Synthetic Pyrethroids

1 Synthetic Pyrethroids MICHAEL

ELLIOTT

Downloaded by 46.161.58.170 on February 13, 2017 | http://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0042.ch001

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 p r o p e r t i e s will be r e q u i r e d f o r as l o n g 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

Elliott; Synthetic Pyrethroids ACS Symposium Series; American Chemical Society: Washington, DC, 1977.

6

SYNTHETIC PYRETHROIDS


t e n y e a r s ago o n l y one s y n t h e t i c p y r e t h r o i d , a l l e t h r i n , was s i g n i f i c a n t i n p r a c t i c e , b u t s i n c e then p r o g r e s s i n d e v e l o p i n g new compounds has been r a p i d , and, as t h e b a s i s f o r f u r t h e r d i s c u s s i o n , a c t i v e compounds now a v a i l a b l e w i l l be r e v i e w e d .

S - B i o a l l e t h r i n (56), F i g u r e 3, has a l l t h e s t r u c t u r a l f e a t u r e s o f n a t u r a l p y r e t h r i n I , except t h a t an a l l y l s i d e c h a i n r e p l a c e s t h e c i s - p e n t a d i e n y l system. I t i s more p o l a r (20) than p y r e t h r i n I w i t h f a s t e r knockdown b u t p o o r e r k i l l i n g power t o most i n s e c t s except h o u s e - f l i e s (3^/5^7) . E a r l y b i o a s s a y s overemphas i s e d t h e p o t e n c y o f a l l e t h r i n because f r e q u e n t l y t h e y were c o n f i n e d t o h o u s e - f l i e s and e v a l u a t e d m a i n l y t h e knockdown r e s p o n s e ; the subtle differences i n basic s t r u c t u r e needed f o r r a p i d knockdown on t h e one hand and h i g h k i l l on t h e o t h e r were n o t r e c o g n i s e d (20). The o u t s t a n d i n g potency o f p y r e t h r i n I a g a i n s t many i n s e c t s p e c i e s was o v e r l o o k e d u n t i l i t was o b t a i n e d pure (55) and u n d i l u t e d by l e s s a c t i v e components (28_) .



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 expense o f h i g h e r mammalian t o x i c i t y . I n s e c t i c i d a l a c t i v i t y of cyclopropanecarboxylates 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 isomers w i l l behave i d e n t i c a l l y .

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 . Downloaded by 46.161.58.170 on February 13, 2017 | http://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0042.ch001

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

ΓΤΤ 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 a l s o d i f f e r e d s i x f o l d i n a c t i v i t y ( F i g u r e 12) (81,82) a l t h o u g h a t a l e v e l o f potency t o h o u s e f l i e s some s i x 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 .

UNSTABLE

RESMETHRIN

(18)

PHENOTHRIN

(β·3)

STABLE

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 y l e s s a c t i v e t h a n resmethrin. In p e r m e t h r i n a d i c h l o r o v i n y l s i d e c h a i n r e 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 Downloaded by 46.161.58.170 on February 13, 2017 | http://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0042.ch001

1

mg. kg

1

1

Solvent, glycerol formal mg. kg"

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). Downloaded by 46.161.58.170 on February 13, 2017 | http://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0042.ch001

1

P r o p e r t i e s o f Recent

Pyrethroids

I n s e c t i c i d e s o f t h i s c l a s s d e v e l o p e d r e c e n t l y , as 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

% M o r t a l i t y o f f l i e s exposed f o r 1 minute t o d e p o s i t s ( a g e i n weeks) 4 6 3 2 0 1

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

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, I.J., Chemy. I n d . (1976) 545. 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.


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26

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Toxicol. (1975/76) 3, 491. Elliott, Μ . , J a n e s , N.F., Pulman, D.A., Gaughan, L.C., U n a i , T . and C a s i d a , J.E. J. A g r . Food Chem. (1976) 24, 270. Owen, J.D. J.C.S. P e r k i n I (1975) 1865.


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