StructureâActivity Correlations for Meta- and Para-Substituted

12 Structure-Activity Correlations for Meta -and Para-Substituted Trifluoromethane Downloaded via YORK UNIV on December 4, 2018 at 00:55:49 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

-sulfonanilide Pre-Emergence Herbicides ANTHONY F. YAPEL, JR. Central Research Laboratories, 3M Co., St. Paul, Minn. 55133

The Hansch equation was used to correlate pre-emergence herbicidal activity with structure for 15 meta- and para -substituted trifluoromethanesulfonanilides (TFMS). Dose -response data were collected for two grasses (Foxtail, Cheat Grass) and a broadleaf (Wild Mustard). The most significant correlations result when the herbicides are separated into meta- and para-substituted compounds and fitted separately. Each herbicidal class exhibits a unique optimum substituent π value in its action on each weed type. Substituents having large, positive Hammett sigma constants enhance herbicidal action whether substituted meta or para to the parent group. The effects of the surfactant Tween 80 on the partitioning characteristics and pre-emergence activity of the TFMS compounds were examined. Hansch relationships which quantitate these effects on herbicidal activity were derived.

A lmost 15 years h a v e elapsed since t h e i n i t i a l preparations of trifluoromethanesulfonanilide

(TFMS)

a n d other r e l a t e d

perfluoroalkane-

sulfonanilides w e r e r e p o r t e d b y B r i c e a n d T r o t t ( I ) a n d B u r d o n et al. ( 2 ) . NH-S0 -CF 2

3

Trifluoromethanesulfonanilide ( T F M S ) I 183 Van Valkenburg; Biological Correlations—The Hansch Approach Advances in Chemistry; American Chemical Society: Washington, DC, 1974.

184

BIOLOGICAL

CORRELATIONS

T H E HANSCH APPROACH

S i n c e that t i m e , m o n o - a n d d i f l u o r o m e t h a n e s u l f o n a n i l i d e s have also b e e n s y n t h e s i z e d ( 3 ) , b u t u n t i l r e c e n t l y the b i o l o g i c a l a c t i v i t y of f l u o r i n a t e d T F M S c o m p o u n d s h a d not b e e n investigated. I n e a r l y 1970, H a r r i n g t o n et al. (4) r e p o r t e d that a b r o a d class of fluoroalkanesulfonanilides a n d N - a c y l substituted fluoroalkanesulfonanilides e x h i b i t e d general a n t i - i n f l a m m a t o r y characteristics. T h e i r b i o l o g i c a l screening studies i n d i c a t e d that t w o m e m b e r s of a series of 3 - b e n z o y l fluoroalkanesulfonanilides [3'-benzoyl-l,l-difluoromethanesulfonanilide ( II ) and ethyl-m-benzoyl-N-(trifluoromethanesulfonyl)carbanilate (III)] were particularly active: N-SO2-CF;

II

III

T h e l o w occurrence of u n d e s i r a b l e side effects i n experiments o n c o m m o n l a b o r a t o r y test a n i m a l s (rats, m i c e , g u i n e a pigs, etc.) c o u p l e d w i t h their h i g h b i o l o g i c a l a c t i v i t y m a d e I I a n d I I I e s p e c i a l l y attractive a n t i - i n f l a m m a t o r y agents. I n late 1970, T r e p k a , H a r r i n g t o n , R o b e r t s o n , a n d W a d d i n g t o n ( 5 ) r e p o r t e d that a n u m b e r of substituted trifluoromethanesulfonanilides b a s e d on I a b o v e e x h i b i t e d p r e - a n d post-emergence h e r b i c i d a l p r o p e r ties. H e r b i c i d a l a c t i v i t y was closely r e l a t e d to the degree of fluorination of the a l k y l s u l f o n a m i d e side c h a i n , w i t h the t r i f l u o r o m e t h a n e s u l f o n a m i d o group s h o w n i n I b e i n g the most potent of a n u m b e r of p a r t i a l l y a n d c o m p l e t e l y fluorinated a l k y l s u l f o n a m i d o parent groups e x a m i n e d . A s s h o w n i n T a b l e I, m o n o - a n d d i s u b s t i t u t i o n i n the a r o m a t i c r i n g of T F M S ( I ) significantly influenced o v e r a l l p r e - a n d post-emergence T F M S a c t i v i t y as w e l l as h e r b i c i d a l selectivity t o w a r d a v a r i e t y of grasses, b r o a d l e a f w e e d s , a n d crops. T h e effect of r i n g s u b s t i t u t i o n o n h e r b i c i d a l selectivity is s h o w n b y the asterisk ( * ) - m a r k e d T F M S m o n o s u b s t i t u t e d derivatives i n T a b l e I. 3-C1, 4-C1, or 3 - N 0 s u b s t i t u t i o n greatly e n h a n c e d the b r o a d leaf selectivity of the T F M S parent c o m p o u n d w h i l e essentially e l i m i n a t i n g h e r b i c i d a l p o t e n c y against grasses. C o n t r a s t i n g l y , m e t h y l s u l f o n y l (-SO0-CH3) s u b s t i t u t i o n i n the p a r a p o s i t i o n e l i m i n a t e d the b r o a d l e a f h e r b i c i d a l a c t i v i t y of T F M S w h i l e g r e a t l y e n h a n c i n g its p r e - e m e r g e n c e a c t i v i t y against grasses. A l t h o u g h the 2-C1 a n d 4 - F m o n o s u b s t i t u t e d series m e m b e r s w e r e h i g h l y active, t h e y d i d not e x h i b i t species selectivity i n t h e i r m o d e of h e r b i c i d a l a c t i o n . T h e 2 , 4 - d i c h l o r o - a n d 2 , 4 - d i f l u o r o T F M S derivatives s i m i l a r l y f a i l e d to e x h i b i t specificity t o w a r d either the grasses or b r o a d l e a f weeds b u t w e r e h i g h l y active against a l l w e e d species 2

Van Valkenburg; Biological Correlations—The Hansch Approach Advances in Chemistry; American Chemical Society: Washington, DC, 1974.

12.

YAPEL, JR.

Trifluoromethanesulfonanilide

185

Herbicides

tested. C r o p s e l e c t i v i t y was also n o t e d for m a n y T F M S series m e m b e r s , w i t h the 2,4-difluoro a n d 2,4-dichloro d e r i v a t i v e s b e i n g p a r t i c u l a r l y selective i n r e m o v i n g grasses a n d b r o a d l e a f w e e d s f r o m c o r n a n d soy beans ( 5 ) . A l t h o u g h structure—activity studies w e r e c a r r i e d out o n t h e s u b s t i t u t e d trifluoromethanesulfonanilides, T r e p k a a n d co-workers ( 5 ) n o t e d that no single p r o p e r t y of the T F M S series m e m b e r s tested c o u l d satis f a c t o r i l y e x p l a i n t h e i r o b s e r v e d h e r b i c i d a l a c t i v i t y a n d selectivity t o w a r d grasses, broadleaves, a n d crops. T h e y c o n c l u d e d that a c o m b i n a t i o n of steric, a c i d i c , l i p o p h i l i c , a n d electronic properties m u s t g o v e r n the p r e a n d post-emergence h e r b i c i d a l a c t i v i t y of the T F M S c o m p o u n d s . Hansch Structure—Activity

Correlations

A l t h o u g h the c o m p l e x h e r b i c i d a l a c t i v i t y a n d selectivity c h a r a c t e r istics of the trifluoromethanesulfonanilides c o u l d not b e c o r r e l a t e d w i t h single m o l e c u l a r properties of series m e m b e r s , w e b e l i e v e d that a n a p p r o Table I .

Pre-Emergence Herbicidal A c t i v i t y of Substituted Trifluoromethane Sulfonamides

(5)

a

4 Four Grass Species, Dosage in lb./acre

b

X

2-C1 *3-Cl *4-Cl 4-F *3-N0 2-SCH *4-S0 CH 2

3

2

3

2-CH3, 4-C1 2-C1, 4-CF3

2,4-di-Cl 2,4-di-F

10

δ

100 0 30 100 50 100 93 40 100 100 100

92 0 0 90 0 100 93 0 57 100 100

2.δ 72

0 0 90 0 100 85 0 30 100 100

Four Broadleaf Species, Dosage in lb./acre

0

10

δ

2.δ

100 100 93 97 100 87 0 100 100 100 100

100 100 72 97 100 60 0 100 97 100 100

92 70 40 97 0 52 0 100 53 100 100

° Pre-emergence activity: 0 = no kill; 100 = complete kill. Tests run in illuminated greenhouse. Grass species: Giant Foxtail (Setaria faberii), Barnyard grass (Echinochloa crusgalli), Crabgrass (Digitaria ischaemum), Quackgrass (Agropyron repens). Broadleaf species: Pigweed (Amaranthus retroflexus), Purslane (Portulaca vieracea), Wild Mustard (Brassica kaber), Annual Morning Glory (ipomoea purpurea). b

c


186

BIOLOGICAL

priate combination

CORRELATIONS

T H E HANSCH

APPROACH

of several m o l e c u l a r properties m i g h t e x p l a i n the

o b s e r v e d b i o l o g i c a l a c t i v i t y . I n this c o n n e c t i o n , H a n s c h (6,7, H a n s c h a n d F u j i t a (10,

11)

have developed

and

8,9)

a mathematical model

c o r r e l a t i n g b i o l o g i c a l a c t i v i t y w i t h t h e p h y s i c a l parameters of

for

molecules.

B i o l o g i c a l a c t i v i t y is c o r r e l a t e d w i t h the o c t a n o l / w a t e r p a r t i t i o n coeffi cients a n d H a m m e t t s i g m a ( σ ) constants (12,13)

c h a r a c t e r i z i n g the c o m

p o u n d s b e i n g evaluated. T h e H a n s c h - F u j i t a m o d e l (10),

w h i c h is u s u a l l y

a p p l i e d to a series of b i o l o g i c a l l y active c o m p o u n d s consisting of a parent m o l e c u l e a n d its s u b s t i t u t e d d e r i v a t i v e s , is i l l u s t r a t e d i n E q u a t i o n 1. Compound in Extracellular Phase Random Walk 1

Site of Action in Cellular Phase

k - >

—

Rate Determining Step 2

Biological Response

(1)

3->7l

S t e p 1 is a r a n d o m w a l k process i n w h i c h the b i o l o g i c a l l y

active

m o l e c u l e u n d e r i n v e s t i g a t i o n makes its w a y f r o m a d i l u t e s o l u t i o n outside a p l a n t o r a n i m a l c e l l to the site of a c t i o n w i t h i n the c e l l . T h e o v e r a l l p e r m e a t i o n event represented b y Step 1 w i l l p r e s u m a b l y be a r e l a t i v e l y s l o w process i n v o l v i n g m a n y p a r t i t i o n s b e t w e e n l i p i d a n d aqueous phases i n a d d i t i o n to a d s o r p t i o n a n d d e s o r p t i o n onto tissues or proteins. F u r t h e r , i n most cases the p a r t i t i o n i n g process w o u l d p r o b a b l y d e p e n d

consider

a b l y o n the m o l e c u l a r s t r u c t u r e a n d p h y s i c a l properties of the b i o l o g i c a l l y active m a t e r i a l . O n c e the c o m p o u n d has r e a c h e d the receptor site or site of a c t i o n w i t h i n ( o r o n t h e surface of) r a t e - c o n t r o l l i n g step

(Step 2)

the c e l l , it is a s s u m e d that one

governs its b i o l o g i c a l a c t i v i t y a n d that

Steps 3 —» η c a n be d i s r e g a r d e d i n expressing the rate of this r e a c t i o n . H a n s c h a n d F u j i t a u s e d a G a u s s i a n p r o b a b i l i t y f u n c t i o n to c h a r a c terize the p a r t i t i o n i n g Step 1 a n d the H a m m e t t f u n c t i o n (log(k/k ) 0

ρσ) to describe the rate Step 2 i n t h e i r m o d e l ( 10,12,13).

=

B y appropriate

m a t h e m a t i c a l treatment, t h e y a r r i v e d at the f o l l o w i n g general 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 w h i c h has c o m e to be t e r m e d the H a n s c h E q u a t i o n . log ( 1 / C ) = Ατ

2

+ B% +

ρσ + D

(2)

I n E q u a t i o n 2, π is a c o m p a r a t i v e substituent constant w h i c h H a n s c h a n d F u j i t a ( J O ) define as: χ = log Ρχ I n E q u a t i o n 3, P

H

-

log Ρ

H

(3)

is the p a r t i t i o n coefficient of a n u n s u b s t i t u t e d p a r e n t

c o m p o u n d , a n d Ρχ is the c o r r e s p o n d i n g p a r t i t i o n coefficient of a s u b s t i -


12.

YAPEL,


JR.

tuted derivative. determined

A s p r e v i o u s l y n o t e d , the p a r t i t i o n coefficients

between

method, π =

187

Herbicides

(log P

1-octanol a n d w a t e r — log P )

x

H

i n the

Hansch

Ρ are

correlation

is a free-energy r e l a t e d parameter s i m i l a r

to the H a m m e t t substituent constant σ (12,

13).

E q u a t i o n 2 shows that

a n y f a m i l y of b i o l o g i c a l l y active c o m p o u n d s w h i c h exhibits a s e c o n d order d e p e n d e n c e o n π w i l l also e x h i b i t a n o p t i m u m π v a l u e ( ττ ) w h i c h 0

is characteristic of that p a r t i c u l a r series. B i o l o g i c a l a c t i v i t y is often r e p o r t e d i n terms of a constant e q u i v a l e n t response ( L D

5 0

, LD

9 0

, ED

5 0

, p e r c e n t g r o w t h , percent k i l l , etc. ) o b t a i n e d

i n a fixed t i m e i n t e r v a l . G e n e r a l l y , this a c t i v i t y is expressed as the c o n c e n t r a t i o n (e.g., L D

5 0

, L D o ) necessary to cause a p a r t i c u l a r response i n 9

the g i v e n t i m e i n t e r v a l . I n a n a p p l i c a t i o n of the H a n s c h e q u a t i o n a i m e d at c o r r e l a t i n g h e r b i c i d a l a c t i v i t y d a t a , C i n E q u a t i o n 2 w o u l d t y p i c a l l y be a n L D

5 0

or L D

9 0

value—i.e.,

the m o l a r e x t r a c e l l u l a r c o n c e n t r a t i o n

( a p p l i c a t i o n d o s a g e ) of the h e r b i c i d e i n q u e s t i o n r e q u i r e d to k i l l

50%

or 9 0 % of a p a r t i c u l a r w e e d t y p e i n a g i v e n t i m e i n t e r v a l . C., π, a n d σ values are c o r r e s p o n d i n g l y

read into a computer,

a n d the

parameters

A, B, p, a n d D are c a l c u l a t e d b y stepwise regression analysis. I n p r i n c i p l e , once these fitting parameters h a v e b e e n d e t e r m i n e d for a g i v e n series of h e r b i c i d a l , p e s t i c i d a l , or p h a r m a c e u t i c a l c o m p o u n d s i n t h e i r a c t i o n o n a p a r t i c u l a r p l a n t or a n i m a l system, the r e s u l t i n g e q u a t i o n c a n be u s e d to p r e d i c t the b i o l o g i c a l a c t i v i t y of other s u b s t i t u t e d c o m p o u n d s i n the series f r o m a k n o w l e d g e of t h e i r o c t a n o l / w a t e r p a r t i t i o n coefficients values)

a n d H a m m e t t substituent constants

equivocal

i n t e r p r e t a t i o n of

final

(σ values).

c o r r e l a t i o n equations

(π

Although un determined

via

H a n s c h analysis is often difficult, clues to e l u c i d a t e the possible m o d e of a c t i o n of a p a r t i c u l a r a c t i v e c o m p o u n d

or r e l a t e d series of c o m p o u n d s

are often a v a i l a b l e f r o m the r e l a t i v e i m p o r t a n c e of the p a r t i t i o n i n g ( π , π ) 2

a n d electronic ( σ ) terms i n E q u a t i o n 2. T h e H a m m e t t σ constants are, of course, a measure of the e l e c t r o n - d o n a t i n g a n d - w i t h d r a w i n g p o w e r of a r o m a t i c ring substituents.

Objectives of the Present Study T h e complex

a c t i v i t y a n d selectivity characteristics of

substituted

t r i f l u o r o m e t h a n e s u l f o n a n i l i d e h e r b i c i d e s w e r e not correlatable w i t h single m o l e c u l a r properties

(see

T a b l e I a n d Ref. 5 ) .

W e were particularly

interested i n d e t e r m i n i n g w h e t h e r the m u l t i p a r a m e t e r H a n s c h e q u a t i o n , w h o s e u t i l i t y a n d a p p a r e n t g e n e r a l i t y has a l r e a d y b e e n substantiated i n c o r r e l a t i o n studies o n e n z y m a t i c systems (14, p h a r m a c e u t i c a l s (18,19, regulators (22),

20,23,24),

15, 16, 17, 25),

pesticides (10, 21),

drugs a n d

and plant growth

c o u l d be u s e d t o p r o v i d e m e a n i n g f u l s t r u c t u r e - a c t i v i t y


188

BIOLOGICAL

CORRELATIONS

T H E

HANSCH

APPROACH

r e l a t i o n s h i p s a m o n g m e m b e r s of the T F M S series. T h e signs a n d m a g n i tudes of the parameters Α, B, , a n d D w o u l d p r o b a b l y d e p e n d u p o n : P

( a ) the g e n e r a l h y d r o p h o b i c i t y or h y d r o p h i l i c i t y of the b i o l o g i c a l l y active series of c o m p o u n d s b e i n g e v a l u a t e d ( b ) w h e t h e r the series w a s b e i n g e x a m i n e d for h e r b i c i d a l , p e s t i c i d a l , or p h a r m a c e u t i c a l a c t i v i t y ( c ) w h e t h e r f o r m u l a t i o n surfactants o r emulsifiers w e r e present w h i c h affected the p a r t i t i o n i n g characteristics of the series m e m b e r s ( d ) the i n d i v i d u a l species of p l a n t , a n i m a l , or insect o n w h i c h the active compounds were being evaluated. I t e m c w a s of p a r t i c u l a r interest since m a n y surfactants are c u r r e n t l y a v a i l a b l e for p r e p a r i n g h e r b i c i d a l f o r m u l a t i o n s for greenhouse

and/or

o u t d o o r field testing. T h e objectives of the c u r r e n t s t u d y w e r e t w o f o l d a n d a i m e d at p r o v i d i n g answers to the f o l l o w i n g questions.

C a n the H a n s c h biological

correlations t e c h n i q u e b e u s e d : ( 1 ) to account for i n d i v i d u a l a n d / o r g r o u p differences i n the p r e e m e r g e n c e h e r b i c i d a l a c t i v i t y a n d specificity of s u b s t i t u t e d t r i f l u o r o m e t h a n e s u l f o n a n i l i d e s t o w a r d grasses a n d b r o a d l e a f w e e d s ? ( 2 ) to assess q u a n t i t a t i v e l y the effects of l o w levels of a c o m m o n f o r m u l a t i o n surfactant ( T w e e n 80) o n the h e r b i c i d a l a c t i v i t y of t r i f l u o r o m e t h a n e s u l f o n a n i l i d e s t o w a r d grasses a n d b r o a d l e a f w e e d s i n terms of: ( a ) changes i n b i o l o g i c a l a c t i v i t y of i n d i v i d u a l series m e m b e r s ? ( b ) shifts i n the range of o p t i m u m h e r b i c i d a l a c t i v i t y f r o m m o r e l i p o p h i l i c to m o r e h y d r o p h i l i c series m e m b e r s ( o r v i c e - v e r s a ) ? ( c ) o v e r a l l changes i n h e r b i c i d a l p o t e n c y of the t r i f l u o r o m e t h a n e s u l f o n a n i l i d e s (e.g., g e n e r a l e n h a n c e m e n t or i n h i b i t i o n of b i o l o g i c a l activity ) ? Experimental C h e m i c a l s . T h e 1-octanol u s e d i n the p a r t i t i o n i n g experiments w a s h i g h p u r i t y E a s t m a n W h i t e L a b e l reagent ( # 8 7 1 , lot 691-1) a n d was o p t i c a l l y transparent at a l l w a v e l e n g t h s ^ 2 2 0 n m . A d d i t i o n a l p u r i f i c a t i o n of the o c t a n o l via d i s t i l l a t i o n w a s not necessary. I m m e d i a t e l y before p a r t i t i o n i n g experiments, h o w e v e r , o c t a n o l samples w e r e w a s h e d w i t h N a O H a n d w a t e r as d e s c r i b e d b e l o w . D e i o n i z e d , d i s t i l l e d w a t e r was u s e d w h e r e necessary, a n d M a l l i n c k r o d t a n a l y t i c a l reagent p e r c h l o r i c a c i d ( # 2 7 6 6 ) w a s u s e d to p r e p a r e the p H 1.0 aqueous phases for p a r t i t i o n i n g studies ( see below ). A l l s u b s t i t u t e d t r i f l u o r o m e t h a n e s u l f o n a n i l i d e ( T F M S ) samples w e r e p r e p a r e d i n the 3 M C o . B i o c h e m i c a l R e s e a r c h L a b o r a t o r y a n d s u p p l i e d b y J . K . H a r r i n g t o n a n d R . D . T r e p k a of that l a b o r a t o r y . G e n e r a l p r e p a r a t i v e procedures for the T F M S c o m p o u n d s a n d r e l a t e d perfluoroa l k a n e s u l f o n a n i l i d e s h a v e b e e n o u t l i n e d (1,2,3,4,5). A d d i t i o n a l details of the s u l f o n y l a t i o n procedures a n d subsequent modifications of the r e s u l t i n g p r o d u c t s w i l l be p u b l i s h e d later.


12.

YAPEL, JR.


Herbicides

189

T w e e n 80 (also k n o w n as A t - P l u s 109 a n d P o l y s o r b a t e 80) is a p o l y o x y e t h y l e n e s o r b i t a n monooleate a n d w a s o b t a i n e d f r o m A t l a s C h e m i c a l Industries, I n c . T h i s n o n i o n i c surfactant has a n H L B ( h y d r o p h i l e l i p o p h i l e b a l a n c e ) of 15.0 a n d is u s e d as a n emulsifier, s o l u b i l i z e r , a n d dispersant. It was u s e d w i t h o u t f u r t h e r p u r i f i c a t i o n at the 0 . 1 % (w/v) l e v e l i n p a r t i t i o n i n g a n d greenhouse h e r b i c i d a l evaluations as d e s c r i b e d below. Determination of Octanol/Water Partition Coefficients. S i n c e oct a n o l / w a t e r p a r t i t i o n coefficient d a t a for t r i f l u o r o m e t h a n e s u l f o n a n i l i d e ( I ) a n d its s u b s t i t u t e d d e r i v a t i v e s h a v e not b e e n r e p o r t e d i n the l i t e r a t u r e a n d since it was not a p p a r e n t that a n y of the substituent π values p r e v i o u s l y d e t e r m i n e d b y F u j i t a et al. (11) w o u l d be d i r e c t l y a p p l i c a b l e to the T F M S h e r b i c i d a l system, a l l T F M S p a r t i t i o n coefficients a n d π values were determined experimentally. T h e fluoroalkanesulfonanilides are v e r y a c i d i c because of the e l e c t r o n - w i t h d r a w i n g p o w e r of the p a r e n t fluoroa l k a n e s u l f o n y l g r o u p ( 5 ) . T h e parent T F M S c o m p o u n d ( I ) , for e x a m p l e , has a p K i n w a t e r of 4.45 at 25 ° C . T h i s i n h e r e n t a c i d i t y extends to a l l T F M S series m e m b e r s a n d r e q u i r e s t h a t the u s u a l p a r t i t i o n coefficient m e a s u r e m e n t p r o c e d u r e d e s c r i b e d b y F u j i t a et al. (11) b e m o d i f i e d to o b t a i n accurate values of l o g Ρ a n d π. T h e o c t a n o l / w a t e r p a r t i t i o n coefficient Ρ is defined as a

C

0

(4)

(1-a)

C

W

w h e r e C is the c o n c e n t r a t i o n of the c o m p o u n d of interest i n the o c t a n o l phase after p a r t i t i o n i n g , a n d C is its c o r r e s p o n d i n g c o n c e n t r a t i o n i n the w a t e r phase. T h e t e r m a is the degree of d i s s o c i a t i o n of the a c i d i c c o m p o u n d i n the w a t e r phase a n d m u s t b e c o n s i d e r e d for a l l i o n i z a b l e c o m p o u n d s . S i n c e a l l the T F M S c o m p o u n d s i n our s t u d y w e r e i o n i z a b l e i n w a t e r , either the degree of d i s s o c i a t i o n ( a ) h a d to be d e t e r m i n e d for a l l m e m b e r s of the series u n d e r the p H c o n d i t i o n s of the p a r t i t i o n i n g , or s o l u t i o n p H c o n d i t i o n s h a d to be adjusted so that the c o m p o u n d s i n q u e s t i o n r e m a i n i n the n o n i o n i z e d state (a -> 0 ) i n the aqueous phase d u r i n g the p a r t i t i o n i n g e x p e r i m e n t (33). T h e latter a p p r o a c h , i n w h i c h w e u s e d a l o w , buffered p H , w a s chosen for this study. T h i s t e c h n i q u e was v e r i f i e d u s i n g the w e l l - c h a r a c t e r i z e d b e n z o i c a c i d system (11). At p H 7.0, for e x a m p l e , b e n z o i c a c i d ( p K = 4.19 at 2 5 ° C ) is v e r y s o l u b l e i n w a t e r since it exists essentially e n t i r e l y i n its i o n i z e d state. B e c a u s e of this i o n i z a t i o n , o c t a n o l / w a t e r p a r t i t i o n i n g experiments at n e u t r a l p H are difficult to c a r r y out a n d i n t e r p r e t . B y c o n d u c t i n g p a r t i t i o n i n g ex p e r i m e n t s at l o w p H ( several units l o w e r t h a n the p K of b e n z o i c a c i d — e.g., p H 1.0), t h e a c i d is m a i n t a i n e d i n its n o n i o n i z e d state (a —» 0 ) , a n d to a n excellent a p p r o x i m a t i o n the p a r t i t i o n coefficient Ρ is g i v e n b y C /C (cf. E q u a t i o n 4 ) . A c c o r d i n g l y , o c t a n o l / w a t e r p a r t i t i o n i n g experiments w e r e d o n e o n b e n z o i c a c i d a n d t w o of its d e r i v a t i v e s ( p - c h l o r o b e n z o i c a c i d a n d m - m e t h o x y b e n z o i c a c i d ) u s i n g the p r o c e d u r e of F u j i t a et al. (11) except that t h e i r d i s t i l l e d - w a t e r phase w a s r e p l a c e d w i t h p H 1.0 w a t e r (0.1N p e r c h l o r i c a c i d ) i n our tests. A s s h o w n i n T a b l e I I , the p a r t i t i o n coefficients so d e t e r m i n e d at l o w p H for b e n z o i c a c i d a n d t h e t w o 0

w

t t

t t

0


w

190

BIOLOGICAL CORRELATIONS

T H E HANSCH A P P R O A C H

d e r i v a t i v e s ( u s i n g Ρ = C /C ) w e r e i n excellent agreement w i t h the u n b u f f e r e d aqueous ( a n d necessarily h i g h e r p H ) values r e p o r t e d b y F u j i t a et al. (11) w h e r e the degree of d i s s o c i a t i o n a w a s u s e d i n the p a r t i t i o n coefficient c a l c u l a t i o n s . 0

w

Table II. Comparison of Partition Coefficients Using p H 1.0 vs. Distilled Water Aqueous Phases Compound

log V\pH 1.0 HCIO* (this study)

log P ; Distilled Water (Ref. 11)

1.86 =b 0.03 2.63 ± 0.03 2.00 =b 0.03

1.85 ± 0.03 2.72 =b 0.03 1.99 ± 0.03

Benzoic A c i d p-Chlorobenzoic A c i d ra-Methoxybenzoic Acid

A l l p a r t i t i o n coefficient measurements o n the 15 t r i f l u o r o m e t h a n e s u l f o n a n i l i d e s w e r e c a r r i e d out u s i n g a p H 1.0 w a t e r phase ( a c i d i f i e d w i t h p e r c h l o r i c a c i d ) . T h e p H of the a c i d i c w a t e r phase r e m a i n e d essen t i a l l y u n c h a n g e d d u r i n g p a r t i t i o n i n g . T h e p K values at 25 ° C i n w a t e r of a l l b u t t w o of the T F M S d e r i v a t i v e s ( 4 - S 0 C H a n d 3 - S 0 C H series m e m b e r s ) w e r e c o n s i d e r a b l y greater t h a n 3.0 so that a l l m a t e r i a l p a r t i t i o n e d i n t o the p H 1.0 w a t e r phase w a s u n i o n i z e d . It w a s thus p o s s i b l e to use the s i m p l i f i e d expression Ρ = C /C to c a l c u l a t e the p a r t i t i o n co efficients. F o r the 4 - S 0 C H - a n d 3 - S 0 C H - T F M S d e r i v a t i v e s , w h o s e aqueous pKaS are k n o w n to b e close to 3.0, p o t e n t i o m e t r i c titrations w e r e c a r r i e d out to establish a c c u r a t e l y t h e p K values [ p K , ° ( 4 - S 0 C H T F M S ) = 2.80; p K , ° ( 3 - S 0 C H - T F M S ) = 3.10]. T h e s e values w e r e t h e n u s e d to d e t e r m i n e a at p H 1.0 w i t h the p a r t i t i o n coefficients c a l c u l a t e d a c c o r d i n g t o E q u a t i o n 4. t t 2

0

2

3

2 5

c

2

2

3

w

2

3

a

a

3

a

2 5

c

2

3

3

T h e 1-octanol u s e d i n p a r t i t i o n i n g experiments was p u r i f i e d b y w a s h i n g three times w i t h IN N a O H , f o l l o w e d b y six w a s h i n g s w i t h d i s t i l l e d , d e i o n i z e d w a t e r . T h e i n i t i a l h i g h p u r i t y of the o c t a n o l e l i m i n a t e d a s u b sequent d i s t i l l a t i o n step. F o r the p a r t i t i o n i n g studies, o c t a n o l s a t u r a t e d w i t h p H 1.0 d i s t i l l e d w a t e r , a n d p H 1.0 d i s t i l l e d w a t e r ( 0 . 1 N p e r c h l o r i c a c i d ) saturated w i t h o c t a n o l w e r e used. A s j u d g e d f r o m o u r p r e l i m i n a r y m o d e l studies at p H 1.0 o n t h e b e n z o i c a c i d series (see above), the pres ence of 0 . 1 N p e r c h l o r i c a c i d i n the aqueous phase h a d no significant effect o n the u l t i m a t e p a r t i t i o n i n g b e h a v i o r of either the b e n z o i c a c i d or T F M S compounds examined. I n a t y p i c a l p a r t i t i o n i n g e x p e r i m e n t , 0.12 to 0.15 g r a m o f the T F M S c o m p o u n d was d i s s o l v e d i n 50 m l of 1-octanol to a final c o n c e n t r a t i o n of f r o m 5 X 1 0 " M to 1.3 X 1 0 " M . T h e o c t a n o l s o l u t i o n of T F M S c o m p o u n d was p a r t i t i o n e d against a n e q u a l v o l u m e of p H 1.0 w a t e r b y a g i t a t i n g for at least a n h o u r o n a m e c h a n i c a l shaker. T h e m i x t u r e w a s t h e n a l l o w e d to s t a n d u n t i l the o c t a n o l a n d w a t e r layers separated. T h e aqueous l a y e r was r e m o v e d , c e n t r i f u g e d to r e m o v e a n y cloudiness, a n d a n a l y z e d b y u l t r a v i o l e t ( U V ) a b s o r p t i o n s p e c t r o p h o t o m e t r y to d e t e r m i n e the c o n c e n t r a t i o n of T F M S c o m p o u n d p a r t i t i o n e d i n t o the aqueous phase. T h e c o n c e n t r a t i o n of the T F M S c o m p o u n d r e m a i n i n g i n the o c t a n o l phase w a s c a l c u l a t e d b y difference. 3

2


12.

Y A P E L , JR.


Herbicides

191

A l l U V d e t e r m i n a t i o n s w e r e m a d e o n a C a r y M o d e l 14 s p e c t r o p h o tometer. T h e a b s o r p t i o n m a x i m a of the 15 p a r t i t i o n e d T F M S c o m p o u n d s i n w a t e r r a n g e d f r o m 259 n m for the 4 - S C H d e r i v a t i v e to 214 n m for the 4 - F a n d 3-C1 d e r i v a t i v e s . A l l U V measurements w e r e m a d e i n 1-cm cuvettes w i t h t y p i c a l p a r t i t i o n e d T F M S c o m p o u n d s e x h i b i t i n g o p t i c a l densities r a n g i n g f r o m 0.5 to 1.5 i n the aqueous phase. L o g Ρ values d e t e r m i n e d b y the a b o v e p r o c e d u r e for the T F M S c o m p o u n d s w e r e precise to better t h a n ± 2 % . 3

Partitioning in the Presence of Surfactant. P a r t i t i o n i n g experiments i n t h e presence of T w e e n 80 w e r e c a r r i e d out i n a m a n n e r i d e n t i c a l to that discussed a b o v e except that 0 . 1 % ( w / v ) of the surfactant w a s t h o r o u g h l y m i x e d w i t h the w a t e r phase before p a r t i t i o n i n g . O c t a n o l / w a t e r p a r t i t i o n i n g studies c a r r i e d out w i t h o n l y 0 . 1 % T w e e n 80 ( a n d no T F M S c o m p o u n d ) present i n i t i a l l y i n d i c a t e d that at e q u i l i b r i u m , t h e surfactant partitions a p p r o x i m a t e l y 6 0 / 4 0 i n f a v o r of the o c t a n o l phase. I n a t y p i c a l o c t a n o l / w a t e r p a r t i t i o n i n g e x p e r i m e n t c a r r i e d out i n the presence of T w e e n 80, the T F M S c o m p o u n d w a s first d i s s o l v e d i n 50 m l o c t a n o l a n d t h e n p a r t i t i o n e d against a n e q u a l v o l u m e of p H 1.0 w a t e r c o n t a i n i n g 0 . 1 % T w e e n 80 as d e s c r i b e d above. A l l samples w e r e c e n t r i f u g e d to ensure the best possible o c t a n o l / w a t e r phase s e p a r a t i o n a n d optical clarity. E q u i l i b r i u m concentrations of T F M S c o m p o u n d s i n the aqueous phase w e r e a g a i n d e t e r m i n e d b y U V . T h e c o n c e n t r a t i o n i n the o c t a n o l phase w a s d e t e r m i n e d b y difference, as u s u a l . A l t h o u g h T w e e n 80 ex h i b i t e d a n a b s o r p t i o n m a x i m u m at 232 n m , the o p t i c a l d e n s i t y of the surfactant at this w a v e l e n g t h i n the aqueous phase of the final p a r t i t i o n e d samples u s u a l l y d i d not exceed 0.2. M o s t of the T F M S c o m p o u n d s e x h i b i t e d a b s o r p t i o n m a x i m a at w a v e l e n g t h s either near 215 ± 5 n m o r near 255 ± 5 n m w h e r e the o p t i c a l d e n s i t y of the p a r t i t i o n e d T w e e n 80 was a l w a y s ^ 0 . 1 . A b s o r p t i o n interference b y the surfactant i n w a v e l e n g t h regions u s e d to measure the concentrations of the final p a r t i t i o n e d T F M S c o m p o u n d s w a s therefore not a p r o b l e m because of the l o w sur factant a b s o r p t i o n i n s p e c t r a l regions of T F M S a b s o r p t i o n . T y p i c a l T F M S o p t i c a l densities at a b s o r p t i o n m a x i m a , for e x a m p l e , w e r e 0.8 to 1.5. A s a p r e c a u t i o n , h o w e v e r , the aqueous phase of a c o n t r o l s a m p l e c o n s i s t i n g of 0 . 1 % T w e e n 80 p a r t i t i o n e d as d e s c r i b e d a b o v e b e t w e e n o c t a n o l a n d p H 1.0 w a t e r was u s e d as a reference ( b l a n k ) i n a l l U V d e t e r m i n a t i o n s . A l l U V a b s o r p t i o n at the w a v e l e n g t h s of interest c o u l d thus b e a s c r i b e d to T F M S a b s o r p t i o n w i t h i n e x p e r i m e n t a l error. It d i d n o t a p p e a r that s u r f a c t a n t - e n h a n c e d o c t a n o l p a r t i t i o n i n g i n t o the w a t e r phase l e d to a n y significant errors i n T F M S c o n c e n t r a t i o n d e t e r m i n a t i o n s . F o r the T F M S c o m p o u n d s w h i c h p a r t i t i o n e d m u c h m o r e strongly t o w a r d the w a t e r layer i n the presence of T w e e n 80 t h a n i n its absence (see T a b l e V I ) , a n opalescent or c l o u d y aqueous phase was f o r m e d because of the e m u l s i f y i n g effect of the surfactant o n the p a r t i t i o n e d c o m p o u n d . I n these cases, a n a l i q u o t of the final p a r t i t i o n e d w a t e r phase was d i l u t e d 1:5 w i t h p H 1.0 w a t e r ; this c l e a r e d the solutions o p t i c a l l y a n d p e r m i t t e d U V deter m i n a t i o n of the p a r t i t i o n e d T F M S c o m p o u n d c o n c e n t r a t i o n . T h e p r e c i s i o n of the l o g Ρ values d e t e r m i n e d for the T F M S c o m p o u n d s i n the presence of 0 . 1 % T w e e n 80 is =b5%.


192



Greenhouse T e s t s . Pre-emergence h e r b i c i d a l evaluations of the 15 T F M S c o m p o u n d s l i s t e d i n T a b l e I V w e r e c o n d u c t e d i n a n artificially i l l u m i n a t e d greenhouse. T w o grass species ( G i a n t F o x t a i l , Setaria sp.; C h e a t G r a s s , Bromus secalinus) and a broadleaf weed ( W i l d Mustard, Brassica kaber) w e r e u s e d i n the tests. F o r each T F M S e v a l u a t i o n , the three w e e d species w e r e p l a n t e d as seeds i n separate r o w s i n the same 6 i n c h d i a m e t e r r o u n d p l a s t i c pot. T h e s o i l w a s a s t e r i l i z e d s a n d y l o a m c o n t a i n i n g 6 8 % s a n d , 2 0 % silt, 9 % c l a y , a n d 2 - 3 % o r g a n i c matter. T h e s o i l w a s p a s t e u r i z e d at 1 8 0 ° F for 30 m i n u t e s before use, a p r o c e d u r e w h i c h k i l l e d pathogens b u t not b e n e f i c i a l s o i l b a c t e r i a . T w o series of r e p l i c a t e d pre-emergence h e r b i c i d a l tests w e r e c o n d u c t e d s i m u l t a n e o u s l y o n the T F M S c o m p o u n d s . I n the first, n o surfactant was u s e d i n the h e r b i c i d a l f o r m u l a t i o n s ; i n the second, T w e e n 80 at the 0 . 1 % ( w / v ) l e v e l w a s a d d e d to the f o r m u l a t i o n s . A l l procedures a n d p r e p a r a t i o n s w e r e i d e n t i c a l for b o t h series except for the presence of the surfactant i n f o r m u l a t i o n s of the second series. S t a n d a r d h e r b i c i d a l f o r m u l a t i o n s i n the absence of surfactant w e r e p r e p a r e d b y d i s s o l v i n g the highest i n t e n d e d dose of each T F M S c o m p o u n d i n a 1 % a c e t o n e - w a t e r s o l u t i o n . T h e s m a l l a m o u n t of acetone (necessary to effect s o l u t i o n of some of t h e m o r e l i p o p h i l i c series m e m b e r s ) was u s e d i n a l l f o r m u l a t i o n s for consistency. S t a n d a r d h e r b i c i d a l f o r m u l a t i o n s i n the presence of surfactant w e r e p r e p a r e d i n a s i m i l a r f a s h i o n , except that the 1 % acetone—water c o n t a i n e d i n a d d i t i o n 0 . 1 % ( w / v ) T w e e n 80. T h e pre-emergence h e r b i c i d a l tests w e r e d o n e at three or f o u r dosage levels r a n g i n g f r o m 1.25 to 20 l b / a c r e for each T F M S d e r i v a t i v e . T h e l b / a c r e d e s i g n a t i o n was o b t a i n e d b y d i v i d i n g the a c t u a l d r y w e i g h t i n grams of T F M S h e r b i c i d e a p p l i e d to e a c h p o t f r o m a n aqueous d r e n c h b y the t o p s o i l surface area i n the p o t ( ~ 0 . 2 f t ) a n d t h e n a p p l y i n g a n a p 2

p r o p r i a t e c o n v e r s i o n factor F o r subsequent c o m p u t e r c o r r e l a t i o n studies, the l b / a c r e d a t a w e r e c o n v e r t e d to m o l e s / a c r e . H e r b i c i d a l f o r m u l a t i o n s c o r r e s p o n d i n g to different dose levels w e r e p r e p a r e d b y d i l u t i n g a l i q u o t s of the s t a n d a r d h e r b i c i d a l f o r m u l a t i o n s w i t h either 1 % acetone—water (tests w i t h no surfactant a d d e d ) or 1 % acetone—water c o n t a i n i n g 0 . 1 % T w e e n 80 (tests w i t h surfactant a d d e d ) . T h u s , i n the surfactant tests, T w e e n 80 w a s k e p t at a constant c o n c e n t r a t i o n o f 0 . 1 % at a l l h e r b i c i d a l dosages. A t o t a l of 80 m l of each h e r b i c i d a l f o r m u l a t i o n w e r e a p p l i e d to each pot as a single d r e n c h i m m e d i a t e l y after seeds w e r e p l a n t e d i n the pre-emergence e v a l u ations. T h e r e a f t e r , pots w e r e b o t t o m - w a t e r e d d a i l y u n t i l plants emerged. T o p w a t e r i n g w a s t h e n u s e d for the rest of the test. P r e - e m e r g e n c e h e r b i c i d a l test d a t a w e r e e v a l u a t e d after 8, 21, a n d 42 days for b o t h test series. T h e h e r b i c i d a l response of each T F M S c o m p o u n d at e a c h t i m e i n t e r v a l w a s r a t e d ( i n terms of % k i l l b y c o m p a r i n g w i t h a control sample containing no herbicidal treatment) on a 0-100 scale ( w h e r e 0 = no a c t i v i t y , 50 = 5 0 % k i l l , 100 = complete k i l l , e t c . ) . N o significant changes i n r e l a t i v e h e r b i c i d a l a c t i v i t y w e r e o b s e r v e d after 21 days. T h e 21-day h e r b i c i d a l a c t i v i t y ratings w e r e u s e d to p r e p a r e l o g - p r o b i t plots f r o m w h i c h L D values w e r e d e t e r m i n e d for each T F M S c o m p o u n d i n the presence a n d absence of T w e e n 80 ( see Results ). 9 0


12.

Y A P E L , JR.


193

Herbicides

A l l h e r b i c i d a l tests w e r e c a r r i e d out s i m u l t a n e o u s l y . E r r o r s a n d variations f r o m s u c h u n c o n t r o l l a b l e factors as seasonal changes i n p l a n t g r o w t h w e r e thus m i n i m i z e d . Computer Correlations. A l l correlations of h e r b i c i d a l test d a t a w i t h τι-- a n d σ-parameters a c c o r d i n g to E q u a t i o n 2 w e r e c a r r i e d out w i t h a n I B M 360 c o m p u t e r u s i n g a least-squares stepwise regression p r o g r a m of c o n s i d e r a b l e v e r s a t i l i t y ( U C L A H e a l t h Sciences P r o g r a m B M D 0 2 R ) . M u l t i p l e c o r r e l a t i o n coefficients ( r ) , p a r a m e t e r a n d e q u a t i o n a l s t a n d a r d errors, a n d F tests w e r e r o u t i n e l y u s e d to j u d g e the goodness of fit of h e r b i c i d a l a c t i v i t y d a t a to the H a n s c h e q u a t i o n . T h r e e - d i m e n s i o n a l p e r spective plots of final e q u a t i o n a l forms w e r e c a r r i e d out o n a C a l c o m p plotter using a program written by E a r l C o o k ( 3 M C o . ) . Results Model Parent Compound Series.

E x p e r i m e n t a l p a r t i t i o n coefficient

d a t a for a v a r i e t y of s u b s t i t u t e d benzenes a n d seven other r e l a t e d p a r e n t compound

series ( p h e n o x y a c e t i c

acid, phenylacetic acid, benzoic acid,

benzyl alcohol, phenol, aniline, nitrobenzene) F u j i t a et al. (11).

T h e -π values (see

w e r e r e p o r t e d i n 1964 b y

E q u a t i o n 3 ) d e r i v e d for i n d i v i d u a l

substituents i n e a c h of the a b o v e - m e n t i o n e d p a r e n t c o m p o u n d series h a v e since b e e n f r e q u e n t l y u s e d ( w i t h v a r y i n g degrees of success) b y m a n y investigators to a p p r o x i m a t e π values for the c o r r e s p o n d i n g substituents i n other r e l a t e d p a r e n t c o m p o u n d s for w h i c h n o e x p e r i m e n t a l p a r t i t i o n i n g d a t a are a v a i l a b l e . F o r e x a m p l e , H a n s c h a n d D e u t s c h (26),

i n a correla

t i o n s t u d y of s t r u c t u r e - a c t i v i t y relationships i n cholinesterase i n h i b i t o r s , used π values d e r i v e d for a r o m a t i c r i n g substituents ( X ) i n the p h e n o x y acetic a c i d series

to a p p r o x i m a t e π values for the same substituents i n p a r e n t series methylcarbamates :

diethylphenylphosphates :

Ο


of

194



a n d even a l k y l p h o s p h o n i c a c i d esters: Ο -P-0-C H , R =

NO

2

alkyl.

5

R N e e l y a n d W h i t n e y (21)

h a v e s i m i l a r l y u s e d the p h e n o x y a c e t i c

acid

series π values i n s t r u c t u r e - a c t i v i t y correlations of the i n s e c t i c i d a l a c t i v i t y of p h e n y l - O - m e t h y l m e t h y l p h o s p h o r a m i d a t e s :

B e f o r e e x p e r i m e n t a l l y m e a s u r i n g the p a r t i t i o n coefficients of o u r 15 t r i f l u o r o m e t h a n e s u l f o n a n i l i d e ( T F M S ) series m e m b e r s , w e too h a d g i v e n serious c o n s i d e r a t i o n to a p p r o x i m a t i n g t h e T F M S substituent π values w i t h a p p r o p r i a t e l y chosen π values f r o m one of the p a r e n t series s t u d i e d b y F u j i t a et al. (11).

above-mentioned

T h e a p p r o p r i a t e c h o i c e of a n

a p p r o x i m a t i n g p a r e n t c o m p o u n d was difficult to m a k e , h o w e v e r , as c a n b e j u d g e d f r o m the i o n i z a t i o n a n d p a r t i t i o n i n g d a t a t a b u l a t e d i n T a b l e I I I for several reasonable m o d e l series chosen f r o m Ref. 11. T h e five p a r e n t c o m p o u n d s i n T a b l e I I I are a r r a n g e d i n order of i n creasing p K (pK

=

a

a

3.17)

of t h e i r i o n i z a b l e p r o t o n i c groups. and phenylacetic acid ( p K

a

=

F o r phenoxyacetic

acid

4.31), the p r i m a r y i o n i z a

t i o n is that of the c a r b o x y l i c a c i d side c h a i n . T h e a c i d i t y of the T F M S parent compound ( p K =

4.45 ) is a t t r i b u t a b l e to the loss of the r e l a t i v e l y

a

l a b i l e p r o t o n f r o m the p a r e n t side c h a i n ( < £ - N H - S 0 - C F 2

CF

8

+

H ) . F o r a n i l i n e , the process w i t h p K +

a

=

3

*± φ - Ν - S O o -

4.63 is associated w i t h

p r o t o n i c i o n i z a t i o n of the a n i l i n i u m c a t i o n . T h e p K

a

=

9.89 process i n

p h e n o l refers to the f o r m a t i o n of p h e n o l a t e a n i o n . A l t h o u g h the p K ' s of p h e n o x y a c e t i c a c i d , p h e n y l a c e t i c a c i d , T F M S , a

a n d a n i l i n e are a l l q u i t e s i m i l a r , d i f f e r i n g b y less t h a n 1.5 p K u n i t s for the most extreme c o m p a r i s o n ( p h e n o x y a c e t i c a c i d vs. a n i l i n e ) , this s i m i l a r i t y ends w h e n the p a r t i t i o n i n g b e h a v i o r of these same p a r e n t c o m p o u n d s is compared. cient (P)

W h e r e a s the l o g a r i t h m of the o c t a n o l / w a t e r p a r t i t i o n coeffi varies o n l y f r o m l o g Ρ =

phenylacetic acid, T F M S (log Ρ =

0.90 for a n i l i n e to l o g Ρ =

1.41 for

3.05) is 1.6 orders of m a g n i t u d e m o r e

l i p o p h i l i c t h a n p h e n y l a c e t i c a c i d , the most h y d r o p h o b i c of the other p a r ent c o m p o u n d s e x h i b i t i n g a s i m i l a r ρ Κ . α

I f the π values for the side chains

of the p a r e n t c o m p o u n d s

l i s t e d i n T a b l e I I I are c a l c u l a t e d u s i n g E q u a

t i o n 5 as s h o w n o n p. 196

t


12.


YAPEL, JR.

Table III. Parent

195

Herbicides

Choice of Model Parent Series

Molecule

Ionization

1. P h e n o x y a c e t i c A c i d ( P O A )

H A ^ H + + pK = 3.17 a

Step A (25°C)

Partitioning"

h

log Ρ = 1.27 T(OCH COOH) 2

-0.86 OCH COOH 2

HA 2. P h e n y l a c e t i c A c i d ( P A A )

HA^±H+ + A pK = 4.31 (25°C)

log Ρ = 1.41 *(CH COOH) -0.72

=

HA^±H+ + A pK = 4.45 (25°C)

log Ρ = 3.05 x(NHS0 CF ) +0.92

=

(a) B H + ^ ± B H + H+ pK = 4.63 (25°C)

l o g Ρ = 0.90 χ(ΝΗ,) = - 1 . 2 3

a

2

CH COOH 2

HA 3. T r i f l u o r o m e t h a n e sulfonanilide ( T F M S )

a

NH-S0 -CF 2

2

3

3

HA 4. A n i l i n e

2

a

NH + 3

BH,+ (b)

B H ^ Β - + H+ pK « 27 (25°C) a

5. P h e n o l

0^

HA^H+ + ApK = 9.89 (25°C) a

l o g Ρ = 1.46 x(OH) = -0.67

OH

HA

" Partitioning data for parent compounds 1, 2, 4, and 5 obtained from Ref. 11. Partitioning data for 3 measured in this study. 6


196



x (parent side chain) = log Ρ (parent c o m p o u n d ) — log Ρ (benzene) = log Ρ (parent c o m p o u n d ) — 2.13 the h y d r o p h o b i c i t y of the - N H S 0 C F 2

3

(5)

side c h a i n i n T F M S is i l l u s t r a t e d

e v e n m o r e g r a p h i c a l l y . T h e large negative π values c h a r a c t e r i z i n g the side chains of p h e n o x y a c e t i c a c i d , p h e n y l a c e t i c a c i d , a n i l i n e , a n d p h e n o l i n d i c a t e t h a t t h e i r s u b s t i t u t i o n i n t o the p a r e n t b e n z e n e r i n g renders the latter s i g n i f i c a n t l y m o r e h y d r o p h i l i c a n d w a t e r s o l u b l e ( over a n o r d e r of magnitude for - N H

2

s u b s t i t u t i o n ) . T h e s u b s t i t u t i o n of - N H S 0 C F 2

3

into

the b e n z e n e r i n g c o n t r a s t i n g l y renders the latter almost a n o r d e r of m a g n i t u d e m o r e l i p o p h i l i c a n d s o l u b l e i n octanol.

T h e gross difference i n

l i p o p h i l i c i t y of the t r i f l u o r o m e t h a n e s u l f o n a n i l i d e side c h a i n r e l a t i v e to the m u c h m o r e h y d r o p h i l i c side c h a i n s of the other p a r e n t

compounds

strongly suggests that similarities i n the side c h a i n p K ' s

( a n d hence

a

o v e r a l l p a r e n t m o l e c u l e a c i d i t i e s ) s h o u l d not b e u s e d as a basis for select i n g the s u b s t i t u e n t ττ values o f a n o t h e r p a r e n t series to

approximate

substituent π values i n the T F M S series. O n e m i g h t i n s t e a d choose as a basis for c o m p a r i s o n the r e l a t i v e e l e c t r o n - w i t h d r a w i n g o r - d o n a t i n g properties of the p a r e n t side c h a i n s i n T a b l e I I I . B o t h the - N H side c h a i n of a n i l i n e a n d the - O H g r o u p i n 2

p h e n o l are strong donators of electrons to the b e n z e n e r i n g . T h e strong e l e c t r o n - w i t h d r a w i n g p r o p e r t i e s of the t r i f l u o r o m e t h a n e s u l f o n y l p o r t i o n of the T F M S side c h a i n , h o w e v e r , w o u l d b e e x p e c t e d to m i t i g a t e d r a s t i c a l l y the c o r r e s p o n d i n g e l e c t r o n - d o n a t i n g tendencies of the n i t r o g e n a t t a c h e d to the b e n z e n e r i n g i n T F M S .

I n a d d i t i o n to the differences i n

p a r t i t i o n i n g properties, it w o u l d also a p p e a r u n w i s e to choose either a p h e n o l or a n i l i n e p a r e n t series to represent the T F M S series because of the e x p e c t e d differences

i n e l e c t r o n - d o n a t i n g properties of t h e p a r e n t

side chains [ w h i c h m i g h t w e l l be e x p e c t e d to influence ( t o a greater or lesser d e g r e e ) the h y d r o p h i l i c i t y or h y d r o p h o b i c i t y of other substituents that m i g h t be p l a c e d i n the b e n z e n e r i n g ] . T h e r e f o r e , e v e n t h o u g h T F M S is a s u b s t i t u t e d a n i l i n e of sorts, there is l i t t l e basis for c o m p a r i n g i t w i t h a n i l i n e . T h e a m i n o h y d r o g e n i n a n i l i n e c o r r e s p o n d i n g to the l a b i l e h y drogen ( p K

a

=

4.45) i n T F M S , for e x a m p l e , has a n e x t r e m e l y h i g h

pK

a

of 27 ( see second i o n i z a t i o n e q u i l i b r i u m for a n i l i n e i n T a b l e I I I ) , f u r t h e r i l l u s t r a t i n g the d i s s i m i l a r i t y of the t w o p a r e n t molecules.

In addition,

the c o m b i n e d e l e c t r o n - w i t h d r a w i n g tendencies of the p h e n o x y a n d c a r boxyl ( i n phenoxyacetic acid) and p h e n y l and carboxyl ( i n phenylacetic a c i d ) do not r e n d e r either of the m e t h y l e n e ( - C H - ) h y d r o g e n s i n the 2

side chains of these p a r e n t m o l e c u l e s p a r t i c u l a r l y a c i d i c . T h i s is i n c o n trast to the c o m b i n e d e l e c t r o n - w i t h d r a w i n g effect of p h e n y l a n d t r i f l u o r o m e t h a n e s u l f o n y l o n the - N H l i n k a g e i n the side c h a i n of T F M S w h i c h is highly acidic.


12.


YAPEL, JR.

197

Herbicides

T h e r e f o r e , it is difficult to define a reasonable basis for selecting a n y of t h e p a r e n t series p r e v i o u s l y e x a m i n e d b y F u j i t a et al. (11) for the T F M S series of the present study. analyses

of

our T F M S

pre-emergence

as a m o d e l

I n d e e d , some i n i t i a l H a n s c h

herbicidal activity data using

F u j i t a s p h e n o x y a c e t i c a c i d s u b s t i t u e n t π values p r o d u c e d v e r y p o o r c o r relations.

W e thus d e e m e d

i t p r u d e n t ( i f not essential) to

determine

e x p e r i m e n t a l l y π values for a l l substituents i n the T F M S series. Table IV.

Trifluoromethanesulfonanilides NHS0 CF 2

Chosen for Herbicide Test" N H S 0 C F3

3

2

Χ

Η 3-Substituted

^-Substituted X 4-CF 4-C1 4-SCH s

3

4-CH3 4-F

4-OCH3

4-S0 CH Η 2

0 h

3

τ»

σ

+ 1.42 +0.91 +0.69 +0.55 +0.20 -0.05 -1.06 0.00

+0.551 +0.227 -0.047 -0.170 +0.062 -0.268 +0.728 0.000

j

Χ 3-CF 3-C1 3-F 3-SCH 3-COCHs 3-OH 3-S0 CH 3

3

2

3

+ 1.45 +0.95 +0.37 -0.20 -0.27 -0.54 -1.20

+0.415 +0.373 +0.337 +0.144 +0.306 -0.002 +0.647

No Tween 80 present. See Table V for standard deviation in χ values.

π Values i n the Absence of Surfactant. T a b l e IV gives π a n d σ values for the 15 t r i f l u o r o m e t h a n e s u l f o n a n i l i d e s e x a m i n e d i n this s t u d y . O c t a n o l / w a t e r p a r t i t i o n coefficients i n the absence of surfactant w e r e d e t e r m i n e d as d e s c r i b e d , a n d substituent π values w e r e c a l c u l a t e d a c c o r d i n g to E q u a t i o n 3 u s i n g l o g ΡΗ = T a b l e III).

3.05 for the Η-substituted p a r e n t c o m p o u n d

H a m m e t t s i g m a constants

p i l a t i o n of Jaffe ( 1 3 ) .

(σ)

were taken from the

(see com

O u r s t u d y w a s r e s t r i c t e d to m e t a - a n d p a r a - m o n o -

substituted T F M S derivatives. Ortho-substituted T F M S derivatives were not i n c l u d e d i n the h e r b i c i d a l tests to e l i m i n a t e the u s u a l difficulties associated w i t h selection a n d i n t e r p r e t a t i o n of H a m m e t t σ constants for 2-substituents.

The

substituted T F M S

derivatives i n T a b l e

IV

were

chosen to s p a n a b r o a d s p e c t r u m of π a n d σ values, π values r a n g e d f r o m + 1 . 4 2 to —1.06 for t h e 4-substituted T F M S d e r i v a t i v e s a n d f r o m

+1.45

to —1.20 for the 3-substituents. C o r r e s p o n d i n g σ constants l i k e w i s e c o v e r e d a f a i r l y b r o a d range of values for b o t h 3- a n d 4-substituents.


For

198



b o t h the m e t a - a n d p a r a - s u b s t i t u t e d T F M S series, the most h y d r o p h o b i c substituent w a s t r i f l u o r o m e t h y l ( - C F ) w h i l e m e t h y l s u l f o n y l ( - S 0 C H ) 3

2

3

w a s the most h y d r o p h i l i c side c h a i n i n e a c h series. T a b l e V gives s u b s t i t u e n t π values m e a s u r e d i n t h e absence of s u r factant for the five p a r e n t series p r e v i o u s l y c o m p a r e d i n T a b l e I I I . E x a m i n a t i o n of the t a b l e i n d i c a t e s that the e x p e r i m e n t a l l y m e a s u r e d T F M S series π values d o not c o i n c i d e w i t h those of a n y of the other p a r e n t series b u t lie r o u g h l y m i d w a y b e t w e e n the c o r r e s p o n d i n g π values of the p h e n o x y a c e t i c a c i d a n d p h e n o l series. I n those cases w h e r e comparisons are possible, π values for the 4 - C H , 4 - F , 4 - O C H , 3 - C O C H , a n d 3 - O H 3

3

3

substituents i n the T F M S series l i e closer to the π values of the corre s p o n d i n g substituents i n the p h e n o x y a c e t i c a c i d series t h a n t h e y d o to those i n the p h e n o l series. I n contrast, π values for T F M S 4-C1, 3 - C F , 3

3-C1, a n d 3 - F substituents l i e closer to c o r r e s p o n d i n g p h e n o l series π values.

O n the basis of the d i r e c t c o m p a r i s o n b e t w e e n p a r e n t series

afforded b y T a b l e V , i t is e v i d e n t t h a t n o n e of the p a r t i t i o n i n g d a t a p r e v i o u s l y p r e s e n t e d b y F u j i t a et al. (11)

for the v a r i o u s m o d e l parent

series a d e q u a t e l y d e s c r i b e the p a r t i t i o n i n g b e h a v i o r of the s u b s t i t u t e d trifluoromethanesulfonanilide herbicides. E f f e c t of Tween 80 on T F M S π Values. T a b l e V I lists o c t a n o l / w a t e r p a r t i t i o n i n g d a t a for the 15 s u b s t i t u t e d T F M S c o m p o u n d s u s e d i n this study.

L o g a r i t h m s of t h e p a r t i t i o n coefficients

absence ( l o g P ) x

given.

a n d presence ( l o g Ρχ')

o b t a i n e d b o t h i n the

of 0 . 1 % ( w / v )

T w e e n 80 are

( P r o c e d u r e s for d e t e r m i n i n g the p a r t i t i o n coefficients Ρχ a n d Ρ χ

h a v e b e e n o u t l i n e d i n t h e E x p e r i m e n t a l section. ) π, π\ a n d ττ" values i n T a b l e V I w e r e c a l c u l a t e d a c c o r d i n g to the f o l l o w i n g r e l a t i o n s h i p s : x = log P — log Ρ Η %' = log Ρχ' - log Ρ Η " = log Ρχ' - l o g P ' x

H

x

(no T w e e n 80 present) ( 0 . 1 % T w e e n 80 present) ( 0 . 1 % T w e e n 80 present)

I n E q u a t i o n 6, π a n d π values are c a l c u l a t e d r e l a t i v e to l o g Ρ Η =

(6)

3.05

f o r the p a r e n t c o m p o u n d ( J ^ - s u b s t i t u t e d T F M S ) d e t e r m i n e d i n the a b sence of surfactant. T h u s , the π v a l u e d e t e r m i n e d for the p a r e n t c o m p o u n d i n the presence of 0 . 1 % T w e e n 80 differs f r o m z e r o (π

Η

=

—0.45).

T h e -κ" substituent constants i n T a b l e V I a n d E q u a t i o n 6 are c a l c u l a t e d r e l a t i v e to the l o g a r i t h m of the p a r t i t i o n coefficient of the p a r e n t T F M S c o m p o u n d d e t e r m i n e d i n the presence of 0 . 1 % T w e e n 80 ( l o g Ρκ

=

2.60). S i n c e T w e e n 80 i t s e l f p a r t i t i o n s 6 0 / 4 0 i n f a v o r of t h e o c t a n o l phase, a significant effect of this surfactant o n the p a r t i t i o n i n g properties of the T F M S series m e m b e r s m i g h t b e expected.

T a b l e V I i n d i c a t e s this to b e

t h e case.

values, i t is e v i d e n t that the

C o m p a r i n g l o g Ρχ w i t h l o g Ρχ


12.


Y A P E L , JR.

Table V .

POA 7>K = 3.17 a

Substituent

Substituent ττ Values for Models"

PAA pK = 4.31 a

TFMS pK = a

445

1. H 2. 4 - C F

3

3. 4-C1

4. 4-SCH3 5. 4-CH3 6. 4 - F 7. 4 - O C H 3 8. 4 - S O 2 C H 3

12. 13.

14. 15.

0.00

0.00

—

—

+0.70 ±0.03

+0.70 ±0.04

—

—

+0.52 ±0.05 +0.15 ±0.01 -0.04 ±0.01

+0.45 ±0.03 +0.14 ±0.01 +0.01 ±0.02

—

—

+ 1.07 ±0.02 +0.76 3-Cl ±0.02 3-F +0.13 ±0.03 +0.62 3-SCH3 ±0.01 3-COCH3 -0.28 ±0.01 3-OH -0.49 ±0.01 3-S0 CH ; -1.26 ±0.05

9. 3-CF3

11.

2

a 6

6

Aniline pK = 4.63 a

TAX)

(X)

10.

199

Herbicides

3

+ 1.16 ±0.03 +0.68 ±0.03 +0.19 ±0.02

— — -0.52 ±0.02 -1.25 ±0.01

0.00 + 1.42 ±0.03 +0.91 ±0.02 +0.69 ±0.02 +0.55 ±0.02 +0.20 ±0.01 -0.05 ±0.01 -1.06 ±0.02 + L45 ±0.03 +0.95 ±0.02 +0.37 ±0.01 -0.20 ±0.02 -0.27 ±0.01 -0.54 ±0.02 -1.20 ±0.03

Phenol pK = 9.89 *(X) a

0.00

0.00

— — —

—

+0.49 ±0.02 +0.25 ±0.02

— — — +0.98 ±0.02 +0.40 ±0.02

— —

+0.93 ±0.01

— +0.48 ±0.01 +0.31 ±0.01 -0.12 ±0.01

— + 1.49 ±0.01 + 1.04 ±0.01 +0.47 ±0.01

—

-0.73 ±0.04

-0.07 ±0.01 -0.66 ±0.01

—

—

No Tween 80 present. Partitioning data for P O A , P A A , aniline, and phenol taken from Ref. 11.

latter quantities h a v e b e e n s u b s t a n t i a l l y r e d u c e d i n the presence of T w e e n 80, i n d i c a t i n g a decrease i n h y d r o p h o b i c i t y a n d increase i n h y d r o p h i l i c i t y of the o r i g i n a l T F M S series m e m b e r s . E x c e p t for the 3 - C F - T F M S d e r i v a t i v e , the π values i n T a b l e V I i n d i c a t e that the r e m a i n i n g 14 series m e m b e r s ( i n c l u d i n g the parent c o m p o u n d ) are significantly m o r e h y d r o p h i l i c i n the presence of T w e e n 80 t h a n w a s t h e o r i g i n a l p a r e n t c o m p o u n d 3


200



i n t h e absence of surfactant. C o n t r a s t i n g l y , before the a d d i t i o n of T w e e n 80, o n l y six of the o r i g i n a l 15 T F M S d e r i v a t i v e s (i.e., 4 - O C H , 4 - S 0 C H , 3

3 - S C H , 3 - C O C H , 3 - O H , and 3 - S 0 C H - T F M S ) were 3

3

2

3

2

3

less l i p o p h i l i c

t h a n the p a r e n t species. Table V I .

Effect of 0.1% Tween 80 on Octanol/Water Characteristics of T F M S Herbicides

Partitioning

d

No Surfactant Substituent 1. H 2. 4 - C F 3. 4-C1

6. 4 - F 7. 4 - O C H 3 8. 4 - S O 2 C H 3 3

12. 3 - S C H 3 13. 3 - C O C H 3

14. 3 - O H 15. 3 - S 0 C H 2

3

Log

X

x

Tween 80 x'

Ρχ'

2.60 2.90 2.60 2.70 2.50 2.50 2.30 1.80 3.20 α 2.80 2.50 2.50 2.10 1.70

0.00 + 1.42 +0.91 +0.69 +0.55 +0.20 -0.05 -1.06 + 1.45 +0.95 +0.37 -0.20 -0.27 -0.54 -1.20

3.05 4.47 3.96 3.74 3.60 3.25 3.00 1.99 4.50 4.00 3.42 2.85 2.78 2.51 1.85

3

4. 4 - S C H 3 5. 4 - C H 3

9. 3 - C F 10. 3 - C l 11. 3 - F

P

Log

0.1%

6

a

-0.25 -0.55 -0.55 -0.95 -1.35

Water phase was too cloudy to measure partition coefficient metrically. x' = log Ρχ' - log P . x " = log Px' - log P '. See text for definitions and details. a

b

0.00 +0.30 0.00 +0.10 -0.10 -0.10 -0.30 -0.80 +0.60 α +0.20 -0.10 -0.10 -0.50 -0.90

-0.45 -0.15 -0.45 -0.35 -0.55 -0.55 -0.75 -1.25 +0.15

spectrophoto-

H

c

H

d

R e f e r r i n g b a c k to T a b l e V I , n o t e t h a t the p a r t i t i o n coefficients those T F M S

series m e m b e r s

substituted w i t h

relatively

of

hydrophobic

g r o u p s (e.g., 4 - C F , 3 - C F ) are s i g n i f i c a n t l y m o r e affected b y the pres 3

3

e n c e of T w e e n 80 t h a n are h y d r o p h i l i c a l l y s u b s t i t u t e d s u l f o n a n i l i d e s ( e.g., 4-S0 CH , 2

3

3-S0 CH , 3-OH). 2

3

The

surfactant thus acts p r i m a r i l y to

w a t e r - s o l u b i l i z e the most h y d r o p h o b i c of the T F M S series m e m b e r s . net effect of this i n c r e a s e d h y d r o p h o b i c

The

s o l u b i l i t y i n the p r e s e n c e of

T w e e n 80 is to compress the range of s u b s t i t u e n t π

values r e l a t i v e to

t h e i r o r i g i n a l s p r e a d i n the absence of surfactant. A l l T F M S d e r i v a t i v e s c o r r e s p o n d i n g l y b e c o m e m o r e u n i f o r m l y s o l u b l e i n w a t e r w h e n the s u r f a c t a n t is a d d e d to the p a r t i t i o n i n g m i x t u r e . T h e ττ" values i n the f a r r i g h t c o l u m n of T a b l e V I b r i n g to l i g h t a n o t h e r i n t e r e s t i n g fact.

T h e y i n d i c a t e t h a t T w e e n 80, i n a d d i t i o n to

l o w e r i n g the o c t a n o l / w a t e r p a r t i t i o n coefficients of a l l T F M S series m e m bers i n a g e n e r a l f a s h i o n , a p p e a r s t o alter the o r d e r of h p o p h i l i c i t y of c e r t a i n i n d i v i d u a l series m e m b e r s .

I n the presence of surfactant, for ex

a m p l e , t h e 4-C1, 4 - C H , a n d 4 - F T F M S d e r i v a t i v e s a l l e x h i b i t e q u a l or 3


12.


YAPEL, JR.

201

Herbicides

e n h a n c e d h y d r o p h i l i c i t y r e l a t i v e to the Η-substituted p a r e n t c o m p o u n d . I n the absence of surfactant, e a c h of these d e r i v a t i v e s is c o n s i d e r a b l y m o r e l i p o p h i l i c t h a n the p a r e n t c o m p o u n d .

H e n c e , one m u s t

conclude

that the w a t e r - s o l u b i l i z i n g a c t i o n of T w e e n 80 o n the 15 T F M S

com

p o u n d s i n v o l v e s m o r e t h a n just a u n i f o r m shift i n the h y d r o p h o b i c i t y of the v a r i o u s series m e m b e r s .

R a t h e r , the surfactant m a y i n t e r a c t i n a

u n i q u e f a s h i o n w i t h at least several of the m e m b e r s i d e c h a i n s to f o r m u n u s u a l l y w a t e r - s o l u b l e m i c e l l a r species. E v a l u a t i o n o f T F M S H e r b i c i d a l A c t i v i t y . T h e h e r b i c i d a l p o t e n c y of the 15 s u b s t i t u t e d T F M S c o m p o u n d s was r a t e d after a 21-day test p e r i o d o n a 0 - 1 0 0 % k i l l scale. H e r b i c i d a l test d a t a w e r e c o l l e c t e d for t w o grass species ( F o x t a i l , C h e a t G r a s s ) a n d a b r o a d l e a f w e e d i n t h e presence a n d absence of 0 . 1 %

(w/v)

( W i l d Mustard)

T w e e n 80. S i n c e the tests

0 . 1 % Tween 8 0 with LD (8.2 mole / a ) 9 0

2

4

6

8 10

20

40

6080

E X T R A C E L L U L A R [TFMS] (moles/acre) Figure

1.

Log-probit plot for the 4-Cl-TFMS tive acting on Foxtail Grass

deriva

Ο

Data points obtained in the absence of 0.1%

Tween 80

φ

Data points obtained in the presence of 0.1%

Tween 80


202



w e r e c a r r i e d out at three or f o u r dosage levels for each T F M S

compound,

it w a s possible to construct l o g - p r o b i t plots f r o m w h i c h L D

9 0

values

c h a r a c t e r i z i n g the p o t e n c y of each h e r b i c i d e c o u l d be d e t e r m i n e d .

The

t h e o r y a n d m e t h o d of a p p l i c a t i o n of l o g - p r o b i t analysis has b e e n p r e sented elsewhere (27,

28, 29, 30).

I n F i g u r e 1 is p r e s e n t e d a t y p i c a l

l o g - p r o b i t p l o t for F o x t a i l grass i l l u s t r a t i n g the m e t h o d of d e t e r m i n i n g LD

9 0

concentrations for the 4-C1 T F M S d e r i v a t i v e i n the presence a n d

absence of 0 . 1 % T w e e n 80. T h e L D

9 0

v a l u e for e a c h of the test c o m -

p o u n d s was defined as the m o l a r e x t r a c e l l u l a r c o n c e n t r a t i o n ( i n m o l e s / a c r e ) r e q u i r e d to k i l l 9 0 % of the w e e d t y p e u n d e r c o n s i d e r a t i o n i n p r e e m e r g e n c e tests c a r r i e d out over a 21-day t i m e i n t e r v a l .

I n a l l cases, a

c a l c u l a t e d least-squares straight l i n e was d r a w n t h r o u g h the e x p e r i m e n t a l points o n the l o g - p r o b i t p l o t .

I n d i v i d u a l d a t a points o n the plots w e r e

the average % k i l l values of the t w o r e p l i c a t e d experiments at e a c h h e r b i c i d a l dosage. better t h a n ± 5 % .

conducted

R e p l i c a t e s g e n e r a l l y a g r e e d i n a c t i v i t y to

S i n c e d a t a p o i n t s t y p i c a l l y f e l l w i t h i n the 1 0 - 9 0 % k i l l

range, no statistical w e i g h t i n g factors w e r e a p p l i e d to the points i n c o n s t r u c t i n g the plots. T h e L D

9 0

v a l u e for each h e r b i c i d e w a s t a k e n as the

e x t r a c e l l u l a r T F M S c o n c e n t r a t i o n (abscissa)

c o r r e s p o n d i n g to the 9 0 %

k i l l p o i n t ( o r d i n a t e ) o n the fitted l o g - p r o b i t line. T a b l e V I I fists the L D

9 0

derivatives i n pre-emergence Mustard.

values d e t e r m i n e d for e a c h of the 15 T F M S tests o n F o x t a i l , C h e a t G r a s s , a n d W i l d

T h e F o x t a i l a n d W i l d M u s t a r d tests w e r e c a r r i e d o u t i n the

Table VII.

LD

9 0

Values for T F M S Pre-Emergence Herbicides

NHSO2CF3

Foxtail

Grass

Wild Mustard (Broadleaf)

JL

Cheat Grass

Substituent

mole/acre No Tween 80

mole/acre No Tween 80

mole/acre 0J7c Tween 80

LDqq, mole/acre No Tween 80

mole/acre 0.1% Tween 80

25.0 4.05 1.95 2.58 43.7 3.7 80.0 2.21 22.6 24.2 23.0 ~

3-OH

3

0

4-F;4-CH

ι

3

- i

H,4-CL--|

o I o

1

τ J WILD MUSTARD)

ι

4-SCH,-H -3-SCH,

_o_ 3-CF.-H

3

0

ι

3

2

O r ('FOXTAIL) _ J 4 - 0 C H — "cb"

" cb~ 3-C0CH J

- 4-S0 CH

B

0

%

247

Herbicides

o ~à)~ ι

_9_ - 4-OCH, -H

o_

, (FOXTAIL)

+

+

(FOXTAIL)

o

•

.

_o_ +

o

"en™ _o_ ~ct>~

" CD " "0 '

-4-SCH,

+

-9•

MUSTARD)

•

-3-Cl rjWILD MUSTARD)

F-

4-CL

"0" •

~ro~

h-3-CF, •

+

Figure 6. π values for para- and meta-TFMS herbicides obtained in the absence (π) and presence (π') of 0.1% Tween 80 (see Table VI for the definition of π and π'). π values are optimum π values corresponding to those shown in the activity surfaces of Figures 2 and 3 and in Table XI. 0


248


T H E HANSCH

APPROACH

the 7Γ o p t i m u m is a g a i n shifted h y d r o p h i l i c a l l y a n d n o w lies b e t w e e n the ττ values of the 4 - F - a n d 4 - O C H - T F M S series m e m b e r s . 3

T h e m e t a - T F M S derivatives a c t i n g o n F o x t a i l a n d W i l d M u s t a r d e x h i b i t s i m i l a r h y d r o p h i l i c shifts of π o p t i m a ( F i g u r e 6 ) .

F o r the m e t a

derivatives a c t i n g o n F o x t a i l , these shifts are less i m p o r t a n t o n a c t i v i t y because of the smaller ττ d e p e n d e n c e of the m e t a substituents r e l a t i v e to the p a r a derivatives i n the presence a n d absence of surfactant (see ure 2).

For Wild

M u s t a r d , however,

Fig

t h e h y d r o p h i l i c shifts i n m e t a

substituent ττ values are q u i t e significant because of the large influence of T w e e n 80 o n m e t a - T F M S p a r t i t i o n i n g characteristics (see

Figure 3d).

T h e i m p l i c a t i o n s of these observations i n h e r b i c i d a l screening tests are i m p o r t a n t . A s m a l l a m o u n t of surfactant a d d e d to a h e r b i c i d a l f o r m u l a t i o n to i m p r o v e p e n e t r a t i o n of the h e r b i c i d e i n t o p l a n t cells m i g h t do just that—i.e., enhance the h e r b i c i d a l a c t i v i t y . A s the plots of F i g u r e s 2 a n d 3 s h o w , h o w e v e r , it is also possible that h e r b i c i d a l a c t i v i t y w i l l be i n h i b i t e d . T h e a d d i t i o n of surfactant i n e v e n s m a l l amounts

could

shift the o p t i m u m of a c t i v i t y i n a g i v e n h e r b i c i d a l f a m i l y of c o m p o u n d s so that a potent c o m p o u n d i n the absence of surfactant becomes ineffec t i v e i n its a c t i v i t y t o w a r d s a p a r t i c u l a r grass or b r o a d l e a f i n the presence of surfactant.

If a surfactant is r o u t i n e l y u s e d to p r e p a r e a l l h e r b i c i d a l

f o r m u l a t i o n s i n screening tests (i.e., evaluations c a r r i e d out at a single r e l a t i v e l y h i g h constant a p p l i c a t i o n dosage—e.g., 20 l b / a c r e ) , a r e l a t i v e l y potent c o m p o u n d

( i n the absence of surfactant) m i g h t be classified as

a n i n a c t i v e h e r b i c i d e ( i n the presence of surfactant ) a n d e l i m i n a t e d f r o m f u r t h e r testing.

O f course, the opposite effect is also possible—i.e., a

r e l a t i v e l y p o o r h e r b i c i d e i n the absence of surfactant c o u l d b e c o m e a potent one i n its presence. P r o p e r c o m p a r i s o n of the a c t i v i t y surfaces i n F i g u r e s 2 a n d 3 for the m e t a - T F M S derivatives a c t i n g o n F o x t a i l a n d W i l d M u s t a r d i n the presence a n d absence of surfactant p r o v i d e s clues as to h o w a surfactant l i k e T w e e n 80 c a n b e u s e d to i m p r o v e t h e i r grass a n d b r o a d l e a f

selec

t i v i t y . F o r example, w h e n surfactant is a d d e d to m e t a - T F M S f o r m u l a tions a p p l i e d to F o x t a i l G r a s s , the r i g h t , l i p o p h i l i c p o r t i o n of t h e a c t i v i t y surface is b e n t d o w n , a n d the grass a c t i v i t y of the m o r e

hydrophobic

m e t a derivatives is strongly depressed ( cf. F i g u r e s 2b a n d 2 d ). If T w e e n 80 is a d d e d to m e t a - T F M S f o r m u l a t i o n s a p p l i e d to W i l d M u s t a r d , h o w ever, the b r o a d l e a f a c t i v i t y of the m o r e h y d r o p h o b i c m e t a derivatives is greatly e n h a n c e d ( cf. F i g u r e s 3 b a n d 3 d ). F r o m a selectivity standpoint, a d d i t i o n of surfactant thus c a n i m p r o v e the pre-emergence a c t i v i t y of h y d r o p h o b i c series members against b r o a d l e a f w e e d s l i k e W i l d M u s t a r d (see

F i g u r e 3 d ) w h i l e s i m u l t a n e o u s l y depressing grass a c t i v i t y (see

ure 2 d ) . enhance

Fig

A t the other extreme of the π scale, surfactant a d d i t i o n w i l l the grass a c t i v i t y of h y d r o p h i l i c series m e m b e r s

a n d depress


12.

YAPEL, JR.


249

Herbicides

b r o a d l e a f a c t i v i t y , especially i f a d e r i v a t i v e w i t h a large, positive σ c o n stant is chosen (e.g., 3 - S 0 C H - T F M S ) . 2

3

S i n c e o u r analysis has d e m o n s t r a t e d that surfactant a d d i t i o n to h e r b i c i d a l f o r m u l a t i o n s c a n p r o d u c e a v a r i e t y of a c t i v i t y - i n h i b i t i n g a n d ac t i v i t y - e n h a n c i n g effects, it is p r u d e n t to a v o i d the i n d i s c r i m i n a t e use of surfactants as penetrant aids a n d f o r m u l a t i n g agents i n h e r b i c i d a l screen i n g tests. H e r b i c i d a l evaluations i n the presence a n d absence of surfactant c o u p l e d w i t h regression analyses of the t y p e discussed here s h o u l d p r o v i d e v a l u a b l e clues as to the most advantageous use of surfactants i n e n h a n c i n g h e r b i c i d a l a c t i v i t y a n d i n p r o v i d i n g better c o n t r o l of grass a n d b r o a d l e a f selectivity.

Summary H a n s c h analyses via c o m p u t e r regression techniques w e r e u s e d to correlate the grass a n d b r o a d l e a f p r e - e m e r g e n c e a c t i v i t y of a series of 15 m e t a - a n d p a r a - s u b s t i t u t e d trifluoromethanesulfonanilides ( T F M S ) w i t h s t r u c t u r a l changes i n t h e p a r e n t m o l e c u l e .

T h e h e r b i c i d a l a c t i v i t y of the

3-substituted series m e m b e r s differs f r o m that of the 4-substituted d e r i v a tives. E a c h series satisfies a different f o r m of the H a n s c h e q u a t i o n i n its a c t i o n o n a p a r t i c u l a r w e e d type.

The

final

c o r r e l a t i o n equations

for

C h e a t G r a s s , F o x t a i l , a n d W i l d M u s t a r d differ. S u b t l e differences i n the a c t i v i t y of the T F M S c o m p o u n d s against the t w o grass species F o x t a i l a n d C h e a t Grass w e r e c l a r i f i e d b y u s i n g H a n s c h stepwise

regression

analyses. H a n s c h analyses have s h o w n that the surfactant T w e e n 80, w h e n u s e d i n h e r b i c i d a l f o r m u l a t i o n s of T F M S derivatives at the 0 . 1 %

(w/v)

c o n c e n t r a t i o n l e v e l , c a n p r o d u c e one or m o r e of the f o l l o w i n g effects i n p r e - e m e r g e n c e h e r b i c i d a l tests, d e p e n d i n g T F M S derivative under evaluation: (a) herbicidal activity, (c)

o n the w e e d t y p e

no effect, ( b )

i n h i b i t i o n of h e r b i c i d a l a c t i v i t y , or ( d )

of o p t i m u m h e r b i c i d a l a c t i v i t y f r o m one T F M S

and/or

enhancement

of

shifting

d e r i v a t i v e to

another

w i t h i n e a c h series. M a t h e m a t i c a l equations r e l a t i n g structure to a c t i v i t y have b e e n d e r i v e d for the T F M S c o m p o u n d s b o t h for the

surfactant

present a n d surfactant absent cases. P a r t i t i o n i n g (π)

effects are i n g e n e r a l m u c h m o r e significant i n c o n

t r o l l i n g the h e r b i c i d a l a c t i v i t y of 4-substituted T F M S c o m p o u n d s t h a n they are for 3-substituted d e r i v a t i v e s , especially i n the absence of sur factant. I n general, substituents c h a r a c t e r i z e d b y large, p o s i t i v e H a m m e t t σ constants

( e l e c t r o n - a t t r a c t i n g substituents)

exhibit enhanced

pre-emer

gence h e r b i c i d a l a c t i v i t y o n a l l w e e d types tested ( F o x t a i l , C h e a t G r a s s ,


250


T H E HANSCH

APPROACH

W i l d M u s t a r d ) r e l a t i v e t o T F M S substituents c h a r a c t e r i z e d b y s m a l l o r negative σ constants. M e t h y l t h i o - T F M S derivatives ( 3 - S C H - T F M S , 4 - S C H - T F M S ) ex 3

3

h i b i t anomalous b e h a v i o r a n d m a y b e o x i d i z e d in vivo t o m e t h y l s u l f i n y l ( - S O C H ) o r m e t h y l s u l f o n y l ( - S 0 C H ) before r e a c t i n g at t h e receptor 3

2

3

site w i t h i n t h e p l a n t or seed. A l t e r n a t i v e l y , they m a y f u n c t i o n b y a m o d e of a c t i o n different f r o m t h e other T F M S p r e - e m e r g e n c e h e r b i c i d e s tested. T h e p a r e n t T F M S ( H - s u b s t i t u t e d ) appears t o f u n c t i o n as a 4-substituted series m e m b e r r a t h e r t h a n as a 3-substituted d e r i v a t i v e . T h e p r e d i c t i v e c a p a b i l i t i e s o f t h e d e r i v e d H a n s c h relationships w e r e d e m o n s t r a t e d f o r several specific cases. T h r e e - d i m e n s i o n a l perspective b e t w e e n ττ, σ, a n d l o g ( l J L D ined.

9 0

plots w h i c h s h o w t h e relationships

) w e r e p r e p a r e d f o r a l l w e e d types e x a m

H e r b i c i d a l a c t i v i t y differences

i n d u c e d b y surfactant a d d i t i o n to

T F M S f o r m u l a t i o n s are d e m o n s t r a t e d b y these plots. Acknowledgments T h e a u t h o r is i n d e b t e d t o J o n B e l i s l e f o r c a r r y i n g out t h e p a r t i t i o n coefficient measurements pects o f this subject.

a n d f o r s t i m u l a t i n g discussions o n various as

T h a n k s are also d u e J . W a d d i n g t o n a n d D . P a u l y

for c a r r y i n g o u t t h e p r e - e m e r g e n c e h e r b i c i d a l tests a n d to J . K . H a r r i n g t o n a n d R . D . T r e p k a for p r o v i d i n g samples o f the T F M S h e r b i c i d e s u s e d i n this study. W e are also g r a t e f u l t o E a r l C o o k a n d R . B o r d e n f o r t h e i r a d v i c e o n various m a t h e m a t i c a l aspects of this i n v e s t i g a t i o n . T h a n k s also to J . W . V a n V a l k e n b u r g f o r m a n y h e l p f u l discussions o n p r o b l e m s

asso

c i a t e d w i t h h e r b i c i d a l f o r m u l a t i o n s a n d t o Κ. H . B i i c h e l a n d J . D u r d e n for several h e l p f u l suggestions.

Literature Cited 1. Brice, T. J., Trott, P. W., U.S. Patent 2,732,398 (Jan. 24, 1956). 2. Burdon, J., Farazmand, I., Stacy, M., Tatlow, J.C.,J. Chem. Soc. (1957) 2574. 3. Farrar, W. V., J. Chem. Soc. (1960) 3058. 4. Harrington, J. K., Robertson, J. E., Kvam, D.C.,Hamilton, R. R., McGurran, K. T., Trancik, R. J., Swingle, K. F., Moore, G. G. I., Gerster, J. F., J. Med. Chem. (1970) 13, 137. 5. Trepka, R., Harrington, J. K., Robertson, J. E., Waddington, J. T., J. Agr. Food Chem. (1970) 18, 1176. 6. Hansch, C., "Annual Reports in Medicinal Chemistry," C. K. Cain, Ed., Vol. 34, p. 347, Academic, New York, 1966. 7. Ibid., Vol. 35, p. 348, 1967. 8. Hansch,C.,Proc. Intern. Pharmacol. Meetg., 3rd (1967) 7, 141. 9. Hansch,C.,Farmaco, Sci. Ed. (1968) 23, 293. 10. Hansch,C.,Fujita, T., J. Amer. Chem. Soc. (1964) 86, 1616. 11. Fujita, T., Iwasa, J., Hansch,C.,J. Amer. Chem. Soc. (1964) 86, 5175.


12.

YAPEL, JR.


Herbicides

251

12. Hammett, L. P., "Physical-Organic Chemistry," p. 184, McGraw-Hill, New York, 1940. 13. Jaffe, H. H., Chem. Rev. (1953) 53, 191. 14. Hansch,C.,Kiehs, K., Lawrence, G. L., J. Amer. Chem. Soc. (1965) 87, 5770. 15. Hansch,C.,Deutsch, E. W., Smith, R. N., J. Amer. Chem. Soc. (1965) 87, 2738. 16. Kiehs, K., Hansch, C., Moore, L., Biochemistry (1966) 5, 2602. 17. Helmer, F., Kiehs, K., HanschC.,Biochemistry (1969) 7, 2858. 18. Hansch,C.,Stewart, A. R., Anderson, S. M., Bentley, D., J. Med. Chem. (1968) 11, 1. 19. Lien, E., Hansch,C.,Anderson, S. M., J. Med. Chem. (1968) 11, 430. 20. Hansch,C.,Lien, E., Biochem. Pharmacol. (1968) 17, 709. 21. Neely, W. B., Whitney, W. K., J. Agr. Food Chem. (1968) 16, 571. 22. Hansch,C.,Muir, R. M., Fujita, T., Maloney, P. P., Geiger, F., Streich, M., J. Amer. Chem. Soc. (1963) 85, 2817. 23. Cammarata, Α., Yau, S. J., J. Med. Chem. (1970) 13, 93. 24. Martin, Y.C.,J. Med. Chem. (1970) 13, 145. 25. Purcell, W. P., Beasley, J. G., Quintana, R. P., Singer, J. Α., J. Med. Chem. (1966) 9, 297. 26. Hansch,C.,Deutsch, E., Biochem. Biophys. Acta (1966) 126, 117. 27. Goldstein, Α., Aronow, L., Kalman, S., "Principles of Drug Action," Chap. 5, Harper and Row, New York, 1968. 28. Trevan, T. W., Proc. Roy. Soc. B. (1927) 101, 483. 29. Finney, D. J., "Probit Analysis," 2nd ed., Cambridge Univ. Press, London, 1952. 30. Fisher, R. Α., Yates, F., "Statistical Tables for Biological, Agricultural and Medical Research," Oliver and Boyd, London, 1938. 31. Fukuto, T. R., Metcalf, R. L., J. Agr. Food Chem. (1956) 4, 930. 32. Jones, R. L., Metcalf, R. L., Fukuto, T. R., J. Econ. Entomol. (1969) 62, 801. 33. Leo, Α., Hansch,C.,Elkins, D., Chem. Rev. (1971) 71, 525. 34. Ostle, B., "Statistics in Research," pp. 529-543, Iowa State University Press, Ames, 1963. RECEIVED

July 27, 1971.


StructureâActivity Correlations for Meta- and Para-Substituted

Recommend Documents

StructureâActivity Correlations for Meta- and Para-Substituted