however, investigations described here on the housefly nervous system and on the crayfish abdominal nerve cord disclose many significant results. The observation that some compounds which are potent insecticides have relatively weak action on the nervous system of crayfish compared with closely related esters which are much less active insecticidally may have important implications. The final group of papers deals with factors concerning the practical application of pyrethroids. Although there is now abundant evidence that pyrethroids with appropriate structures are sufficiently stable to control agricultural pests, it is important to establish precisely how long they persist and the nature and toxicity of their metabolites i n various environments. The results so far indicate that although some of the newer compounds are relatively photostable, they are readily metabolized by organisms which have esteratic or oxidative mechanisms to non-toxic products which do not accumulate i n mammalian systems. The papers presented thus span the many rapidly advancing aspects of pyrethroid studies and indicate that some of the newer pyrethroids discussed may make valuable, practical contributions to insect control within a short time. The symposium "Synthetic Pyrethroids: Recent Advances" arranged by the Division of Pesticide Chemistry of the American Chemical Society at the 1976 Autumn meeting i n San Francisco was therefore particularly opportune. It was complemented by a meeting of the Pesticides Group of the Society of the Chemical Industry i n London i n November 1976 on "Newer Applications of Pyrethroids."* The Division of Pesticide Chemistry chose to honor me at this time w i t h the Burdick and Jackson International A w a r d for Pesticide Chem* Pestic. Sci. (1977) 8 (in press). viii
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
istry. I am conscious of the prestige of the A w a r d , and it is noteworthy that the Division should make this characteristically warm and generous gesture to a British chemist i n the 100th year of the American Chemical Society and at the time of the Bicentennial celebrations of the Declaration of American Independence. It is also appropriate to recognize and to acknowledge the broad base of international research on which the work of my colleagues and myself rests and into which it is integrated. The A w a r d having been given for work on pyrethroid insecticides, it is fitting to recall the wisdom which led F . B. LaForge i n the United States and Frederick Tattersfield and Charles Potter, successive heads of the Insecticides and Fungicides Department, Rothamsted Experimental Station, to continue to investigate the insecticidal action and chemical properties of pyrethrum. Potter at Rothamsted and Stanley Harper at the Universities of Southampton and London discerned the long-term advantages of continuin persistent insecticides with low mammalian toxicity even when immediate applications appeared limited by the development of major groups of synthetic insecticides. I owe a considerable debt to Stanley Harper and Charles Potter for help and support over a long period and more recently to Norman Janes, whose scientific and personal cooperation has been of rare and outstanding quality. D a v i d Pulman has contributed greatly to our work by his skill and perseverance. W e thank Roman Sawicki, Paul Needham, and Andrew Farnham for many bioassay results, essential to our progress, and many other colleagues for valuable help and discussions. Harpenden, Herts., England December 1976
MICHAEL ELLIOTT
ix
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
INTRODUCTION The following remarks are those of Professor Ryo Yamamoto, Professor Emeritus of the Tokyo University of Agriculture. He represents the many Japanese chemists who have made distinguished contributions to the knowledge of natural and synthetic pyrethroids. Professor Yamamoto was investigating the structure of the pyrethrins in Japan during the period when Staudinger and Ruzicka were working in Switzerland.
It is an honor and a great pleasure for me to introduce D r . Elliott's award collection "Synthetic Pyrethroids" and to offer my congratulations. I am an old chemist. It was 1923 when I first derived frans-caronic acid from the natural pyrethrins and demonstrated the presence of the cyclopropane structure in the chrysanthemic acid moiety i n Tokyo. N o w in 1976, I am an active member of Pesticide Science Society of Japan and still interested particularly in the science of pyrethroids. I am deeply impressed by the development of pyrethroid chemistry: from structural assignment of natural pyrethrins to recent developments of synthetic pyrethroids. These are all puzzling, and I can hear the early rumblings of what may become "Pyrethroid Age." I am very pleased to learn that permethrin by D r . Elliott and S-5602 by the Sumitomo group are particularly promising for agricultural uses and those interested i n pyrethroids are developing newer and newer ideas. Further development of pyrethroids w i l l be accelerated not only by studying the chemistry but also by elucidating the biological aspects, particularly the mode of action. Here is a wonderful area of research and development for all. San Francisco, Calif. August 1976
RYO YAMAMOTO
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In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
1 Synthetic Pyrethroids MICHAEL
ELLIOTT
Rothamsted Experiment Station, Harpenden, Hertfordshire, A L 5 2JQ, England
I n s e c t i c i d e s w i t h a range o f physical, chemical and biological propertie as p r e s e n t methods o f c r o p p r o t e c t i o n c o n t i n u e and until d i s e a s e s t r a n s m i t t e d by i n s e c t s no l o n g e r a f f e c t man and his livestock. I d e a l l y , b o t h e s t a b l i s h e d and new p r o d u c t s will be used efficiently (1,2) in rational ly c o n c e i v e d p e s t management schemes, (3,4) i n some cases complemented by new approaches t o i n s e c t control. (5,6,7,8). M i l l i o n s o f human b e i n g s owe their freedom from s t a r v a t i o n and p r o t e c t i o n from d i s e a s e t o insecti cides. N e v e r t h e l e s s , t h e p r e s e n t range o f compounds is i n a d e q u a t e because r e s i s t a n t i n s e c t s p e c i e s have emerged t o d i m i n i s h their e f f e c t i v e n e s s f o r some appli cations, because t h e y have been judged u n d u l y persis tent o r e x c e s s i v e l y t o x i c t o men and mammals o r because they a r e n o t sufficiently selective between p e s t s and beneficial insects. New insecticides with superior p r o p e r t i e s are needed; t o i n d i c a t e what improvements might be p o s s i b l e some o f the p h y s i c a l and biological p r o p e r t i e s o f the c l a s s e s o f insecticides at present available will first be r e v i e w e d . Table I - Properties of Classes of I n s e c t i c i d e s Approximate Solu bility i n water, p.p.m.
Systemic Action
> 40
+ and -
>
1
+ and -
to
<
1
4 to 9
<
1
Polarity, Log P*
Class Carbamates
-1 t o 3
Organophosphates
1 to
Organochlorines
5.5 7
Pyrethroids
* Ρ = Octanol-water
5.5
R
partition
coefficient
1
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
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2
SYNTHETIC PYRETHROIDS
T a b l e 1 shows t h a t most carbamates {9) and many organophosphates (10) a r e r e l a t i v e l y p o l a r , w a t e r - s o l u b l e compounds, a number o f which have u s e f u l s y s t e m i c and translaminar properties. In c o n t r a s t , most organoc h l o r i n e i n s e c t i c i d e s a r e n o n - p o l a r , s t a b l e and t h e r e f o r e r e l a t i v e l y p e r s i s t e n t compounds (11.,L2) . The n a t u r a l p y r e t h r i n s ( ] ^ , 1^,3^,15,16^,17,18,19) and a l l t h e s y n t h e t i c p y r e t h r o i d s used a t p r e s e n t a r e a l s o nonp o l a r compounds, as i n d i c a t e d by t h e i r o c t a n o l - w a t e r p a r t i t i o n c o e f f i c i e n t s (20,21), and have v e r y s m a l l s o l u b i l i t y i n water. They a l s o , t h e r e f o r e , have no systemic o r translaminar p r o p e r t i e s . Unlike the o r g a n o c h l o r i n e compounds, however, they a r e u n s t a b l e and n o n - p e r s i s t e n t , r e s t r i c t e d i n t h e i r a p p l i c a t i o n s by t h e s e c h a r a c t e r i s t i c s and because they a r e more com p l e x and more e x p e n s i v groups o f i n s e c t i c i d e s b i n e , as f a r as p o s s i b l e , t h e most v a l u a b l e p r o p e r t i e s o f t h e s e groups. Table I I - T o x i c i t i e s of Classes of I n s e c t i c i d e s to I n s e c t s and Mammals^ Class
Rats
Carbamate Organophosphate Organochlorine Pyrethroid
b
Insects
c
1
Ratio 1
45 mg.kg" (15) 2.8 mg.kg"" (27) 67 "
11
16
(83)
2.0 "
"
(50)
33 91
230 "
"
(21)
2.6 "
"
(26)
2000 "
"
(11) 0.45"
"
(35) 4500
^Geometric means o f no. o f d a t a items i n b r a c k e t s From p u b l i s h e d acute o r a l LD50 v a l u e s F r o m p u b l i s h e d v a l u e s , p r i n c i p a l l y t o 4 s p e c i e s , by topical application. C
S i m p l i f i e d b i o l o g i c a l d a t a f o r t h e f o u r groups o f i n s e c t i c i d e s i n T a b l e I I demonstrate a r e l a t i v e advan tage f o r p y r e t h r o i d s . The l e v e l o f i n s e c t i c i d a l a c t i v i t y a t t a i n a b l e w i t h carbamates, organophosphates and o r g a n o c h l o r i n e compounds i s remarkably s i m i l a r (22,22) ^ a p a r t from a few s p e c i a l cases (2Λ) i n t e n s i v e r e s e a r c h o v e r t h r e e decades (25) has f a i l e d t o d i s c o v e r a c c e p t a b l e compounds i n these c a t e g o r i e s w i t h g e n e r a l l y g r e a t e r p o t e n c y t o a wide range o f s p e c i e s . In c o n t r a s t , i n v e s t i g a t i o n o f p y r e t h r o i d s d u r i n g t h e same p e r i o d , w i t h much s m a l l e r t o t a l r e s e a r c h e f f o r t , has r e v e a l e d compounds w i t h p r o g r e s s i v e l y i n c r e a s i n g a c t i v i t y , up t o f o u r o r f i v e times h i g h e r than t h a t o f the o t h e r c l a s s e s t o most i n s e c t s p e c i e s (26). a n c
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
1.
ELLIOTT
Synthetic Pyrethroids
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R e l a t i v e s a f e t y i s i n d i c a t e d by t h e r a t i o o f t o x i c i t i e s t o r a t and i n s e c t (Table I I , column 4 ) . In t h i s r e s p e c t p y r e t h r o i d s are a l s o c l e a r l y s u p e r i o r , because they a r e both v e r y a c t i v e a g a i n s t i n s e c t s and r e l a t i v e l y n o n - t o x i c t o mammals. The scope f o r s t r u c t u r a l v a r i a t i o n i n p y r e t h r o i d s and the r e s t r i c t e d a t t e n t i o n g i v e n t o them suggest t h a t d e t a i l e d knowledge o f t h e c h e m i c a l and biochemical b a s i s f o r t h e i r i n s e c t i c i d a l a c t i o n might show how r e l a t e d compounds w i t h improved p r o p e r t i e s c o u l d be d i s covered. T h e r e f o r e p r o g r e s s i n r e s e a r c h and d e v e l o p ment i n t h i s c h a l l e n g i n g a r e a i s r e v i e w e d i n t h i s and subsequent c o n t r i b u t i o n s t o the symposium. Structure
and
Activit
The e v o l u t i o n o f s y n t h e t i c p y r e t h r o i d s can be a s s e s s e d a p p r o p r i a t e l y by r e l a t i n g t h e i r a c t i v i t y t o t h a t o f p y r e t h r i n I which has an LD50 o f 0.33ug per female h o u s e - f l y (27) and p r o v i d e s a c o n v e n i e n t p r o t o t y p e and s t a n d a r d . In the f i g u r e s i n t h i s p a p e r , s u c c e s s i v e f i l l e d boxes show t e n f o l d changes i n a c t i v i t y r e l a t i v e t o p y r e t h r i n I , compounds l e s s a c t i v e b e i n g on the l e f t o f the arrow and t h o s e t e n , one hundr e d and one thousand t i m e s more a c t i v e than t h i s s t a n d a r d t o the r i g h t . Thus p y r e t h r i n I I , which w i t h pyr e t h r i n I i s t h e most i m p o r t a n t c o n s t i t u e n t o f n a t u r a l pyrethrum (18^19/28) and d e c a m e t h r i n , w i t h LD50 v a l u e s per h o u s e - f l y o f 0.20ug (.29) and 0.0003ug (30), respect i v e l y a r e r e p r e s e n t e d as shown i n F i g u r e 1. The s t r u c t u r e s o f p y r e t h r i n I ( e s p e c i a l l y e f f e c t i v e f o r k i l l (_31) ) , o f p y r e t h r i n I I (a good knockdown agent) and o f d e c a m e t h r i n i l l u s t r a t e f e a t u r e s r e q u i r e d f o r h i g h e s t a c t i v i t y i n t h i s group o f i n s e c t i cides. A l l t h r e e compounds are c y c l o p r o p a n e c a r b o x y l i c a c i d e s t e r s w i t h two methyl groups on C-2 and an u n s a t u r a t e d s i d e c h a i n on C-3, t r a n s t o the c a r b o x y l group i n the n a t u r a l e s t e r s , c i s i n the s y n t h e t i c compound. The r e l a t i v e d i s p o s i t i o n i n space o f s u b s t i t u e n t s a t the c a r b o x y l i c a c i d c e n t r e , C - l , i s i m p o r t ant, compounds o f the o p p o s i t e s t e r e o c h e m i c a l configur a t i o n , ( S ) , b e i n g much l e s s a c t i v e (32); (a nomenc l a t u r e a p p r o p r i a t e f o r t h i s s e r i e s i s d i s c u s s e d by E l l i o t t e t a l . , (_33) ) . The a c i d i n each e s t e r i s combined w i t h a secondary a l c o h o l o f which the h y d r o x y l group i s e i t h e r p a r t o f a n e a r l y p l a n a r c y c l o p e n t e n o l o n e r i n g (34) as i n p y r e t h r i n s I and I I o r i s a t t a c h e d t h r o u g h a t e t r a h e d r a l carbon atom t o an aromatic r i n g . A centre of u n s a t u r a t i o n ( c i s - b u t a d i e n y l , or phenyl) i s l i n k e d v i a a methylene o r
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
SYNTHETIC PYRETHROIDS
4
Figure 1.
The natural pyrethrins compared with a synthetic ester
oxygen b r i d g e and a 3 o r 4 carbon s p a c i n g u n i t t o t h e c h i r a l c e n t r e which b e a r s t h e hydroxy1 group. From t h e i r work i n t h e y e a r s 1910-1916 ( p u b l i s h e d i n 1924 (35)) i t i s c l e a r t h a t S t a u d i n g e r and R u z i c k a , who, l i k e R. Yamamoto (_36,31_,38), were eminent p i o n e e r s o f pyrethrum c h e m i s t r y , r e c o g n i s e d many o f t h e f e a t u r e s i n the s t r u c t u r e s o f pyrethroids necessary f o r i n s e c t i cidal activity. They knew t h a t t h e c o n s t i t u e n t a l c o h o l s and a c i d s were o n l y a c t i v e when combined w i t h one a n o t h e r , and t h a t an i n t a c t e s t e r - l i n k a g e was i m p o r t ant. The gem-dimethyl group on t h e c y c l o p r o p a n e r i n g was r e q u i r e d and a c t i v i t y d i m i n i s h e d by s a t u r a t i n g t h e s i d e c h a i n s i n a c i d i c and a l c o h o l i c components. S t a u d i n g e r and R u z i c k a d e t e c t e d i n s e c t i c i d a l a c t i v i t y i n t h e chrysanthemate o f t h e c y c l o p e n t e n o l o n e (Figure 2) which had an a l l y l r a t h e r t h a n a p e n t a d i e n y l s i d e chain. T h i s concept o f a s h o r t e r unsaturated s i d e c h a i n was l a t e r used by S c h e c h t e r , Green and L a Forge (39^,40,41,42) when they d e v e l o p e d a l l e t h r i n , t h e f i r s t important s y n t h e t i c p y r e t h r o i d . Dienic unsaturation i n t h e a l c o h o l i c s i d e c h a i n was t h e r e f o r e n o t n e c e s s a r y to a t t a i n a p r a c t i c a l l e v e l of i n s e c t i c i d a l a c t i v i t y . S t a u d i n g e r and R u z i c k a a l s o d e t e c t e d i n s e c t i c i d a l a c t i v i t y i n e s t e r s o f p i p e r o n y l a l c o h o l ( F i g u r e 2) (as
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
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5
l a t e r d i d Synerholm (£3)) and 4 - i s o p r o p y l b e n z y l (cumin y l ) a l c o h o l , foreshadowing t h e important s e r i e s o f b e n z y l e s t e r s such as t h o s e o f 3-phenoxybenzyl a l c o h o l (31,44) i n modern p y r e t h r o i d s . They f u r t h e r examined compounds i n c o r p o r a t i n g open c h a i n e q u i v a l e n t s o f cyclopropane carboxylates, envisaging i n p r i n c i p l e the n o n - c y c l i c compounds which Ohno and h i s co-workers i n 1974 (£5,4j>) demonstrated t o be i m p o r t a n t i n s e c t i cides; t h e gem-dimethyl group o f t h e c y c l o p r o p a n e was r e t a i n e d as i s o p r o p y l , w i t h an u n s a t u r a t e d c e n t r e p l a c e d on t h e <*-carbon atom o f t h e a c i d . Development o f t h e r e l a t i v e l y complex b a s i c c h e m i s t r y o f t h e n a t u r a l p y r e t h r i n s and r e l a t e d s y n t h e t i c compounds was g r e a t l y a s s i s t e d by s p e c t r o s c o p i c methods, u l t r a v i o l e t (£7,£8) and i n f r a r e d i n i t i a l l y (49) and more r e c e n t l and mass s p e c t r o m e t r i techniques i n v e s t i g a t i o n of the viscous, unstable, h i g h - b o i l i n g l i q u i d s and t h e i r i s o m e r i z a t i o n (j>2,j[3,S4) and degradat i o n p r o d u c t s (55) was r e l a t i v e l y d i f f i c u l t . Until
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
6
SYNTHETIC PYRETHROIDS
t e n y e a r s ago o n l y one s y n t h e t i c p y r e t h r o i d , a l l e t h r i n , was s i g n i f i c a n t i n p r a c t i c e , b u t s i n c e then p r o g r e s s i n d e v e l o p i n g new compounds has been r a p i d , and, as t h e b a s i s f o r f u r t h e r d i s c u s s i o n , a c t i v e compounds now a v a i l a b l e w i l l be r e v i e w e d .
S - B i o a l l e t h r i n (56), F i g u r e 3, has a l l t h e s t r u c t u r a l f e a t u r e s o f n a t u r a l p y r e t h r i n I , except t h a t an a l l y l s i d e c h a i n r e p l a c e s t h e c i s - p e n t a d i e n y l system. I t i s more p o l a r (20) than p y r e t h r i n I w i t h f a s t e r knockdown b u t p o o r e r k i l l i n g power t o most i n s e c t s except h o u s e - f l i e s (3^/5^7) . E a r l y b i o a s s a y s overemphas i s e d t h e p o t e n c y o f a l l e t h r i n because f r e q u e n t l y t h e y were c o n f i n e d t o h o u s e - f l i e s and e v a l u a t e d m a i n l y t h e knockdown r e s p o n s e ; the subtle differences i n basic s t r u c t u r e needed f o r r a p i d knockdown on t h e one hand and h i g h k i l l on t h e o t h e r were n o t r e c o g n i s e d (20). The o u t s t a n d i n g potency o f p y r e t h r i n I a g a i n s t many i n s e c t s p e c i e s was o v e r l o o k e d u n t i l i t was o b t a i n e d pure (55) and u n d i l u t e d by l e s s a c t i v e components (28_) .
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
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Continued i n v e s t i g a t i o n of the s t r u c t u r a l r e q u i r e ments f o r h i g h i n s e c t i c i d a l a c t i v i t y i n p y r e t h r o i d s l e d t o t h e compound b i o r e s m e t h r i n ( 5 8 , 5 9 0 ( F i g u r e 3 ) , i n which the c y c l o p e n t e n o l o n e n u c l e u s has been r e p l a c e d by the s t e r i c a l l y e q u i v a l e n t f u r a n r i n g , and t h e u n s a t u r a t e d a l k e n y l s i d e c h a i n by an a r o m a t i c n u c l e u s . Bio r e s m e t h r i n was the f i r s t s y n t h e t i c p y r e t h r o i d t o show e q u a l o r h i g h e r k i l l i n g a c t i v i t y than the n a t u r a l com pounds a g a i n s t many i n s e c t s p e c i e s ( 2 6 ^ 3 J i ' _ 5 8 ) and, a welcome p r o p e r t y u n a n t i c i p a t e d d u r i n g the d e v e l o p m e n t a l work, lower mammalian t o x i c i t y ( 6 0 ) . With the same f u r a n a l c o h o l , but the more l i p o p h i l i c e t h a n o c h r y s a n t h e m i c a c i d i n the compound KO t h r i n (R/U 1 1 , 6 7 9 ) ( 6 _ 1 , 6 2 , 6 κ 3 ) M a r t e l and co-workers i n c r e a s e d i n s e c t i c i d a l a c t i v i t y s t i l l more ( 3 1 ) a l t h o u g h at t h e expens Insecticidal activit was r a i s e d even more by a n o t h e r m o d i f i c a t i o n at t h e same s i t e i n t h e m o l e c u l e : substituting chlorine for the m e t h y l groups i n the i s o b u t e n y l s i d e c h a i n ( 6 4 , 6 5 , 66). T h i s t r a n s f o r m a t i o n a l s o had t h e i m p o r t a n t con sequence o f e l i m i n a t i n g t h e p r i n c i p a l p h o t o s e n s i t i v e c e n t r e i n the a c i d (6J7,68[) . Correspondingly, replac i n g the p h o t o l a b i l e 5 - b e n z y l - 3 - f u r y l m e t h y l u n i t o r o t h e r p r e v i o u s a l c o h o l s w i t h 3-phenoxybenzyl gave t h e compound b i o p e r m e t h r i n (61) the f i r s t s y n t h e t i c p y r e t h r o i d w i t h adequate s t a b i l i t y f o r f i e l d use. Insec t i c i d a l a c t i v i t y i s m a i n t a i n e d on a l e a f s u r f a c e f o r two weeks o r more i n b r i g h t s u n l i g h t , w i t h o u t u n d u l y l o n g p e r s i s t e n c e i n the s o i l (.69 , 7 0 ) . Biopermethrin a l s o r e t a i n e d the low o r a l and i n t r a v e n o u s mammalian t o x i c i t y o f the u n s t a b l e s y n t h e t i c p y r e t h r o i d s ( 6 J 7 , 7 1 ) * C o n f o r m a t i o n and A c t i v i t y o f
Pyrethroids
The n a t u r a l p y r e t h r i n s and t h e s y n t h e t i c com pounds j u s t r e v i e w e d a r e a l l f l e x i b l e m o l e c u l e s . In the l i g h t o f p r e s e n t knowledge t h e i r i n s e c t i c i d a l a c t i o n i s b e s t i n t e r p r e t e d as an a b i l i t y t o adopt a c o n f o r m a t i o n i n which a l l t h e s t r u c t u r a l f e a t u r e s e s s e n t i a l f o r potency a r e a p p r o p r i a t e l y o r i e n t e d w i t h r e s p e c t t o each o t h e r and t o a complementary r e c e p t o r . A c h a r a c t e r i s t i c o f p y r e t h r o i d s i s the s e n s i t i v i t y o f t h e i r i n s e c t i c i d a l a c t i o n t o changes i n s u b s t i t u e n t s a t c e r t a i n i m p o r t a n t c e n t r e s by which e i t h e r the b a l a n c e o f conformers p r e s e n t i s d i s t u r b e d , o r c o n t a c t of the molecule with a r e c e p t o r i s o b s t r u c t e d . V a l u a b l e i n d i c a t i o n s o f t h e c h a r a c t e r i s t i c s o f the r e c e p t o r and c o n f o r m a t i o n s needed f o r optimum i n s e c t i c i d a l a c t i v i t y can be g a i n e d by the f o l l o w i n g d e t a i l e d
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
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SYNTHETIC PYRETHROIDS
examination of the s e n s i t i v e p o s i t i o n s i n the molecule. One such i m p o r t a n t s i t e i s the c h i r a l c e n t r e i n t h e a c i d component t o which the c a r b o x y l group i s attached (Figure 4). E s t e r s o f cyclopropane carboxyl i c a c i d w i t h s u b s t i t u e n t s i n t h e (R) c o n f i g u r a t i o n shown, whether t h e s i d e c h a i n i s t r a n s o r c i s t o t h e c a r b o x y l group, are a c t i v e , whereas e s t e r s o f t h e (S) epimers a r e i n a c t i v e , o r much l e s s a c t i v e . Similarly ( S ) - i s o p r o p y l a r y l a c e t a t e s , which c o r r e s p o n d t o ( I R ) chrysanthemates i n t h e i r c h i r a l arrangement o f s u b s t i t u e n t s (45>,£6,12) , are much more a c t i v e t h a n t h e i r (R) epimers. This i s strong evidence that i n t e r a c t i o n w i t h a c h i r a l r e c e p t o r i s i n v o l v e d i n the l e t h a l a c t i o n , s i n c e i n a l l phenomena i n v o l v i n g m i g r a t i o n and p a r t i t i o n , f o r example a t a phase boundary each memb e r o f a p a i r o f isomer
X* H, alkyl ,alkenyl, halo, etc.
Figure 4.
Potency of esters from [R]- and [S]-forms of cyclopropane and phenylacetic acids
The p o t e n c y o f e s t e r s o f cyclopropanecarboxylic a c i d s i s a l s o s e n s i t i v e t o s u b s t i t u t i o n a t o r on the s i d e c h a i n a t C-3. ( F i g u r e 5) . Some compounds w i t h a t r a n s - d i c h l o r o v i n y l s u b s t i t u e n t (see, f o r example,
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
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9
compounds i n F i g u r e 4, χ = C l ) a r e p o w e r f u l i n s e c t i cides. An a d d i t i o n a l m e t h y l s u b s t i t u e n t g r e a t l y diminishes potency; the a c t i v i t y o f a l k e n y l c y c l o p r o p a n e c a r b o x y l a t e s ( F i g u r e 5) (73.*74.) a l s o lowered by a 1-methyl s u b s t i t u e n t . An analogous d e p r e s s i o n o f a c t i v i t y by m e t h y l s u b s t i t u t i o n o c c u r s i n the éC-isop r o p y l a r y l a c e t a t e s o f Ohno e t a l (4S,46j , where o r t h o - s u b s t i t u t e d a r y l compounds are much l e s s a c t i v e . In the t h r e e s e r i e s o f compounds i n F i g u r e 5 t h e added m e t h y l groups are a t s i t e s i n the m o l e c u l e where t h e y may d i s t u r b p r e f e r r e d c o n f o r m a t i o n s , as d i s c u s s e d i n the s u c c e e d i n g paper (74) o r may b l o c k a c c e s s t o an e s s e n t i a l p o s i t i o n on the r e c e p t o r s i t e . i s
Figure 5.
Influence of methyl suhstituents on acid components of various esters
These examples show t h a t the a c i d s i d e c h a i n a t t a c h e d a t C-3 o f the c y c l o p r o p a n e r i n g i s a p o s i t i o n where s t r u c t u r a l changes g r e a t l y i n f l u e n c e i n s e c t i c i d a l activity. In t h e v a r i a t i o n s shown i n F i g u r e 6, a c t i v i t y a g a i n depends on the n a t u r e o f the s u b s t i t u e n t at t h i s s i t e . Thus, i f t h e r e are no m e t h y l groups a t C-3 o r C - l ( c f . F i g u r e 5) e x t r e m e l y h i g h i n s e c t i c i d a l a c t i v i t y i s a t t a i n e d i n e s t e r s w i t h Z- and E-butadienyl and - p e n t a d i e n y l s u b s t i t u e n t s t r a n s , and, t o a s m a l l e r e x t e n t , c i s t o the (1R) c a r b o x y l c e n t r e (33,75). F u r t h e r , some e s t e r s o f 3 - d i h a l o v i n y l s u b s t i t u t e d a c i d s are o u t s t a n d i n g l y p o t e n t i n s e c t i c i d e s (30,^4,6j5) ; i n t h i s s e r i e s , the c i s e s t e r s a r e u s u a l l y more a c t i v e
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
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SYNTHETIC PYRETHROIDS
11
+Z
isomer
I I Γ CI or Br
CI Br
1
CI or Br
CI Br
Figure 6. Side chains of esters of 5benzyl-3-furyl methyl alcohol that are very effective for kill
t h a n t h e t r a n s (66). E s t e r s w i t h oximino e t h e r subs t i t u e n t s a t C-3 are a l s o a c t i v e i n s e c t i c i d e s (76.) . A l t h o u g h r a p i d i t y o f knockdown i s l e s s i m p o r t a n t t h a n a c t i v i t y f o r k i l l i n most a p p l i c a t i o n s , t h i s i s an i n t e r e s t i n g p r o p e r t y a l s o markedly i n f l u e n c e d by m o d i f i c a t i o n s o f the C-3 s u b s t i t u e n t . In F i g u r e 7, r e l a t i v e knockdown e f f i c i e n c y i s i n d i c a t e d r a t h e r t h a n kill. The p y r e t h r a t e r e l a t e d t o b i o r e s m e t h r i n i s a b e t t e r knockdown agent than b i o r e s m e t h r i n i t s e l f (20), w h i l e the d i f l u o r o v i n y l compound (NRDC 173) (6j6) i s even more a c t i v e i n t h i s r e s p e c t . The t h i o l a c t o n e , K a d e t h r i n , R/U 15,52 5 a c t s more r a p i d l y a g a i n s t housef l i e s than any o t h e r compound y e t r e p o r t e d (77). The d e l i c a t e b a l a n c e between s t r u c t u r e and a c t i v i t y i n py r e t h r o i d s i s demonstrated by the f a c t t h a t the r e l a t e d 3-phenoxybenzyl e s t e r (73) almost c o m p l e t e l y l a c k s knockdown a c t i v i t y . In most compounds, as w i t h Kade t h r i n , good knockdown i s o n l y a c h i e v e d a t t h e expense of k i l l i n g a c t i v i t y . However, the d i f l u o r o v i n y l e s t e r ( F i g u r e 7) i s an e x c e p t i o n i n t h i s r e s p e c t , be cause i t combines good knockdown a c t i o n w i t h k i l l i n g power t h r e e t i m e s as g r e a t as t h a t o f b i o r e s m e t h r i n (66,18,79).
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
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Figure 7. Modification of acid side chain for knockdown
Like cyclopropanecarboxylates, the a c t i v i t y of the o c - i s o p r o p y l a r y l a c e t a t e s i n t r o d u c e d r e c e n t l y by Ohno and co-workers (£5,£6) i s v e r y s e n s i t i v e t o s t r u c t u r e and s u b s t i t u t i o n . The d i c h l o r o i s o s t e r e o f t h e i s o p r o p y l compound ( F i g u r e 8, R = 3-phenoxybenzyl o r oC-cyano-3-phenoxybenzyl) i s i n a c t i v e , p o s s i b l y because hydrogen c h l o r i d e i s e l i m i n a t e d e x t r e m e l y r a p i d l y t o give a monochlorolefin lacking the s t r u c t u r a l charact e r i s t i c s f o r i n s e c t i c i d a l action. The i s o s t e r i c amine and carbamate (73) a r e a l s o i n a c t i v e .
Figure 8.
Compounds related to a-isopropylphenyl acetates I
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
SYNTHETIC PYRETHROIDS
12
Ohno e t a l . (45>,_46) a l s o showed t h a t e t h y l s u b s t i t u t e d compounds had i n s e c t i c i d a l a c t i v i t y o n l y s l i g h t l y below t h a t o f t h e i s o p r o p y l d e r i v a t i v e s ( F i g ure 9 ) . However, b o t h t h e r e l a t e d d i e t h y l and monomethoxy compounds shown were i n a c t i v e (7J3) .
R'
R'
OHNO «t al. 1974 Figure 9.
Compounds related to a-isopropylphenyl acetates II
In another s e r i e s o f v a r i a t i o n s examined (73) ( F i g u r e 10) t h e a r o m a t i c c e n t r e was d i s p l a c e d by an oxygen o r methylene b r i d g e t o a p o s i t i o n more r e mote from t h e c h i r a l c e n t r e . The compounds were n o t active. Two f u r t h e r compounds, one a p h e n y l c y c l o p r o pane, t h e o t h e r a t e t r a h y d r o n a p h t h a l e n e i n which t h e i s o p r o p y l group was l o c k e d i n e i t h e r o f two ways were also non-toxic; t h e y show t h a t i n b o t h c y c l o p r o p a n e c a r b o x y l a t e s and i s o p r o p y l a r y l a c e t a t e s a p r e c i s e s t r u c t u r e i n t h e a p p r o p r i a t e c o n f i g u r a t i o n i s needed f o r i n secticidal activity. These a d d i t i o n a l r e s u l t s s u p p o r t the c o n c l u s i o n (4j5) t h a t t h e i n s e c t i c i d a l a c t i v i t y o f b o t h c y c l o p r o p a n e c a r b o x y l a t e s and o < - i s o p r o p y l a r y l a c e t a t e s depends on common s t r u c t u r a l f e a t u r e s . Such examples i l l u s t r a t e how g r e a t l y i n s e c t i c i d a l a c t i v i t y i s i n f l u e n c e d by s m a l l changes i n t h e s t r u c t u r e o f a c i d i c components o f p y r e t h r o i d s . The a l c o h o l i c c o n s t i t u e n t s a r e e q u a l l y s e n s i t i v e , as compounds s u b s t i t u t e d a t t h e oc-methylene groups o f e s t e r s o f f u r f u r y l , f u r y l m e t h y l , and b e n z y l a l c o h o l s e x e m p l i f y ( i n Figure I I R i s a representative cyclopropanecarboxyl a t e w i t h R' = H, Me o r CN).
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
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Figure 10.
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Pyrethroids
Compounds related to a-isopropylphenyl acetate III
Esters o f 5-benzyl-3-furylmethyl a l c o h o l (R' = H) are u s u a l l y two t o t h r e e times as p o t e n t as t h o s e o f 3-phenoxybenzyl a l c o h o l and some t e n times more p o t e n t than t h o s e o f 5 - b e n z y l f u r f u r y l a l c o h o l . A m e t h y l sub s t i t u e n t (R = Me) almost e l i m i n a t e s a c t i v i t y o f a 3, 5 - d i s u b s t i t u t e d f u r a n e s t e r and d e p r e s s e s t h a t o f 3phenoxybenzyl d e r i v a t i v e s . E s t e r s of oc-cyanoalcohols (R = CN) a r e most i n t e r e s t i n g . The cyano s u b s t i t u e n t has l i t t l e i n f l u e n c e on t h e a c t i v i t y o f 2 , 5 - d i s u b s t i t u t e d f u r a n d e r i v a t i v e s , d e p r e s s e s t h a t o f 3,5-furans 1
1
Low activity whan R'- CH-CH ,COCH ,C0 CH, 2
3
2
C H 2 O C H 3 . C H 2 C I . C H (0CHs)2
MATSUO at al.. 1976 Figure 11.
Influence of substituents at the α-methylene group
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
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SYNTHETIC PYRETHROIDS
and i n c r e a s e s t h e a c t i v i t y o f 3-phenoxybenzyl e s t e r s t o produce t h e most e f f e c t i v e a l c o h o l i c c o n s t i t u e n t f o r p y r e t h r o i d s y e t r e p o r t e d (30,66,,80) . O t h e r more b u l k y s u b s t i t u e n t s a t t h i s s i t e i n t h e molecule depress o r e l i m i n a t e a c t i v i t y (80). The p o t e n c y o f e s t e r s o f (+)-ot-cyano-3-phenoxyb e n z y l a l c o h o l s t i m u l a t e d attempts t o i s o l a t e pure i s o mers. The mixed e s t e r s (NRDC 156) o f t h e ( 1 R ) - c i s - d i b r o m o v i n y l a c i d i n hexane gave c r y s t a l s (m.p.100 ; NRDC 161, decamethrin) and a l i q u i d s t i l l c o n t a i n i n g some NRDC 161 (30). The c r y s t a l l i n e isomer was e s t i m a t e d t o be about s i x times as t o x i c as t h e l i q u i d , i t s e l f l i t t l e more a c t i v e than t h e 3-phenoxy-benzyl e s t e r (32). Whether s i g n i f i c a n t o r c o i n c i d e n t a l , i t i s n o t a b l e t h a t t h e e s t e r s o f t h e two o p t i c a l forms o f a l l e t h r o l o n e also d i f f e r e d six f o l although a t a l e v e hundred times lower. 0
RS
R
S
S/R
HOUSEFLIES (MOLAR BASIS) Figure 12.
Relative potencies of esters of chiral ahohoh
Because t h e e s t e r o f t h e ( S ) - c y a n h y d r i n had such g r e a t a c t i v i t y , t h e 2- and 6-cyano-3-phenoxybenzyl e s t e r s ( F i g u r e 13) were s y n t h e s i s e d , w i t h t h e p o s s i b i l i t y t h a t i n one o r o t h e r compound t h e l o c a t i o n o f t h e c c - c y a n o group would be s i m u l a t e d by t h e e x t r a cyano substituent. However, b o t h e s t e r s were i n a c t i v e (730 . The e s t e r l i n k ( F i g u r e 14) i s a n o t h e r s i t e where s m a l l changes i n s t r u c t u r e g r e a t l y i n f l u e n c e a c t i v i t y . The s u b s t i t u t e d p h e n y l e s t e r (top) which l a c k s t h e methylene group o f , t h e b e n z y l e s t e r s i s i n a c t i v e (73) and a l t h o u g h , as n o t e d , some c y a n o h y d r i n e s t e r s
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
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Pyrethroids
Figure 13.
<*-, 2-, and 6-cyano-3-phenoxybenzyl esters
(centre) a r e p o t e n t not. A common f a c t o t h e changed c o n f o r m a t i o n s i n d u c e d a t t h i s c e n t r a l l i n k , which would g r e a t l y i n f l u e n c e t h e o v e r a l l shape o f t h e molecule.
Figure
14.
Modifications ester bond
at the
Some u n s a t u r a t i o n i s p r e s e n t i n t h e s i d e c h a i n o f t h e a l c o h o l i c component o f a l l p o w e r f u l p y r e t h r o i d s d e s c r i b e d so f a r , b u t a g a i n s m a l l changes remove a c t i v i t y ( F i g u r e 15). Thermal i s o m e r i s a t i o n o f p y r e t h r i n I t o a compound w i t h t h e t r a n s - c i s d i e n i c system c o n j u g a t e d w i t h t h e r i n g , as shown (520 almost e l i m i n a t e s a c t i v i t y , and a l t h o u g h t h e b e n z y l f u r a n bioresmet h r i n i s i n s e c t i c i d a l , the corresponding phenylfuran i s
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
16
SYNTHETIC PYRETHROIDS
Figure 15.
Esters of alcohols with various side chains
a g a i n almost i n a c t i v e (83 ,84_) . The 4 - p r o p e n y l b e n z y l chrysanthemate i s much l e s s a c t i v e than t h e 4 - a l l y l compound (85^/86^) · The l o c a t i o n o f u n s a t u r a t i o n w i t h r e s p e c t t o t h e n u c l e u s i s t h e r e f o r e i m p o r t a n t / shown a l s o by t h e i n a c t i v i t y o f the compounds i n F i g u r e 16, which a r e r e l a t e d t o 3-phenoxybenzyl e s t e r s , b u t have an e x t r a methylene group.
Figure 16.
Esters of 3-phenoxybenzyl and related alcohols
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
1.
ELLIOTT
Synthetic
Pyrethroids
17
The f i e l d o f s y n t h e t i c compounds w i t h s t r u c t u r e s r e l a t e d t o the n a t u r a l p y r e t h r i n s i s d e v e l o p i n g v e r y r a p i d l y and may perhaps be c o n s i d e r e d i n a s t a t e comp a r a b l e t o t h a t o f organophosphates and carbamates some twenty y e a r s ago. T h e r e f o r e m o d i f i c a t i o n of some o f t h e s t r u c t u r e a c t i v i t y p r i n c i p l e s d i s c u s s e d may be necessary with f r e s h d i s c o v e r i e s . However, p r e s e n t knowledge r e v i e w e d h e r e i s c o n s i s t e n t w i t h the c o n c l u s i o n i n d i c a t e d e a r l i e r t h a t the i n s e c t i c i d a l a c t i o n o f t h e s e compounds r e q u i r e s a number o f s i t e s on the m o l e c u l a r framework t o be a p p r o p r i a t e l y o r i e n t e d so t h a t i n t i m a t e c o n t a c t w i t h a complementary c h i r a l s u r face or structure i s p o s s i b l e . The p r o b a b i l i t y t h a t t h i s p a r t i c u l a r o r i e n t a t i o n w i l l be a c h i e v e d may depend on t h e b a l a n c e o f conformers i n which the m o l e c u l e exists. Such c o n c e p t s p r o v i d thoug pre sent n e c e s s a r i l y s u p e r f i c i a l , i n t e r p r e t a t i o n of the s e n s i t i v i t y of the i n s e c t i c i d a l a c t i o n of p y r e t h r o i d s t o s m a l l changes o f s u b s t i t u e n t o r c o n f i g u r a t i o n a t c e r t a i n centres; i t implies that t h e i r l e t h a l action i n v o l v e s the i n t a c t m o l e c u l e s , u n l i k e t h a t o f organophosphates and carbamates where c h o l i n e s t e r a s e i s phosp h o r y l a t e d o r c a r b a m o y l a t e d (87,88) i n a b i o c h e m i c a l r e a c t i o n i n which the n a t u r e o f the l e a v i n g group i s not c r i t i c a l . An e x c i t i n g q u e s t i o n , t o which f u r t h e r r e s e a r c h may p r o v i d e an answer, i s whether the m o l e c u l e i s i n t h e f u l l y a c t i v e c o n f o r m a t i o n a t the moment o f f i r s t c o n t a c t , o r forms a bound complex by a sequence o f s t e p s f o l l o w i n g i n i t i a l impact a t one o f the a c t i v e c e n t r e s - the s o - c a l l e d " z i p p e r " concept (89). P h o t o s t a b i l i t y and
Mammalian T o x i c i t y
T h i s s u r v e y o f s y n t h e t i c p y r e t h r o i d s has shown the r a p i d advance i n knowledge o f the r e l a t i o n s h i p o f i n s e c t i c i d a l a c t i v i t y to s t r u c t u r e , c o n t r i b u t i n g to fundamental u n d e r s t a n d i n g o f b i o c h e m i c a l p r o c e s s e s i n insects. Two o t h e r r e g i o n s o f r e s e a r c h i n f l u e n c e the development o f s y n t h e t i c p y r e t h r o i d s f o r p r a c t i c a l a p p l i c a t i o n i n the f i e l d . These are the r e l a t i o n s h i p s of s t r u c t u r e t o p h o t o s t a b i l i t y and t o mammalian t o x i city. F o r many y e a r s , i t was r e c o g n i s e d t h a t i f the n a t u r a l p y r e t h r i n s and a l l e t h r i n c o u l d be i n d u c e d t o p e r s i s t on l e a f s u r f a c e s i n s u n l i g h t , t h e y might be very v a l u a b l e f o r c o n t r o l l i n g a g r i c u l t u r a l crop pests, e s p e c i a l l y i f t h e i r other favourable c h a r a c t e r i s t i c s c o u l d be r e t a i n e d . However, the n a t u r a l p y r e t h r i n s
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
18
SYNTHETIC
PYRETHROIDS
a r e n o t o r i o u s l y u n s t a b l e and attempts t o p r o t e c t them from UV l i g h t w i t h f i l t e r s (90), as i n c l u s i o n compounds (91) and o t h e r w i s e a r e o n l y p a r t l y s u c c e s s f u l , p a r t i c u l a r l y as t h e p y r e t h r i n s are a l r e a d y more e x p e n s i v e than competing i n s e c t i c i d e s . R e c e n t l y , i n a more d i r e c t approach p h o t o s t a b l e p y r e t h r o i d s have been e v o l v e d , (2j6 ,45>,£6 ,62,9_2 ,92) which may assume an i m p o r t a n t r o l e i n i n s e c t c o n t r o l i n the f u t u r e . F i g u r e 17 shows some s t a g e s i n t h e development o f p y r e t h r o i d s s t a b l e enough t o use i n t h e f i e l d . The f i g u r e s i n brackets are i n s e c t i c i d a l potencies against Anopheles s t e p h e n s i r e l a t i v e t o DDT (70,94). The as t e r i s k s show p h o t o l a b i l e s i t e s i n the m o l e c u l e s .
UNSTABL
RESMETHRIN
(18)
PHENOTHRIN
(β·3)
CYPERMETHRIN (38) (NRDC 149)
DECAMETHRIN (NRDC 161)
(630)
ACTIVITY AGAINST A.STEPHENSI ( DDT -1-0 ) DATA OF BARLOW AND Η ADA WAY
* — • C O M P O U N D INSUFFICIENTLY STABLE FOR AGRICULTURAL USE
C l
S 5602 Figure 17.
Development of photostable pyrethroids
I n v e s t i g a t i o n s w i t h pure p y r e t h r i n I (55^.95) and r e l a t e d compounds (6J3) i d e n t i f i e d c e n t r e s i n t h e s t r u c t u r e s s e n s i t i v e t o p h o t o s e n s i t i s e d a t t a c k by oxygen,
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
1.
ELLIOTT
Synthetic
Pyrethroids
19
the more i m p o r t a n t ones b e i n g the s i d e c h a i n o f c h r y s anthemic a c i d and the c i s - p e n t a d i e n y l s i d e c h a i n . S y s t e m a t i c s y n t h e s i s and t e s t i n g (59) o f a s e r i e s o f compounds r e l a t e d t o p y r e t h r i n I l e d t o r e s m e t h r i n , a more p o w e r f u l i n s e c t i c i d e i n which a s t a b l e a r o m a t i c r i n g had been s u b s t i t u t e d f o r t h e p h o t o s e n s i t i v e d i e n e s i d e c h a i n but which had a p h o t o l a b i l e f u r a n r i n g (67, 96). A f u r t h e r s t e p was t h e r e c o g n i t i o n t h a t a meta s u b s t i t u t e d benzene r i n g was e q u i v a l e n t i n some r e s p e c t s t o t h e 3,5-furan i n r e s m e t h r i n (31) and i n the compound p h e n o t h r i n (44) where t h e methylene b r i d g e i s a l s o r e p l a c e d by an oxygen l i n k , t h e a l c o h o l i c component i s p h o t o s t a b l e . However, p h e n o t h r i n s t i l l cont a i n s the l a b i l e chrysanthemate c e n t r e , so i s not s u f f i c i e n t l y s t a b l e f o r most a g r i c u l t u r a l a p p l i c a t i o n s and, moreover, i s g e n e r a l l thrin. In p e r m e t h r i p l a c e s t h e i s o b u t e n y l u n i t of c h r y s a n t h e m i c a c i d w i t h enhancement o f i n s e c t i c i d a l a c t i v i t y and, a l l p h o t o l a b i l e c e n t r e s h a v i n g been e l i m i n a t e d , the compound i s more s t a b l e on l e a f s u r f a c e s than many organophosphates and carbamates. N o n e t h e l e s s , when exposed t o systems a c t i v e i n m e t a b o l i s m o f o r g a n i c compounds, f o r example, m i c r o o r g a n i s m s i n the s o i l , i t i s degraded s u f f i c i e n t l y r a p i d l y t o a l l a y any c o n c e r n about undue a c c u m u l a t i o n . Theot-cyano group i n c y p e r m e t h r i n g i v e s s t i l l g r e a t e r i n s e c t i c i d a l a c t i v i t y , a l b e i t w i t h somewhat i n c r e a s e d mammalian t o x i c i t y . As d e s c r i b e d , i n v s t i g a t ing the c o m b i n a t i o n s o f o p t i c a l and g e o m e t r i c a l isomers o f t h e d i h a l o v i n y l a c i d s w i t h the c y a n o h y d r i n s l e d t o the d i s c o v e r y o f the o u t s t a n d i n g l y p o t e n t compound d e c a m e t h r i n (NRDC 161) which a p p a r e n t l y has each c e n t r e i n t h e optimum c o n f i g u r a t i o n f o r a c t i v i t y . Decamet h r i n (30,32.) which i s a l s o a d e q u a t e l y s t a b l e (97,98) f o r f i e l d use (70,9£,£9) i s s i x t e e n times as a c t i v e as c y p e r m e t h r i n and s i x hundred times as a c t i v e as DDT t o A. S t e p h e n s i (94) and i s the most p o w e r f u l l i p o p h i l i c i n s e c t i c i d e yet synthesised. A f u r t h e r important s t a g e i n t h e e v o l u t i o n o f p y r e t h r o i d s f o r use i n a g r i c u l t u r e was t h e d i s c o v e r y of the a c t i v i t y o f e s t e r s o f oc-cyano-3-phenoxybenzyl a l c o h o l w i t h non-cyclopropane a c i d s such as o C - i s o p r o p y l - 4 - c h l o r o p h e n y l a c e t i c a c i d . Most i n f o r m a t i o n has so f a r been p u b l i s h e d on f e n v a l e r a t e ( s u m i c i d i n , S 5602) (45,46,70). The o t h e r important a r e a o f i n v e s t i g a t i o n which i n f l u e n c e s development and p r a c t i c a l a p p l i c a t i o n o f s y n t h e t i c p y r e t h r o i d s i s the m o l e c u l a r b a s i s f o r mamm a l i a n t o x i c i t y , t o which important c o n t r i b u t i o n s have been made by groups l e d by J . E . C a s i d a i n t h e U n i v e r s i t y o f C a l i f o r n i a a t B e r k e l e y and by J . Miyamoto o f
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
20
SYNTHETIC PYRETHROIDS
the Sumitomo C h e m i c a l Company. The t o p i c i s c o v e r e d i n more d e t a i l l a t e r i n t h i s symposium and here t h e d i s c u s s i o n i s r e s t r i c t e d t o some emerging p r i n c i p l e s . The o r a l t o x i c i t i e s t o mammals o f many s y n t h e t i c p y r e t h r o i d s a r e so low (60,71) (8000-10,000 mg.kg." f o r female r a t s ) t h a t comparing them g i v e s l i t t l e g u i d a n c e t o t h e s t r u c t u r a l f a c t o r s i n f l u e n c i n g mammalian t o x i c i t y . I n t r a v e n o u s t o x i c i t i e s t o female r a t s , u s u a l l y some t e n t i m e s g r e a t e r than t h e o r a l v a l u e s a r e more u s e f u l . I n view o f t h e i r r e p u t a t i o n , p y r e t h r i n I and p y r e t h r i n I I , e s t e r s o f secondary a l c o h o l s , have u n e x p e c t e d l y h i g h i n t r a v e n o u s t o x i c i t i e s (60) ( F i g u r e 18). I n c o n t r a s t , b i o r e s m e t h r i n , an e s t e r o f t h e same 1
Pesticide Biochemistry and Physiology
Figure 18.
Intravenous toxicities to female rats (60)
trans s u b s t i t u t e d cyclopropane a c i d but with a primary a l c o h o l , i s some s i x t y t i m e s l e s s t o x i c by t h i s r o u t e (60). The same f u r a n a l c o h o l e s t e r i f i e d w i t h a c y c l o propane a c i d h a v i n g two s u b s t i t u e n t s (methyl groups) c i s t o t h e c a r b o x y l l i n k a g e (NRDC 108) (60) a g a i n has h i g h i n t r a v e n o u s t o x i c i t y , p r o b a b l y due t o s t e r i c h i n drance o f e s t e r c l e a v a g e . The t o x i c i t y o f c i s m e t h r i n (NRDC 119) (100), w i t h i s o b u t e n y l and methyl groups c i s t o t h e e s t e r f u n c t i o n i s s i m i l a r , and i s somewhat i n -
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
1.
ELLIOTT
Synthetic
21
Pyrethroids
c r e a s e d ( i n NRDC 142) (101) by s u b s t i t u t i n g c h l o r i n e for methyl. However, a compound d e r i v e d from NRDC 142 by changing t h e a l c o h o l i c component t o 3-phenoxybenzyl a l c o h o l has d i m i n i s h e d t o x i c i t y , p r o b a b l y because a n o t h e r s i t e , a t t h e 4 - p o s i t i o n on t h e phenoxy r i n g , is available for oxidative detoxification. 3-Phenoxybenzyl a l c o h o l , therefore, i s a p a r t i c u l a r l y favourable a l c o h o l i c component o f p y r e t h r o i d s , f o r i t i s n o t p h o t o l a b i l e y e t g i v e s e s t e r s o f low mammalian t o x i c i t y because i t can be d e t o x i f i e d by o x i d a t i v e and e s t e r a t i c attack a t several s i t e s . These c o n c e p t s a r e c o n s i d e r ed i n more d e t a i l i n o t h e r papers i n t h i s symposium, and e l s e w h e r e . (102,103,104,105). 1
P r o p e r t i e s o f Recent
Pyrethroids
Insecticides o d i s c u s s e d above, combine potency t o i n s e c t s g r e a t e r than t h a t o f o t h e r c a t e g o r i e s o f i n s e c t i c i d e s w i t h lower mammalian t o x i c i t y , l i m i t e d p e r s i s t e n c e i n s o i l (j59,70) and f i e l d s t a b i l i t y adequate t o c o n t r o l i n s e c t pests o f a g r i c u l t u r a l crops. The changes i n each o f t h e s e p r o p e r t i e s w i t h v a r i a t i o n o f s t r u c t u r e have so f a r been c o n s i d e r e d o n l y g e n e r a l l y and i n c o n c l u d i n g , i t i s a p p r o p r i a t e t o emphasise p r o g r e s s i n r e a l i s i n g the i n s e c t i c i d a l potency l a t e n t i n the s t r u c t u r e o f p y r e t h r i n I by a s p e c i f i c example. F o r t h i s purpose, F i g u r e 19 compares t h e a c t i v i t y o f p y r e t h r i n I w i t h t h a t o f d e c a m e t h r i n , t h e most p o w e r f u l i n s e c t i c i d e y e t synthesised. To some s p e c i e s o f i n s e c t , d e c a m e t h r i n
MEDIAN LETHAL DOSES (mg.kg ') PHAEDON COCHLEAR IAE
PER I PLAN ETA AMERICANA
0-33
MUSCA DOMESTICA
16
ANOPHELES STEPHENSI
GLOSSINA AUSTEN I
24
0-37
002
0004
UNSTABLE, VISCOUS LIQUID
0032
0056
003
S T A B L E , CRYSTALLINE (M.P.100)
Figure 19.
Pyrethrin I and decamethrin compared
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
22
SYNTHETIC PYRETHROIDS
may be s e v e r a l h u n d r e d - f o l d as a c t i v e as t h e n a t u r a l compound. I t s p r o p e r t i e s , a white c r y s t a l l i n e s o l i d w i t h a m e l t i n g p o i n t o f 100° ( 3 0 ) , and a s t r u c t u r e f u l l y c o n f i r m e d by X-ray a n a l y s i s (106) c o n t r a s t w i t h t h o s e o f p y r e t h r i n I , which even i n t h e p u r e s t form y e t a t t a i n e d (9_5) i s an u n s t a b l e , v i s c o u s l i q u i d . Figure 19 g i v e s r e s u l t s o f l a b o r a t o r y t e s t s b u t f i e l d p e r f o r mance i s e q u a l l y i m p r e s s i v e , as i n d i c a t e d by t h e r e s u l t s o f Hadaway and Barlow (9_4) i n an experiment t o e x p l o r e t h e p o t e n t i a l o f p e r m e t h r i n and d e c a m e t h r i n a g a i n s t t h e T s e t s e f l y (Table I I I ) . Table
I I I - Residual T o x i c i t y to Tsetse F l i e s (Glossina a u s t e n i ) o f I n s e c t i c i d a l D e p o s i t s on I v y Leaves*
Compound
Rate -1 g.ha
Endosulfan
500
100
92
50
17
Dieldrin
500
100
88
54
4
Permethrin
500
100
100
100
25
96
96
-
22
100
100
100
100
100
100 88
Decamethrin
4. 7 1.0
1 minute t o d e p o s i t s ( a g e i n weeks) 4 6 3 2 0 1
94
-
-
-
100
100
100
-
100
69
100
100
-
100
100
-
79
-
* Data adapted from Hadaway, Barlow, T u r n e r (94)
-
and Flower
On a waxy l e a f s u r f a c e , t h e i n v o l a t i l i t y , p h o t o s t a b i l i t y and g r e a t i n s e c t i c i d a l a c t i v i t y o f t h e s e compounds r e s u l t i n d e p o s i t s s t i l l t o x i c t o f l i e s a t s i x weeks and a t r a t e s o f a p p l i c a t i o n l / 2 0 t h , l / 1 0 0 t h and even l / 5 0 0 t h o f t h o s e o f endosulphan and d i e l d r i n . Future Prospects
f o r Pyrethroids
These r e s u l t s , w i t h compounds shown i n i n i t i a l s t u d i e s t o degrade w i t h i n weeks i n many s o i l t y p e s (69, 70) i n d i c a t e t h e g r e a t p o t e n t i a l o f a p p r o p r i a t e members of t h i s group o f compounds f o r p r a c t i c a l a p p l i c a t i o n s . Important f e a t u r e s a r e t h e many s t r u c t u r a l v a r i a t i o n s p o s s i b l e p r o v i d i n g a range o f u s e f u l c o m b i n a t i o n s o f i n s e c t i c i d a l a c t i v i t y , insect species s p e c i f i c i t y , mammalian t o x i c i t y and e n v i r o n m e n t a l s t a b i l i t y t o match d i f f e r i n g requirements. The r a p i d l y d e v e l o p i n g
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
1.
ELLIOTT
Synthetic
Pyrethroids
23
knowledge o f r e l a t i o n s h i p s between c h e m i c a l s t r u c t u r e s and t h e i r i n s e c t i c i d a l a c t i v i t i e s , mammalian t o x i c i t i e s and p h o t o s t a b i l i t i e s s u g g e s t s t h a t c o n t i n u e d r e s e a r c h w i l l d i s c l o s e a number o f i n s e c t i c i d e s w i t h improved p r o p e r t i e s i n t h i s group o f compounds. Acknowledgements I thank Mr. F. Barlow and Dr. A.B. Hadaway, and (the l a t e ) Dr. J.M. Barnes and Mr. R.D. V e r s c h o y l e f o r r e s u l t s o f t e s t s w i t h i n s e c t s and mammals, r e s p e c t i v e l y and Drs. I . J . Graham-Bryce and N.F. Janes f o r much help i n preparing t h i s manuscript. Literature 1. 2. 3. 4.
5. 6. 7. 8. 9.
10.
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Toxicol. (1975/76) 3, 491. Elliott, Μ . , J a n e s , N.F., Pulman, D.A., Gaughan, L.C., U n a i , T . and C a s i d a , J.E. J. A g r . Food Chem. (1976) 24, 270. Owen, J.D. J.C.S. P e r k i n I (1975) 1865.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
2 Preferred Conformations of Pyrethroids MICHAEL ELLIOTT and NORMAN F. JANES Rothamsted Experimental Station, Harpenden, Hertfordshire, AL5 2JQ, England
The importance of molecular shape as a factor influencing i n s e c t i c i d a w e l l - e s t a b l i s h e d (1,2,3); the s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s recognised so f a r are best interpreted by assuming that the whole molecular i n t e r a c t s at a s i t e i n the insect with s p e c i f i c s t e r i c requirements for optimum fit (4). Because all known active pyrethroids are f l e x i b l e molecules (eg. pyrethrin 1 (Figure 1) and decamethrin (Figure 6)) most s t r u c t u r e - a c t i v i t y studies frequently do not give d i r e c t information about conformations adopted at the s i t e of a c t i o n . Any method of i n v e s t i g a t i n g the shapes which pyrethroid molecules tend to adopt therefore deserves attention as the features revealed could p e r s i s t when the molecule is acting i n s e c t i c i d a l l y . One such approach used with other types of b i o l o g i c a l l y - a c t i v e molecule i s to study the preferred conformations predicted by t h e o r e t i c a l calculations (5). With pyrethroids e s p e c i a l l y , some information on the arrangement of the molecule i n the s o l i d state i s also a v a i l a b l e , because c r y s t a l structures of several pyrethroids have now been determined by X-ray analysis (6,7,8). This paper describes preliminary attempts to i d e n t i f y features which may be b i o l o g i c a l l y s i g n i f i c a n t using a simplifed approach based on these methods. Method Preferred conformations can be predicted q u a l i t a t i v e l y from Dreiding molecular models by v i s u a l i s i n g atomic i n t e r a c t i o n s , but for quantitative p r e d i c t i o n , c a l c u l a t i o n of the energies involved i s necessary. In the present work the following function (9) consisting simply of a repulsive and an a t t r a c t i v e term for nonbonded i n t e r a c t i o n between 2 atoms was u s e d : 29
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
30
SYNTHETIC
Ε = A exp
PYRETHROIDS
(-Cr) - Br
V a l u e s o f A, Β and C f o r v a r i o u s p a i r s o f atoms have been s u g g e s t e d (10). N e i t h e r t h i s f u n c t i o n , n o r more sophisticated relationships using molecular o r b i t a l s (eg. (13.) ) a s s e s s a c c u r a t e l y t h e a c t u a l energy l e v e l s i n v o l v e d , b u t , as Hoffmann s u g g e s t s (11), even t h e s i m p l e r f u n c t i o n s w i l l o f t e n i n d i c a t e r e l i a b l y the p o s i t i o n o f minimum energy, i . e . t h e p r e f e r r e d c o n f o r mation. In t h i s approach, t h e c o o r d i n a t e s o f each atom o f a p a r t i c u l a r conformer a r e measured from t h e D r e i d i n g model/ whence t h e c o o r d i n a t e s o f any d e s i r e d conformer can be g e n e r a t e d by computer, u s i n g G i b b s ' r o t a t i o n a l m a t r i x method (12). This process repeated for a s e r i e s o f rotamers energy i n each c a s e bond s t u d i e d (see F i g u r e s 2-4, 7, 9 ) . The v e r t i c a l a x i s on each graph i s c a l i b r a t e d i n a r b i t r a r y energy u n i t s , based on t h e b a r r i e r c a l c u l a t e d f o r ethane, and t h e h o r i z o n t a l a x i s r e p r e s e n t s a f u l l r o t a t i o n about the bond. C l e a r l y t h e r e s u l t s f o r any one bond w i l l be i n f l u e n c e d by t h e d i s p o s i t i o n o f t h e r e s t o f t h e m o l e c u l e , so i t i s i m p o r t a n t t o i n t e r p r e t c o r r e c t l y the o r i g i n s o f t h e energy b a r r i e r s i n d i c a t e d by t h e computation. The computer i s t h e r e f o r e programmed t o c a l c u l a t e t h e t o t a l energy f o r each rotamer, and i n a d d i t i o n t o l i s t t h e p a i r s o f atoms r e s p o n s i b l e f o r the major c o n t r i b u t i n g interactions. R e s u l t s and
Discussion
The p r o c e d u r e was f i r s t a p p l i e d t o p y r e t h r i n 1 ( F i g u r e 1) which has seven s i n g l e bonds about which rotation i s relatively free. The r o t a t i o n graph f o r bond 2 ( F i g u r e 2) has two maxima which a r i s e from i n t e r f e r e n c e between t h e c i s - m e t h y l group and e i t h e r
ETHANE
Interference by cis-methyl group » maxima
10H
UNITS
Figure 1.
Interference across ester bond decides which valley is deeper & wider
Pyrethin I 360' Figure 2.
Rotation graph for bond 2
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
2.
ELLIOTT
A N D JANES
Preferred
31
Conformations
oxygen atom o f t h e e s t e r l i n k . One o f t h e c o r r e s ponding v a l l e y s i s f i l l e d by i n t e r a c t i o n s between t h e c i s - m e t h y l group and t h e b u l k y a l c o h o l i c group on 0-27, so t h e o t h e r v a l l e y i s most l i k e l y t o c o n t a i n t h e p r e f e r r e d conformer. F o r bond 3, s t e r i c c o n s i d e r a t i o n s o n l y ( F i g u r e 3) i n d i c a t e a wide v a l l e y w i t h t h e two l a r g e r groups d i s t a n t from each o t h e r . However, f o r t h i s bond, other c o n s i d e r a t i o n s apply. S u t t o n (13) c o n c l u d e d t h a t e s t e r s p r e f e r one o f two p l a n a r c o n f o r m a t i o n s , so t h a t , w i t h maximum ρ- ττorbital o v e r l a p , some d o u b l e bond c h a r a c t e r d e v e l o p s i n t h e c e n t r a l bond. The importance o f t h i s i n f l u e n c e was c o n f i r m e d by subse quent X-ray c r y s t a l l o g r a p h i c s t u d i e s (surveyed by Cornibert e t a l . (14)) In p y r e t h r o i d s with t h e i r c e n t r a l e s t e r bond, i n f l u e n t i a l i n determinin e a r l i e r (1). The r o t a t i o n graph ( F i g u r e 3) emphasises t h a t p r o b a b l y o n l y t h e t r a n s o i d conformer i s i m p o r t a n t i n p y r e t h r i n 1, t h e c i s o i d form b e i n g r e l a t i v e l y hindered.
0
26 Wide valley includes transoid form
32-
10
2 valleys, one deeper, with C=0 and C Η 29 skew
Cisoid form sterically disfavoured
Ο Figure 3.
Rotation graph for bond 3
Figure 4.
360* Rotation graph for bond 4
The graph f o r bond 4 ( F i g u r e 4) has e s s e n t i a l l y one v a l l e y , w i t h t h e c a r b o n y l group n e a r e r t o H-29 than t o t h e l a r g e r groups on t h e r i n g . This valley i s s p l i t because o f f s e t t i n g t h e c a r b o n y l t o e i t h e r s i d e o f H-29 i s s l i g h t l y f a v o u r e d e n e r g e t i c a l l y , and one o f f s e t p o s i t i o n i s preferred t o the other. S i m i l a r p r o c e d u r e s were a p p l i e d t o t h e r e m a i n i n g s i n g l e bonds i n p y r e t h r i n 1; t h e r e s u l t s a r e compared ( F i g u r e 5) w i t h those a c t u a l l y o b s e r v e d (6) i n t h e c r y s t a l l i n e s t a t e f o r a c l o s e l y r e l a t e d compound (S-bioallethrin 6-bromo-2,4-dinitrophenylhydrazone).
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
SYNTHETIC PYRETHROIDS
32
Found in crystalline 128° 106 180 190 99 derivative of allethrin
241
-
B
2
Preferred angles in Pyrethrin I and crystals of an allethrin derivative
The two e s t e r s d i f f e r o n l y i n t h e l e n g t h o f t h e s i d e c h a i n ( a l l y l o r p e n t a d i e n y l ) and i n t h a t t h e c a r b o n y l group has been c o n v e r t e d t o a hydrazone i n t h e c r y s t a l l i n e compound. The a n g l e s f o r t h e bonds near t h e centre o f the molecule are s t r i k i n g l y s i m i l a r , but t h e r e a r e d i f f e r e n c e s between t h e c o n f o r m a t i o n s c a l c u l a t e d and o b s e r v e d f o r t h e s i d e c h a i n s ; p o s s i b l y i n t e r m o l e c u l a r f o r c e s a r e more s i g n i f i c a n t i n t h e c r y s t a l , and i n f l u e n c e o b t r u d i n g groups more than c e n t r a l ones. A l s o t h e s t r u c t u r a l d i f f e r e n c e s between t h e compounds may a f f e c t t h e i n t e r a c t i o n s i n v o l v i n g t h e a l c o h o l i c side chain.
Figure 7.
Rotation graph for bond 1
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
2.
ELLIOTT AND JANES
Preferred
33
Conformations
Decamethrin ( F i g u r e 6) i s e x c e p t i o n a l l y s u i t a b l e f o r t h e p r e s e n t purpose because i t i s a c r y s t a l l i n e dibromo compound, m.p. 100°, and the s t r u c t u r e may t h e r e f o r e be determined d i r e c t l y by X-ray a n a l y s i s (1)· F u r t h e r , i t i s a c o n s i d e r a b l y more p o w e r f u l i n s e c t i c i d e (15) tham most o t h e r p y r e t h r o i d s , and thus p r o b a b l y approaches more n e a r l y the optimum shape when i t a c t s i n the i n s e c t . The r o t a t i o n graph ( F i g u r e 7) f o r bond 1 i n deca m e t h r i n i s more c o m p l i c a t e d than i n t h e examples above because r o t a t i o n s about i t and about o t h e r s i n t h e m o l e c u l e ( p a r t i c u l a r l y bond 2) a r e more i n t e r d e p e n d e n t . In one form o f t h e m o l e c u l e t h e r e i s a wide v a l l e y f o r t h e s i d e c h a i n , b u t as i n t e r f e r e n c e i n c r e a s e s t h i s narrows, and t h e r e i s p r e f e r e n c e f o r one p a r t i c u l a r conformation. The u n c e r t a i n b u t 13C magneti d i c a t e s t h a t i t may be s i g n i f i c a n t i n s o l u t i o n . F i g u r e 8 shows t h o s e carbon atoms i n d e c a m e t h r i n and i t s epimer a t t h e ©<-carbon whose c h e m i c a l s h i f t s differ. In t h e f u l l y extended m o l e c u l e , t h e s i d e c h a i n carbon atoms a r e d i s t a n t from t h e <*-carbon and i n v e r s i o n t h e r e would n o t be e x p e c t e d t o produce measurable s h i f t s . RorS
No sterically preferred conformation
ETHANE UNITS # Atoms with different chemical shifts in the two isomers
Figure 8. C nmr spectra of deca methrin and a stereoisomer 13
Ο
Figure 9.
3βΟ'
Rotation graph for bond 5
The d i f f e r e n c e s d e t e c t e d s u g g e s t t h a t t h e s i d e c h a i n spends a s i g n i f i c a n t p r o p o r t i o n o f t h e time c l o s e r t o the a l c o h o l i c p a r t o f the m o l e c u l e , i n d i c a t i n g appre c i a b l e i n t e r f e r e n c e such as changes t h e v a l l e y shape i n F i g u r e 7. The c a l c u l a t i o n s f o r bond 5 i n d e c a m e t h r i n ( F i g u r e 9) i n d i c a t e no p r e f e r e n c e f o r any p a r t i c u l a r conformer d e s p i t e m u l t i p l e s u b s t i t u t i o n on the bond. The f u l l r e s u l t s f o r decamethrin ( F i g u r e 10) a r e l e s s d e f i n i t e
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
34
SYNTHETIC PYRETHROIDS
Calculated for free molecule
°
r
3 0 1
Found in crystal 271° 218 Figure 10.
preference
180
104
309
minimise interdependent interference 44
19
Preferred in the crystal
t h a n w i t h p y r e t h r i n 1, a l t h o u g h t h e t r a n s o i d form o f t h e e s t e r i s s t i l l i n d i c a t e d b o t h by c a l c u l a t i o n and by observation. F u r t h e r , o n l y bond 4 i s d e f i n i t e l y n o t w i t h i n a v a l l e y o f the r o t a t i o n graph. Thus, f o r some bonds, p a r t i c u l a r l y t h o s e i n t h e c e n t r e o f p y r e t h r i n 1, s i m i l a r i t i e s are o b s e r v e d . The q u e s t i o n t h e r e f o r e a r i s e s as t o how s i g n i f i c a n t t h e s e preferences are f o r i n s e c t i c i d a l a c t i v i t y . Comparing the energies a s s o c i a t e d with the v a r i o u s p e r t u r b a t i o n s t o which t h e m o l e c u l e may be s u b j e c t e d i n t h e i n s e c t w i t h the s t r e n g t h of conformational p r e f e r e n c e p r o v i d e s a p a r t i a l answer. Thus, d u r i n g t r a n s p o r t t h e p e r t u r b a t i o n s w i l l p r o b a b l y be comparable t o t h o s e f o r a m o l e c u l e i n s o l u t i o n , where t h e r m a l k i n e t i c energy i s s u f f i c i e n t t o overcome t h e r o t a t i o n a l b a r r i e r s between conformers about a s i n g l e bond; t h e nmr s i g n a l s o f p y r e t h r o i d s i n s o l u t i o n a t ambient temperature a r e sharp because conformers a r e i n t e r c o n v e r t e d r a p i d l y enough on t h e nmr time s c a l e t o produce a spectrum r e p r e s e n t i n g t h e i r w e i g h t e d average. At the s i t e of a c t i o n , the molecule w i l l experience a d d i t i o n a l f o r c e s due t o b i n d i n g , which may a l s o overcome t h o s e i n v o l v e d i n conformational preference. I t i s not s u r p r i s i n g t h e r e f o r e t h a t no d i r e c t r e l a t i o n s h i p has been d i s c e r n ed. However, one concept o f b i o l o g i c a l a c t i o n s u g g e s t s t h a t as the m o l e c u l e reaches and b e g i n s t o i n t e r f e r e w i t h the t a r g e t , there i s a c r u c i a l p e r i o d d u r i n g which i t (or p a r t s o f i t i n s u c c e s s i o n (16) )must achieve the c o r r e c t o r i e n t a t i o n f o r f i t ; the probab i l i t y o f b i n d i n g then depends t o some e x t e n t on conformational preference. Expressed otherwise, i f the optimum c o n f o r m a t i o n i s l e s s e a s i l y adopted, perhaps
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
2.
E L L I O T T AND JANES
Preferred
Conformations
35
t h r o u g h s t e r i c h i n d r a n c e w i t h i n the m o l e c u l e , i n s e c t i c i d a l a c t i v i t y may be diminished. The g r e a t i n s e c t i c i d a l a c t i v i t y o f d e c a m e t h r i n may be r e l a t e d t o l a c k o f s t r o n g l y p r e f e r r e d conformat i o n s about some o f t h e i m p o r t a n t bonds, so t h a t h i n drance t o the m o l e c u l e a d o p t i n g the optimum shape w i t h i n the c r u c i a l p e r i o d at the a c t i o n s i t e i s m i n i mised. S i g n i f i c a n t l y , Owen showed (8) t h a t o t h e r c r y s t a l l i n e c i s - d i h a l o v i n y l compounds, a l s o p o w e r f u l i n s e c t i c i d e s , adopt c o n f o r m a t i o n s about bond 1 ( F i g u r e 10) d i f f e r e n t from t h a t i n decamethrin. The i n s e c t i c i d a l d a t a i n F i g u r e 11 are a l s o c o n s i s t e n t w i t h t h i s suggestion. The 3 - s u b s t i t u e n t can be changed q u i t e d r a s t i c a l l y w i t h o u t l o s i n g i n s e c t i c i d a l a c t i v i t y (17, 18); f o r example, a m e t h y l group ( i n A) can be removed (B) and r e p l a c e d elsewher i t destroys a c t i v i t s t e r i c h i n d r a n c e and c o n f o r m a t i o n a l p r e f e r e n c e are much s t r o n g e r i n t h e s e l a s t two compounds (D & E ) . The p r e f e r r e d c o n f o r m a t i o n may be l e s s a p p r o p r i a t e , and t h e r e f o r e the optimum shape f o r f i t much l e s s e a s i l y achieved. 5-Benzyl-3-furylmethyl esters
Relative insecticidal activity (housef lies)
Figure 11. A possible correlation between insecticidal activity and disturbance of conformation
Acknowledgements We thank Dr. J.D. Owen, o f the Department o f Molec u l a r S t r u c t u r e s , Rothamsted E x p e r i m e n t a l S t a t i o n , f o r many f r u i t f u l d i s c u s s i o n s r e l e v a n t t o t h i s work and Dr. I . J . Graham-Bryce f o r c o n s t r u c t i v e comments and continued support.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
36
SYNTHETIC PYRETHROIDS
Abstract P r e f e r r e d c o n f o r m a t i o n s f o r two p y r e t h r o i d s a r e calculated from s i m p l e models based solely on non -bonded atomic interactions. The c o n f o r m a t i o n s corres pond closely w i t h t h o s e found in the crystalline state f o r some bonds, b u t differ f o r o t h e r s , particularly t h o s e near t h e e x t r e m i t i e s o f the m o l e c u l e . Despite r a p i d r o t a t i o n about s i n g l e bonds in solution, the shpae o f the p r e f e r r e d c o n f o r m a t i o n may be significant for insecticidal a c t i o n , i n f l u e n c i n g the probability t h a t t h e p y r e t h r o i d will adopt t h e a p p r o p r i a t e shape as it approaches the t a r g e t site. Some r e l e v a n t biological r e s u l t s are d i s c u s s e d . Literature 1. 2. 3.
4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
14. 15. 16. 17. 18.
Cited
Elliott, M. Chemy I n d . (1969) 776. Elliott, M. Bull Wld Hlth O r g . (1971) 44, 315. Elliott, Μ., Farnham, A . W . , J a n e s , N.F., Needham, P.H. and Pulman, D . A . in "Mechanism o f P e s t i c i d e Action", A.C.S. Symposium S e r i e s No. 2, e d . G . K . Kohn, p . 80. Elliott, M. p r e c e d i n g p a p e r . K i e r , L.B. in " B i o l o g i c a l C o r r e l a t i o n s - The Hansch A p p r o a c h " , Advances in C h e m i s t r y S e r i e s No. 114, American C h e m i c a l S o c i e t y , 1972. B e g l e y , M.J., C r o m b i e , L., Simmonds, D.J. and W h i t i n g , D . A . J.C.S. P e r k i n I (1974) 1230. Owen, J.D. J.C.S. P e r k i n I (1975) 1865. Owen, J.D. J.C.S. P e r k i n I (1976) 1231. Hill, T.L. J. Chem. P h y s . (1948) 16, 399. H o p f i n g e r , A.J. " C o n f o r m a t i o n a l P r o p e r t i e s o f M a c r o m o l e c u l e s " , Academic P r e s s , New Y o r k , 1973. Hoffmann, R. J. Chem. P h y s . (1963) 39, 1397. G i b b s , J.W. "Vector A n a l y s i s " , Y a l e U n i v e r s i t y P r e s s , 1901, p . 339. S u t t o n , L.E. in " D e t e r m i n a t i o n o f O r g a n i c S t r u c t u r e s by P h y s i c a l Methods" ( E . A . Braude and F.C. Nachod, eds.), V o l . 1, p . 405, Academic P r e s s , New Y o r k , 1955. C o r n i b e r t , J., H i e n , N.V., Brisse, F . and M a x h e s s a u l t , R . H . Can. J. Chem. (1974) 52, 3742. Elliott, Μ., Farnham, A . W . , J a n e s , N.F., Needham, P . H . and Pulman, D . A . N a t u r e (1974) 248, 710. Burgen, A.S.V., R o b e r t s , G . C . K . and Feeney, J.C. Nature (1975) 253, 753. Elliott, Μ . , Farnham, A . W . , J a n e s , N.F., Needham, P . H . and Pulman, D . A . Pestic. Sci. (1976) 7, 492. Elliott, Μ., Farnham, A . W . , J a n e s , N.F., Needham, P . H . and Pulman, D . A . Pestic. Sci. (1976) 7, 499.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
3 Pyrethroid Insecticides Derived from Some Spiroalkane Cyclopropanecarboxylic Acids R. H . DAVIS and R. J. G. SEARLE Shell Research Ltd., Shell Biosciences Laboratory, Sittingbourne Research Centre, Sittingbourne, Kent ME9 8AG, England
The h i s t o r i c a l developmen roughly i n t o three stages on the s t r u c t u r a l e l u c i d a t i o n of the n a t u r a l p y r e t h r i n s , t h i s was followed by a search f o r simpler a l c o h o l components from which to form e s t e r s with the n a t u r a l acids and in the l a s t decade considerable a t t e n t i o n has been devoted to expanding the v a r i e t y of acids that can give p y r e t h r o i d esters of s i g n i f i c a n t i n s e c t i c i d a l a c t i v i t y on a broad spectrum of s p e c i e s . The success of t h i s l a t t e r work i s demonstrated by the s e l e c t i o n of a c i d s t r u c t u r e s shown (Figure 1).
The structure-activity relationships derived from the work on acid components may be briefly summarised as follows:(a)
The cyclopropane ring i s not essential for activity (1 ).
(b)
Trisubstitutedcyclopropane acids bearing unsaturated substituents give high a c t i v i t y ; several such substituents are known and geometrical configuration can be important (2).
(c)
In unsymmetrical acids activity is highly dependent on chirality (_3, 4_) . (The only exception i s 2,2-dimethylcyclopropanecarboxylic acid (5).)
(d)
Geminal dimethyl groups are an essential structural requirement (3).
(e)
Few tetrasubstitutedcyclopropanecarboxylic acids give active esters (6).
37
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
SYNTHETIC PYRETHROIDS
38
Although search
many
for
agricultural suitable
of
these
stable
observations
pyrethroids
pests
was
started,
some
scope of
for
the
new
synthesis.
allethronyl
it
and
although
use,
it
was of
groups
such
soon
this
these
rings
in
the
well-known used
were
the
many
of
and
in
with
the
the
with
In second
and
interestingly, the
the
gives
1
:
Ring offers
a
a
A
acid
in
of
an
(Figure give
by
by
of
a
9^,
alkane
10),
as
of
was
ready
In
those
also
(Figure
the
an
type the
the
is
4)
1,2
migration evidence
readily
mono,
cyclopropanecarboxylic
that
contracts acid. d i ,
acids
of
and
is
with
in
which
In
this, a
f
the i t
the
- C
base
the
use
well-
has
been
semibenzilic
hydroxide
concerted C
which
of
avoids to
(13)
of
only
contrast
aqueous
method
similar
adds
to
displacement
of
carbonyl
unsymmetrical
ion
bond
mechanism
is
2-bromo-2,3,3,4,4-pentamethylto
the
corresponding
The
scope
of
t r i ,
tetra
and
to
methyleneand,
(12).
useful
by an
was
produces
This
acids
the
for
which
uses
products
mechanism
followed
the
cyclopropane-
materials
ot-haloketones
operative.
atom
observation
allows
of
unsymmetrical
where
ketene-olefin
methylenecyclopropane
superficially
rearrangement
possible
contraction
cases
cycloaddition
possible
interesting
ring
the
cyclobutanones. to
was
two
other
to
the
diazoacetate
olefin the
a
starting
2)
ethyl
cyclobutanone
sequence
case
Although
cyclopropanecarboxylic thus
(cf.
same
one
contraction
dimethyIketene
Further
cyclobutanone
view
dimethyl
(Figure
available,
prepare
isomeric
carbon
5).
benzyl
In
spirofused
with
the
(11).
ring
typical
this
3) only
readily
to
these
underwent
base
to
of
olefin
cyclopropanecarboxylic
that
ion
(6)
agronomic
geminal
by
α-halocyclobutanones
carbonyl
described for
acids
of
(11)
method
the
a c t i -
2,2,3,3-
substituted
contraction
Favorski
afforded
first
of
to
not
mechanistically
shown
(Figure
replacing
of
afforded
photostable.
unreported
dimethyIketene
diazoester.
halide
several and
both
known
the
been
of
rearrangement
of
our
dearth
insecticidal
unstable
1 mixture
preparation of
that
the acids
esters had
too
active of
which
used
prior
possible
addition a
was
were
acid.
cyclobutane
8)
the
aqueous
olefin
halogenated
carboxylic
acid
be
the
when
control
require
chloroketene
cycloadditions
to
Ç7, both
previously
methods.
treated
of
would
cyclopropanation
appropriate
one
that
Previously
effect
α-chlorocyclobutanones
then
appeared
to
studied.
Synthesis
when
used
tetramethylcyclopropane
give
interrelated
reacted
evident
results,
to
esters
acid
systematically
was
available
be
pyrethronyl
tetramethylcyclopropanecarboxylic and,
of
not
could
tetrasubstitutedcyclopropanecarboxylic
vity
esters
were
that
be
the
ring
pentamethylcontraction
pentasubstituted-
prepared.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
3.
DAVIS A N D SEARLE
Derived
Pyrethroid
Insecticides
39
R - H : R = C K , C H C H , CH « C H 3
3
2
2
#
R - R = CH, COOH
R = C H : R = COOCH3 3
R = R - F, CI, Br
H C\ /CH 3
0
H C
CH
3
3
3
γ
H C 3
-COOH H C 3
Figure 1.
Some acids which give active pyrethroid esters
H C 3
y=< H C^
Ph P 3
H„C
3
+ \
Ph P0 3
|
NLCHCOOEt
NaOH H C
H C
3
3
-COOH
-COOEt
H C
H C
3
3
Figure 2.
Synthesis from diazoester-olefin addition
COOH Figure 3.
Synthesis from chloroketene-olefin cycloaddition
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
40
SYNTHETIC
PYRETHROIDS
CH, H C3
H C 3
Br,
COOH
Figure 4.
aq-ICjCOs
Synthesis from dimethylketene-olefin
cycloaddition
General mechanism
Ο
II
C—Β a Hal
12Hal
Specific example H C 3
H C-
aq. KjCOg
3
-Br
H C3
H C 3
CHFigure 5.
Ring contraction of a-halocyclobutanones
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
T.u. = Tetranychus urticae
VII
VI
3
3
CH
IV
\
D> D>
=1/
55
Resmethrin
230
<7
16
1500
330
290
80
76
3
1
<
6 118
5
0.1
0.025
0.025
0.025
0.1
0.025
4.2 5.3 7.6
2.6 4.6
3.9
10.0
6.5
h-«
C O
δι
•-H
s
s*
a-
Ο i-
13.5
w
S 8.9
6.8
5.?
9 0
K» min
2.1
2.8
5.7
5.2
9.5
6.4
0.4
4.8
0.1
3.8
0.05
0.025
% Concentration
5 0
KD min
Knockdown activity
cyclopropanecarboxylates
245 4
620
1
15
24
1
<
14
68
18 1
45
24
<
B.m.
T.u.
Parathion = 100
Comparative activities of some spiroalkane
5
100
12
4
28
CN
38
8
5
3
41 170
430
44
3 4
IMeopynamin
3
3
3
3
600
49
S-Bioallethrin
CH
CH
CH
CH
Figure 6.
H C
3
3
CH
CH
II
V
3
2
CH
3
CH
S.I.
Toxicity index M.d.
η
R
III
1
Compound no.
Μ
CO
>
>
SYNTHETIC PYRETHROIDS
42
Figure 7.
Synthesis route to
Toxicity index η
M.d.
S.I.
Parathion = 100 T.u.
B.m.
Knockdown activity % Concentration K D
5 0
KD
min
min
3
32
530
<1
23
0.1
6.8
8.9
5
<1
<1
<1
<1
0.4
>10.0
>10.0
Figure 8.
Activity of two
9 0
spiroalkanedichlorovinylcyclopropanecarboxylates
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
3.
DAVIS AND SEARLE
Derived
Esterification with
a
variety
tested
on
a
of
(M.d.),
the
as
cotton
is
many
of
the
also with
Although (VII)
the
was
comparison spiro
scientific
dimethyl
derived
a
groups
with
the
parent were
toxic
s t i l l
some
synthesise
in
of
retained
known
which
other
active
acid
acid
type
(14,
(Figure
shown,
the
example
methylenecyclobutane
gave
external
the
and
proton (d,
trans which
J8Hz)
the
compound.
acids
thus
which
(Figure
spiro
compounds
in
gave
tends a n d may
Replacement
of
within
Knockdown not
(c)
The in
geminal
certain
activity
Limiting
the
of
atoms
less
observation
pyrethroids
requirement
or
size
leads will
and
is
:
the
of
activity
1 mixture
by
the
of
vinylic
65.95
ppm
J8Hz)
for
the
spirodihalovinyl activity
experience
of
with
as:groups
leads
houseflies
to
with
and
column
1
insecticidal
several
this
reminiscent for
by
prepared
at
the
dimethyl
have
rationalisation
observed
the
on
on
of
been
chloral
(d,
previous
limits,
activity
by
latter
much
two
ppm
replaced dihalo-
internal a
specturm
65.33
summarised
affected
comprehensive
at
reinforce
be
into
thus
where
the
of
distinguishable
n.m.r.
and
of
'essential
were
of have
separated
materials,
to
insecticidal (b)
the
acid
was
converted
were
15)
mixture
E s t e r i f i c a t i o n of
8)
compound
was
types
condensation
equal
latter
These
cis
prepared
ring,
an
ultimately
appeared
trans
(a)
and
acids.
for
of
insects,
the It
structures
vinylcyclopropanecarboxylic
cis
feature
to
lack
toxicity.
analogues
and
such
on
tetramethyl
less
some
olefins
effect
standards,
far,
chromatography
in
studied.
compounds
to
rings.
In
(B.m.)
significant
Thus
7).
ot-cyano-
houseflies
insecticides
commercial is
been
6).
from on
ticks
pyrethroid
and
compounds,
groups,
interest
spiroalkane
(Figure
activity
cattle
routes have
significant
these
dimethyl
geminal by
that
esters
above which
The knockdown
with
(I),
those
and
resmethrin.
acid
nevertheless
geminal of
in
(S.l.)
the
species
good
commercial
by
43
materials
acarine
shown
comparable
analogous
viewpoint,
have
compound
spiro
prepared novel
and
leafworm and
Insecticides
particularly
existing
S-bioallethrin
houseflies
acids gave
insect
alcohol,
with
particularly
it
of
compounds,
3-phenoxybenzyl comparison
the
alcohols
range
Several
of
Pyrethroid
by
to
a
spirofused
reasonable
species. is
excellent
and
is
modification. spirofused
greatest to
be
ring
to
five
carbon
activity.
taken
into
account
structure-activity of
the
in
DDT a n d
'axial its
in
any
relationships
group
1
size
analogues
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
(16).
44
SYNTHETIC PYRETHROIDS
Acknowledgements We thank Dr. C.B.C. Boyce and Dr. J.H. Davies for many useful discussions, Dr. J.S. Badmin for help in preparing the biological data and Shell Research L t d . , for permission to publish this paper. Abstract Several cyclopropanecarboxylie acids containing spirofused cycloalkane rings have been synthesised and their esters with α-cyano-3-phenoxybenzyl alcohol have been examined for insecticidal activity. Some of these compounds show moderate activity on caterpillars and rapid knockdown of houseflies. Existing structure-activity relationships in pyrethroids are reviewed in the light o Literature Cited 1.
2. 3. 4. 5.
6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
Ohno, Ν . , Fujimoto, K., Okuno, Υ., Mizutani, T., Hirano, Μ., Itaya, Ν . , Honda, T., and Yoshioka, Η . , Agr. B i o l . Chem., (1974) 38, 881. Elliott, Μ., Farnham, A.W., Janes, N.F., Needham, P.H., Pulman, D . A . , Nature, (1973) 244, 456. Elliott, Μ., Farnham, A.W., Janes, N.F., Needham, P.H., Pulman, D . A . , ACS Symposium Series No.2, (1974) 1, 80. Miyakado, Μ., Ohno, Η . , Okuno, Y., Hirano, Μ., Fujimoto, Κ . , Yoshioka, H . , Agr. B i o l . Chem., (1975) 39, 267. Barlow, F., Elliott, Μ., Farnham, A.W., Hadaway, A.B., Janes, N.F., Needham, P.H., and Wickham, J.C., Pesticide Science, (1971) 2, 115. Matsui, Μ., and Kitahara, T., Agr. B i o l . Chem., (1967) 31, 1143. Ger. Patent 2,231,312 to Sumitomo. Searle, R . J . G . , and Woodall, R . E . , unpublished results. U.S. Patent 3,823,177 to Procter Gamble. Elliott, Μ., B u l l . Wld. Hlth. O r g . , (1971) 44, 315. Conia, J.M., and Salaun, J.R., Accounts of Chemical Research, (1972) 5, 33. Isaacs, N . S . , and Stanbury, P . , J. Chem. Soc., Perkin II (1973), 166. Kende, A . S . , Organic Reactions, (1961) 11, 261. Farkas, J., Kouriim, P . , and Sorm, F., Chem. L i s t y , (1958) 52, 688. Elliott, Μ., Farnham, A.W., Janes, N.F., Needham, P.H., and Pulman, D.A., Pesticide Science, (1975) 6, 537. Holan, G . , B u l l . Wld. Hlth. O r g . , (1971) 44, 355.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
4 Recent Progress in Syntheses of the N e w and Most Potent Pyrethroids NOBUSHIGE ITAYA, TAKASHI MATSUO, NOBUO OHNO, TOSHIO MIZUTANI, FUMIO FUJITA, and HIROSUKE YOSHIOKA Synthesis Laboratory, Pesticide Division, Institute for Biological Science, Sumitomo Chemical Co. Ltd., 4-2-1 Takatsukasa, Takarazuka, Hyogo 665, Japan
There have been disclose stable pyrethroids in whic derivative are incorporated as alcohol moieties "Figure 1". 3-Phenoxybenzyl alcohol and i t s α-cyano derivative had originally been discovered to be useful as esters of chrysanthemic acid, i . e . S-2539 or Phenothrin (1,2), and S-2703 (3,4), the potent pyrethroids. Moreover, the former pyrethroid has been known to be more resistant to photo-irradiation than the pyrethroids with other alcohol moieties such as 5-benzyl-3-furylmethyl alcohol (5). But, the photo-stabilities of these pyrethroids had been assessed to be still insufficient under agricultural f i e l d conditions On the other hand, the acid moieties recently developed, i . e . 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxylic acid (6,7) and α - ( 4 - c h l o r o p h e n y l ) - i s o v a l e r i c acid (8,9) have the double bonds stabilized by the two electron-withdrawing chlorine atoms or by the aromatization forming the chloro-substituted benzene ring. 2,2,3,3-Tetramethylcyclopropanecarboxylic acid has apparently no double bond. Therefore, the esters of these acids are much more stable to photo-irradiation than the esters of chrysanthemic acid. Among these new pyrethroids, S-3206 or Fenpropanate (3,4), NRDC-143 or Permethrin (10), NRDC-149 or Cypermethrin (11) and S-5602 or Fenvalerate (8,9) are being assessed to be most promising insecticides for agricultural use owing to their extraordinarily high potency and sufficient f i e l d persistency. Meanwhile, there have been a variety of synthesis studies seeking for the best chemical processes for production of the respective new pyrethroids. In this connection, we now briefly review a number of known synthetic pathways and report new routes leading to the important synthetic pyrethroids and some of their essential intermediates. Method of
esterification
Figure 2 f i r s t represents a conventional method to prepare 45
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
SYNTHETIC PYRETHROIDS
46
CHR ι
C Ν
R.
S-2703
S-2539
1
OR PHENOTHRIN
S-3206 OR FENPROPANATE
NRDC-143
NRDC-W9
OR PERMETHRIN
OR C Y P E R M E T H R I N
α S-5602 OR
Figure 1.
oy
FENVALERATE
Potent synthetic pyrethroids
ο (-CH ) 3
OoiX T.MIZUTANI JAP.
Figure 2.
ET A L .
PAT.11106
Bf
(1976)
Intermediates of 3-phenoxybenzyl esters
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
4.
ITAYA E T A L .
Most Potent
Pyrethroids
47
3-phenoxybenzyl a l c o h o l , which i s an i n t e r m e d i a t e o f P h e n o t h r i n a n d P e r m e t h r i n , a n d i n t r o d u c e s i n c o n t r a s t a new m e t h o d o f t h e p r e p a r a t i o n o f 3 - p h e n o x y b e n z y l e s t e r s w i t h a new i n t e r m e d i a t e . So f a r , b o t h t h e a c i d a n d t h e a l c o h o l a r e p r i m a r i l y t h e r e q u i s i t e s f o r t h e p r e p a r a t i o n o f t h e s y n t h e t i c p y r e t h r o i d s . The c o n v e n t i o n a l method t o p r e p a r e t h e 3-phenoxybenzyl e s t e r c o m p r i s e s the o x i d a t i o n o f 3-phenoxytoluene by a u t o - o x i d a t i o n a t t h e methyl group t o form 3-phenoxybenzoic a c i d , t h e c o n v e r s i o n o f t h e a c i d i n t o the methyl e s t e r and t h e r e d u c t i o n o f the e s t e r w i t h a c o s t l y h y d r i d e r e a g e n t t o y i e l d t h e o b j e c t i v e a l c o h o l , w h i c h i s t o be e s t e r i f i e d with the optional a c i d chloride to give the f i n a l pyrethroid ester. On t h e o t h e r h a n d , t h e new r o u t e c o m p r i s e s two c h a r a c t e r i s t i c s t e p s . The f i r s t s t e p i s t h e p r e p a r a t i o n o f t h e q u a r t e r n a r y ammonium s a l t , 3 - p h e n o x y b e n z y l t r i e t h y l ammonium b r o m i d e ( 1 2 ) and t h e second s t e p i the sodium s a l t o f t h The p r e p a r a t i o n o f t h e ammonium s a l t i s a c h i e v e d b y t h e b r o m i n a t i o n o f 3-phenbxytoluene a t t h e methyl group f o l l o w e d by the q u a r t e r n i z a t i o n w i t h t r i e t h y l a m i n e . We i n i t i a l l y i n t e n d e d t o p r e p a r e p u r e 3 - p h e n o x y b e n z y l b r o m i d e , w h i c h i s t o be c o n v e r t e d i n t o t h e o b j e c t i v e e s t e r w i t h t h e s o d i u m s a l t o f t h e o p t i o n a l a c i d , b u t we e n c o u n t e r e d two m a j o r d i f f i c u l t i e s i n t h i s a t t e m p t . One o f w h i c h was t h a t t h e s e l e c t i v i t y f o r t h e b e n z y l b r o m i d e was n o t h i g h e n o u g h t o n e g l e c t t h e f o r m a t i o n o f t h e b e n z a l b r o m i d e a n d a number o f b y - p r o d u c t s b r o m i n a t e d a t t h e a r o m a t i c n u c l e i . The a n o t h e r d i f f i c u l t y was l a c k of heat s t a b i l i t y o f the bromination mixture, t h a t i s e s s e n t i a l f o r t h e r e c t i f i c a t i o n t o i s o l a t e t h e b e n z y l bromide from t h e mixture. T h e s e d i f f i c u l t i e s were s u c c e s s f u l l y o v e r c o m e b y t h e q u a r t e r n i z a t i o n p r o c e d u r e . T h u s , t h e r e s u l t i n g ammonium s a l t c a n be i s o l a t e d i n a pure s t a t e a s e i t h e r c r y s t a l s by f i l t r a t i o n o r an aqueous s o l u t i o n l e a v i n g o t h e r w a t e r - i n s o l u b l e m a t e r i a l s i n a n o r g a n i c l a y e r on phase s e p a r a t i o n , and t h e y i e l d i s q u a n t i t a t i v e on t h e b a s i s o f t h e b e n z y l b r o m i d e c o n t e n t . In order t o i n i t i a t e the e s t e r i f i c a t i o n r e a c t i o n , a mixture o f t h e a q u e o u s ammonium s a l t a n d t h e s o d i u m s a l t o f t h e o p t i o n a l a c i d i s b o i l e d i n a proper organic solvent t o a z e o t r o p i c a l l y remove w a t e r . T r i e t h y l a m i n e i s r e l e a s e d i n s e q u e n c e o f t h e e s t e r i f i c a t i o n a n d a few p e r c e n t o f N , N - d i e t h y l - 3 - p h e n o x y b e n z y l a m i n e and t h e e t h y l e s t e r o f t h e a d o p t e d a c i d a r e d e t e c t e d i n t h e c r u d e p r o d u c t , w h i c h a p p a r e n t l y r e s u l t f r o m t h e N-C b o n d c l e a v a g e o f N - e t h y l b o n d i n s t e a d o f t h e N - b e n z y l b o n d c l e a v a g e " F i g u r e 3". The t e r t i a r y amine c a n be removed b y a c i d - w a s h i n g a n d t h e e t h y l e s t e r c a n be d i s t i l l e d o f f u n d e r r e d u c e d p r e s s u r e . The y i e l d o f the f i n a l b e n z y l e s t e r i s o v e r 90% a n d t h e p u r i t y o f t h e b e n z y l e s t e r i s o v e r 90%. T h i s new m e t h o d i s more p r a c t i c a l t h a n t h e c o n v e n t i o n a l method, because t h e u s e o f a c o s t l y and dangerous h y d r i d e
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
SYNTHETIC PYRETHROIDS
CH2R MAIN
Acid Na NEt
PRODUCTS
NEt
3
NaBr
3
MINOR
0-o-^^NEt
2
BY-PRODUCT!
Acid ethyl ester CK
or
Figure 3.
New
NaOH ptc N.OHNO ET PTC = PHASE TRANSFER
Figure 4.
FARKAS METHOD
CATALIST
AL.
UNPUBLISHED
(1971)
Syntheses of acid moieties (S-3206 and S-5602)
CI C l / ^ = <
+ ^CHCOzEt
DV acid -£ ~' t
CIS/TRANS = 5/5
SAGAMI
METHOD
>^M>H + CR^OEt^ CIS/TRANS = 3/7
KURARAY
METHOD
* Υ θ Η + CHf
CIS/TRANS = 3/7
OHC NRDC METHOD
Figure 5.
CO2B + Pr>3P+ CCU
Syntheses of acid moieties (NRDC-143 and NRDC-149)
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
4.
ITAYA ET A L .
Most Potent
Pyrethroids
r e a g e n t and the p r e p a r a t i o n o f the c a n be a v o i d e d . Syntheses
of acid
corresponding acid
49 chloride
moieties
The a c i d m o i e t y o f S-3206, 2,2,3,3-tetramethylcyclopropanecarboxylic acid still a p p e a r s t o be b e s t p r e p a r e d by t h e c a r b e n e r e a c t i o n w i t h e t h y l d i a z o a c e t a t e and 2 , 3 - d i m e t h y l - 2 - b u t e n e ( 1 4 ) . a - ( 4 - C h l o r o p h e n y l ) - i s o v a l e r i c a c i d f o r S-5602 c a n be p r e p a r e d in a q u a n t i t a t i v e y i e l d b y t h e h y d r o l y s i s o f t h e c o r r e s ponding n i t r i l e , t h a t i s most s i m p l y o b t a i n e d from 4 - c h l o r o p h e n y l a c e t o n i t r i l e by t h e a l k y l a t i o n w i t h i s o p r o p y l c h l o r i d e a n d a q u e o u s s o d i u m h y d r o x i d e , where a p h a s e t r a n s f e r c a t a l y s t i s e s s e n t i a l t o c o n d u c t t h e r e a c t i o n (150 " F i g u r e 4". In c o n t r a s t , the a c i d m o i e t f NRDC-143 d -149 2,2 dimethyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxyli we c a l l D V - a c i d f o r s h o r t d i f f e r e n t pathways w i t h p a r t i c u l a r c o m p l i c a t i o n s and d i f f e r e n t c i s / t r a n s i s o m e r c o m p o s i t i o n s " F i g u r e 5". T h u s , in F a r k a s method (J), the s a f e and s t e a d y h a n d l i n g o f e t h y l d i a z o a c e t a t e and the p r e p a r a t i o n o f 1 , 1 - d i c h l o r o - 4 - m e t h y l 1 , 3 - p e n t a d i e n e a p p e a r t o be m a j o r p r o b l e m s . I n Sagami method (16) a n d K u r a r a y method ( Γ 7 ) , e t h y l o r t h o a c e t a t e i s a common r e q u i s i t e , w h i c h d o e s n o t seem t o be a v a i l a b l e y e t a t a n e c o n o m i c p r i c e . M o r e o v e r , t h e C l a i s e n r e a r r a n g e m e n t s a r e t o be c o n d u c t e d in t h e e a r l y s t a g e o f t h e m e t h o d s , where e t h y l o r t h o a c e t a t e a n d t h e r e s p e c t i v e o l e f i n i c a l c o h o l s undergo rearrangements a f f o r d i n g the c o r r e s p o n d i n g o l e f i n i c e s t e r s in m o d e r a t e y i e l d s . I n NRDC method (6), t h e W i t t i g r e a c t i o n may be a n e c e s s a r y method f o r t h e p r e p a ration of p a r t i c u l a r stereoisomers. F i g u r e 6 shows one o f t h e new r o u t e s l e a d i n g t o D V - a c i d , where t h e s t a r t i n g m a t e r i a l s a r e t h e c a r o n a l d e h y d e e s t e r a n d c h l o r o f o r m ( 1 8 ) . The m i x t u r e o f t h e a l d e h y d e e s t e r a n d c h l o r o f o r m i s t r e a t e d w i t h potassium hydroxide to a f f o r d the c h l o r o f o r m adduct o f the aldehyde, which i s converted i n t o the a c e t a t e w i t h a c e t i c a n h y d r i d e and r e d u c e d w i t h z i n c d u s t t o y i e l d t h e D V - a c i d e s t e r in a 65% y i e l d . A l t e r n a t i v e l y , t h e c h l o r o f o r m a d d u c t o f t h e c a r o n a l d e h y d e e s t e r c a n be s y n t h e s i z e d f r o m e t h y l 2 , 2 - d i m e t h y l 3 - a c e t y l c y c l o p r o p a n e c a r b o x y l a t e (19) by t h e c h l o r i n a t i o n a t t h e a c e t y l m e t h y l g r o u p . I n t h i s p a t h w a y , t h e W i t t i g r e a c t i o n c a n be r e p l a c e d by the t r e a t m e n t s w i t h c h l o r o f o r m , a c e t i c a n h y d r i d e and zinc dust. The f i r s t s t e p o f t h e a n o t h e r r o u t e t o t h e D V - a c i d i s t h e s y n t h e s i s o f 3 , 3 - d i m e t h y l - 4 - ( 2 , 2 - d i c h l o r o v i n y l ) - b u t a n o l i d e (20), w h i c h i s o b t a i n e d in a 40% y i e l d b y t h e c o n d e n s a t i o n o f 1,1,1t r i c h l o r o - 2 - h y d r o x y - 4 - m e t h y l - 3 - o r - 4 - p e n t e n e (21) a n d v i n y l i d e n e c h l o r i d e in t h e p r e s e n c e o f a 90% s u l f u r i c a c i d a t a t e m p e r a t u r e a r o u n d - 1 0 ° C " F i g u r e 7". The s u b s e q u e n t c l e a v a g e o f t h e l a c t o n e r i n g w i t h methanol and hydrogen c h l o r i d e y i e l d s methyl 3,3d i m e t h y l - 4 , 6 , 6 - t r i c h l o r o - 5 - h e x e n o a t e , w h i c h i s t h e same i n t e r -
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
50
SYNTHETIC PYRETHROIDS
m e d i a t e a s t h a t o f K u r a r a y method a n d i s c o n v e r t e d i n t o t h e DVa c i d e s t e r in a h i g h y i e l d . F i g u r e 8 shows an assumed m e c h a n i s m o f t h e l a c t o n e f o r m a t i o n , in w h i c h t h e m i x t u r e o f t h e t r i c h l o r o a l c o h o l s (Compound V I ) i s c o n v e r t e d i n t o t h e more s t a b l e s i n g l e i s o m e r (Compound V I * ) a n d v i n y l i d e n e c h l o r i d e b e h a v e s l i k e e t h y l o r t h o a c e t a t e to cause the C l a i s e n type rearrangement. In t h i s p a t h w a y , v i n y l i d e n e c h l o r i d e c a n be u t i l i z e d in p l a c e o f e t h y l orthoacetate. In the l i g h t o f c o n t i n u i n g route s c o u t i n g t o the DV-acid, we now i n t r o d u c e a n o t h e r new p a t h w a y s t a r t i n g f r o m t h e known e n o n e , 4 , 4 - d i m e t h y l - 5 - h e x e n - 2 - o n e (22) , w h i c h i s o b t a i n e d b y e i t h e r the rearrangement o f the p r e n y l e n o l e t h e r o f e t h y l a c e t o a c e t a t e f o l l o w e d by the h y d r o l y s i s and d e c a r b o x y l a t i o n o f the r e s u l t i n g k e t o e s t e r w i t h sodium h y d r o x i d e , o r the G r i g n a r d r e a c t i o n o f m e s i t y l o x i d e w i t h v i n y l magnesium c h l o r i d e in t h e presence o f cuprous c a t i o The a d d i t i o n o f c a r b o X I I ) was a c h i e v e d in t h e p r e s e n c e o f a ' r e d o x c a t a l y s t such as C U 2 C I 2 in e t h a n o l a m i n e t o g i v e 4,4-dimethyl-5,7,7,7-tetrachloroh e p t a n - 2 - o n e in more t h a n 80% y i e l d . When t h e t e t r a c h l o r o k e t o n e (Compound XIV) was t r e a t e d w i t h aqueous m e t h a n o l i c sodium h y d r o x i d e a t a t e m p e r a t u r e around 0°C, 2 , 2 - d i m e t h y l - 3 - ( 2 , 2 , 2 - t r i c h l o r o e t h y l ) - c y c l o p r o p y l methyl ketone was q u a n t i t a t i v e l y o b t a i n e d in a 9 t o 1 c i s / t r a n s r a t i o " F i g u r e 10". The r i n g c l o s u r e m a j o r l y a f f o r d i n g t h e c i s i s o m e r may be e x p l a i n e d b y t h e a s s u m p t i o n t h a t t h e e n o l a t e a n i o n and t h e t r i c h l o r o m e t h y l group behave as a b i d e n t a t e l i g a n d f o r the sodium c a t i o n , in a n a l o g y w i t h t h e r e f e r r e d example where t h e c y c l o p r o p a n e d i c a r b o x y l a t e o f c i s c o n f i g u r a t i o n i s o b t a i n e d (24). The c i s c y c l o p r o p y l m e t h y l k e t o n e (Compound XV) h a s b e e n d i s c l o s e d t o be t h e k e y i n t e r m e d i a t e f o r t h e D V - a c i d o f an o p t i o n a l c i s / t r a n s i s o m e r r a t i o by c h o o s i n g two d i f f e r e n t s e q u e n c e s (25,26) " F i g u r e 11". T h u s , t h e c i s r i c h D V - a c i d was o b t a i n e d t h r o u g h t h e f o l l o w i n g s t e p s , i . e . the o x i d a t i o n o f the c i s c y c l o p r o p y l methyl k e t o n e w i t h s o d i u m h y p o c h l o r i t e a t a t e m p e r a t u r e a r o u n d 5°C a f f o r d e d t h e c o r r e s p o n d i n g t r i c h l o r o a c i d (Compound XVI) a n d t h e e l i m i n a t i o n o f hydrogen c h l o r i d e from the t r i c h l o r o e t h y l group o f t h e a c i d w i t h a q u e o u s m e t h a n o l i c s o d i u m h y d r o x i d e y i e l d e d t h e 90% c i s DV-acid. 1
The 90% t r a n s D V - a c i d was o b t a i n e d t h r o u g h t h e o t h e r s t e p s . The c i s c y c l o p r o p y l m e t h y l k e t o n e (Compound XV) was f i r s t t r e a t e d w i t h s o d i u m h y d r o x i d e in b o i l i n g m e t h a n o l t o c o n v e r t t h e t r i c h l o r o e t h y l group i n t o the d i c h l o r o v i n y l group, w h i l e the c i s to t r a n s e p i m e r i z a t i o n simultaneously o c c u r r e d a t the C - l carbon atom y i e l d i n g t h e t r a n s d i c h l o r o v i n y l k e t o n e (Compound X V I I ) . The f i n a l s t e p was t h e o x i d a t i o n o f t h e m e t h y l k e t o n e g r o u p w i t h s o d i u m h y p o c h l o r i t e t o a c a r b o x y l i c a c i d g r o u p t o a f f o r d 90% trans DV-acid. A l l t h e s e s t e p s f r o m t h e t e t r a c h l o r o k e t o n e (Compound XIV)
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
Most Potent
ITAYA E T A L .
Pyrethroids
:p2Me
OAc
Cl C-
AC 0
3
2
(ΙΠ)
(ID
Zn
DV acid CC^Me ester
Q
Y.
Figure 6.
AL. (1975)
OH
-co^t (IV)
ET
UNPUBLISHED
6 5 Z FROM (I)
cip ^
N.ITAYA
NaBri; c i c - < 3
(II)
(V)
New method hyde ester).
>^ ^Μ^^Λ
Γ
Η+
+ o t h
e s) r
(νΠ)Τγ. 40X
(VDCCI3
MeOH £ > ^ > ( ^ e NaOMe ^ > = X c 0 M e 2
H C l
( v n n
Cl
DV acid ester Y.
90X FROM ( V U )
CIS/TRANS -
Figure 7.
3/7
N.ITAYA ET
AL.
UNPUBLISHED(1976)
New method to prepare the DV acid (from 1,1,1-trichloro-2-hydroxy-4-methyl-3- or -4-pentene)
Figure 8.
Assumed mechanism of the lactone formation
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
SYNTHETIC
PYRETHROIDS
A,
COoEt EtOH EtO>_. ^ ^ O H ^F^O ^ T ^ E t -EtOH
(IX)
XP2B
(X)
(XII)
or
>1
"MgQ (ΧΠ)
(ΧΠΙ) Figure 9.
Helvetica Chimica Acta
Methods first method was presented by Brack et al (22).
0(Χ
^ Λ Χ Λ
(ΧΠ)
C
C
l
3
c
l
ΛΧλ
N§OH (XIV)
C
C
l
33 l
(XV) (XV
Y.
Y. 797.
CIS/TRANS =
\b -
C2H5-C
o c H
3 a h.
5
W _/gc
ocV'
9/1
QUANT.
N i
Me Me
'"
(XV)
(XIV)
Modern Synthetic Reactions
Figure
10.
0
Formation of cis-cyclopropylmethyl and assumed mechanism (24)
u^ca
3
ketone
cis DV acid
(XVI)
Y. 85% CIS/TRANS =
9/1
CIS/TRANS =
9/1
v4& MATSUO ET A L .
(χνπ)
UNPUBLISHED
Y
F.FUJITA
trans DV acid ;,S/TRANS =
1/9
UNPUBLISHED
(i976)
Y. 877. CIS/TRANS =
Figure 11.
(1975)
ET A L .
1/9
Formation of cis- and trans-DV acid from cis-cyclopropylmethyl ketone
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
4.
ITAYA E T A L .
Most Potent
53
Pyrethroids
t o e i t h e r o f t h e c i s o r t h e t r a n s D V - a c i d may be c o n d u c t e d in o n e p o t r e a c t i o n . And, i f t h e DV-acid o f an o p t i o n a l c i s / t r a n s r a t i o i s p r e f e r r e d , i t may be done b y a p r o p e r s e l e c t i o n o f t h e r e a c t i o n c o n d i t i o n s in t h e c y c l o p r o p a n e r i n g c l o s u r e a n d t h e s u b s e q u e n t s t e p s . T h e p r e s e n t method h a s a n u n i q u e a d v a n t a g e o v e r t h e o t h e r methods, s i n c e t h e p y r e t h r o i d s d e r i v e d from t h e D V - a c i d have d i f f e r e n t i n s e c t i c i d a l n a t u r e s , d e p e n d i n g o n t h e c i s / t r a n s isomer r a t i o s .
T a b l e I.
RELATIVE TOXICITIES OF CIS AND TRANS ISOMERS HOUSEFLY
COMPD.
ISOMER
(TOPICAL APPLICATION) LD (Y/FLY) 5 0
GERMAN COCKROACH (FILM COTACT METHOD) LC
2
5 0
(MG/M )
HRDC-M3 TRANS
0.020
(1.0)
1.7
(1.0)
CIS
0.0032
(1.9)
0.16
(2.2)
TRANS
0.0060
(1.0)
0.35
(1.0)
NRDC-119
Table I represents ther e l a t i v e i n s e c t i c i d a l potencies o f t h e c i s a n d t r a n s NRDC-143 a n d -149, in w h i c h t h e c i s i s o m e r s a r e n e a r l y t w i c e more t o x i c t o i n s e c t s t h a n t h e c o r r e s p o n d i n g trans i s o m e r s , T h e r e f o r e , t h e c i s p y r e t h r o i d s a r e more p r e f e r r e d t h a n the t r a n s p y r e t h r o i d s from t h e potency c r i t e r i a and t h i s i s t h e f i r s t r e p o r t o f t h e s e l e c t i v e method f o r t h e c i s d o m i n a n t D V - a c i d .
Literature Cited 1.
2.
3. 4.
Itaya,Nobushige; Kitamura,Shigeyoshi; Kamoshita,Katsuzo; Mizutani,Toshio; Nakai,Shinji; Kameda,Nobuyuki; Fujimoto, Keimei; Okuno,Yoshitoshi; Japan. 71 6,904 Fujimoto,Keimei; Okuno,Yoshitoshi; Itaya,Nobushige; Kamoshita,Katsuzo; Mizutani,Toshio; Kitamura,Shigeyoshi; Nakai,Shinji; Kameda,Nobuyuki; Japan. 71 21,473 Matsuo,Takashi; Itaya,Nobushige; Okuno,Yoshitoshi; Mizutani, Toshio; Ohno,Nobuo; Kitamura,Shigeyoshi; Japan. 76 5,450 Matsuo,Takashi; Itaya,Nobushige; Mizutani,Toshio; Ohno,Nobuo; Fujimoto,Keimei; Okuno,Yoshitoshi; Yoshioka,Hirosuke; Agr.Biol.Chem.(1976) 40, 247.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
54 5. 6. 7. 8.
9.
10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.
SYNTHETIC PYRETHROIDS
Fujimoto,Keimei; Itaya,Nobushige; Okuno,Yoshitoshi; Kadota, Tadaomi; Yamaguchi,Takashi; Agr.Biol.Chem.(1973) 37, 2681. Elliott,Michael; Farnham,Andrew W.; Janes,Norman F . ; Needham, Paul H . ; Pulman,David Α . ; Nature,Lond.(1973) 244, 456. Farkaš,Jiří; Kouřím,Pavel; Šorm,František; Chem.listy(1958) 52, 688. Fujimoto,Keimei; Ohno,Nobuo; Okuno,Yoshitoshi; Mizutani, Toshio; Ohno,Isao; Hirano,Masachika; Itaya,Nobushige; Matsuo, Takashi; Japan.Kokai 74 26,425 Ohno,Nobuo; Fujimoto,Keimei; Okuno,Yoshitoshi; Mizutani, Toshio; Hirano,Masachika; Itaya,Nobushige; Honda,Toshiko; Yoshioka,Hirosuke; Agr.Biol.Chem. (1974) 38, 881. Elliott,Michael; Farnham,Andrew W.; Janes,Norman F . ; Needham, Paul H . ; Pulman,David Α . ; Nature,Lond.(1973) 246, 169. Elliott,Michael; Farnham,Andrew W.; Janes,Norman F . ; Needham Paul H . ; Pulman,Davi Mizutani,Toshio; Ume,Yoshitaka; Matsuo,Takashi; Japan. 76 11,106 Mizutani,Toshio; Ume,Yoshitaka; Matsuo,Takashi; Japan.Kokai 75 46,648 Matsui,Masanao; Kitahara,Takeshi; Agr.Biol.Chem. (1967) 31, 1143. Ohno,Nobuo; Umemura,Takeaki; Watanabe,Tetsuhiko; Japan.Kokai 76 63,145 Kondo,Kiyoshi; Matsui,Kiyohide; Negishi,Akira; Takahatake, Yuriko; Japan.Kokai 76 65,734 Mori,Fumio; Ohmura,Yoshiaki; Nishida,Takashi; Itoi,Kazuo; Japan.Kokai 76 41,324 Itaya,Nobushige; Matsuo,Takashi; Magara,Osamu; (unpublished) Payne,George B . ; J.Org.Chem. (1967) 32, 3351. Itaya,Nobushige; Fujita,Fumio; (unpublished) Colonge,Jean; Perrot,André; Bull.Soc.Chim.France. 1957, 204. Brack,K.; Schinz,H.; Helv.Chim.Acta. (1951) 34, 2005. Von Fraunberg,Karl; Ger.Offen. 2,432,232. House,Herbert O.; "Modern Synthetic Reactions. 2nd Edition" W.A.Benjamin,Inc. Menlo Park,California 1972 Matsuo,Takashi; Itaya,Nobushige; Magara,Osamu; (unpublished) Fujita,Fumio; Itaya,Nobushige; Matsuo,Takashi; (unpublished)
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
5 Insecticidally Active Synthetic Pyrethroid Esters Containing a 3-(2,2-Dichlorovinyloxy)benzyl
Fragment
PHILIP D. BENTLEY and NAZIM PUNJA ICI Plant Protection Division, Jealott's Hill, Berkshire, England
Progress of syntheti pyrethroid in term f thei structure - activity led to three important acid and two alcohol fragments :
Chrysanthemic acid and i t s halo, analogues (x = methyl and halogen)
Isopropyl-4-substituted phenylacetic acid (e.g. R = a l k y l , halogen)
3-phenoxybenzyl and α-cyano alcohol
(R = Η and CN)
The combination of each of the acids with the corres ponding alcohols has thus produced i n s e c t i c i d a l l y active pyrethroid esters e.g. :-
55
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
56
SYNTHETIC PYRETHROIDS
phenothrin
NRDC 161
NRDC 143
S 5602
Examination of the alcohol fragment shows that both these alcohols (and many others) comprise of a primary alcohol or cyanohydrin attached to an aromatic or heteroaromatic ring to which is also attached in a 1,3-arrangement a freely rotating phenoxy or benzyl group.
We wished to investigate this freely rotating phenoxy group and to replace it with the dichlorovinyloxy function to give, e.g. :-
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
5.
BENTLEY
AND
PUNJA
Insecticidally
Active
Pyrethroid
Esters
57
A molecular model of 3-(2,2-dichlorovinyloxy) benzyl alcohol retained the structural, special and rotational requirements believed to be essential for insecticidal a c t i v i t y . 1,2-Elimination i n a trichloroethyl group to give 1,1dichlorovinyl group has been applied, using zinc, to several systems. There are notabl elimination :1,2
We, therefore, needed as our precursor, either the acetate or the sulphone moitey :-
3
A paper by Von Hess and Moll which described the reaction of substituted phenols with anhydrous chloral i n the presence of acetyl chloride gave us a direct entry into this synthesis.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
58
SYNTHETIC
PYRETHROIDS
Addition of 3-cresol to an ethereal solution of anhydrous chloral at room temperature, followed by triethylamine and acetyl chloride, gave l-acetoxy-2,2,2-trichloroethyl 3-tolyl ether. The latter was dissolved in glacial acetic acid and reacted with zinc dust at ca. 50°, to give 3-(2,2-dichlorc— vinyloxy) toluene. Bromination of the 3-(2,2-dichlorovinyloxy) toluene with N-bromosuccinimide gave 3-(2,2-dichlorovinyloxy) benzyl bromide. There was no evidence of nuclear bromination.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
5.
B E N T L E Y AND
puNjA
Insecticidally
Active
Pyrethroid
Esters
Reaction of the bromide with the potassium carboxylate (prepared from anhydrous potassium carbonate and the acid in acetone) of chrysanthemic acid, 3,3-dimethyl-2-(2,2dichlorovinyl) cyclopropanecarboxylic acid and isopropyl-4t o l y l acetic acid gave the corresponding pyrethroid esters related to their i n s e c t i c i d a l l y active analogues.
"V ^ cook
—
>
g>=
Sommelet reaction of the bromide with hexamethylene tetramine gave a crystalline quarternary ammonium s a l t , which upon treatment with aqueous acetic-hydrochloric acid, gave 3-(2,2-dichlorovinyloxy)-benzaldehyde. The aldehyde upon treatment with hydrogen cyanide gave 3-(2,2-dichlorovinyloxy)-benzaldehyde cyanohydrin. The cyanohydrin was in turn reacted with the acid chloride (prepared from the acid and thionyl chLoride) of chrysanthemic acid, 3,3-dimethyl 2-(2,2-dichlorovinyl) cyclopropanecarboxylic acid and isopropyl 4-tolyl and 4-chlorophenyl acetic acid gave the corresponding pyrethroid esters related to their i n s e c t i c i d a l l y active analogues.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
59
60
SYNTHETIC
PYRETHROIDS
Ate.
By analogous procedure, the corresponding 2- and 4(2,2-dichlorovinyloxy) benzyl esters were also prepared. Structure-Activity Relations The following generalisation can be made. 1. As in the NRDC series with 3-phenoxybenzyl alcohol, only the pyrethroids containing the 3-(2,2-dichlorovinyloxy) benzyl fragments are insecticidally active. The 2- and 4substituted compounds are inactive. 2. As in the NRDC series, the 3-(2,2-dichlorovinyloxy) benzyl fragment attached tothe c i s -3 3-dimethyl-2-(2,2dichlorovinyl) cyclorpropanecarboxylic acid gives more activ pyrethroid esters than with the trans - acid. D-acid gives higher activity than the DL-add. f
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
5.
B E N T L E Y AND PUNJA
Insecticidally
Active
Pyrethroid
Esters
61
3. As in the NRDC series, the cyanohydrin gives more active pyrethroid esters than the primary alcohol. 4. On representative test insect species (Plutella, Phaedon, Musca and Aedes), the insecticidal activity of the pyrethroid esters containing the 3-(2,2-dichlorovinyloxy) benzyl fragment are somewhat less active than t h e i r corresponding NRDC counterparts. 5. The spectrum of activity of these pyrethroid esters correspond to that of the NRDC series of pyrethroids, e.g. activity is good against Lepidoptera, Coleoptera and Diptera, f a i r against Homopter 6. The rationale for structure-activity relationship thus parallels that of the NRDC pyrethroids containing the 3-phenoxybenzyl fragment. The change from phenyl to dichlorovinyl group thus only affects the degree and not-the nature and spectrum of insecticidal a c t i v i t y . References 1. 2. 3.
Deodhar G. W., J. Indian Chem. Soc., (1934), 11, 83. Kay I. T . and Punja N . , J. Chem. Soc. C, (1968) 3011. Hess Von B. and Moll R . , J. Prakt Chem. (1974), 316. (2), 304.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
6 Pyrethroid-Like Esters of Cycloalkane Methanols and Some Reversed-Ester Pyrethroids M A L C O L M H. BLACK Wellcome Research Laboratories, High St., Berkhamsted, Hertfordshire, HP4 2DY, England
of
Two a s p e c t s o synthetic pyrethroid
P y r e t h r o i d - L i k e E s t e r s of Cycloalkane Methanols. A common f e a t u r e in t h e a l c o h o l i c components o f more effective pyrethroid esters (e.g. pyrethrin I , r e s m e t h r i n and p h e n o t h r i n ) is an u n s u b s t i t u t e d s i d e c h a i n s u p p o r t e d by a p l a n a r r i n g c o n t a i n i n g at l e a s t one olefinic bond. However, it has been c l a i m e d (1,2) t h a t an olefinic group can p l a y a similar r o l e t o the cyclic n u c l e u s ; f o r example
62
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
6.
B L A C K
Esters of Cycloalkane Methanols
63
1
as
II "frai 5 2 ; » II
O"^
II
<* *> PCS
β
«ο
o?
CUD
.Is
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
β»
64
SYNTHETIC PYRETHROIDS
4-aryl-trans-2-butene-1-yl chrysanthemates (I, R=R"=H, R'=Cl) have been shown t o be more effective against h o u s e f l i e s than allethrin (1). The c o r r e s p o n d i n g cis- b u t e n y l e s t e r s were not d e t e c t a b l y a c t i v e . It was, t h e r e f o r e , o f i n t e r e s t t o a s c e r t a i n whether the potency o f t h e t r a n s - b u t e n y l c h r y s a n t h e m a t e s c o u l d be r e t a i n e d w i t h o u t the olefinic bond, solely by p r o v i d i n g t h e a l c o h o l w i t h a rigid t r a n s arrangement o f b e n z y l and h y d r o x y m e t h y l g r o u p s . An indication t h a t such a result might be realised was s u g g e s t e d by a r e p o r t (3) t h a t the 4 - p h e n y l b u t y l c h r y s a n t h e m a t e , I I , was t w i c e as t o x i c t o h o u s e f l i e s as t h e 4 - p h e n y l - 2 - b u t e n y l chrysanthemate (I, R=R'=R"=H). Although surprising, such a result might be a t t r i b u t e d t o the p r e f e r e n c e o f t h butyl ester II t e x i s t in a transoid conformation As t h e d e s i r e d s t r u c t u r a l f e a t u r e s are p r o v i d e d by s m a l l s a t u r a t e d c a r b o c y c l i c r i n g s , the c o r r e s p o n d i n g c i s and t r a n s - c y c l o p r o p y l , I I I a , b , and c y c l o b u t y l , I V a , b , analogues were examined. P r e p a r a t i o n o f Compounds. 4-Phenyl-2-butene~J~yl ( + ) - t r a n s - c h r y s a n t h e m a t e , I , was p r e p a r e d by t h e method of Sota e t a l . , ( . 1 ) , 4-phenyl-butyl (+)-trahis-chrysanthemate TlÎ]T"from t h e 4 - p h e n y l - b u t a n o l (4) and ( + ) - t r a n s c h r y s a n t h e m o y l c h l o r i d e and t h e c y c l o a l k y l m e t h y l ( + ) t r a n s - c h r y s a n t h e m a t e s I I I and IV as shown ( F i g u r e l ) . A n a l y t i c a l and s p e c t r a l d a t a were c o n s i s t e n t w i t h t h e proposed s t r u c t u r e s . R e s u l t s and D i s c u s s i o n . The a c t i v i t i e s f o r k i l l o f h o u s e f l i e s , a r e shown in T a b l e I. I n disagreement w i t h t h e r e p o r t (3,), t h e b u t y l e s t e r , I I , was o n l y one q u a r t e r as p o t e n t " a s t h e t r a n s - b u t e n y l e s t e r , I. T h i s r e s u l t c o u l d be a t t r i b u t e d t o d i f f e r e n t t e s t methods and s p e c i e s s u s c e p t i b i l i t y . Of t h e c y c l o a l k y l m e t h y l c h r y s a n t h e m a t e s , o n l y t h e t r a n s - c y c l o p r o p y l analogue, I l l b , showed d e t e c t a b l e a c t i v i t y , a p p r o x i m a t e l y h a l f t h a t o f t h e t r ans-buteny1 e s t e r , I , b u t s i g n i f i c a n t l y greater than the b u t y l e s t e r I I . I f the a c t i v i t y o f t h e t r a n s - c y c l o p r o p y l analogue depended upon t h e r i g i d t r a n s arrangement o f b e n z y l and h y d r o x y m e t h y l groups, t h e r e l a t e d t r a n s - c y c l o b u t y l analogue, IVb, would a l s o be e x p e c t e d t o be a c t i v e . S i n c e it was a c t u a l l y l e s s a c t i v e , t h e potency o f t h e t r a n s - c y c l o p r o p y l compound is p r o b a b l y a s s o c i a t e d w i t h t h e n a t u r e o f t h e c y c l o p r o p a n y l r i n g , t h e h y b r i d o r b i t a l s o f which, u n l i k e t h o s e o f c y c l o b u t a n e , can p r o v i d e it w i t h some o f t h e c h a r a c t e r i s t i c s o f an olefinic bond, a p p a r e n t l y necessary f o r u s e f u l a c t i v i t y w i t h i n t h i s s e r i e s o f
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
6.
BLACK
Esters of
Cycloalkane
Methanoh
Table
chrys .O , C H 2
Compound
65
I.
X - CH 2
LD5O
X
γ/ο
Isomer Alone
I
-CH=CH
II
-CH2—
-
trans
+P.B.(1:5)
Relative Potency Synergised
0.3
40
>6.0
>2.4
<5
3.4
0.7
17
0.43
CH2
Ilia
-CH
CH
-
cis
Illb
- C H — CH
-
trans
IVa
/ / -CH—CH
-
cis
>6.0
>2.4
<5
IV b
/ / -CH—CH
-
trans
>6.0
>2.4
<5
Bioallethrin
0.42
0.12
100
compounds. Reversed E s t e r
Pyrethroids.
P y r e t h r o i d - l i k e e s t e r s o f c y c l o p r o p a n e methanols a n c * other r e l a t e d compounds ( T a b l e I I ) have been examined t o determine the e f f e c t on a c t i v i t y o f modifying the e s t e r l i n k . A l l were c o n s i d e r a b l y l e s s p o t e n t t h a n t h e p a r e n t e s t e r s and a c a r b o n y l group a d j a c e n t t o t h e c y c l o p r o p a n e r i n g appears t o be essential for pyrethroid-like activity. However t h e compounds t h a t l a c k t h i s a p p r o p r i a t e l y p l a c e d c a r b o n y l group a l s o l a c k t h e s p a t i a l c h a r a c t e r i s t i c s o f the n o r mal e s t e r l i n k a g e . T h e r e f o r e , in t h i s work, p y r e t h r o i d - l i k e compounds ( T a b l e i l l , V-VEH) r e t a i n i n g t h e s p a t i a l c h a r a c t e r i s t i c s o f t h e normal e s t e r l i n k a g e but l a c k i n g c a r b o n y l groups a d j a c e n t t o t h e c y c l o p r o p a n e r i n g , were examined. Reversal of the e s t e r l i n k a g e provides these f e a t u r e s and a l s o r e t a i n s a r e g i o n o f p o l a r i t y in t h e l i n k a g e
(jL'ÎL>Z)
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
66
SYNTHETIC PYRETHROIDS
Figure 2. SOCl /C H ; 2
6
6
Reagents: (i) (n-Bu) SnH; (ii) Li/0 (υ) CH N /Ag 0; (vi) TsCl/pyridine oxy phenyl] 3
2
2
2
2
[-70°]; (Hi) ClCOOEt/Et N; (iv) [R = l-benzyl-3-furyl andMe-phen-
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
s
6.
Esters of Cycloalkane
B L A C K
67
Methanoh
Table I I ,
COMPOUND
R.T. 130
tet-CO-NH-CH -bf 2
R.T.
COMPOUND chr-CH -0-CO-bf
<1
2
tet-CO-CH -CH -bf
47
chr-NH-CO-0-CH -bf
<1
tet-CH -CO-0-all
<1
chr-NH-CO-O-all
<1
chr-CO-CH -all
16
c h r - C O - O - a l l (allethrin)
chr-CH -0-all
<1
t e t - C O - 0 - C H - b f ( N R D C 108)
R.T.
= Relative toxicity
(Allethrin =
tet
= 2,2,3,3-Tetramethylcyclopropyl.
bf
= 5-Benzyl-3-furyl.
all
= 2-Allyl-3-methylcyclopent-2-ene-4-yl»
chr
=
2
2
2
2
tet-CH .OH-CH -CH -b 2
2
2
2
2
100
1600
100).
2,2,-Dimethyl-3-(2-methylpropenyl)-cyclopropyl.
near t o t h a t o f t h e normal e s t e r . P r e p a r a t i o n o f Reversed Esters» The compounds were s y n t h e s i s e d as shown in F i g u r e 2 . A n a l y t i c a l and s p e c t r a l d a t a were c o n s i s t e n t w i t h t h e proposed structures. The α - i s o p r o p y l - p h e n y l a c e t a t e , IX and NRDC 1 0 8 were p r e p a r e d by r e p o r t e d p r o c e d u r e s ( 7 , ^ , 8 ) . R e s u l t s and D i s c u s s i o n . The a c t i v i t i e s , a g a i n s t h o u s e f l i e s , b o t h a l o n e and s y n e r g i s e d w i t h p i p e r o n y l b u t o x i d e a r e shown in T a b l e I I I . A l l t h e r e v e r s e d e s t e r p y r e t h r o i d s a r e l e s s potent than the parent e s t e r s 5 however, t h e y a r e s i g n i f i c a n t l y more a c t i v e t h a n p r e v i o u s l y r e p o r t e d compounds t h a t l a c k a c a r b o n y l group a d j a c e n t t o t h e c y c l o p r o p a n e r i n g . It was s i g n i f i c a n t t h a t w i t h b o t h c y c l o p r o p y l and p h e n y l -
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
68
SYNTHETIC
PYRETHROIDS
Table I I I .
No.
COMPOUND
ESTER LINK
LD50 %l%
F.o.S.
ALONE
+P.B.(1:5)
R
5.14
1.35
3.8
NRDC 108
Ν
0.022
0.012
1.8
VII
R
4.8
0.98
4.9
VIII
R
c.6.0
1.35
4.5
IX
Ν
0.475
0.1
4.75
0.42
0.12
3.5
—
V
VI
BIOALLET.HRIN
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
6.
B L A C K
Esters of Cycloalkane
Methanoh
69
p r o p y l e s t e r s , t h e b e n z y l f u r a n moeity c o n f e r r e d g r e a t e r a c t i v i t y t h a n t h e phenoxyphenyl m o i e t y . The p h e n y l p r o p y l e s t e r , V I I I , has o n l y o n e - t e n t h t h e a c t i v i t y o f t h e p a r e n t e s t e r , I X j t h e c y c l o p r o p y l e s t e r , V, s u f f e r ed an even g r e a t e r r e d u c t i o n ( c . l / l O O t h ) . This s u g g e s t e d t h a t t h e potency o f r e v e r s e d e s t e r s might be improved f u r t h e r by u s i n g o t h e r s y n e r g i s t s . The compounds were t h e r e f o r e t e s t e d w i t h FMC 1 6 8 2 4 , a s y n e r g i s t c l a i m e d ( 9 . ) t o be h i g h l y effective for tetramethrin. As shown in T a b l e IV, i n c r e a s e in a c t i v i t y was r e a l i s e d w i t h t h e c y c l o p r o p y l f u r a n a c e t a t e V. T h i s compound was t e s t e d f u r t h e r w i t h an analogous s y n e r g i s t FMC 1 1 5 2 3 . A s i m i l a r and s l i g h t l y improved r e s u l t was o b t a i n e d , r e v e a l i n g an a c t i v i t y a p p r o a c h i n g that of b i o a l l e t h r i n
Figure S.
The r e d u c t i o n in a c t i v i t y t h a t accompanies r e v e r s a l o f t h e e s t e r l i n k a g e might be a s c r i b e d t o a change in t h e geometry o f t h e l i n k a g e , as shown in F i g u r e 3 (x = a p p r o x i m a t e l y 1 0 ° ) . T h i s c o u l d a l t e r the s t r u c t u r a l i n t e r a c t i o n s o f t h e " a l c o h o l i c " p o r t i o n a t t h e s i t e o f a c t i o n . However, t h e r e s u l t s o f t h i s s t u d y demonstrate t h a t , p r o v i d i n g t h e l i n k a g e has s i m i l a r s p a t i a l c h a r a c t e r i s t i c s t o t h e normal e s t e r , a c a r b o n y l group a d j a c e n t t o t h e c y c l o p r o p a n e r i n g is not an e s s e n t i a l r e q u i r e m e n t f o r p y r e t h r o i d - l i k e a c t i v i t y .
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
70
SYNTHETIC
PYRETHROIDS
Table IV.
No.
COMPOUND
ESTER LINK
LD50 %/% ALONE
+16824(1:5)
F.o.S.
—*
R
V
R
VI
5.14
>6.0
0.19
27
|0.16|
11
2.3
>2.6
NRDC 108
Ν
0.022
0.020
1
VII
R
4.8
1.0
4.8
VIII
R
2.0
3
BIOALLETHRIN
-
c6.0
0.42
0.12
+
P-OCH CsCH 0
2
I
CI OCH CH(CH ) 2
3
2
FMC 11523
FMC 16824
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
-
6.
Esters of Cycloalkane
BLACK
Methanoh
71
E v a l u a t i o n o f I n s e c t i c i d a l Activities» Compounds were t e s t e d by t o p i c a l a p p l i c a t i o n o f c e l l o s o l v e s o l u t i o n s ( 0 . 6 μΐ a l o n e and 0 . 2 4 μΐ w i t h p i p e r o n y l b u t o x i d e ) on t h e dorsum o f t h e t h o r a x o f female h o u s e f l i e s (Musca domestica - l a b o r a t o r y s u s c e p t i b l e s t r a i n ) by a micrometer s y r i n g e . The dose t o g i v e an L D 5 0 , based on t h e m o r t a l i t y t w e n t y - f o u r hours a f t e r t r e a t m e n t , was e s t a b l i s h e d . The maximum dose f o r compounds t e s t e d a l o n e was 6 V and f o r t h o s e i n combination with p i p e r o n y l butoxide (1:5) 2 . 4 2 Γ · Literature (1) (2) (3) (4) (5) (6) (7) (8) (9)
Cited.
S o t a , K., e t al. B o t y u - K a g a k u ( 1 9 7 3 ) 38 181 Osbond, J.M. & 1,961,777. Elliott, Μ . , Bull. W l d . Hlth. Org., ( 1 9 7 1 ) , 44, 315-324. B a k e r , R.H., M a r t i n , W . B . , J. O r g . Chem., ( 1 9 6 0 ) , 25, 1496. M a t s u i , M., e t al., Bull. A g r . Chem. Soc., J a p a n , ( 1 9 5 6 ) , 20, 89. K a t s u d a , S., Japanese P a t e n t 8498, ( 1 9 6 1 ) . B e r t e a u , P.E., C a s i d a , J.E., J. A g r . Food Chem., (1969) 17. 9 3 1 . Belgium P a t e n t , 801,946. U . S . Patents. 3,885,031; 3,557,259.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
7 Insecticidal Activities of Synthetic Pyrethroids YOSHIYUKI INOUE, SHIGEKI OHONO, TAKAO MIZUNO, YASUO YURA, and KEISUK MURAYAMA Central Research Laboratories, Sankyo Co. Ltd., No. 2-58 Hiromachi 1-chome, Shinagawa-ku, Tokyo 140, Japan
Pyrethroids (natural coming increasingly important because they possess a unique combination of desirable properties including exceptionally good insecticidal activity, low mammalian toxicity, and rapid bio degradation. These features, c o m b i n e d with their b r o a d spectrum of insecticidal activities, h a v e made t h e m commercially successful, and also environmentally safe. There have been desired synthetic insecticide having higher toxicity on insects, lower cost, lower mammalian toxicity a n d some u n i q u e properties for actual uses. In general, the uses o f pyrethroids are mainly limited by high cost and by their instability for certain possible uses.
RESULTS AND DISCUSSION recognized by Nakada and collaborators (1) t h a t several compounds were isolated by pyrolysis of allethrin heated a t 400°C. Two of t h e compounds obtained by t h e pyrolysis were indanone derivatives as shown in Fig. 1. These indanones showed themselves weak insecticidal activities. The activity was measured by using first instar nymphs of the American cockroach as first screening insect. According to this method, each compounds dissolved in a c e t o n e were deposited into a 20 ml glass vial. After evaporating the solvent, 10 nymphs of the cockroach were introduced into the vial. Then the vial was covered with a plastic lid. Mortality of nymphs after 24 hours was measured. As shown in Fig. 2 the degree of effectiveness against nymphs of the cockroach was presented by using a mark from A to E. In the case of A, 100 per cent kill of nymphs of cockroach was obtained by using 1 ygr of the compound. These indanones obtained by pyrolysis have a It was
72
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
7.
INOUE
E T
AL.
Insecticidal
Figure 1.
Activities
Pyrolysis of allethrin
0 Ε
Β
Degree of effectiveness A
C
Insecticidal effect 1 jjg
100 /o e
kill
Β
1 0 jjg
1 0 0 °/.
C
1 0 0 jjg
1 0 0 7o
kill kill
D
1000
jjg
1 0 0 °/o
Ε
1000
jjg
0 °/o
kill
Dose: j j g / v i a l test insect . f i r s t instar nymphs of the American cockroach. Figure 2.
Degree of effectiveness
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
74
SYNTHETIC
PYRETHROIDS
s t r u c t u r a l s i m i l a r i t y t o a l l e t h r o l o n e . Thus, i n d a n o l ester of crysanthemic a c i d was s y n t h e s i z e d . This c o m p o u n d d i d n ' t show i n s e c t i c i d a l a c t i v i t y . Therefore, more s i m p l i f i e d d e r i v a t i v e s w e r e s y n t h e s i z e d . As a r e s u l t , 1 - i n d a n y l c h r y s a n t h e m a t e i n d i c a t e d i n s e c t i c i d a l a c t i v i t y t h o u g h t h e a c t i v i t y was l e s s than that of a l l e t h r i n . T h e r e f o r e m o d i f i c a t i o n s o f i n d a n y l and r e l a t e d b e n z o f u r a n y l o r b e n z o t h i o p h e n y l compounds were c a r r i e d out. C h e m i c a l s t r u c t u r e and t h e i r i n s e c t i c i d a l a c t i v i t i e s a r e shown in F i g . 3. The m e t h y l g r o u p a t imp o s i t i o n was effective but benzyl or chloro s u b s t i t u ent were n o t effective. Further introduction of m e t h y l g r o u p was n o t effective. 2,3-Dihydro-7-methyl3-benzofuranyl chrysanthemate which c a l l ES-56 ex hibited activity. Synthetic rout Fig A c c o r d i n g t o o u r s y n t h e t i c r o u t e , t h e f i r s t s t e p is e t h e r f o r m a t i o n w i t h o - c r e s o l and c h l o r o a c e t i c a c i d . Conversion with t h i o n y l c h l o r i d e t o the a c i d c h l o r i d e f o l l o w e d by F r i e d e l - C r a f t c y c l i z a t i o n w i t h a l u m i n i u m c h l o r i d e gave 7 - m e t h y l - 2 , 3 - d i h y d r o b e n z o f u r a n o n e . Reduction o f the ketone leads t o 7-methyl-2,3-dihydrobenzofuranol . E s t e r i f i c a t i o n o f the benzofuranol with c h r y s a n t h e m i c a c i d c h l o r i d e r e s u l t s in f i n a l p r o d u c t . The a c t i v i t i e s o f ES-5 6 w e r e c o m p a r e d w i t h known pyrethroids. Insecticidal a c t i v i t i e s of pyrethroids against nymphs o f t h e c o c k r o a c h a n d t e r m i t e a r e shown in T a b l e 1. U s i n g d r y f i l m m e t h o d , 0.1 y g r o f p e r m e t h r i n killed 10% o f c o c k r o a c h o r 8 5% o f t e r m i t e . P e r m e t h r i n was most effective. The a m o u n t o f 0.1 y g r o f d - t r a n s o f ES-56 k i l l e d 20 p e r c e n t o f c o c k r o a c h . T a b l e 2 shows t h e r e s u l t o f i n s e c t i c i d a l a c t i v i t y o f p y r e t h r o i d s a g a i n s t common h o u s e f l y b y t o p i c a l a p p l i c a t i o n method. LD o f ES-56 was 0.41 y g r p e r f l y . d - t r a n s P h e n o t h r i n a n d r e s m e t h r i n s h o w e d h i g h e r insecticidal activity. T a b l e 3 shows t h a t t h e i n s e c t i c i d a l a c t i v i t y o f p y r e t h r o i d s a g a i n s t t h r e e s p e c i e s o f c o c k r o a c h was examined by t o p i c a l a p p l i c a t i o n method. Only d - t r a n s p h e n o t h r i n a n d r e t h m e t h r i n w e r e more effective than ES-56. The p e r s i s t e n c e o f ES-5 6 a n d r e s m e t h r i n a r e shown in T a b l e 4 u s i n g t e r m i t e , C o p t o t e r m e s f o r m o s a n u s . E a c h amount o f 0.1 mg a n d 1 mg o f p y r e t h r o i d s w e r e a d d e d in a g l a s s v i a l p r e v i o u s l y m e n t i o n e d , a n d mort a l i t y was m e a s u r e d a f t e r 1 t o 12 8 d a y s . I n the case 5 0
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
1. v
o f
:
:
C
Τ
( f i r s t
(Coptotermes
C o c k r o a c h
T e r m i t e
nymphs
o f
f o r m o s a n u s ) .
i n s t a r
0
85 10
100
P e r i p l a n e t a
a m e r i c a n a ) .
100
100
100
100
P e r m e t h r i n ( d l - c i s , t r a n s = 1
100
0
10
5 100 100
100
100
100
P h e n o t h r i n ( d - t r a n s )
100
30
0 100
100
100
100
100
R e s m e t h r i n
100
0
0 0
0
25
30
100
100
P h t h a l t h r i n
0 0
0
0
0 0
0
0 0
0
85
60
100
100
100
100
A l l e t h r i n
0
0 0
20
100
100
100
100
56)
100
o f
100
( t r a n s
0
τ
yg
0
353
0
0
100
100
c
100
τ
0.01
100
c
yg
100
τ
0.1
100
yg
ES-56
1
c
yg
o f
τ
10
(%)
nymphs
c
yg
a g a i n s t method.
M o r t a l i t y
d r y f i l m
p y r e t h r o i d s by
τ
100
t e r m i t e
e f f e c t
C
:1)
and
I n s e c t i c i d a l
c o c k r o a c h
P y r e t h r o i d s
T a b l e
CO
ο
S* «·».
I
et*
ο
ϊ
I
76
SYNTHETIC
Table
PYRETHROIDS
2. I n s e c t i c i d a l a c t i v i t y o f ES-56 a n d o t h e r P y r e t h r o i d s on t h e h o u s e f l y by t o p i c a l a p p l i c a t i o n method. LD50
Compounds
(yg/fly)
ES-56
0.41
Allethrin
1.44
Phthalthrin
1.55
Resmethrin
0.10
PhenothrinC d-trans)
0.09
Furamethrin
0.55
Proparthrin Butethrin
3
T ^
0.33
X
CH
3
CH
Substituents X
none
CH2
C
0
Β
S
Β
Figure
S.
1-CH C —
c
3
3
(Y) 4-CH C H
2-CH3
3-CH3
4-CH
c
c
Β
C
c
Β
A
Β
D
Β
Β
3
2
6
5
—
Modifications of indanyl and related benzofuranyl or benzothiophenyl compounds
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
18.9 31.1 100yg=0 % 7.6 3.5 63.0 49.0 49.0
20.9 49.0 100yg=10% 15. 5 14.4 21.9 24.5 55.9
2.32 4.75 10 .70 1.20 1.23 6.90 4.11 1 1 . 20
ES-56
Allethrin
Phthalthrin
Resmethrin
PhenothrinCd-trans)
Furamethrin
Proparthrin
Butethrin
Ρ.americana
Ρ.fuliginosa
(yg/cockroach)
Β.germanica
5
LD ο
3. I n s e c t i c i d a l a c t i v i t y o f ES-56 a n d o t h e r P y r e t h r o i d s on t h e 3 s p e c i e s o f c o c k r o a c h e s b y t o p i c a l a p p l i c a t i o n method.
Compounds
Table
3
CO
I
Ci
I
Ci*
a
TO
r
>
I
78
SYNTHETIC
ff^,
NaOH γ. 97 ./.
S^O^ CH
2
^OH CH
COOH I
ClCH COOH
3
1) S0C1
*
-QH
>=
^
CH C H 3
3
^ ^ CH
0
^
3
COCt
Pyridine or CH
1=0
2
2) Al C l Y. 65 ./.
3
Reduction
.
PYRETHROIDS
Et3N
Y. 9 3 ./.
3
/C=CH-CH-CHCO
0 T
-
Compound E S - 5 6 (dl-cis . trans) CH
3
CH
Reduction : Na BH4
3
in
C
H
3
MeOH-i - Propyl
ether
Y.
87 ./.
H /5% 2
Figure 4.
Synthesis of (dl-cis,
trans-mixture).
T a b l e 4. T h e p e r s i s t e n c e o f e f f e c t i v e n e s s against termite.
ι
Mortality
Dose
Compounds j ES-56 i 0.1
lday
7
100
i 1.0 R e s m e t h r i n \ 0.1 1.0
(mg)
Dry
film
(%)
14
28
56
64
100
100
100
100
5
0
100
100
100
100
100
100
0
100
55
100
100
0 100
128
0
0
0
0
0
0
0
0
method.
o f 1 mg o f E S - 5 6 , t h e e f f e c t t o k i l l 1 0 0 % o f t e r m i t e s c o n t i n u e d f o r 64 d a y s . Whereas t h e c o r r e s p o n d i n g e f f e c t o f r e s m e t h r i n w a s o n l y 14 d a y s . A l a b o r a t o r y t e r m i t e t e s t was c a r r i e d o u t u s i n g -Coptotermes f o r m o s a n u s . T h e t e s t b l o c k was J a p a n e s e c e d a r a n d t h e s i z e o f t h e b l o c k was l x l x l cm. The b l o c k was t r e a t e d w i t h m e t h a n o l s o l u t i o n o f e a c h com p o u n d s a n d t h e v o l u m e o f a b s o r b e d s o l u t i o n was 300 m l per m . T h e e x p o s u r e t o t e r m i t e was c a r r i e d o u t f o r 15 d a y s w i t h o u t w e a t h e r i n g . Then, w e i g h t l o s s o f t h e b l o c k a n d s u r v i v a l o f t h e t e r m i t e were measured. The r e s u l t s a r e shown in T a b l e 5. P e r m e t h r i n s h o w e d t h e strongest effects against termite. B u t ES-56 was a l s o effective. 2
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
20.6
10.4
2
100
100 100
0 100
23 . 6 20 . 6
100
100
30 0
100
100
28
Wood p i e c e : J a p a n e s e c e d a r ( C r y p t o m e r i a j a p o n i c a ) 10 χ 10 χ 10 T e r m i t e : C o p t o t e r m e s f o r m o s a n u s j E x p o s u r e p e r i o d : 15 d a y s . Solvent : methanol, S u r f a c e t r e a t m e n t : 30 0 m l / m
Untreated
26.6
18 .2
0
Allethrin
Phthalthrin
14 . 4
4.4
0
Phenothrin (d-trans)
0
9. 9
7.8
0
Resmethrin
100
100
0.002
(%)
22
26
0 0
0 .02
0.2
Surviving
test.
11 . 1
0
0
13 .1
0. 002
Permethrin ( d l - c i s , d l - t r a n s , 1 : 1)
9.4
0.02
l o s s (%)
0
0.2
Weight
ES-56
s=:::::
5. R e s u l t s o f t e r m i t e
^* =^c^r----^ of ^ attack ^ " " ^ ^ ^ t i ^ T ^ — ^^hi^taori Pyrethroids ^^^-^)
Table
mm.
CD
-α
CO
Ci
ϊ
2!
§ M
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
Temperature(°C) 93
112
120 132
180 136
138
300
140
360
142
420
3.3 0
0
0
0
0
Resmethrin
60
0
0
0
0
0
0
Phthalthrin
(second)
0
0
0
0
0
0
Allethrin
Time
70.0
60.0
46. 7
36.7
23.3
0
ES-56
60
50
40
30
(%)
20
240
Knockdown
10 m i n .
Compounds
Tabe 6. K n o c k d o w n e f f e c t b y v a p o u r o f p y r e t h r o i d s on t h e h o u s e f l y .
ο i
1
3
Ω
ni
CO
ο
00
7.
INOUE
Insecticidal
E T A L .
Activities
81
A new b o x t y p e a p p a r a t u s was d e v i c e d f o r f u m i gation or mist spraying test. T h e s i z e o f t h e b o x was 30 χ 30 χ 30 cm. T e s t i n s e c t s w e r e i n t r o d u c e d i n t o the box a f t e r f u m i g a t i o n o r m i s t s p r a y i n g w i t h o u t leak ing o f the i n s e c t i c i d e . The d i a g r a m is shown in F i g . 5. The k n o c k d o w n e f f e c t b a s e d o n v a p o u r a c t i o n o f p y r e t h r o i d s was m e a s u r e d b y u s i n g common h o u s e f l y . One mg o f e a c h compound was h e a t e d up t o 142°C o f t h e heater during 7 minutes. Then, t h e t e s t i n s e c t s were i n t r o d u c e d i n t o t h e box and t h e percentage o f knock down was d e t e r m i n e d . The r e s u l t s a r e shown in T a b l e 6. ES-56 s h o w e d b e t t e r r e s u l t t h a n a l l e t h r i n , p h t h a l t h r i n and r e s m e t h r i n . The i n s e c t i c i d a l a c t i v i t y o f ES-56 was i n c r e a s e d when c o m b i n e d w i t h s a f r o x a n 1-dodecylimidazole U s i n g t h e box the e f f e c t o f mist spraying y t e s t e d u s i n g 0.4% a c e t o n s o l u t i o n . The r e s u l t s a r e shown in T a b l e 7. The k n o c k d o w n e f f e c t was i n c r e a s e d when 1 - d o d e c y l i m i d a z o l e was a d d e d . The i n s e c t i c i d a l e f f e c t o f s a f r o x a n e was s t r o n g e r t h a n t h a t o f 1dodecylimidazole.
Table
7. M i s t s p r a y i n g t e s t a g a i n s t h o u s e f l y b y u s i n g a new b o x a p p a r a t u s .
Compounds
Concentration (%)
KT (min.)
Mortality (%)
5 0
Allethrin
0.4
55.2
2.5
ES-56
0.4
39.8
5.0
ES-5 6 +
Safroxane
0.4 + 2
32.8
50.0
ES-56 +
^Dodecyl imidazole
0.4 + 2
29.1
37.5
Solvent : acetone Amount o f s p r a y : 0 . 6 5 m l / 3 0 x 3 0 x 3 0 c m
I n t h e c a s e o f t h e m i x e d r a t i o , 1 t o 5, b e t t e r s y n e r g i s t i c e f f e c t s were o b s e r v e d . The i n s e c t i c i d a l a c t i v i t y o f t h i n wood t r e a t e d w i t h p y r e t h r o i d s c o n t a i n i n g s y n e r g i s t s was t e s t e d a f t e r exposing t o u l t r a v i o l e t l i g h t . I n t h i s experiment, w e a t h e r - O m e t e r h a v i n g o n e c a r b o n a r c l a m p was u s e d . The i r r a d i a t i o n t i m e was f r o m 3 t o 12 h o u r s . After i r r a d i a t i o n , t h e f i r s t i n s t a r nymphs o f t h e A m e r i c a n
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
82
SYNTHETIC
PYRETHROIDS
30cm
Insect
•A ο
ο
Fun
CO
Hole for spraying Packing Sample pan
Heater Figure 5.
A diagram of new box-type testing apparatus
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
7.
INOUE
E T
AL.
Insecticidal
Activities
83
c o c k r o a c h were c o n t a c t e d on t h e s u r f a c e o f t h e t h i n wood a n d t h e m o r t a l i t y was m e a s u r e d . The r e s u l t s a r e shown in T a b l e 8.
Table
Pyrethroids
ES-56
8.
I n s e c t i c i d a l a c t i v i t y o f wood treated with pyrethroids after exposing to u l t r a v i o l e t l i g h t Mortality
Synergists
(%)
Ohr*
3
6
9
12
100
80
30
0
0
100
100
100
25
0
100
0
0
0
0
Safroxane
; loo
0
0
0
0
1-Dodecyl imidazole
J 100
0
0
0
0
Safroxan 1-Dodecy imidazole
Resmethrin
* I r r a d i a t i o n time Concentration : 0.2% a c e t o n e Mixed r a t e , 1 : 1 W e a t h e r - 0 m e t e r was u s e d .
solution
ES-56 was w e l l p r o t e c t e d by t h e a d d i t i o n o f s y n e r g i s t s from u l t r a v i o l e t l i g h t . As a p a r t o f t h e t o x i c i t y s t u d i e s o f E S - 5 6 , L D 5 0 (mg/kg) was e x a m i n e d . The r e s u l t s a r e s h o w n in T a b l e 9. The t o x i c i t y o f c o m p o u n d 56 w o u l d be l e s s t h a n that of a l l e t h r i n . I n c o n c l u s i o n , ES-56 h a s b e t t e r i n s e c t i c i d a l a c t i v i t y and r e l a t i v e l y l o n g e r r e s i d u a l e f f e c t . Moreover, l o w e r c o s t is t o be e x p e c t e d . T h e r e is much o f w o r k y e t t o be d o n e in f u n d a m e n t a l t e s t s o n t h i s new pyrethroid. We a r e now m a k i n g e x t e n s i v e e f f o r t f o r f u r t h e r d e v e l o p m e n t o f t h i s compound, e s p e c i a l l y t o x i c o l o g i c a l s t u d i e s o n it. REFERENCES 1. N a k a d a y , Y u r a . Y a n d M u r a y a m a Κ : Bull. Chem. S o c . J a p . ( 1 9 7 1 ) , 4 4 , 1724
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
3412
3590
661
692
Peroral
5 0
(mg/kg)
1758
1863
334
326
Subcutaneous
LD
ES-56
: m o u s e , m a l e 5 1 3 , f e m a l e 416 r a t , m a l e 1 0 8 4 , f e m a l e 1217
female
Allethrin
(wister)
male
female
(ddy)
Rat
male
sex
Mouse
Animals
T a b l e 9. T o x i c i t y o f compound
/
3 ml 3 ml
>
4000
>
3524
3000 ~
Percutaneous
I
Ο
1
00
8 Neurophysiological Study of the Structure-Activity Relation of Pyrethroids T. NARAHASHI, K. NISHIMURA, J. L. PARMENTIER, and Κ. ΤΑΚΕΝΟ Department of Physiology and Pharmacology, Duke University Medical Center, Durham, N. C. 27710 M. ELLIOTT Rothamsted Experimental Station, Harpenden, Hertfordshire, AL5 2JQ, England
Much information is tween the s t r u c t u r e and of insecticides, i n c l u d i n g DDT and its d e r i v a t i v e s , organophosphates, carbamates and p y r e t h r o i d s ( 1 ) . A common procedure in such s t u d i e s is to compare activities of compounds with systemat ically a l t e r e d s t r u c t u r e s . To i n t e r p r e t such r e s u l t s rationally, the complex nature of the t o x i c a c t i o n of insecticides, illus trated diagrammatically in Figure 1 ( 2 , 3) must be recognized. The first step in the a c t i o n of an insecticide is penetra tion i n t o the i n s e c t body, v i a the cuticle, mouth or r e s p i r a t o r y system. The i n s e c t i c i d e t h a t enters will migrate to various t i s s u e s by the open circulation system. Some of the insecticide may be d e t o x i f i e d before reaching the t a r g e t site; mixed f u n c t i o n o x i d a s e s , f o r example, are known to be involved in the metabolic degradation of a v a r i e t y of organophosphates, c a r bamates and DDT analogues. With some compounds metabolic products are more t o x i c than the o r i g i n a l insecticides; their formation is termed " a c t i v a t i o n " . For example, o x i d a t i o n of parathion to paraxon increases potency to inhibit c h o l i n e s t e r a s e s by a f a c t o r of 1 0 . Eventually, either the original or the activated insecticide reaches and influences the target site, usually the nervous system. The symptoms of poisoning are a variety of secondary and tertiary disturbances in the insect, and death finally results from these integrated toxic actions. Unlike mammals, insects do not die by a single dysfunction of a key organ. Mammals, for example, suffer respiratory failure or cardiac arrest following intoxication by the insecticide, whereas the death of insects involves a complex series of reactions in various organs such as metabolic exhaustion and paralysis of the entire nervous system. This outline of insecticidal action indicates that the relative insecticidal activity of different compounds is the outcome of a complex series of interacting processes. Comparison of overall potencies, therefore, cannot elucidate fully 5
85
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
86
SYNTHETIC
PYRETHROIDS
structure-activity r e l a t i o n s h i p s , but must be supplemented by s t u d i e s on primary activities a t the t a r g e t f o r thorough c l a r i f i c a t i o n . This approach has indeed been used widely in studying organophosphates and carbamates (^, b) which i n h i b i t c h o l i n e s t e r a s e s . With these groups, such experiments are t e c h n i c a l l y s t r a i g h t f o r w a r d , s i n c e c h o l i n e s t e r a s e s can be handled in v i t r o . However, f o r i n s e c t i c i d e s which do not i n h i b i t c h o l i n e s t e r a s e s the s i t u a t i o n is more c o m p l i c a t e d ; a t a r g e t s i t e preparation p e r m i t t i n g many experiments in a short time w i t h minimum expense is r e q u i r e d . As d i s c u s s e d , most i n s e c t i c i d e s a f f e c t the nervous system, so the best model would be a nerve p r e p a r a t i o n . Few such s t u d i e s w i t h nerve preparations have been made. However, attempting to d e f i n e structure-activity relationships for rotenoids Fukami et al[. (6J compared rotenone d e r i v a t i v e s f o r t h e i r potency a g a i n s t i n s e c t s , and f o r a b i l i t y to i n h i b i t glutamic dehydrogenase a t i v e e f f e c t i v e n e s s wa a few d e r i v a t i v e s which showed weak insecticidal action despite strong i n h i b i t i o n of enzymic a c t i o n and b l o c k i n g of nervous conduction. For f i v e s y n t h e t i c p y r e t h r o i d s Berteau et à]. (7) found a good c o r r e l a t i o n between insecticidal potency, mammalian t o x i c i t y and b l o c k i n g of nervous conduction. Recently Burt and Goodchild {8, 9^, JO) using a sucrose gap technique tested the e f f e c t s of a l a r g e number of s y n t h e t i c p y r e t h r o i d s on g i a n t f i b r e s and c e r v i c a l n e r v e - g i a n t f i b r e synapses of the cockroach, P e r i p l a n e t a americana L. They compared the n e u r o t o x i c i t i e s w i t h the a c t i o n of the compounds on l i v i n g i n s e c t s , concluding t h a t although a r a t i o n a l p a t t e r n of r e l a t i o n s h i p s was apparent f o r o v e r a l l t o x i c i t y , no comparable connection could be discerned f o r n e u r o t o x i c i t y , except t h a t n e u r o t o x i c i t y tended to i n c r e a s e with p o l a r i t y . Neither s i t e of a c t i o n was l i k e l y to c o n t a i n a c r i t i c a l s i t e of a c t i o n f o r p y r e t h r o i d s . I n t e r e s t i n g r e s u l t s were a l s o obtained with DDT analogues (2> 11» JiL)- Although insecticidal potency c o r r e l a t e d w e l l with a b i l i t y to i n c r e a s e the negative ( d e p o l a r i z i n g ) a f t e r - p o t e n t i a l and to induce r e p e t i t i v e a f t e r - d i s c h a r g e s f o r most of the d e r i v a t i v e s t e s t e d , s t r i k i n g anomalies were found w i t h other derivatives. For example, s u b s t i t u t i n g amino or hydroxy groups f o r the ρ , ρ ' - c h l o r i n e s of ρ , ρ ' - D D T made the compound i n s e c t i c i d a l l y i n a c t i v e ( 1 3 ) , y e t the analogues were still a c t i v e on the nerve ( 1 2 ) , but in a manner, b l o c k i n g r a t h e r than e x c i t a t o r y . Thus t h e i r a c t i o n is e n t i r e l y d i f f e r e n t from t h a t of the parent compound, ρ , ρ ' - D D T . The structure-activity r e l a t i o n s h i p can t h e r e f o r e only be f u l l y defined by experiments using the t a r g e t s i t e jm v i t r o . Methods A simple method has been developed whereby potency to a f f e c t the nervous system of a l a r g e number of compounds can be
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
NARAHASHi E T
AL.
Neurophysiological
Studies
INTEGUMENT ACTIVATION
Τ
i DETOXICATION
ACCUMULATION]
EXCRETION NERV ACTIVATION
3
ACCUMULATION
DETOXICATION NEURONE EXCITABLE
MEMBRANE
NERVOUS
SYMPTOMS
ENZYME OF
τ
POISONING
ι
AUTOTOXIN DEATH Japanese Journal of Medical Science and Biology
Figure 1.
Process of toxic action of an insecticide (2)
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
88
SYNTHETIC
PYRETHROIDS
compared (14). Natural p y r e t h r o i d s and a l l e t h r i n are known to s t i m u l a t e and then paralyze various nerve preparations (15, 1 6 , U , 18, 19, 20, 2 1 ) . The compounds used in t h i s work were prepared as described p r e v i o u s l y (22, 2 3 , 24, 25) or by standard procedures, and t h e i r s t r u c t u r e s , w i t h stereochemical f e a t u r e s (26J, are shown in Table I. I n s e c t i c i d a l activities were determined by t o p i c a l a p p l i c a t i o n of measured drops of acetone s o l u t i o n s to the a d u l t , female h o u s e f l y , Musca domestica L. ( 2 7 ) . Of several nerve preparations examined, the i s o l a t e d c r a y f i s h nerve cord was most s e n s i t i v e to various i n s e c t i c i d e s and e a s i e s t to handle (14). The nerve cord discharges impulses spontaneously, a t a frequency g r e a t l y increased by low c o n c e n t r a t i o n s of p y r e t h r o i d s . Figures 2 i l l u s t r a t e s an experiment w i t h allethrin. The abdominal nerv Procambarus c l a r k i or Orconeste P l e x i g l a s s chamber equipped with a p a i r of w i r e e l e c t r o d e s , van Harreveld s o l u t i o n (207.3 mM NaCl, 5.4 mM KC1, 13.0 mM C a C l 2 H 0 , 2.6 mM M g C l ' 6 H 0 , 1.9 mM Trizma HC1, 0.4 mM Trizma Base with a f i n a l pH adjusted to 7.55) (28) was used as the bathing medium, and when it had been drained by s u c t i o n , the nerve cord preparation was hung on the e l e c t r o d e s , and spontaneous impulse discharges were recorded. Four nerve cord p r e p a r a t i o n s , mounted in separate chambers, were used s i m u l t a n e o u s l y , and each switched e l e c t r o n i c a l l y at r e g u l a r i n t e r v a l s v i a a p r e a m p l i f i e r to an o s c i l l o s c o p e , an audiomonitor and an e l e c t r o n i c counter. The counter d i s p l a y e d the frequency of impulse discharges in d i g i t a l form. In some experiments, the output of the counter was fed i n t o a d i g i t a l - t o - a n a l o g c o n v e r t e r , in t u r n connected to a s t r i p c h a r t recorder to r e g i s t e r the analog form of the frequency as a f u n c t i o n of time. A more d e t a i l e d account of t h i s method w i l l be published elsewhere. For each of the four nerve cord p r e p a r a t i o n s , the number of discharges was counted f o r a period of one second 15 times a t an i n t e r v a l of 1-2 seconds, g i v i n g the mean frequency of discharges per second. This procedure was repeated 3 times every 10 m i n u t e s , and the o v e r a l l mean value was c a l c u l a t e d from the 45 measurements. Then the lowest c o n c e n t r a t i o n of a t e s t compound ( u s u a l l y 1 χ 10" M) prepared from a stock s o l u t i o n in e t h a n o l , was a p p l i e d to the nerve. Frequency counts were made 10, 20 and 30 minutes a f t e r applying the t e s t compound. A f t e r the l a s t count, the c o n c e n t r a t i o n of the t e s t compound was increased 10f o l d , and three sets of counts were made every 10 minutes. These procedures were repeated u n t i l the c o n c e n t r a t i o n of the t e s t compound reached 1 χ 10" M, the highest value t e s t e d . The ethanol concentration in the t e s t s o l u t i o n was 0.1% (v/v) at the highest t e s t compound c o n c e n t r a t i o n of 1 χ 10" M, and had no e f f e c t on the spontaneous discharges of the nerve c o r d . Dose-response curves were constructed by p l o t t i n g o v e r a l l 2
2
2
2
8
5
5
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
8.
N A R A H A S H I
E T A L .
Neurophysiological
Studies
89
[ χ I0" M Allethrin 7
400r
10
20
30
40
50
60
70
80
Time (min ) Figure 2. Frequency of impulse discharges from the abdominal nerve cord of the crayfish before and during application of allethrin at a concentration of 1 X JO M -7
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
3-phenoxybenzyl 6-cyano-3-phenoxybenzyl 6-chloro-3-phenoxybenzyl 4-benzoyloxybenzyl 3-phenoxymethylbenzyl 3-phenoxy-4-methylbenzyl 7-phenoxy-tetrahydronaphth-l-yl a-cyano-3-phenoxybenzylamide of 3-phenoxybenzyl 5-benzyl-3-furylmethyl
5-benzyl-3-furylmethyl
3,4,5,6-tetrahydrophthalimidomethyl
(+)-a-cyano-3-phenoxybenzyl
3-phenoxybenzyl
5-benzyl-3-furylmethyl
a-cyanopiperonyl
5-benzyl-3-furylmethyl
1 2 3 4 5 6 7 8 9 10
11
12
13
14
15
16
17
>
>
[1R, trans]-chrysanthemate [1R, trans]-chrysanthemate [1R, trans]-chrysanthemate [1R, trans]-chrysanthemate [1R, trans]-chrysanthemate [1R, trans]-chrysanthemate [1R, trans]-chrysanthemate [1R, trans]-chrysanthemic a c i d [1R, cis]-chrysanthemate a c i d [1R, t r a n s ] - 2 , 2 - d i m e t h y 1 - 3 - ( 2 , 2 - d i f l u o r o v i n y l ) c y c l o p r o pane-carboxylate [1R, c i s ] - 2 , 2 - d i m e t h y l - 3 - ( 2 , 2 - d i f l u o r o v i n y l ) c y c l o p r o p a n e carboxylate [1R, c i s ] - 2 , 2 - d i m e t h y l - 3 - ( 2 , 2 - d i f l u o r o v i n y l ) c y c l o p r o p a n e carboxylate [1R, t r a n s ] - 2 2 - d i m e t h y 1 - 3 - ( 2 2 - d i c h l o r o v i n y l ) c y c l o p r o pane-carboxylate [IS, t r a n s ] - 2 , 2 - d i m e t h y 1 - 3 - ( 2 , 2 - d i c h l o r o v i n y l ) c y c l o p r o pane-carboxylate [1RS, c i s ] - 2 , 2 - d i m e t h y l - 3 - ( 2 , 2 - d i c h l o r o v i n y l ) c y c l o p r o pane-carboxylate [1RS, c i s , t r a n s ] - 2 , 2 - d i m e t h y l - 3 - ( 2 , 2 - d i c h l o r o v i n y l ) c y c l o propane-carboxy1 ate [1RS, c i s , t r a n s ] - 3 - m e t h y l - 3 - i s o b u t e n y l c y c l o p r o p a n e c a r boxylate
A c i d i c Compound
The S y n t h e t i c P y r e t h r o i d s Used
A l c o h o l i c Component
I.
Compound No.
Table
CO
C O
α
Ο
Ω
a
3
ο
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37
Compound No.
5-benyzl-3-furylmethyl 5-benzyl-3-furylmethyl 5-benzyl-3-furylmethyl 5-benzyl-3-furylmethyl a-cyano-3-methoxybenzyl 3-phenoxybenzyl 3-phenoxybenzyl 3-phenoxybenzyl 3-phenoxybenzyl 3-phenoxybenzyl 3-phenoxybenzyl 3-phenoxybenzyl 3-phenoxybenzyl 3-phenoxybenzyl 3-phenoxybenzyl 3-phenoxybenzyl 3-phenoxybenzyl 3-phenoxybenzyl 3-phenoxybenzyl 3-phenoxybenzyl
A l c o h o l i c Component
A c i d i c Compound (+)-a-isopropyl-2-fluorophenylacetate (+)-a-isopropyl-4-isopropylphenyl acetate 2-naphthoate 4 - t e r t i arybutylbenzoate [1R, trans]-chrysanthemate a,α-diethyl-4-chlorophenylacetate (+)-a-isopropyl-3,5-dimethylphenyl acetate (+)-α-i s o p r o p y l - 3 , 4 - d i m e t h y l p h e n y l acetate (+)-α-i s o p r o p y l - 4 - e t h y l p h e n y l acetate (+)-α-isopropyl-2-fluorophenylacetate (+)-α-i sopropyl-3-methylphenyl acetate (+)-α-methyl-α-isopropyl-4-chlorophenylacetate (+)-α-cyclohexyl-4-chlorophenylacetate (+)-i n d a n - 1 - c a r b o x y l a t e 3 methyl-3-(4-methylphenyl)-butyrate (+)-6-chloro-2-methyl-1,2,3,4-tetrahydronaphthoate (+)-α-cyclopentyl-4-chlorophenylacetate (+)-2,2-dichloro-3,3-dimethylcyclopropanecarboxylate (+)-α-dimethyl ami n o - 4 - c h l o r o p h e n y l a c e t a t e phenyl-isopropylcarbamate :
Table I (continued)
1
CD H-
C O
S-
en ?
S
Ο
ο
a.
S
1
t-
>
S
CO
>
»>
00
92
SYNTHETIC
PYRETHROIDS
mean values f o r 45 counts in the c o n t r o l and in each c o n c e n t r a t i o n of a t e s t compound a g a i n s t the logarithm of the c o n c e n t r a t i o n . The frequency of impulse discharges passed through a maximum with i n c r e a s i n g c o n c e n t r a t i o n . By connecting each measurement by a s t r a i g h t l i n e , the c o n c e n t r a t i o n a t which the frequency increased to 200% of the c o n t r o l was e s t i m a t e d , and designated N S o (nerve s t i m u l a t i o n to 200%). Some compounds did not s t i m u l a t e the nerve to increase the impulse frequency to 200% of the c o n t r o l even a t 1 χ 10" M. Burt and Goodchild (19) examined the s e n s i t i v i t y of the terminal ganglion of the abdominal nerve cord of P e r i p l a n e t a americana to p y r e t h r i n I by a method s i m i l a r in p r i n c i p l e and obtained comparable r e s u l t s . 20
5
Nerve A c t i o n Vs. I n s e c t i c i d a l A c t i o n The s y n t h e t i c p y r e t h r o i d s d i f f e r e d g r e a t l y in t h e i r a b i l i t y to s t i m u l a t e spontaneous impulse discharges of the c r a y f i s h abdominal nerve c o r d . The value of NS oo is p l o t t e d a g a i n s t the l e t h a l dose 50 ( L D ) r e l a t i v e to t h a t of bioresmethrin (0.005 ng/insect) (Figure 3 ) . I f nerve potency alone determined insecticidal activity, a l l measurements would f a l l on a l i n e with a d e f i n i t e s l o p e . However, many of the compounds deviated g r e a t l y from such a simple r e l a t i o n s h i p . For example, compounds I, 9, 13 and 15 were approximately e q u a l l y t o x i c to i n s e c t s , y e t t h e i r nerve s t i m u l a t i n g potencies were g r e a t l y d i f f e r e n t , the N S o r a t i o of 15 to 9 being more than 1 0 . Correspondingly, v a r i a t i o n s of nerve potency in compounds with s i m i l a r insecticidal activity were observed with the compound 14 which had a high N S o of 1.5 χ Ι Ο " M and 37 and f o u r other compounds which d i d not s t i m u l a t e the nerve a t 1 χ 10" M. Thus the d i f f e r e n c e is nerve potency between these two groups is over 600. Some compounds had approximately the same nerve potency, y e t d i f f e r e d c o n s i d e r a b l y in t h e i r insecticidal potency. For exam p l e , the compounds 10 and 23 had comparable N S o v a l u e s , but the former was 200 times effective as an i n s e c t i c i d e . L i k e w i s e , the compound 9 was almost equipotent to 14 in respect to the nerve a c t i o n , y e t the former was about 50 times more effective as an i n s e c t i c i d e . The compound 13 was one-tenth as potent on the nerve than 14, y e t 5 0 - f o l d more a c t i v e i n s e c t i c i d a l l y . 2
50
3
20
8
20
5
20
Comparison of Isomers and Analogs Very i n t e r e s t i n g d i f f e r e n c e s in activity were d i s c l o s e d by comparing isomers and analogs f o r t h e i r e f f e c t s on the nerve. For example the 5 - b e n z y l - 3 - f u r y l m e t h y l ( + ) - c i s - f l u o r o v i n y l e s t e r , I I , was h i g h l y potent on the nerve with a N S o value of 1.75 χ 10" M, whereas the corresponding (+)-trans isomer, 10, was 5 3 - f o l d l e s s effective with a N S value of 9.2 χ 10" M. However, the insecticidal potencies were l e s s d r a s t i c a l l y 20
9
2 0 0
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
8
N A R A H A S H I
Neurophysiological
E T A L .
1
III
ΐττη
1—Γ I I I I Μ|
— - INEFFECTIVE
Studies
93
Γ ΊI 1 II Ι Ι |
"Τ
#15
• 8
.2,19,2734,37
• 26
.
2
• 17,20,30,33—
9
• 4
•3. • 25
• 18
:
• 31
Γ*
• 24
• 36
lllll I
"Ξ
• 32
Ζ
• 6
• 28
—
• 12
• 1 =*
—
. 10
II 1
• 23
-
• 3 • 9 • 14 8
ΙΟ"
M I !
-TTT1
8.
-
• 11
1II1 1 1
ζ.
—
INEFFECTIVE i
• ι ι ι ι iiil 0.1
ι ι I I Mill
1
10 RELATIVE L D
5 0
I I ι null 100
t
(BIORESMETHRIN = 1)
Figure 3. Relationship between the concentration to stimulate the impulse fre quency of the crayfish abdominal nerve cord to 200% of the control (NS ) and the lethal dose 50 (LD ) against the housefly for synthetic pyrethroids 200
50
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
SYNTHETIC
94
Table I I .
Comparison of 5 - B e n z y l - 3 - f u r y l m e t h y l
f o r T h e i r S t r u c t u r e s , NS oo and L D 2
Compound No.
Stereochem istry
Pyrethroids
Values
50
NS (Χ Ι Ο
•
2 u 0
R
PYRETHROIDS
- 8
*
Relative M) LD 50
11
[1R, c i s ]
F
0.175
0.33
10
[1R, trans]
F
9.2
0.5
15
[1RS,
Cl
Bioresmethrin
cisj
[1R, trans]
CH
*Lowest value corresponds to highest + No s t i m u l a t i n g e f f e c t at 1 χ 10
-5
t 3
5
1.25 1
potency.
M.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
8.
NARAHASHi
ET
Table I I I .
AL.
Neurophysiological
Studies
95
Comparison of 3-Phenoxybenzyl
f o r T h e i r S t r u c t u r e s , NS oo and L D 2
Compound No. 1
[1R, trans]
CH
3
9
[1R, ç i s . ]
CH
3
[1R, trans]
CI
t
[IS, trans]
CI
1.5
[1R, c i s ]
CI
13 (NRDC 168)
*
* Ri
14
+
Values
50
Stereochem istry
Biopermethrin (NRDC 147)
*
Pyrethroids
R
2
2
(Χ Ι Ο
- 8
12
CN
- 5
15
M)
Relative LD50
1.25
1.9
Lowest value corresponds to highest
No s t i m u l a t i n g e f f e c t at 1 χ 1 0
NS oo
2 0.6 100 2
potency.
M.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
96
SYNTHETIC
PYRETHROIDS
d i f f e r e n t , t h e ( + ) - c i s f o r m b e i n g more p o t e n t t h a n t h e ( + ) - t r a n s f o r m by a f a c t o r o f o n l y 1.5 ( T a b l e I I ) . Again, 5-benzyl-3f u r y l m e t h y l ( + ) - t r a n s - c h r y s a n t h e m a t e ( b i o r e s m e t h r i n ) showed h i g h n e r v e and insecticidal p o t e n c i e s , but the e q u a l l y a c t i v e i n s e c t i c i d e , 1 5 , an e s t e r o f t h e r a c e m i c c i s f o r m o f t h e a c i d w i t h c h l o r i n e r e p l a c i n g methyl g r o u p s , d i d not s t i m u l a t e nerves ( T a b l e I I ) a l t h o u g h it r e t a i n e d n e r v e b l o c k i n g power. 3-Phenoxybenzyl ( + ) - t r a n s - c h r y s a n t h e m a t e , 1 , was 6 . 3 - f o l d l e s s p o t e n t on t h e n e r v e t h a n its c i s f o r m , 9 , y e t 1 . 6 - f o l d more p o t e n t as an i n s e c t i c i d e ( T a b l e I I I ) . B i o p e r m e t h r i n was much l e s s p o t e n t on t h e n e r v e t h a n its ( - ) - t r a n s f o r m , 1 4 , y e t 1 6 7 f o l d more a c t i v e as an i n s e c t i c i d e ( T a b l e I I I ) . The a - c y a n o - 3 p h e n o x y b e n z y l ( + ) - c i s - d i c h 1 o r o v i n y l e s t e r , 1 3 , was 1 0 - f o l d l e s s p o t e n t on t h e n e r v e t h a n t h e 3 - p h e n o x y b e n z y l ( - ) - t r a n s e s t e r , 1 4 , b u t 50 t i m e s more p o t e n t as an i n s e c t i c i d e ( T a b l e III). Conclusions Most o f t h e i n s e c t i c i d a l l y a c t i v e p y r e t h r o i d s s t i m u l a t e d t h e i s o l a t e d c r a y f i s h abdominal nerve c o r d , i n c r e a s i n g the f r e q u e n c y of impulse d i s c h a r g e s . Such s t i m u l a t i n g a c t i o n p a r a l l e l e d a b i l i t y t o k i l l i n s e c t s w i t h some o f t h e compound, b u t o t h e r s , a l t h o u g h p o t e n t on t h e n e r v e , were weak insecticides, and v i c e versa. Some o f t h e d i s c r e p a n c i e s may be due t o d i f f e r e n t i a l c u t i c l e p e n e t r a t i o n and d e t o x i c a t i o n , b u t t h e s e f a c t o r s do n o t adequately account f o r a l l the d i f f e r e n c e s ( f o r example, those between t h e 5 - b e n z y l - 3 - f u r y l m e t h y l ( + ) - t r a n s - and ( + ) - c i s d i f l u o r o v i n y l i s o m e r s , 10 and 11) and a n o m a l i e s ( s u c h as t h e lack of nerve s t i m u l a t i n g activity of the potent i n s e c t i c i d e 5-benzyl-3-furylmethyl ( + ) - c i s - d i c h 1 o r o v i n y l e s t e r , 1 5 , and t h e inversion in activity o f t h e ( + ) - and ( - ) - t r a n s i s o m e r s o f permethrin). The r e s u l t s i n d i c a t e t h a t p r o p e r t i e s and activities, o t h e r t h a n t h o s e c o n s i d e r e d and e v a l u a t e d in t h e p r e s e n t w o r k , may be more d i r e c t l y r e l a t e d t o insecticidal a c t i o n o f some pyrethroids. Acknowledgements. T h i s s t u d y was s u p p o r t e d by a g r a n t f r o m the N a t i o n a l I n s t i t u t e s of H e a l t h (NS06855). T e c h n i c a l a s s i s t a n c e f r o m Pamela Van B u s k i r k and s e c r e t a r i a l a s s i s t a n c e f r o m V i r g i n i a A r n o l d and A r l e n e M c C l e n n y a r e g r e a t l y a p p r e c i a t e d . M i c h a e l E l l i o t t t h a n k s h i s c o l l e a g u e s in t h e Department o f I n s e c t i c i d e s and F u n g i c i d e s , Rothamsted E x p e r i m e n t a l S t a t i o n , f o r p r e p a r i n g and e v a l u a t i n g most o f t h e compounds used and f o r many v a l u a b l e d i s c u s s i o n s and comments.
Literature
Cited
1. M e t c a l f , R. L . and McKelvey, J. J., J r . "The Future f o r I n s e c t i c i d e s . Needs and P r o s p e c t s , 524 p p . , John Wiley & Sons, New York, 1976.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
8.
NARAHASHI
ET
AL.
Neurophysiological
Studies
97
2. Narahashi, T., Jap. J. Med. Sci. Biol. (1964), 17, 46. 3. Narahashi, T., E f f e c t s of i n s e c t i c i d e s on e x c i t a b l e t i s s u e s . In Beament, J. W. L., Treherne, J. E. and Wigglesworth, V . B., "Advances in Insect P h y s i o l o g y " , Vol. 8, p. 1-93, Academic P r e s s , London and New York, 1971. 4. Fukuto, T. R . , Bull. World Health Org. (1971), 44, 31. 5. M e t c a l f , R. L., Bull. World Health Org. (1971), 44, 43. 6. Fukami, J., Nakatsugawa, T. and Narahashi, T., Jap. J. A p p l . Entom. Z o o l . (1959), 3, 259. 7. Berteau, P. E., C a s i d a , J. E. and Narahashi, T., Science (1968), 161, 1151. 8. B u r t , P. E. and G o o d c h i l d , R. E., Rothamsted Experimental S t a t i o n , Ann. Rep. (1975) (Part 1 ) , 155. 9. B u r t , P. E. and G o o d c h i l d , R. E., Rothamsted Experimental S t a t i o n , Ann. Rep. (1976) in 10. B u r t , P. E. and G o o d c h i l d press. 11. Yamada, M. and Narahashi, T., Bull. Entom. Soc. Amer. (1968), 1 4 , 208. 12. Wu, C. H., van den Bercken, J. and Narahashi, T., P e s t i c i d e Biochem. P h y s i o l . (1975), 5, 142. 13. M e t c a l f , R. L . and Fukuto, T. R . , Bull. World Health Org. (1968), 38, 633. 14. Narahashi, T., Environmental Health E f f e c t s Research S e r i e s (1976), (EPA-600/1-76-005, EPA, Research T r i a n g l e Park, N . C.). 15. Lowenstein, O., Nature (1942), 150, 760. 16. Narahashi, T., J. Cell. Comp. P h y s i o l . (1962), 59, 61. 17. Welsh, J. H. and Gordon, H. T., J. Cell. Comp. P h y s i o l . (1947), 30, 147. 18. Yamasaki, T. and Ishii, T., Oyo-Kontyu (J. Nippon Soc. A p p l . Entom.), 7, 157. 19. B u r t , P. E. and G o o d c h i l d , R. E., Entomol. Exp. A p p l . (1971), 14, 179. 20. Camougis, G. and D a v i s , W. M., Pyrethrum Post (1971), 11, 7. 21. Camougis, G., Mode of a c t i o n of pyrethrum on arthropod nerves. In C a s i d a , J. E., "Pyrethrum", 211-222, Academic P r e s s , New York and London, 1973. 22. Elliott, M., Farnham, A . W., Janes, N. F., Needham, P. H. and Pulman, D. Α . , Nature (1973), 244, 456. 23. Elliott, M., Farnham, A. W., Janes, N . F., Needham, P. H., Pulman, D. A. and Stevenson, J. H., Nature (1973), 246, 169. 24. B u r t , P. E., Elliott, Μ., Farnham, A. W., Janes, N . F., Needham, P. H. and Pulman, D. Α . , P e s t i c i d e Sci. (1974), 5, 791. 25. Elliott, M., Farnham, A. W., Janes, N. F., Needham, P. E. and Pulman, D. Α . , P e s t i c i d e Sic. (1975), 6, 537. 26. Elliott, M., Janes, N. F. and Pulman, D. Α . , J. Chem. Soc. Perkin I (1974), 2470. 27. Farnham, A. W., P e s t i c i d e Sci. (1973), 4 , 513. 28. van H a r r e v e l d , Α . , P r o c . Soc. Exp. Biol. Med. (1936), 34, 428.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
9 Central vs. Peripheral Action of Pyrethroids on the Housefly Nervous System T. A. MILLER and M . E . ADAMS Department of Entomology, University of California, Riverside, Calif. 92502
Despite years of research pyrethroids have defie tion as peripheral or centrally acting has not been possible to date. On one hand, pyrethroids act in a manner resembling DDT, which is known to be a peripheral neurotoxin in insects (1). The activities of both DDT (1) and pyrethrum (2) exhibit a negative dependence on temperature, being more toxic at lower temperature. Both DDT and pyrethroids produce negative after potentials, and repetitive discharge to single stimuli in axons (3). And both DDT and pyrethrum are extremely sensitive in causing trains of sensory nervous impulses when perfused on leg preparations of insects (4, 5, 6). The actions of DDT and a l l e t h r i n are also similar on the l a t e r a l - l i n e organ of the clawed toad, Xenopus laevis (7). Despite the impressive actions of pyrethroids on sensory nerve structures and the similarity between the actions of DDT and pyrethroids on isolated preparations on the nervous system, there is evidence of actions by pyrethroids on the central nervous system. Burt and Goodchild (8) found that speed of knockdown was proportional to the distance between the site of topical application and the central nervous system. They considered this to suggest strongly that knockdown, even the rapid knockdown reported by Page and Blackith (9), is due to an action on the central nervous system. Burt and Goodchild (10) found that the isolated and perfused central nervous system of Periplaneta amerieana was sensitive to extremely low concentrations of pyrethrin I (below 5 X 10 M ) . In contrast, DDT was without effect on the thoracic ganglia of Peviptaneta even when applied in emulsions of 4.5 X 10 M concentration (6). This latter observation is the best demonstration of a difference between the actions of DDT and pyrethroids. The ultimate actions of pyrethroids, then, could involve central and peripheral nervous structures—which of these might be involved during poisoning has been d i f f i c u l t to show u n t i l in vivo recording methods were developed to record the activity 8
3
98
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
9.
M I L L E R
of
flight
(11, a
A N D
motor
12,
13,
central
the it
whole was
poisons central was
house
that
ize
f l y during
the pattern
was u n i q u e 12).
patterns
of
poisons,
it
acting
results
were
of
from
since
motor
neurons
Using
recorded that
poisoning
the monitoring
of
this
activity
similar
method,
d u r i n g DDT
centrally
the pyrethroid
was c o n c l u d e d
of
from
acting
trans-
t o DDT a n d u n l i k e
that
trans-Barthrin
(12). challenged
extensive
the actions
flight
activity
and d i s t i n c t
showed
f l y during
allows
poisoning.
of
Furthermore,
nervous
a more
between
99
System
house
preparation
intact
peripherally that
the intact
This
coordination
These so
of
15).
neural
(11,
Barthrin
units
14,
found
poisoning
Action in the Nervous
A D A M S
informally
examination
by Paul
was u n d e r t a k e n
Burt
to
(16),
character-
pyrethrins.
Methods Three
pyrethroids
Tetramethrin
hydrophthalimidomethyl fast a
knockdown
sample
wer
(synonyms=neopynamin,
from
Berkhamsted.
b u t poor
chrysanthemate
toxicity
Richard Hart, This
sample
perties
(+)eis
on insects
Wellcome
Research
was r e p o r t e d l y
2,3,4,5-tetra= to have
(17).
We
very obtained
Laboratories,
a +25/75
0
was chosen
(NRDC
was s a i d
eis/trans
mixture. cis-
Cis-methrin
phthalthrin,
chrysanthemate)
119).
tetramethrin
for intermediate
Cis-methrin
is
k i l l
and knockdown
pro-
5-Benzyl-3-furylmethyl
chrysanthemate:
eismethrin The
third
compound
examined
Procida
Chemical
Company
Othrin,
Bioethanomethrin)
through
was RU11679, Wellcome
provided
Research
5-Benzyl-3-furylmethyl
by the
(synonyms=k-
(+)trans
ethanochrysanthemate.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
100
SYNTHETIC
For
purposes
o f comparison,
carbamate
insecticide
furanyl-7
W-methyl
and
dissected Nervous using
bathed
in
dissolved The to
a grease
then
acetone,
removal
impulses
tungsten
wire
cuticle was
droplets
flight
elsewhere muscles
(20).
large
portion
line
is
the cuticle
place.
shown
Only
silver
sufficiently
large
these
cells
Compounds
For the
thoracic
wire
of
in
T h ef r o n t
surface
segment
once
IV-dissecting
were
in
was l e f t
perfused
onto
saline
and also
were
then
removed
intact
to monitoring Since
in
acetone.
implanted
mounted
with
upside
andthe ventral The furcasternite
as
its
removal
caused
ganglion.
t h e exposed described
used
with
diameter
ym
of pyrethroids on
was exposed.
to the thoracic
Calliphora
medium,
muscles, were
study.
thepotentials a r e
females
of legs
just
amplification.
o f house
ganglion
to be
this
o f 25
directly
toxicity
flies,
major
muscles
t o t h e t i p o f abdomen
the appropriate
disturbance
Compounds
applied
two p a i r s
t h emesothoracic
innervated,
in
flight
wires
without
The
of
a n d waxed i r t
used
of the inherent
of the thoracic
excessive usually
were
ganglion
electrodes
down.
a r esingly
measurements
were
a
of the thoracic
a r eplaced
of interest
steel
occupy
insertions
wires
flight
of the mid
of the thorax.
muscle
muscles
recorder
detail f o r muscoid
cells
side
The position
a s t o be connected 220
muscle
the f i b r i l l a r
or stainless
o r Brush
simple.
from
in
pattern
on the rear area
t h emuscles
recorded
electrode
t o p i c a l l y in Ο . ΐ λ
described
on either
and electrode
over
oscilloscope muscle
f i b r i l l a r
allows
etched
through the
to wet the tarsus.
the general
F i g . 1.
dorsolongitudinal
non-insulated
was i n j e c t e d
of dorsolongitudinal
originate in
applied
enough
cavity
thorax
accurately
Potentials are
of giant
on thedorsal
through
saline.
the opening
solution
h a s been
follows
Themuscles
quite
into
An indifferent
on the anterio-dorsal
located
were
times
was punched
were
The arrangement
of the thoracic
of insertion
bristles
t h e femur.
preparation
S i xpairs
( F i g . 1).
Compounds 20
Anelectrolytically
diameter
which was j u s t
13).
and insert
area
in
Compounds
Musea domestiaa
flies
box
near
motor
(12,
in
urn)
t h e femur.
o f acetone
The
were
through
Enough
pro
tissues
f l y
1 m i l (25
in
of the cockroach,
the l e g .
t o wax a s above.
of the tibia
placed
the tibia
were
6).
wer
l e g o f t h e house l e g was stapled
in
(19).
the
intact
to ordinary
Exposed
a t least
of the tarsus.
t h e hemolymph
(5,
nerve
according
a t p H 6.9
into
f l y l e g ,
l e g preparations
(18).
diluted
was i n j e c t e d
Nervous the
electrode saline
after
asthe
f l y in b o t h
andWeiant
the crural
recorded
a carbonate
displace
acic
were
in
solution
left
by Roeder
ascending
amerieana,
t h e house
o f t h e house
Cockroach
developed
impulses
included
motor
preparations.
those
Pevvplaneta cedures
preparations
l e g , theflight
essentially
as well
(2,2-dimethyl-2,3-dihydrobenzo=
carbamate).
Physiological cockroach
DDT w a s u s e d
carbofuran
PYRETHROIDS
thoracic
by Berridge
b y Thomson
(22)
ganglion (21)
as
f o r Phormia.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
9.
M I L L E R
A N D A D A M S
Action in the Nervous System
101
Figure 1. Dorsal view of thoracic musculature of Musca domestica. Two dorsolongitudinal flight muscles (DLM) run longitudinally in the dorsal thorax, each comprised of six fibers. The six fibers of each DLM are stacked unihterally and are designated 1-6 from ventral to dorsal Recordings were made by inserting fine wires just below the cuticle into the appropriate motor unit. The desired unit was located in relation to the major bristles depicted in the map with circles.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
102
SYNTHETIC
The
saline
pH was a d j u s t e d
compounds. study
Theprocedure
There f i b r i l l a r
are 2 dorsolongitudinal each
a r e single
have
a single
dorsal-most
tion
separate
true
The
by a
of
c e l l
In
This
in
(23); cides,
is
concerning The
(23). that
to
activate
remain
of
under almost
two
innerva-
one neuron
neurons
in
and each
a D L M is
nerve
impulse
of a neighboring
thought
to be a
that
strong
neurons. o f anymotor
A similar
the left
on the units
condition
of
DLM.
lateral
of
likely
the right
Thenature
unit
of the
the
left
occurs
of
these
connec-
at
present.
of neuro-active
only
in
innervation
o f c i r c u i t r y a r e n o t known
to emphasize
4 of
central
DLM a r e w e a k l y
inhibitory
the action
in
(23).
lateral
has similar
Musca
influence
unit
and the other
axons
the units
sufficient
a few basic
i n s e c t i -
properties
t h e DLM u n i t s .
when
individual control used
t h e wing
DLM f l i g h t
in
motor
of firing
a l l normal
with
of
presumed
lateral
7
Hz a t 20°C
(12).
temperature
reflexly
of
similar,
t h e wing
on loss
of
lowrate
Thebasal
rate
of
or
units
downstroke.
t h e DLMf l i g h t
rather
continues (12). tarsal
are reinforced
motor
of
f i r e
and below.
decapitation
on, the units
units
motor
Thef l y can increase
each
inhibition.
t h e motor
the flight
t h e DLM f l i g h t
t h e power
at a
room
start
Once
t h e DLM m u s c l e s f o r the generation
At rest,
or without
feedback.
of a l l of
over
flight
stupor
units
conditions,
f i r e
around
cold
flight.
or decrease
during
downstroke.
spontaneously
always
only
spontaneously prostrate
on by sensory
rate
is
any one neuron
of analyzing
to initiate
increase
The
of
motor
the details
unison
The
each
bifurcates
flight
to involve
to cause
fact,
axon
ascending
no r e s e t t i n g
force
near
them.
pattern
an antidromic
rhythm
is
between
a r e presumably
In
unit
t h e 5 motor
assumed
impulses
which
contact
is
f l y has lost
in
in
that
between
It
purposes
it
of
such
connection
to units
however,
n e u r o n whose
A motor
the firing
connection
thought
For
units.
each
Calliphova
is
motor
since
4
5 R a n d 6 R in F i g . 1 )
the l e f t DLM.
and implies
tions
innervating
DLM ( l a b e l l e d
t h e 12
through
cells
connections
connected
1
of
fibers
innervates.
Antidromic
Musoa
Fibers
the muscle
connected
DLM have
neuron
giant
T h e same
DLM ( 2 3 , 2 4 ) .
right
cells.
called
neuron
functional
nervous
the
previous
Musca
Each
fibers.
canreset
inhibitory
motor
single
Calliphora,
unit
a r e sometimes
the right
5 motor
it
functionally
DLM
addition of
a
( D L M ) in
( F i g . 1).
the muscle
5 motor
comprise
muscle
in
muscles
6 fibers
multinucleate
reaching
is
cells
fibers
fibers
innervated
before
containing
muscle
they
the
in
and Discussion
domesticcLy
one
after
briefly
(14).
Results
are
to 6.9 and rechecked was d e s c r i b e d
PYRETHROIDS
to
decrease to However,
motor
units
as a result of firing
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
is
of
9.
M I L L E R
A N D
A D A M S
Action in the Nervous
System
103
P r e l i m i n a r y s t u d i e s suggest t h a t a group of nerve c e l l b o d i e s a r e l o c a t e d n e a r t h e l e f t l a t e r a l edge o f t h e g a n g l i o n and in b e t w e e n t h e p r o t h o r a c i c and m e s o t h o r a c i c n e u r o m e r e s . T h i s group of c e l l s i n c l u d e s t h e 5 motor neurons i n n e r v a t i n g the l e f t DLM. A l t h o u g h no e v i d e n c e e x i s t s , one may assume a s a w o r k i n g h y p o t h e s i s t h a t l a t e r a l i n h i b i t o r y c o n n e c t i o n s between t h e s e 5 neurons occur w i t h i n t h e i r immediate l o c a l i t y . The m o t o r n e u r o n s s e n d axons d o r s a l l y out the main d o r s a l n e r v e which l e a v e s the gang l i o n a t a p o i n t above the c e l l b o d i e s . The m o n o p o l a r n e u r o n s a l s o send b r a n c h e s d o r s a l l y t h e n a r c h i n g toward t h e mid l i n e o f the g a n g l i o n to presumably connect w i t h symmetrical branches of t h e r i g h t DLM m o t o r n e u r o n s . The f i n e d e t a i l s o f t h e s e l a t t e r c o n n e c t i o n s a r e unknown, b u t t h e y a r e p r e s u m e d t o s u p p o r t t h e c o u p l i n g b e t w e e n r i g h t DLM and l e f t DLM u n i t s . I n s e c t Leg B i o a s s a y s t r a i n s of ascending sensory impulses from t o p i c a l treatment to the house f l y l e g ( F i g . 2) o r p e r f u s i o n of p y r e t h r o i d s through the c o c k r o a c h l e g ( F i g . 3) were f a i r l y s i m i l a r . Compounds p r o d u c i n g f a s t knockdown w e r e more effective in producing t r a i n s of s e n s o r y p u l s e s . T e t r a m e t h r i n was s l i g h t l y more p o t e n t t h a n c i s - m e t h r i n on t h e h o u s e f l y l e g ( F i g . 2 ) , b u t b o t h t e t r a m e t h r i n and c i s - m e t h r i n w e r e f a r b e t t e r t h a n k - O t h r i n in p r o d u c i n g ascending t r a i n s of neuron impulses. The p o t e n c y o f k - O t h r i n was more s i m i l a r t o t h a t o f DDT t h a n t h e two p y r e t h r o i d s e x h i b i t i n g knockdown p r o p e r t i e s . F l i g h t Motor B i o a s s a y s . F l i g h t motor p a t t e r n of a normal f l y d u r i n g t e t h e r e d f l i g h t shows t h a t m o t o r u n i t s a r e a c t i v a t e d a t t h e same r a t e w i t h s l i g h t d i f f e r e n c e s in e x a c t t i m i n g ( F i g . 4 ) . T o p i c a l t r e a t m e n t o f the house f l y w i t h 1 yg o f c a r b o f u r a n c a u s e s h y p e r a c t i v i t y in a few m i n u t e s , t h e n c o n v u l s i o n s in a b o u t 5 minutes. By 1 0 m i n u t e s f o l l o w i n g t r e a t m e n t , t h e f l i g h t m u s c l e p o t e n t i a l s show u n c o u p l i n g b e t w e e n t h e l e f t and r i g h t DLM u n i t s ( F i g . 5, t r a c e s m a r k e d : 6R & 6 L ) . C o m p a r i s o n b e t w e e n 6 L and 5 L shows t h a t t h e m u s c l e p o t e n t i a l s o v e r l a p e x a c t l y r e f l e c t i n g t h e i r common i n n e r v a t i o n by t h e same m o t o r n e u r o n . T h i s " u n c o u p l i n g " between i n d i v i d u a l u n i t s of the f l i g h t m o t o r n e u r o n s i m p l i e s t h a t c a r b o f u r a n is a c t i n g on t h e c e n t r a l n e r v o u s s y s t e m w i t h o u t an a c t i o n on the p e r i p h e r a l n e r v o u s system. No c o n c l u s i o n s c a n be drawn c o n c e r n i n g t h e s i t e o r mode o f a c t i o n of c a r b o f u r a n in c a u s i n g t h i s a b n o r m a l u n c o u p l i n g r e s p o n s e because other c e n t r a l l y a c t i n g n e u r o t o x i n s a l s o cause u n c o u p l i n g : p i c r o t o x i n , l i n d a n e , d i e l d r i n and o r g a n o p h o s p h a t e s . DDT e x e r t s l i t t l e o r no d i r e c t a c t i o n o n t h e c e n t r a l n e r v o u s s y s t e m , b u t c a n be r e a d i l y c h a r a c t e r i z e d by m o n i t o r i n g f l i g h t motor p o t e n t i a l s ( 1 2 ) . L e t h a l d o s e s o f DDT c a u s e a g r a d u a l i n c r e a s e in f l i g h t m o t o r activities and s p l i t t i n g o f f l i g h t p o t e n t i a l s i n t o 2 and s o m e t i m e s m u l t i p l e s p i k e s ( F i g . 6 , a r r o w s ) . This i n c r e a s e in a c t i v a t i o n e v e n t u a l l y l e a d s t o a s t a t e o f c o n s t a n t
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
104
SYNTHETIC
Latency (min.)
PYRETHROIDS
FLY LEG T3 tetramethrin
6
5
4 3 - L o g Concentration (ug/.1 ul)
2
Ο
1
Figure 2. Dose-response relationships for insecticides applied to the isolated metathoracic leg of Musca. Dose is expressed on the abscissa as (-)log concentration vs. latency to sensory trains in the crural nerve. Latency is short for tetramethrin and cis-methrin, but significantly longer for k-Othrin, which lacks activity at lower concentrations. Barthrin and DDT analogs have effects in the range of k-Othrin.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
9.
M I L L E R
A N D A D A M S
Action in the Nervous
Latency(min.)
105
System
Ρ a m e n c a n a - T 3 Perfusion
20 h
.001
.01
.1
1
10
Concentration (ppm) Figure 3. Flot of dose vs. latency to sensory trainsinthe isolated metathoracic leg of the cockroach, Periplaneta american. The same trends apply here as in Musca, although cis-methrin assumes a more intermediate position between tetramethrin and k-Othrin.
4R-*-4—X—~L-«-*X- >,.L—^-L-—X
eRn^T-f^f
1
f
L-
f "t "'f—
Figure 4. Flight motor pattern of a normal housefly during tethered flight. Each trace represents a discrete motor unit. A common firing frequency is maintained by all motor units, but a loose phase relationship prevents units from firinginunison. The pohrity of 6R and 6L is reversed for comparison. Calibration: 100 msec.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
SYNTHETIC PYRETHROIDS
106 motor
output
even
in
several
deep
examination also
pheral the
of
showed Thus,
the
a
uncoupling
seen
system,
in
by
the
time
DDT a n a l o g s
in
in
other By
carbofuran, separated
by
in
motor
flight
rates
with
pyrethroids and
units
is
further
throids
were
isolated ent
central
with
to
bursts
a c t i -
such
of
high
The
period
as
varying
of
one
of
frequency of
length
to
Immediately
inactivity
the
preceding
active
was
burst.
insecticides
characterization
during
nervous
very
centrally
the
distinguish
of
the
and
action
between
of
central
poisoning.
central
examined
on
the
system
single
One m i n u t e began
nervous
coupled
both
between
the
and
4L).
recorded between
or
leg
to
peripheral action, preparations
obtain
pyre-
and
on
the
some m e a s u r e
of
inher-
This
not
yet
fly
was
exhibiting
obtained
from
records
this
dose,
sidered
from
at are
units.
tetramethrin
of
occurred
this
1
few and
and
is
flies
down",
but
at
minutes
1/2
in
discharge
hyperactivity
house
"knocked
the
a l l
hours
lost
under this of
abdomen
flight (Fig. (Fig. 6R
a l l
same
arrows)
8, and
units
times
and
pauses
of
the
the
nervous
(Fig. system
investigation. and
poisoning
the
was
Within
locomotory
ability
of
this
sublethal
dose
of
tetramethrin
there
was
house
similar
minutes
and
period
The record
very
4
6L
occa-
were
at con-
several
hours. At
and
the
an
a
4R)
4R w i t h
units
over
still
6R,
treatment,
point
from
was
one in
0.1
very
of
later.
recovered
at
muscle
8,
however,
cf.
where
common
discharge
first
8
8,
approximately
determined
the
the
pattern,
(Fig.
F i g .
to
the
hyperactivity
same m u s c l e
seen
obtained the
the
be
origin
been
of
following
has
overall
muscles
active
The
units
on
discharges
left
exaggerated
arrow).
treatment,
and
can
2 minutes
The
treated developed
multiple
impulses.
right
When flies
following
between
are
house
showing
potentials
At sional
Poisoning.
tetramethrin,
quickly.
to
in
potency.
potentials
9,
a
examination,
insecticides,
strength
between
evidence
also
motor at
treatment
increase
cursory
acting
of
the
enables
Tetramethrin yg
from
peripheral actions As
flight
recorded
following
steady from
convulsive
inactivity.
it
a
and,
peri-
important
the
activity
a
remains
a bursts
crucial
for
DDT a s
inactivity
difference
analogs
(12).
of
in
brief
preparation
DDT
hours
that A
well.
produce
relative
predictable
This DDT
to
complete
The by
units
this
Another
overall
centrally
convulsive
preceding roughly
as
the
tended
the
Note
insecticides
activity
poisoning.
motor
units
contrast,
of
characterized
flight
motor
poisons. of
to
action
central
recordings
after
were
the
similar
between
7).
coupled.
on
trans-Barthrin,
acting
nature
(Fig.
remains
centrally
by
from
motor
activity
and
caused
difference, considerable
of
treatment
flight
main difference
poison
was
after
the
pyrethroid,
pattern
the
nerve
vation
hours
poisoning,
some
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
M I L L E R
A N D A D A M S
Action in the Nervous System
6R 6L ULUillliUJ llllllillllllllMllllllllllUllllli I 51 ΓΤΓΤΠΓΤΓΎΙΒΙΙΒΓ 111 mm uni iniimi 11II III 11111II ι II11 Figure 5. Disruption of coordination between motor units 6L and 6R caused by a lethal dose (1 μβ) of carbofuran. This effect on central coordination is characteristic of cholinesterase poisons. The firing of 5L mirrors that of 6L, indicating common input from a single motor neuron. Calibration: 1 sec.
4L 4R
Jt-JU-JU-i-JU-JU—-Jul—L-JuJt-—I
X^XJ^XUJ^^XXXiXik^
6R Figure
6. Flight motor pattern during tethered flight 1 hr after treatment with 1 pg DDT. Splitting of spikes is evident (arrows). Coupling between individual motor units is maintained despite symptoms of hyperactivity and locomotory in coordination at this stage of poisoning. Calibration: 100 msec.
4L.IUU \ HHUU44U-4U-14RÎ111 6L uni
1 I H H J U j l - U L 1 ίίίΐ i ί lima nu u ι • u ιι mi \
6RJIUJ—ll
ι ill,
j,ιιι
ii ι . ί I ll
ji
ι
ι
Figure 7. Condition of the flight motor almost 4 hr after treatment with 1 g DDT. The insect is in tetany and flight motor activation is almost continuous, yet the coupling between units is intact. Calibration: 0.5 sec.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
108
SYNTHETIC
evidence
of
abdomen ment
uncoupling.
produced more
( i . e . ,
doses
applied
(%s-methrin the
abdomen
burst more
in
than
accompanied One
after
by
after
near
still
period
ing
X
trace
a l l
traces
cis-methrin
lost
LD50
(cf.
locomotory There
11,
dots)
to
occur
produced
15
which
(25
10).
top
the treat-
ganglion).
treatment
(Fig.
10,
on
thoracic
of
the
The
f ly
on
exaggerated
discharges
or
A)
B).
house
highly
could
This
occur
activity
in
was
treatment
a b i l i t y
in
was
greater
while
high
in
single
the
house
the
first
evidence
frequency
fly
was
several of
uncoupling
short
burst
units.
Poisoning
symptoms.
symptoms
10,
(Fig.
the
quiescence Othrin
(Fig.
treatment.
k-Othrin
did
thoracic
Topical
(Fig.
continued
doses
tetramethrin as
hyperactivity.
hour
discharges
the
2 minutes
following
having
one
of
c i s - m e t h r i n produced
units
unit
hour
prostrate, minutes
within
single
one
nearer
\xg o f
0.1
doses
uncoupling
Poisoning.
with
discharges
occurred
Higher
obvious
PYRETHROIDS
for
lasted
for
Topical
which were
symptoms
hours
treatment
LD50)
the
no
other
d e s c r i p t i o n of
o
t
n
n
before of
qualitatively
than
term
the
house
abdomen
e
the
exaggerated period)
appearance
flies
hastened
similar
an
still
to
by
0.1
the
of yg
or
poisonof
k-
appearance
responses
to
of
lower
doses. 14 ated
minutes
burst
uncoupling. occurred muscle than
20
(Fig.
(Fig.
minutes 13).
13,
with
in
the
than
its
The
same m u s c l e
phenomenon w i l l CNS
Assays.
nervous
time
from
treatment
by
pyrethroids
case)
appearance over
a
of
range
The
high
system
potency
parison
k-Othrin.
to
that
the
tral
site
and
in
view was
fact,
of
of in
pyrethroids of
CNS
of
flight
same
13,
compare
motor
units
to
uncoupling
the
uncoupling
to
further
study
elsewhere.
of
pyrethroids
fly
was
(thoracic motor
on
the
determined.
concentrations
the
the
i n i t i a l l y
(Fig. that
subjected
house
in
obvious
susceptible
some
uncoupling
units
units
detail
exposed
in
of
potency
the
2
exagger-
plus
ganglion
in
saline
units
was
cenThe
in to
this the
plotted
concentrations.
in
potency
of
k-Othrin
arrows),
more
details
being
various
uncoupling of
are
of
suggested
more
greater
the
in
pairs This
relative
of
yg 12,
pronounced
was
however,
in
(CNS)
surprising their
6R).
perhaps
on
The
tral
6R)
opposing
muscles;
reported
treatment
4R w i t h
during poisoning
be
0.1
(Fig.
u n c o u p l i n g between
unit
were
between
by
recorded
after
compare
opposite
units
treatment
were
u n c o u p l i n g between
6L
and
following
discharges
action
t e t r a m e t h r i n on
its
poorer
In
fact,
the in
comparing
same
range
of
similar
were the
thoracic
tetramethrin possessed
Unfortunately,
our
sample
the
toxicity
of
(Fig.
CNS p r e p a r a t i o n house
f l y
the
three
pyrethroids,
14).
This
in
in
f i t
at
ganglion
of
the
house
best
com-
suggested
potency the
was
to
the
cenfly
f i t .
t e t r a m e t h r i n was
a
mixture
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
of
M I L L E R
A N D A D A M S
6L
Action in the Nervous
System
en
U—Jk- WUULU-A- -I |T I I! 'I'M! « !
4L
iT^t|îfî(^Mf~~1
4R ••^^-•ffr rV,V ~1 , |
Υ.
Figure 8. Flight motor output 1 min after a topical dose of 0.1 / A g tetramethrin. Symptoms of hyperactivity were obvious and accompanied by slight splitting of flight motor potentials
6R - 4 J U J L — U J J J U 4L
—|f^--ipT|^——Υ^γ^Υ^γνγ
Figure 9. An exaggerated burst (arrow) in 6L occurs 2 min after treatment with 0.1 μg tetrameth rin. Slight uncoupling is evident between 6L and 6R and 4R (hollow arrow). Calibration: 100 msec.
4L
U4JM#.
—HHUJ
ο 6
ΜΙεμ-
i\Mm
1
— f f M * i —
—
^
—
Figure 10. Topical treatment with 0.1 μ-g cis-methrin elicited exagger ated burst discharging in motor units separately (a.) or in unison (b). Calibration: 100 msec.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
110
SYNTHETIC
PYRETHROIDS
Figure 11. Flight potential pattern 1 hr after treatment with 0.1 μ-g cis-methrin. Flight motor is uncoupled and hursts of high frequency discharge occur separately in different
4R
-—~—*^$mmi
6L 6R
f j
^
^
-
^0Hh ^
^
f —
'
— —
Figure 12. Onset of high frequency discharge (arrows) and uncoupling of flight motor coordination 14 min after treatment with 0.1 pg of k-Othrin (25 X LD ). Calibration: 100 msec. 50
4RÎ
,1
1 • • 1 • ι η •! 4 •..
6L frftTtiTftirrnrnninrwrnfriHrTrHT ι ί éRi'Hririi-rri'fitiiriTHiTiii ffr t i n Figure 13. Pronounced uncoupling between flight motor neurons 20 min after treatment with 0.1 μg k-Othrin. Calibration: 1 sec.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
.—
9.
M I L L E R
and
cis CNS
The
of
of
CNS
provide
the
trains
Toxicity
compound
time,
less
of
using
of
can
long
It
of
activity
nervous
toxicity
a
are
determine
the
in
3.
CNS
a
i . e . ,
for
a
lethal
misleading
may
be
examined
and
Barthrin
without
axons.
i f
a
sufficiently dose
Structure-activity
be
1.
a b i l i t y
sensory
process,
in
(leg
with
peripheral
detoxication
the
activity
conclusions:
correlated
temporal
or
at
properties. would
to
peripheral
preliminary
impulses
metabolism
data
and
for
is
accumulate
knockdown
111
instructive
pyrethroids
pyrethroids
can
be
System
isomers.
basis
in
resist
it
would
resolved
properties
produce
2.
the
analysis does
Knockdown to
isomers.
trans
activity
assays)
Action in the Nervous
A N D A D A M S
regard-
studies
accounting
for
metabolism. These throids
hypotheses
examined
here
by
as
comparing
shown
in
the
Table
3
pyre-
I.
KNOCKDOWN 2
COMPOUND
Min
on
Treated
Trains
Paper
1.0
KD
Min.
CNS
ng
10
M
yg/fly
Uncoupling
X
Alone
Min.
Min.
PB
SR
TETRAMETHRIN
5.75
0.5
18.7
+
7
.29
.07
CIS-METHRIN
7.97
0.8
24.9
+
7
.08
.03
2.8
1.2
20.7
+
5
.005
.003
1.7
2.3
>60
.66
.2
3.3
k-OTHRIN
31.2
BARTHRIN
TABLE central
I.
Comparative
nervous
action
knockdown,
and
toxicity
k-Othrin
at
1.7
has
onyl
butoxide
of
the
compounds
with
a
synergistic
k-Othrin higher other
synergistic
Barthrin action
are
Barthrin
are
reported
for
which than
As
a
a
2)
pyrethroids 2
Although
as of
there
I.
at
are
3.3 more
with
piper-
Tetramethrin higher
than
readily.
tetramethrin
is
in a
trains
the
by
Dr.
the
Even
with
sensory
nervous nervous between nerve
actions on
can
E l l i o t t
for
its
centrally
that
the be
of
DDT
toxic
the
owe
active
house
their
syn-
potency
In
effect,
responses
mask
system. knockdown
impulses
for
and
fly
by
modern
system.
peripheral
central
correlation of
bioassay but
account
of
pyrethroids
central and
could that
peripheral in
(Barthrin),
the
action
effects
produce
that
pioneered of
the
similar
suggest
action
sites
important
to
very
DDT-like action
improved are
DDT m o r e
coincidence, are
factors
action,
26). of
(Fig.
ratio
Table
detoxified
CNS p o t e n c y
These
ability
and
that
thetic
more
4
in
poor
of
an
ratios
(25,
virtue
there
of
latter
sensory
pyrethroids.
synergistic
compared
has
Barthrin
to
the
lowest
4
resembling
pyrethroids. leg.
ratio
suggesting
synergists
the
peripheral
for
4
and the
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
the 4
the
112
SYNTHETIC
PYRETHROIDS
" J
1
10 MINUTES
100
(log scale)
Figure 14. Dose-response curves for pyrethroids applied directly on the exposed CNS in saline. Dose is plotted on ordinate as (—) log concentration in mol/h against mean time to uncoupling on the abscissa. Tetramethrin shows slightly higher potency than cis-methrin or k-Othrin, but all fall in approximately the same range.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
9.
MILLER
AND
ADAMS
Action in the Nervous
System
113
p y r e t h r o i d s examined, t h i s does not prove that knockdown is caused e n t i r e l y by p e r i p h e r a l a c t i o n s . Uncoupling i n d i c a t e s chemical poisoning in the c e n t r a l nervous system. However, we do not know yet i f c e n t r a l nervous poisoning can occur without uncoupling or before uncoupling. T h e r e f o r e , the f r i e n d l y disagreement between Paul Burt and ourselves concerning c e n t r a l versus p e r i p h e r a l poisoning w i l l not be r e s o l v e d u n t i l more is known about the c e n t r a l s i t e and mode of a c t i o n of p y r e t h r o i d s . There is l i t t l e doubt, however, that some p y r e t h r o i d s are a c t i n g both on p e r i p h e r a l nerves and on the CNS. At p r e s e n t , it is not e n t i r e l y p o s s i b l e to assess the con t r i b u t i o n from p e r i p h e r a l a c t i o n and that from c e n t r a l a c t i o n to symptoms of p o i s o n i n g . Acknowledgement The authors wish t P o t t e r of Wellcome Research L a b o r a t o r i e s , Berkhamsted, England f o r p r o v i d i n g compounds and f o r t h e i r very u s e f u l d i s c u s s i o n s . Some of the r e s u l t s included here are from work by V . Salgado and J. Kennedy to be published in greater d e t a i l elsewhere. The r e s e a r c h was supported in p a r t by Environmental P r o t e c t i o n Agency Grant No. R-804345-01. The contents do not necessar i l y r e f l e c t the views and p o l i c i e s of the Environmental P r o t e c t i o n Agency, nor does mention of trade names or commercial products c o n s t i t u t e endorsement or recommendation f o r use. Literature 1.
2.
3. 4.
5. 6.
7.
Cited
Vinson, Ε. B. and C. W. Kearns. (1952). Temperature and the action of DDT on the American roach. J. Econ. Ent. 45: 484. Blum, M. S. and C. W. Kearns. (1956). Temperature and the Action of Pyrethrum in the American Cockroach. J. Econ. Ent. 49: 862. Narahashi, T. (1971). Effects of insecticides on excitable tissues. Adv. Insect Physiol. 8: 1. Singh, K. M., S. Pradhan and C. Dakshinamurti. (1972). Differential susceptibility of insect neuron to i n s e c t i cides. Indian J. Ent. 34(4): 263-271. Roeder, K. D. and E . A. Weiant. (1946). The s i t e of action of DDT in the cockroach. Science N.Y. 103: 304-306. Roeder, K. D. and E . A. Weiant. (1948). The effect of DDT on sensory and motor structure of the cockroach leg. J. Cell Comp. Physiol. 32: 175-186. van den Bercken, J., L . M. A. Akkermans and J. M. van der Zalm. (1973). DDT-like action of a l l e t h r i n in the sensory nervous system of Xenopus laevis. Europ. J. Pharmacol. 21: 95-106.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
114
8.
9.
10.
11.
12. 13.
14.
15.
16. 17. 18.
19.
20. 21. 22. 23. 24.
SYNTHETIC PYRETHROIDS
Burt, P. E. and R. E. Goodchild. (1974). Knockdown by pyrethroids: its role in the intoxication process. Pestic. Sci. 5: 625-633. Page, A. B. P. and R. E . Blackith. (1949). The mode of action of pyrethrum synergists. Ann. appl. Biol. 36: 244249. Burt, P. E. and R. E. Goodchild. (1971). The site of action of pyrethrin I in the nervous system of the cockroach, Periplaneta americana. Ent. exp. & Appl. 14: 179-189. M i l l e r , T., L . J. Bruner and T. R. Fukuto. (1971). The effect of l i g h t , temperature, and DDT poisoning on housef l y locomotion and flight muscle activity. Pestic. Biochem. Physiol. 1: 483. M i l l e r , T. and J. M. Kennedy. (1972). Flight motor activity of house f l i e s as affected by temperature and insecticides Pestic. Biochem. M i l l e r , T. and J. M Kennedy (1973) of house f l y temperature, flight muscle potentials, heartbeat and locomotion during insecticide poisoning. Pestic. Biochem. Physiol. 3: 370. M i l l e r , T., J. M. Kennedy, C. Collins, and T. R. Fukuto. (1973). An examination of temporal differences in the action of carbamate and organophosphorus insecticides on house f l i e s . Pestic. Biochem. Physiol. 3: 447. M i l l e r , T. A. (1976). Distinguishing between carbamate and organophosphate insecticide poisoning in house f l i e s by symptomology. Pestic. Biochem. Physiol. 6: 307-319. Burt, P. E. (1974). Personal communication. Hart, R. J. (1975). Personal communication. Wilkens, L . A. and G. E . Wolfe. (1974). A new electrode design for en passant recording, stimulation, and i n t r a cellular dye infusion. Comp. Biochem. Physiol. 48A: 217-220. M i l l e r , T. and J. James. (1976). Chemical sensitivity of the hyperneural nerve-muscle preparation of the American cockroach. J. Insect Physiol. 22: 981-988. Nachtigall, W. and D. M. Wilson. (1967). Neuromuscular control of dipteran f l i g h t . J. Exp. Biol. 47: 77. Berridge, M. J. (1966). Metabolic pathways of isolated Malphigian tubules of the blowfly functioning in an artificial medium. J. Insect Physiol. 12: 1523-1538. Thomson, A. J. (1975). Regulation of crop contraction in the blowfly, Phormia regina Meigen. Can. J. Zool. 53: 451-455. Mulloney, B. (1970b). Organization of f l i g h t motor neurons in Diptera. J. Neurophysiol. 33: 86-95. Wilson, D. M. (1968). The nervous control of insect flight and related behavior. Adv. Insect Physiol. 5: 289.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
9.
25.
26.
M I L L E R AND ADAMS
Action
in the Nervous
System
115
Jao, L . T. and J. E . Casida. (1974). Esterase inhibitors as synergists for (+)-trans-Chrysanthemate insecticide chemicals. Pestic. Biochem. Physiol. 4: 456-464. Miyamoto, J. and T. Suzuki. (1973). Metabolism of tetramethrin in houseflies in vivo. Pestic. Biochem. Physiol. 3: 30.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
10 Synthetic Route to the A c i d Portion of Permethrin
M. S. GLENN and W. G. SCHARPF FMC Corp., Agricultural Chemical Division, Box 8, Princeton, N.J. 08540
The d i e n e was Kourim, and Sorm (1
originally
A l t h o u g h the P r i n s r e a c t i o n proceeded i n good yield w i t h o n l y a s m a l l amount o f polymer f o r m a t i o n , a c e t y l a t i o n and r e d u c t i o n r e q u i r e d l a r g e amounts o f p y r i d i n e and z i n c which were too c o s t l y f o r c o m m e r c i a l i z a t i o n . The o v e r a l l yield o f 1,1-dichloro-4-methyl-1,3-pentadiene was o n l y 38%. Our r e a c t i o n sequence c o n s i s t e d o f t h r e e s t e p s w i t h an overall yield o f 57%, a l t h o u g h y i e l d s were not maximized. Only low c o s t , c o m m e r c i a l l y - a v a i l a b l e c h e m i c a l s were u s e d . The Darzens-Kondakov reaction o f 1 , 1 - d i c h l o r o ethene w i t h i s o b u t y r y l c h l o r i d e proceeded as f o l l o w s :
116
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
10.
GLENN
AND
SCHARPF
Permethrin
117
Synthesis
The reaction was developed by Heilbron, Jones, and J u l i a (2); improved by Soulen et al. (3) who used carbon t e t r a c h l o r i d e as a d i l u e n t ; and f i n a l l y by A t v i n , Levkovskaya, and Mirskova (4) who used po tassium carbonate to remove a mole of hydrogen c h l o r ide. The thermal removal of hydrogen chloride was difficult for t h i s compound and required steam dis tillation followed by f r a c t i o n a l distillation. We found that removal of hydrogen chloride was best achieved by using sodium carbonate. The reaction pro ceeded smoothly at 16 gram moles and gave a minimum of 67% distilled y i e l d . Other Lewis acids such as stan nic chloride and f e r r i c chloride gave zero or a poor yield respectively. The reduction of the ketone to the alcohol was attempted by the c a t a l y t i (platinum oxide and chloride), reduction was not obtained.
Ο
OH
A standard reduction (60 using an equimolar amount of commercial aluminum isopropoxide gave an 82% y i e l d of the alcohol. When one-quarter mole of f r e s h l y pre pared aluminum isopropoxide was used per mole of ketone, a 62% y i e l d of the alcohol was i s o l a t e d . Equimolar amounts of f r e s h l y prepared isopropoxide afforded a 94% y i e l d of the d i s t i l l e d a l c o h o l . The Prins reaction of isobutyraldehyde and 1,1-dichloroethene d i d not give the desired alcohol because of a l d o l formation. The dehydration of the alcohol gave 1,1-dichloro4-methyl-l,3-pentadiene and smaller amounts of the corresponding 1,4-diene. The r e s u l t s from various a c i d i c c a t a l y s t were shown in the following table.
2)
OH H+ Acid Clay K S 0 * pTSA 2
2
(Superfiltrol)
7
KHSO4 H3PO
Superfiltrol*
1) 89% 26 20 14 57 83
2) 0.5%
9 0.5
*Azeotropic removal
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
118
SYNTHETIC
PYRETHROIDS
The b e s t commercial method used 1.0-1.5% o f a c i d c l a y a t 100-120° and an i n e r t gas t o a i d in t h e removal o f water. A f t e r t h e e v o l u t i o n o f water was completed the d i e n e was d i s t i l l e d d i r e c t l y from t h e r e a c t i o n flask. S i n c e t h e 1,4-diene may be i s o m e r i z e d t o t h e 1,3-diene w i t h £-toluenesulfonic a c i d , a t o t a l y i e l d o f 90% was o b t a i n e d . The a c i d c l a y , S u p e r f i l t r o l , was a low v o l a t i l e m a t e r i a l o b t a i n e d from t h e F i l t r o l Company, Los A n g e l e s , C a l i f o r n i a . The r e a c t i o n o f t h e d i e n e w i t h e t h y l d i a z o a c e t a t e as d e s c r i b e d by F a r k a s (1) was r e p e a t e d t o g i v e a 37% c o n v e r s i o n and a 71% y i e l d o f e t h y l 3 - ( 2 , 2 - d i c h l o r o vinyl)-2,2-dimethylcyclopropanecarboxylate. The c o s t e v a l u a t i o n f o r 1 , l - d i c h l o r o - 4 - m e t h y l 1,3-pentadiene gav unit t f $1.87 d based on t h e p r i c e o The c o m m e r c i a l i z a t i o preparatio e t h y l d i a z o a c e t a t e and its r e a c t i o n t o form t h e e t h y l e s t e r o f t h e p e r m e t h r i n a c i d would be s i m i l a r t o t h a t o f p a s t a l l e t h r i n s y n t h e s i s (7).
1. 2. 3. 4. 5. 6. 7.
Literature Cited J. F a r k a s , P . K o u r i m , and F. Sorm, Coll. Czech. Chem. Comm., 24, 2230 (1959). I. H e i l b r o n , E . R. J o n e s , and M. Julia, J. Chem. Soc., 1949, 1430. R. L. S o u l e n , D . G . K u n d i g e r , S. S e a r l e s and R. A . Sanchez, J. O r g . Chem., 32, 2661 (1967). A . S. A t a v i n , G . G . Levkovskaya and Α . Ν . M i r s k o v a , J. O r g . Chem. (USSR), 9, 318 (1973). R. Adams, J. Amer. Chem. Soc., 47, 3064 (1925). A . L. W i l d s , O r g a n i c R e a c t i o n s , I I , 178 (1944). H . J. Sanders and A . W. Taft, I n d u s t r i a l and E n g i n e e r i n g Chem., 46, 414 (1954).
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
11 Novel Routes to 1,1-Dichloro-4-methyl-1,4-pentadiene and 1,1-Dichloro-4-methyl-1,3-pentadiene M A N U E L A L V A R E Z and M O R R I S L. F I S H M A N F M C Corp., Agricultural Chemical Division, Box 8, Princeton, N.J. 08540
P y r e t h r o i d s , in activity as insecticides toxicity. The n a t u r a l p y r e t h r o i d s cannot be used commercially to protect agricultural c r o p s m a i n l y because o f their h i g h c o s t and their poor photostability. The synthesis of 3-phenoxybenzyl-3-(2,2-dichlorovinyl)2,2-dimethylcyclopropanecarboxylate
(NRDC 143)
has
been r e p o r t e d (1). T h i s m a t e r i a l has h i g h insecticidal activity and low mammalian toxicity. It a l s o has greater photostability than t h e n a t u r a l p y r e t h r o i d s .
NRDC
143
N R D C 143 has been p r e p a r e d from its c o r r e s p o n d i n g ethyl ester. Acid hydrolysis of ethyl 3-(2,2-dichlorov i n y l ) - 2 , 2 - d i m e t h y l c y c l o p r o p a n e c a r b o x y l a t e 1 formed 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane c a r b o x y l i c a c i d 2. Treatment o f 2 w i t h t h i o n y l c h l o r i d e gave t h e c o r r e s p o n d i n g a c i d c h l o r i d e 3, in an 80% o v e r all yield from 1. Treatment o f 3 w i t h 3-phenoxybenzyl a l c o h o l formed t h e d e s i r e d N R D C 143.
1
2
NRDC
143
3
119
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
120
SYNTHETIC
PYRETHROIDS
I ^CH Cl-C-CH-CH -C
e~, - C l "
-CI
0
ΓΗ
H
C l C-CH-CH -C Z i
C l C-CH-CH -C 2
X
2
N
C H
3
C H
^
C H
2
C l C - C H - C H -C n
2
2
I
X
OH
C CHH
3
OH
(-)| Cl-C-CH-CH -C 2. 2.
* proton
I
^
C
H 2
C l CH-CH-CH -C
CH. source
CH^ 8
C l C = C H - C H -C
2
n
2
^
C H
2
\
Figure 1
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
11. ALVAREZ AND FISHMAN
121
Dichloromethy Pentadienes
Compound 1 has been prepared by the method of Farkas (2). Condensation of c h l o r a l w i t h isobutylene gave 1,1,1-trichloro-2-hydroxy-4-methyl-4-pentene 4 and its isomeric 3-pentene 13. A c e t y l a t i o n of 4 and 13, w i t h a mixture of a c e t i c anhydride and p y r i d i n e gave 2 - a c e t o x y - 1 , 1 , 1 - t r i c h l o r o - 4 - m e t h y l - 4 - p e n t e n e 5 and its corresponding isomer, 14. Treatment of the acetoxy mixture w i t h z i n c - a c e t i c a c i d gave the expected 1,1-dichloro-4-methyl-1,4-pentadiene 6 and the 1,3-pentadiene 7. Isomerization of 6 and 7 with p - t o l u e n e s u l f o n i c a c i d gave the d e s i r e d 1 , 1 - d i c h l o r o 4-methyl-1,3-pentadiene 7 which upon treatment w i t h e t h y l diazoacetate gave the e t h y l cyclopropanecarboxylate 1. A1C1 OH C1 CCH0 + (CH ) C=CH 3
3
° C I
3
2
H
OAc
C > N > X 13
A c
2°
pyridine
>
c i
3
c > ^
OAc +
c
3
l
c
^ v A g - > 14
JETSA^
z
2
2 ^
A
In order to avoid the z i n c r e a c t i o n , routes more amenable to commercialization were s t u d i e d . Some electrochemical reductive e l i m i n a t i o n s of and other 2 - s u b s t i t u t e d analogs of 4 to intermediate 6 were studied in our l a b o r a t o r i e s . Some e l e c t r o c h e m i c a l pathways for the e l e c t r o chemical r e d u c t i v e e l i m i n a t i o n o f ^ t o the d e s i r e d d i e n e £ are shown in Figure 1. Compound could be r e duced by a one e l e c t r o n step to first form the d i c h l o r o r a d i c a l which could e i t h e r dimerize at t h a t p o i n t or acquire another e l e c t r o n to form the carbanion. The carbanion could then be protonated by a proton source, such as a p r o t o l y t i c s o l v e n t , to form 1 , 1 - d i c h l o r o 2-hydroxy-4-methyl-4-pentene β , or undergo e l i m i n a t i o n to form d i r e c t l y the d e s i r e d diene As expected for organo c h l o r i n e compounds, the r a t e of two e l e c t r o n a d d i t i o n was r a p i d enough that r a d i c a l formation was not s i g n i f i c a n t and the observed products were con s i s t e n t w i t h the formation of a carbanion intermediate. A d i v i d e d e l e c t r o l y s i s c e l l , as diagrammed in Figure 2, was used in the e l e c t r o c h e m i c a l r e a c t i o n s so that o x i d a t i o n of the s t a r t i n g m a t e r i a l or product could not occur at the anode. The cathode and anode are g e n e r a l l y separated by means of a permeable b a r r i e r such as f r i t t e d d i s c s or i o n exchange membranes. Three
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
SYNTHETIC
PYRETHROIDS
PO TENTIΟSTAT
V
Reference Electrode
Salt Bridge
r
1
Diaphragms Figure 2.
Schematic representation of ekctrolysis experiment
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
11.
A L V A R E Z
A N D
FiSHMAN
Dichloromethyl
123
Pentadienes
e l e c t r o d e s were used in each experiment; a c a t h o d e , an anode and a r e f e r e n c e e l e c t r o d e such as t h e s a t u r a t e d calomel e l e c t r o d e . By u s i n g t h e r e f e r e n c e e l e c t r o d e , the cathode p o t e n t i a l can be e a s i l y c o n t r o l l e d a t a p r e - s e t v a l u e r e l a t i v e t o a r e f e r e n c e e l e c t r o d e which is s i t u a t e d as near t o t h e cathode s u r f a c e as is experimentally possible. A c e n t e r compartment ( s a l t bridge) f i l l e d with a catholyte (fluoroborates) g r e a t l y m i n i m i z e s intercompartment d i f f u s i o n o f c a t h o l y t e and anolyte. D i l u t e s u l f u r i c a c i d is a c o n v e n i e n t a n o l y t e and t h e o v e r a l l anode r e a c t i o n is e l e c t r o l y s i s o f water to oxygen and p r o t o n s . A photograph o f one e l e c t r o l y s i s c e l l used in our l a b o r a t o r i e s is shown in F i g u r e 3. E l e c t r o l y s i s o f ^ i n dimethylformamide, u s i n g a mercury c a t h o d e , gave a p r o d u c t which c o n s i s t e d o f 35.2% o f 6, a c c o r d i n analysis. The mass s p e c t r of ^ p r e p a r e d v i a the F a r k a s r o u t e . A d o u b l e s a l t b r i d g e was used in t h i s experiment t o reduce t h e l e a k age o f p r o t o n s o u r c e s from t h e r e f e r e n c e e l e c t r o d e . Dimethylformamide was used as t h e s o l v e n t in t h i s r e a c t i o n m a i n l y because it is an a p r o t i c s o l v e n t which c o o r d i n a t e s w i t h t h e OH group t o f a v o r r e d u c t i v e e l i m i n a t i o n o f t h e OH group. However, t h e r e was still s u f f i c i e n t proton activity from t o form OH
OH
ci.c
Hg-DMF ^
+
Cl C
Cl HC 0
The e l e c t r o r e d u c t i o n o f compounds w i t h b e t t e r l e a v i n g groups than hydroxy and a l s o f r e e o f l a b i l e p r o t o n s were s t u d i e d . E l e c t r o l y s i s o f in a c e t o n i t r i l e u s i n g a mercury cathode gave a p r o d u c t which c o n t a i n e d 41% o f t h e d e s i r e d d i e n e a c c o r d i n g t o gc. OAc
cue
Hg-CH CN
>
CI
3
In the s e a r c h f o r an even b e t t e r l e a v i n g group, we chose t o make the m e t h a n e s u l f o n a t e . Treatment o f 4^with m e t h a n e s u l f o n y l c h l o r i d e gave 1 , 1 , 1 - t r i c h l o r o 4-methyl-4-penten-2-yl m e t h a n e s u l f o n a t e J),, mp 60-61°C, in a 69% y i e l d : nmr ( C D C I 3 ) , otitis 3.2 ( s , 3H, - O S O 2 C H 3 ) , no e v i d e n c e o f h y d r o x y l p r o t o n s ; ms, 185 (M-CH SQ , 3C1 p r e s e n t ) , 149 (185-HC1, 2C1 p r e s e n t ) , m o l e c u l a r i o n (280) o b s e r v e d o n l y w i t h c h e m i c a l i o n i z a tion; Anal. Calc. f o r C H C 1 0 S : C, 29.84; H, 3.91; 3
2
7
CI,
37.83; S, 11.37.
1 1
Found:
3
3
C, 29.89; H, 4.06;
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
CI,
SYNTHETIC PYRETHROIDS
124
37.76; S, 11.48. E l e c t r o c h e m i c a l r e d u c t i v e e l i m i n a t i o n of^9, in a c e t o n i t r i l e u s i n g a p l a t i n u m cathode gave the de sired d i e n e ^ i n a nearly quantitative y i e l d . The c u r r e n t e f f i c i e n c y in t h i s c a s e was e s s e n t i a l l y q u a n t i tative. OH
C
1
OSO CH 2
C
3
^
^
—
C
1
3
C
^
4,
^
3
pt-CH C N
?
C I C ^
^
JL
In some i n s t a n c e s , s y n t h e s i z e d samples o f the above methane s u l f o n a t e decomposed a f t e r s t o r a g e g i v i n g b l a c k , t a r r y and a c i d i c p r o d u c t s . The f o l l o w i n g mech anism is s u g g e s t e d f o
H
polymeric
material
χ S i n c e the methane s u l f o n a t e ^ may be u n s t a b l e , a compound w i t h a b e t t e r l e a v i n g group than an a c e t o x y one but not as good as a mesyloxy one was p r e p a r e d . Treatment o f ^ w i t h t h i o n y l c h l o r i d e gave 1 , 1 , 1 - t r i chloro-4-methyl-4-penten-2-yl c h l o r o s u l f i n a t e which c o u l d not be i s o l a t e d in pure form by normal distillation. The b o i l i n g p o i n t o f JlO. was 69-82° ( 0 . 0 9 - 0 . 1 mm) (62% p u r i t y by vapor phase chromatograph i c a n a l y s i s ) . GC-MS a n a l y s i s o f the d i s t i l l e d p r o d u c t e s t a b l i s h e d t h a t the main component gave m/e 284 (Μ), 248 (M-HC1) and 185 ( M - S O 2 C I , 3 CI p r e s e n t ) . Electro c h e m i c a l t r e a t m e n t o f 1Q, in a c e t o n i t r i l e u s i n g a p l a t i n u m cathode gave a p r o d u c t which c o n t a i n e d 10% o f the d e s i r e d d i e n e a c c o r d i n g t o gc. OH
.
osoci
C l3 ^ . ' c "A A 4^
"CI,
l
Cl^C 3
10
^
2
é
>
P T - C H
3
O R
CA
C 2
6
Treatment o f w i t h phosphorus t r i c h l o r i d e gave l,l,l,4-tetrachloro-2-hydroxy-4-methylpentane l l mp 79-81°C in a 25% y i e l d , nmr ( C D C I 3 ) , otitis 4.4 (m, 1H, -CHOH), otitis 2.25 (m, 2 H , - C H 2 - ) , 6tms 1.7 (s, 6 H , - C ( C H ) ) ; A n a l . C a l c f o r C ^ H ^ C l O : C, 30.00, H,4.17; C I : 59.17. Found: C, 29.89; H, 4.27; CI, 59.09. y
3
2
0
4
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
11.
ALVAREZ AND F i s H M A N
Dichloromethyl
Pentadienes
Figure 3
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
125
126
SYNTHETIC
PYRETHROIDS
Figure 4
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
11.
A L V A R E Z
A N D
FiSHMAN
Dichlowmethyl
127
Pentadienes
Reaction of with phosphorus pentachloride gave 1,l,l-trichloro-4-methyl-2,4-pentadiene 12, MS, 185 (MH+, 3C1 present), 149 (MH+-HC1). ^
OH CUC
As shown p r e v i o u s l y , c o n d e n s a t i o n o f c h l o r a l w i t h i s o b u t y l e n e gave a m i x t u r f d 13^ Acetylatio o f 13^ w i t h a m i x t u r gave 2 - a c e t o x y - l , 1 , l - t r i c h l o r o - 4 - m e t h y l - 3 - p e n t e n , bp 85-90°C (4-4.3 mm) (2) in an 82% y i e l d . Electro c h e m i c a l r e d u c t i v e e l i m i n a t i o n o f 14 in a c e t o n i t r i l e u s i n g a mercury cathode gave the e x p e c t e d d i e n e ia 48% y i e l d based on gc a r e a %. n
AC20
OAc
v
pyridine '
c
l
2
3
e
Hg-CH
c
CN
14
The electrochemical reactions can be run in a large divided e l e c t r o l y s i s c e l l , shown in Figure 4, which is s i m i l a r in design to a commercial u n i t . Flow c e l l s can also be used in these electrochemical ex periments. Acknowledgments The authors wish to thank Messrs. Ken Goldsmith and Harold Jarrow for t h e i r t e c h n i c a l assistance, Mr. Robert Rosen f o r help in i n t e r p r e t i n g mass spectra and Mr. Robert Schipmann for construction of the e l e c t r o l y sis cells. Literature Cited 1. Burt, P. E., Elliott, M., Farnham, A. W., Janes, Ν. F., Needham, P. H. and Pulman, D. Α., P e s t i c Sci. (1974), 5, 791-799. 2. Farkas, J., Kourim, P. and Sorm, F., C o l l e c t i o n Czechoslov. Chem. Commun. (1959), 24, 2230-2236.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
12 New Synthesis of the Acid Moiety of Pyrethroids KIYOSI KONDO, KIYOHIDE MATSUI, and AKIRA NEGISHI Sagami Chemical Research Center, 4-4-1 Nishi-Ohnuma, Sagamihara, Kanagawa 229 Japan
Since the discover bromo analogue (2) cation of natural pyrethroids has been renewed owing to their potential use as agricultural pesticides as well as household insecticides. The reaction of ethyl diazoacetate with 1,1-dichloro-4-methyl-1,3-pentadiene was originally used by Farkas (3) in the synthesis of the acid moiety of permethrin. Most of the acid moi eties, however, were usually prepared by the ozonolysis of the parent chrysanthemate followed by conden sation of the resulting 2-formyl-3,3-dimethylcyclopropanecarboxylate (caronaldehyde) with appropriate Wittig reagents (4,5) .
We have developed a new and generally applicable meth od for the preparation of these potentially useful synthetic pyrethroids. The method is based on the reaction between a l l y l i c alcohol and orthoester to produce γ-unsaturated carboxylate, followed by the addition of carbon tetrahalide to the double bond, or a l l y l i c bromination with N-bromosuccinimide. The dehydrolhalogenation of the resulting halides afforded the desired cyclopropanecarboxylates. Synthesis of the Dihalovinyl Analogues of Chrysanthe mate The condensation of 3-methyl-2-butenol
(I) with
128 In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
12.
KONDO
ET
Synthesis of the
AL.
t r i e t h y l
o r t h o a c e t a t e
c a t a l y s t
was
method
( l i a )
p e r f o r m e d
d e s c r i b e d
by
Acid
at
in
Moiety the
presence
li+0-l60°
Johnson
(6)
to
give
3 , 3 - d i m e t h y l - ^ - p e n t e n o a t e
( i l i a )
s i m i l a r l y
c o n d e n s a t i o n
of
of
III
I
can
w i t h
of
a c c o r d i n g
t u t e d
analogue
129
the
e t h y l
(7.).
The be
a p p r o p r i a t e
a c i d
to
α - s u b s t i
p r e p a r e d
by
the
o r t h o c a r b o x y l a t e s
(8,9). 0
Λ Α
+ R
C H
1
2
c a t .
C ( O E t )
r
OH
R
II a:
R
b;
R =Me
X
:
R ^ H , R
c:
R =Me,
The
e f f e c t
the
y i e l d
Table R
1
1 =
of
X=C1
v a r i a t i o n is
of
of
p h e n o l
1:1.05 1:2
p h e n o l
H3PO4
Me
1:3 1:2 1:2 1:2 1:2 1:2
E t * *
1:1.5
Η Η Η
*
The based
**
H
3
2
R ^ H , R =H,
X = B r ,
c:
R*=H,
X=X
d:
R
X
1
=
in
X=X =Cl f
f
M e ,
r e a c t i o n
X=C1
=Br
T
X=X =Cl f
c o n d i t i o n
Table
Time
P 0 * a c i d
i - b u t y r i c
a c i d
I.
Y i e l d
of
amount
of
25 25 6 k
76 60 81
27
III
65 70
93
23
p h e n o l
23 23 2k
69 51 70
p h e n o l
25
57
H g ( 0 A c )
2
h y d r o q u i n o n e
T r i m e t h y l
CX 1
^ - P e n t e n o a t e s
o x a l i c
on
X
(hr)
1:2
Η
1
a:
C a t a l y s t *
Η Η
-Me
b:
1:11
Η Η
of
summarized
P r e p a r a t i o n
m o l . r a t i o
IV
X=C1
the III
1
R
A
X=Br
1
of
I.
=H,
R- H
b:
1
R a:
III
=H
1
base
b:
1
c a t a l y s t
was
usually-
1-5
mole
I o r t h o b u t y r a t e
was
u s e d .
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
%
on
130
SYNTHETIC
t u r e
When
t h e
o f
a n d l i a , t h e r e
I
r e a c t i o n
3 - m e t h y l - 2 - b u t e n y l p r o d u c t the
in
a c e t a t e can,
must
t h e
t h e
a d d i t i o n
o f
T h u s ,
h e a t i n g
p e r o x i d e 80°
hexanoate When
in
(AIBN),
e t h y l
89%
o f
t h e
c a r b o n
was
a d d i t i o n
b . p .
u s e d .
Some
Table
I I .
R
CX 4
o r
o f
t o
e i t h e r by
I l i a
h-
t h e in
a n d
t h e
p r e s
b e n z o y l -
f o r
20
h r s
at
b r o m o t r i c h l o r -
y i e l d .
as
t o
examples a r e
o f
Other
CX4
t o
(l^viS^iJi) > f o r
t h e
c a n a l s o t h e in
be
r e s u l t s
Table
w i t h
I I .
U-Pentenoates Temp.
C a t a l y s t
l i g h t
I V c ,
i n i t i a t o r s ,
o l e f i n s ,
c o l l e c t e d
c a r b o n
v i s i b l e
c a t a l y s t s
i n c l u d i n g
o b t a i n e d o f
analogue
complexes
effective
analogues
w i t h
t e t r a b r o m o
p o l y h a l o a l k a n e s t y p i c a l
m m . , was a d d i t i o n
i r r a d i a t i o n
60%
in
r a d i c a l
m e t a l - a m i n e
A d d i t i o n
Time
Y i e l d IV
H
C C U
BPO
H
CCI 4
F e C l
H
e c u
C u ( O A c )
H
e c u
C u
H
C B r C U
AIBN
H
C B r C l
3
BPO
H
C B r C l
3
H
CBr 4
AIBN
H
C B r
hV
Me
e c u
Me
C B r C l
Me
e c u
F e C l
3
6 H
2
0 - B u N H
E t *
CCI 4
F e C l
3
6 H
2
0 - B u N H
4
2
3
6 H
2
2
0 - B u N H - B u N H
0 - B u N H
F e C l
3
6 H
2
2
80
20
86
120
20
87
90
20
87
90
20
85
100
10
89
80
20
87
120
15
52
5
45
10
60
2
2
0 - B u N H
2
120^130 r.
t .
20
70
100
10
81
2
120
10
49
2
120
10
80
BPO 3
t o
i r r a d i a t i o n .
w i t h
1 0 2 - 1 0 5 ° / 0 . 1 by
w e l l - k n o w n
α - s u b s t i t u t e d
1
I l i a
m m . ,
o f
r a t e .
a z o b i s i s o b u t y r o n i t r i l e
S i m i l a r l y ,
t r a n s i t i o n
a r e
seems
a n d r e a c t i o n
3 , 3 - d i m e t h y l - 4 - b r o m o - 6 , 6 , 6 - t r i c h l o r o -
c o r r e s p o n d i n g
which
o r t h o -
o r t h o e s t e r d i s t i l l a t i o n .
t e t r a h a l i d e
o f
p r o d u c e d as
a t t a i n
o f
a c i d
t e t r a c h l o r i d e
t o
lkk°/0.2
t o
amount
o f
b y
f r a c t i o n a l
(10)
t e t r a b r o m i d e
such
o r d e r
as
p h o s p h o r i c
t r e a t e d
p r e s e n c e
y i e l d .
b . p .
m i x
b . p
( i V b ) ,
t h e
molar f o r m a t i o n
3 , 3 - d i m e t h y l - U , 6 , 6 , 6 - t e t r a c h l o r o -
I l i a
t h e
1:1
t h e
excess
a c h i e v e d
s o l u t i o n c a r b o n
t h e
y i e l d
e a s i l y
a
in
e s t e r
hexanoate
o f
e t h y l
methane
in
o f
( i V a ) ,
t h e
o f by
i n i t i a t o r
(BPO)
a f f o r d e d
Most
in
excess
examined,
was
r a d i c a l
an
r e c o v e r e d
view
I I I
from
o b s e r v e d
T h u s ,
I I I ,
u s e d .
be in
pentenoate ence
y i e l d . o f
c a t a l y s t s
b e s t
The
20$
be
s t a r t e d
was
3 , 3 - d i m e t h y l - 4 - p e n t e n o a t e
y i e l d
however,
Among be
c a .
maximum
was
PYRETHROIDS
130^140
BPO
Me-es t e r
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
o f
12.
KONDO
Synthesis of the Acid
E TAL.
Treatment l e n t s t i o n
o f
base
o f
t h e
s i m u l t a n e o u s l y
c a r b o x y l a t e e s t e r
V
u s e d .
T a b l e
V .
w i t h
a f f o r d
examples
on
R e a c t i o n
h a l i d e
base t-BuOK
THF
IVa
t-BuOK
THF
shown
t h e
in
IVa
t-BuONa
THF
IVa
NaOEt
EtOH
IVa
KOEt
IVa
NaNH
IVc
NaOEt
EtOH
IVd
NaH
DME
The
k 3
60° r .
t .
3. 5 3
5°
2
r . t .
under
EtOH
t h e
80° 22° 80°
sequence
was
1. 5 5- 5 18 20
r . t .
d i r e c t
I l i a
1. 5 2
r . t .
THF-EtOH
2
above
t o
o f
w i t h
The
c h l o r i d e
t o
as
a
c o n d i t i o n
BPO c a t a l y z e d t h e
above
v i s c o u s
c h r o m a t o g r a p h y . two
molar
THF
t o
e s t e r
70
Va
50/50
73
Va
50/50
92
Va
3k/66
9h
Va
26/74
96
Va
50/50 20/80
9k
Vb
o f
c i s
The
e s t e r o f
t o
has
produce ( V I ) ,
p e r m e t h r i n
i n d i c a t e s
a n d t r a n s
t h a t
was
V I I
V I I I it
in
now
been
p e r m e t h r i n .
was 75$
1 5 5 - 1 5 8 ° /
c a r b o n
t e t r a
3-phenoxybenzyl
p u r i f i e d then
y i e l d . o f
( V I I ) by
1:1
in
in
82$
column
t r e a t e d
t - b u t o x i d e
c o n s i s t s
T h u s , a l c o h o l
3 - p h e n o x y
b . p .
o f
a f f o r d e d
sodium
79 55
-
Vc
a d d i t i o n
o i l , w h i c h
e q u i v a l e n t s
give
s p e c t r u m
η
^5/5.5
3 , 3 - d i m e t h y l - 4 , 6 , 6 , 6 - t e t r a c h l o r o h e x a n o a t e y i e l d
V
3-phenoxybenzyl
3 - , 3 - d i m e t h y l - U - p e n t e n o a t e
mm.
V
Va
r e a c t i o n s
p r e p a r a t i o n
t r e a t e d
e s t e r - e x c h a n g e
b e n z y l
I I I .
- P r o d u c t
80°
e s t e r
r e s u l t i n g
c o n d i t i o n s
T a b l e
C o n d i t i o n s
60°
a p p l i e d
e q u i v a
s o l v e n
IVb
0.3
o f
r e a c t i o n
r
i n g
molar
d e h y d r o h a l o g e n a -
D i h a l o v i n y l c y c l o p r o p a n e c a r b o x y l a t e s
S t a r t
the
two
a n d
r a t i o
t h e
a r e
131
d i h a l o v i n y l c y c l o p r o p a n e -
c i s i t r a n s
depending
T y p i c a l
IV
c y c l i z a t i o n
t o
The
v a r i e d
I I I .
e s t e r
i n d u c e d
Moiety
w i t h anhydrous
The nmr m i x t u r e
i s o m e r s .
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
o f
132
SYNTHETIC
PYRETHROIDS
V I I I
At
t h e
was
m i d d l e
o b s e r v e d
m e d i a t e s ,
As
t h e
stage t h e
I X ,
X ,
r e a c t i o n
d i s a p p e a r , excess
in
t h e
r e a c t i o n o f
a l l
from
t h r e e
t h e s e
c o n v e r t e d
t h e
system
d e h y d r o h a l o g e n a t i o n
o f
V
t o
t h e
f i n a l
by
t r e a t m e n t
The w i t h
l i n k a g e
t h e
tons
c o u p l i n g
in
t h e
nmr
t e t r a c h l o r i d e room
o f
tends t o
t h e
i n t e r m e d i a t e
p i p e r i d i n e
olefinic on
stage o f
t h e
V ,
t h e r e i n t e r -
in
IX
t o
i n d u c e
a f f o r d
in
IX
c a n
was
s p e c t r u m .
2 , 2 - d i m e t h y l - 3 - ( 2 ( X I I ) ,
s e l e c t i v e l y
a t
80°
f o r
a s s i g n e d
(15
Hz)
The
I V a w i t h
a f f o r d e d
o f
f u r t h e r e s p e c i a l l y
r e a c t i o n .
benzene
c o n s t a n t
u s u a l l y
The p r e s e n c e
be
b r o m o t r i c h l o r o m e t h a n e
adduct
t e m p e r a t u r e
t o
i n t e r m e d i a t e s
V .
c h l o r o e t h y n y l ) e y e l o p r o p a n e c a r b o x y l a t e at
IV
p o s s i b l e
a n d X I .
p r o c e e d s ,
b e i n g
base
o f
f o r m a t i o n
t h e
o f
15
t o
h r s .
be
t h e
r e a c t i o n
p r e p a r e d
adduct
o f
p y r r o l i d i n e i n t e r m e d i a t e
IVb
The
t r a n s
based
olefinic
p r o -
t h e
c a r b o n
in
DMF a t
X
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
12.
KONDO
ET
Synthesis of the Acid
AL.
s e l e c t i v e l y . mediate
XI
p o t a s s i u m was
used
c i s -
the
s t a r t i n g
t r a n s - X I c o u l d
w i t h d i r e c t
of
t r a n s f o r m e d
the
d i e n y l
of
to
of
the
IVa
was
IVb o f
c o n -
t h e s e
smoothly
or
When
m i x t u r e
i n t e r -
i n t o
c o n d i t i o n
to
i n t e r -
sodium
V
by
b e i n g
t r e a t -
used
in
V .
o f
Chrysanthemate group
1 - b u t e n y l ,
i n c r e a s e s
in
or
1 , 3 - b u t a -
s i g n i f i c a n t l y
the
(15).
homologues of
IV
the
1:1
A l l
d i m e t h y l v i n y l
a l s o
activity
sequence
same
1 - p r o p e n y l ,
s u b s t i t u e n t
insecticidal t h e s e
the
Homologues
M o d i f i c a t i o n c h r y s a n t h e m a t e
w h i l e
t r a n s - X I .
o f w i t h
s o l v e n t .
almost
o b t a i n e d ,
under
IV
h y d r o c a r b o n
to
c o n v e r s i o n
S y n t h e s i s
t r e a t i n g
m a t e r i a l ,
was
be
base
p r e p a r a t i o n
by
in
p r e d o m i n a n t l y
mediates ment
s e l e c t i v e
a t t a i n e d
t - b u t o x i d e as
and
v e r t e d
The was
133
Moiety
can
be
p r e p a r e d
by
the
f o l l o w i n g
r e a c t i o n s .
OH R /%J\/
+
R
1
C H
C ( O R
2
2
)
Ï
v
—
3
R
1
XIV
X I I I NBS
,2
0 0
R
R
1
Y
V/
R
3
The the
s t a r t i n g by
XV
p r i a t e above
G r i g n a r d a l c o h o l
p r e s e n c e e s t e r s
of
XIV
b r o m i n a t e d c h l o r i d e
in
XV
o f
p h e n o l in
good
w i t h the
w i t h
of
a l c o h o l
m e s i t y l
X I I I
o x i d e
was
p r e p a r e d
w i t h
LAH
3 - m e t h y l c r o t o n a l d e h y d e
r e a g e n t s .
X I I I
γ, (S-unsaturated e s t e r
a l l y l i c
r e d u c t i o n
c o n d e n s a t i o n
Br
1
XVI
e i t h e r
Y - R /
and at
H e a t i n g
t r i e t h y l l V o °
y i e l d s .
of
the
e s t e r
was
in
p r e s e n c e
produce
p o t a s s i u m
of
XV.
BPO
to
Treatment
t - b u t o x i d e
in
of
in
the
the
γ , ô - u n s a t u r a t e d
XIV
N - b r o m o s u c c i n i m i d e e s t e r s
by a p p r o -
m i x t u r e
o r t h o a c e t a t e
a f f o r d e d The
a
or
w i t h
c a r b o n o f THF
t h e n t e t r a -
ε - b r o m o -
the
r e s u l t i n g
gave
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
f i n a l l y
134
SYNTHETIC
the
d e s i r e d
t u t e d as
c y c l o p r o p a n e c a r b o x y l a t e
analogues
d e s c r i b e d
X I I I
and
The
c y c l i z a t i o n
R a
I V . R
1
H
"were
above,
t r i e t h y l
b u t y r a t e .
T a b l e
( l é )
s t a r t i n g
step
a r e
and
R
Et
o f
P r o d u c t
3
w i t h
t h e
a l l y l i c or
in
Table
Yield(JÏ)
XV
XVI
6k
91
85
R e a c t i o n for
C o n d i t i o n s
C y c l i z a t i o n
t - B u O K / T H F k
Et
Me
85
91*
66**
t - B u O K / T H F
c
H
Et
Et
88
92*
69**
t - B u O K / T H F
-30°C:
86*
60
H
77**
Et
Me
k8
H
t - B u O K / T H F
22
83
1.5
Crude step
**
y i e l d s . w i t h o u t
I s o l a t e d The
y i e l d s
c y c l i z e d i s o m e r s .
the
crude
p r o d u c t
was
almost
1:1
at
m e r i z a t i o n
o f
e s t e r s
XVIb^and
96Ο-965
c m " " .
a t t a c h e d
though c o u l d
the not
Two t i o n
o f
XV
to
o f
to
the
the
a
c i s
XVIa
i s o m e r s . in
i s o -
t h e r m o d y n a m i c a l l y
s t r o n g
geometry
isomer
o f
t h a t
smooth
s p e c t r a
c y c l o p r o p a n e o f
c i s
t - b u t o x i d e
the
t h e
o f
o f
o f
t h e
r i n g
would
as
minor
a
t h e
a b s o r p t i o n
at olefinic
be
t r a n s ,
component
e x c l u d e d . X V I .
bromide
r e a c t i o n
s t i t u t i o n
next
s p e c t r u m
t r a n s
w i t h
i n d u c e d
e x h i b i t e d
T h e r e f o r e , to
in
m i x t u r e nmr
r e v e a l e d
a n d
I n f r a r e d
s i d e - r e a c t i o n s
hydrogen the
XVIc
XVa
c i s
a
t h e
m i x t u r e
isomer
( ΐ χ ) .
p r e s e n c e be
o f
t h i s
c i s
XVIa
u s u a l l y
from
however,
t h e
t r a n s
bond
m i x t u r e
80°,
s t a b l e
used
X I V .
example,
d e r i v e d o f
on
was
F o r
t r e a t m e n t
t - b u t a n o l
based
e s t e r
t r a n s
a
6 h r
p u r i f i c a t i o n .
and
F u r t h e r
were
p r o d u c t s
Crude
h r
t - B u O K / T H F
0^5°C:
*
h r
1 h r
-10°C: e
f o r
I V .
H
Et
o r t h o -
c o n d i t i o n s
b
Me
manner,
a l c o h o l
t r i m e t h y l
60°C:
d
a - s u b s t J U
s i m i l a r
Chrysanthemate
XIV H
The
a
r e a c t i o n
summarized
Homologues
2
in
o r t h o p r o p i o n a t e
r e s u l t s
X V I ,
p r e p a r e d
PYRETHROIDS
w i t h
The
were one
l e a d i n g XVb
h a l o g e n
t o
and by
o b s e r v e d was
t h e
d i e n e ,
X V c .
t - b u t o x y
The
in
t h e
c y c l i z a
1 , 2 - e l i m i n a t i o n w h i c h o t h e r
a n i o n
to
o c c u r r e d was
t h e
g i v e
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
t h e
o f in s u b
12.
KONDO
e s t e r
ET
Synthesis of the Acid
AL.
X V I I .
c i a l l y
The
when
exposed
to
p e t i t i v e
the the
the
r e s u l t
in
bromoester
of
ι.
\
the
a n a l o g u e s , p r e p a r e d w i t h ( R
3
XVd
the
a l c o h o l s in
87
and
75$
of
com
and
the
might
α-hydrogen
XVe.
Both
be
s u p
d:
R
1
=
e:
R
A
= E t ,
R =Me
and
s t y r y l
e s t e r s
X H I f
The
r e a c t i o n s of
b u t a d i e n y l
c o n d e n s a t i o n
were
t e m p e r a t u r e .
1
of
e s p e
XV
e f f e c t i v e l y
r e a c t i o n
syntheses
a l l y l i c
= p h e n y l )
in
c o u l d
γ , ό - u n s a t u r a t e d
by
a c i d i t y
OBu
R
of
u n d e s i r e d
e s p e c i a l l y the
o b s e r v e d
c y c l i z a t i o n .
t h e s e
however,
l o w e r i n g
R
For
of
was
analogues
i n s u f f i c i e n t
XV,
s i d e - r e a c t i o n s , by
r e a c t i o n
a f o r e m e n t i o n e d
o c c u r r e n c e
be
p r e s s e d
l a t t e r
a - s u b s t i t u t e d
135
Moiety
M e ,
X l V f
R
2
and
t r i e t h y l
( R 3 = v i n y l )
y i e l d s ,
X l V g
were
o r t h o a c e t a t e
and
X H I g
r e s p e c t i v e l y .
t -BuOK
Br
= Et
2
V
S
Λ
V v X l V f
,
Ph
v
Ph
NBS
»
v V
o f
(9k% XIX
o f
p r o d u c t y i e l d ) (85$
of
p r o d u c t s
u n s a t u r a t e d
I n s p e c t i o n major
A>\X
>
Ph XXI
XIX
s t r u c t u r e t h e s e
t-BuOK
I Br
XlVg
The
XX
XVIII
t h e i r from
and
y i e l d ) .
nmr X l V f
t h a t
o b t a i n e d
e s t e r s
was
by
not
the
so
b r o m i n a t i o n
s i m p l e .
s p e c t r a
suggested
was
ω-bromoester
from
the
X l V g
Treatment
of
was
the
t h e s e
t h a t
the XVIII
γ-bromoester
crude
b r o m i n a t i o n
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
136
SYNTHETIC
PYRETHROIDS
products with potassium t-butoxide in THF below 0° produced the expected cyclopropanecarboxylates XX, b.p.
62-65°/0.1 mm., and XXI, b.p. 112-ll8°/0.1 mm., in 59 and 58$ yields based on XIV, respectively. Acknowledgements. The authors are grateful to Mr. Miss
T .
T a k a s h i m a ,
Y .
Takahatake
M r . f o r
T .
K o i z u m i ,
t h e i r
M r .
c a p a b l e
K.
Sugimoto,
a n d
a s s i s t a n c e .
Literature Cited, 1. Elliott, M., Farnham, A.W., Janes, N.F., Needham, P.H., Pulman, D.A., and Stevenson, J.H., Nature (1973) 246, 169. 2. Elliott, M., Farnham, A.W., Janes, N.F., Needham, P,H., and Pulman, D,A., Nature (1974) 248, 710. 3. Farkas, J., Kourim, P., and Sorm, F., Coll. Czech. Chem. Commun. (1959) 24, 2230. 4. Crombie, L., Doherty, C.F., and Pattenden, G., J. Chem. Soc. (C) (1970), 1076. 5. Elliott, Μ., Janes, N.F., and Pulman, D.A., J. Chem. Soc., Perkin I (1974), 2470. 6. Johnson, W.S,, Werthman, L., Bartlett, W.B., Brocksom, T.J., Li, T., Faulkner, D.J., and Petersen, M.R., J. Amer. Chem. Soc., (1970) 92, 7 4 l . 7. Babler, J.H. and Tortorello, A.J., J. Org. Chem. (1976) 4 1 , 885. 8. Harrison, R.G. and Lythgoe, B., Chem. Commun. (1970), 1513. 9. Bolton, I.J., Harrison, R.G., and Lythgoe, B., J. Chem. Soc. (C) (1971), 2950. 10. Kharasch, M.S., Jensen, E.V., and Urry, W.H., J. Amer. Chem. Soc. (1947) 69, 1100. 11. Kharasch, M.S., Jensen, E.V., and Urry, W.H., J. Amer. Chem. Soc. (1946) 68, 154. 12. Asscher, M. and Vofsi, D., J. Chem. Soc. ( 1 9 6 1 ) , 2261. 13. Suzuki, T. and Tsuji, J., Tetrahedron Lett. (1968), 913; J. O r g . Chem. (1970) 35., 2982. 14. Matsumoto, H., Nakano, T., and Nagai, Y., Tetrahedron Lett. (1973), 5l47. 15. Elliott, Μ., Farnham, A.W., Janes, N.E., Needham, P.H., and Pulman, D.A., Nature (1973) 244, 456. 16. Itaya, N., Okuno, Y., Horiuchi, F., Higo, Α., Honda, T., Mizutani, T., Ohno, N., Kitamura, S., and Matsuo, T., Japan kokai 74-75725, Chem. Abst. (1975) 82, 81723f. 17. Julia, Μ., Julia, S., Bemont, Β., and Tchernoff, G., C. R. Acad. Sci. (1959) 248, 242.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
13 Photochemical Reactions of Pyrethroid Insecticides R O Y L. H O L M S T E A D , J O H N E . C A S I D A , and L U I S O. R U Z O Pesticide Chemistry and Toxicology Laboratory, Department of Entomological Sciences, University of California, Berkeley, Calif. 94720
The natural pyrethrin synthetic chrysanthemate agricultural insect pests because of insufficient s t a b i l i t y in l i g h t and a i r ( l ) . Considerable progress has been made in improving the photostability of pyrethroids by suitable formulation ( e . g . , microencapsulation and inclusion complexes) and by adding antioxidants or UV screens. However, the most effective stabilization is achieved by replacing the photol a b i l e groups by others that give enhanced s t a b i l i t y to the overall molecule and equal or increased insecticidal activity (2,3). Knowledge of the photochemical reactions of the earlier pyrethroids contributed to the development of this new generation of photostabilized pyrethroids. It is now necessary to define the photochemistry of these newer compounds and the significance of their photoproducts as residues and environmental contaminants. This review considers the types of photolytic reactions of pyrethroids with emphasis on permethrin (3), NRDC l 6 l (4) and S 5602 (5). Isornerization of the Cyclopropane Ring and of Alkenyl Substituents Epimerization of [lR]-cyclopropanecarboxylate insecticides greatly reduces or destroys their insecticidal activity. As a corollary, epimerization of suitable [IS]-compounds yields the insecticidal conformation. The trans- and cis-isomers also differ in potency and persistence. Photoisomerization of the cyclopropane ring therefore has important consequences. Irradiation (\ > 200 nm) of [ l R ] - or [1RS]-trans- or - c i s chrysanthemic acid or its simple a l k y l esters in hexane with isobutyrophenone or related sensitizers yields equilibrium mixtures of the corresponding [ l R , t r a n s ] - , [IS,trans]-, [ l R , c i s ] and [lS,cis]-compounds in the approximate ratio 32:32:18:18 (6-9) (Figure l ) . The postulated mechanism involves cleavage 137
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
138
SYNTHETIC
PYRETHROIDS
Figure 1 of
t h e C - l t o C-3 bond
diradical
w h i c h may
k possible
the
fragment it
may
rearrange I,
isomerized
on glass
cyclopropane s i l i c a
themates
studies
isomerization isobutenyl
cyclopropane solution nm)
mixture or
in
as deposits sunlight
tion
phase
with
the resulting
NRDC l 6 l s o l u t i o n s ,
in
methanol
o f thin after
a
films
are also
leads
in
thin
in
exposed
photoisomerizaoccurs
undergoing
further
(\ >
290 n m )
On i r r a d i a t i o n
o f isomerization in
2-propanol;
to sunlight, (l4).
on exposure
methanol
Photo-
films
or cis-permethrin
more
( λ >290
occurring
than
(12).
solutions,
degree
both
t o an equilibrium
on glass
mixture
irradiation detected
in
Irradiation
surfaces
occurs
trans-
on glass
by replacing
the isomerization
isomer
small
in
over
undergo
extent
(12-14).
films
andconsiderably
6 days
the acid moiety
aqueous
(see below).
of
obtained
preference
significant
also
I n dilute
chrysan-
a n da i r so that
maytake
g e l or s o i l
o f permethrin
exposure
irradiated
These
ring.
or as thin
on s i l i c a
(13)
at the
light
in
andc i s - e s t e r s ,
(12).
o f isomerization
or cis-permethrin
hexane
photodecomposition
derivatives
in
acid nor
trans-resmethrin
sunlamp X L L ) «
reactions
(\ > 2 9 0 n m ) o f e i t h e r
rapidly
to a
d i d not
o f the
by a dihalovinyl substituent
trans-
o f trans-
rapidly
or a
reactions
isomerization
isomerization to
group
on hydrolysis
with
unstable
other
or
irradia
cis-chrysanthemic
Theabsence
photostabilized
ands o l i d
o f either
more
neither
o f the cyclopropane
Pyrethroids
the senecioate
2h h r s u n l a m p
after
was c o n f i r m e d
are relatively
t h e d i r a d i c a lmay
t o give
TlR,trans]-chrysanthemates
even
sunlight
a a n yo f
(7,9).
was r e c o v e r e d
esters.
ring
g e lwith
short-term
the
Thus,
acid
t o form to y i e l d
dimethrin a n dtetramethrin)
products
(10).
photodecomposed
cleavage
insecticidal
a l l e t h r i n ,
meso-cis-caronic
on
Alternatively,
to a lactone
on k
Studies
tion
isomers.
ring
t h e C - l t o C-3 bond
b y C-2 t o C-3 bond
(pyrethrin reveal
o f the cyclopropane
reform
occurs
on
30$ t r a n s - i s o m e r
is
The senecioate o f permethrin
a n d NRDC
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
13.
HOLMSTEAD ET
l6l
as
thin
sunlight
tion
films
to
and
trans7cis-isomerization
occurs
rate
is
via
the
markedly
sensitizers
(6-8).
of
NRDC l 6 l
on
irradiation
where
sensitizers
(\
but
sensitizer
permethrin
is
in
water
290
nm)
chrysanthemic
with
also
isomerization >
for
excited
increased
in
is
state
since
to
acid the
case
the
hexane
only in
is
with
and
acid
reaction
the
the
the
its
other
moiety
observed
presence
major
and
isomeriza
isobutyrophenone
the
photodebromination
substituents
to
group
(Figure
t r i p l e t
This
photoisornerization, converted
of
of
triplet
reaction
without
(13).
Alkenyl
enyl
sunlight
139
Reactions
lk).
(12,
The esters
Photochemical
AL.
a
of
in
i . e . ,
cyclopropyl jasmolin
the
the
I
rethronyl moiety
a l l y l
group
substituent
gives
the
of
and
also
undergo
allethrin
the
is
Z(cis)-pent-2-
Ε(trans)-isomer
(15)
2).
hv
Oxidation
of
F u n c t i o n a l Groups
Photooxidation themates
and
of
various
the
earlier
moieties
of
residual
persistence.
allethrin, yields acids, tion
of of
at
products ester
which
the
possible Figure
alcohol I
and
the
in
moiety
were
oxidation furylmethyl on
glass
major
thin
films
I,
on
glass
Saponification
of
pyrethroid liberates
compounds
originate
double
bond
pathways
to
account
3.
Although products
not
examined, the
their
pyrethrin
or
to
chrysan-
alcohol
limits
of
(10 ) .
each
in
Moieties
the
other
and a l l y l
groups
are
and
pyrethroids
for
of
compounds very
compounds
from
l a b i l i t y
oxida
isobutenyl
these
derived
high
from
the
the
12-16
of
the pyrethrin
indicates
susceptible
to
that photo-
(10).
Resmethrin or
case
from
as
the
group
allethrin relative
pentadienyl
light
each
identified
substituent;
in
greatly
tetramethrin
in
and A l c o h o l
substituent
groups
pyrethroids
trans-methyl
are
shown
isobutenyl
Acid
Photodecomposition
products the
the
functional
dimethrin and
11-15
mixture
the
of
in
group
sunlamp or
as
other
undergo
irradiation
deposits
on
photodecomposition
isobutenyl
substituent
to
with
rapid oxidation in
aqueous
s i l i c a
route give
gel R-
medium
5-benzyl-3exposed or
as
k).
epoxidation
at
and
to
sun
thin
(Figure
(ll)
involves the
the when
S-epoxides.
films One
the Formation
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
140
of
SYNTHETIC
the
the
poses by
other
furan by
the
to
a
as
photoproducts a
cyclic
following
rearrangement
detected or
major
ring
its
hydrogen
benzyl
group
benzyl
cation
to
pathways:
the
give
the
the
(ll);
position
hydroxy
r a d i c a l to
give
peroxide
reduction
derivative
r a d i c a l from or
i n i t i a t e d by
cyclopentenolone
epoxide
to
is
ozonide-type
lactone the
to
(i)
a
oxidation which d i o l is
migration
of
symmetrical ( i l l ) ;
of
decom-
followed
which
benzyloxy
PYRETHROIDS
also a
to
proton the
migration lactone
of
the
(IV)
(11). No p h o t o o x i d i z e d identified
to
(Ik)
5602
the
and
S
date
a c i d moiety
resistant
to
in
derivatives
r e t a i n i n g the
ester
group
the
on p e r m e t h r i n
(12),
NRDC
l6l
bond
of
(12). and
The the
studies
halogen-substituted
3-phenoxybenzyl
group
double appear
to
photooxidation.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
be
are
quite
13.
HOLMSTEAD
Reductive The tion
Photochemical
E T A L .
Dehalogenation
the acid
duces t h e p o s s i b i l i t y halide.
permethrin halogen
Less
group
of reductive extensive
irradiated
(λ
monodechlorinated
derivative
moiety
b u t always
in
larger
amounts
minor
o f these
o n NRDC 1 6 1 .
Thus,
preference
steric
accounts l 6 l
of
debromination
products
from
l6l
been
have
either
is
light
Photoelimination The
the
in
hexane
proceeds
This
steric
o fd i -
unity
is
i . e . ,
(13).
not
the
The
f o r photodebromination
is
or thin
(12-14),
amount
preference
o f NRDC l 6 l ,
material
product
monodebrominated
n o t formed
films
(l4).
no secondary
monodechloro-permethrin
hexane
o f Carbon
with
on irradia Inthe
oxidation
o r monodebromo-NRDC
sources
o f photodecarboxylation
on the structure
Photoelimination
linkage
light
group o f
containing
short
Dioxide
or other (l6).
free
This
dioxide
a n dr e l a t e d radical
type
in
o f the acid
o f carbon
certain pyrethroids
an α-cyano
ester
in
to
(12).
depends
conditions. reaction contain
in
importance
generally
l 6 l
l i k e l y
the findings
the trans-debrominated
necessary
solutions
is
with
dechlorination o f the chlorophenyl
evident
wavelength
it
on analogy o f NRDC
o f the
Figure 5
approximates is
wave
observed.
Reductive 5602
ratio donor
carried out t o date
somewhat
at shorter
not assigned,
(13).
debrominated
benzene
ando f the a c i d 5);
the stereochemistry
the a c i d moiety
o f a hydrogen
o f either
studies
(Figure
irradiation, a small
formed
with
NRDC l 6 l s i n c e
tion
S
is
gives the
ester
f o r ~ 80$> o f t h e t o t a l
debromo-NRDC
starting
is
product
so that
on prolonged
trans/cis
"with
carbon-
4%
debromination
derivatives;
presence
func
intro
to a
relative
are obtained
Although
permethrin
with
evident
(12)
12 %
5)
it
expected
290 n m ) in w a t e r
>
amounts
the trans-dehalogenated
(Figure
is
on their
o f the parent
\ > 220 n m ) .
(e.g.,
monodechlorinated
a
but
photodehalogenation
dehalogenation
products
N R D C 161
be
isobutenyl
strengths.
Permethrin
lengths
f o r the labile
to photooxidation
t h a n w i t h NRDC l 6 l b a s e d
bond
141
o f Dihalovinyl Substituent s
d i h a l o v i n y l replacement
stabilizes
vinyl
Reactions
ester is
a
compounds
stabilizing
o f reaction
photolysis
andi r r a d i a t i o n
is
prominent which group
α to
negligible
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
in
142
SYNTHETIC
unsubstituted
esters
major
f o r S 5602
pathway
(Figure (12).
6)
such
a n d in h e x a n e ,
o f S 5602
t h e case
o f ERDC
l 6 l
in
methanol
(Figure
6)
(13)
than
with
combination acid
Ester
in
with
acid
products
C
,
CI
solvents
photoproduct
smaller
probably
on
(12).
amount
due t o a
r a d i c a l
o f other
bond
ether
is
a
significant
( l l ) but apparently
dimethrin
a n dt e t r a m e t h r i n
t h e newer
pyrethroids
a n da
cyano
the transalcohol
conditions
methyl
is
o f the benzylic
formed
from
reactions
gives
in
W ^ V " A r ^
1
is
water
a
esters
yields
W
Xa
o
alcohol
•
h
methanol
o f these (12)
a^XA,O H
26%
11%
29%
13%
atoms
carbon.
o r hexane in
major
halogen
a t the benzyl
photolysis
the methyl
C
It
contain
a n dc i s - d i c h l o r o v i n y l acids
whereas
o f 3-phenoxybenzyl
permethrin
reaction f o r
not f o r pyrethrin
(10).
which
group
o f trans -permethrin
phenoxybenzyl l a r
the
f o r 28 d a y s
b u t in m u c h
difference
is
a n dother
t h e major
a n dt h e v a r i e t y
o f the ester
moiety
irradiation major
is
it
Cleavage
a l l e t h r i n , the
o f S 5602
a n dc i s - r e s m e t h r i n
reaction
but
> 2 9 0 n m ) in m e t h a n o l
t o NRDC l 6 l .
Photolysis I,
This
o f the s t a b i l i t y
Bond
trans-
(χ
g e l to sunlight
a n dhexane
S 5602.
portion
available
derivative
on s i l i c a
In
(12)
acetonitrile-water
Thedecarboxylated
exposure
the
as permethrin on irradiation
PYRETHROIDS
and3under
acids
(Figure
Thus, as simi
and t h e 7 ) .
c i s -
+ HO^Ar 28%
hv \>290^
Permethrin l6l
gives
undergoes the trans-
acetonitrile-water the
viscosity
2-propanol), cleavage
with
analagous
NRDC
a n dt h e i r is
reactions
3
53% (12).
methyl
esters
increases
a relative
in
in
in
(13 ) .
As
ethanol and
the extent
phase,
NRDC
hexane a n d
methanol
(methanol,
decrease
l 6 l a n d in t h e s o l i d
in
Figure 7
Similarly,
a n dc i s - d i b r o m o v i n y l acids
o f the solvent there
CH 0^Ar
OCH3
CH3OH
o f
ester
sunlight,
this
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
13.
H O L M S T E A D
ceases
E T
t o be t h e major
Dimerization
o f Free
Irradiation S
Photochemical
AL.
5602
in
r e a c t i o n pathway ( l U ) .
Radicals
( λ > 2 9 0 n m ) o f N R D C l 6 l in h e x a n e
several
generated
143
Reactions
solvents
(12)
leads
during the photolysis
process
NRDC 161 Ihexane " U>290
NC
NRDC 161 S 5602
4%
NRDC 161 S5602
3%
(Figure
of
Ar
A
/~\ Ar Ar
I
CN
k
t h e cyano
the free
The m a i n of
bond
correspond
portion
S 5602
which
discussed give
is
v i a coupling
cleavage
to the d,l-mixture
ofthe
o f the pyrethroid.
formed
above.
from
This
i d e n t i c a l mass
recombination
chloride
from t h e
dimer
spectra
a n d t h e meso
o f a-isopropyl-£-chlorobenzyl
same
form. also
is
observed
and probably Direct
photoly
generates t h e
dimer.
Further
Photodecomposition
Pyrethroids of
photoproducts
of
theprimary
moiety
benzyl
acid,
shown
major
obtained
pyrethroids,
Figure
amounts in
product
9.
a n dgreat
further
F o rexample, benzoic
Small
alcohol in
and methanol.
hexane
odor
whereas
in
o f
photo-
(\ > 2 9 0 n m )
a n d 3-hydroxybenzaldehyde
NRDC l 6 l in
further
and phenylacetic
v a r y i n g amounts
amounts
variety
reactions
the alcohol
degrades
acid
on photoly
( l ^ ) a n d S 5602
o f the free
hexane,
o f 3-phenoxybenzaldehyde
hexane in
from
Permethrin photolysis
o n NRDC l 6 l p h o t o l y s i s
pyrethroids
number
o f resmethrin
3-hydroxybenzyl
are
large
products.
( l l ) .
products
o f t h e a-cyano
observed
a large
Products
contributing t o the unpleasant
sis
in
Cleavage
originate
benzaldehyde,
resmethrin
yields
yield
on photolysis
alcohol,
Several
o f Ester
o f which
cleavage
the latter
in w a t e r (12).
generally most
liberated
decomposed
and
from
formed
from hemolytic
o f the alcohol
reaction
g l e as 2 peaks
sis
to
a r epresumably
generated
dimeric product
Figure 8
0 /ο
thea-isopropyl-O-chlorobenzyl radical resulting
decarboxylation on
,.
group
radicals
oxygen-carbon
Dimers
CN
H
Ar containing
8).
ando f radicals
| hexane "Ίλ>290
V
NRDC 161 14% S 5602
(13)
o f free
S 5602
h
^
t o dimers
methanol
methanol
and water
a r e formed
Theb e n z o y l it
(12),
cyanohydrin are with
cyanide
reacts
is
both a
further
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
to
144
SYNTHETIC
NRDC 161 hv I methanol λ>290
PYRETHROIDS
S 5602 I methanol hv X>290
"
I F
CN
•O^Ar
•
CN
CN
JL. OCH O^Ar
HO^Ar
3
H O^Ar
Figure 9
give methyl 3-phenoxybenzoate; authentic benzoyl cyanide in methanol is readily converted to the methyl ester upon heating at 50° or on photolysis (13). Other products include the alde hyde of the dibromovinyl acid (which yields a great variety of additional products on further photolysis) and the dibromovinylcyclopropane derivative or its ring-opened isomer. Analogous reactions occur in the acid moiety on photolysis of S 5602. Discussion The first steps have been taken in understanding pyrethroid photochemistry, a f i e l d that w i l l undoubtedly undergo tremendous growth within the next few years. This knowledge is useful in further s t a b i l i z i n g the pyrethroids to photodecomposition but it also signals certain peripheral problems. The early pyre throids were too unstable in l i g h t and a i r for extensive use in agriculture whereas currently available pyrethroids are sufficiently stable so that weekly or biweekly applications pro vide excellent pest insect control. Further stabilization may increase the r i s k of unfavorable environmental persistence. The large number and great variety of photoproducts provide a challenge to analytical chemists and toxicologists responsible for devising methods of residue analysis and experiments to evaluate the use safety of these highly effective insecticides. Abstract Natural and synthetic pyrethroids undergo one or more of the following types of reactions upon photolysis in organic solvents (hexane, methanol), in water or as thin films: isomerization of the cyclopropane ring and of alkenyl substituents; oxidation of functional groups in the acid and alcohol
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
13.
HOLMSTEAD E T A L .
Photochemical Reactions
145
moieties; reductive dehalogenation of dihalovinyl substituents; photoelimination of carbon dioxide, particularly with α-cyanobenzyl compounds; ester bond cleavage yielding the free acid and alcohol moieties; dimerization of free radicals generated during the photolysis process; further photodecomposition of ester cleavage products. The relative importance of these reactions is dependent upon the structure of the pyrethroid and the photolysis conditions. Acknowledgements The authors thank Donald Fullmer and Tadaaki Unai for valuable suggestions and assistance. This study was supported in part by grants from: National Institutes of Health (2 P01 ESOOCA-9); Agricultural Chemical Div. FMC Corp. Middleport N.Y.; Agricultural Chemical Goldsboro, N.C.; Sumitom Uclaf-Procida, Paris, France; Mitchell Cotts & Co. Ltd., London, England; Wellcome Foundation Ltd., London, England; National Research Development Corp., London, England. Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Elliott, M., in "Pyrethrum the Natural Insecticide" (Casida, J. Ε., Ed.) (1973) Academic Press, New York, N.Y., p. 55 ff. Elliott, M., Farnham, A. W., Janes, N. F., Needham, P. H., Pulman, D. Α., Stevenson, J. Η., Proc. Seventh Br. Insec. Fung. Conf. (Brighton) (1973) 721. Elliott, M., Farnham, A. W., Janes, N. F., Needham, P. Η., Pulman, D. Α., Stevenson, J. H., Nature (1973) 246, 169. Elliott, M., Farnham, A. W., Janes, N. F., Needham, P. Η., Pulman, D. Α., Nature (1974) 248, 710. Matsuo, T., Itaya, N., Mizutani, T., Ohno, Ν., Fujimoto, K., Okuno, Y., Yoshioka, H., Agr. Biol. Chem. (1976) 40, 247. Sasaki, T., Eguchi, S., Ohno, M., J. Org. Chem. (1968) 33, 676. Sasaki, T., Eguchi, S., Ohno, M., J . Org. Chem. (1970) 35, 790. Ueda, K., Matsui, Μ., Tetrahedron (1971) 27, 2771. Bullivant, M. J., Pattenden, G., Pyrethrum Post (1971) 11(2), 72. Chen, Y-L., Casida, J. E . , J. Agr. Food Chem. (I969) 17, 208. Ueda, Κ., Gaughan, L. C., Casida, J. E . , J. Agr. Food Chem. (1974) 22, 212. Holmstead, R. L . , unpublished results.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
146 13. 14. 15. 16.
SYNTHETIC PYRETHROIDS
Ruzo, L. O., Holmstead, R. L., Casida, J. E., Tett. Lett. (1976) 35, 3045. Ruzo, L. O., unpublished results. Bullivant, M. J., Battenden, G., J. Chem. Soc. (1976) 249. Holmstead, R. L., Fullmer, D. G., J. Agr. Food Chem. (1976) accepted for publication.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
14 Permethrin Degradation in Soil and Microbial Cultures DONALD D. KAUFMAN and S. CLARK HAYNES Agricultural Environment Quality Institute, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, Md. 20705 EDWARD G. JORDAN and ANTHONY J. KAYSER Department of Botany, University of Maryland, College Park, Md. 20742
Pyrethroids are on cides known. Although natural and synthetic pyrethroids are excel lent insecticides, their i n s t a b i l i t y in light and a i r has limited their use in protecting agricultural crops. Recent work (1) has demonstrated, however, that the most labile groups in pyrethroids can be replaced by others which provide greater s t a b i l i t y and equal or increased insecticidal a c t i v i t y . Knowledge of the pathways by which natural and synthetic pyre throids are metabolized i n mammals (2-11), or photochemically de graded (1, 12-14), has developed rapidly i n the last several years. A literature survey indicated that despite their long history of use, essentially nothing is known about the degradation or persis tence of pyrethroids in soil. This paper describes the results of a cursory investigation of the degradation and persistence of permethrin [m-phenoxybenzyl c i s , trans-(+)-3-(2,2-dichlorovinyl)2,2-dimethylcyclopropanecarboxylate] (FMC 33297, Ν DC 143) in s o i l (15). A more detailed report w i l l be published elseshere. Degradation in Aerobic Soil Aerobic s o i l metabolism studies were performed with soils placed in a simple flow-through system which permits simultaneous measurement of loss by volatilization and metabolic CO evolution from s o i l (16). Chemical and physical characteristics of the soils used are l i s t e d in Table 1. C-Carbonyl (acid) and Cmethylene (alcohol) permethrin (Fig. 1) were used i n these inves tigations. Material applications were made i n 0.1 ml benzene to a final concentration of 0.2 lb/A of the cis/trans mixture after which each sample was thoroughly mixed, watered to 75% moisture content at 1/3 bar moisture, and incubated at 25°C. Sodium azide was used as a microbial inhibitor i n soils to assess the contribu tion of s o i l microbial activity to permethrin degradation. At the conclusion of the incubation period, the soils were extracted and processed as shown in F i g . 2. 2
14
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
1 4
148
SYNTHETIC
Figure 1.
PYRETHROIDS
C-labeling pattern of C-permethrin indicating carbonyl and methylene hbeling positions 14
14
Treated S o i l Incubation
t i c , glc etc.
Bound residues
^
Soluble \^
Fulvic acid
Memphis s i l t
characteristics of s o i l s .
O.M.
% Mois. content pH 1/3 b a r
0..7
5. 8
37.6
CEC Sand (meq/lOOgm)
Silt
% Clay
16.3
20.8
54.0
25.2
8.5
48.8
44.0
7.2
1..0
5. 9
23.7
33.6
20.8
32.0
47.2
6..1
5. 9
45.5
8.8
17.0
50.6
32.4
2. .3
7. 5
32.6
48.0
42.0
9.7
1..2
7. 2
22.4
loam
Dubbs loam Sharkey C l a y Hagerstown s i l . c l a y loam San Joaquin sandy loam
• r e s i d u a l (humin) combustion
Soil extraction procedure
Chemical and p h y s i c a l
S o i l type
Alkaline extraction
Humic acid
Figure 2.
Table I.
<4
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
14.
K A U F M A N
Degradation carbonyl-
and
Hagerstown of
the
1 1 +
bation. ment 1 4
1 Z +
s i l t y
clay
incubation.
that
these The was
evolved
1 1 +
also
from
examined.
microbial evolution
of
l
Less
1%
of
soil
was
plugs.
either label ated
than
recovered
into
s o i l . obtained
was
These
obtained
thrin was
2.
removed azide
remained humic
l
l
1
4
f
vic
acid
whereas thrin the
tion.
from
was
in
was
the
whereas clay
the
significant. inhibi-
treated
-permethrin
was
1 1 +
the
when
that
i s
the
l l f
either
presented C-balance
l i +
C-carbonyl-perme-
soil
were
residual
are
residual
23-33%
of
incorpor-
complete
and
C residues
losses
procedure
the
the
polyure-
containing
permethrin
of
u l t i -
in
the
negligible
a nearly
from
by
products
extraction
soil
and
C-permethrin.
trapped
C-methylene-
the
in
were
observed
organic
labeled
greater
activity
lh
C
with
no
microbial
extractable of
the
material
l i +
from
C
activity
(fulvic
of
differences
the
and
in
rates as
Hagerstown
s i l t y
clay
rates
of
loam.
1
the of
evidenced
soil
A very
slow
permesoils
acid
frac-
microbial
matter of
l t f
were
C0
2
fine
C-carbonsoil
evolution sandy
observed
degradation
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
of
fractions.
l i +
different by
the ful-
humin,
association
a n d Dubbs
degradation
in
treated
degradation
loam
the
fulvic
organic with
the of
^C-carbonyl
in
C-methylene
and the
experiments
intermediate
s i l t
in
soil of
of
than
1 I f
of
The bulk
was p r e s e n t
In a z i d e
pesticides
Rapid degradation
a n d Memphis
acid
importance
various
in
forms
fraction.
of
distribution
portion
fulvic
the
the
observed
the
fractions.
was p r e s e n t
indicate with
greater in
portion
C-labels
in
matter
permethrin
the humin
degradation
were
(Fig. 4).
Sharkey
1 1 +
products
observed
loam,
the days
from
the microbial
l l f
that
14.5-18.8%
A somewhat
results
permethrin
types
l i f
was p r e s e n t in
of both
various
of
34
however,
degradation
of
Approximately
soil
distinctly
Significant yl
of
with
both
residue
These
activity the
70%
soil
extraction
soils.
within
residue
bulk
the Only
and humin. a
incu-
and humin).
activity
permethrin
62%
i n i t i a l l y
than
time,
the
the
degradation
indicate
differences
C-activity
C
was
this
of
C-
f
experi-
after
2
i n i t i a l l y present
indicate
or
the
associated
days
the permethrin
products
from both
Nearly
acids,
in
forms
activity
data
soils.
treated
Slight
C
results
by methanol
inhibitor. the
with
treated
***00
of
0.3%
by v o l a t i l i z a t i o n
Data Table
1 1 +
both
volatile
i t s e l f
occur
than
27
another
considered
from
involved
from
2
the
as
be
at
concentrations
is
C0
These
permethrin would
f
in
material
doubtful
Less
after
evolution
2
l
experiment
and 58.7%
as
l
the
treate
activity l
C0
in
carbonyl-labeled
reversed
labeled
evolution
C0
the azide
soil
is
from both
2
rapidly
C-carbonyl-
can a c t u a l l y
2
mate
thane
It
of high lh
1 I +
C0
the
( F i g . 3A)
2
lh
from
evolved
C-methylene
differences on
the
1 1 +
In an i n i t i a l
were
had been
permethrin.
azide
of
C0
experiments
the
influence
sodium
soils
64.5%
permethrin
from
1 I +
differences
of
occurred
a n d 52%
as
149
evolution
(Fig. 3).
evolved
final
In both
rapid
C-carbonyl
in
loam
( F i g . 3 B ) , where
more
tor
subsequent
the methylene,
had been
These
C-methylene
l l f
with
C-methylene-permethrin
C from
permethrin
Permethrin Degradation
E T A L .
in rate
150
SYNTHETIC
Table I I .
h
l4
ll+
C - B a l a n c e in C-permethrin t r e a t e d Hagerstown s i l t y c l a y loam
C-Label
% recovered as ExtractV o l a t i Lies Residual able Plug i^co2
position
Carbonyl Carbonyl + NaN
3
Methylene Methylene + NaN
Table I I I .
11+
l l +
3
0.2
18. 8
27.3
110.8
0.3
0.4
71..5
22.9
95.1
58.7
0.1
14.,5
25.4
98.7
0.1
0.1
67.,7
32.6
100.5
C - D i s t r i b u t i o n in s o i l
3
Methylene Methylene + NaN
14
o r g a n i c matter
(Bound r e s i d u e )
S o i l o r g a n i c matter f r a c t i o n Humin Humic Fulvic
C-Label position
Carbonyl + NaN
Total
64.5
Carbonyl
3
Table IV. C - B a l a n c e in
Soil
PYRETHROIDS
14
48.6
9.7
41.6
70.5
3.4
26.1
32.3
15.7
52.1
54.3
13.8
31.9
C-carbonyl-permethrin
type
% Volatiles 1*+C0 Plug 2
treated
soils
recovered as Extractable
Residual
Total
2. 2
0.,6
86.7
10..6
100., 1
Dubbs f i n e sandy loam
46. 0
0,,7
17.1
38,.7
102.,5
Memphis s i l t
31. 5
2, .4
18.6
45,,0
97..5
Hagerstown s i l t y c l a y loam
51. 0
0..4
22.5
26,.0
99..9
Sharkey
31. 1
0,.3
40.7
28,.5
100.,6
San Joaquin sandy loam
clay
loam
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
14.
K A U F M A N
E T
was
observed
in
permethrin
was
particularly associated
Permethrin
A L .
the
San
evolved
slow
with
chemical
or
possible
insights,
soils
table
amounts the
the
the were to
San
be
in
soil
to or
system
of that
not
the
§
in
days
more
the
1 L f
(Table
the
aqueous
s o i l or
is
other known.
analysis
of
the
formed 4
C
awaits
were
of
the extrac-
lower
soils.
Again, 1
acid
extrac-
were
only
residual
fulvic
1
+
as
C-activity
and
humin
of
these
order l l f
i t
Also,
to
30
as
and
to
observed
in
and
*COz.
incubated
a
soils
was
hexane
the
toward
incubated s o i l
(Table
however, any
to
trend
fractions Hexane
the
total
residual
anaerobic
degradation.
soils,
The
anaerobically
incubation
remove
flood-
recoveries
increased
in
soils.
the
doubtful
aerobically C
fractions, period.
trap
treated
humin
4
of
ll
suggest
in 1
incubated
total
from
days
would
In into
interest.
an
flood-
introduced
seem
to
of
be
residual two
high would
also
the
C-permethrin
was
the
in
contained
atmosphere.
phase
aerobically
This
acid
C
aqueous
greater
from
the
the
converted
from
6).
nitrogen
of
on
are
much
were
appears used
possible
extracts of
to
as i
f
C-
slight-
of 1 I f
the l
Although
confirmation
is
7).
the
C-methane
analysis. Identification chromatographic treated
degraded
identification
been
examined
soils
anaerobically
the
appeared
phase
a
1%
Based
than
also
permethrin
layer
C-permethrin
rapidly
in
activity
Product
in
incubation
during
further
Thin
the
treated
however,
had
fulvic
and
extractant
1
amounts
whereas
the
each
5).
than
formation.
the
i n i t i a l more
in
C - p e r m e t h r i n was
Memphis
of
containing
contrasts
portion
isotope
^C-methylene
The
soils,
distribution within with
and
bulk
^ C C ^ from
(Table
product
methane
are
this
C-
this
presently
by
C - p e r m e t h r i n was
present
6)
There
with
1 4
less
C-label
4).
major
associated
l i +
soils,
either
determined.
incubation
polar
s o i l ,
as
was
C-products
1 £ f
soils
1 1 +
not
obtained
the
(Table
of
(17)
additional
(Tables
Soil
is
obtained were
of
Dubbs
with
soils,
treated
the
incubated
ly
in
the
not
differences
Intermediate
the
loam.
flasks
trapped
extractable
activity
clay
more
Several
the
fractions
was
of
2
from
not was
much
87%
Sharkey
degradation s i l t y
aerobic
from
and
experiments,
biometer
system
Whether
vary
of
or
Anaerobi
Anaerobic
The
were
C-balances
l i f
Nearly
associated
in
Hagerstown
60
2.2%
degradation
characteristics
Joaquin s o i l .
matter
ed
contrast
good 4).
obtained
organic
Degradation
ed
only
Whether
microbiological
however,
Hagerstown
previous
appeared soil
(Table
from
from
the
loam: days.
permethrin
physical
Exceptionally
in
28
151
extracts.
five ted
*C02
of
Some
sandy in
l
unique
soil soil
Joaauin as
rate
some
Degradation
of
in
soil
soil
three
to
analysis
of
revealed
that
a
of
number
products
was
soil
the
extracts
parent
products.
established
from
material
is
Tentative by
TLC.
3-(2,2-dichloroviny1)-2,2-dimethy1eye1opropanecarboxylie
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
These acid,
152
SYNTHETIC
14
Figure 3. Degradation of ^-car bonyl (acid) and C -methylene (al cohol) permethrin in Hagerstown silty clay loam
PYRETHROIDS
C Alcohol
14
0
4
8
12 16 2 0 24 Days Incubation
S 60f
Ζ
Hagerstown sicl 50|^ ^ ^ D u b b s fsl
ω
Sharkey c ^ . .
.£ 3ft § 2ft
X Figure 4.
12 16 20 Days incubation
Degradation of C-carbonyl 14
24
28
32
permethrin in five soib
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
28
32
36
K A U F M A N
E T A L .
Permethrin
Degradation
lt+
Table V.
14
D i s t r i b u t i o n o f C from C - c a r b o n y l - p e r m e t h r i n s o i l o r g a n i c matter (Bound r e s i d u e )
% S o i l type
San Joaquin sandy Dubbs f i n e sandy Memphis s i l t Hagerstown
1 4
Fulvic
loam loam
loam
C present in Humin Humic
81.2
0.5
18.3
50.2
5.0
44.9
64.6
1.2
34.2
s i l t y cla
Sharkey c l a y
Table V I .
^-Distribution
llf
from C - p e r m e t h r i n in a n a e r o b i c Hagerstown s i l t y c l a y loam
11+
1 H
C-label
position
li+
C0
C r e c o v e r e d as Extractable C h l o r o - AqueResiHexane form ous dual Methanol
30-days i n c u b a t i o n Carbonyl Methylene
0.2 0.1
8.2 12.4
58.2 81.0
60-days i n c u b a t i o n Carbonyl Methylene
0.3 0.1
6.8 12.6
64.4 48.4
n.d.* 27.2 3.7 12.2
23.2 11.6
2.9 12.6
Total
93.8 109.4
97.6 85.3
n.d. = not determined
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
154
SYNTHETIC
3-phenoxybenzyl and
alcohol,
the parent
radioproducts were
For
These
less
to
be
compounds which
of
aerobic s o i l .
s o i l ,
diate
in
activity hol
were
only
These
between
the
in
of
however,
were
ize
were
from
identify
amount
at
for s o i l
San
Joaquin
relatively
the
0-1.5%
Cis and
category
B,
recovered
and*
from
D and B. of
this
These
the
1
C
4
investigation
3-phenoxybenzyl comprised
from
other
the
less
2-20% of
in
polar of
the
alco
category
D.
degradation
are intermediate
a n d 2-51%
of
of
the
their
c i s , C
i l f
activity
in
trans activ
from
the
of
i . e . ,
to
than
chromatographic and trans in
however,
characteristics
or
trans
the
ratios
of
their the
in
28
assumes their
with
no major
of
in
soil
in
in
forms of
appears
was
in
and the
Such
a
adsorptive
The c a l c u l a t e d
are presented
sep
also
dissipation
the residue.
work,
figure.
excellent i t
the
to
detailed this
the
Table
labeling
labeled
provided of
and a
make
the exception
differences
permethrin
to
present
determine
rates
extractability.
extracted
volume
Additional
used
ratio
label character
between
both
of permethrin,
individual
cis/trans
cate
the
are presented
agreement
days.
systems
further
a known
employing
accurately
isomers
carbonyl
to
permethrin
data
that,
exhibited this
or both
was p o s s i b l e
o f permethrin
more
in
metabolites. to
i t
Good
indicate
cis
determine
minor
These
experiments
less
to
needed
the residual
the
calculation,
the
is
concentrated
1/2-life
be needed
changes
but seldom work
which
appearing label
f o r TLC work,
data
compounds
the methylene
t h e more
were
the
to
polar
Compounds
experiments.
These
short
Since
resulting
perme
described
1.5%
in
which
contained
extraction.
obtained
will
possible
labels,
many
of
s o i l ,
to
additional
metabolism
permethrin.
aration
s o i l ,
to
used
between
t h e most
quantitations
was
however,
They
They
unique
was u s e d
the time
patterns
trans
soils.
group
0.5%
a l l distinct
the o r i g i n .
a l l extracts
approximate
of
from
and methylene
Since
8
Ε contained
frequently
and/or
soils
of
of
separating
midway
aerobic
Considerable
standard
compounds
category. or
in
2-
on
soils.
movement
carbonyl
on
and represent
present
systems
examined.
and the o r i g i n .
Category
alone.
cis
C-materials
dichlorovinyl acid
and chromatograph
gory
the
label,
compounds
p a r t i a l l y
and standards
l i t t l e
1 1 +
quantities
polarity
extracted
the
The solvent
and the
products,
anaerobic
three
polar
or anaerobic
compounds of
Two o r
least
either
appearing (A-E) based
In the experiments
carbonyl
only
products
ity
B.
aerobic
66-94%
present
capable
permethrims
than
in
to
extracted.
and a c i d ,
the
also
occurred
isolated.
categories
(Fig. 5). A,
C-products
generally
C-compounds 5
products
predominant
compound
polarity
compounds were
are the
a n d 43 9
the
either
represented
Two t o
polar
category only
from
permethrin
generally
polarity
l 4
These
the
products
the into
category
less in
contain
the products
trans
in
are
appear
they
divided
increasing
thrin
the total
acid. as
other
however,
discussion
were
present
These
herein,
1% o f
appeared
Numerous
products,
of
plates
progressively appear
than
purposes
dimensional
generally
on TLC p l a t e s .
detected.
quantities
and 3-phenoxybenzoic
materials
PYRETHROIDS
in
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
c i s / -
Table
9.
KAUFMAN
E T AL.
Table V I I .
Permethrin
Degradation
155
D i s t r i b u t i o n o f C in s o i l o r g a n i c matter f r a c t i o n s o f a n a e r o b i c a l l y incubated s o i l s . lh
li+
C Label position
30 days
incubation
Carbonyl
24.7
4.3
71.0
Methylene
33.4
11.2
55.4
Carbonyl
68.5
10.6
20.9
Methylene
55.9
19.9
24.3
60 days
incubation
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
SYNTHETIC
PYRETHROIDS
SOLVENT SYSTEMS; BENZENE:FORMATE:ETHER ( I X ) t
HEXANE:BENZENE:ACETONE 6 X )
•
a
•Ο ο
30953
30952
35171
30960
•
•
3006
Ο
Β Ο
Ο
C
0 *
.
00
#
D
.
ORIGIN
Ε
Figure 5. Two-dimensional TLC phte illustrating positions of standards and categories (A-E) of C-soil metabolic products generally isolated from C-permethrin-treated soil. Solid spots: C-products common to all C-labels; shaded spots: significant C-products of specific C-labels; open spots: minor C-products. Standards: 30062, dichlorovinyl acid; 30952, 3-phenoxybenzyl acid; 30953, 3-phenoxybenzyl ahohol; 30960, trsLns-permethrin; 35171, cis-permethrin. 14
14
14
14
14
14
14
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
14.
K A U F M A N
E T A L .
Permethrin
157
Degradation
c i s,trans-Permethrin remaining a f t e r incubation period.
Table V I I I .
Experiment
indicate
C-permethrin
Incubation (days)
remaining
methylene
carbonyl Aerobic I
27
7.3
7.6
A e r o b i c II n o n s t e r i l e
34
11.4
11.3
34
65.3
57.7
30
38.0
25.5
Dubbs f s l
28
6.9
San Joaquin s i
28
58.0
Memphis s i l
28
15.1
Hagerstown s i c l
28
15.5
Sharkey
28
27.7
sterile Anaerobic
Five
soils
clay
Table IX.
Cis/trans ratio of residual s o i l experiments.
Aeration status
Original isotope Aerobic I II n o n s t e r i l e sterile Anaerobic 30 days 60 days Five s o i l s Dubbs f s l San Joaquin s i Memphis s i l Hagerstown s i c l Sharkey c l a y
11+
C-permethrin
cis/trans ratio of carbonyl
46/54 64/36 60/40 56/44 62/38 57/43
1u
in
C-permethrin methylene
22/78 30/70 30/70 28/72 40/60 31/69
64/36 57/36 71/29 57/43 67/43
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
158
SYNTHETIC
Since
the
trans
figure
that
this
This
observation
which
isomer
indicates
Microbial A azide
play
a
role
degradation into
pure
permethrin
as
clay
a
selected culture
ide
ion,
In
with
and
l
in
for
that
the
toxic
the
and 1 I f
1 I f
to
did
its
in
(Table
or
that
(6,7)
hydrolyzed.
and
soil
attempt
culture
in
capable In
s o i l . and
of
an
with
sodium
microorganTwo
observing
solutions,
energy.
actively
chloride
used
growing as
micro-
to
iso-
metabolizing
i n i t i a l
5
g
cell
enrich-
Hagerstown
suspension
inoculum.
for
This
type
of
degradation
of
organism
activity
liberation
permethrin
microbial
liberation
solutions
concentrations degrading
luxuriant
found
(18).
free
chlor-
products,
of the
soil
were
CÛ2
used
in
i t
these
of
a
wide
evolution
either is the
cell
Both
extracted. with
At
growth
the
The
the
f
C-
of
micro-
the
conclu-
were
removed
culture
major
s o i l
i
culture
variety
concentrations. and/or
l
conceivable
investigations
microorganisms,
f i l t r a t i o n .
associated
l i +
Although
growth
these
or
containing
medium
portion
residue
or
of
the
cell
10). of
culture
This
had
in
the
in
s o i l
would
there
ratio
experiments
be
that
was
were
w i l l
TLC revealed of
the
very
where
under
the
l i t t l e
hydrolyzed necessary
at
to
that
However,
some
essentially
permethrin
particularly interesting
suggest
isomers
investigation
by
occurred.
cis/trans
is
experiments, the
extracts
indeed
This
obtained
that
ion
culture
filtrates
occurred
results
this
others
readily
permethrin to
inoculated
was
volatile
degradation
pronounced. and
of
monitored
medium b y
solutions.
Further
indicate
esterase-amidase
were
experiments
was
changes
ved,
was
an
presence
culture
microbial
the
in
carbon
of
permethrin
culture
culture
3)
C-carbonyl permethrin.
Examination no
nonsterile
assumed
isomer.
m
of
no
the
activity
debris
of
known
support
these
the
C
of
in
§
microorganisms
Schlecht
permethrin
organisms from
work
obtained
performed
s o i l
ml
microbial
or
were
of
be
evolution.
2
methylene
sion
can
a
solutions
Essentially
solution
the more
degradation
flask
5
5
evolution
occurred
with
i t
degraded
is
permethrin
each
oxysporum
All
C0
easily
isomer
2
were
source
loam.
was
f
the
of
experiment,
t
figure,
and
consistent
results
culture
inoculated
Fusarium
decreasing rapidly
trans
(Tables
in
experiment,
third
be
experiments
late
s i l t y
the
most
the
of
soils
bial
was
would that
comparison
enrichment
ment
is
the
Degradation
treated
isms
is
PYRETHROIDS
in
changes
were
conditions
isomer about
further
of more
of
effect the
in
view
same
these obserrate.
substantiate
phenomenon.
Summary The is
results
rapidly
occurs
more
of
degraded rapidly
these in
investigations
s o i l .
than
with
Degradation the
cis
indicate of
isomer.
the
that trans
The
permethrin isomer
results
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
X.
ml
5
soil
F.
oxysporum
culture
in
0.2 0.0
0.2 0.2
Carbonyl
Methylene
0.1
1.1
0.9
-
66.5
84.2 86.6
0.9 78.2
6.2
68.7
1.7
5.0
69.1
74.6
2.2 2.9
77.0 0.9
Total
79.6
39.7
51.3
67.8
Combustion
Residual
1.6
22.7
-
1.2
13.7
2.4
Methylene
0.4 0.1
6.0
(filtrate)
Extractable
from
experiments.
Residual
Aqueous
2.8
(media)
Extractable
0.0 0.1
1
metabolism
% i^c recovered
microbial
Plug
1.1
2
2
Carbonyl
0.4
Carbonyl
co
Volatiles
*C-permethrin
lt
Methylene
Label
C-Balance
soil
extract
gm
5
Enrichment
Pure
l t f
Inoculum
Table
CD
1—*
Ol
s*
I
3
s?
§"
Ci
I
>
2!
s
I—«
160
SYNTHETIC
H,Cv/CH
3
<\ A >=c^c-o-.?Y/ CI
/
Η
PYRETHROIDS
II
Η
W —y
\
H CyCH, 3
+
H O - C H
COOH
\ —
CI
HjC C H ,
c=cA
CI
CI
/
4- C O , H O O C - ^
OH
i
HO CO,
Figure 6\
obtained iments that
with
microbial
products, permethrin benzyl
metabolism
i s
i s
apparent moieties
products
results
on
findings,
these
in
The conversion acid
further as
that
o f
aldehyde.
substantiate include
hydroxylated
the major
Further
this
the
1
pathway
through
s o i l
soils
acid
C - l a b e l
shown
exper indicate
degradation mechanism
in
alcohol i s
possible
parent
o f
and 3-phenoxy as
of 1 < +
both
C02.
F i g . 6 to
the formation
Other
hydroxylated
s o i l
metabolism 4
investigation
pathway.
various
cleavage
o f
3-phenoxybenzyl
Additional
in
degradation
the dichlorovinyl
occurs
and
treated
identifying
(Fig. 6).
presumably
azide
involved.
in
the tentative
benzoic
presumably
also
the evolution
posed.
responding
i s
to
cultures,
and sodium
obtained
hydrolysis
alcohol
H O - / 3
and i s o l a t e d
nonsterile
on r e s u l t s i t
+
Tentative degradation pathway of permethrin in soil
enrichment
comparing
Based
y
Η
i s
Based pro
3-phenoxyo f
the
needed
products
compounds,
products.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
cor
to as
would well
14.
KAUFMAN E T AL.
Permethrin Degradation
161
Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
E l l i o t , M . , Farnham, A. W., James, N. W., Needham, P. Η., Pulman, D. Α . , Stevenson, J. H. Nature (London) (1973), 246, 169. Abemathy, C. O., Veda, K., Engel, J. L., Gaughan, L. C., Casida, J. Ε., Pestic. Biochem. Physiol. (1973), 3, 300. Casida, J. E . in "Pyrethrum the Natural Insecticide," Casida, J. E . , E d . , Academic Press, New York, Ν. Y . , (1973) pp 101-120. Casida, J. E., Veda, K., Gaughan, L. C., Jas, L. T., Soderlund, D. M., Arch. Environ. Contam. Toxicol, in press (1976). E l l i o t , M . , Janes, N. F., Kimmel, E. C., Casida, J. E., J. Agric. Food Chem. (1972), 20, 300. Miyamoto, J., Nishida, T., Veda, Κ., Pestic. Biochem. Physiol. (1971), 1, 293. Miyamoto, J., Suzuki, T., Nakae, C., Pestic. Biochem. Physiol. (1974), 4, 438. Suzuki, T., Miyamoto, J., Pestic. Biochem. Physiol., (1974) 4, 86. Veda, Κ., Gaughan, L. C., Casida, J. E., J. Agric. Food Chem. (1975a), 2, 106. Veda, Κ., Gaugham, L. C., Casida, J. E., Pestic. Biochem. Physiol., (1975b), 5, 280. Elliott, M . , Janes, N. F., Pulman, D. Α., Gaugham, L. C., Vnai, T . , and Casida, J. E . , J. Agric. Food Chem., (1976), 24, 270. Chen, Y . - L . , Casida, J. E., J. Agric. Food Chem., (1969), 17, 208. E l l i o t , M . , Janes, N. F., in "Pyrethrum the Natural Insecti cide, "Casida, J. E . , E d . , Academic Press, New York, N.Y., (1973) , p. 86. Veda, Κ., Gaughan, L. C., Casida, J. E . , J. Agric. Food Chem. (1974) , 22, 212. Kaufman, D. D . , Jordan, E. G . , Abst. 172nd ACS Mtg. Pestic. Chem. D i v . , (1976), No. 33 (San Francisco, C a l i f . ) Kearney, P. C., Konston, Α., J. Agric. Food Chem., (1976), 24, 424. Bartha, R., Pramer, D . , Soil S c i . (1965), 100, 68. Blake, J., Kaufman, D. D . , Pestic. Biochem. Physiol., (1975), 5, 305-313.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
15 Substrate Specificity of Mouse-Liver Microsomal Enzymes in Pyrethroid Metabolism DAVID M. SODERLUND and JOHN E. CASIDA 1
Pesticide Chemistry and Toxicology Laboratory, Department of Entomological Sciences, University of California, Berkeley, Calif. 94720
Rapid detoxificatio chronic toxicity to mammals of the pyrethrins and other chrysanthemates ( 1 , 2 ) . Increased insecticidal potency in the newer synthetic pyrethroids has been achieved by replacing some of the biodegradable groupings by substituent s that retain overall insecticidal configurations but are more refractory to metabolism (3). Currently important pyrethroids include 9 acid moieties [A-I; shown as 1R,trans (A-F) or most insecticidal isomer (G, I] and 9 alcohol moieties [ a - i ; the most insecticidal isomer of a-c and is shown] as follows (Figure l ) : h
acid
A: C: D: E:
R R R R
= = = =
moieties
CHF ' CI Br H alcohol
I
H
moieties
Figure 1 <
Present address: Insecticides and Fungicides Department, Rothamsted Experimental Station, Harpenden, Hertfordshire, AL5 2JQ, England.
1
162
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
15.
SODERLUND
The most
extensive
pyrethroids
involves
(1,
h
In
r a l
modification
5).
9
throids mouse
Enzyme Substrate Specificity in Pyrethroids
A N D CASIDA
the
information
studies
present of
the
l i v e r microsomal for
Mouse powders
Enzyme
microsomal
preparations and
oxidative
reactions
only,
an
or
Radiolabeled of
However,
in
this
of
approach
of
of
as
various
sites
pseudo-first esterase
of
follow
W I
by
Υ ι
Substrate
with
simul To
(e.g.,
study is tetra-
small
of
rates
and
rates
(K^ χ
the
number
of
in
is
the
a
related
function
as the
account
derivatives oxidase
0.21+0.05 m i n results
into
comparison
to
and
into
given where
1θ3)
labeled
systems
as
take
site 8).
substrates
oxidase
not are
summarized
(5.,
substrate
do
quantita
system
pyrethroids
esterase of
and
defining
k
.
which
regions
compound
(W-Z)
(Figure
2).
Figure 2
of
P y r e t h r o i d - H y d r o l y z i n g Enzymes
hydrolysis
is
highly
in
and
limited
dependent
region ¥,
acid moiety.
a more
[lR,trans3-
used
The
as
5-benzyl-3-furylmethyl with
oxidase
pyrethroid molecule
the
with
in
are
propane evident
the
thereby
C1R,trans]-resmethrin
particularly
3
by
variety
oxidase
configuration, in
7).
acetone
preparation
identification
disappearance
data
Specificity
C-3
using (6,
hydrolysis.
inhibitor
the
rates
ζ
lyrethroid
their
microsomal
esterase
constants
for
d i v i d i n g the
I
pyre
moieties
substrates.
unlabeled
[lR,trans]-resmethrin
X
structu kk
w i t h NADPH w i l l
pyrethroid
study
attack.
order
rate
and
l i m i t e d by
great
the
The m e t a b o l i s m using
a
the
Thus,
(k).
of
with
preparations
pyrethroid
permit
attack
is
Metabolism
determined
plus
in
fresh
substrates
examination
time
the
the
The p r e s e n t
compounds. were
oxidase
of
enzymes
paraoxon
metabolic
pyrethroids. permit
alcohol
individual pyrethroid metabolites
preferences
effect
and
fortified
oxidize
irreversible
ethylpyrophosphate tion
the
examined
preparations
active
hydrolyze with
and
metabolism
microsomal
was
acid
esterase
taneously pretreated
above
esterases
Fresh microsomal
liver
Studies
hepatic
contain
enzymatic
investigation,
on b i o d e g r a d a b i l i t y
consisting
Methods
on
w i t h mouse
163
This
esters; series
[lR,cis]-acids
is a
of
the
on
side
the
illustrated similar
f
>
in
cyclo
Figure
relationship
3-phenoxybenzyl
(R =Cl
molecular
chain at
CH^ >
esters
Br).
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
is
164
SYNTHETIC
yy^LioR >
^^^^ΐΓ^)
=
HYDROLYSIS
Ρ
^JLXor
R
PYRETHROIDS
-y^ioR * RHXAOR
>
R' = CI > F > CH> Br 326 300 166 128 40 [1RS]
R all substituents /=
3
<6
<6
Figure 3. The dependency of pyrethroid hydrolysis on molecular con figuration is illustrated with 5-benzyl-3-furylmethyl esters
Only
trans-substituted
hydrolyzed or
a
at
a l l .
at
gem-dimethyl The
at
this
group
are
dibromovinyl esters
with
a
but
are
s t i l l
dimethyl- substituted be
important
in
these
primary alcohols
esters
position
with
are
esters
also
undergo
more
Thus, the
are
cis-substituent
are
Esters
hydrolyzed
cis-
or
bond
less
gem-
trans-substituents ester
not or
isobutenyl
cleavage.
than
or
dichlorovinyl
rapidly while
substituent
esters.
a
rapid
susceptible
positioning
a
hydrolyzed poorly with
h y d r o l y z e d most
cyclopentylidenemethyl
rapidly to
of
rates;
trans-substituted
difluorovinyl and
esters
appreciable
at
the
appear esteratic
site(s). Relatively available dimethyl only
for
few
assay
group
in
compounds because
of
determining
structural variants
in
with
variations
in
region
the
importance
of
the
i n s e c t i c i d a l potency
this
region
examined
chloropherryl-a-isopropylacetates
(ig^
propyl
gem-dimethyl
the
group
enantiomers)
not
rapid
slowly
group
hydrolyzed
(analagous
properly position
hydrolytic Rate
X
are
the
both where
which
remainder
£-
the
iso-
substituent
of
(ig^
most
trans-
to
chain of
The
the
esters
suggesting side
(9).
are
that in
the
the
j>-
region
W)
ester
for
and
their of
the
and
to
structural
between
the
S(+ ) -£-chlorophenyl-a-
non-insecticidal stereochemistry
oxidative
variations
insecticidal
metabolism
[is]at
are
and
this
R(-)-
position
considered
on
else
(10 ) . Region
the
and
effects
hydrolytic
the
observed
[lR] -cyclopropanecarboxylates the
to
attributable
sometimes
isopropylacetates analogs;
relative
were
attack.
differences
region
the
in
The p r i m a r y a l c o h o l
cyclopropanecarboxylates,
chlorophenyl does
for
esters.
are
substituted
in
substitutes
cyclopropane
Ih),
X
gem-
most
Y,
the
important
hydrolysis
(Figure
free
or
substituted
determinant
in
the
a
-methylene
alcohol
position,
moiety
for
k).
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
is
15.
SODERLUND
Enzyme
A N D CASIDA
Substrate Specificity in Pyrethroids
53 Figure 4.
Only at
primary
in
benzyl
tert-butyl
at <
of the rate
U-10$>
binding
those
moiety
with
center.
rapidly
in
cleaved,
fSerefore
l i k e l y
(especially
with
alcohol
positioning The
Figure acid
h
followed
in
esterified
esters
directly
or by
interference
activity
in
region
compounds
for
and a d i s t a l yield
for 5 primary decreasing
an
group
propargylfurylmethyl
unsaturated
alcohol
[lR,trans]-
( A d , A e ) a r e most
order
by
re'smethrin
evident with
with
the esteratic
limited
pyre chain
site(s). on pyrethroid series
of
in alcohols
[lR,trans3-dichlorovinylchrysanthemic
(]}).
Substrate The
Specificity oxidase
rates
o f
is
center
side
[1R,trans]-chrysanthemates a more
It
k).
of the
the acid
Y and Ζ together
with
the
(Figure
compounds)
may cooperate
Ζ of
assay
8-fold
and unsaturated
with
n-alkyl
site(s).
tfiat
o f regions
the are
a t t h e ^ - p o s i t i o n may
and proparthrin
at
also
where
(Ai)
the molecule
also
alcohols
f o r the corresponding
components
the spacer
or
is
(Ag) a n d t e t r a m e t h r i n
illustrated
is
rates
furamethrin
hydrolyzed
m
function
these
hydrolyzed
tjt-position
and cr ethylbenzyl
the available
spacer in
are
specificity
simple
for insecticidal
moieties
effect
hydrolysis (jf-h)
;
either
limited
hydrolysis
phenothrin
throid
bond
a planar
chrysanthemates
of
Substitution
Modifications
variation
in
acids at the
This
at the esteratic
requirements
alcohol
(Af),
(6).
the ester
proper The
to
substituted
sec-butyl, analogs
stabilize
the
o f appropriate
Esters
[lR^transj-chrysanthemates
hydrolyzed
with
esters
rates.
resismrit^o^T^o^olysis.
isopropyl, or
alcohol
A a , A b , A c , A h , Dh and Ih) are poorly
completely seen
<6
The free or α-methylene determinant
appreciable
(e.g.,
6
165
tyrethroid-Oxidizing
for pyrethroids
reflect
Enzymes t h e sum o f
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
166
SYNTHETIC
several region or
concurrent therefore
absence
effects
of
on
The
oxidative
must
markedly
with
rate by
of
trans-
cis-configurât ion
or
but this
side
(Aaj
8)
of
of
chain methyl (e.g.
oxidation. rapidly tuted moiety (Ff) tlïe in
not
addition
each
presence
to
steric
esters
substituent
only
slightly
substituent
in
may
be
region
altered
(Figure
W
by
the
5).
^X^OQ
with
Îne
a
the
at
this
preventing
due
attack
are
reduce
these
compounds effect the
are
to
of
there
low
oxidase
impaired group
other
areas
present of
rapid
the
an
the
at
this
number
however, site
of
susceptibility are
oxidized
optimal
oxidation in
rate
to
more
for
the
subwith
acid
thiolactone
ethanoresmethrin
chain hydroxylation
to
an
of
the
the
allethrin
dibromovinyl-substi-
be
side
or
since
alterations
nature
or
in
potential
group
may
The
limits
overall
sulfoxidation
points
at
the
attack
substitution (12);
one
dichlorovirryl
to
in
speculative
on
a c i d moiety eliminate
position.
either
oxidase
halogen
difluorovinyl-
relatively
due
so
DgJ necessarily
indicating that
these
The
is
undergo
to
cyclopentylidenemethyl
dependent
the
=
11)
necessarily
probably
the
may b e
in
halogen
either
size
G is and
sites a
Esters
than
stituent group
by
esters,
(Afj
permethrin,
hydroxylation does
groups
resmethrin
substitution attack
not this
R
in
the
107
and
position
in
of
enzyme(s).
rate
OXIDATION
The
light
5-benzyl-3-frirylmethyl
oxidation
trans cis
Variations
in
sites
the
whether
undergoes or
processes.
interpreted
oxidatively-labile
interactions
oxidation
affected
be
PYRETHROIDS
effect
of
molecule;
sites
of
this
by
group
however,
oxidation
for
unknown. in
region
Y
substituent
on
oxidation
(Figure
rates
6).
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
is
The
cyclic
oxidized
secondary
but
oxidized.
the
The
alcohol
esters
are
readily
esters
are
slowly
reduced
Dh)
this
modification
limits
side
chain
acid
alcohol
of
The
and
with
effect moiety
santhemate, the
than due
the to
The also
this
the
sites
tetramethrin, The
3
6
the
the
effects
to
corresponding
Substrate
in
binding with Figure
and
not
rates
most in
known
esters
indicates
of
alcohol
in
of
to
the
known. influenced
by
oxidation.
the
The
moiety
chry-
portion
rethronyl
of
and
oxidative
oxidized
Y
and
and
moieties
Relation
in
substitution
cyclohexene
attack
more
rapidly
esters
perhaps
or,
more
likely,
Ζ
on
oxidation
cis-chrysanthemates
(jMi)
dichlorovinyl-substituted
Specificity
gem-dimethyl
compounds.
regions trans-
that
rap i d l y - o x i d i z e d
sites
alcohol
analogs
isobutenyl
the
is
to
the
are
former
with
the
hydroxylation
are
chains
are
Dg)
5 - b e n z y l - 3 - f u r y Ime t h y 1
attack
combined
the
side
esters
α-cyano
both
region
hydroxylated
(13).
the
which ^-cyano
in
of
Ζ
3-phenoxybenzyl
applicable
by
oxidase
readily
in
aryl
oxidation
corresponding
illustrated
on
mechanism
region
at
(phenothrin)
effect
on
increased
facilitated
attack
of
molecule The
moiety
The
propargylfurylmethyl (2,8).
oxidase
(A^
acid-moiety
of
is
rates^for
and permethrin
the
susceptibility
alcohol of
the
moiety
interferes the
phenothrin
(permethrin).
(e.g.,
oxidation
(Ah,
group
of
a-c)
ct-cyano-substituted^h)
esterified acids
Overall
are
with
(D).
Pyrethroid
Biodegradab i l i t y The
data
oxidation of
overall
to
the
presented
rates
for
above
on
pyrethroids
biodegradability
individual hydrolysis are
since
experimentally-determined
applicable
their oxidase
sum
to
and
considerations
corresponds
plus
esterase
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
closely rates.
SYNTHETIC
168 The
pseudo-first
[1R,cis]-permethrin between trans-
trans-
and
relative
order
rate
(Figure
7)
cis-isomers:
to
the
curves
for
illustrate very
cis-isomer;
[lR,trans]-
the
rapid
PYRETHROIDS
typical
hydrolysis
approximately
and differences
of
the
equal
oxidation
esterase
curve
Time, min
Figure 7
rates;
close
to
the
esterase
to
the
oxidase
more
rapid The
rapid
only only
overall
trans-isomer alcohol
correspondence curve curve
of
in
(oxidase
compared
to
the
in
the the
plus
the
of
hydrolytic
case
of
plus the
the
esterase) rate
trans-substituted and
of
trans-isomer cis-isomer;
metabolism
and
and
of
the
cis-isomer.
o v e r a l l biodégradation esters
oxidase case
oxidative
is
attack
BIODEGRADABILITY -
greatest
acids
since
(Figure
for
primary
they
undergo
8).
ESTERASE + OXIDASE
Figure 8 Intermediate
rates
other
with
esters
rethrins, on
whose
oxidation.
relatively have
the
are
overall Esters
resistant
lowest
found
for
acid moieties of to
overall
the
cis-substituted
restricting
biodégradation
depends
almost
a-cyano-3-phenoxybenzyl both
oxidation
esterase
plus
and
analogs,
hydrolysis, alcohol
hydrolysis
oxidase
and
rates
of
the
entirely are
and the
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
thus
15.
Enzyme
SODERLUND A N D CASIDA
compounds
examined.
known
from
these
differences
the
other
Qt-cyano
The
series are
of
Metabolism
vivo
Studies the
esters
Figure
mice
i ) ,
9;
50
block
a
treated are
by
in
the
rate
this
variations
group,
limiting
metabolism mg/kg,
(PB,
6
Figure
these thereby
(Table
I).
the
but
effect
prior
9;
150
pyrethroid
less
toxic
of
correlates
with to
an
the
mg/kg,
1
Toxicity
establish
than
with
trans-isomers.
mice
hr
enzymes
creases
of of
with
intraperitoneally
generally
finding which
pretreatment
inhibitor to
with
overall
instances,
evident
Microsomal Metabolism
trans-esters
(Table
rapid
also
169
substituent.
Correlation
that
a c i d moiety-dependent are
overshadowed
and
in
Substrate Specificity in Pyrethroids
In
esterase
the
the
several
inhibitor
pyrethroid)
or
hr
the
prior
cis-
more
to
an
(DEF,
oxidase
pyrethroid)
in
linking
metabolic
susceptibility
and
toxicity
synergists
Mice
pretreated
susceptible
than
with
trans-ethanoresmethrin, and
S-5602.
transvery A l l
and
low of
is
hydrolysis
i t
is
DEF or
not
possible
not
The
the in
specificity
vivo of
somal
preparations. do
not
cis-analogs
y i e l d give
>
to
at
general is
not
other
one
rule
since
predict data
than
those
maintain
their
have
microsomal
relaenzyme
allethrin with
the
synergized. factor
with
mouse
in
hepatic
for
liver
a Thus,
synergism enzymes.
microsomes
characteristics
may
also
synergizability. patterns
pyrethroid
metabolites
significant
of
pyrethroids
esterase(s)
Primary alcohol ester
1^9
pretreatment. also
k)
least
distribution and
trans-NRDC
synergist-dependent
ref.
significantly
to
more
trans-resmethrin,
show
rate
10-fold
cis-permethrin,
synergist
also
in
metabolism
the
with
see
present
toxicity
acids Tïâble
a
rate
compound-dependent
by
(i.e.,
known
I;
rates
enzymes
PB a r e
trans-permethrin)
even
PB f r o m m e t a b o l i s m
Detoxification influence
and
(Table
at
DEF or
poisoning
pyrethroids
currently
metabolism this
to
trans-cyanophenothrin,
the
toxicity
esters
but
low
by and
of
increases
low
system, very
of
cis-phenothrin
the
tively
Four
level
toxicity
either
normal mice
amounts
determined
esters
of
in
the
excreta
of
ester
reflect in
the
micro-
trans-substituted but
their
metabolites
II).
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
[1R]
[1RS]
Permethrin
[lR]
[1R]
l6l
NRDC
d
[lR]
î h c
>
with
a
-S-alcohol;
e
HEM
Yf
Af
moieties
5
_S-alcohol
15 >500
DEF
2.2 >32 cis-ester
1.3 >20 >20
>188
none
none
none
trans
isomers.
and
58 28 10
k2
esters
320 >1500 1000 10
esters
cis
of
11
with
1.2 3.1 5.0 2.0
>10
1.6 >20
>6o
none
k.l
7 6 3-5
--
tt
k.Q
—
25 none
none
cis
none
a -- R S - a l c o h o l ;
k.2
none a
PB
factor
trans
increase
Pyrethroids
cis
Toxicity
and Synergism
/Xr (J
alcohol
30 > 500 > 500
2°
'
ΎΛ c?
alcohol
>1500 >1500 >1000 >1500
1°
tt
50
trans
Τ.ΤΊ
Toxicity
no t r a n s / c i s
with
and
alcohol
Acid
Intraperitoneal
^trans-ester
[lR]
available;
[ l R , c i s ] - e s t e r
data
S-3206 s-5602 [ R S 3
[1RS]
lk9
NRDC
Cyanophenothrin
Allethrin
Ethanoresmethrin
[1R]
Phenothrin
^ 0
Mouse
configuration
and
I.
Resmethrin
acid
Compound
Table
-- R S - a l c o h o l ;
15 15 15 ±2
15
k,lk
Ref.
I—»
3
ο
η
o'
15.
SODERLUND A N D CASIDA
Table
II.
Resmethrin
Ester
Enzyme
Metabolites
and -Permethrin, Acid and
Compound Resmethrin Permethrin
Substrate
of
Specificity in Pyrethroids
[lR,trans]-
Rat
in
[lR,cis]-
vivo
Ester
alcohol
metabolites,^
moieties
trans
Af
and
171
<0.1 <0.1
cis
9 9
Ref. 11 12
Esters of secondary alcohols ( i . e . , a l l e t h r i n , pyrethrin i ) are much more resistant to hydrolysis in vivo (8). The difference HL v i v hydrolytic susceptibility between the cis-esters and the rethrins is no in vivo hydrolysis of cis-esters may be due to a low level of microsomal esterase activity not measurable by the method used, to esterases in tissues or tissue fractions other than the l i v e r microsomes, or to more efficient hydrolysis of previouslyhydroxylated esters. There is some indirect evidence from in vivo studies on resmethrin ( l l ) and permethrin (12) that the cis-isomers may hydrolyze in part as hydroxylated esters. The substrate specificity of the mouse l i v e r microsomal enzymes generally reflects the available in vivo results on mammalian toxicity and metabolite patterns. Knowledge of in v i t r o structure-biodegradability relationships should therefore be useful in interpreting in vivo metabolism studies and in designing pyrethroids with favorable mammalian toxicology. 0
in
Abstract Pyrethroid structure-biodegradability relationships were examined with esterases and oxidases of mouse l i v e r microsomes. The esterases are most important in metabolizing primary alcohol esters of cyclopropanecarboxylic acids with trans side chains such as isobutenyl or dihalovinyl substituents at cyclopropane C-3. The mixed-function oxidase system dominates the metabolism of a l l secondary alcohol esters and primary alcohol cis-substituted-cyclopropanecarboxylates. An α-cyano group in the alcohol greatly reduces the rate of both enzymatic hydrolysis and oxidation. Mice pretreated with an appropriate esterase or oxidase inhibitor usually show increased suscepti bility to pyrethroid intoxication. Acknowledgment s We thank Charles Abernathy, Michael Elliott, Judith Engel and Kenzo Ueda, current or former colleagues in this laboratory, for assistance and helpful suggestions. This study was supported
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
172
SYNTHETIC PYRETHROIDS
in part by grants from: National Institutes of Health (2 P01 ES000U9); Agricultural Chemical D i v . , FMC Corp., Middleport, N.Y.; Agricultural Chemicals D i v . , ICI United States I n c . , Goldsboro, N. C ; McLaughlin Gormley King C o . , Minneapolis, Minn.; Sumitomo Chemical C o . , Osaka, Japan; Roussel-UclafProcida, Paris, France; Mitchell Cotts & Co. L t d . , London, England; Wellcome Foundation L t d . , London, England; National Research Development Corp., London, England. Literature Cited 1.
Casida, J. E., Ueda, Κ., Gaughan, L. C., Jao, L. T., Soderlund, D. Μ., Arch. Environ. Contam. Toxicol. (1975/76) 3, 491. 2. Miyamoto, J., Environ. Health Perspec. (1976) 14, 15. 3. Elliott, M . , Farnham Pulman, D. Α . , ACS Symp. Ser. (1974) 2, 80. 4. Abernathy, C. O., Ueda, Κ., Engel, J. L., Gaughan, L. C., Casida, J. Ε . , Pestic. Biochem. Physiol. (1973) 3, 300. 5. Ueda, Κ., Gaughan, L. C., Casida, J. E., Pestic. Biochem. Physiol. (1975) 5, 280. 6. Soderlund, D. M . , Ph.D. thesis, University of California, Berkeley (1976). 7. Soderlund, D. Μ., Casida, J. E., Pestic. Biochem. Physiol. (1977) accepted for publication. 8. Elliott, M . , Janes, N. F., Kimmel, E . C., Casida, J. E., J. Agr. Food Chem. (1972) 20, 300. 9. Elliott, M . , B u l l . Wld Hlth Urg. (1971) 44, 315. 10. Soderlund, D. Μ., Casida, J. E., ACS Symp. Ser. (1977) this volume. 11. Ueda, Κ., Gaughan, L. C., Casida, J. E., J. Agr. Food Chem. (1975) 23, 106. 12. Gaughan, L. C., Unai, T . , Casida, J. E., J. Agr. Food Chem. (1977) in press. 13. Miyamoto, J., Sato, Y . , Yamamoto, K . , Endo, M . , Suzuki, S . , Agr. Biol. Chem. (1968) 32, 628. 14. Jao, L. T., Casida, J. E., Pestic. Biochem. Physiol. (1974) 4, 456. 15. EngeI, J. L., Casida, J. E., unpublished results.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
16 Stereospecificity of Pyrethroid Metabolism in Mammals DAVID M. SODERLUND and JOHN E. CASIDA 1
Pesticide Chemistry and Toxicology Laboratory, Department of Entomological Sciences, University of California, Berkeley, Calif. 94720
For high insecticidal activity, pyrethroids must have a precise steric relationshi the alcohol moiety and the gem-dimethyl group or an equivalent substituent in the acid moiety ( l ) . This generally requires a 1R configuration in the cyclopropanecarboxylic acid and an α-S configuration in the alcohol. Inversions at these optical centers drastically alter the potency without greatly changing the physical properties. Pyrethroid insecticides are commonly used as isomeric mixtures or, i f a single isomer is involved, the residues sometimes undergo photochemical isomerization and epimerization. Metabolic studies on isomeric mixtures may not reflect the rates and sites of attack on the most bioactive components i f metabolic stereoselectivity i s encountered. It is therefore important to define the stereospecificity in metabolism of the optical antipodes and i t s relevance in pyre throid toxicology and residue persistence. We previously reviewed the influence of trans- and c i s substituents on the metabolism of cyclopropanecarboxylates (2-4). This report considers the stereoselectivity in in vitro and in vivo mammalian metabolism of various isomers of resmethrin, permethrin, S-5439 and S-5602 (Figure l ) .
resmethrin
permethrin Figure 1.
S-5439 (X H) S-5602 (X = CN) S
Structures of compounds examined
Present address: Insecticides and Fungicides Department, Rothamsted Experimental Station, Harpenden, Hertfordshire, AL5 2JQ, England. 1
173
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
174
SYNTHETIC
Resmethrin Methyl
and Site
either
l i v e r
microsomes
trans-
they
the
[I S , t r a n s ] - i s omer
ase
hydrolyze
i s reflected plus
Isobutenyl
(Figure
(Table
o f
with
i ) .
the greater
preference
varies
t h e [ l R ] - a n d [is]-isomers a t essentially
[lR,trans]-resmethrin in
oxidase)
Site groups
oxidize
or cis-resmethrin
but rate
f o rHydroxylation o f
Groups
Mouse of
Preference
PYRETHROIDS
This
t h e same
1.7-times
difference
faster in
rates than
hydrolysis
overall biodegradability
(ester-
[lR,trans]-resmethrin. f o rhydroxylation
both
o f the isobutenyl
t h e chrysanthemate
isomer
and
methyl
species
2).
trans
r 53 m 83'*
OR
m 85
m 95' •Preferred hydroxylation site, ratinvivo. Pesticide Biochemistry and Physiology Figure 2. Stereoselectivity in hydroxylation of isobutenyl methyl groups of resmethrin isomers by mouse (m) and rat (r) microsomes (R = 5benzyl-3-furylmethyl) (5). The percent metabolism at an indicated methyl group is relative to the sum for both methyl groups calculated by summating the identified acid-moiety metabolites.
With
t h e mouse
group
isomers with
enzyme,
while
thecis(Z)
site
tions. vitro
Where
preference In vivo
results
position
butonly data
from
i s reversed
data
o f thetrans(E)
the [lR,trans]-
methyl
the [lS,cis]-isomer
[lR,cis]-isomer. the
hydroxylation
i s preferred with both
f o rrats
i s strongly
slightly
preferred
t h e r a t enzyme
from
that
preferred with the
a r e available,
w i t h mouse
(6) a r e consistent
f o r the [lR,cis]-isomer
methyl
and [IS,trans]-
with
preparat h e in
b u tn o t f o r t h e [ l R , t r a n s ] -
isomer. It
h a sbeen
reaction is
most
result
occurs
proposed within
important from
with
formation
tion
o f t h emethylene
from
other
undefined
(£) that
the series
an oxidative o f resmethrin
[lS,cis]-resmethrin. o f unstable group
cleavage
isomers a n d
This
hydroxylated
adjacent
ester
cleavage
esters
t o theester
may
by oxida-
function or
mechanisms.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
<3.
twice
rates;
47±2
109±9
with
26±6
30±5
29±*+
20±3
1R
f o rthe first-eluting
enantiomers
isomer.
A
oxidase
c
8 .
[lR,trans]-
1 3
+
11£L
23 ±2
R(-)
26±3
123 ±J4
26+5
69±5
IS
b y g l c a n dm e t a b o l i s m
rates a r e
C
Oxidase
(k)
by g l cbutno differences are
o f
15 f L
28l2
S(+)
29±8
112 ± 2
29±7
100+26
IR
Esterase
M i c r o s o m a l Enzymes
metabolism
13 ± 2 6±l
R(-)
22 ±2
17
26±3
20:4*
IS
a r e separable
a r e separable
enantiomers
plus
H i T
23+X
Si±)
the esterase
C
h±L
9±L
R ( - )
alcohol
°alcohol
b
rates
(100);
as great
i n metabolism
'
IS
Cyclopropanecarboxylates
rate
b y Mouse
metabolism
Oxidase
Relative
f o r Pyrethroid Enantiomers
p-Chlorophenyl-a-isopropylacetates
SHI"
<2
77±h
<3
79±8
as the standard
pseudo
approximately
observed
resmethrin
formalized
a-BS-S-5602
cis-Permethrin
trans-Permethrin
cis-Resmethrin
1R
Rates
Esterase
Metabolism
first-order
Comparative
JFyrethroid
I .
t rans-Re smethrin
Table
ι—» α οι
S:
3
I
S*
Ci «».
Ο
•8
GO
I
C O
>
>
j
J—« Ρ
SYNTHETIC PYRETHROIDS
176
Permethrin
and Site
Preference
for Hydroxylation of
gem-Dimethyl
Group Mouse more
microsomes
rapidly than
difference
between
differences with Table
than
assay
t h e 100
[lR,trans]-isomer trans]-, lent the
rat liver -
io$yr
27$)
The ed
hydrolyzed i ) .
rate
than
ratio sis
give
hydrolysis
activity
fortified above
atoms,
relative
thereby
mechanism
alcohol,
Mouse
acids
on heating
to
form
alcohol
from
0
was formed
γ-lactones
and then hydroxy
formation
degraded ester
a n ^0
or
(Table
both
the of
a-
m
e
(Table
thylene,
resmethrin II)
with
of
the
in
overcome
authentic
2-cis~rrydroxymethyl under that
acidic
(Figure
3).
T
and alcohol
of analysis
with N,0-bis(trimethylsilyl)acetamide
by treating
(8)
conditions
an unstable
extracts
(IMS) d e r i v a t i v e ,
the
this
h
e
hydroxy instability
was v e r i f i e d b y t h e f i n d i n g
of lactone
II)
deuterium
was i n c o r p o r a t e d
artifact
trimethylsilyl
is
at
to reaction
microsomes
in
retains
CU i n c u b a t i o n s or the
l e d to the hypothesis
the authentic
but no
cleavage
by glc-ci-ms
evidenced b y ms^comparison and
of
other
oxidase
l i v e r
cleavage
0^
consider-
provided an opportunity
Product analysis
The p r o p e n s i t y
hydroly-
normally
with
attack
(8).
of
tetraethylpyrophosphate and
resmethrin).
0
rate
difference
on g l c analysis
MDPH-dependent ester
However,
is
metabolism.
for oxidative
from both
the
importance in
out oxidative
lactone
quantitative
steps
ruling
as
revers
biodégradation oxidase
illustrates
suggested
product
ester
overall
[lR,trans]-permethrin-a-d^
(7).
see above).
carboxylic
to
is
-
[lR,trans]-isomer
are evident
This
31$;
IS,trans
isomers
The e s t e r a s e :
the 3-phenoxybenzyl
that
γ-lactone
of
(3).
the proposed
atmosphere
19$;
[lS,transJ-permethrin is
f r o m mouse microsomes
incubated with
revealed
of
greater
with
case
(lR,cis-
[lR,trans ]-permethrin but not of (pretreated
Equiva
a n d in t h i s
the
the relative
i n i t i a l
product,
w i t h NADPH)
investigate (see
of
isomers
esterase
or
in
[IS,
the [IS,trans]-isomer
o f 3-phenoxybenzyl
amounts
metabolites
were
a
lS,trans=6.U)
the enantiomers
permethrin
(5;
isomer
and hydroxylation as
the
a
hydrolysis
this
for the
-
of
for the
respectively.
(lR,trans
rapidly than
[1R,trans]-permethrin.
to be a
the experiments
metabolized
so that
evident
10-fold
51$ metabolism
active
extensively
more
The g r e a t e r
Large ed
in
l i t t l e rate
are also
level
metabolism
are less
is
These
specificity with permethrin
(lR,trans=2.6;
between
a n d 3*1$
with resmethrin
to
involved
the trans-isomers
ΐ Λ - f o l d
sufficient
I ) .
(substrate
and [IS,cis]-isomers,
a r e more
esterase
(Table
which gives
37
a n d 20,
than
from that
(Table
level
preparations
cis-isomers
IS,cis
nmole
[lR,cis]-
but there
of the trans-isomers
condition
^5 m i n i n c u b a t i o n )
I;
1.8-fold
[lR,trans]-permethrin
the cis-isomers
for oxidation
a different
higher
oxidize
[IS,trans]-permethrin
on g l c .
of
This
the microsomal (BSA) t o form t h e
2-cis-TMSO-[lR,trans]-
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
II.
Mass
)
a
= standard
i . d . OV-101
assignments
χ 2 m
10°c/min;
%
Sources—std
given
-
—-y
0
only
and W
f o r t h e most
on Chromosoru
synthesis,
(3.8$)
from
- - - - - - —
0
—
—
isotopes
173(5)
171(6)
357(56)
355(W
+
reaction; I5O-3OO C a t the i o n clusters.
program
185(20)
185(19)
183(23)
185(100)
183(100)
185(100)
183(100)
[3-PhOPhCDj
[3-PhOPhCH2]^
( r e l . intensity)
f o r microsomal in
Mouse
( is obutane),
a n dT h e i r
[M-Cl] ~
m/e
Ci-ms
temperature
= gas phase mesh), abundant
(6O-8O
—-5
—
^83(97)
in-a-d
(^0
Ik.2
1
2 - c i s - T M S ^ 0 - [ l R , trans] - Permethr 0
1+81(91)
)
lk.2
(
2 - c i s - T M S O - [1R, t r a n s ] - Permet h r i n 0
*+79(95)
Ik.2
2 - c i s - T M S O - C 1 R S , t r a n s ] - P e r m e t h r in ( s t d )
(^O^)
-d
209(100)
k.l
γ- L a c t o n e - ^ 0
( s t da n d ^ O ^ )
t
207(100)
k.l
γ-Lactone
2
1 ft a n d Og)
t
203(9)
6 Λ
1 f\ ( °C>
2
201(10)
6 Λ
S-PhOPhCI^OH ( s t d )
3-PhOPhCD OH
393(30)
(std)
12.8
0
[1R,trans]-Permethrin- -d
Q
391(35)
12.8
+
[lR,trans]-Permethrin (std)
R t
(source )
Glc
(7)
[lR,trans]- Permethrin-g-dg
and Derivatives
[M+l]
a
Metabolites
o f [lR,trans]-Permethrin,
Oxidase
Spectra
Microsomal
>b min
Compound
Table
or
esο
3
2r*
s*
Ci
•8
>
>
Ό Ο
>
1 I
§
ο
1 Ψ
H
i" S*
II
g ο
"-κ
II
?
I
ο
Kb.
3
CTQ S
Ά
H-«
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
16.
permethrin-Qt-d ,
identified by glc-ci-ms
p
authentic Figure
IMS d e r i v a t i z a t i o n ionization
metabolites
permethrin authentic
of the
the
(Table
was u s e d
[ l R ] - and [is]-isomers with
II,
glc
conditions
and
2-cis-TMSO-derivatives
given and
Ik.9» ik.k
derivatives
of
in
isomers
an authentic
Table
II,
Each
andc i s -
of the One o f t h e
(8).
only
[1RS]-standard.
the V-TMSO-, the
Rt values
Using
2-trans-TMSO-
o f t r a n s - p e r m e t h r in g i v e
c i s - p e r m e t h r in g i v e
min, respectively.
(glc-ci-ms)
was a v a i l a b l e
min, respectively;
lk.2
quantitation
of trans-
t h e IMS d e r i v a t i v e s
2-cis-TMS0-[lR,cis]-permethrin, and not as
for
and identification
h y d r o x y - [ 1RS]-permethrin
a metabolite
lk.0
technique
detector)
by comparison
compounds,
of
compound
179
k).
The
as
comparison with
BSA-aerivatized non-deuterated
(glc-flame of
Stereospecificity in Pyrethroid Metabolism
S O D E R L U N D A N D CASiDA
Rt
values
corresponding
of
and
lk.8 ik.k 9
o f the TMS-derivatives o f the
hydroxy-trans -permethr fragmentation
pattern
(Figur
k -TMSO-trans-permethrin
(upper
r
the
spectrum)
smaller
clusters
i o n minus
HC1
([M-Cl]
t r a n s - TMS 0- t r a n s - p e r m e t h r in ( m i d d l e 3-phenoxybenzyl
silyloxy
function
corresponding (lower
same
general
TMS
the presence
(i.e.,
2-trans-
ization
using of a
the metabolites
mouse one
group,
is
oxidation
in
cluster Mass
less
spectra
revealed
the
trans-permethrin
the k permethrin
of
to
as
several
eliminate
component either
in
above
ci-ms the
C - l a n d C-3
is
assumed
spectra
a metabolite
the
(9)
iso-
with
possibility Since
cyclopropane
vivo
site
Figure
preference 5.
carry
peak
epimer-
C - l or
C-3
configuration
t o b e t h e same
as
With
for hydroxylation
of
the 2-cis-methyl of
at the V-phenoxy only
specific
hydroxylates
with with
the trans-isomers,
out stereospecific
hydroxylating
significant
preferentially permethrin
at
and the 2-trans-methyl
is
clusters
ester.
shown
hydroxylation
isomers
of
in
and r a t microsomes
methyl
as t h e i r
reaction
isomer-dependent
permethrin Aryl
at
the parent is
ion
ion
was d e t e r m i n e d
minor
isomers
by
differences.
necessary
second
of
The
smaller
and 2-cis-TMS0-trans-permethrin).
of permethrin
permethrin
patterns
intercomparison
where
n o t a known m e t a b o l i c of
identified
fragmentation.
for hydroxylation
is
that
with
m/e
2-
of the trimethyl-
quasi-molecular
ion intensity
a g l c peak
is
by
and
2-cis-TMSO-trans-permethrin
further
a n d r a t microsomes
derivatives
through
+
TMSO-cis-permethrin isomers
preference
b y mouse
.
+
([M+lT ,
and loss
m / e 389)
a large
fragmentation
with minor
Site mers
,
and [M-Cl]
+
and l i t t l e
the corresponding
analogs
of
gives
m / e kl9)
+
of
[M+l]
ion
( n i / e 271)
, m / e kkk).
spectrum)
( m / e 183)
([M-OTMS]
to
spectrum)
([M+l] ,
cation
characterized
cation
for the quasi-molecular
and for this
k79) the
is
-trimethylsilyloxy-3-phenoxybenzyl
1
k
oxidation of
of
[lR,trans]-
[lS,trans]-pemethrin. position
o f the trans -
the r a t oxidase. the cis-esters;
the 2-cis-position
and the 2-trans-position
both
of
Methyl
t h e mouse of
group enzyme
[lR,cis]-
[IS,cis]-permethrin
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
but
180
SYNTHETIC
m 0\ /98±l r 0/7 A 6 I ± 4
m96±2\ fO r53±6J7 /10 1 / γ Ο
m28±3i r45±6 r63±5J7 A l 0 ± 2 // m27±3\ rr27: 27±6V V 0
m56±2ï f I3±2 Γ29±Ν7Λ37±8 f f m3l ±1 1 y o r34±8/7
m 4±2\ >47±6/7
^AK^o^Q/
IS
PYRETHROIDS
\AAoR'0-(y
Journal of Agricultural and Food Chemistry
Figure 5. Stereoselectivity in hydroxylation of gem-dimethyl group and phenoxy ring of per methrin isomers somes (R = benzyl). The percent metabolism at an indicated site is relative to the sum for all sites.
with the
the
rat
enzyme
V - p o s i t i o n
enzyme
this
pattern
is
a major
in
vivo
is
pathway
reversed. with
both
Ifydroxylation cis-isomers
in
at both
systems.
Studies
on
metabolism
of
[ l R ] - and [lRsT-permethrin
in
vivo
(Figure
and
6)
in
in
vitro
of
the
rats
(Figure
trans
trans-
provide 5)
and
data
cis-isomers
for
comparing
specificities.
cis
IR-79 1RS-69
IR-69 1RS-56
Figure 6. Stereoselectivity in hydroxylation of gem-dimethyl group of permethrin isomers by rats in vivo (R = 2,2 dichlorovinyl; R' = 3-substituted-benzyl) (9). The percent metabolism at an indicated methyl group is relative to the sum for both methyl groups calculated by summating identified acid-moiety metabolites.
The
[lR]-isomers to
overall
specificity
cleavage
that
show c l e a r
similar
found
reaction
in
with
methyl
vitro the
complicates
group
and, as
preference
expected,
[1RS]-isomers. these
The
comparisons
in
there in
vivo is
vivo
since
less ester
oxidation
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
16. of
SODERLUND
the
Stereospecificity in Pyrethroid
A N D CASIDA
hydrolysis
hydroxylation
products
site
methyl
may
than with
group
involve
the
a
esters
lack
of
acid
moiety
of
[1R,trans] -permethrin
preference
in
in
differences
in
specificity
between
different
vivo
The
most
vivo
S-5602
and
are
(Table
with
I,
the
S(+)-
explain
in
the the
the
and
in
and
S-j?602)
s t r i k i n g enantiomer-dependent
rates
Thus,
hydroxylation of
may
p-Chlorophenyl-q-isopropylacetates
metabolism
181
preference
themselves.
(£)
in
Metabolism
vitro
studies.
differences
and R(-)-isomers
in S-5^39
of
7).
Figure
Time, min
Figure 7.
Metabolic rates for S-5439 isomers in mouse microsomal systems (7)
The
i n s e c t i c i d a l S(+)-S-5^39
the
non-insecticidal R(-)-isomer
rate.
However,
rapidly
as
oxidation
that
degradation
of
rates
the
(esterase
relationships
also
about
half
the
The
R-
partially rates not is
separable
assigned.
With
difference
S-5602
(Table
glc
Only
one
and
either
metabolite in
both
enantiomers
glc
so
the
are
evident
of
very the
one
of
about with
are
only I).
S-5602
isomer
are
in
metabolism
α-cyano
twice the
similar.
rates
configurations
the
as
bio-
(Table
each
absolute
twice
total
isomers
differences
the
oxidized
not
and
species
further
in
mouse rat
that
R(-)-S-5602,
glc-ci-ms
were
proceeds
S-5602 but
while
moderate
resulting
corresponding S-5^39
techniques
studies or
differences
investigated
S-5^39 metabolite
derivatization with
the
a
as
are
enantiomers
r a p i d l y as
enantiomers
of
the S(+)-
i ) .
Enantiomer S-5^39 were
so
oxidase)
for
slowly
hydrolyzed at
S(+)-isomer
plus
although
hydrolyzed and a
and
by
measured
other,
of
of
is
the
hold
and S-ct-cyano
can be
both
of
hydrolyzed very
R(-)-isomer
These
those
is
rat
formed
peak
used was
on b o t h the
the
S(+)-
systems,
in the
for
microsomal
a
S(+)-
the
permethrin after
and from
study.
TMS
R(-)-isomers
L a r g e r amounts than
oxidation
TMS d e r i v a t i z a t i o n
detected
microsomes.
from
a n d mouse
by
the
of
this
R(-)-isomer
finding consistent
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
with
182
SYNTHETIC
available
oxidase
This
rate
metabolite
and methane
glc-ci-ms
3-phenoxybenzyl (Table
I I I ) .
data
f o r these
i s tentatively with
andwithout
Isobutane
spectra
establishing
give
that
spectra
alcohol
out
derivatization, 2
the
group
group
with
unstable alcohol
It
i s
a peak
a t short
a
oxidation
analogous
This
times
time
by g l c with alcohol
with
peaks
identical
are probably
i . e . hydroxylation
chiral
than
of a
center.
f o r both
isomers
o f S-5^39
hydroxylated (Figure
to find
since
only
and the U-position
sites
S-5^39
that
propyl
ester
is
probably γ-lactone and
8).
o n mouse
the methyl
position
the tertiary-position o f t h e phenoxy
for hydroxylation.
glc or glc-ci-ms
properties
However,
appropriate
o r r a t microsomal,
group
no
i s
of thei s o are
also
metabolites
f o r these
metabolism
of
compounds S-5^39«
Discussion lyre thro id greatly
hydrolysis
facilitated
stituent
in
Proposed metabolism of S-5439 by mouse and rat microsomes
surprising
detected
i s analyzed
f o r 3-phenoxybenzyl
to the corresponding
in
are
peak,
rather
t
hydroxylated
with
while
the acid
retention
reaction
peak
as the base
appear
i f not dérivâtized
group
in
retention
second
on g l c and cleaves
potential
as
(TMSO-S-
as the base
cation
the metabolite
The short
permethrin.
Figure 8.
occurs
o f the γ-lactone,
a n d r a t enzymes
methyl tion
peaks
introduces
The major mouse
When
i t gives
CI spectra.
2 diastereomers
methyl
o f t h e TMS d e r i v a t i v e
t h e 3-phenoxybenzyl
moiety.
overlapping
methane
I ) .
isobutane
BSA d e r i v a t i z a t i o n
i o n cluster
hydroxylation
the plus
(Table
by
2-(V-chlorophenyl)-3-methyl-^-hydroxybutyrate
5^+39) s h o w t h e q u a s i - m o l e c u l a r methane
enantiomers
identified
PYRETHROIDS
b y mouse m i c r o s o m a l
by a trans-isobutenyl
a t cyclopropane
esterases
or equivalent
C-3 b u t i s a f f e c t e d
t o a much
i s sublesser
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
(isobutane)
+
483(60)
483(100)
6 Λ
3-Phenoxybenzyl a l c o h o l (methane)
e
201(3*0
211(100)
+
183(100)
183(100)
1§3(5)
[PhOFhCHj
'Conditions same as f o r TMSO-derivatives o f permethrin (footnote b, Table I I ) ; assignments given o n l y f o r most abundant i s o t o p e s in the i o n c l u s t e r s ; °partially r e s o l v e d i n t o 2 peaks ( 5 . 0 and 5.2 min) w i t h g l c c o n d i t i o n s as in Table I I (footnote b) b u t i s o t h e r m a l a t 175°C, each component g i v i n g the same mass spectrum.
5.8
Products from g l c o f u n d e r i v a t i z e d m e t a b o l i t e
15.2
15.2
Y-Lactone (methane)
1
TMSO-S-5 +39 (methane)
TMSO-S-5^39
[M+l]
M e t a b o l i t e as TMS d e r i v a t i v e
a
Glc Rt, min
Products
m/e ( R e l . i n t e n s i t y )
Mass Spectra o f the T r i m e t h y l s i l y l o x y - D e r i v a t i v e and Degradation o f a S-5^39 Mouse and Rat Microsomal Oxidase M e t a b o l i t e
Compound ( c i reagent gas)
Table I I I .
1
28
h-
So"*
ο
S
3
S*
(Λ Ci
•3
ο
on c?
t
>
>
I
I—» 05
184
SYNTHETIC PYRETHROIDS
degree by the optical configuration at cyclopropane C - l (3>4, 10 ). The £-chlorophenyl-a-isopropylacetates, with only one optical center in the acid moiety, show greater enantiomerdependent differences in hydrolysis rates. Variable degrees of stereospecificity are involved in pyrethroid hydroxylation by mouse microsomal oxidases. With resmethrin the geometrical configuration of the acid (trans or cis) is most important in determining the preference between the isobutenyl methyl groups while [lR]- and [is]-enantiomer d i f f e r ences are minor. The preferred site for hydroxylation of per methrin isomers is dependent on the configuration at C - l ; thus, the [lR]-isomers show a preference for 2-cis-methyl hydroxyla tion and the [is]-isomers for 2-trans-methyl hydroxylation. With the trans-permethrin isomers the stereospecificity of gemdimethyl hydroxylation is absolute and there are marked rate differences between enantiomers rate differences in methyl hydroxylation of the S-5^39 enantio mers. Mouse and rat microsomes sometimes differ in site pre ference for methyl hydroxylation ( i . e . , isobutenyl groups of [lR,trans]- and [lR,cis]-resmethrin and gem-dimethyl groups of [ l R , c i s ] ~ and [IS,cis]-permethrin) and in the significance of a r y l hydroxylation ( i . e . , [lR,trans]- and [IS,trans]-permethrin). In studies on pyrethroid metabolism, toxicology and r e s i dues, i t must be recognized that the extent and significance of metabolic stereospecificity may vary with different esters and their optical antipodes and with different species. Abstract Metabolism rates of the optical antipodes of pyrethroids by mouse l i v e r microsomal enzymes differ by at least 1.7-fold in the following cases: hydrolysis of [1R,trans]- vs [1S,trans]resmethrin; hydrolysis of S(+)- vs R(-)-S-5439 and -S-5602; methyl hydroxylation of [1R,trans]- vs [1S,trans]-permethrin; methyl hydroxylation of S(+)- vs R(-)-S-5439; oxidation of S(+)- vs R(-)-S-5602; hydrolysis and oxidation of αR- vs αS-R(-)-S-5602. Various degrees of stereospecificity are encountered with mouse and rat l i v e r microsomal oxidases in the preferred methyl group for hydroxylation, i.e., trans(E) VS cis(z) in the isobutenyl moiety of the 4 resmethrin isomers and 2-trans vs 2-cis in the 4 permethrin isomers. Stereospecificity in methyl hydroxyla tion of [1R]- and [1RS]-preparations of trans- and cis-permethrin i s also evident with rats in vivo. Acknowledgements We thank Michael Elliott, Loretta Gaughan, Roy Holmstead, Kenzo Ueda and Tadaaki Unai, current or former colleagues in this laboratory, for assistance and helpful suggestions. This study was supported in part by grants from: National Institutes
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
SODERLUND AND
16.
CASIDA
StereospecificityinPyrethroid Metabolism 185
of Health (2P01 ES00049); Agricultural Chemical D i v . , FMC Corp., Middleport, N . Y . ; Agricultural Chemicals D i v . , ICI United States I n c . , Goldsboro, N . C . ; McLaughlin Gormley King Co., Minneapolis, Minn.; Sumitomo Chemical C o . , Osaka, Japan; Roussel-UclafProcida, Paris, France; Mitchell Cotts & Co. L t d . , London, England; Wellcome Foundation L t d . , London, England; National Research Development Corp., London, England. Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Elliott, M . , Farnham, A. W., Janes, N. F., Needham, P. H . , Pol man, D. Α . , ACS Symp. Ser. (1974) 2, 80. Casida, J. E., Ueda, Κ., Gaughan, L. C., Jao, L. T., Soderlund, D. Μ., Arch. Environ. Contam. Toxicol. (1975/76) 3, 491. Soderlund, D. M . this volume. Soderlund, D. M . , Casida, J. E., Pestic. Biochem. Physiol. (1977) accepted for publication. Ueda, Κ., Gaughan, L. C., Casida, J. E., Pestic. Biochem. Physiol. (1975) 5, 280. Ueda, K . , Gaughan, L. C., Casida, J. E . , J. Agr. Food Chem. (1975) 23, 106. Soderlund, D. Μ., Ph.D. thesis, University of California, Berkeley, 1976. Unai, T . , Casida, J. E., ACS Symp. Ser. (1977) this volume. Gaughan, L. C., Unai, T . , Casida, J. E., J. Agr. Food Chem. (1977) in press. Miyamoto, J., Suzuki, T . , Nakae, C., Pestic. Biochem. Physiol. (1974) 4, 438.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
17 Permethrin Metabolism in Rats and Cows and in Bean and Cotton Plants LORETTA C. GAUGHAN, TADAAKI UNAI, and JOHN E. CASIDA Pesticide Chemistry and Toxicology Laboratory, Department of Entomological Sciences, University of California, Berkeley, Calif. 94720
The discovery tha 2,2-dimethylcyclopropaiiecarboxylate (permethrin) combines outstanding insecticidal activity, low mammalian toxicity and adequate s t a b i l i t y in l i g h t and a i r has focused attention on the potential of synthetic pyrethroids in agricultural pest insect control (1,2). Most permethrin preparations are [1RS, trans,cis]-mixtures, the [lR,trans]- and [lR,cis]-isomers being the insecticidal components (3). The importance of understanding permethrin biodegradation prompted the present study on the comparative metabolism of [ l R , t r a n s ] - , [1RS, t r a n s ] - , [ l R , c i s J - and [1RS,cis]-permethrin in rats (4,5) and of [1RS,trans]- and [1RS,cis]-permethrin in cows and in bean and cotton plants. [ C] Permethrin Preparations and Experimental Procedures for Rats and Cows 14
Eight [ C] permethrinpreparations were used with specific activities ranging from 1.7 to 58.2 mCi/mmole (Figure l ) . The [lR]-isomers were prepared as previously reported (4) and the [1RS]-isomers were provided by FMC Corporation (Middleport, N . Y . ) . Rats (male, albino, Sprague-Dawley strain) treated with a 14
1RS,trans (rat, cow, plant)
IRS,c/s (rat, cow, plant)
Figure 1. Eight preparations of Cpermethrin (specific activity, mCi/mmol) 14
186
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
17.
G A U G H A N
single mg/kg
oral were
dose held
sacrificed
o f each 4-
in
theurine
cochromatography compounds
(6)
glucuronides lites
in
in
both
acid
moiety
findings tions of
treated rumen as
standard or with metabo
enzymes
and base
(β-
t o
obtain
identification were
a l lproducts
were
with
chromatofree
chromatographed
systems,
the latter
t o
o [-^"C p r e p a r a t i o n s a n d-C*(0)-
that
labels
o f the [ \ 0 a c i d
preparations the acid
the [lR]-
in
used
in
gave the
the alco These
t o detect a l l
moieties,
a n d [1RS]-isomers with
in
prepara
can be used
and a l c o h o l
so the [lRS]-isomers were
rats
p r o d u c t i o n , in a n y c a s e .
either
from
in
labels
respec
gave
almost
specific
the studies
with
activities cows a n d
organisms. Cows
1
t o move
solvent
(methanol tot i c
Individual
f o r t h e - C H ^ - and phenoxy
results,
tissues.
with
metabolites
metabolites
and w i t h n o ^ C O p
55.9-58.2 mCi/mmole
other
Urinary
2
I n addition,
and
) derivatives
acid
1-4
then
subjected
f3).
or with
f o r t h e C1 C*=
or [^C]alcohol
CO
hydrolyzed with
comparing a l l 8
results and
(CH^N
systems
and n e u t r a l
themetabolites
identical of
solvent
indicate
tively.
also
sulfatase)
decomposition
moiety
were
enzymatically
Thef e c a l
studies
feces,
at
and
μ ΐ ) a n d in t h e f e c e s
f o r t i c c©chromatographic
acidic
similar
cages
g e l chromatoplates
derivatization.
acidic
The very hol
aryl
the origin.
minimize
o f urine,
methylated
b y t i c were
products
and without from
on s i l i c a
preparations
metabolism
(40-100
synthesized
glucuronidase,
graphed
in
t o 40-230 mg f e c e s )
o r their
isolated
cleavage
o f the 8 labeled
o r l4-days
equivalent
187
Metabolism
f o r radioanalysis
Metabolites extract
Permethrin
E T A L .
(lactating
with
Jersey,
3 consecutive
o f the 4 labeled
mg/kg
were
held
arrangements
daily
doses
preparations
12- or l4-days
b y FMC
Corporation)
by intubation
into the
o f [1RS]-permethrin
prior
to sacrifice
and
a t analyses
above.
[ ^ C ] P e r m e t h r in M e t a b o l i t e s The
[1RS,trans]-isomer
radiocarbon
than
hol-labeled
preparations
Table
I .
Percent
and
label
Rats
a n d Cows
o f permethrin yields
L1RS,cis]-permethrin with
Urinary
[1RS,cis3Isomer
in
and with
either
Radiocarbon
[^C]Permethrin
position
rats
from
more
either
urinary
acid-
o r cows
or
[1RS, t r a n s J - a n d
Preparations Rats
alco
(Table
Cows
1RS,trans Acid
82
39
Alcohol
79
47
Acid
54
29
Alcohol
52
22
1RS,cis
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
i ) .
188
SYNTHETIC
The m a j o r i t y and
in
sive
o f themetabolites
the feces
ester
cleavage
trans-permethrin pared
t o
the
cows.
appear
These
or conjugation
than
with
in
theurine
with
rats
indicate
more
exten
results
o f themetabolites
with
c i s - p e r m e t h r in a n d in r a t s
as
com
cows.
The cation
with
PYRETHROIDS
t i c cochromatographic
i s illustrated
acid
moiety
in
technique
Figure
2 with
f o rmetabolite
t h emetabolites
o f [1RS,trans]-permethrin
in
rats
i d e n t i f i from
a n d cows.
hydroxy esters
L4'-H0,/-H0 /-H0-CI CA \ 2
Per
/-HO 4'-HO
Φ
.
7
lactone
CI CA-conjugate 2
|K>CI CA-glucuronide 2
^HO-CI CA-glucuronide 2
t Figure 2. Metabolites from acid moiety of (1RS, trans)-permethrin. Ο represents rat; . , cow; and 3 , rat and cow.
The
solvent
separates resolves the to
system
permethrin,
trans-
the
group
acid moiety
before Most
(t-HO;
2
However,
only
gem-dimethyl additional contrast,
cows group,
give
rats
form
from
rats
on analysis).
a n d cows.
o f ClpCA
atthe
and an
o f the acid moiety.
glucuronides
from
(t-HO-Cl^CA;
hydroxylated
conjugate
at
relative
cyclization
cyclization
b y both
metabolites
unidentified metabolite only
(from
2
ester
then
(V - H O , t - H O ) ,
derivatives
o f c-H0-Cl CA
t h e glutamate
group
derivative
a n di t s h y d r o x y
a r e formed
system
i t s V - H O derivative
c-HO),
o r as an a r t i f a c t
o f themetabolites
development
with monohydroxylation
i t s dihydroxy
(C1 CA)
o f
solvent
o f t h e gem-dimethyl
and the lactone
excretion
direction
i t s derivatives
hydroxylation,
c-HO-Cl^CA),
first
:
and t h e second
or cis-position
the carboxyl
phenoxy
f o r the
t h e conjugates
2 — • (benzene-sat'd formic acid)-ether (I0 3)x2
In
o f t h e HO-Cl^CA
derivatives. Studies preparation to
define
(Figure case,
the sites
3).
with
o f t h e type
indicated
o f [1RS,trans3There
o f metabolic
attack
arek principal
an additional
above
with
each
labeled
and[1RS,cis3-permethrin
site
in
sites
f o r rats
rats
served
a n d cows
o f attack
administered
in
each [1RS,cis3-
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
17.
GAUGHAN
Permethrin
E T AL.
189
Metabolism
Ester hydrolysis φ : trans » cis Preferred methyl for hydroxylation (£,3) cis {2) in 1RS,trans :
trans (3) in \RS,cis Phenoxy hydroxylation (4,5): 4'inrat and cow 2' in rat, cis only
Figure 3.
permethrin. with
a t thecis-position
group
isomers
in
permethrin Eight moiety
(Figure tion the
4 ) .
rats in
a n d cows
rats
ester
with
trans-
in
than
Γ1RS,trans]-permethrin
U-RS,cis]-permethrin.
a t theV - p o s i t i o n T
-position
hydroxylated
from
the feces
o f theh possible group
compound
cis-permethrin derivative
rapid
(h)
The
with
both
( 5 7 "with c i s -
only.
a r eidentified Three
( 2 )
in
and a t the2
metabolites
2-trans-hydroxy
stable
(j)
i s hydroxylated
a t t h e gem-dimethyl
hydroxy
( l ) i s more
Oxidatio
a t thetrans-position
phenoxy
hol
hydrolysis
cis-permethrin.
selectively and
Ester
Sites of metabolic attack from rat and cow
isomer
i s present
trans
cow Figure 4.
appear
from
esters in in
both
theacid from
or alco
a n d cows monohydroxyla-
cowf e c e s
t h emore
appears with
in
o f rats
b u t only
metabolically-
r a tfeces. trans-
The V
and c i s -
cis
rot, cow
Rat and cow hydroxy ester metabolites
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
-
190
SYNTHETIC
permethrin
a n d in b o t h
derivative
appears
in
both
rats
a n d cows
administered These
a b i l i t y
in
a n dcows. cows
with
with
differences
ester
o f rats
T h eV - H O , t - H O trans -permethrinand
cis-permethrin.
ci s - p e r m e t h r i n c o n t a i n s
species
extensive
rats
only
Thefeces
the 2'-hydroxy
areattributable
hydrolysis
in
cows
than
to carry outaryl
PYRETHROIDS
in
in
part
rats
o f
rats
derivative. to
less
and the
hydroxylation a t t h e 2*-
position. The are
acid moieties
mostly
excreted
glucuronides. both
species
hydroxy part
from
[1RS]-trans-
rats
a n d cows
T h eo t h e r except
acids
with
in
that
metabolites in
cows
arenot detected
glutamic
acid
a n d- c i s - p e r m e t h r i n
as the corresponding are also
t h e same
the glucuronides
a n dCl^CA
(Figure
in
o fthe
i s conjugated
in
5).
cr^-^-coo Species
free
glue
free
+ +
++ ++*
+
Rat Cow
glue + +
also glutamate conjugate of trans-QC\à Figure 5. Metabolites from acid moiety of (1RS, trzns)-permethrin and (IRS,tra.ns)-permethrin, rat and cow The and to
liberated in
the corresponding benzoic
rats, and in
alcohol moiety
[1 R S , c i s] - p e r m e t h r i n i s as a glycine
acid which
conjugate
as t h e glutamate cows
b u t absent
rats
+ -
• •
o f [1RS, t r a n s ] further
i s excreted in
6).
free glue + +
• +
oxidized free
rats
which i s t h e major
(Figure
Species free gly glue glut Rat Cow
part
andglucuronide
conjugate
in
on cleavage
t h e most
in
a n d cows
metabolite
3-Fhenoxybenzyl
4'
2'
++
+
+
Figure 6. Metabolites from the alcohol moiety of (1RS, transj-permetnrin and (1RS, cis)-permethrin, rat and cow alcohol amount the
i s excreted
sulfate
amount tive
in
appears The
shown
only
complete in
in
in
rats
cows
o f t h e k'-hydroxy
cowu r i n e
permethrin is
free
o f glucuronide
in
rats
a n dcows
only. acid,
a n dt h e s u l f a t e
in
pathway
i n c l u d i n g t h e 2k
F i g u r e 7. excreted
radiocarbon
except
i s present
trace
r a t metabolite, in
small
o f the 2 -hydroxy 1
deriva-
r a t urine.
metabolic
metabolites
andas a
T h em a j o r
This in
pathway
amounts
f o r 5 minor
f o r trans-
and c i s -
identified metabolites accounts
o f >1% o f t h e a d m i n i s t e r e d fecal
(5.)
f o r a l lpermethrin
metabolites
o fc i s -
permethrin.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
h-» CO h-
Figure 7.
The complete metabolic pathway for trans- and cis-permethrin
1
So**
Ο
δ"
3" 2. 3
a
I
I
is
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
192
SYNTHETIC
PYRETHROIDS
Experimental Procedures for Bean and Cotton Plants and L CJPermethrin Metabolites in Plants Bean and cotton plants treated topically on the leaves and bean plants treated by stem injection with the h [-^C]preparations of [1RS ]-permethrin were held for up to 21 days in the greenhouse. The leaves were washed with methanolchloroform (2:1) and then extracted with this solvent mixture or the whole plants were extracted in the same manner. Plant metabolites were identified and analyzed by the methods used for the mammalian metabolites, except that β-glucosidase, cellulase and acid were employed for conjugate cleavage. An extract of bean plants Ik days after stem injection with [1RS,trans]-permethrin contains the parent compound, hydroxylated permethrin, the free dichlorovinyl acid and i t s hydroxy derivatives, phenoxybenzy acid. These products appear as one spot in the n-butanolacetic acid-water solvent system (Figure 8) but they are resolved in the benzene (formic acid)-ether system. The products at Rf 0 Λ 7 and 0.6l are conjugates of hydroxylated permethrin while the Rf Ο.56 product is an unidentified conjugate from the acid moiety. The identified conjugates include the glycosides of the dichlorovinyl acid and of 3-phenoxybenzyl alcohol. Permethrin on bean and cotton leaves undergoes transcis isomerization to the extent of 6-13$ in 21 days. The penetrated portion yields metabolites similar to those found in the injected bean plants. In a l l cases, trans-permethrin is more rapidly metabolized than cis-permethrin. These preliminary results with plants indicate the importance of photodecomposition and metabolic oxidation and hydrolysis in the dissipation of permethrin residues. Abstract Permethrin metabolites excreted by rats and cows include 8 mono- and dihydroxy derivatives of the trans- and c i s esters, the acid moieties from ester cleavage and their 2-transand 2-cis-hydroxy derivatives, 3-phenoxybenzyl alcohol, and 3-phenoxybenzoic acid and i t s 2'- and 4'-hydroxy derivatives. These metabolites are excreted without conjugation or as glucuronides and glycine and glutamic acid conjugates of the carboxylic acids and as sulfates of the phenolic compounds. Permethrin on bean and cotton leaves undergoes t r a n s - c i s photoisomerization and the absorbed material yields hydroxy esters and their glycosides, hydrolysis products and their glycosides, and 3-phenoxybenzoic acid, trans-Permethrin generally undergoes more rapid biodégradation than c i s - p e r methrin, in part because of the greater hydrolysis rate of the trans- compound.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
17.
GAUGHAN E T A L .
PermethHn
Permethrin HO-Permethrin
Permethrin HO-Permethrin C|)=\X OH CIvHO-, l C I M ^ O H V
193
Metabolism
0.81
0.81
HO-Permethrin glyc.-^0.6 I Unk. glyc. from acid-*>Q moiety 5
0.61 -^HO-Permethrin glyc.
6
0.47«*-H0-Permethrin glyc.
HO-Permethrin glyc.-*0.47 0.34«-glyc0^ glyc-K). 3 4 0 butonol-acetic acid-water (e ι ι) Figure 8.
Bean metabolites of (1RS, trans)-permethrin, stem injection
Acknowledgment s We thank Michael E l l i o t t for assistance and helpful suggestions. This study was supported in part by grants from: National Institutes of Health (2 FOI ES000U9); Agricultural Chemical D i v . , FMC Corp., Middleport, N.Y. ; Agricultural Chemicals D i v . , ICI United States I n c . , Goldsboro, N. C ; Sumitomo Chemical Co., Osaka, Japan; Roussel-Uclaf-Procida, Paris, France; Mitchell Cotts & Co. L t d . , London, England; Wellcome Foundation L t d . , London, England; National Research Development Corp., London, England. Literature Cited 1. Elliott, M., ACS Symp. Ser. (1977) this volume. 2. Elliott, M., Farnham, A. W., Janes, N. F., Needham, P. Η., Pulman, D. A., Stevenson, J. Η., Nature (1973) 2k6, 169. 3. Elliot, M., Farnham, A. W., Janes, IT. F., Needham, P. H., PuLbnan, D. Α., Pestic. Sci. (1975) 6, 537. k. Elliott, Μ., Janes, N. F., Pulman, D. Α., Gaughan, L. C, Unai, Τ·, Casida, J. E., J. Agr. Food Çhem. (1976) 2h, 270. 5. Gaugnâh, L. C, Unai, T., Casida, J. E., J. Agr. Food Chem. (1977) in press. 6. Unai, T., Casida, J. E., ACS Symp. Ser. (1977) this volume.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
18 Synthesis of Permethrin Metabolites and Related Compounds T A D A A K I U N A I and J O H N E . C A S I D A
Pesticide Chemistry and Toxicology Laboratory, Department of Entomological Sciences, University of California, Berkeley, Calif. 94720
Considerable progres metabolism of the trans- and cis-isomers of 3-phenoxybenzyl 3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylate (permethrin) in rats (1-3), in cows (3), in insects (4), in bean and cotton plants (3) and in microsomal mixed-function oxidase systems from mammalian l i v e r (5) and insects (4), in part be cause of the a v a i l a b i l i t y of authentic standards from synthesis for use in cochromatographic comparisons with the metabolites. This report outlines synthesis routes used to prepare these monohydroxy- and dihydroxy-derivatives of trans- and c i s permethrin, their hydrolysis products, and certain further o x i dized or conjugated derivatives of the hydrolysis products. 3 - ( 2,2 -D ichlor ovinyl ) - 2 - hydroxyme t hyl-2 - methylcyclopropane carboxylic Acids There are 4 possible isomeric acids with hydroxylation at one of the gem-dimethyl positions (Figure 1; the IR isomers are shown). [lR,/AuV7s]-permethrin metabolites
[lR,c/s]-permethrin metabolites ^—OH HO—y
CK
cK h & 7 : COOH 2-c/s-hydroxy
R
'C00H
2-//w?s-hydroxy
«
j
c
CI' 2-£/'s-hydroxy [H or DCC
[Η Γ or DCC
COOH cr 2-//O/7S-hydroxy
+
+
CK /-lactone
/-lactone
Figure 1
The 2-cis-hydroxymethyl acids undergo p a r t i a l conversion to the
194
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
18.
UNAI
A N D
corresponding complete diimide
γ-lactones
conversion (DCC).
crystalline tic zene
These
(saturated
with
from
oxidation
6
compounds
in
conditions and
N,N -dicyclohexylcarbof
are easily
by subjecting formic
acidic
with
isolated
the appropriate
using
hydroxy
glacial
acetic
acetates
cis-compound
dichlorodiene
as
mixtures
2 developments
acid)-ether
(10:3)
acids
isomeric
with
(referred
and 2
to
ben
t o as
γ-lactones
l,l-dichloro-U-methyl-l,3-pentadiene
dichlorodiene the
strong
195
system).
k isomeric
The
under
g e l chromatoplates
BFE solvent
prepared
Metabolites
on treatment
materials
on s i l i c a
the
Permethrin
CASIDA
in
(Figure
acid,
which yields
a ratio 2)
plus
o f 83 other
were
b y SeOp
the desired
for the transproducts
a n d 17 f o r
including the
trans-aldehyde.
6 compounds shown in Fig. I Figure 2 The m i x t u r e
o f acetoxy
diazoacetate tion
[CCI»-ether
hydrolysis
(93:7)3
(NaOH
lactonization of
appropriate
in
permethrin
Hydroxy Derivatives
pared,
i f
(6),
Alcohol
of the
and 3-Fhenoxy-
isomeric
The 6 benzoic
with
suitable
[Cu Clp, 2
,
-10°C,
the desired
methoxy
synthesize
U-methoxyphenols
the 2
t
- , 3 -
(7)
(from
l
while
previ
most
a r e new compounds. ether
by the Ullmann demethylation
t h e BFE solvent
steps
are
system
acetate
with
benzene,
or reduction The acids
with benzene-ethyl
was r e a c t e d
prepared
(thiophene-free
oxidation
acetate-methanol
3-bromobenzoate
(DMF)],
pre
likely
of the diphenyl
intermediates
and alcohols. with
were
routes,
derivatives
formation
2 min) or A1C1-
acids
are resolved
benzene-ethyl
derivatives
derivatives
a c i d were
not being
synthesis
alcohol
involved
t i c on 2 developments
alcohols To
acid
2 h r ) , and appropriate
reflux,
compounds
dimethylformamide
p
(CH C l
obtain
procedure
monohydroxy
a n d 3-phenoxybenzoic
usually by different
general
reaction
by
possible
alcohol
not a l l of the 6 benzyl
linkage BBr
Each
as a metabolite
isomer.
the remaining 2-hydroxy
metabolites.
The
Finally,
t i c (BFE) a n d
[1RSJ-compounds.
found
o f 3-Phenoxybenzyl
o f t h e Ik
3-phenoxybenzyl
ously
ethyl
separa
Acid
Twelve of
(HCl),
the 6 desired i s
by t i c
diesters.
acidification
and lactones
directly with
followed
o f the isomeric
MeOH),
acids
was r e a c t e d
a t 120-130°C,
(DCC) y i e l d e d
t h e hydroxy
benzoic
compounds
a n d C u powder
to
separated
andthe
(6:1)
or
(15:5:1). a n d h -hydroxy
with
T
t h e sodium
the phenols
compounds, salts
o f 2-,
a n d N a H in D M F ) .
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
methyl 3- a n d
196
SYNTHETIC
Dernethylation hydride
in
and
reduction
benzene
the
carbomethoxy
and
acids,
compounds
respectively
To p r e p a r e
the
an
(Figure
3).
U-hydroxy
v a n i l l i n
and bromobenzene
ester
Ullmann
and
the
(CH Ν
,
was
of
3-nydroxy-5-methoxytoluene
For
synthesis
of
5-hydroxy
with
5
gave
5-methoxy-3-phenoxytoluene
further
[KMhO^,
ILO-pyridine
reactions
The
reaction
(Figure
6-hydroxy
5)
of
(6),
derivatives
were
of
with
sodium
before
bromide
acetone) (Figure
of
the
the
prepared
dimethyl
methoxy
of
ether iso-
converted
to k).
(Figure
the
the
[LiAlH^
sodium
salt
me t h y l a t i o n
of
then
treatment
with
bromobenzene
subjected
methoxy
to
acid
and
above.
with
the
was
by
of
acetone),
w h i c h was
5-bromosalicylaldehyde (KMaO^,
salt
alcohol
salt to
MeOH) alcohols
reduction
sulfate, this
in
diphenyl
compounds,
(1:2)]
as
for
prepared
dimethyl
NaH.
the
sodium acid
desired
was
with
oxidation
Ullmann
the
(NaOH hydroxy
(KMnO^,
min)
to
3 5-olihydroxytoluene An
5
(THF)]
the
the
hydroxy
0°C,
tetrahydrofuran
of
oxidized
resulting
in
desired
derivatives,
reaction
ether,
bis(2-methoxyethoxy)aluminum
hydrolysis
the
from
demethylated,
or
gave
aldehyde
methyl
[sodium
(Vitride®)]
PYRETHROIDS
aldehyde
sulfate
phenolate
and
further
by
methylation
then and
reaction oxidation
treatments
as
6).
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
of
18.
UNAI
A N D
The
2 -, f
corresponding
V -
and
and 6-hydroxy benzyl
conjugated
form in
appear
2-3 with
as
metabolites
biological
alcohols of
trans-
acids in
and
free
and/or
the
or cis-
systems.
and Dihydroxypermet h r i n
in
meric EtJtf
197
6-hydroxy-3-phenoxybenzoic
various
The t r a n s - and tion
Metabolites
V -
permethrin Mono-
Permethrin
CASIDA
the
hydroxy in
cis-isomers
a c i d moiety acids
(Figure
DMF s o l u t i o n
hr
(Figure
7).
of
lactonization
of
l)
with
product
was
(6:1)
or
by
N
2
gas
the
at
p u r i f i e d by
was
not
h
isoand
for
preparative
tic
acetate-
observed a
the
bromide
80-90°C
and benzene-ethyl
p u r i f i c a t i o n but
occurred with
monohydroxyla-
heating
3-phenoxybenzyl
with
Isomerization
reaction
permethrin with
synthesized
ampoules
acetate
(15:5:1).
conditions
in Each
benzene-ethyl
methanol
were
under
small
amount
2-cis-hydroxymethyl
these of
compounds.
Figure 7 For 2'-
and
synthesis
trans-ester methoxy
of
V-positions with
esters
a
the of
cis-esters
the
phenoxy
V-hydroxy
prepared by
the
with monohydroxylation at ring
and
substituent, acid
the
the
chloride
the
corresponding appropriate
method
were
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
treated
198
SYNTHETIC
with
BBr-
esters
(CH C1 , 2
as
corresponding major
products, ester)
hydroxy
esters)
isomeric
either desired
or
for
in
to
the
yield
preparative
tic
desired
acetate
isolations. of
w i t h benzene (6:1)
case
the
trans-ester
(Figure
with
a
as
(for
the
2 -
(for
the
k -
Reesterification
3-phenoxybenzyl
the
bromide
of
1
1
the
bromide
cis-dichlorovinyl acid yielded
(including
monohydroxy
and
3-phenoxybenzyl
benzene-ethyl
derivatives
the
dichlorovinyl acid of
the
or
each
min)
and
derivatives
with
trans-
ester
stituent)
using
hydroxy
the
2
products
hydroxy
hydroxy 2
-10°C,
2
minor
PYRETHROIDS
with
the
2 -hydroxy
sub
1
b ). 1
BBr, ,0H
CK
11
^ COOH
V
ΓΊ
Br—^
Figure 8
acid 9)
Esters
hydroxylated
moiety
and
were
prepared by
hydroxylation k
with
the
at
h
at
both
-position
1
esterifying
the
2-trans-methyl
the
the
trans-methyl
-hydroxy-3-phenoxybenzyl
1
the of
2
to
alcohol isomeric
the
bromide
of
the
moiety acids
carboxyl (Figure
(Figure with
(Figure
l)
9).
Λ)Η
TOOH
C -4 - ^ ^ c o O H
B r - — ^0 —
ci—f^
CI Each
of
the
mono-
described
above
ester)
a metabolite
more
is
of
the
Amino A c i d
from acids
the
L-amino
10).
The
amino the or
of
are
in
as
glutamate
Figure 9
acid
2
cis-permethrin
T
permethrin
-hydroxy-trans in
one
conjugates
were
of
the
prepared trans-
acid
THF-benzene
pyridine
in
and
as
and
3-phenoxybenzoic
the
their
methyl
cis-dichloromethyl
esters
solution
the
glycine
with
glycine,
trans-
but
with
cows.
in
and
rats,
not
cows
serine the
and
cis-acid insects
from
glutamic
Phenoxybenzoic and
of
(Figure
cis -dichlorovinyl acid metabolites
cows
or
examined.
chlorides
and
of
trans-
or
the
with
and
in
derivatives of
Conjugates
conjugate
with
dihydroxy exception
systems
conjugated
insects
glutamic
of
acid
acid
acids
acid
conjugated
and the
Sulfate
trans-
permethrin a
(with
biological and
Twelve esters vinyl
^cœ—-^^Nx^
CI
is
detected
acid
and
is
with
insects.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
18.
U N A I A N D CASIDA
Permethrin Metabolites Structures
199
RinEach Structure -H = glycine -CH = alanine 3
CHOH = serine 2
f\ f\ ? ^^C^^CONH-CH-COOMe
-CHCHCOOMe = glutamic acid 2
2
Figure 10
The sulfate conjugate of V-hydroxy-3-phenoxybenzoic acid, found as a major permethrin metabolite in rats, was prepared by sulfation of the aci (Figure l l ) . The produc by preparative t i c with n-butanol-acetic acid-H 0 (6:1:1). The starting material was obtained on hydrolysis of this sulfate with sulfatase or 3N HC1. CIS0H in , . f^i fY° *" sulfatase HO-C^^XT^ I ] I Figure 11 3
ίΓϋ fY° ι-ς^^^Τ^ I
H
p y r i d i n e
or
S0
H+
Abstract Mono- and dihydroxy derivatives of [1RS]-trans- and [1RS]cis-permethrin, their ester hydrolysis products, and conjugates of the acid moieties and of 3-phenoxybenzoic acid and 4'hydroxy-3-phenoxybenzoic acid were prepared for v e r i f i c a t i o n and stereochemical assignments of the free and conjugated [ C]metabolites of the [ C] permethrin isomers. At least 2 d i f f e r ent solvent systems were used in each case for cochromatographic identification, with and without derivatization of the compounds. Twenty-nine of the products synthesized are identified as per methrin metabolites in free or conjugated form. These com pounds were important in assigning structures for the permethrin metabolites formed in various organisms and enzymatic systems. They should also be useful standards in studies on metabolism of related pyrethroids. 14
14
Acknowledgments The authors thank Loretta Gaughan, Roy Holmstead, Toshio Shono, David Soderlund and Kenzo Ueda for valuable suggestions and assistance. This study was supported in part by grants from: National Institutes of Health (2 P01 ES00CA-9); Agricultu r a l Chemical D i v . , FMC Corp., Middleport, N.Y.; Agricultural
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
200
SYNTHETIC
PYRETHROIDS
Chemicals D i v . , ICI United States I n c . , Goldsboro, N. C.; Sumitomo Chemical Co., Osaka, Japan; Roussel-Uclaf-Procida, Paris, France; Mitchell Cotts & Co. L t d . , London, England; Wellcome Foundation L t d . , London, England; National Research Development Corp., London, England. Literature Cited 1. 2. 3. 4. 5. 6. 7.
Elliott, M . , Janes, N. F., Pulman, D. Α . , Gaughan, L. C., Unai, T . , Casida, J. E., J. Agr. Food Chem. (1976) 24, 270. Gaugnan, L. C., Unai, T . , Casida, J. E., J. Agr. Food Chem. (1977) in press. Gaughan, L. C., Unai, T . , Casida, J. E., ACS Symp. Ser. (1977) this volume. Shono, T . , Unai, Soderlund, D. Μ., Casida, J. E., ACS Symp. Ser. (1977) this volume. Ungnade, H. E., Rubin, L., J. Org. Chem. (1951) 16, 1 3 H Miyamoto, J., Suzuki, T . , Nakae, C., Pestic. Biochem. Physiol. ( 1 9 7 4 ) ,4,438.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
19 Synthetic Pyrethroids: Residue Methodology and Applications
1
D. A. GEORGE, J. E. HALFHILL, and L. M. McDONOUGH Yakima Agricultural Research Laboratory, Agricultural Research Service, U.S. Department of Agriculture, Yakima, Wash. 98902
The shortcomings of DDT [ l , l , l - t r i c h l o r o - 2 , 2 - b i s = (p-chlorophenyl )ethane stimulated research into the development of other broad spectrum insecticides that could provide high insecticidal activity combined with low mammalian toxicity and moderate persistence. Compounds related to natural pyrethrum (synthetic pyrethroids) have been developed in recent years that show promise of meeting these requirements. Natural pyrethrum (Fig. 1) i s an ester with synthetic variations of both the acid and alcohol portion of the molecule providing promising insecticides. Field studies indicate that Bioethanomethrin® [(5-benzyl3-furyl)methyl trans-(+)-3-(cyclopentylidenemethyl)-2,2dimethylcyclopropanecarboxylate] and FMC 33297 [m-phenoxybenzyl cis,trans-(±)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane= carboxylate] (Fig. 2), showed promise of controlling insects of certain vegetable crops. Consequently, we investigated methods of detecting their residues. We report here a direct method u t i l i z i n g gas chromatography and electron capture detection for FMC 33297. In addition, we developed a method based on derivatives of the alcohol and acid moieties of the saponified pyrethroid molecule for both pyrethroids (1). This latter method should work equally well with other synthetic pyrethroids (Fig. 3). The sample i s saponified, the alcohol moiety i s extracted with methylene chloride, the water portion i s then a c i d i f i e d , and the acid moiety i s extracted with methylene chloride. Trichloroacetyl chloride with pyridine i s used to form a trichloroacetate ester from the alcohol and trichloroethanol 1/ This paper reports the results of research only. Mention of a pesticide in this paper does not constitute a recommendation for use by the U.S. Department of Agriculture nor does i t imply registration under FIFRA as amended.
201
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
SYNTHETIC
202
CHRY3ANTHEMATE3
PYRETHROIDS
PYRETHRATES
3 PYRETHRIN I
Ο
PYRETHRIN Π
8
CINERIN I
CINERIN Π
JASMOLIN 1
JASMOLIN
Figure 1.
Π
Natural pyrethrums: chrysanthemates and pyrethrates
Figure 2. Synthetic pyrethroids Bioethanometrin and FMC 33297
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
19.
GEORGE
with
pyridine
ester
with
increases
with
The the
This the
the derivatives
equipped
derivatized both
at
8 microns,
a
capture
products
5.68
used
to
form
compound
t h e nanogram gas
an
in
the
range
chromatograph
detector.
support at
to
by a
the
( F i g . 4).
is
pyrethroids,
is
trichloro
sensitivity
spectra
frequency
of
use of
are determined
an electron
infrared
vibrational
203
and dicyclohexylcarbodiimide
the acid.
derivatives when
Residue Methodology
E T A L .
expected
microns
the aromatic
structures
The carbonyl ether
and the carbon-chloride
for the
trichloroacetate
stretching
bands
for
stretching frequency
are near
14
is
a n d 17
microns. The the
esters
carbonyl
C-O-C the
from
the acid
stretching
t r i p l e t
at
8.7,
carbon-chloride
moiety
frequency
8.9,
and 9.1
stretching
for both
at
5.78
pyrethroids
microns,
microns
a
( F i g . 5).
frequencies
are at
show
strong Again,
14
a n d 18
microns. The
high
structures ion
was f o u n d
331.9773). was base from was
324.0445
peak
of
the trichloroacetate
corresponding
the molecule. at
m/e
to
2
The
ester
the loss peak
of
of
the trichloroethanol
(calculated
m/e
337.9200)
ester,
i o n from
the trichloroethanol
the
loss
of
2
ion ester
of
a method
in
greater
detector;
of
5 to
50
sensitivity
of
the
m/e
183.0808.
corresponding
for determining was u s e d .
t h e compound
the result nanograms. with
at
peak of
to
163.0058.
molecule
make
the loss
The
was m / e
The base
to
was f o u n d
m/e
derivative
derivative
ester,
was d e v e l o p e d
the complete
the molecule
capture
at
ester
345.9765).
is
a
residues
The 2
sensitive
standard
However,
we
to
curve
obtained
the derivatization
method.
Studies emulsifiable
lentils
as
oz/acre)
a 14
collected were
concentrate
spray
2 times
a n d 21 after
h r , and a f t e r
samples
The
m/e
the loss
m/e
ester
the molecule,
was f o u n d
3
which
sensitivity
10-fold
168
in
atoms
electron
(10
2
addition,
chlorine
were
of
C0 CH CC1 ,
FMC 3 3 2 9 7
An
to
( F i g . 7).
peak
to
at
the trichloroacetate
corresponding
base
Residue
ester
324.0449).
was f o u n d
(calculated
The
a
m/e
the trichloroethanol
trichloroacetate
a
m/e
corresponding
346.9764
trichloroacetate
with
(calculated
the trichloroethanol
ion for the trichloroacetate
was m / e
ion of
337.9185
the
molecular
2
molecular
molecular
In
The
Bioethanomethrin
(C0 CH CCl3).
2
FMC 33297
of
the
(calculated
The base
149.1323,
( F i g . 6).
of
331.9789
ion of
be m/e
found
the
be m/e
The molecular to
C H 0 Cl3 2
to
formed ester
found
171.0804,
of
the derivatives
for the trichloroacetate
derivative
3
resolutio
of
the
selected
days
the
at
of
before
first
of
harvest.
spray
2nd t r e a t m e n t randomly
Bioethanomethrin
the rate at at
0 h r ,
700
g
Foliage 66
applied
residues
h r , and
0 h r a n d 72
throughout
was
Ai/hectare
the plot,
hr.
The
placed
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
204
SYNTHETIC
2 R CH -O-C-CCl.
c i c-coci
2
R -CH 0H o
1"1)\ OH , MeOH / U-ΛΙΙ / - --^ 2) H,0 \
Q
R -C-O-CH^R
λv
Λ
Ζ
+
+
PYRETHROIDS
Ô
0
C-CH OH
c
ι R -COOH
R -C-0-CH -Cl 2
pyridine - DCC Figure 3.
Derivative step (DCC is dicyclohexylcarbodiomide)
WAVENUMBfl (CM>
0.00
—
Ί IΓ T
.1 ο
11
.20
II
S
f
w
f
30
— 1
.40 .5 0 60 .70 1.00 25
30
40
3000
2.5 3.0
5.0
60
2000
4.0
5
0
70
β ϋ
1300
6.0
7
ΙΟ 0
l? 0
4
0
1000 8 0 0
0
80
10.0 12 0
ιβ 0
600
14
0
WAVELENGTH (MICRONS)
Figure 4.
6Ο
Infrared spectra of trichloroacetate ester derivatives
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
16 0
18
0
3
19.
GEORGE
in
plastic
samples
bags,
were
subsamples 200
removed
ml methylene
sodium The
foliage to
extract
liquid
of
Baker s
through The
in
lentils
and
the residue
The
acetonitrile
as
compare were
168-hr by
hexane
were
Table
to
0.6
Table
in
50 m l o f
analyzed.
between
foliage
time.
of
loss
Immediately Control
the harvest
with
between
from
after to
g
1.5%
was t h e
and
same
to
dryness,
acetonitrile.
zero
was
of
samples
after
No
1.0
residue ppm)
and
residues
foliage of
700
at g
oz/acre).
found
(ppm)±/
Trichloroethanol ester derivative
1
0.350
0.447
.035
.066
168
.000
.000
Treatment
2
0
.647
.689
72
.000
.000
corrected
the no
to
66
were
residues
derivative
on l e n t i l
derivative
0
0.1
an a p p l i c a t i o n
ester
(hr)
of
ester
Trichloroacetate
and
sampling
the
showed
derivative.
Bioethanomethrin (10
derivatives
by t h e end o f
( i n the range ester
the 2
the 7-day
spraying,
o r check
Treatment
Results
(20
passed
and the residue
during
Residues
sampling
was
l e n t i l s .
intervals
Ai/hectare
1/
hexane
determined
Recoveries
Residues
treatment
subjecting
an
ppm a n d d e c l i n e d
various
Interval
methylene
column
hexane
Extraction
84.2% f o r t h e t r i c h l o r o a c e t a t e
I.
oxide
was e v a p o r a t e d
was e v a p o r a t e d
for the trichloroethanol in
analyzed.
the
and then
was e l u t e d
the extract
The r a t e I.
method.
found
anhydrous until
hexane,
g
sample.
sampling
averaged 80.3%
solution
in
either
through
an aluminum
After
also Then
favorably.
0.4
with
in
Bioethanomethrin
were
residues
shown
with
up by e v a p o r a t i n g
was p a r t i t i o n e d
the foliage The
is
in
50
2 minutes
was r e f r i g e r a t e d
the residue
frozen
hexane.
for the foliage.
redissolved
The
thoroughly;
blended
and f i l t e r e d
0536).
the column,
and mixed
for analysis,
chromatography
acetonitrile
the laboratory.
was c l e a n e d
Analyzed
T
at
chopper
The f i l t r a t e
redissolving
it
a
chloride,
sulfate.
chloride,
as
and frozen
put through
were
205
Residue Methodology
E T A L .
to
100% b a s e d
on
recoveries.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
206
SYNTHETIC
PYRETHROIDS
WAVENUMSER (CM"') 0.00 J
ο
11
.20
Κv Λ if 1 Λι II >
rw
1
30 .40 .5 0 .60 .70 1.00
CO CD <
.I
5.0
4.0
3000
0.00
-\
ν
-L
2.5 3.0 Ο
Λ
6.0
7.0
8.0
10.0 12 0
14.0 16 0 18.0
6.0
7.0
8.0
Κ>.0 12.0 14.0 16.0 18.0
200
ο
.20 .3 0 40 .5 0 60 .7 0 1.00 2.5 3.0
4.0
5.0
WAVELENGTH Figure 5.
(MICRONS)
Infrared spectra of trichloroethyl derivatives
lOOi 80 60 >I-
40
LA
<7) 20 50 ω
lOOj
Ρ
80
PT'H
iT
100
1
'"1 I • 1
Π I I
1
ISO
1
1 • 1
1
2
40 20
100
1
150
1
1
200
1 ' 1 • 1
1
300
1 ' I Ί 350
/ - c i
νγν\, 1
1
1
ι 1' ι 1 1 1 1
1
250
1
1
300
m/β
Figure 6.
1
Cl Ρ
ι n " ' " f Γ'ΐ ι Ί • ι ' ι ' Ί 1 ι 1 • ι • ι 1 1 1
1
250
ο..
60
Κ
1
200
Mass spectra of Bioethanomethrin derivatives
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
1
Γ''Ί 1111 350
1
I I1 1
Ρ I'
1
GEORGE E T A L .
19.
We to
also
cabbage
(0.1 the
of
ml of
through
a
and f o l i a g e
samples
the extract
consisted
7.5
g
chloride
silica
FMC 3 3 2 9 7
methylene
chloride.
was d i s s o l v e d aluminum oxide through
1.5%
hexane
ether
gas
Residues II.
in
After
level.
the
leaves
first
found
samples
range
FMC
33297,
and
92.5% We
of
98.9%
were
at
taken
extraction,
168
to
2.0
methylene of
the
chromatographed
residues
had been
were
eluted
was e v a p o r a t e d ,
was d e t e r m i n e d was a l s o
test,
by
and 1 ml electron
analyzed
after
168
by the
168
to
about
h r , 3 days
Check
samples
showed
( i n the range
of
derivative,
and 89.7%
Check (in
ester
derivative
derivative. at
the rate of
Table
of
vine
112
g
and pod
The sampling,
a r e t h e same
ppm a n d d e c l i n e d period,
residues
for underivatized
and 7 days. in
No
in
30%
Recoveries
consisting
a r e shown
95%
the residue
treatment.
102.3%
peas
procedures
0.9
24-hr
green
Samples
the
hr.
hr after
ppm) a v e r a g e d
in
was n o
approximately
f o r the 3 methods.
lb/acre).
first
at
spraying,
a n d 70% w i t h i n
FMC 3 3 2 9 7
a r e shown there
t h e 3 methods
for the trichloroacetate
0 h r , 24
were
the eluate,
3 techniques
as
those
III.
used
I n i t i a l
approximately
30%
50% b y 7 2
h r , a n d 80%
after
no r e s i d u e s
for the 3
methods.
0.1
to
t h e u n d e r i v a t i z e d FMC 3 3 2 9 7 ,
ester
of
of
20 m l more
50 m l p e n t a n e
range
heads
The r e s u l t s
the
Recoveries for
30 m l
with
ppm a n d d e c l i n e d
period
and cleanup
cabbage.
hr.
with
eluted
for the trichloroethanol ester (0.1
during
was 1.4
0.04
applied
residues
prewashed
t h e sample
between
no r e s i d u e s
Ai/hectare
for
sample)
The eluate
by the
t h e cabbage
showed
the
for
Bioethanomethrin. chromatography
(10
t h e FMC 33297
Immediately
24-hr in
as
crop
the residue
determined
difference
in
AI/hectare
same
method.
significant
were
g
g
After
By D u n c a n ^ m u l t i p l e
outer
liquid
FMC 3 3 2 9 7
112
the
and l i q u i d
g).
pentane.
probability the
were
pentane
(20
chromatography,
dérivâtization Table
in
of
of
of
were with
evaporation
the column,
was a d d e d .
capture
a rate
treated
g e l column,
After
through with
concentrate
at
solution
residues
residue passed
f o r 4 weeks
207
Sampling and extraction
a methylene
chloride.
Methodology
an e m u l s i f i a b l e
a week
lb/acre).
Cleanup 40
applied
once
l e n t i l
Residue
1.0
84.6%
ppm) a v e r a g e d for the
101.8%
trichloroacetate
for the trichloroethanol
ester
derivative. Comparison thus
indicates
residues; Also,
when
the other a
faster
dérivâtization data
of that
than
either
by the dérivâtization
procedure
can be used
method
is
then
method
is
available,
technique
we o b t a i n e d
persistent
the results
indicate
available
can be used that
for
methods determine
corroboration.
f o r FMC 3 3 2 9 7 ,
for corroboration.
FMC 3 3 2 9 7
Bioethanomethrin
as
to
residues
are
the
The
more
residues.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
SQIOHHXaHAd
soz
OIXaHXNAS R E L A T I V E
I N T E N S I T Y
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
19.
Table
II.
FMC 3 3 2 9 7 4
spray
(0.1
209
Residue Methodology
GEORGE E T A L .
residues
on outer
applications
once
cabbage
a week
of
leaves 112
g
after Ai/hectare
lb/acre).
Residue
found
1/ (ppm)—
Interval between treatment
Trichloro-
and
acetate
sampling
No.
(hr)
of
Avg. 24
Avg. 168
FMC
Results
were
corrected
derivative
ester derivative
2.29
2.61
2.81
.95
1.17
.76
.92
.63
.52
1.34
1.41
1.38
1.25
1.01
16
.86
.99
25
.77
.23
55
1.38
.77
92
1.07
.75
.97
0.10
0.06
0.06
.32
.42
.32
.72
.80
.73
.38
.43
.37
Avg. U
33297
ethanol
ester
Underivatized
treatments
Trichloro-
to
100% b a s e d
on r e c o v e r i e s
found
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
210
SYNTHETIC
Table
III.
FMC 3 3 2 9 7
residues
application
of
on green
112
peas
g Ai/hectare
Residues
after (0.1
found
between
treatment sampling
and (hr)
FMC
33297
ester derivative
Trichloro ethanol ester derivative
0
0.98
0.60
24
.69
.55
.60
72
.59
.39
.28
on r e c o v e r i e s
found.
168 i /
acetate Underivatized
spray-
lb/acre).
(ppm)!/
Trichloro Interval
a
PYRETHROIDS
Results
0.96
.1 were
corrected
to
100% b a s e d
Abstract Analytical methodology was developed for determining residues of 2 synthetic pyrethroids, Bioethanomethrin® [(5benzyl-3-furyl)methyl trans-(+)-3-(cyclopentylidenemethyl)-2,2dimethylcyclopropanecarboxylate] and FMC 33297 [m-phenoxybenzyl cis,trans-(+)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane= carboxylate]. After saponification of a pyrethroid, trichloroacetyl chloride i s used to form an ester from the alcohol moiety, and trichloroethanol i s used to form an ester from the acid moiety. The derivatives were determined by electron capture gas chromatography. Infrared and mass spectral data support the expected structures of the derivatives formed. The use of the 2 derivatives enhances the reliability of the results. In addition, underivatized FMC 33297 was determined by electron capture gas chromatography. Equivalent residue data were obtained by the 3 analytical techniques. With these methods, residue data were determined for 2 pyrethroids (Bioethanomethrin and FMC 33297) on l e n t i l foliage, l e n t i l s , green peas, and cabbage. The data indicate that residues declined 70 to 100% within 7 days of treatment. Literature Cited 1.
George, D. Α . , and McDonough, L. M . , J. Assoc. Off. Anal. Chem. (1975) 58, 781-4.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
20 Gas Chromatographic Determination of Residues of the Synthetic Pyrethroid F M C 33297 R. A . SIMONAITIS and R. S. C A I L Stored-Product Insects Research and Development Laboratory, Agricultural Research Service, U.S. Department of Agriculture, Savannah, G a . 31403
FMC 33297 (m-phenoxybenzy vinyl)-2,2-dimethylcyclopropanecarboxylate), also known as NRDC 143, PP 5579 and permethrin, is a photostable synthetic pyrethroid with low mammalian toxicity which has been shown by Bry and Lang (l)to have promise as a protectant for woolen fabrics against insect damage. Davis et a l . (2) have found FMC 33297 to be promising against insect pests of growing cotton. Gillenwater and his coworkers at the Stored-Product Insects Research and Development Laboratory in Savannah, Georgia (private communication), have found FMC 33297 to be an effective protectant for stored grain commodities. The compound (structural formula shown in Figure l ) was synthesized by E l l i o t t et a l . (3) in their search for synthetic pyrethroids having low mammalian toxicity and more s t a b i l i t y than the natural pyrethroids that were nevertheless equally active against insects. Berkovitch (k) reported that FMC 33297 was 1.4 times as potent as resmethrin ((5-benzyl-3-furyl)methyl cis,trans-(±)-2,2-dimethyl-3-(2-methyl= propenyl)cyclopropanecarboxylate) to house f l i e s , Musca domestica L., and 3.2 times as effective to mustard beetles, Phaedon cochicariae Fab., and that i t had comparable mammalian t o x i c i t y . E l l i o t t et a l . (3), Berkovitch (4), and Bry et a l . (5.) reported that FMC 33297 was many times more stable when exposed to light than previously synthesized pyrethroids or natural pyrethrins. Preliminary experiments showed that FMC 33297 was effective against various insect pests of stored grains. Consequently, a This paper reports the results of research only. Mention of a pesticide in this paper does not constitute a recommendation for use by the U.S. Department of Agriculture nor does i t imply registration under FIFRA as amended. Mention of a commercial or proprietary product in this paper does not constitute an endorsement of this product by the U. S. Department of Agriculture. 1
211
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
212
SYNTHETIC
method
was
grains
such
needed as
cornmeal
and
duration
of
flour
a
procedure
for
of
determine and
so
highly
corn
we
protection
describes isomers
to
wheat
could
33297
on
of
the
commodity.
milled
of
and
on
products
application
gas-liquid
residues
33297
FMC
on m i l l e d
study
afforded
sensitive
determining
FMC
residues and
PYRETHROIDS
unmilled
such
rates This
paper
chromatographic
the
cis
unmilled
and
corn
as
and
the
(GLC) trans
and
wheat.
Method Apparatus (a)
Gas
Packard
19311); id
1
mv
300°C
with
(°C)
Q
electrometer 1.
Range
trans
Condition
conditions.—Hewlett injector,
these
isomers
of
10"
x
packed
digital
A
1 0
33297
f u l l
were
port 30,
scale
9.5
min
State
2k
300;
at
gas 2^0; l6,
attenuation
times
for
10.0
and
hr
temperature
air
at
retention
80-100
on
column
hydrogen
the
w/w
Inc.,
conditions:
injection
28,
conditions FMC
newly
300,
(carrier)
31
setting,
a
0V-225
phase
Laboratories,
Operating
detector
nitrogen
Under
liquid
Sciences
purging.
250,
oven
(ml/min)
5%
with
(Applied
nitrogen
column
flows
and
automatic
flam
l680l).
PA
with
with
recorde packed
Gas-Chrom
equipment
instrument
column
College,
and
5700A
equipped
glass
mesh
Reagents,
chromatographic
model
integrator,
and
the
cis
min,
respectively. (b)
Chromatographic
Chromaflex, t i p ,
50
ml
(c)
reservoir Alumina,
received
(Fisher
(d) grade flask
and
Dilute bracket
dilute
the
(e) sulfate
(Fisher
column
to of
percent
acetate
to
mixture
reach
L with
ca
ethyl 900 room
with of of
capillary
08360).
NJ
80-200 m e s h ; u s e a s 15235). 33297, a n a l y t i c a l
into
Primary
100
ml
volumetric
Secondary
standards.—
hexane
obtain
to
secondary
(20-25
samples
grade);
standards ethyl
and
should
ug/ml). acetate,
anhydrous
sodium
Co.). and
alumina
liquid
chromatographic
solvent
mixture
before
anhydrous
acetate
ml
hexane.
pesticide
solvents with
g
cleanup:
PA
solvents.—Acetonitrile,
(all
mixture.—For
shaking
I
lkl05).
NY
0.1±0.001
concentration
Scientific
a l l
Activity
standard
mm b o r e
Vineland,
standards.—FMC
with
column
2
cm χ
Pittsburgh,
Concentration
and
pentane
Eluant
by
volume
alumina 8
Co.,
Middleport,
primary
Reagents and
(f )
Co.,
pesticide
expected
cleanup.—Dry
Glass
Aoid.—Brockman
standards.
hexane,
1
(Kontes
mm w i t h
yg/ml).—Weigh
aliquots
secondary
13
Scientific
Analytical (lOOO
column.—For
cm χ
(FMC C o r p o r a t i o n ,
standard
Three
23
plain,
pentane
in in
temperature,
sodium
pentane 1
sulfate (v/v):
L volumetric
and
adjust
to
(ca Add
25 30
flask, f i n a l
adding
to
g/L). ml
ethyl
mix,
volume
pentane.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
let of
20.
Preparation consistency mixed tions
31^03)
Solvent
50
mixture
10
funnel
acetonitrile
phase
in
phases
in
funnel
with
rinses
t o second
stopper,
m l mark
second 50
t o second
separatory separatory 1 min;
of
by shaking
beaker from
column
dried with
solvent
Elute
column in
125
with
75
o n 60°C w a t e r
residue
in
hexane flask
concentration
sodium
bath
under
t o 25
ml Erlenmeyer
t o dryness
g
which
under d r y
has been at -5°C
andhold
chromatographic
alumina.
c a 10
in
which sample
F i l l
column
pentane
and collect
eluate
just
a 2 ml v i a l
to
Dissolve
centrifuge
to give
a n d wash
washings.
of dry a i r .
volume
250 m l
Transfer
Concentrate
stream
Tap sides
Place
m l pentane
sulfate.
to a calibrated
yg/ml.
phases, Add lower
containing the
250
Prepare
acetate
of the appropriate
o f 20
flask
D i s c a r d pentane
flask.
andtransfer
Transfer
t o chromatographic
m l 3% e t h y l
ml Erlenmeyer
pentane
separatory
o f adsorbent.
ml drypentane.
dryness
volumetric
packing
cleanup
second
pentane
sulfate,
a n d 11
plug
anhydrous
the
cleanup.
a n dwet column w i t h
partition
c a 15
with
even
pentanelower
Combine
ml pentane,
sodium
ml
Reextract
separate.
just
flask
m l mark.
Transfer
the
first
Place
Cleanup.
wool
from
flask.
With
in
an additional
acetonitrile.
10
column
with
containing
layer.
anhydrous
glass
t o produce
sides eluate
with
phase
l e t layers
in
A d d 100
funnel
and evaporate
residue
a 25
funnel.
ml Erlenmeyer
Chromatographic
under
been
bath
chromatographic
containing
column
has
water
sample
1 min.
Rinse
funnel
t o 250
Dissolve
Liquid
separatory
then
of dry a i r .
pentane.
and shake
ml pentane-saturated
D i s c a r d pentane
column
with
funnel.
phase
liquid
F o r each
funnels.
calibrated with
ml Erlenmeyer
(acetonitrile)
stream.
with
f o r 1 min.
a stream
acetonitrile
250
into
and shake
o n 100°C
acetonitrile
ml separatory
separatory
acetonitrile.
for
2V
point
ready f o r
the concentrated
stopper,
Drain
funnel
under
has been
t h e second
ml o f pentane.
separatory
bath
that
acetonitrile,
(acetonitrile)
Saturate o f solvents
transfer
t o t h e 25
volume
saturated
dried
Whatman
ml Erlenmeye
quantitatively
separatory
air
Stored-
o
m l o n 60°C w a t e r
pentane,
flask
seal, and
Savannah,
At this
at -5°C u n t i l
s e t u p t w o 250
ml aliquot
t o 125
commodity
25
3:1
t o be analyzed,
Dilute
through
fine
specifica-
Laboratory,
extract
freezer
P a r t i t i o n Cleanup.
by shaking
Transfer
to
in
(tumbler
and stopper.
to
thoroughly
of Agriculture,
a n dDevelopment F i l t e r
g
ml pentane,
rev/min
Department
grain
analysis.
pentane
about
j a r , a d d kOO
1 pt bottle,
into
canbe stored
further
sample
U.S.
Research
or equivalent.
paper
extracts
q t mason
Grind
200±0.1
Transfer
f o r 3 h r a t 10
from
Insects
213
andExtraction.
homogenizer.
to 1
available
f i l t e r
o f Sample
food
by tumbling
Product GA
in
commodity
extract
Residue Determinations
AND CAIL
siMONAiTis
tube
or
the desired 2/3
f u l l
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
with
SYNTHETIC
PYRETHROIDS
Figure 1. Structural formula of FMC 33297: C H Cl O ; 391.31 g/mol; LD ; CA 2000 (approximately 20% cis, 80% trans isomers) 2î
20
2
3
50
PERCENT O
CORN
* 10
H
M
1
20
H
' 30
M
' 40
H
50
H
^
4 H
70
* 80 ' 90
'
100
CORNMEAL WHEAT FLOUR Figure 2. Effectiveness of solvent partition cleanup. Average % nonvolatile material removed by solvent partition from 25 g of commodity extract.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
s i M O N A i T i s A N D CAIL
20.
an
aliquot
septum
of
cap.
the
Gas
in
Adjust 3
inject
until
integrator
Place
vials
and
aliquots
counts
sample
as
the
v i a l
-5°C
at
Analysis.
equipment
μΐ
Average
33297
cap
freezer
215
with
until
Bring
GLC o p e r a t i n g
containing
contain
sampler. FMC
and
Determinations
an
aluminum
ready
for
gas
analysis.
chromatographic
sampler,
that
a
Chromatographic
temperature. Gas
sample
Store
chromatographic
Residue
of
of
two
consecutive
solutions.
solutions as
conditions. analytical
analytical
integrator
a l l
conditions
standard
Inject
counts
With
room under
automatic
standard
solution
injections
vary
<10%.
before
after
vials
each
and
to
described
and
twice
with
calculate
automatic
percentage
follows: W
C
% FMC 33297 = — x — x D χ 100 where
^s
=
unknown;
weight
£s
=
per
average
integrator
Results
and
The
cent
average
of
standard;
integrator
counts
for
unknown;
cleanup
procedure
described
p a r t i t i o n i n g between
followed
by
liquid
column.
With
of
cornmeal,
a
the
l . l U , 0.11,
0.77j
quantities
of by
discerned
after
33297
FMC
for
reagent
the
The plotting of
FMC
The 3
blank
yl
could
with
no
the
of
of
£u
=
factor.
be
a
the
and
Figure source
the
The
0.2
B,
acid
a
alumina g
sample
residues
2
of
shows
extracts
the
of
residue
each
was
cleanup.
(il)
for
an
cleanup.
trans in
run to
FMC
33297
The
reten
isomers The
the
peaks
determine
retention
of
solvents
interference.
had
25
a
respectively.
k was
detector
injected. the
linear
from
impurities for
an
Figure
obtained and
a
used.
whether
Although time
peaks
which
would
analysis. of
counts
of
on
nonvolatile
cis
utilizes
acetonitrile
nonvolatile
removed
after
the
integrator
Untreated with
in
paper
and
described,
had
No
and
impurity peak
linearity
injection
t i f i e d
(i)
elution
shown
this
chromatographic
from
be
percent
dilution
cleanup
chromatograms
A
33297
to
gas
C originated
response
found
liquid
i n d i c a t e d by
observed,
interfere
residues
by
reagents
were
weight
standards;
respectively.
partition.
before
the
g,
are
identified A
the
in
procedure
and wheat
0.26
and
shows
solution
times
flour,
solvent
3
Figure tion
D =
pentane
chromatographic
extraction
nonvolatile
commodity
standard
for
Discussion
liquid-liquid
corn,
=
counts
flame over
response
obtained
volume
injected
ionization
the
range
was
versus was
detector
examined
determined the
to
from
kept
constant.
33297
FMC 15
by
concentration
to
U85
was ng
per
volume. corn, to
cornmeal,
22.0
ppm o f
flour, FMC
and wheat
33297
were
and
samples
extracted
and
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
for
SYNTHETIC
Γ~ 15
τ
—r10
PYRETHROIDS
Ί5—I—Γ
TIME (MIN) Figure 3. Gas-liquid chromât ο grams of FMC 33297 stand ard solution (35 ^g/ml) before (I) and after (11) cleanup: A , trans isomer peak; B, cis isomer peak; C , unknown reagent impurity peak
30
25
20
15
! 10
TIME (MIN)
Figure 4. Gas-liquid chromatogram of FMC 33297 reagent blank: A , retention time for trans isomer peak; B, retention time for cis isomer peak; C , impurity peaks introduced by reagents used for cleanup
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
87.5
93.2
0.73
l.k
U.l
10.8
20.5
0.80
1.6
k.k
11.0
22.0
93.2
98.2
91.2
100
0Λ0
Q.kO
recovery
%
105
<0.2
ppm
Found
recoveries
Corn
Average
0.21
I.
0.20
0.0
ppm
Added
Table
ppm
Found
20.3
10.3
k.5
1.5
0.76
0.37
0.19
%
from
92.3
93.6
102.3
93.8
95.0
92.5
95.0
recovery
Cornmeal
KMC 33297
<0.2
of
20.2
10.5
U.l
1.5
0.75
0.37
0.18
<0.2
ppm
Found
fortified
%
91.8
95.5
93.2
93.8
93.8
92.5
90.0
20.h
10.0
k.O
l.k
0.73
0.35
0.19
<0.2
ppm
Found
commodities.
recovery
Flour
food
%
92.7
90.9
90.9
87.5
91.2
87.5
95.0
recovery
Wheat
-α
to h-1
es Ο es
I
Ci CO
ίο
>
>
CO
1
CO
218
SYNTHETIC
CORN
-π
30
CORN
"So
UNTREATED
1
1
26
20
04
PPM
25
20
ι
«
ι
10
>
I
6
0
ι
30
«
10 (MIN)
6
0
30
1
26
CORN
miE Figure 5.
PYRETHROIDS
10.2
26
1
20
1
16
1
10
1
6
J~ 0
PPM
20
15
S
6
0~
TIME (MIN)
Gas-liquid chromatograms of corn commodity extracts unfortified and for tified with FMC 33297: A , trans isomer peak; B, cis isomer peak
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
20.
SIMONAITIS
AND
CAIL
Residue Determinations
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
219
220
SYNTHETIC
PYRETHROIDS
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
20.
s i M O N A i n s AND C A i L
WHEAT
Figure 8.
(MIN)
221
Determinations
WHEAT 0.2
UNTREATED
TIME
Residue
PPM
TIME
(MIN)
Gas-liquid chromatograms of wheat commodity extracts unfortified and fortified with FMC 33297: A , trans isomer peak; B, cis isomer peak
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
222
SYNTHETIC
analyzed, for 92
as
shown
separate 103$
to
by
results
determinations
for
90
cornmeal,
reported
ranged 95$
to
in
for
Table
88
I.
to
105$
flour,
and
from
PYRETHROIDS
Recoveries for 88
corn, 95$
to
for
wheat. Chromâtograms without peaks
were
levels FMC
33297
f a i r l y
well
ppm.
the
0.2
i t
that
To
peak
noise
resolved
even
for
was
possible of
of
use the
the
fortified were
to
concentration
isomer 0.05
of
to
of
at
the
level
ppm b a s e d
of
greater
method be
the
studied.
obtain
could
and isomer
concentration
quantization
heights
sensitivity trans
The
observed
commodities
the
with
5-8.
at the
peak
commodities
Figures
peaks
limited
to
calculate height
any
the in
used on
i t
was
to
give
twice
level.
Statistical commodity results
of
reported
interference
times
a minimum d e t e c t a b l e the
extracts
been
integrator was
sensitivity. found
No
retention
Although ppm,
the
have
10
of
of
33297
FMC
analysi
fortified
are
Table
II.
0.5,
at
reported
in
Standard for
a
tions
level
and
on
each
U.7
ppm was
performed.
The
II.
deviations
series
treatment
Fortification
1.2,
Table
of
of
five
a
single
determination
independent
commodity
determina-
fortified
at
three
levels.
Standard Corn
deviation
Cornmeal
for
commodity
Flour
Wheat
(Ppm)
ο.βο
0.030
0.019
0.020
0.029
1.2
0.092
0.020
0.031
0.018
h.l
0.070
0.06l
0.0^9
0.1U
Abstract A simple and rapid gas-liquid chromatographic (GLC) method was developed for the determination of residues of the i n s e c t i cide FMC 33297 (m-phenoxybenzyl cis,trans-(±)-3-(2,2-dichloro= vinyl)-2,2-dimethylcyclopropanecarboxylate), also known as NRDC 143, PP 557, and permethrin, in corn, cornmeal, flour, and wheat. The commodity was extracted with pentane and cleaned up by a solvent partition followed by l i q u i d chromatography. The FMC 33297 residue was determined by GLC with a flame ionization detector. The results were compared with known standards that had undergone the same cleanup procedures. With electronic
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
20. SIMONAITIS AND
CAIL
Residue Determinations
223
integration, the method was quantitative to concentrations of FMC 33297 to 0.2 ppm; with peak height measurement of the trans isomer peak, the method was sensitive to 0.05 ppm. Recoveries at levels of 0.20 to 22 ppm ranged from 88 to 105%. Reproduci bility was good. The standard deviation for five determinations at levels of 0.60 to 4.7 ppm was 0.018 to 0.14% absolute for the four commodities. Literature Cited 1.
Bry, R. Ε . , & Lang, J. H. J. Ga. Entomol. Soc. (1976) 1 1 ,
2.
Davis, J. W., Harding, J. Α . , & Wolfenbarger, D. A. J. Econ. Entomol. (1975) 6 8 , 373-374. Elliott, M . , Farnham, A. W., Janes, N. F., Needham, P. H . , Pulman, D. A., & Stevenson 169-170. Berkovitch, I. Int. Pest Control (1974) l 6 . 20. Bry, R. E., Simonaitis, R. Α . , Lang, J. H . , & Boatright, R. E . Soap/Cosmetics/Chem. Spec. (1976) 52, 31-33, 98.
3. 4. 5.
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
INDEX
Acetonitrile 212 Acid moieties, syntheses of 49 Activities for kill 10, 64, 68 Agricultural crop pests 17 Air, pyrethroid instability in light and 147 Alanine 199 Alkenyl cyclopropanecarboxylates, activity of 9 Allethrin 4,17, 64, 81, 88 Allethrolone 7 Allethronyl esters 38 Allylic alcohol 133 Allylic bromination 128 Anopheles stephensi 18 Antidromic nerve impulse 102 Application of pyrethroids 201 Axons 102
Β
14
liquid 207 thin layer 151,188 Chrysanthemate ( s ) 137 cycloalkylmethyl 64 dihalovinyl analogues of 128 homologs of 134 mixture 99 of simple alcohols 165 Chrysanthemic acid 55 C-methylene (alcohol) permethrin 147 Cockroach 83,86,100 nymphs of the American 72 C o evolution 149,158 Condensation of ammonium 47 Conformations of pyrethroids, preferred 29 Corn 215 Cornmeal 215 Cotton insects pests of 211 leafworm, activity on 43 plants 191 α-Cyano alcohol(s) 55 esters of 13,167 α-Cyano group 19,25,143 Cyanohydrin(s) 19,143 ester of the [S]14 irans-Cyanophenothrin, poisoning by 169 6-Cyano-3-phenoxybenzyl esters, 2-, and 15 Cycloalkane methanols, pyrethroidlike esters of 62 Cyclobutanone 38 Cyclopropanecarboxylates .3,128,164,175 Cyclopropanecarboxylic acids 45,173 Cyclopropane ring 37 photoisomerization of 137 Cypermethrin 18,19,45 Cultures, permethrin degradation in soil and microbial 147 14
Bathrin 99,106, 111 Bean 191 Benzaldehyde 143 Benzoic acid 143,190 Benzyl alcohol 143 Benzyl furan moiety 69 5-Benzyl-3-furylmethyl alcohol 45 5-Benzyl-3-furylmethyl esters .13, 163, 166 5-Benzyl-3-furylmethyl group 139 Binding probability 34 S-Bioallethrin 6 Biodégradation 72,174 Bioethanomethrin 203 on lentil foliage, residues of 205 Biopermethrin 6, 96 Bioresmethrin 6,10,96 Bromination of 3-phenoxyltoluene .... 47 Bromobenzene 196 N-Bromosuccinimide 128,133 trans-Butenyl chrysanthemates, potency of the 64
Cabbage leaves Carbamates Carbene reaction Carbofuran carbamate insecticide Carbon dioxide Carbon tetrahalide
Caronaldehyde 128 Cattle ticks, activity on 43 C-carbonyl (acid) permethrin 147 Chiral alcohols, potencies of esters of 14 Chiral receptor 8 Chirality 37 p-Chlorophenyl-a-isopropyl acetates (S-5439 and S-5602) 175,181,184 Cholinesterase 17, 85 Chromatography
205 1, 85 49 106 100 141 128
1 4
2
225
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
226
SYNTHETIC
D DDT 43, 85, 98,100,103 shortcomings of 201 Decamethrin 3,18,29 and a stereoisomer, C spectra of .. 33 Degradation of permethrin, soil microorganisms in 147,158 Dehalogenation of dihalovinyl substituents, reductive 141 1.1- Dichloro-4-methy 1-1,3- and 1,4pentadiene 119-127 cost of 118 preparation of 49 Dichlorovinyl acid 191 metabolites from permethrin 198 3- ( 2,2-Dichlorovinyl ) -2,2-dimethylcyclopropanecarboxylic acid 151 3- ( 2,2-Dichlorovinyloxy )benzalde hyde cyanohydrin 5 3- ( 2,2-Dichlorovinyloxy ) benzyl fragment 55 Dieldrin 103 Difluorovinyl ester 10 Dihalovinyl crystalline, cis35 cyclopropanecarboxylates 131 groups 164 substituents, reductive dehalogena tion of 141 Dihydroxypermethrin 197 Dimethrin 138 2.2- Dimethyl-3- ( 2,2-dichlorovinyl ) cyclopropanecarboxylic acid (DV-acid), preparation of 49 gem-Dimethyl group 37,164,173,188 hydroxylation of 176 with permethrin 181 oxidation at the 189 4,4-Dimethyl-5-hexen-2-one 50 Dose-response curves 88 Dreiding molecular models 29 1 3
Electrochemical reactions 121,127 Electrolysis 123 Enzymes in pyrethroid metabolism, microsomal 162 Epimerization, photochemical isomerization and 173 ES-56 74,81 Esterase(s) -amidase activity 158 in pyrethroid hydrolysis 163 specificity with permethrin isomers 176 Ester(s) allethronyl 38 5-benzyl-3-furylmethyl 166
PYRETHROIDS
Esters (Continued) chrysanthemic acid 45 α-cyano-substituted 167 hydrolysis 189 isobutenyl 164 metabolites 171 propargylfurylmethyl 167 pyrethronyl 38 trichloroacetate 203 trichloroethanol 210 γ,δ-unsaturated 133 Esterification 45 of spirodihalovinyl acids 43 frans-Ethanoresmethrin, poisoning by 169 Ethyl acetate 4,212 Ethyl diazoacetate 38, 49,118,128
Fenvalerate 19,45 Flour 215 F M C 11523 69 F M C 16824 69 F M C 33297 ( ra-phenoxybenzyl-cis, trans- ( + ) -3- ( 2,2-dichlorovinyl ) 2,2-dimethylcyclopropanecarboxylate) 211 percentage calculation 215 residues 207 Fulvic acid 149,151 Fumigation 81 Furamethrin 165 Fusarium oxysporum 158 G
Gas Chromatography 211 Geminal dimethyl groups .37,164,173,188 Gibbs' rotational matrix method 30 β-Glucosidase 191 Glucuronides 188 Glutamic acid 190,198-199 Glutamic dehydrogenase 86 Glycine 190,198,199 H Halocyclobutanones, ring contraction of a38 Hexane 151,205,212 Housefly ( ies ) 64, 74, 81,100,211 activity on 43 female 71,88 nervous system, action of pyrethroids on the 98 Humic acid 149 Humin 149,151
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
227
INDEX Hydroxylation of gem-dimethyl group Hydroxylation of isobutenylmethyl groups Hyperactivity
176 174 106
I Inclusion complexes 137 Indanones 72 1-Indanyl chrysanthemate 74 Insect pests of cotton 211 Insecticidal activities 35, 71 of cyclopropanecarboxylates 7 neuro 102 requirements for 165 toxic 85 of wood treated with pyrethroids .. 83 Insecticidal deposits on ivy leaves .... 22 Isobutenyl esters 16 Isobutenylmethyl groups, hydroxylation of 174 Isomerization and epimerization, photochemical 173 Isomerization of permethrin, trans-cis 191 α-Isopropylphenylacetates 11 Isopropyl-4-substituted phenylacetic acid 55 Isovanillin 196
Κ Kadethrin Ketene-olefin cycloadditions Knockdown agents effect on vapor action of pyrethroids rapidity of
10 38 98,111 3 81 10
L Lactone(s) 176,195 formation 50 LD values 3 Lentils 203 foliage, residues of bioethano methrin on 205 Lethal action 8,17 Lethal doses, median 21 Light and air, pyrethroid instability in 147 Lindane 103 Lipophilic insecticide, most powerful 19 Liquid chromatography 207 5 0
M Mammalian toxicity 72,186, Mass spectra of permethrins Metabolic pathway in mammals for permethrin (rats) Metabolism rates of pyrethroid enantiomers
211 177 147 190 175
Metabolites from acid moiety of permethrin .190-192 from permethrin, dichlorovinyl 198 synthesis of permethrin 194 Methane, C moeity 151 Methrin 99,111 poisoning 108 Methylene chloride 201 α-Methylene group, substituents at .... 13 Methyl substituents on acid compo nents of various esters, influence of 9 Microbial activity, soil 147 Microbial inhibitor in soils, sodium azide as a 147 Microencapsulation 137 Microorganisms in degradation of permethrin, soil 158 1 4
Microsomal oxidases, mouse Microsomes, mouse Microsomes, rat Mist spraying test Molecular configuration of the side chain at cyclopropane C-3 in the acid moiety Monohydroxypermethrin Mouse intraperitoneal toxicity and synergism of pyrethroids liver microsomal enzymes liver microsomes microsomal oxidases Mustard beetles
184 179 179 81
163 197
170 163 174 184 211
Ν NADPH 176 Nerve cord, crayfish 88 impulse discharge frequency 96 poison, central 106 poison, peripheral 106 preparations 86 Nervous conduction 86 Nervous system action of pyrethroids on the housefly 98 central 98 peripheral 98 potency of pyrethroids on the central 108 Neurotoxicities 86 Neurotoxin, peripheral 98 Nitrogen 212 atmosphere of 151 N R D C 143 56,119,211 irans-NRDC 149, poisoning by 169 N R D C 161 56,137,139-141
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
228
SYNTHETIC
Ο Olefin, cyclopropanation of an 38 p-7r-Orbital overlap 31 Organochlorines 1 Organophosphates 1, 85,103 K-Othrin 6,103, 111 poisoning 108 Oxidation at the gem-dimethyl group 189
Parathion 85 Paraxon 85,163 Peas, green 207 cis-Pentadienyl side chain 19 Pentane 212 4-Pentenoates, preparation of 129 Periplaneta americana 9 Permethrin ( m-phenoxybenzyl trans- ( + ) -3- ( 2,2-dichlorovinyl ) 2,2-dimethylcyclopropanecarboxylate) 18,45,74,131,137,141 147,166,171,175,190 acid moiety of 116,128 biodégradation 186 in soil and microbial cultures 147 cis/trans ratio of 158 C metabolites in rats and cows .... 187 dichlorovinyl acid metabolites 198 isomers, esterase specificity 176 mass spectra of 177 metabolic pathway of in rats 190 metabolism 186 metabolites from acid moiety of 190-192 metabolites, synthesis of 194 photoisomerization 138 poisoning by 169 preparations 186 in rats, metabolic pathway of 190 soil microorganisms in degradation of 158 trans-cis isomerization 191 Pest management 1 Phenothrin 18,19,45, 56,62,165 Phenoxybenzoic acid 154,191,198 hydroxy derivatives of 3195 3-Phenoxybenzyl alcohol 154,191 hydroxy derivatives of 3195 esters 163 group 45,55 triethylammonium bromide 47 Phenoxylphenyl moiety 69 Phenylacetic acid 143 Phenylcyclopropane 12 Photochemical isomerization and epimerization 173 1 4
PYRETHROIDS
Photochemical reactions of pyrethroid insecticides 137 Photodecarboxylation 141 Photodecomposition products 143 Photolysis of the ester bond of resmethrin 142 Photooxidation 140 Photostability 17,119 Phthalthrin 81 Picrotoxin 103 Piperonyl alcohol 4 Planar conformation in determining activity 31 Plants, cotton 191 Potassium ί-butoxide 133 Potency of analogs of pyrethroids 92 Potency of isomers of pyrethroids 92 Propargylfurylmethyl esters 167
preferred angles in 32 Pyrethrin II 3 Pyrethroids 1 acidic components of 12 action of on the housefly nervous system 98 application 201 biodegradability, substrate specificity in 167 conformations 7 developments of the basic structure 6 esters, insecticidally active synthetic 55 hydrolysis, esterases in 163 insecticides 37,173 activities of synthetic 72 activity of wood treated with 83 photochemical reactions of 137 potency of 162 instability in light and air 147 knockdown effect on vapor action of 81 mammalian toxicity of 119 metabolism, microsomal enzymes in 162 metabolism, stereochemistry in 173 mouse intraperitoneal toxicity and synergism of 170 nerve action of synthetic 92 oxidation of funtcional groups in .... 139 oxidizing enzymes 165 photostable 18 potency of 53 on the central nervous system . . . 108 preferred conformations of 29 preparation of reversed ester 65, 67 structure-activity of 3 residue methodology of 201 residues, determination of 211 synthesis of the acid moiety of 128 toxicity of I l l , 169 Pyrethronyl esters 38
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
INDEX
229
Pyrethrum Pyrolysis of allethrin Pyrrolidine
98,201 72 132
R Rats, intravenous toxicities to female 20 Redox catalyst, C u C l in ethanolamine 50 Residue of Bioethanomethrin on lentil foliage 203 Residue methodology of pyrethroids 201 Resmethrin 18, 19, 62, 74, 81, 139, 163,165,171,173,175,176,184 photolysis of the ester bond of 142 Reversed esters, preparation of 67 Rotational barriers 34 Rotation graphs 31 Rotenoids 86 2
Substrate specificity in pyrethroid biodegradability Sucrose gas technique Sulfoxidation Superfiltrol (acid clay) Synergism of pyrethroids, mouse intraperitoneal toxicity and
167 86 166 117 170
2
S
S-5439 173 S-5602 56,137,140,143,173 Saponification 139 Serine 199 Sodium azide as a microbial inhibitor in soils 147 Soil microbial activity 147 and microbial cultures, permethrin degradation in 147 microorganisms in degradation of permethrin 158 permethrin degradation in aerobic 147 permethrin degradation in anaerobic 151 sodium azide as a microbial inhibitor in 147 Spiroalkane cyclopropanecarboxylic acids 37 Stereochemistry in pyrethroid metabolism 173 Steric hindrance 35 Structure-activity of pyrethroids 3 Structure of pyrethroids, develop ments of the basic 6
Τ Termite (Coptotermes formosanus) .. 75 Tetraethylpyrophosphate 163 Tetrahydronaphthalene 12 Tetramethrin 69,99,108, 111, 138,165 poisoning 106 Tetra-substituted cyclopropane carboxylic acids 37 Thermal isomerization of pyrethin I.. 15 Thin layer chromatography 151 Toad (Xenopus leavis), clawed Toxicity (ies) to female rats, intravenous on insects mammalian of pyrethrins and synergism of pyrethroids, mouse intraperitoneal synergist-dependent to Tsetse flies, residual Trichloroacetate ester Trichloroethanol ester Tsetse flies, residual toxicity
98 20 2, 72, 99 7, 17 162 170 169 22 203 210 22
U γ-Unsaturated carboxylate γ,δ-Unsaturated esters
128 133
V Vitride
196 W
Wheat Wood treated with pyrethroids, insecticidal activity of
In Synthetic Pyrethroids; Elliott, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.
215 83
