Pesticide Synthesis Through Rational Approaches - ACS Publications

14

Downloaded by UNIV OF MASSACHUSETTS AMHERST on October 25, 2017 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch014

The Treatment of Ionizable Compounds in Quantitative Structure-Activity Studies with Special Consideration to Ion Partitioning ROBERT A. SCHERRER Riker Laboratories, St. Paul, MN 55144 The use of distribution coefficients for the QSAR treatment of ionizable compounds has been extended to consideration of ion-pair partitioning into biolipid phases. Two experimental methods for determining ion-pair partition coefficients are described. One is a single-phase titration in water-saturated octanol, in which case (for acids) log P = log Ρ + pKa - pKa'. The other is a two -phase titration (octanol/water) from which the ratio (Ρ + 1)/(Ρ + 1) can be calculated. An example outcome is that the uncoupling activity of phenols can be represented by an equation in log D instead of log D and pKa. i

i

i

A high percentage of b i o l o g i c a l l y a c t i v e compounds are i o n i z e d a t p h y s i o l o g i c a l pH. In most cases (exceptions w i l l be noted below), the p a r t i t i o n i n g o f the i o n i z e d species has been assumed to be n e g l i g i b l e and has been neglected. We neglected t h i s c o n s i d e r a t i o n ourselves i n our e a r l i e r work on the use of d i s t r i b u t i o n c o e f f i c i e n t s i n QSAR. A problem one faces i n t h i s area i s the p a u c i t y of data on i o n - p a i r p a r t i t i o n c o e f f i c i e n t s . I would l i k e t o d e s c r i b e two r e l a t i v e l y simple means f o r determining t h i s property by t i t r a t i o n and present some examples where I think the i o n i c species may be the a c t i v e form. This symposium i s an appropriate p l a c e t o d i s c u s s i o n p a r t i t i o n i n g because many h e r b i c i d e s have the p o t e n t i a l t o a c t i n the i o n i z e d form i n b i o l i p i d phases. That i s t o say, a t p h y s i o l o g i c a l pH, the b i o l i p i d phases o f membranes, o r g a n e l l e s , e t c . , w i l l c o n t a i n a high percentage of i o n , and i n f a c t , the i o n may be the predominant s p e c i e s . Examples o f such h e r b i c i d e s are c o l l e c t e d i n Figure 1· There are three a t t r i b u t e s of these agents t h a t f a v o r i o n p a r t i t i o n i n g : (1) low pKa, (2) high l i p o p h i l i c ! t y , and (3) the p o t e n t i a l f o r c h e l a t i o n i n the i o n p a i r . F i r s t , note that these acids are not j u s t a c i d i c , but

0097-6156/84/0255-0225$06.50/0 © 1984 American Chemical Society

Magee et al.; Pesticide Synthesis Through Rational Approaches ACS Symposium Series; American Chemical Society: Washington, DC, 1984.


PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES

OH

C0 H

C0 H

2

CN ioxynil

9

Cl aciflurfen

2,3,6 - TBA

OCH C0 H 2

2

C0 H 2

°]ff"' CI^^CI

Cl 2, 4, 5 - Τ

2

CI^^C0 H 2

tricamba

HNSQ CF

jUf

dichloropicolinate

3

^ S 0

2

N H ë N H - ^ > C H

S0

2

3

US 4,370,480(1983) to DuPont B r

perfluidone

Figure 1.

Na+ B r - / Q V N NO, ' \ ^ " 2 Br US 4,367,339 (1983) to American Cyanimide l

w

H e r b i c i d e s with l i p o p h i l i c

anions.



14.

QSAR Studies of Ionizable Compounds

SCHERRER

227

they are h i g h l y a c i d i c , with ^ - h a l o and o-ni t r o c a r boxy l i e a c i d groups, m u l t i p l e halogen s u b s t i t u t i o n , and 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 f u n c t i o n . Second, many are a l s o h i g h l y l i p o h o p h i l i c , such as a c i f l u r f e n with a t r i f l u o r o m e t h y l c h l o r o phenoxy s u b s t i t u t i o n , the t r i b r o m o a n i l i d e , and again, a l l the, p o l y c h l o r o - s u b s t i t u t e d compounds. A t h i r d f e a t u r e that some possess i s a heteroatom a t a f a v o r a b l e distance from the a n i o n i c s i t e f o r c h e l a t i o n i n the s a l t form, such as i n the oxyacetic a c i d and the s u l f o n y l u r e a . R. Sauers pointed out e a r l i e r i n t h i s symposium that i n c h l o r s u l f u r o n and r e l a t e d compounds the ortho aromatic nitrogens are c r i t i c a l f o r a c t i v i t y . Electron-donating groups on the h e t e r o c y c l i c r i n g [which would enhance c h e l a t i o n ] f a v o r a c t i v i t y . The oximated β - t r i o n e d e r i v a t i v e s described by I . Iwataki i n t h i s volume can a l s o form c h e l a t e d s a l t s . These are p r o p e r t i e s which favor high l i p i d concentrations of i o n p a i r s . They w i l l be elaborated on as we go along. Distribution Coefficients In developing some of the r e l a t i o n s h i p s , i t i s h e l p f u l to use a four-quadrant diagram i n which each quadrant represents a species i n a l i p i d or water phase. The diagram below shows a t y p i c a l d i s t r i b u t i o n of an a c i d , AH, between two phases where ion p a r t i t i o n i n g i s assumed to be n e g l i g i b l e . The p a r t i t i o n c o e f f i c e n t , P, i s the r a t i o of the concentration of AH i n the o c t a n o l to the c o n c e n t r a t i o n of AH i n the aqueous phase. The d i s t r i b u t i o n c o e f f i c i e n t , D, i s the r a t i o of the c o n c e n t r a t i o n i n the o c t a n o l to that of a l l forms i n the water. This i s a l s o c a l l e d the apparent p a r t i t i o n c o e f f i c i e n t .

AH OCTANOL

WATER A

AH

[AH Ρ

]

2[AH ] w

D

+ H

[AH ] 2 [AHj+fA]

Log D i s given by Equation 1 where o< i s the degree of i o n i z a t i o n , but the approximations, Equations 2 and 3, can be used when the pH i s more than a u n i t away from the pKa toward i o n i z a t i o n . A convenient t a b l e i s a v a i l a b l e f o r determining oc f o r various pH-pKa d i f f e r e n c e s (jU ·



228

l o g D = l o g Ρ + l o g (1-OC)

(1)

(for acids)

l o g D = l o g Ρ + pKa - pH

(2)

( f o r bases)

l o g D = l o g Ρ - pKa + pH

(3)


Regression Analyses Using Log D Log D accounts f o r where the "dose" i s , so t o speak. The d i s t r i b u t i o n depends on the pKa as w e l l as the pH of the medium. The advantage of u s i n g l o g D i s that i t i n c o r p o r a t e s these f a c t o r s , so, f o r simple processes such as a b s o r p t i o n , d i s t r i b u t i o n c o e f f i c i e n t s " e x p l a i n " the whole p r o c e s s . An example from our e a r l i e r work (2) i s the c o l o n i c absorption o f a c i d s ranging from phenols t o strong c a r b o x y l i c a c i d s . The a b s o r p t i o n r a t e i s given by an equation i n v o l v i n g only l o g D terms· 2

l o g % ABS = -0.079(log D ) + 0.236 l o g D + 1.503

(4)

(n = 10; r = 0.982; s = 0.096; F = 96) K u b i n y i (3) used d i s t r i b u t i o n c o e f f i c i e n t s of the same s e r i e s of compounds with h i s b i l i n e a r model f o r a b s o r p t i o n t o o b t a i n an even c l o s e r c o r r e l a t i o n , Equation 5. / J i s a constant r e l a t e d t o the model. l o g % ABS = 1.033 l o g D - 0.921 l o g 00+1) + 2.953 (n = 10; r = 0.994; s = 0.063; F = 154.71)

(5)

We've looked a t many other analyses of "simple" processes, but my f a v o r i t e i s a c o r r e l a t i o n f o r the a b s o r p t i o n of an a c i d and a base i n the same equation, — n o t only that, but with each one a t s i x d i f f e r e n t pH's, (Figure 2). The data are from Schurmann & Turner (4_); the base i s p r o p r a n o l o l and the a c i d , 4-n-hexylphenylacetic. Only a s i n g l e parameter i s r e q u i r e d , l o g D, Equation 6. Kubinyi*s b i l i n e a r equation gives an even b e t t e r c o r r e l a t i o n (5^), Equation 7. (This i s a s p e c i a l v e r s i o n of the b i l i n e a r model which s e t s the c o e f f i c i e n t s of each term equal.) log K

a b s

log K

a b s

= 0.348 l o g D - 1.651 (6) (n = 12; r = 0.966; s = 0.163; F = 140) = 0.448 l o g D - 0.448 logij^D+D - 1 .689 log/? = -2.792 (n = 12, r = 0.988; S = 0.102)

(7)

In more complex processes c o r r e l a t i o n equations may r e q u i r e e l e c t r o n i c , s t e r i c , or other f a c t o r s which c o n t a i n i n f o r m a t i o n


14.

229

QSA R Studies of Ionizable Compounds

SCHERRER


about the mechanism of a c t i o n . For example, Equation 8 shows the c o r r e l a t i o n of uncoupling of o x i d a t i v e phosphorylation by the phenols i n Table I I . T h i s i s a property possessed by many h e r b i c i d e s (6) but i s u s u a l l y an undesired property when i t occurs i n drugs. One can say from the c o e f f i c i e n t s (J_) t h a t the more a c i d i c the phenol of a given l o g P, the more a c t i v e i t w i l l be as an uncoupler, even though there w i l l be l e s s compound i n the l i p i d phase. We w i l l see l a t e r t h a t these two terms can be replaced by the s i n g l e parameter, l o g D of the sodium s a l t . l o g 1 = 0.471 l o g D - 0.618 pKa + 7.58 (n = 23; r = 0.946; s = 0.351; F = c

(8) 86)

Ion P a r t i t i o n i n g M a r t i n (7) has w r i t t e n a p e r c e p t i v e a n a l y s i s of the p o s s i b l e ways i n which an i o n i z e d species may behave i n various models and c o n t r i b u t e to or be r e s p o n s i b l e f o r a given a c t i v i t y . QSAR studies t h a t have d e a l t with i o n - p a i r p a r t i t i o n i n g i n c l u d e a study of f i b r i n o l y t i c s {8) and the e f f e c t of benzoic acids on the K i o n f l u x i n mollusk neurons (9^) · Schaper ( 10) r e c e n t l y reanalyzed a large number of absorption s t u d i e s to i n c l u d e terms f o r the absorption of i o n i z e d s p e c i e s . Because s p e c i f i c values were not a v a i l a b l e f o r l o g P^, he l e t the r e l a t i o n between l o g P i and l o g Ρ be a parameter i n a n o n l i n e a r r e g r e s s i o n a n a l y s i s . In most cases he used the approximation that the d i f f e r e n c e between the two values i s a constant i n a given s e r i e s . T h i s same assumption was made i n the e a r l i e r s t u d i e s (8^,9 ). our work suggests t h a t the pKa of an a c i d can i n f l u e n c e t h i s d i f f e r e n t i a l (see below). The i n f l u e n c e of s t r u c t u r e on the l o g P^ of protonated bases or quaternary ammonium compounds i s much more complex (11,12) and p o i n t s out the d e s i r a b i l i t y of being able to e a s i l y measure these v a l u e s . +

Sodium S a l i c y l a t e P a r t i t i o n i n g . Our e a r l i e r work was based on the assumption t h a t the i o n i z e d species does not s i g n i f i c a n t l y p a r t i t i o n i n t o the b i o l i p i d phase. I t turns out that even a t low l e v e l s of p a r t i t i o n i n g , l i p i d i o n concentrations can be s i g n i f i c a n t . S a l i c y l i c a c i d provides a good example. Figure 3 shows the l o g D, or apparent l o g P, f o r s a l i c y l i c a c i d over a broad pH range. There i s a f l a t p o r t i o n a t low pH where l o g D = l o g Ρ of the unionized a c i d . There i s an i n f l e c t i o n a t the pKa and a decreasing p r o p o r t i o n of a c i d i n the l i p i d phase with i n c r e a s i n g pH, f o l l o w i n g the equation i n d i c a t e d . F i g u r e 4 shows the d i s t r i b u t i o n of sodium s a l i c y l a t e . I t s l o g Pj, measured i n pH 8.5 phosphate b u f f e r i s -1.44 (11). Again there i s an i n f l e c t i o n a t the pKa with a d e c l i n i n g l o g D with decreasing pH f o l l o w i n g the equation f o r bases. I t i s i n t e r e s t i n g to superimpose these two p l o t s (Figure 5) · Even though the d i f f e r e n c e i n l o g Ρ between the a c i d and



OH I

0.00

OCH CHCH N H Q O y

-0.50 Downloaded by UNIV OF MASSACHUSETTS AMHERST on October 25, 2017 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch014

, 0

9 a , K

y

b

·

Calcd. -1.00

-1.50

-2.00

-2.50 -2.50

-2.00

-1.50 log Κ

-1.00

-0.50

0.00

Observed abs.,

Figure 2. Buccal a b s o r p t i o n a t s i x pH's an a c i d , Equation 6.

of an amine and

LogD AH

Log D

A H

= Log Ρ

Δ Η

+ pKa -

pH

F i g u r e 3· Octanol/water d i s t r i b u t i o n of s a l i c y l i c over a range of pH v a l u e s .


acid


SCHERRER


H

1 1 h

3

4

ι

pKa

L

5

D

H—I—h8

6

9

PH

10

LogD A-Na+ = LogPA-Na+

L

P

° 9 A"NA+ = ° 9 A N a

+

" P

K a +

P

H

Figure 4. Octanol/water d i s t r i b u t i o n of sodium s a l i c y l a t e over a range of pH values.

Figure 5. O v e r l a y i n g F i g u r e s 3 and 4 shows that the anion i s the dominant o c t a n o l - s o l u b l e species a t pH 7.4. the pKa' i s 6.7.



232

PESTICIDE SYNTHESIS T H R O U G H RATIONAL A P P R O A C H E S

the i o n i s 3.70, the concentration o f sodium s a l i c y l a t e i n the l i p i d a t pH 7.4 i s 5X greater than the n e u t r a l form. Could the anion be the a c t i v e species f o r some o f the p r o p e r t i e s of s a l i c y l i c acid? I t turns out, i n t e r e s t i n g l y , t h a t a s i m i l a r a n a l y s i s of the antiinflammatory agents indomethacin (13) and phenylbutazone (J_4) shows that i n o c t a n o l a t pH 7.4 the sodium s a l t s w i l l be the dominant species by f a c t o r s of 5.3 and 10, r e s p e c t i v e l y . Note from Figure 5 that the more a c i d i c a compound, the f u r t h e r t o the l e f t the d e c l i n i n g phase begins and the l e s s favored the a c i d form a t p h y s i o l o g i c a l pH. This bears on the h i g h l y a c i d i c h e r b i c i d e s i n F i g u r e 1. Again r e f e r r i n g t o Figure 5, where the two l i n e s cross a t pH 6.7, the concentrations of a c i d and anion i n the o c t a n o l phase are equal. What i s t h i s other than the pKa i n octanol? I d e f i n e the pKa i n o c t a n o l t o be equal t o the pH o f the aqueous phase which i s i n e q u i l i b r i u m with the system when the o c t a n o l concentrations of the two species a r e equal. I t i s a challenge, though, t o see i f t h i s pKa can be determined d i r e c t l y . When the i o n - p a i r p a r t i t i o n i n g i s i n d i c a t e d i n the quadrant diagram (below) i t becomes obvious t h a t a c i r c l e of e q u i l i b r i a i s present. Knowing the o c t a n o l pKa, the l o g Ρ and the aqueous pKa should allow one t o c a l c u l a t e the p a r t i t i o n c o e f f i c i e n t of the i o n p a i r . From these e q u i l i b r i a one can w r i t e that the d i f f e r e n c e i n l o g Ρ between the a c i d and i t s s a l t i s the same as the d i f f e r e n c e between the pKa's (Equation 9 ) . The c l o s e r the pKa's, the more l i p i d s o l u b l e the i o n p a i r w i l l be, r e l a t i v e t o the a c i d . I n t e r n a l hydrogen bonding o r c h e l a t i o n that s t a b i l i z e s an i o n p a i r w i l l a f f e c t the o c t a n o l s t a b i l i t y more than the aqueous s t a b i l i t y , where i t i s l e s s needed, and so w i l l decrease the d e l t a pKa. C h e l a t i o n should t h e r e f o r e favor b i o l i p i d s o l u b i l i t y of i o n p a i r s . Ultimate examples are a v a i l a b l e i n some ionophores. This i s one of the p r o p e r t i e s of some of the h e r b i c i d e s I pointed out e a r l i e r . _+

A Na o

AH OCTANOL

WATER

NaOH -> A + Ν _ w a

AH

l o

9

PAH "

1°9

p

i

=

P

K

A

*

"

P

K

A

#

I n c i d e n t a l l y , the r e l a t i o n s h i p i n Equation 9 was discussed by K o l t h o f f e t a l . (15) back i n 1938. In t h e i r case the p a r t i t i o n


14.

SCHERRER


233

c o e f f i c i e n t s were f o r ethanol/water and were determined by s o l u b i l i t i e s , s i n c e they c o u l d not be d i r e c t l y measured.


Log P^ by T i t r a t i o n i n Water-Saturated Octanol We decided t o t r y a d i r e c t t i t r a t i o n i n water-saturated o c t a n o l . What we hoped t o achieve, i f not d u p l i c a t i n g l i t e r a t u r e values, was t o o b t a i n p a r t i t i o n c o e f f i c i e n t s p r o p o r t i o n a l t o " t r u e " values so t h a t r e g r e s s i o n analyses could be run and would be meaningful. Secondly, t h i s should be a r a p i d method to assess s t r u c t u r a l f e a t u r e s i n a s e r i e s f o r t h e i r e f f e c t on i o n - p a i r pa r t i t i oni ng· In c o l l a b o r a t i o n with Jon B e l i s l e , o c t a n o l pKa values were measured f o r a s e r i e s of benzoic a c i d s and phenols. A coupled e l e c t r o d e c a l i b r a t e d i n aqueous b u f f e r s was used. The h a I f - n e u t r a l i z a t i o n p o t e n t i a l was measured s i n c e the Henderson-Hasselbalch equations would not apply. The t i t r a n t was 0.1 îî sodium hydroxide i n isopropanol:methanol 4:1. The t i t r a n t was only 6% o f the t o t a l volume a t h a I f - n e u t r a l i z a t i o n , so the medium was e s s e n t i a l l y o c t a n o l - l i k e . The r e s u l t s are l i s t e d i n Table I and some benzoic a c i d values are p l o t t e d i n Figure 6. The c a l c u l a t e d l o g P^ values i n Table I are s l i g h t l y h i g h e r than the l i t e r a t u r e reported v a l u e s . The pKa of benzoic a c i d i n o c t a n o l i s 3.55 u n i t s higher than i n water. From Equation 9, t h e A l o g Ρ i s 3.55 compared with the measured d i f f e r e n c e o f 4.14 i n 0.1 Ν sodium hydroxide. T h e Δ l o g Ρ f o r s a l i c y l i c a c i d i s c a l c u l a t e d to be 3.35 compared with the d i r e c t l y measured value 3.70. The most i n t e r e s t i n g f i n d i n g i s t h a t the slope of the benzoic a c i d l i n e i s 1.49 and n o t 1.0 (Equation 10). These r e s u l t s suggest that, c o n t r a r y to the c u r r e n t assumption (11), theApKa, and t h e r e f o r e the Δ l o g P, f o r benzoic a c i d s i s not a constant. The stronger the a c i d , the l e s s t h e A p K a and the more l i p o p h i l i c the s a l t w i l l be i n r e l a t i o n t o i t s a c i d . T a f t ( 16) has observed t h a t the pKa's of the s t r o n g e s t a c i d s i n a s e r i e s are o f t e n l e s s a f f e c t e d by changes i n s o l v e n t , l i k e l y because t h e i r ions are more s t a b l e and need l e s s s o l v a t i o n . T h i s i s another reason f o r saying the h i g h l y a c i d i c h e r b i c i d e s i n F i g u r e 1 w i l l tend t o have l i p o p h i l i c s a l t s . Exceptions t o the g e n e r a l p a t t e r n i n F i g u r e 6 are n i t r o s a l i c y l i c a c i d s (Table 1) and the ^ - c h l o r o b e n z o i c a c i d s . N i t r o s a l i c y l i c a c i d s a l t s are more l i p o p h i l i c than expected from t h e i r aqueous pKa. The o-chlorobenzoic a c i d s are l e s s l i p o p h i l i c than a m or p-benzoic a c i d would be of the same pKa. The 2,6-dichlorobenzoic a c i d p o i n t should perhaps be on a separate l i n e p a r a l l e l t o the in and p-benzoics. From the values i n Table I, the f o l l o w i n g c o r r e l a t i o n s can be made f o r p r e d i c t i n g the pKa , and t h e r e f o r e l o g P i , f o r s i m i l a r compounds. The 95% confidence l i m i t s are i n d i c a t e d . 1



234


Table I .

H a I f - N e u t r a l i z a t i o n pH f o r Benzoic Acids and Phenols i n Water-Saturated O c t a n o l .

Benzoic a c i d substitution H 3-Br 3-OH 4-CI 3,4-Cl

a

pKa 4.19 3.82 4.08 3.98 3.66

2

pKa 7.74

3.55

7.23 7.65 7.31 6.90

3.41

4-CH3

4.37

7.93

3-NO2

3.47

6.53

4-N0

3.41

4-(0H)

2

3.33

2,3-(0H)

2

2.91

6.64 6.71 6.26 5.61 6.32 7.05 6.14

2,5-(0H)

2

2.97

6.21

2,6-(0H)

2

3.80 5.76

3.91 2.19

2

2-CI

2.94

2,5-Cl

2

2,6-Cl

2

2.47 1 .59 2.97

2-0H 2

F

5-OCH3,

2-0H

.08 2.62 2.63 2.30 2.96

5-N0 ,

2-OH

2.12

1

5-Br 2 - 0 H f

5-C1,

2-0H

3,5-Cl , 2-0H 2

2

3,5-(N0

2

)

2

,

2-0H(ppt)

0.70

, b

pKa•-pKa (Corresponds t o log Ρ-log P i , Eg

5.79

5.15 6.20

3.57 3.33

3.24 3.56 3.06 3.23 3.77 3.79 4.02 3.35

3.72 3.23 3.24 2.72 3.14 3.16 2.85 3.24 1 .79 1.49

Phenol s u b s t i t u t i o n 2.56 12.66 3-CH3 10.10 2.67 11 .23 8.56 2-CI 2.56 11.94 9.38 4- CI 2.60 10.78 8.18 3.5- C l 2.65 10.50 7.85 2,4-Cl 2.76 9.55 6.79 2.6- C l 2.45 10.40 7.95 4-CN 2.54 9.70 7.16 4-N0 2.38 5.92 3.54 2,6-Cl ,4-N0 2.43 9.66 7.23 2-N0 1.72 2.4- ( N 0 ) 5.82 4.10 1 .81 7.03 5.22 2.5- ( N 0 ) 1.62 5.20 2.6- ( N 0 ) 3.58 L i t e r a t u r e values. T i t r a n t : 0.1 Ν NaOH i n isopropanol:methanol 4:1; 1 e q u i v a l e n t of t i t r a n t was c a . 12% o f f i n a l volume. 2

2

2

2

2

2

2

a

2

2

2

2

2

2

D



SCHERRER


9.00

pKa in Water F i g u r e 6. H a l f - n e u t r a l i z a t i o n p o t e n t i a l s of benzoic a c i d s i n water-saturated o c t a n o l v s . t h e i r corresponding aqueous pKa values.



236

JL- and j g - s u b s t i t u t e d benzoic a c i d s pKa' = 1.49 (±0.24) pKa + 1.48 (±0.93) (n = 8; s = 0.888; r = 0.975)

(10)

2

s a l i c y l i c a c i d s , except n i t r o - s u b s t i t u t e d pKa

1

= 1.38 (±0.19) pKa + 2.17 (±0.50) (n = 9; s = 0.146; r = 0.978)

(11)


2

cr-nitrophenols pKa' = 1.22 (±0.17) pKa + 0.79 (±0.82) (n = 4; s = 0.104; r = 0.998)

(12)

2

phenols

(not .Qrnitro-substituted)

pKa' = 1.02 (±.05) pKa + 2.39 (±0.40) (n = 9; s = 0.112; r = 0.977)

(13)

2

Test o f Octanol T i t r a t i o n Procedure. In order t o see how c l o s e we were t o r e a l i t y with these t i t r a t i o n s , the antiinflammatory s u l f o n a n i l i d e , R-805, nimesulide, was examined because the anion has a d i s t i n c t i v e UV a b s o r p t i o n . R-805 has pKa 5.9, l o g Ρ 2.6, and a pKa i n o c t a n o l of 8.82. With t h i s data the l o g P-^ f o r the sodium s a l t i s c a l c u l a t e d from Equation 9 t o be -0.3. R-805 was e q u i l i b r a t e d between two phases a t pH's such t h a t the o c t a n o l contained i o n i z e d species (e.g. 39% of the 805 was i n the o c t a n o l and 69% o f t h i s was the i o n ) . The l o g P^'s observed a t two pH's were -0.37 and -0.35. 1

N0

2

R-805, nimesulide

QSAR Using Log D-; and Log Pj . The uncoupling a c t i v i t y of the phenols from which Equation 8 was d e r i v e d , was reanalyzed u s i n g log (Table I I ) . The a c t i v i t y h i g h l y c o r r e l a t e s with the l i p i d c o n c e n t r a t i o n of the i o n p a i r , Equation 14. This i s s a t i s f y i n g i n view of a proposed mechanism of uncoupling (17)



2

2

2

2

2

2

2

3

2

4

2

2

2

2

e

c

pKa 9.99 8.56 9.43 9.12 7.98 7.51 7.94 6.22 6.44 5.74 4.95 7.23 7.16 8.36 4.10 5.22 3.71 10.10 10.28 9.59 5.33 3.54 3.39 e

e

e

e

e

e

e

e

Log P^c -1 .15 -0.50 -0.10 -0.05 0.56 0.68 0.69 1.13 1 .46 1 .62 1 .63 -0.62 -0.56 -0.53 -0.20 0.21 0.08 -0.58 -0.63 0.14 0.75 0.58 0.61 Log D 1 .48 2.17 2.41 2.52 2.96 2.92 3.11 2.36 2.89 2.36 1 .57 1 .35 1 .47 2.02 -1 .88 -0.26 -2.22 1 .98 1 .97 2.72 1 .08 -1 .00 -1 .04 Log D-jâ -3.64 -1.59 -2.03 -1.67 -0.04 0.38 0.11 1.13 1 .46 1 .62 1 .63 -0.80 -0.72 -1.45 -0.20 0.21 0.08 -3.18 -3.41 -1.95 0.75 0.58 0.61

Obsd. 2.10 2.79 3.05 3.38 4.17 4.17 4.17 4.34 5.14 5.48 5.70 2.84 3.96 3.49 4.72 4.32 3.94 2.30 2.28 3.17 4.47 4.80 5.11

Eq.14 2.00 3.26 2.98 3.21 4.21 4.47 4.30 4.93 5.13 5.23 5.23 3.74 3.79 3.34 4.12 4.36 4.28 2.28 2.14 3.03 4.69 4.59 4.61

Uncoupling, l o g 1/C

O r i g i n a l d a t a o f S t o c k d a l e , M., a n d S e l w y n , M., E u r . J . B i o c h e m . 1971, 2 1 , 565. P h y s i c a l c o n s t a n t s , R e f . 1. t>From T a b l e I . C a l c u l a t e d f r o m E q u a t i o n 9. ^From E q u a t i o n 1; l o g ( 1 - ) v a l u e s f o r b a s e s from R e f . 1. C a l c u l a t e d from E q u a t i o n 13.

5

F 2,6-Cl -4-N0 2,6-Br -4-N0

2-naphthol

4-CH3

3-CH3

2,6-(Ν0 >2

5

2

2

2

Log Ρ 1 .48 2.17 2.41 2.52 3.08 3.22 3.24 3.64 3.98 4.12 4.12 1 .81 1 .98 2.02 1 .52 2.02 1 .57 1 .98 1 .97 2.72 3.25 2.96 3.07

pKa» octanolb 12.62 11.23 11 .94 11.69e 10.50 10.05 10.49e 8.73 8.96e 8.24 7.44e 9.66 9.70 10.91 5.82 7.03 5.20 12.66 12.88 12.17 7.83 5.92 5.85

a

Uncoupling of O x i d a t i v e Phosphorylation by Phenols a t pH 7.5 and Physicochemical Constants U s e d

Substitution H 2-CI 4-CI 3-CI 2,4-Cl 2,5-Cl 2,4-Br 2,4,6-Cl 2,4,6-Br3 2,3,4,6-Cl Cl 2-N0 4-N0 3-N0 2,4-(N0 ) 2,5-(N0 )

Table I I .



238

which i n v o l v e s s h o r t c i r c u i t i n g the energy storage c a p a c i t y of a c e l l by t r a n s f e r r i n g cations i n one d i r e c t i o n and protons i n the other. From Equation 14 one could say t h a t the r a t e - l i m i t i n g step i s t r a n s f e r of the c a t i o n . log

1 1 C


log

c

= 0.471 l o g D - 0.618 pKa + 7.58 (n = 23; r = 0.946; s = 0.351; F =

86)

(8)

= 0.614 l o g D + 4.23 (n = 23; r = 0.940; s = 0.361; F =

160)

(14)

L

The data of L e v i tan and Barker (9^) on the a b i l i t y of c a r b o x y l i c a c i d s to promote potassium i o n conductance i n mollusk neurons (Table I I I ) was reexamined. One can w r i t e Equations 15 and 16 f o r simple benzoic a c i d s , but s a l i c y l i c acids do not give a good c o r r e l a t i o n i n l o g P i alone (r = 0.785). l o g RA = 1.04 l o g D - 1.09 pKa +5.67 (n = 13; r = 0.985; s = 0.122; F =

159)

(15)

l o g RA = 0.984 l o g P i +1.52 (n = 13; r = 0.968; s = 0.162; F =

165)

(16)

The L e v i t a n and Barker s e r i e s has a l s o been examined by Hansch (18), who reported that the benzoic a c i d s , s a l i c y l i c acids and four miscellaneous acids could a l l be c o r r e l a t e d u s i n g l o g V±, Equation 17. The d i f f e r e n c e i s i n the c a l c u l a t i o n of log P i values which were obtained by s u b t r a c t i n g constants from the l o g Ρ values, 3.69 f o r s a l i c y l i c acids and 4.36 f o r benzoic a c i d s . l o g 1 = 0.839 l o g P + 331 (n = 30; r = 0.979; s = 0.177) ±

(17)

c

Log Ρ by a Two-Phase T i t r a t i o n At t h i s p o i n t I want to emphasize t h a t the procedure I am about to d e s c r i b e bears no r e l a t i o n to the previous t i t r a t i o n method, though c o n f u s i n g l y s i m i l a r . The l a t t e r i s a single-phase t i t r a t i o n i n o c t a n o l , while t h i s i s an aqueous-phase t i t r a t i o n i n the presence of o c t a n o l . The two-phase t i t r a t i o n was f i r s t described i n 1963 (19) as a means to simultaneously determine a p a r t i t i o n c o e f f i c i e n t and pKa. S e v e r a l v a r i a t i o n s have appeared s i n c e (20-24), but none has seemed to gain f a v o r . I l i k e the s i m p l i f i e d approach of Clarke (25,26) who uses the method to determine p a r t i t i o n c o e f f i c i e n t s a f t e r s e p a r a t e l y determining (or knowing) the pKa. Figure 7 shows a t y p i c a l t i t r a t i o n . The aqueous t i t r a t i o n curve i s on the l e f t . In the presence of an equal volume of o c t a n o l , the pKa s h i f t s 1 .9 pK u n i t s , which i s about the l o g Ρ of benzoic a c i d . The exact r e l a t i o n s h i p s , c o r r e c t i n g f o r volume


14.

SCHERRER

239

QSAR Studies of Ionizable Compounds r— ο ο τ— (Ν CO CO ιη ιη V0 ϋ ο co CO in Γ — VO ιη CO • • • • • • • • • • • • • CU Ο ο ο ο ο Ο ο Ο ο ο1 ο Ο U I 1 ι ι I

1

ϋ ιη 00 ιη σ> ο Ό ιη ϋ «— CN CN CO τ- r— ο ιη CO (0 ο τ— ο Ο ο Ο Ο ν— ο ο ο 1 υ ι I ι

CO CO ο ο I I


0) Ο Ο 00 Ο Ο 00 Ο ΓΟ Ο ^ (Ν Ο (Ν .Γ*» Ο ^ I γο σ> νο m m ιη ο τ ο ο ο ο ο ο ο ο ο ο ο ι ι I I I I s

ο c s 10 c ο υ

C0

vO

r*r-r^a>r^cocNt-cocy>co*3* Oinint^vovocNcococNCNco ο ο τ ο ο ο ο Ο t- r- 1

ϋ

•ο 0)

Φ χ— ο CO CO co CO in vo • • vo• • r- VO• • • • vo VO•

(d

00 CN 00 ^* CN 00 VO τ— t— ο 00 CO σ» vo ο σ» CO • • • • • CO CO CN CO CO CO CO CO co

CO

>

β

Ο

τ-Η c ο c •Η ο 4-1 •Η C0 4J CO cr 3 ω cr ω

ε ο ε ο 14-1 u M-4 Ό CD Ό CD

(0

PU

1—1 U-l

CD

in CO vo CN

φ ϋ ϋ •α ο υ α)

Pesticide Synthesis Through Rational Approaches - ACS Publications

Recommend Documents