Synthetic pyrethroids

Synthetic Pyrethroids Michael Elliott, EDITOR Rothamsted Experimental Station A symposium sponsored by the Division of ...

Author: Michael Elliott

119 downloads 1120 Views 4MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!
Report copyright / DMCA form

DOWNLOAD PDF

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

Copyright ©

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


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


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.


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


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


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



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

xi


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

) 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 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


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_) .


1.

ELLIOTT

Synthetic

7

Pyrethroids

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


8


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,


1.

ELLIOTT

Synthetic Pyrethroids

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


10


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).


1.

ELLIOTT

Synthetic

11

Pyrethroids

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



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).


1.

ELLIOTT

Synthetic

Figure 10.

13

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


14


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


1.

ELLIOTT

15

Synthetic

Pyrethroids

Figure 13.

,£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,


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


20


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 -


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


22


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


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.

11. 12.

13. 14.

Cited

Graham-Bryce Graham-Bryce, I.J., P r o c . Roy. Soc.(1977) i n the press. H u f f a k e r , C . B . and Croft, B.A., E n v i r o n . H e a l t h Perspec. (1976) 14, 167. M e t c a l f , R.L. and Luckman, W . H . , ( e d i t o r s ) "Introd u c t i o n t o I n s e c t P e s t Management" W i l e y - I n t e r s c i e n c e , New York and L o n d o n , 1975. S i d d a l l , J. E n v i r o n . H e a l t h P e r s p e c . ( 1 9 7 6 ) 14, 119. W r i g h t , J.E. E n v i r o n . H e a l t h P e r s p e c . (1976) 14, 127. C a r d é , R.T. E n v i r o n . H e a l t h P e r s p e c . (1976) 14, 133. K n i p l i n g , E.F. E n v i r o n . H e a l t h P e r s p e c . (1976) 14, 145. K u h r , R.J. and Dorough, H . W . , "Carbamate Insecticides: C h e m i s t r y , B i o c h e m i s t r y and T o x i c o l o g y " CRC P r e s s , C l e v e l a n d , O h i o , 1976. E t o , Μ . , "Organophosphorus P e s t i c i d e s : O r g a n i c and Biological Chemistry" CRC P r e s s , C l e v e l a n d , O h i o , 1974. B r o o k s , G.T., " C h l o r i n a t e d I n s e c t i c i d e s " CRC P r e s s , C l e v e l a n d , O h i o , 1973. M e t c a l f , R.L. "Organic Insecticides, Their C h e m i s t r y and Mode o f A c t i o n " , I n t e r s c i e n c e , New Y o r k , 1955. G n a d i n g e r , C . B . "Pyrethrum Flowers" M c L a u g h l i n Gormley K i n g Co., M i n n e a p o l i s , M i n n e s o t a , 1936. G n a d i n g e r , C . B . "Pyrethrum Flowers" Supplement t o Second Edition, (1936-1945). McLaughlin Gormley K i n g Co., M i n n e a p o l i s , M i n n e s o t a , 1945.


24

15.

16. 17.

18. 19.

20. 21.

22. 23. 24. 25.

26.

27. 28.

29. 30. 31. 32. 33. 34. 35. 36.


N e l s o n , R.H. "Pyrethrum Flowers" T h i r d Edition (1945-1972) M c L a u g h l i n Gormley K i n g Co., Minnea polis, M i n n e s o t a , 1975. C a s i d a , J.E. "Pyrethrum, t h e N a t u r a l I n s e c t i c i d e " Academic P r e s s , New Y o r k , 1973. M a t s u i , M. and Yamamoto, I.,in " N a t u r a l l y O c c u r r i n g I n s e c t i c i d e s " , ( J a c o b s o n , M. and C r o s b y , D.G., E d s . ) M a r c e l Dekker, Inc., New York 1971. Crombie, L. and Elliott, M. Fortschritte der Chemie O r g a n i s c h e r N a t u r s t o f f e (1961), 19, 120. Elliott, M. and J a n e s , N.F., i n "Pyrethrum, t h e N a t u r a l I n s e c t i c i d e " (J.E. C a s i d a , Ed.), Chap. 4. 55. Academic P r e s s , New Y o r k , 1975. B r i g g s , G.G., Elliott, M., Farnham A . W and J a n e s , N.F. P e s t i Briggs, G.G., ham, P.H., Pulman, D.A. and Young, S . R . Pestic. Sci. (1976) 7, 236. O ' B r i e n , R.D. " I n s e c t i c i d e s : A c t i o n and Metabo l i s m " Academic P r e s s , New York and London, 1967. C o r b e t t , J.R. "The B i o c h e m i c a l Mode o f A c t i o n o f P e s t i c i d e s " Academic P r e s s , London, 1974. K r u e g e r , H . R . and C a s i d a , J.E. J. E c o n . E n t . (1957) 50, 356. M e t c a l f , R.L. and M c K e l v e y , J.J. Jr. "The F u t u r e 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 " John W i l e y and Sons, Inc., New Y o r k , 1976. Elliott, M. in "The F u t u r e 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 " ( M e t c a l f , R.L. and M c K e l v e y , J.J.Jr., Eds), 163, John W i l e y and S o n s , Inc., New Y o r k , 1976. Farnham, A . W . Pestic. Sci. (1973) 4, 513. S a w i c k i , R.M., Elliott, M., Gower, J.C., S n a r e y , M. and T h a i n , R.M. J. Sci. Food Agric. (1962) 13, 172. S a w i c k i , R.M. and Elliott, M. J. Sci. Food Agric. (1965) 16, 85. Elliott, Μ . , Farnham, A . W . , J a n e s , N.F., Needham, P.H. and Pulman, D.A., Nature (1974) 248, 710. Elliott, M . Bull. W l d . 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. ACS Symp. S e r . (1974) 2, 80 Elliott, Μ . , J a n e s , N.F. and Pulman, D.A. , J.C.S. P e r k i n 1, (1974) 246. 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 (1975) 1230. S t a u d i n g e r , H . and R u z i c k a , L., H e l v . Chem. A c t a , (1924), 7, 177. Yamamoto,R., J.Tokyo Chem.Soc. (1919), 40, 126.


1. ELLIOTT

37. 38. 39. 40.

41.

42. 43. 44.

45.

46.

47. 48. 49. 50.

51. 52. 53. 54. 55. 56.

57. 58. 59. 60.

Synthetic

Pyrethroids

Yamamoto, R. J. C h e m . S o c . J a p a n . ( 1 9 2 3 ) , 44, 311. Yamamoto, R. and Sumi, M. J. C h e m . S o c . J a p a n , (1923), 44, 1080. S c h e c h t e r , M.S., G r e e n , N . and L a F o r g e , F.B., J. Amer.Chem.Soc. (1949) 71, 3165. R o a r k , R . C . "A D i g e s t o f I n f o r m a t i o n on Allethrin", U . S . Dept. Agric. B u r . Entomology and P l a n t Q u a r a n t i n e , Agric. R e s . Admin. Ε 846 S e p t . 1952. R o a r k , R . C . and N e l s o n , R . H . "A Second D i g e s t o f I n f o r m a t i o n on Alletrhin and R e l a t e d Compounds." U . S . Dept. Agric, Agric. Res. S e r v i c e , ARS-3312, 1955. Elliott, M., J. Sci. Food Agric.(1954) 5, 505. Synerholm, M.E., U . S P a t e n t 2,458,656 (1949) Fujimoto, Κ . and Yamaguchi, T., Agric. (1973) , 2681. Ohno, Ν., F u j i m o t o , Κ . , Okuno, Y., M i z u t a n i , T., H i r a n o , Μ . , I t a y a , Ν., Honda, T . and Y o s h i o k a , H . Agric. Biol. Chem. (1974) 38, 881. Ohno, Ν., F u j i m o t o , Κ . , Okuno, Υ., M i z u t a n i , T., H i r a n o , Μ . , I t a y a , Ν., Honda, T . and Y o s h i o k a , H . Pestic. Sci. (1976) 7, 241. G i l l a m , A.E. and West, T.F., J. Chem. S o c . (1942) 671. Elliott, M. J. Chem.Soc. (1964) 1854. Elliott, M. J. A p p l i e d Chem. (1961) 11, 19. B r a m w e l l , A.F., Crombie, L., Hemesley, P., P a t t e n d e n , G., Elliott, M. and J a n e s , N.F., T e t r a h e d r o n (1969) 25, 1727. Crombie, L., P a t t e n d e n , G . and Simmonds, D.J., Pestic. Sci. (1976) 7, 225. Elliott, M. J. Chem. S o c . (1964) 888. Elliott, M. J. Chem. S o c . (1965) 3097. P a t t e n d e n , G . and S t o r e r , S., J.C.S. Perkin I , (1974), 1606. Elliott, M. J. Chem. S o c . (1964) 5225. Rauch, F., L h o s t e , J. and Birg, M.L., M e d e d e l i n gen F a k u l t e i t Landbouw Wetenschappen Gent (1972), 37, 755. Elliott, Μ . , Needham, P . H . and Potter, C., A n n . Appl. Biol. (1950) 37, 490. Elliott, Μ . , Farnham, A.W., J a n e s , N.F., Needham, P . H . and P e a r s o n , B . C . Nature (1967), 213, 493. Elliott, Μ . , J a n e s , N.F. and Graham-Bryce, I.J., P r o c . E i g h t h . B r . I n s e c . F u n g . C o n f . (Brighton) (1975) 373. V e r s c h o y l e , R . D . and B a r n e s , J.M., Pestic. B i o chem. P h y s i o l . (1972) 2, 308.


26

61. 62. 63.

64. 65.

66. 67.

68. 69. 70.

71. 72.

73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83.


L h o s t e , J. and Rauch, F . C . R . A c a d . Sci. ( P a r i s ) (1969) 268, 3218. V e l l u z , L., M a r t e l , J. and N o m i n é , G . C . R . A c a d . Sci. ( P a r i s ) (1969) 268, 2199. L h o s t e , J., M a r t e l , J and Rauch, F . P r o c e e d i n g s o f t h e 5 t h British I n s e c t i c i d e and F u n g i c i d e C o n f e r e n c e (1969) 554. 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 (1973) 244., 456. Burt, P.E., Elliott, Μ . , Farnham, A . W . , J a n e s , N.F., Needham, P . H . and Pulman, D.A. Pestic. Sci. (1974) 5, 791. Elliott, Μ . , Farnham, A . W . , J a n e s , N.F., Needham, P . H . and Pulman, D.A. Pestic. Sci. (1975) 6, 537. Elliott, Μ . , Farnham A . W . J a n e s N.F., Needham P.H., Pulman (1973) 246, 169 Chen, Y - L and C a s i d a , J.E., J. Agric.Food Chem. (1969) 17, 208. Kaufmann, D.D., J o r d a n , E.G., K a y s e r , A.J. and C l a r k Haynes, S., ACS Symp. S e r . (1977) t h i s volume B a r l o w , F., Hadaway, A.B., F l o w e r , L.S., G r o s e , J.E.H. and T u r n e r , C.R., Pestic. Sci. (1977) 8, (in the p r e s s ) . Miyamoto, J. E n v i r o n . H e a l t h P e r s p e c . (1976)14,15 M i y a k a d o , Μ . , Ohno, Ν., Okuno, Υ., H i r a n o , Μ . , F u j i m o t o , K . and Y o s h i o k a , H . Agric. Biol. Chem. (1975) 39. 267. Elliott, Μ . , Farnham, A . W . , J a n e s , N.F. and Pulman, D.A. U n p u b l i s h e d r e s u l t s . Elliott, M. and J a n e s , N.F. , ACS Symp. S e r . (1977) this volume. Elliott, Μ . , Farnham, A . W . , J a n e s , N.F., Needham, P . H . and Pulman, D.A., Pestic. Sci. (1976) 7 , 4 9 9 . Elliott, Μ . , Farnham, A . W . , J a n e s , N.F., Needham, P . H . and Pulman, D.A. Pestic. Sci. ( 1 9 7 6 ) , 7 , 492. L h o s t e , J. and Rauch, F . , Pestic. Sci. (1976), 247. Brown, D.G., B o d e n s t e i n , O . F . and N o r t o n , S.J., J. Agric. F o o d . Chem. (1973) 21, 767. N o r t o n , S.J., B o d e n s t e i n , O . F . and Brown, D . G . Botyu-Kagaku (1976) 41, 1. Matsuo, T., I t a y a , Ν., M i z u t a n i , T., Ohno, Ν., F u j i m o t o , Κ . , Okuno, Υ., Y o s h i o k a , H . Agr.Biol. Chem. (1976) 40, 247. Rauch, F., L h o s t e , J. and Martel, J. Pestic. Sci. (1974) 5, 651. Wickham, J.C. Pestic. Sci. (1976) 7, 273. Elliott, Μ . , J a n e s , N.F. and P e a r s o n , B . C . Pestic. Sci. (1971) 2, 243.


1.

ELLIOTT

Synthetic

Pyrethroids

84.

27

Elliott, Μ., Farnham, A . W . , J a n e s , N.F. and Needham, P . H . Pestic. Sci. (1974) 5, 491. 85. Elliott, Μ., J a n e s , N.F., Jeffs, K.A., Needham, P . H . and S a w i c k i , R . M . Nature (1965) 207, 938. 86. Elliott, Μ . , J a n e s , N.F. and P e a r s o n , B.C. J. Sci. Food Agric. (1967) 18, 325. 87. S p e n c e r , E.Y. in "The F u t u r e 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 " ( M e t c a l f , R . L . and M c K e l v e y , J.J.,Jr. Eds) 295, John W i l e y and Sons Inc., New Y o r k , 1976. 88. F u k u t o , T . R . in "The F u t u r e 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 " ( M e t c a l f , R . L . and M c K e l v e y , J.J.,Jr. Eds) 313, John W i l e y and Sons Inc., New Y o r k , 1976. 89. Burgen, .A.S.V., Roberts G.C.K and Feeney J.C. Nature (1975) 90. M i s k u s , R . P . an Chem. (1972) 20, 313. 91. K a t s u d a , Y . and Yamamoto, S. Chem. A b s . (1976) 85, 138639. 92. Elliott, Μ., Farnham, A . W . , J a n e s , N.F., Needham, P.H., Pulman, D . A . and S t e v e n s o n , J.H. P r o c . Seventh B r . I n s e c . Fung. C o n f . (Brighton) (1973) 721. 93. Elliott, M. E n v i r o n m e n t a l H e a l t h P e r s p e c t i v e s (1976) 14, 3. 94. Hadaway, A.B., B a r l o w , F., T u r n e r , C . R . and Flower, L.S. Pestic. Sci. (1976) 7, in the p r e s s . 95. Elliott, M. and J a n e s , N.F. Chemy I n d . (1969) 270. 96. Ueda, K., Gaughan, L.C. and C a s i d a , J.E. J. Agric. Food Chem. (1974) 22, 212. 97. Ruzo, L.O., H o l m s t e a d , R . L . and C a s i d a , J.E. T e t . L e t t . (1976) 35, 3045. 98. H o l m s t e a d , R.L., C a s i d a , J.E. and Ruzo, L . O . ACS Symp. S e r . (1977) t h i s volume. 99. M a r t e l , J. and C o l a s , R. P r o c e e d i n g s o f the B e l t wide C o t t o n Research C o n f e r e n c e , L a s Vegas (1976) in the p r e s s . 100. W h i t e , I.N.H., V e r s c h o y l e , R.D., M o r a d i a n , M . H . and B a r n e s , J.M. Pestic. Biochem. P h y s i o l . (1976) 6, 491. 101. B a r n e s , J.M. and V e r s c h o y l e , R . D . ( p e r s o n a l communication). 102. A b e r n a t h y , C.O., Ueda, K., E n g e l , J.L., Gaughan, L.C. and C a s i d a , J.E. Pestic. Biochem. P h y s i o l . (1973) 3, 300. 103. Ueda, Κ . , Gaughan, L.C. and C a s i d a , J.E. Pestic. Biochem. P h y s i o l . (1975) 5, 280. 104. C a s i d a , J.E. , Ueda, Κ . , Gaughan, L.C., J a o , L.T. and S o d e r l u n d , D . M . A r c h . E n v i r o n . Contam.


28

105.

106.


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.


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


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


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).



32

Found in crystalline 128° 106 180 190 99 derivative of allethrin

241

-

B ^M>H + CRÔEt^ CIS/TRANS = 3/7

KURARAY

METHOD

* Υ θ Η + CHf3P+ CCU

Syntheses of acid moieties (NRDC-143 and NRDC-149)


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 -


50


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)


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


SYNTHETIC

PYRETHROIDS

A,

COoEt EtOH EtO>_. ^ ^ O H ^FÔ ^ 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


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.


54 5. 6. 7. 8.

9.

10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.


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)


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


56


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. :-


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.


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.


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.


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


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.


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


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


β»

64


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


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

6.0

>2.4

6.0

>2.4

I

78

SYNTHETIC

ff^,

NaOH γ. 97 ./.

SÔ^ CH

2

ÔH 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



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


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


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


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



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


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


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)


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


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



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


a-cyanopiperonyl


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


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


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


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.


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.


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.


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.


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


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.


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.


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.


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


is

of

9.

M I L L E R

A N D

A D A M S


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


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.


9.

M I L L E R

A N D A D A M S


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.



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


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.


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


of

M I L L E R

A N D A D A M S

6L


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.


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.


.—

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)


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


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.


9.

MILLER

AND

ADAMS


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.


114

8.

9.

10.

11.

12. 13.

14.

15.

16. 17. 18.

19.

20. 21. 22. 23. 24.


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.


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.


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


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


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).


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


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


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


SYNTHETIC

PYRETHROIDS

PO TENTIΟSTAT

V

Reference Electrode

Salt Bridge

r

1

Diaphragms Figure 2.

Schematic representation of ekctrolysis experiment


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;


CI,


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


11.

ALVAREZ AND F i s H M A N

Dichloromethyl

Pentadienes

Figure 3


125

126

SYNTHETIC

PYRETHROIDS

Figure 4


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.


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 .


%

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^viSîJi) > 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


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 .


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


12.

KONDO

ET


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


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


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


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

XVIbând

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


t h e

o f in s u b

12.

KONDO

e s t e r

ET


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


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


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


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.


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


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


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


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.


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

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 -

+ HOÂr 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 0Âr

OCH3

CH3OH

o f

ester

sunlight,

this


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%

2

201(10)

6 Λ

S-PhOPhCIÔH ( 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-«


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


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

ÂKô^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


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


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



(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


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


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.


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


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


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-


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


-

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.


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


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.


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.


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


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 ) .


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).


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


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.


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 , . fî 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


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.


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


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


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

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


trichloroacetate

a

m/e

corresponding

346.9764

trichloroacetate

with

(calculated


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


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


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.


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
.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

Synthetic pyrethroids

Synthetic Distinction

Pyrethroids.. From Chrysanthemum to Modern Industrial Insecticide

Synthetic Dreams

Carbohydrates (Best Synthetic Methods) (Best Synthetic Methods)

Synthetic Men of Mars

Synthetic Metal Containing Polymers

New Synthetic Methods

Synthetic Men of Mars

Synthetic Analgesics. Diphenylpropylamines

Functional Synthetic Receptors

Synthetic and Structured Assets

Synthetic projective geometry

Synthetic Organic Chemistry

The Synthetic Man

Synthetic Men of Mars

Synthetic and structured assets

Synthetic Metal Containing Polymers

Handbook of Synthetic Photochemistry

The Synthetic Man

Computational Synthetic Geometry

Synthetic Differential Geometry

General and synthetic methods

Synthetic Men of Mars

Synthetic Men of Mars

Synthetic geometry of manifolds

Synthetic Men of Mars

Synthetic Men Of Mars

Handbook of Synthetic Photochemistry

Indoles (Best Synthetic Methods)

Synthetic pyrethroids

Synthetic Distinction

Pyrethroids.. From Chrysanthemum to Modern Industrial Insecticide

Synthetic Dreams

Carbohydrates (Best Synthetic Methods) (Best Synthetic Methods)

Synthetic Men of Mars

Synthetic Metal Containing Polymers

New Synthetic Methods

Synthetic Men of Mars

Synthetic Analgesics. Diphenylpropylamines

Functional Synthetic Receptors

Synthetic and Structured Assets

Synthetic projective geometry

Synthetic Organic Chemistry

The Synthetic Man

Synthetic Men of Mars

Synthetic and structured assets

Synthetic Metal Containing Polymers

Handbook of Synthetic Photochemistry

The Synthetic Man

Computational Synthetic Geometry

Synthetic Differential Geometry

General and synthetic methods

Synthetic Men of Mars

Synthetic Men of Mars

Synthetic geometry of manifolds

Synthetic Men of Mars

Synthetic Men Of Mars

Handbook of Synthetic Photochemistry

Indoles (Best Synthetic Methods)

Recommend Documents