Pesticide Synthesis Through Rational Approaches - American

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Partitioning in Pesticide Mode of Action and Environmental Problems A. J. LEO Chemistry Department, Pomona College, Claremont, CA 91711 The hydrophobic parameter, as measured by logP (octanol/ water), has been used to optimize transport or binding of bioactive molecules to bacteria, organelles and in tact animals. It now appears that the optimal log Ρ is the same for animals as for plants (2.0-2.5). The direct relationship between logP (o:w) and logP (oc) (the or ganic component of soil) and between logP (o:w) and bioaccumulation in aquatic organisms makes this a useful parameter to model environmental transport and fate, especially since good progress is being made in calculat ing it from structure. The capabilities and current problems of both manual and computer calculation pro cedures is discussed. As the t i t l e of t h i s symposium suggests, i t i s becoming r a r e i n deed when " e i n g l i i c k l i s h e r z u f a l l " (1) turns up a marketable p e s t i c i d e . I t i s almost a c e r t a i n t y t h a t , i n t h i s f i e l d , the f u t u r e belongs to those who develop some s o r t of design r a t i o n a l e . R a t i o n a l design, however, i m p l i e s some knowledge of mode of action, and t h i s i n f o r m a t i o n u s u a l l y f a l l s f a r short of the u l t i m a t e ; i . e . , knowledge of the three-dimensional s t r u c t u r e of a t a r g e t enzyme, of the a c t i v e or a l l o s t e r i c s i t e s which can prevent normal sub s t r a t e p r o c e s s i n g , and of the d i f f i c u l t i e s which an i n h i b i t o r might encounter i n being transported, unmetabolized, t o the t a r g e t site. In t h i s paper the focus i s on some of the simpler aspects of mode of a c t i o n . These can be h e l p f u l i n r a t i o n a l p e s t i c i d e design even before much of the mechanistic d e t a i l s have been e l u c i d a t e d . More s p e c i f i c a l l y , the d i s c u s s i o n w i l l cover some current e f f o r t s t o apply the knowledge of hydrophobic f o r c e s a t the molecular design stage: to i n s u r e optimized p a s s i v e t r a n s p o r t to the a c t i v e s i t e , to i n c r e a s e the b i n d i n g o f i n h i b i t o r to enzyme, and t o p r e d i c t some i n c r e a s i n g l y important environmental e f f e c t s , such as bioaccumulation and s o i l t r a n s p o r t . Thus t h i s paper w i l l not address the problem of discovering new t o x i p h o r e s , but, r a t h e r the o p t i m i z i n g of some new lead w i t h respect t o these f a c t o r s . At f i r s t these f a c t o r s might seem p e r i p h e r a l , but nonetheless they 0097-6156/84/0255-0213$06.00/0 © 1984 A m e r i c a n C h e m i c a l S o c i e t y

214

PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES

have o f t e n s p e l l e d the d i f f e r e n c e between commercial failure.

success and

QSAR i n the H i l l Reaction In the search f o r more e f f e c t i v e post-emergent h e r b i c i d e s , many l a b o r a t o r i e s have measured the i n h i b i t i o n of photosystem I I i n c h l o r o p l a s t s ; i . e . , the H i l l r e a c t i o n . In a c o n t i n u i n g i n v e s t i gation of t h i s system, (2) Corwin Hansch s group at Pomona College, i n cooperation with BASF i n Germany, analyzed two sets of phenyl s u b s t i t u t e d ureas: 17 1 , l - d i m e t h y l - 3 - p h e n y l , and 38 l-methoxy-l-methyl-3-phenylurea analogs a c t i n g on spinach c h l o r o p l a s t s (Table I ) . In a l l cases, i n c l u d i n g comparisons 1

Table I

Ureas as H i l l Reaction I n h i b i t o r s

I. Substituents 1. H 4. 3-0CH3 2. 3-NOs 5. 3-nBu 3. 3-CFs 6. 3-0(CHg)sPh f

16.

3-0CHgPH-2 ,4 --CI2

II. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Substituents H 3-t-Bu 3-F 3-CN 3-0-CHsPh 3-CHsOH 3-OH 3-NOs 3-CFs 3-0(CH2) 0Ph 3-OCHsO-Adm 3-CI, 4-0CHsPh 3-Cl,4-OCHsCOAdm 4

f

14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

7. 3-OH 8. 3-NHs 9. 3,4-Cls

10. 11. 12.

4-COPh 4-F 4-CyRex

17.

3-CI ,4-C02CH(CH2-i-Pr)2

(Flourenyl) 4-NO2 4-NHs 4-OCH2PI1 4-0(CH2)2Ph4 -Me 4-CH=C(CN)2 4-NHEt 4-N(Et)2 '4-COCH3 4-Br 4-F 4-C02Et 4-COPh f

27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

13. 14. 15.

4-t-Bu 4-i-Pr 4-0-n-Dec

4-i-Pr 4-NHSO2CH3 4-Cy-Hex 4-0(CH2)2-CyHex 4-0CH(CH3)CH2-CyHex 4-0(CH2>40Ph 4-0CH2C0Adm 4-0(CH2)2-a-Naph 4-(CH2)2Ph 4-(CH2>4Ph 4-(CH2)3Ph-4 -Cl 4-(CH2)3Ph-4 -Ph f

f

with other t o x i p h o r i c groups, the b i o l o g i c a l a c t i v i t y i s expressed i n terms of I 5 0 , which i s the molar c o n c e n t r a t i o n of i n h i b i t o r causing a 50% i n h i b i t i o n of the H i l l r e a c t i o n (Table I I ) . B a s i c a l l y , t h i s work confirmed an e a r l i e r study which found the hydrophobic e f f e c t of the phenyl s u b s t i t u e n t s to be the dominant

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Partitioning in Pesticide MOA

f e a t u r e i n the QSAR, and no e l e c t r o n i c term proved to be s i g n i f i c a n t . A b i l i n e a r term f o r l o g Ρ and a branching f a c t o r f o r s u b s t i t u e n t s i n the 4 - p o s i t i o n d i d prove m a r g i n a l l y s i g n i f i c a n t and could be a p p l i e d to the methoxyureas a l s o (Table I I I ) . I t

Table I I

I n h i b i t i o n of H i l l Reaction i n Spinach C h l o r o p l a s t s

pl50 =

η = 17 r

1. 0.54(±.17)logP + 4.32(±.53) 2. 0.66(±.20)logP - 1 . 1 8 ( ± 1 . 3 ) l o g ( 3 i

s

log P

n

.875 .584 1OgP 0

F Λ ,..

(15)48.7

+ l ) + 4.11(±.55) .906 .549 5.83 (13) 1.98

3. 0.81(±.17)logP - 1 . 0 8 ( ± . 5 9 ) l o g ( 3 i

l08 0

?

+D

- O.llBr(±.07)+4.01 (± .41)

.957 f

Br

f

.390 5.21 (12)13.8

i s branching f a c t o r f o r 4 - p o s i t i o n ; equals MR f o r smaller of

Ri or Rs in-Y

w i l l be noted that i n Equation 2, Table I I f o r example, the upward slope of the i n i t i a l l i n e a r p o r t i o n of the r e l a t i o n s h i p at low l o g Ρ values i s given by the c o e f f i c i e n t , +0.66. The down ward slope at high l o g Ρ values i s given by the sum of the c o e f f i c i e n t s of the f i r s t two terms: +0.66 - 1.18 = -0.52. Thus a simple p a r a b o l i c equation given by: a l o g Ρ - b ( l o g P) would serve very w e l l f o r Equation 2, but i t would p o o r l y f i t Equation 3 i n e i t h e r the dimethyl (Table I I ) or methoxymethyl (Table I I I ) s e r i e s . I t w i l l be noted that i n i s o l a t e d spinach c h l o r o p l a s t s , one hardly needs to worry about making an i n h i b i t o r too hydrophobic; i . e . optimal l o g Ρ = 5.2 f o r the Ν,Ν-dimethyl- and 5.4 f o r the methoxymethyl-ureas. In c o n t r a s t to the i s o l a t e d c h l o r o p l a s t s t u d i e s , one sees from a l i s t of commercially s u c c e s s f u l herbicides f o r which l o g Ρ values have been measured or c a l c u l a t e d , (Table IV) that g e t t i n g the h e r b i c i d e to the c h l o r o p l a s t i n the l i v i n g p l a n t places much g r e a t e r r e s t r i c t i o n s on i t s h y d r o p h o b i c - h y d r o p h i l i c balance. Indeed, the average l o g Ρ of t h i s s e t i s only 2.54. s


216

Table I I I

I n h i b i t i o n of H i l l Reaction i n Spinach C h l o r o p l a s t s by N-methoxyureas / T ' A f*

/OCHs

\\-NHC0N

V

X

pl50 =

CH 3 η = 38 r

s

logP

1. 0.65(±.15)logP + 3.73(±.47)

.832

.749

la.0.84(±.27)logP* + 3.39(±.61)

.907

.555

Q

Fi ,, (36) 80.9

2. 0.67(±.ll)logP - 0.14(±.06)Br + 3.85(±.37) .907 3. 1.02(±.18)logP - 0.95(±.43)log(3

lOgP 1o

.577

(35) 25.6

+l)-0.l7(±.05)Br

+ 3.37(±.37) .944 .465 5.40 log P* = measured p a r t i t i o n c o e f f i c i e n t s ; η = 12 B r = branching f a c t o r as defined i n F i g . 2. f

(33) 10.3

f

Table IV

£Η Cl Y /

\\-NHC0N

Log Ρ of Commercial H e r b i c i d e s

3

X

V

Bromacil =2.02 C l

Diuron =2.68

Cl - / T \ N H C O C H C H 2

M

C l

B r X (

3

.. ....

P r o p a n i l =(3.50)

C

H

A

)3

C

\ ^

/

CH2CH3 H

S

Μ, S

^

C

H

3

Sencor =1.70 /CHs

C

1

_ / /

XV-NHCOM'

Π

^1

C

H

3

3 Cl

NHCh islHCHsCHs

7

Linuron =2.76

A t r a z i n e =2.60

3.20

2.75

Average l o g Ρ = 2.54 ( ) = calculated log Ρ

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LEO

F i g u r e 1.

Optimizing both Transport and H i l l Reaction I n h i b i t i o n

hydrophobic

NHCONRs

hydro\ / philic Hydrophobic c h a i n should extend to l i m i t of enzyme's hydro phobic area; p o l a r group (X) does not then decrease b i n d i n g but enhances t r a n s p o r t . T h i s i n f o r m a t i o n suggests a design r a t i o n a l e which may s a t i s f y both requirements. I t i s p i c t u r e d i n F i g u r e 1. One s t a r t s with a toxiphore w i t h reasonable i n t r i n s i c a c t i v i t y ( i . e . , w i t h i s o l a t e d c h l o r o p l a s t s ) . Hydrophobic b i n d i n g to the enzyme can then be increased w i t h a c h a i n or r i n g - c h a i n combination attached to the para p o s i t i o n . The hydrophobic r e g i o n of the enzyme cannot extend i n d e f i n i t e l y , and there i s a good p o s s i b i l i t y that i t opens i n t o solvent space. Therefore a p o l a r fragment, X, can be placed f a r enough out so i t cannot a f f e c t t h i s b i n d i n g (and t h e r e f o r e H i l l i n h i b i t i o n ) but i t s t i l l could b r i n g the s o l u t e l o g Ρ i n t o the optimal 2.0 to 3.0 range. A matter of p h i l o s o p h i c a l r a t h e r than p r a c t i c a l s i g n i f i c a n c e i s the c l o s e s i m i l a r i t y i n the optimal h y d r o p h o b i c i t y f o r the random-walk process i n p l a n t s and animals. In a s e r i e s of papers dating bact to 1968, Hansch (3) has shown that drugs a c t i n g r a t h e r n o n - s p e c i f i c a l l y i n the animal c e n t r a l nervous system, such as a n e s t h e t i c s and b a r b i t u r a t e s , a l s o have an optimal l o g Ρ i n the 2.0 to 2.5 range (Table V ) . Table V

CHa-CHa^ CHs

I

^

/"'ΛΝ^"" CHa^

Log Ρ of some CNS

Cl

Methoxyflurane

Ck Cl

P e n t o b a r b i t a l =2.10

Depressants

=2.21

lr

^CH-dî-O-CHFa :H-O-OF

CL ^CH-CF Cl

3

Ethrane =

2.10

Halothane =2.30

The eleven equations shown i n Table VI express the a c t i v i t y of a group of H i l l Reaction i n h i b i t o r s (4-11). A common s t r u c t u r a l f e a t u r e , i n a l l the sets except Number 5, seems to be a n i t r o g e n atom having c o n s i d e r a b l e double bond c h a r a c t e r . A c t i v i t y i s


218

s t r o n g l y dependent on h y d r o p h o b i c i t y , while the r o l e of e l e c t r o n i c e f f e c t i s minimal or absent. Just the i n t e r c e p t i t s e l f i s a f a i r measure of i n t r i n s i c a c t i v i t y , keeping i n mind that d i f f e r i n g ex perimental c o n d i t i o n s could account f o r as much as 0.5 d i f f e r e n c e i n the i n t e r c e p t v a l u e . The i n t e r c e p t of 0.56 f o r benzimidazoles i s i n the range of n o n - s p e c i f i c t o x i c i t y caused by a l c o h o l s and other simple n e u t r a l molecules; i . e . , 0 to 1.0 (12). So i t would seem unwarranted to speak of a t o x i p h o r e i n the 2-CF3-benzimida z o l e moiety. On the other end of the s c a l e are the 1 , 2 , 4 - t r i a zinones i n v e s t i g a t e d by Draber with an i n t r i n s i c a c t i v i t y 10,000 f o l d greater (11). f

Table VI

f

I n t r i n s i c A c t i v i t y i n H i l l Reaction

p l s o = (a) l o g Ρ +

Inhibition

φ)

Coefficient (a) 1.35 1. 2-CF3-benzimidazoles (4) 0.71 2.*N-Ph-i-propylcarbamates (5) 0.77 3.*N-Ph-ethylcarbamates (5) 1.23 4. i - b u t y r i c a c i d a n i l i d e s (5) 0.46 5. d i p h e n y l ethers (6) 0.75 6. N - a r y l - p y r r o l o n e s (7) 1.07 7.**phenoxyphenyldimethyl ureas (6) 1.12 8 . * * 3 - a l k o x y u r a c i l s (8) 1.03 9. l-Ph-3-methyl ureas (9) 0.85 10. a z i d o t r i a z i n e s (10) 0.86 11. 1,2,4-triazinones (11)

Intercept

Φ) 0.56 0.87 1.34 1.74 2.30 3.15 3.20 3.78 4.27 4.27 4.84

η 25 9 7 10 18 32 14 23 15 17 11

r .93 .95 .957 .935 .927 .852 .935 .991 .957 .857 .864

* Has sigma term; probably c o r r e c t s a c a l c u l a t e d l o g Ρ. ** Has small b i - l i n e a r component; (7.) i n c l u d e s DCMU a l s o .

Environmental

Effects

Obviously i t i s important to know as much as p o s s i b l e about the mode of a c t i o n of p e s t i c i d e s on NON-target organisms i f the d i f f e r e n t i a l between them (pest and non-pest) i s to be maximized. But again some i n t e l l i g e n t choices can be made based on knowledge of some simpler 'modes of a c t i o n ' , such as: how does an organism c o l l e c t a higher c o n c e n t r a t i o n of a p e s t i c i d e than i s i n the environment i n which i t i s l i v i n g ? And how does a chemical t r a v e l through s o i l , water and a i r and a r r i v e at l o c a t i o n s f a r from any s i t e of a p p l i c a t i o n ? In a c l a s s i c study, Neely, Branson and Blau (13) showed that the r a t e of uptake and e l i m i n a t i o n of chemicals i n t r o u t was r e l a t e d to the chemical's octanol/water p a r t i t i o n c o e f f i c i e n t . Just as a drop of o c t a n o l would e q u i l i b r a t e w i t h one m i l l i o n times the c o n c e n t r a t i o n of some PCBs as the water which surrounded i t , so

13.

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219

would a t r o u t i n Lake Michigan. One of the most thorough s t u d i e s of the bioaccumulation of s o l u t e s i n v a r i o u s aquatic organisms has been undertaken by the Environmental Research Laboratory at Duluth, Minn. (14). In the e f f o r t of modeling t r a n s p o r t through s o i l s , a t t e n t i o n has been focused on the p a r t i t i o n i n g of s o l u t e s between water and the organic component of s o i l . Kenaga (15) and Briggs (16) have accumulated much v a l u a b l e data to support the r o l e of a hydrophobic parameter i n s o i l t r a n s p o r t and have shown that there i s a r e l a t i o n s h i p between Log Ρ (octanol/water) and Log Ρ (org. comp. s o i l / w a t e r ) , but the r e l a t i o n s h i p s d i f f e r some what f o r d i f f e r e n t c l a s s e s of chemicals. P r e d i c t i n g Hydrophobicity from S t r u c t u r e In s p i t e of c o n s i d e r a b l e e f f o r t to s i m p l i f y i t by HPLC and other techniques (17, 18), measurement of octanol/water p a r t i t i o n c o e f f i c i e n t s remains a demanding and c o s t l y a c t i v i t y . Even though the number of chemicals f o r which hydrophobic parameters are needed f o r environmental hazard assessment i s huge, f o r t u n a t e l y the precision necessary f o r bioaccumulation or t r a n s p o r t modeling i s not so demanding. For a 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 by r e g r e s s i o n a n a l y s i s , we expect a parameter p r e c i s i o n of +0.1. For most environmental assessment, a p r e c i s i o n of ±0.3 i s adequate. I t appears p o s s i b l e to reach t h i s lower l e v e l of p r e c i s i o n with a r a p i d , cheap computer c a l c u l a t i o n based on a w e l l - t e s t e d manual procedure (19) . The program, CLOGP, w i l l operate on s t r u c t u r e s i n d i v i d u a l l y s u p p l i e d by the operator, or e l s e i t w i l l accept connection t a b l e s normally a part of a l a r g e s t r u c t u r a l l y - d i v e r s e chemical f i l e . I t i s designed to operate on the new generation of desk-top computers using e i t h e r Fortran-77 or Unix language. Before i l l u s t r a t i n g the o p e r a t i o n of CLOGP-3, the point should be made c l e a r that c a l c u l a t i o n and measurement should be considered as complimentary t o o l s r a t h e r than one being a r e p l a c e ment f o r the other. Of course c a l c u l a t i o n i s the only a l t e r n a t i v e f o r the p e s t i c i d e design chemist when he must make a d e c i s i o n about what analogs to s y n t h e s i z e . Measurement ' a f t e r the f a c t might show that a compound, synthesized at some great expense, was out of the d e s i r a b l e l o g Ρ range. When both measurements and c a l c u l a t i o n s are a v a i l a b l e , d i s c r e p a n c i e s between the two values can r a i s e some i n t e r e s t i n g p o s s i b i l i t i e s : Not i n f r e q u e n t l y the measured v a l u e i s wrong; sometimes the measured v a l u e i s lower because of an a p p r e c i a b l e amount of i o n i z a t i o n was not allowed for; or e l s e a tautomeric form was not considered. Sometimes a p o s i t i v e d e v i a t i o n (Calculated-Measured) can i n d i c a t e that con formation i n the aqueous phase r e s u l t s i n overlapping of hydro phobic p o r t i o n s of the s o l u t e , while a negative d e v i a t i o n might be i n t e r p r e t e d as h y d r o p h i l i c o v e r l a p . An example of the l a t t e r i s seen with adenosine, which has a negative d e v i a t i o n even though adenine and r i b o s e are reasonably w e l l c a l c u l a t e d . I t should be 1


220

obvious, t h e r e f o r e , that to get the maximum b e n e f i t from use of the CLOGP program one must at l e a s t be f a m i l i a r w i t h the theory upon which the c a l c u l a t i o n s are based. I t i s q u i t e an investment i n time to l e a r n all the r u l e s necessary f o r manual c a l c u l a t i o n but i n the process one may l e a r n a great d e a l about the r e l a t i v e s o l v a t i o n f o r c e s which compete i n the aqueous and the l i p i d phases. The most advanced computer v e r s i o n , CLOGP-3, i s r e a l l y a log Ρ modelling system; that i s , a l l the numerical data to operate i t r e s i d e s i n t a b l e s which can conveniently be changed or updated. F i g u r e 2 i l l u s t r a t e s two kinds of s t r u c t u r e entry which can provide the s u i t a b l e connection t a b l e input f o r benzoic a c i d : F i g u r e 2.

Computer Storage of 2-dimensional S t r u c t u r e as L i n e a r Array

^""^-C^

1)

WLN:

2)

SMILES:

Benzoic A c i d

QVR clccccclC(=0)0 C1=CC=CC=C1C(=0)0 OC(=0)clcccccl

or, or, ( s t a r t i n g point a r b i t r a r y )

1) Wiswesser L i n e N o t a t i o n (WLN), (20) or 2) SMILES. The l a t t e r method, developed by David Weininger, c o n s i s t s of a l i n e a r array of atomic symbols and numbers which i n d i c a t e r i n g bonds 'broken' to maintain l i n e a r i t y . T h i s c h a r a c t e r s t r i n g , hydrogen-suppressed to save space, i s converted to a unique format by means of graph theory and thence to a connection t a b l e (21). In c o n t r a s t to the e f f o r t r e q u i r e d to l e a r n to w r i t e WLN, where the encoder i s r e s p o n s i b l e f o r uniqueness, SMILES can be mastered by a chemist i n f i v e minutes. Used to enter new s t r u c t u r a l 'fragments' i n t o the program, SMILES promotes both speed and accuracy i n t h i s most c r i t i c a l step. Table VII i l l u s t r a t e s the entry format f o r the carboxamido fragment. Measurements from a number of s o l u t e s have e s t a b l i s h e d the v a l u e s f o r many of i t s bond 'environments' and i t s s u s c e p t i b i l i t y to proximity e f f e c t s . Table V I I I shows the fragment data f o r N-oxy-urea. I t i s immaterial which d i r e c t i o n the operator chooses to enter the fragment s t r u c t u r e , because the program de velops a unique sequence f o r fragments j u s t as i t does when d e a l ing w i t h complete s t r u c t u r e s . Of course the operator must use care to a s s o c i a t e the c o r r e c t bonding designations with the a p p r o p r i a t e d a t a . Two c a l c u l a t i o n s using t h i s fragment w i l l serve to i l l u s t r a t e some f e a t u r e s of the program.

13.

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221


Table V I I

Data Entry f o r Carboxamido Fragment

Fragment S t r u c t u r e : (one of s e v e r a l a l t e r n a t e s which program converts t o GSMILE) 1, 3

Entered SMILES: *C( =0)N* :

GSMILE :

C(= 0)(N*)*

English:

NH-Amide

SIGMA RHO RHO PROXTYPE OCLASS OCLASS

1 1 3

0.32 0.72 1.08 2.0 12 18

1 3

Table V I I I Fragment S t r u c t u r e :

Entered SMILES: GSMILE: English:

Attchm:

Bond types: aa Aa AA aA AY AV VA ZA

M M M M M E E C

= = = = =

a A Y V Ζ

-1.06 -1.81 -2.71 -1.51 -1.52 -2.26 -2.11 -2.5

to to to to to

aromatic I s o l . Carbon a l i p h a t i c I.C. s t y r y l I.C. v i n y l I.C. benzyl I.C.

Data Entry f o r N-oxy-Urea Fragment 0 G—> ^-NHC-N^

*NC(=0)N(*)0*

C(=0)(N(0*)*)N* 1-oxy-1,3-Urea

PROXTYPE OCLASS 7 RHO 7

2.0 17.0 1.08

AAa M -2.13 Note: Bond types AAa a r e given i n order of a s t e r i s k s yi GSMILE; i . e . , a l i p h a t i c to -0- and -N and aromatic to -NHf

?

v

Other f a c t o r s being equal, the l a r g e r the s o l u t e molecule the higher i t s l o g Ρ. But the fragment values l i s t e d i n the computer computation of l o g Ρ f o r the p-nitrophenyl-N-methoxyurea and i t s 2,4-dichloro analog (Table I X ) , c l e a r l y show that the p o l a r i t y of the n i t r o group overcomes i t s b u l k i n e s s ; i . e . , the n i t r o i s negative while the smaller C l i s s t r o n g l y p o s i t i v e . The n i t r o group does enhance hydrophobicity by an e l e c t r o n i c e f f e c t (22, 23) because of the presence of the very s u s c e p t i b l e urea s u b s t i t u e n t with i t s -NH- attachment. I t i s evident that two c h l o r i n e s u b s t i t u e n t s a l s o produce a s i z e a b l e e l e c t r o n i c enhance ment of h y d r o p h o b i c i t y . However t h i s i s more than c a n c e l l e d when

222


Table IX

Examples of CLOGP-3 OUTPUT

NAME: 3-(p-nitrophenyl)-l-methoxy-l-methylurea SMILES:

CON(C)C(=0)Nclccc(ccl)N(=0) (=0)

/ Ο2Ν-Λ

=

=

\ OCHs Λ-NHCON^

Class Type Value Comment Contribution Description EXFRAGMENT CARBON 0.40 2 A l i p h a t i c i s o l a t i n g carbon(s) EXFRAGMENT CARBON 0.78 6 Aromatic i s o l a t i n g carbons EXFRAGMENT HYDROG 2.30 10 Hydrogens on I.C. EXFRAGMENT BONDS -0.24 (combined)2 c h a i n and 0 a l i c y c l i c (net) FRAGMENT #1 -2.13 MEASURED l-Oxy-1,3-urea FRAGMENT #2 -0.03 MEASURED N i t r o 1 P o t e n t i a l i n t e r a c t . 1 used ELECTRONIC SIGRHO 0.648 InRing CLOGP V e r s i o n 3.04 1.728 ANSWER 1.74 (Measured) B. NAME : 3-(2,4-dichlorophenyl)-1-methoxy-l-methylurea

,0CH

3

-NHC0N

SMILES:

CON(C)C(=0)Nclc(Cl)cc(Cl)ccl

Cl-

Contribution Description Class Type Value Comment A l i p h a t i c i s o l a t i n g carbon(s) EXFRAGMENT CARBON 0.40 Aromatic i s o l a t i n g carbons EXFRAGMENT CARBON 0.78 Hydrogens on I.C. EXFRAGMENT HYDROG 2.07 EXFRAGMENT BONDS -0.24 (combined)2 c h a i n and 0 a l i c y c l i c (net) FRAGMENT #1 -2.13 MEASURED l-Oxy-1,3-Urea FRAGMENT #2 0.94 MEASURED C h l o r i d e FRAGMENT #3 0.94 MEASURED C h l o r i d e 2 P o t e n t i a l i n t e r a c t . ; 1.5 used. ELECTRONIC SIGRHO 0.454 InRing 1 normal ortho i n t e r a c t . ORTHO RING 1 -0.56 2.654 ANSWER Log Ρ not measured, but 3 , 4 - d i c h l o r o isomer = 3.20; and a p p l y i n g ortho c o r r . =2.64 (second estimate)

one c h l o r i n e i s i n the 2 - p o s i t i o n (24). T h i s negative ortho e f f e c t appears r e l a t e d t o both the s t e r i c and sigma i n d u c t i v e v a l u e s of the two s u b s t i t u e n t s i n v o l v e d , but as y e t i t cannot be c a l c u l a t e d de novo, and so i t must be looked up i n a t a b l e when log Ρ i s manually c a l c u l a t e d . The a b i l i t y of the computer t o both save time and prevent e r r o r s i s r e a d i l y apparent t o anyone who has attempted c a l c u l a t i o n of a d i v e r s e s e t of s t r u c t u r e s . A f i n a l example i n Table X shows the l o g Ρ computation which CLOGP-3 performs on a t r a z i n e . I f the t h r e e ' I s o l a t i n g Carbon atoms i n the r i n g were t r u l y i s o l a t i n g , the n e g a t i v e fragments would predominate and a v a l u e of -1.15 would be obtained. The 1

13.

LEO

Table X

NAME: SMILES :

223


Example of CLOGP-3 OUTPUT

Atrazine CC(C)Nclnc(NCC)ne(Cl)nl

Cl

SIHCH2CH3

Class 5 EXFRAGMENT CARBON 1,,00 3 EXFRAGMENT CARBON 0,,39 12 EXFRAGMENT HYDROG 2,,76 EXFRAGMENT BRANCH-0,.22 (Group) 1 EXFRAGMENT BONDS -0,,60 5 FRAGMENT #1 -1, 03 MEASURED FRAGMENT #2 -1, 12 MEASURED FRAGMENT #3 -1, 03 MEASURED FRAGMENT #4 -1, 12 MEASURED FRAGMENT #5 0 94 MEASURED FRAGMENT #6 -1 12 MEASURED FRAGMENT REDUCE 0 84 3 ELECTRONIC SIGRHO 3 232 InRing 8 2 922 ANSWER 2.75 MEASURED

A l i p h a t i c i s o l a t i n g carbon(s) Aromatic i s o l a t i n g carbons Hydrogens on I.C. non-halogen, p o l a r group branch chain and 0 a l i c y c l i c (net) Secondary amine Aromatic n i t r o g e n (Type 2) Secondary amine Aromatic n i t r o g e n (Type 2) Chloride Aromatic n i t r o g e n (Type 2) D e l o c a l i z e d TYPE 2 fragments* P o t e n t i a l i n t e r a c t . ; 3.69 used* *see text

strong i n d u c t i v e e f f e c t of the r i n g nitrogens on the amino sub s t i t u e n t s increase hydrophobicity by a programmed f a c t o r of 4.07 log u n i t s , * b r i n g i n g the c a l c u l a t e d v a l u e i n good agreement w i t h the measured. E l e c t r o n i c parameters a r e f r e q u e n t l y important i n QSARs f o r whole organisms, but i t may be r e l e v a n t to d i s t i n g u i s h e l e c t r o n i c i n f l u e n c e s i n the transport process, when the p e s t i c i d e i s merely a s o l u t e , from those a c t i n g on the target enzyme when the chemical is a ligand. Summary Hydrophobicity i s o f t e n an important, or even a dominant, param eter i n h e r b i c i d a l a c t i v i t y . At the present s t a t e of the a r t , i t might be f a i r t o s t a t e that de novo c a l c u l a t i o n of l o g Ρ may not be s u f f i c i e n t l y accurate f o r r e g r e s s i o n a n a l y s i s , but coupled w i t h measurements of one or two key analogs, i t may e l i m i n a t e the need to measure each and every chemical i n the s e t . C e r t a i n l y de novo c a l c u l a t i o n can be used as a p r e d i c t i v e t o o l p r i o r t o s y n t h e s i s , and i t can serve q u i t e adequately f o r the l e s s demanding r e q u i r e -

224

PESTICIDE SYNTHESIS T H R O U G H

RATIONAL APPROACHES

ments of bioaccumulation and environmental t r a n s p o r t models. At the present time, the use of the hydrophobic parameter i n r a t i o n a l p e s t i c i d e design seems to be l i m i t e d more by the l a c k of r e l i a b l e p a r t i t i o n i n g data than by the l a c k of experience or the u n f a m i l i a r i t y of workers i n t h i s f i e l d . I t w i l l be some time before published measurements can overcome t h i s l a c k , but i n combination with r e l i a b l e c a l c u l a t i o n , the f u t u r e of t h i s approach looks q u i t e promising.

Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

Hansch, C.; J. Chem. Educ. 1974, 51, 360. Kakkis, E . ; Palmire, V.; Strong, C.; Bertsch, W.; Hansch, C.; Schirmer, U. J. Agric. Food Chem. (submitted) Hansch, C. Drug Dev. Res. 1981, 1, 267. Büchel, K.; Draber, W. in "Progress Photosynthesis Research"; 1968, 3, 1777. Hansch, C. ibid., 1969, 3, 1685. van den Berg, B; Tipker, J. Pestic. Sci. 1982, 13, 29. Brugnoni, G.; Moser, P.; Trebst, A. Z. Naturforsch. 1979, 34C, 1028. Brown, B.; Phillips, J.; Rattigan, B. J . Agric. Food Chem. 1981, 29, 719. Seewald, I,; Michel, H.; Klepel, M.; Held, P.; Ohmann, E.; Barth, Α.; Metzger, U. in "Quantitative Structure-Activity Analysis'; Akademie Verlag, Berlin, 1978, 77. Gabbott, P. in "Progress Photosynthesis Research, 1969, 3, 1712. Draber, W.; Dickore, K.; Büchel, K.; Trebst, Α.; Pistorius, E. Naturwiss. 1968, 55, 446. Hansch, C.; Dunn III, W. J . Pharm. Sci. 1972, 61, 1. Neeley, W.; Branson, D.; Blau, G. Environ. Sci., Technol. 1974, 8, 1113. Veith, G.; Macek, K.; Petrocelli, S.; Carroll, J . "Aquatic Toxicity" ASTM STP 707, Eaton, Parish & Hendricks, Eds., Philadelphia, 1980, p. 116. Kenaga, E. Environ. Sci. Technol. 1980, 14, 553. Briggs, G.; Austr. J . Soil Res. 1981, 19, 61. Unger, S. H.; Feuerman, T. F. J . Chromatog. 1979, 176, 426. Braumann, T.; Weber, G.; Grimme, L. H. J . Chromatog. 1983, 261, 329. Hansch, C.; Leo, A. "Substituent Constants for Correlation Analysis in Chemistry and Biology". Wiley Interscience, New York. 1979, Ch. IV. Smith, E . ; Baker, P. "The Wiswesser Line-Formula Chemical Notation (WLN)" 3rd Ed., CIMI, New Jersey, 1975. Weininger, D. in preparation. Fujita, T. J . Pharm. Sci. 1983, 72, 285. Brandstrom, A. Acta Pharm. Suec. 1982, 19, 175. Leo, A. J.C.S. Perkin II. 1983, 825.

RECEIVED

December 23, 1983

Pesticide Synthesis Through Rational Approaches - American

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