Pesticide Chemistry in the 20th Century - American Chemical Society

13 Benzoylphenyl Ureas—A New Group of Larvicides Interfering with Chitin Deposition

Downloaded by NANYANG TECH UNIV LIB on April 24, 2015 | http://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0037.ch013

A. VERLOOP Research Laboratories, Philips-Duphar B.V., The Netherlands C. D. F E R R E L L Thompson-Hayward Chemical Co., Kansas City, Kan. 66110

The development of s e l e c t i v e crop p r o t e c t i o n compounds based on the interference with c h i t i n deposition i n fungi and i n s e c t s has been one of the aims i n p e s t i c i d e design for several decades. A major development i n t h i s area was the discovery of the mode of a c t i o n of the f u n g i c i d a l a n t i b i o t i c polyoxin D by Misato et al. i n the period of 1 9 6 8 1970 (1)· In these and subsequent studies the Japanese group c l e a r l y demonstrated that polyoxin D and r e l a t e d compounds i n t e r f e r e d with c h i t i n synthesis i n several fungi by i n h i b i t i n g c h i t i n synthetase, the ultimate enzyme i n the b i o s y n t h e t i c pathway. This i s i l l u s t r a t e d i n Figure 1 where the l a s t part of t h i s pathway i s given. Other Japanese workers (2) found that the synthetic phosphorus-containing compound kitazin also prevented the i n c o r p o r a t i o n of UDP-N-acetylglucosamine i n chitin. However t h e i r further studies revealed that i n t h i s case the primary a c t i o n was probably not on chitin synthetase itself but that k i t a z i n prevented the permeation of the substrate through the cytoplasmic membrane so that it was unable to reach the target enzyme (Figure 1 ) . In contrast to the s i t u a t i o n mentioned i n respect to f u n g i c i d a l a c t i v i t y , no i n s e c t i c i d e s were described i n the l i t e r a t u r e prior to 1 9 7 0 , the activity of which was based on interference with chitin formation. Now, i n the course of i n v e s t i g a t i o n s centered on the Philips-Duphar h e r b i c i d e d i c h l o b e n i l the d e r i v a t i v e Du 19111 (I) was prepared.

237

In Pesticide Chemistry in the 20th Century; Plimmer, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.

238

PESTICIDE C H E M I S T R Y I N T H E 2 0 T H C E N T U R Y

FUNGICIDES

INTERFERING WITH CHITIN FORMATION

UDP- Ν - acetylglucosamine


(κ)

• I γ

Permeation through cytoplasmic membrane

U D P - N - acetylglucosamine @

• ^

Chitin synthetase

Chitin ®

POLYOXIN

D Ο COOH

HOOÇ ÇOHNCH

/Ο

HoNCH

I HÇOH CH OCONH2 2

©

OH

OH

KITAZIN

(C^HgO^- Ρ - S - C H Ο

2

Figure 1.


13.

VERLOOP

AND

Benzoylphenyl

FERRELL

CI

CI C II

Cl

239

Ureas

0

-

Ν I

-

C II

0

Η

Ν

Cl

Η


(I)

D u r i n g the s c r e e n i n g p r o g r a m no h e r b i c i d a l or phytotoxic e f f e c t s were f o u n d , b u t i t was observed that larvae of several insects, including Pieris brassicaejshowed a b n o r m a l s y m p t o m s some 5 o r 6 days a f t e r i n g e s t i o n of the compound. The l a r v a e stopped f e e d i n g and hung from the l e a v e s , suggesting that they were starting to m o u l t . But i n s t e a d of s h e d d i n g their exuviaethey turned b l a c k and d i e d . Closer examination r e v e a l e d that the a p o l y s e d larvae were moving within t h e i r intact exuviae but that they were t o t a l l y or p a r t l y u n a b l e to shed these exuviae and to w r i g g l e out (^). H i s t o l o g i c a l examination of affected larvae revealed severe lesions i n the endocuticular tissue. Hence the newly formed cuticle h a d to be a v e r y d e l i c a t e one, u n a b l e to r e s i s t the muscular traction and the i n c r e a s e d t u r g o r during moulting, so t h a t a f f e c t e d larvae would not succeed in casting their exuviae(ji ) · S o f t l a r v a l e n d o c u t i c l e consists m a i n l y of c h i t i n and p r o t e i n , integrated as a c o m p l i c a t e d n e t w o r k , so t h a t t h e r e a r e different ways i n w h i c h Du 19111 might affect its formation, i n c l u d i n g an i n f l u e n c e on c h i t i n f o r m a t i o n . Further studies, to be d i s c u s s e d l a t e r , soon revealed that an e f f e c t o n c h i t i n was t h e m o s t p r o b a b l e mode of action. The h i g h i n s e c t i c i d a l a c t i v i t y o f Du 19111 against the l a r v a l stages of s e v e r a l lepidopterous, coleopterous and d i p t e r o u s i n s e c t s and i t s unique mode o f a c t i o n p r o m p t e d u s t o s y n t h é t i s e several hundreds of b e n z o y l p h e n y l u r e a s and to evaluate their i n s e c t i c i d a l potency i n laboratory tests and s m a l l s c a l e f i e l d t r i a l s (4^, ^ , 6) . T h e s e and other studies l e d to the u l t i m a t e choice of diflubenzuron (il) as the o p t i m a l d e r i v a t i v e for further development.


PESTICIDE C H E M I S T R Y IN T H E 2 0 T H C E N T U R Y

240

F

w


ρ

π

v

r.

v

Ο

Η

Ο

H

w

(II) A f t e r t h e i n t r o d u c t i o n o f d i f l u b e n z u r o n (7.) many a u t h o r s published laboratory and f i e l d studies on i t s i n s e c t i c i d a l spectrum. These studies cannot be d i s c u s s e d i n the context of the present paper. They have been summarized elsewhere (8^, 2., 10, 11) · However, i t is relevant to m e n t i o n t h a t i n several studies, a d d i t i o n a l l y to the l a r v i c i d a l effect of diflubenzuron, a c t i v i t i e s on the eggs of various insect species have been found (j_2, 1k , 15 « 16 ,

17 »

18).These o v i c i d a l effects can e i t h e r be obtained by t o p i c a l a p p l i c a t i o n to the eggs or by f e e d i n g to gravid female insects. In either case the phenomena are s i m i l a r : normal development of the primary stages of the l a r v a e i n the eggs takes place but the organisms are u n a b l e to leave the eggs by r u p t u r i n g them, because again the f o r m a t i o n of the endocuticle is disturbed. This very interesting "broadening" of the i n s e c t i c i d a l spectrum of d i f l u b e n z u r o n has been discussed i n details elsewhere (j^) . A survey of the state of development of d i f l u b e n z u r o n i n the USA has been g i v e n by F e r r e l l and V e r l o o p at the A . C . S . M e e t i n g , A u g u s t 1975 (20): d i f l u b e n z u r o n can be a p p l i e d at v e r y low r a t e s i n agriculture (soybeans, cotton, apple orchards),in forestry, for mosquito and f l y c o n t r o l and p r o b a b l y i n s t o r e d g r a i n . T h e same p a p e r h a s summarised also i t s low t o x i c i t y to mammals a n d t o n o n t a r g e t organisms. In the meantime i t s commercial i n t r o d u c t i o n has begun in some E u r o p e a n c o u n t r i e s and i n Egypt. Registration i n the U . S . A . and commercial i n t r o d u c t i o n by the Thompson-Hayward C h e m i c a l Company i s e x p e c t e d at short notice. However, i t i s not our i n t e n t i o n to discuss further these fascinating p r a c t i c a l p o s s i b i l i t i e s of the b e n z o y l p h e n y l ureas f o r i n s e c t control. In the following part o f t h i s p a p e r we w o u l d r a t h e r discuss the s c i e n t i f i c background of the d i s c o v e r y of diflubenzuron, concentrating on the f o l l o w i n g aspects:


13.

VERLOOP

-

AND

Benzoylphenyl

of

241

Ureas

i t s s e l e c t i o n from the benzoylphenyl i t s fate i n the environment, i t s mode o f a c t i o n .

Selection


FERRELL

urea

series,

diflubenzuron

A f t e r t h e d i s c o v e r y o f Du 1 9 1 1 1 * many h u n d r e d s of r e l a t e d b e n z o y l p h e n y l ureas were synthetized and screened with respect to larvicidal activity. These e f f o r t s were guided by t h e study o f q u a n t i t a t i v e 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 (QSAR) f o l l o w i n g t h e Hansch approach. I n t h i s method linear free-energy r e l a t e d and other e l e c t r o n i c , hydrophobic, and steric substituent constants are used f o r a q u a n t i t a t i v e a n a l y s i s o f t h e p o s s i b l e ways i n w h i c h s u b s t i t u e n t s may m o d u l a t e b i o a c t i v i t y i n a c o n g e n e r i c s e r i e s . I n t h e QSAR s t u d i e s o f b e n z o y l p h e n y l u r e a s t h e e l e c t r o n i c Hammett α-constants a n d t h e h y d r o p h o b i c H a n s c h π-constants w e r e u s e d . To m e a s u r e t h e steric influences, steric substituent constants o f a n e w t y p e (Β Ί , B 2 , B 3 , BZj., a n d L ) w e r e applied which had r e c e n t l y been introduced by us and which give improved c o r r e l a t i o n s i n comparison with the steric E constants used i n the l i t e r a t u r e h i t h e r t o (21, 2 2 ) .The c o n s t a n t s B-|toB^ a r e m e a s u r e s o f t h e widths o f substituents i n four rectangular d i r e c t i o n s . The L-constant accounts f o r the length of a s u b s t i tuent . QSAR f o r t h e l a r v i c i d a l e f f e c t s o f b e n z o y l p h e n y l u r e a s on P i e r i s b r a s s i c a e a n d Aëdes a e g y p t i larvae were s t u d i e d f o r t h e f o l l o w i n g subseries; 1. b e n z o y l p h e n y l u r e a s s u b s t i t u t e d i n t h e a n i l i n e ring, 2. benzoylphenyl ureas substituted i n the benzoyl ring, 3. benzoylphenyl ureas substituted i n the "bridge". The p r e s e n t d i s c u s s i o n w i l l be c o n f i n e d m a i n l y t o subseries 1 above and t o t h e r e s u l t s w i t h Pieris b r a s s i c a e . The o t h e r s t u d i e s and a more complete study o f s u b s t i t u e n t s o f t h e a n i l i n e r i n g w i l l be published e l s e w h e r e ( . 2 ^ , 2 ^ + ) .The most significant equations f o r the l a r v i c i d a l a c t i v i t i e s of 2,6-dichlorobenzoylphenyl ureas as functions o f para- and meta-substitution i n the aniline ring were : For para-substituents -Log E D C Q = + ÏÏ + 2.37 α 0 . 2 7 B ^ +0.87 η = 31, r = 0.8^3, s = 0 . ^ 9 9 , F = 15.9^ S

1,10

0.40L -


PESTICIDE C H E M I S T R Y IN T H E 2 0 T H

242

For


-Log

paraΈΏ

50

and =

CENTURY

meta-substituents

+

0.93

-

1.28L

η

=

48,

τι +

1.89

σ

+

r

0.796,

=

-

0 . 3 ^ L

P

a

r

a

3.36

m e t a

s

=

0.564,

F

=

14.59

In these analyses ED^Q is the concentration required f o r a 509e r e d u c t i o n o f t h e d e v e l o p m e n t o f P i e r i s brassicae L . , η i s the number o f compounds i n the series, r is the correlation c o e f f i c i e n t , s is the standard d e v i a t i o n , and F i s the F - v a l u e which indicates the s i g n i f i c a n c e of the correlation found. From the r e s u l t s given i t can be c o n c l u d e d t h a t the inclusion of meta-substituents leads to essentially the same r e g r e s s i o n e q u a t i o n as the one w i t h o n l y para-substituents. E v i d e n t l y a l l types of substituent influences play a r o l e . The s i g n of the α-term means that e l e c t r o n - w i t h d r a w i n g groups enhance the l a r v i cidal a c t i v i t y , w h i c h was a l s o concluded by Yu and K u h r i n a r e c e n t p a p e r o n QSAR o f t h e l a r v i c i d a l effect of a series of seven 2,6-dichlorobenzoylphenyl ureas on Hylemya p l a t u r a (25 ) · T h e s e a u t h o r s con cluded from t h e i r analysis that hydrophobic effects were n e g l i g i b l e . However, i t is quite evident from the present results w i t h the much l a r g e r series that a l s o h y d r o p h o b i c and s t e r i c i n f l u e n c e s manifest themselves. An a n a l y s i s of a l l these effects leads to the conclusion that the substituents s h o u l d be electron attracting, l i p o p h i l i c , "short", and "thick", in order to c o n t r i b u t e m a x i m a l l y to the a c t i v i t y of the molecule ( 2J[) · I n f a c t the experimental a c t i v i t i e s o f the p - C l - and p - I - d e r i v a t i v e s were found to be about 100 t i m e s less than p r e d i c t e d but i n repeated t e s t s the p r e d i c t i o n s were f o u n d to be correct. Further studies r e v e a l e d that i n the f i r s t tests very coarse particles o f t h e s e two d e r i v a t i v e s had been used, w h i l e the t e s t i n g of the other derivatives had been performed with f i n e p a r t i c l e s . This focused attention f o r the f i r s t time on the g r e a t importance of p a r t i c l e s i z e i n the e v a l u a t i o n of the b e n z o y l phenyl ureas. The s e r i e s d i s c u s s e d i n c l u d e d Du 19111 > the f i r s t compound f o u n d , but the analyses indicated t h a t o t h e r d e r i v a t i v e s were more a c t i v e . F r o m two or t h r e e o f the most a c t i v e compounds PH 6 Ο - 3 8 ( i l l ) was c h o s e n b e c a u s e i t was f o u n d t o b e t h e one w h i c h c o u l d be s y n t h e t i z e d most e c o n o m i c a l l y on an i n d u s t r i a l scale. C o n s e q u e n t l y PH 6 Ο - 3 8 was taken f o r p r e l i m i n a r y development b o t h i n the USA and i n Europe. It i s i n t e r e s t i n g to note t h a t PH 6Ο-38 was one o f the compounds r e t e s t e d a f t e r the QSAR studies.


13.

VERLOOP

AND

FERRELL

Benzoylphenyl

243

Ureas

Ν I

Η

Η

~


(m) However, a t t h i s s t a g e the r e s u l t s o f a n o t h e r a r e a o f our r e s e a r c h o f the b e n z o y l p h e n y l u r e a s , i . e . the e n v i r o n m e n t a l s t u d i e s , were g o i n g to have a v i t a l i n f l u e n c e on the f u r t h e r s e l e c t i o n o f the b e s t compound. A p r e l i m i n a r y s t u d y w i t h a r a d i o a c t i v e p r e p a r a t i o n o f ^ t h e " p a r e n t " compound Du 19111 > labeled with C a t the c a r b o n y l group o f the b e n z o y l ring, r e v e a l e d t h a t t h i s compound was v e r y s t a b l e i n a g r i c u l t u r a l s o i l s : a h a l f l i f e o f more t h a n s i x months was f o u n d . A more e x t e n s i v e s t u d y was c a r r i e d out w i t h the f i r s t c a n d i d a t e f o r development, PH 6 0 - 3 8 , l a b e l e d ( w i t h ^C) at the same p o s i t i o n , A h a l f l i f e i n s o i l s o f 6 - 1 2 months was a g a i n o b t a i n e d . I t was a l s o found t h a t 2 , 6 - d i c h l o r o b e n z a m i d e was the p r i n c i p a l l a b e l e d m e t a b o l i t e . Now t h e r e a r e s e v e r a l p o s s i b l e r o u t e s f o r the h y d r o l y s i s o f the b e n z o y l p h e n y l u r e a s , as i s i l l u s t r a t e d i n F i g u r e 2, where r o u t e A would l e a d to o r t h o - s u b s t i t u t e d b e n z o i c a c i d s and p - c h l o r o - p h e n y l u r e a w h i l e r o u t e s 2 and 3 would b o t h r e s u l t i n o r t h o - s u b s t i t u t e d benzamides and p - C l - a n i l i n e as the p r i m a r y c o n v e r s i o n p r o d u c t s . E v i d e n t l y r o u t e s 2 o r 3 were the p r e f e r r e d ones i n the case o f PH 6 Ο - 3 8 w i t h X = CI (28). The f a c t t h a t r o u t e 1 was o f minor i m p o r t a n c e i n the case o f X = CI was f a m i l i a r to us b e c a u s e o r our e a r l i e r work on the f a t e o f our h e r b i c i d e d i c h l o b e n i l , or 2 , 6 - d i c h l o r o b e n z o n i t r i l e , i n s o i l s . D i c h l o b e n i l i s degraded q u i t e e a s i l y i n t o 2,6d i c h l o r o b e n z a m i d e , but t h i s compound, BAM, i s very s t a b l e i n s o i l s w i t h a h a l f l i f e o f a t l e a s t two y e a r s , as i s i l l u s t r a t e d i n F i g u r e 3 (.26, 27 ) * We knew t h a t a s h i f t o f a t l e a s t one c h l o r i n e atom from the o r t h o - p o s i t i o n to the meta- o r p a r a p o s i t i o n r e s u l t e d i n much more s o i l - d e g r a d a b l e benzamides but t h i s c o u l d not be a p p l i e d h e r e , because we had l e a r n e d from o t h e r QSAR s t u d i e s w i t h the b e n z o y l p h e n y l u r e a s mentioned e a r l i e r t h a t the 2 , 6 - p o s i t i o n o f t h e ( c h l o r i n e ) s u b s t i t u e n t s was essential for a high l a r v i c i d a l a c t i v i t y . However, we a l s o knew t h a t the s m a l l e r f l u o r i n e atoms would s t i l l p e r m i t o f a h i g h r a t e o f h y d r o 1



244


N-Lc-Î-N-/~~Vci w

(

1

x

Ç> ^ y C O O H

+

HgN-C-N-^^-CI

/A

2,3 [J> ^ ~ ^ - C O N H + H N — ^ ~ ^ C I + C Q 2

2

2

X=CI, Major route 2,3; PH 60-38 X = F, Figure 2.

Major route 1 ; dif lubenzuron

Possibilities of the hydrolytic cleavage of 2,6-substituted benzoylphenyl urea


13.

VERLOOP

AND

FERRELL

Benzoylphenyl

Ureas

l y s i s o f 2,6-difluorobenzamide i nsoils, h a l f l i f e o f 2-3 w e e k s , a s i s i l l u s t r a t e d


8-10

\ / · _ ,^\V \z=(

* Figure 3.

N HΛΤΤΤ0 2 - 3 w e e k s

Ο VTT

2

OH

weeks"

245

with a i nFigure

3·

Further degradation

Further

4-6 weeks' d e g r a d a t i o n

F Degradation of 2,6-dichlorobenzamide in the soil

(BAM) and 2,6-difluorobenzamide

On p u t t i n g o n e a n d o n e t o g e t h e r t h e s y n t h e s i s o f t h e f l u o r i n e a n a l o g u e o f PH 60-38 s u g g e s t e d i t s e l f as a p o s s i b l e means o f o b t a i n i n g a h i g h e r r a t e o f d e g r a d a t i o n i n s o i l s v i a r o u t e 1. T h i s i d e a proved very f r u i t f u l : thepredictions o f a faster deg r a d a b i l i t y and o f t h eprimary metabolic pathway of t h e f l u o r i n e analogue, PH 6θ-4θ o r d i f l u b e n z u r o n ( i l ) , i n s o i l s were b o t h found t o be c o r r e c t . M o r e o v e r , t h e l a r v i c i d a l a c t i v i t y o f t h e new d e r i v a t i v e was a p p r e c i a b l y h i g h e r than t h a t o f PH 6Ο-38, w h i c h was a c o m p l e t e a n d p l e a s a n t sur prise f o r us a t that time. Of c o u r s e t h i s new f i n d i n g i n i t i a t e d t h e s y n t h e s i s o f a l a r g e number o f 2 , 6 - d i f l u o r o b e n z o y l p h e n y l u r e a s a n d a g a i n QSAR w a s u s e d f o r t h e o p t i m i s a t i o n o f t h e s e r i e s . A combined a n a l y s i s of t h e 2,6-difluorobenzoyl and 2,6-dichlorobenzoyl s u b s e r i e s (iv) was p e r f o r m e d b o t h a s a f u n c t i o n of v a r i a t i o n o f the substitution pattern i n the aniline ring.

(IV)


PESTICIDE C H E M I S T R Y I N T H E 2 0 T H C E N T U R Y

246

The d i f f e r e n c e s i n t h e two s u b s e r i e s are accounted f o r w i t h t h e a i d o f t h e dummy p a r a m e t e r which was made z e r o i n t h e 2 , 6 - d i c h l o r o b e n z o y l subseries (R-j = C l ) a n d u n i t y i n t h e 2 , 6 - d i f l u o r o b e n z o y l subseries (R-j = F ) . I n t h i s a n a l y s i s a l s o a number o f compounds were i n c l u d e d i n w h i c h t h e a n i l i n e n i t r o g e n was s u b s t i t u t e d w i t h a m e t h y l g r o u p ; here t h e dummy p a r a m e t e r was u s e d , w i t h U£ = 0 i f R = H , and = 1 i f R = CH^. The resulting regression equations were: F o r R^ = para-substituents


2

-Log

2

ED^

0

+

1.40D η

For -Log

R^ = m e t a ED

π + 2 . 3 5 σ - 0.40L

=+1.10

0.70D

= 48, r and

-

0 . 2 4

-

0.61D

B

0.27B^

+ 0.84

2

= 0.909,

5 = 0.408,

F = 32.63

para-substituents π + 1.99

= + 0 . 9 5

η

-

1

-

z

+

2

= 70,

p

a

r

a

-

σ 1 .

3

0 L

0 . 3 4 L m

e

t

a

+

p

a

r

a

1.40

D L

+ 3.38 r

= 0.892,

s

= 0.535,

F =

34.37

It can be concluded that these equations are very similar to the equations discussed earlier f o rt h e 2,6-dichlorobenzoyl subseries as f a r as the elec tronic, hydrophobic, andsteric influences are concerned. Thec o e f f i c i e n t s o f t h e dummy p a r a m e t e r s lead to the conclusion that the 2,6-difluorobenzoyl subseries i s about 25 t i m e s more a c t i v e on Pieris brassicae than the 2,6-dichlorobenzoyl series, whereas methyl substitution at the a n i l i n e nitrogen systematically decreases the activity by a factor of about f i v e ( 2 3 ) . The s i m i l a r i t i e s i n t h e i n f l u e n c e s o f t h e d i f f e r e n t parameters i n t h e two s u b s e r i e s suggested t h a t t h e optimum compound f o r development should s t i l l contain the p - C l - a n i l i n e moiety, so that d i f l u b e n z u r o n was u l t i m a t e l y s e l e c t e d as the f i n a l benzoylphenyl urea derivative to be developed as a news e l e c t i v e insecticide.

Fate

o f diflubenzuron i n the

environment.

Soils (28, 2 £ ) . L e t us f i r s t discuss the rate of degradation o f diflubenzuron i n a g r i c u l t u r a l s o i l s . T h e h a l f l i f e f o u n d i n i t i a l l y w a s 8 - 16 w e e k s ,


13.

VERLOOP

Benzoylphenyl

AND FERRELL

247

Ureas


depending on the type o f s o i l ( T a b l e l ) . T h i s was s t i l l rather high i n comparison with the h a l f l i f e of 2 - 3 weeks f o u n d f o r t h e model compound 2,6difluorobenzamide. Further studies revealed the probable explanation o f this discrepancy. I t was f o u n d t h a t t h e h a l f l i f e o f d i f l u b e n z u r o n was l a r g e l y dependent o n t h e form i n w h i c h i t was b r o u g h t into the s o i l , as i s i l l u s t r a t e d i n Table 1.

Table 1. I n f l u e n c e o f p a r t i c l e size on apparent o f d e g r a d a t i o n o f d i f l u b e n z u r o n ( 2 8 , , 22.) ·

rate T-g-

i n weeks

PH

60-38

25

-

50

8-25

i n several

soils

Formulation

Diflubenzuron

8

-

16

0.5-1

S u s p e n s i o n , mean particle s i z e ^ΙΟρι. Suspension, particle

-

Approx.1

Aqueous

_ Pestic.

suspension •

mean

size

2^u

solution

_ >pestic . solution

J> m e t a b o l i t e s

In the i n i t i a l experiments particles with an average s i z e o f '\0ja h a d b e e n u s e d , b u t a h a l f l i f e o f 0.5 1 week was f o u n d when p a r t i c l e s with an average size o f 2u w e r e a p p l i e d . T h i s i n t e r e s t i n g p h e n o m e n o n might be caused by the s p e c i f i c p h y s i c a l properties of d i f l u b e n z u r o n : owing to i t s v e r y l o w aqueous s o l u b i l i t y o f a b o u t 0.2 ppm t h i s i n s e c t i c i d e , like other p e s t i c i d e s with a low s o l u b i l i t y , w i l l be present i n the s o i l as a d i s p e r s i o n i n the concen t r a t i o n a p p l i e d . Thus i n the equation given i n Table one t h e a p p a r e n t h a l f l i f e may b e g o v e r n e d b y t h e r a t e o f d i s s o l u t i o n , k-| , o r b y t h e t r u e r a t e o f degradation, k2· On u s i n g p a r t i c l e s with an average s i z e o f 2u, k2 i s a p p a r e n t l y r a t e d e t e r m i n g because i n t h a t c a s e t h e h a l f l i f e o f 0.5 1 week i s s i m i l a r to t h a t f o u n d when a t r u e s o l u t i o n i s a p p l i e d . T h e rate of dissolution of particles i s generally cor related l i n e a r l y with their surface

American Chemical Society Library 1155 16thCentury; St. N.Plimmer, W. J., et al.; In Pesticide Chemistry in the 20th ACS Symposium Series; American Chemical Society: Washington, DC, 1977. Washington, D. C. 20038


248

PESTICIDE C H E M I S T R Y IN T H E 2 0 T H

CENTURY

a r e a , so t h a t k-j w i l l d e c r e a s e i f l a r g e r p a r t i c l e s are a p p l i e d . With c r y s t a l s l i k e those of d i f l u b e n z u r o n - h a v i n g a h i g h m e l t i n g p o i n t and consequently a h i g h energy of c r y s t a l l i s a t i o n - the r a t e of d i s s o l u t i o n o f l a r g e r p a r t i c l e s m i g h t b e so l o w t h a t k-j b e c o m e s r a t e d e t e r m i n i n g , i . e. k j < ^-2* W i t h t h e r e l a t e d c o m p o u n d PH 6 0 - 3 8 , ( I I I ) , a comparable but s m a l l e r e f f e c t of the p a r t i c l e size on t h e a p p a r e n t r a t e o f d e g r a d a t i o n i n s o i l s was o b s e r v e d a s i s i l l u s t r a t e d i n T a b l e 1. T h e influence o f t h e t y p e o f s o i l on t h e r a t e o f d e g r a d a t i o n o f d i f l u b e n z u r o n i s much l e s s i m p o r t a n t , b e c a u s e w i t h f i v e a g r i c u l t u r a l s o i l s and t h r e e h y d r o s o i l s , i n c l u d i n g t h e s o i l t y p e s recommended b y t h e EPA and t h e G e r m a n BBA, the v a r i a t i o n i n the h a l f l i f e was only a factor of approximately two. The r a t e o f d e g r a d a t i o n o f d i f l u b e n z u r o n i n a t e r r e s t r i a l s o i l was a l s o s t u d i e d b y M e t c a l f e t a l . (30), who f o u n d p r a c t i c a l l y no d e g r a d a t i o n k w e e k s a f t e r a p p l i c a t i o n o f an a c e t o n i c s o l u t i o n o f d i f l u b e n z u r o n t o a i r - d r i e d s o i l . We, however, o b s e r ved that d i f l u b e n z u r o n c r y s t a l l i z e d from a c e t o n i c s o l u t i o n "on" s o i l w i t h a p a r t i c l e s i z e o f l a r g e l y >10 /u. T h e c o m m e r c i a l WP f o r m u l a t i o n o f d i f l u b e n z u r o n has a s t a n d a r d i z e d p a r t i c l e s i z e o f 1 - 5 ρ w i t h an a v e r a g e v a l u e o f 2 yU, so t h a t t h e s e h i g h e r h a l f l i f e v a l u e s o b t a i n e d w i t h l a r g e r p a r t i c l e s a r e o f no practical significance. This standardisation of the p a r t i c l e s i z e i s a l s o n e c e s s a r y because of i t s g r e a t i n f l u e n c e on 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 e n z o y l p h e n y l u r e a s . T h i s was a l r e a d y m e n t i o n e d i n t h e d i s c u s s i o n o f t h e QSAR s t u d i e s . T h e influence o f p a r t i c l e s i z e on t h e l a r v i c i d a l a c t i v i t y o f d i f l u b e n z u r o n was f u r t h e r i l l u s t r a t e d e l s e w h e r e · T h e s e i n f l u e n c e s m i g h t h a v e t h e same e x p l a n a t i o n as t h a t o f t h e e f f e c t o f p a r t i c l e s i z e on t h e r a t e of degradation i n s o i l s . More d e t a i l e d s t u d i e s o f t h e m e t a b o l i c pathways o f d i f l u b e n z u r o n i n s o i l s have been c a r r i e d out w i t h radioactive preparations labeled i n four different p o s i t i o n s of the molecule f o r a study of the u l t i mate f a t e o f t h e p r i m a r y d e g r a d a t i o n p r o d u c t s . T h e s e s t u d i e s w i l l be m e r e l y summarized i n t h i s p a p e r . A more e x t e n s i v e d i s c u s s i o n i s p u b l i s h e d elsewhere (22.). I n a l l e x p e r i m e n t s d i s c u s s e d h e r e , d i f l u b e n z u r o n was a p p l i e d t o t h e s o i l a s a n a q u e o u s s u s p e n s i o n o f 2-yu p a r t i c l e s a t a c o n c e n t r a t i o n o f 1 pg/gram s o i l , r o u g h l y c o r r e s p o n d i n g to a d o s e o f 300 grams a . i . p e r h e c t a r e . The first



13.

VERLOOP

AND

FERRELL

Benzoylphenyl

249

Ureas

a s p e c t s t u d i e d was t h e n a t u r e of the primary degra dation process of d i f l u b e n z u r o n , by comparing the d e g r a d a t i o n i n normal s o i l s and i n steam-sterilized s o i l s . A representative example of the r e s u l t s with a preparation labeled with i n the a n i l i n e ring and w i t h a sandy loam s o i l i s i l l u s t r a t e d i n T a b l e 2. It can be seen t h a t i n the n o n s t e r i l e s o i l o n l y 2°/o o f d i f l u b e n z u r o n was l e f t a f t e r f o u r w e e k s . B u t i n the s t e r i l e soil s o m e 9k°/o o f t h e a p p l i e d d i f l u b e n z u r o n was s t i l l p r e s e n t after this p e r i o d . It can be c o n c l u d e d t h a t the d e g r a d a t i o n i s o f a m i c r o biological nature.

T a b l e 2. Fate of d i f l u b e n z u r o n - r i n g - U - C i n sterile and n o n - s t e r i l e sandy loam s o i l a f t e r 4 weeks (Percentage of i n i t i a l amount o f d i f l u b e n z u r o n ) (28, 22) Sterile

Extractable

Extractable

C

PH 6θ-4θ

Nonsterile

96

43

9k

2

4

27

14 Non-extractable

C

A general survey of the m e t a b o l i c pathways of d i f l u b e n z u r o n i n s o i l s i s g i v e n i n F i g u r e 4. It was a l r e a d y mentioned that the main primary degradation process was a m i c r o b i o l o g i c a l h y d r o l y s i s o f the " b r i d g e " o f t h e m o l e c u l e i n s u c h a way ( r o u t e A) that j p - c h l o r o p h e n y l u r e a and 2,6-difluorobenzoic a c i d were f o r m e d . Let us f i r s t d i s c u s s the "urea" part of the d i f l u b e n z u r o n m o l e c u l e . p - C h l o r o p h e n y l u r e a was i d e n t i f i e d b y t h i n - l a y e r chromatography (tic), reversed isotope dilution analysis (rid), and mass s p e c t r o m e t r y (ms). U p t o 10°/o o f t h e l4c-aniline l a b e l a p p l i e d t o t h e s o i l was r e c o v e r e d as p-chlorophenyl urea, d e p e n d i n g on the type of s o i l , ~ w h i c h clearly illustrates that t h i s pathway i s of primary importance. The r a t e of the d e g r a d a t i o n processes i s i l l u s t r a t e d i n t h e u p p e r h a l f o f F i g u r e 5> with r e s p e c t to an a g r i c u l t u r a l sandy loam s o i l . It can b e s e e n t h a t b e t w e e n 2 a n d 28 w e e k s t h e a m o u n t of extractable radioactivity is practically identical w i t h the amount o f p - c h l o r o p h e n y l u r e a found.


PESTICIDE

250

co +

CENTURY

C-,F-deriv

H0 2

2

(phys.-chem., ring 3 ) H

(chem.,14c) Downloaded by NANYANG TECH UNIV LIB on April 24, 2015 | http://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0037.ch013

C H E M I S T R Y IN T H E 2 0 T H

^~^CONH

COOH

2

(riXtlc.)

(rid,ms,tlc.)

4 N-i-C-i-N-fVci H

H

C0

2

(rid,ms,tlc.)

(Hydrolysis, Chem.) Figure 4. Proposed pathways of the degradation of diflubenzuron in agricultural soils and hydrosoils. Abbreviations: rid = reversed isotope-dilution; ms = mass spectrometry; tic = thin layer chromatography.



13.

VERLOOP

AND FERRELL

Benzoylphenyl

Ureas

251

The f a t e o f t h i s p r i m a r y m e t a b o l i t e i s f u r t h e r i l l u s t r a t e d i n t h e lower h a l f o f F i g u r e 5 where the degradation o f p - c h l o r o p h e n y l urea i s g i v e n when t h i s ^ C - a n i l i n e r i n g - l a b e l e d compound was a p p l i e d t o t h e same t y p e o f s o i l i n a s e p a r a t e experiment. I n both studies a h a l f l i f e o f about 10 w e e k s w a s f o u n d f o r t h i s m e t a b o l i t e . The decrease of p-chlorophenyl urea can rather quantitatively be e x p l a i n e d b y t h e g r a d u a l f o r m a t i o n o f bound r e s i d u e s . We a r e c u r r e n t l y s t u d y i n g t h e n a t u r e o f the bound r e s i d u e s , f o r i n s t a n c e b y means o f e x traction procedures which avoid the formation of a r t e f a c t s . T h i s method has r e v e a l e d that t h e bound residues c o n t a i n j3-chlorophenyl urea as w e l l as s m a l l amounts o f p - c h l o r o a n i l i n e · Free p-chloroa n i l i n e o r i t s f u r t h e r p o s s i b l e d e g r a d a t i o n productsy e.g. c h l o r i n a t e d a z o - and azoxybenzenesywere not present i n the extractable residues. The main d e g r a d a t i o n pathway o f d i f l u b e n z u r o n i n s o i l s would lead to the formation also o f 2,6d i f l u o r o b e n z o i c a c i d as a primary m e t a b o l i t e . Starting with diflubenzuron preparations labeled w i t h I ^ C a n d -^H i n t h e b e n z o y l r i n g , 2,6-dif luorobenzoic a c i d has indeed been i d e n t i f i e d b y t h i n layer chromatography (tic), gas chromatography (glc), reversed isotope dilution analysis (rid), a n d mass spectrometry (ms). Because o f i t s r a p i d further degradation i n agricultural soils with a h a l f l i f e of less than k weeks, t h e maximum amount o f 2,6d i f l u o r o b e n z o i c a c i d f o u n d w a s 20^ of the diflubenz u r o n a p p l i e d . T h e f a t e o f t h e a c i d was s t u d i e d further with a diflubenzuron preparation labeled with i n the carbonyl group o f the benzoyl moiety. The major part of this labeled material was i d e n t i f i e d b y c h e m i c a l a n a l y s i s a f t e r about 12 weeks as C0£, p r o v i n g t h a t d e c a r b o x y l a t i o n i s t h e f i r s t step i n the degradation o f 2,6-difluorobenzoic acid. F u r t h e r i n f o r m a t i o n was o b t a i n e d w i t h d i f l u b e n zuron l a b e l e d w i t h 3H i n t h e b e n z o y l r i n g . In this study, u p t o 50°/o o f t h e t r i t i u m l a b e l a d d e d t o a c l a y h y d r o - s o i l was i d e n t i f i e d as t r i t i a t e d water. As m e n t i o n e d e a r l i e r , hydrolysis according to route 2 or 3 leading to p - c h l o r o a n i l i n e and 2,6d i f l u o r o b e n z a m i d e i s t h e ' m a i n pathway i n t h e slow degradation of the "sister" c o m p o u n d P H 60-38. As e x p e c t e d t h i s pathway was d e m o n s t r a t e d a l s o i n the case o f d i f l u b e n z u r o n , though as a minor process: 2,6-difluorobenzamide has been identified i n a m o u n t s o f a t t h e m o s t 2°/o o f t h e a p p l i e d d o s e b y means o f t h i n l a y e r c h r o m a t o g r a p h y ( t i c ) and rever-



1004

Figure 5. Rate of degradation of diflubenzuron (upper half) and of p-chlorophenyl urea (lower half) in an agricultural sandy loam soil Percent recovery of applied dose.


13.

VERLOOP

AND

FERRELL

Benzoylphenyl

253

Ureas


sed isotope d i l u t i o n a n a l y s i s (rid). In separate experiments w i t h 3 H - d i f l u o r o b e n z a m i d e i t was found to be d e g r a d e d r a p i d l y i n t o 2,6-difluorobenzoic a c i d w i t h a h a l f l i f e o f a b o u t two w e e k s i n a clay hydrosoil ( F i g u r e 6). In this experiment the h a l f l i f e o f t h e 2 , 6 - d i f l u o r o b e n z o i c a c i d f o r m e d was a g a i n about k weeks ( 2^.) · Plants. I n c o n t r a s t to the degradation of diflubenzuron i n the i n s e c t i c i d e i n p l a n t s a f t e r rather simple. Table leaves two greenhouse

fast and complicated soils, the f a t e of leaf application is

3· Persistence of d i f l u b e n z u r o n on p l a n t months a f t e r t o p i c a l a p p l i c a t i o n i n a s t u d y (^J.) · percentage

of

applied

dose

maize

cabbage

100

Fraction soybean

apple

TER

93

86

9k

Diflubenzuron

96

89

95

k

TBR

97

TR

TER TBR TR

= Total = Total = Total

2 88

5 99

100

5

105

extractable residue. bound r e s i d u e . residue.

T h i s i s i l l u s t r a t e d i n T a b l e 3> where an analysis is presented of plant leaves two m o n t h s a f t e r app l i c a t i o n o f l a b e l e d d i f l u b e n z u r o n as an aqueous suspension of 2 u particles on soybean, apple, maize and cabbage p l a n t s i n a greenhouse study. It can be


254

PESTICIDE

C H E M I S T R Y IN T H E 2 0 T H C E N T U R Y

RECov£Ry


%I

Figure 6. Degradation curves of 2,6-difluorobenzamide and 2,6-difluorobenzoic acid after incubation of clay hydrosoil with Η-2,6-difluorobenzamide. Recovery in percen tage of applied dose. 3


13.

VERLOOP

AND FERRELL

Benzoylphenyl

255

Ureas

observed that ^ 95°/o o f t h e a n a l y s e d radioactivity was f o u n d i n t h e e x t r a c t a b l e f r a c t i o n a n d t h a t i t consisted completely of unaltered diflubenzuron. At h a r v e s t , 4 - 5 months a f t e r a p p l i c a t i o n , t h e c r o p s were a n a l y z e d ( T a b l e 4).


T a b l e 4. R e s i d u e s i n c r o p s , 4 - 5 months after leaf application of ^H-1^C-iabeled diflubenzu ron (calculated a s ppmd i f l u b e n z u r o n ) (31) Total

3

H

Total

λ

^0

Soybean,

milled

beans

< 0.02

glucose

N-acetyl

glucosamine

1

6-P

6-P^

N-acetylglucosamine

I

UDP-N-acetylglucosamine Figure 10.

^ fructose

1

6-P

glucosamine

6-P

1-P

^ c h i t i n

Biosynthetic pathway of chitin synthesis from glucose

The a l t e r n a t i v e p o s s i b i l i t y t o e x p l a i n t h e mode o f a c t i o n i s t h e i n h i b i t i o n o f one o f t h e enzymes i n the pathway o f c h i t i n b i o s y n t h e s i s , i l l u s t r a t e d i n Figure 10. C o n s i d e r i n g t h e r a p i d i t y o f t h e p r o c e s s , a direct i n h i b i t i o n w i t h o u t h o r m o n a l i n t e r f e r e n c e was most p r o b a b l e . Post et a l . compared the r a t e s o f incorporation o f ^C-labeled glucose into the u l t i mate c h i t i n p r e c u r s o r , uridine diphosphate N-acetylg l u c o s a m i n e o r UDPAG, i n b o t h n o r m a l a n d D u 19111treated P i e r i s larvae and found that these rates d i d not d i f f e r s i g n i f i c a n t l y · Hence the c o n c l u s i o n 1

seemed j u s t i f i e d t h a t t h e " p a r e n t " c o m p o u n d D u 19111 did not inhibit an intermediate step between glucose and UDPAG. T h i s l e d t o t h e h y p o t h e s i s t h a t either the u l t i m a t e enzyme o f t h e pathway, c h i t i n synthetase, was b l o c k e d o r t h a t a c l o s e l y r e l a t e d p r o c e s s w a s a f f e c t e d b y D u 19111. D e u l e t a l . f o u n d i n a n o t h e r study that diflubenzuron inhibited the incorporation of ^ C - l a b e l e d UDPAG i n t h e c h i t i n f r a c t i o n o f P i e r i s brassica cuticles a n d t h u s t h e y a r r i v e d a t t h e same conclusion with respect t o t h a t c o m p o u n d 0^2) . O f course the ultimate proof that diflubenzuron blocks c h i t i n synthetase i n Pieris brassicae larvae can only be o b t a i n e d b y i n h i b i t i o n e x p e r i m e n t s with the pure i s o l a t e d enzyme. But the i s o l a t i o n o f c h i t i n synthetase from insects i s a notoriously d i f f i c u l t problem 1



13.

VERLOOP

AND

FERRELL

Benzoylphenyl

Ureas

265

and our e f f o r t s i n t h a t a r e a have n o t as y e t l e d to success· In this context the comparison of the i n s e c t i c i d e d i f l u b e n z u r o n w i t h the f u n g i c i d e p o l y o x i n D i s interesting i n more t h a n one r e s p e c t . It not only c l o s e s the c i r c l e i n our paper, so t o speak, but i t can also furnish strong circumstantial evidence to support our hypothesis o f t h e mode o f a c t i o n of diflubenzuron. M a r k s a n d Sowa w e r e t h e f i r s t to com pare d i f l u b e n z u r o n and p o l y o x i n D i n t h e i r effects on the ^ - e c d y s o n - d e p e n d e n t i n - v i t r o synthesis of c h i t i n by the cockroach (Leucophaea maderae) leg regenerates . These authors found that both compounds almost completely i n h i b i t e d the incorpora tion of ^ C - l a b e l e d D-glucosamine i n t o the c h i t i n fraction. In a later study with ^C-labeled N-acetylD-glucosamine similar results were o b t a i n e d , and the I50 v a l u e o f i n h i b i t i o n o f c h i t i n s y n t h e s i s was f o u n d t o b e 6.11 χ 10 -10M f o r d i f l u b e n z u r o n and 7.53 x 10-7 M f o r p o l y o x i n D (kS). The difference in i n t r i n s i c a c t i v i t y can p a r t l y be e x p l a i n e d by the roughly hundredfold accumulation of d i f lubenzuron i n the i n s e c t tissue. 1

These i n t e r e s t i n g r e s u l t s prompted us to compare d i f l u b e n z u r o n and p o l y o x i n D i n t h e i r effects on Pieris brassicae larvae (^£,2.) · I n p r e l i m i n a r y s t u d i e s i t had been found that p o l y o x i n D d i d not affect the larvae v i a leaf feeding but that i n j e c t i o n re sulted i n l a r v i c i d a l effects. H i s t o l o g i c a l examina tion revealed t h a t b o t h compounds gave similar effects, i . e . the d i s t u r b a n c e of the r e g u l a r endocuticular layers and the formation of globular coagulated particles as d i s c u s s e d e a r l i e r f o r Du 19111. F u r t h e r i n f o r m a t i o n w a s o b t a i n e d b y i n c o r p o r a tion studies a s i s i l l u s t r a t e d i n T a b l e 8. After leaf f e e d i n g o f p o l y o x i n D no e f f e c t on the incorpo ration of radiolabeled glucose c o u l d be observed, even at a tenfold higher dose. But q u i t e comparable e f f e c t s were o b t a i n e d w i t h the two c o m p o u n d s after incubation with a preliminary " i n v i t r o " system. After injection, when p a r t of the permeability barriers i n the larvae is absent, polyoxin D i n h i b i t s the glucose incorporation, but less so t h a n diflubenz u r o n . The c o n c l u s i o n seems o b v i o u s t h a t the i n t r i n sic e f f e c t s o f b o t h compounds are p r a c t i c a l l y iden t i c a l b u t t h a t p o l y o x i n D i s much more h i n d e r e d by the p e r m e a b i l i t y b a r r i e r s present i n the Pieris brassicae larvae. On t h e s t r e n g t h of the evidence presented by Misato and co-workers that polyoxin D is a competitive i n h i b i t o r of c h i t i n synthetase, a


266


similar zuron

conclusion

seems

for

j u s t i f i e d

the

mode

of

action

of

difluben-

( 49 )

14


T a b l e 8. I n h i b i t i o n of incorporation -D-glucose into c h i t i n fractions of P i e r i s larvae by d i f l u b e n z u r o n and p o l y o x i n D , as of controls.

o f (6C) brassicae percentage

Diflubenzuron

Polyoxin

D

Dose (nmoles)

Dose Inhibi(nmoles ) t i o n ( ^ )

Method

Oral uptake larvae v i a feeding

by leaf

10-20

Inhibit i o n (°/o)

95

200

Ο

Injection into larvae,simultaneous with glucose

3

90

50

45

Injection into larvae, 3 hours p r i o r to glucose

-

-

50

95

Incubation with skin + adhering tissue

30

80

80

80

In a d d i t i o n to the e f f e c t s of d i f l u b e n z u r o n on the chitinase and phenoloxidase l e v e l s , observed by Ishaaya a n d C a s i d a (46 ) , o t h e r b i o c h e m i c a l influences o f d i f l u b e n z u r o n a n d D u 19111 have been d e s c r i b e d i n the l i t e r a t u r e ( T a b l e 9). A common f e a t u r e of a l l t h e s e e f f e c t s i s t h e i r a n a l y s i s one o r more days a f t e r t r e a t m e n t . As any e f f e c t s of these b e n z o y l p h e n y l u r e a s become v i s i b l e on the l i v i n g insects o n l y at the time o f the n e x t m o u l t , when susceptible larvae die, investigators are prompted to search for defects up to a c o n s i d e r a b l e time a f t e r application. In comparison w i t h the v e r y f a s t i n h i b i t i o n of c h i t i n synthesis discussed above, i n our opinion these studies can at the most i n d i c a t e "secondary" effects. A c o n s i d e r a b l e number o f e f f e c t s of this t y p e can be expected to be f o u n d and p u b l i s h e d i n the future·


13.

VERLOOP

AND

Benzoylphenyl

FERRELL

T a b l e 9 . "Secondary" e f f e c t s ureas i n i n s e c t s . Compound

Insect

(52)

Pieris b r a s s i c a e L. Thaumetopoae p i t y o campa S.


Du

19111

larvae

L.

D i f l u b e n z - Musc a u r o n ( 46 ) d o m e s t i c a

L.

D i f l u b e n z - Musca domestica uron (5l)

L.

Diflubenz- Pieris uron (42.) brassicae

L.

19111

of

benzoylphenyl

Analysis Effect (days after treatment) 1,2 3 » 12

2

Pieris brassicae

Du (ito)

267

Ureas

Increase followed by d e c r e a s e o f respiratory m e t a b o l i s m and of pentose-cycle. Slightly increased b i o s y n t h e s i s of non-chitinous materials* Increase of c h i t i n a s e and phenoloxidase activity. Increased a c t i v i t y o f ^£-ecdysonmetabolizing enzymes and i n crease of microsomal o x i d a s e activity· S l i g h t l y increased b i o s y n t h e s i s of nonchitinous material·

Summarizing, dif lubenzuron f e a t u r e s mentioned i n the i n t r o d u c t i o n o f t h i s p a p e r can be completed as f o l l o w s : The new i n s e c t i c i d e has f a v o u r a b l e e n v i r o n m e n t a l p r o p e r t i e s because i t i s n o n - p e r s i s t e n t i n s o i l s and i t has a low b i o l o g i c a l m a g n i f i c a t i o n . I t i s s t a b l e on p l a n t s and i n i n s e c t s , hence i t has a l o n g r e s i d u a l a c t i v i t y . I t r e p r e s e n t s the b e s t c h o i c e from the s e r i e s o f the b e n z o y l p h e n y l u r e a s . I t i s a r e v e r s i b l e i n h i b i t o r of c h i t i n synthesis i n i n s e c t s , p r o b a b l y by b l o c k i n g c h i t i n synthetase.



268


Abstract. The development of s e l e c t i v e crop p r o t e c t i o n compounds based on the i n t e r f e r e n c e with c h i t i n d e p o s i t i o n i n fungi and i n s e c t s i s one of the aims in p e s t i c i d e d e s i g n . P o l y o x i n D and kitazin have been s u c c e s s f u l l y developed along these l i n e s i n the field of f u n g i c i d e s some years ago. The benzoylphenyl ureas, which e x h i b i t a c t i v i t y against the l a r v a l sta ges of s e v e r a l i n s e c t species by i n t e r f e r i n g with chitin d e p o s i t i o n i n the endocuticle and thus with the moulting process, were first introduced i n 1 9 7 2 . The study of t h i s new s e r i e s u l t i m a t e l y l e d to the development of 1 - ( 4 - c h l o r o p h e n y l ) - 3 - ( 2 , 6 - d i f l u o r o benzoyl) urea (common name diflubenzuron) as a new s e l e c t i v e l a r v i c i d e with favourable environmental p r o p e r t i e s . In the present paper t h i s development has been d i s c u s s e d , based on the l i t e r a t u r e as w e l l as on new r e s u l t s from our l a b o r a t o r i e s , with main emphasis on: 1) The o p t i m i s a t i o n of the s e r i e s by chemical synthesis guided by the study of quantita tive 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 ; 2) The ratio nal development of the s o i l degradable d i f l u b e n z u r o n from its more p e r s i s t e n t predecessors and its metab olic pathways i n soil, p l a n t s , animals and model ecosystems. 3) The mode of a c t i o n of d i f l u b e n z u r o n at the h i s t o l o g i c a l and molecular b i o l o g i c a l l e v e l . Literature 1. 2. 3. 4. 5· 6. 7. 8. 9.

cited

Endo, Α . , K a k i k i , Κ . , and Misato, T., J . B a c t e r i ol. (1970), 104, 189 and preceding papers. Maeda, T., Abe, Η . , K a k i k i , Κ . , and Misato, T., Agr. B i o l . Chem. (1970), 34, 700. Mulder, R., and G i j s w i j t , M. J., P e s t i c . S c i . (1973), 4, 737. Wellinga, Κ . , Mulder, R., and van Daalen, J . J., J . Agr. Food Chem. (1973), 21, 348. Wellinga, Κ . , Mulder, R., and van Daalen, J . J., J . Agr. Food Chem. (1973), 21, 993. Van Daalen, J . J . , Meltzer, J . , Mulder, R., and Wellinga Κ . , Naturwissenschaften (1972), 59, 312. Mulder, R., and Swennen, Α. Α . , Proc. 7th British I n s e c t i c i d e and Fungicide Conf. (1973), 729 E l i n g s , Η . , and Dieperink, J . G . , Mededelingen van de F a c u l t e i t Landbouwwetenschappen, Gent (1974), 39, 833. B i j l o o , J . D . , P h y t i a t r i e phytopharmacie (1975), 24, 147,


13.

10. 11.

12.


13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25· 26. 27. 28. 29. 30. 31. 32.

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AND

FERRELL

Benzoylphenyl

Ureas

269

Van Busschbach, E . J . , P h y t i a t r i e phytopharmacie (1975), 24, 159. Nölle, Η. Η . , Van Busschbach, E. J . , and Verloop, Α . , Mitteilungen aus der B i o l . Bundesanstalt f . Land- und Forstwirtschaft B e r l i n - Dahlem (1975) 165, 161. Ascher, K. R. S., and Nemny, Ν. Ε., Phytopara sitica (1974), 2, 131. T a f t , Η. Μ . , and Hopkins, A. R., J . Econ. Ento mol., (1975), 68, 551. Moore, J r . , R. F . , and T a f t , Η. M . , J . Econ. Entomol. (1975), 68, 96. C a r t e r , S. W., J . Stored Prod. Res. (1975), 11, 187. Holst, Η . , Z. f. P f l . Krankh. (1975), 82, 1. Wright, J . Ε . , and Spates, G. E., J. Econ. Ento mol. (1976), 69, 365. Grosscurt, A. C . , Mededelingen van de F a c u l t e i t Landbouwwetenschappen, Gent (1976), 41, ( i n press). Grosscurt, A. C . , paper i n p r e p a r a t i o n . F e r r e l l , C. D . , and Verloop, Α . , A b s t r . Pap., 170th Meet., Amer. Chem. Soc. (1975), PEST 35. Verloop, Α . , Hoogenstraaten, W., and T i p k e r , J . , Abstr. Pap., 167th Meet., Amer. Chem. Soc. (1974), CHLT 011. Verloop, Α . , i n "Drug Design" (E. J . A r i ë n s , e d . ) , V o l . 7 (1976), pp 255 - 311. Academic Press, New York. Verloop, Α . , and T i p k e r , J . , submitted to P e s t i c . Sci. T i p k e r , J . , Wellinga Κ . , and Verloop, Α . , Symposium P e s t i c i d e s Group, S . C . I . (London, Feb. 1977). Yu, C.-C., and Kuhr, R. J . , J . Agr. Food Chem. (1976), 24, 134. Verloop, Α . , Residue Reviews (1972), 43, 55. Nimmo, W. B . , and Verloop, Α . , Ζ. f. P f l . Krankh. (1975), V I I , 147. Verloop, Α . , Nimmo, W. Β., and De Wilde, P. C . , A b s t r . Pap., 8th I n t . Plant P r o t e c t i o n Congress, Moscow (1975). Verloop, Α . , Nimmo, W. B . , and De Wilde, P . C . , submitted to P e s t i c . S c i . Metcalf, R. L . , Lu, P . - Y . , and Bowlus, S., J. Agr. Food Chem. (1975), 23, 359. Nimmo, W. Β., Verloop, Α . , and De Wilde, P. C . , submitted to P e s t i c . S c i . Still, G. G . , personal communication.


270 33. 34. 35· 36. 37.


38. 39. 40. 41. 42. 43. 44. 45. 46. 47·

48. 49· 50. 51.

PESTICIDE CHEMISTRY IN THE 20TH CENTURY Ruzo, L. O., Zabik, M. J., and Schuetz, R. D . , J . Agr. Food Chem. (1974), 22, 1106. De Wilde, P. C . , unpublished r e s u l t s , Philips— Duphar. Meltzer, J . , Houtman, A. C . , and Van der Kolk, B. J . , unpublished r e s u l t s , Philips-Duphar. Deul, D. Η., and Vos, C . , paper i n preparation. Still, G. G . , and Leopold, R. Α . , A b s t r . Pap., 170th. Meet., Amer. Chem. Soc. (1975), PEST 5. Metcalf, R. L . , Sanga, G. Κ . , and Kapoor, I. P . , Environm. S c i . Technol. (1971), 5, 709. Post, L. C . , and Willems, A. G. Μ., paper i n preparation. Post, L. C . , and Vincent, W. R., Naturwissenschaften (1973), 60, 431. Post, L. C . , De Jong, B. J . , and Vincent, W. R., Pest. Biochem. P h y s i o l . (1974),4,473. Deul, D. H., De Jong, B. J . , and Kortenbach, J . Α. Μ., submitted to Pest. Biochem. P h y s i o l . Ker, R. F . , J . Insect. P h y s i o l . , i n press. Hunter, Ε., and Vincent, J . F . , E x p e r i e n t i a (1974), 30, 1432. Deul, D. H. et al., unpublished. Ishaaya, I . , and Casida, J . Ε., Pest. Biochem. P h y s i o l . (1974), 4, 484. Marks, E . P . , and Sowa, Β . Α . , i n "Mechanism of P e s t i c i d e A c t i o n " (G. K. Kohn, e d . ) , ACS Sympo sium S e r i e s , V o l . 2 (1974), PP. 144 - 155, Amer. Chem. Soc., Washington, D.C. Sowa, Β . Α . , and Marks, E . P . , Insect Biochem. (1975), 5, 855. G i j s w i j t , M. J., Deul, D. Η . , and De Jong, B. J . , submitted to Pest. Biochem. P h y s i o l . Moreau, R., Castex, C . , and Lamy, Μ., Ann. Z o o l . E c o l . anim. (1975), 7, 161. Yu, S. J . , and T e r r i e r e , L . C . , L i f e S c i . (1975), 17, 619.


Pesticide Chemistry in the 20th Century - American Chemical Society

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