Water Partition Coefficient of Ortho-Substituted Aromatic Solutes

Octanol/Water Partition Coefficient of Ortho-Substituted Aromatic Solutes TOMOKO SOTOMATSU*, MASAO SHIGEMURA*, YOSHlYUKl MURATA*, AND TOSHIO FUJlTA** Received January 21, 1992, from the *Department of Agricultural Chemistry, Kyoto Univetsily, Kyoto 606-01, and *EMIL PROJECT, Fujitsu Accepted for publication December 2, 1992. Kansai Systems Laboretory, 2-2-4Shiromi, Chuoku, Osaka, 540, Japan.

(9of some mono- and di-orthe substituted aromatic compounds was measured in a 1-octanollwater system. For each series of compounds with the same functional group, the malue (thedifferencein the log Pvalue between the substituted and unsubstituted compound)was analyzed on the same basis as the values of meta- and para-substituted isomers by an extended Hammett-Taft procedure. In the procedure, we considered the intramolecular electronic and steric effects, operating between substituents and governing the relative hydrogen-bondingsolvation with partitioning solvents for solutes in which internal hydrogen-bond formation can be ignored. The T value for mono- and di-orthesubstituted derivativeswas adequately included in the correlation equation for the values of the meta- and parasubstituted derivatives in each series. The effect of di-orthosubstituents on partition behaviors could be roughly expressed by the sum of the effects of the 2- and 6-position substituents.

(2)

Abstract 0 The partition coefficient

The molecular log P (partition coefficient) value measured in the 1-odanoUwatersystem and the substituent parameter ?r, (the increment in the log P value or Alog P ) that accompanies the introduction of the substituent X are important hydrophobicity parameters in studies of quantitative structur+activity relationships (QSARs) of bioactive compounds.1 The ?rx value of a certain substituent X varies among different solute systems when intramolecular electronic and steric interactions between substituents being introduced into the molecule and already existing there are of importance. For the meta- and para-disubstituted benzene system X-C,H,-Y, in which Y is a fixed functional group capable of hydrogenbonding solvationwith partitioning solvents and X is variable substituent incapable of the solvation, the variation in the .nx or ?r (XIPhY) value from the corresponding T (X/PhH)value in mono-substituted benzene (X-C,H,-H) as the reference generally follows the Hammett-type linear-freeenergy relationship such as eq 11.2:

Equation 1shows that the variations in the rXvalue among various solute systems are due to variations in the solvation of the fixed functional group Y with 1-octanolrelative to fhat with water. These variations are governed by the electronwithdrawing property of X in terms of ux and a constant f i representing the susceptibility of the relative solvation of Y to the electronic effect of X substituents. In cases in which a set of X includes substituents capable of hydrogen bonding, the “backward”effect of the fixed Y on the solvation of hydrogen-bondableX substituents should also be operative. We have shown that the total effects of hydrogenbonding solvations of Y and X substituents on A?rx for certain series of disubstituted benzenes are separable into the “forward” and “backward’ components and, in effect, they are approximately additive. Thus, eq 1can be extended to eq 21s2: 776 I Journal of Phannaceutical Sciences Vol. 82, No. 8, August 1993

Equation 2 is regarded as one of examples in which the separability postulate3 applies to the interacting effects between Y and X substituents, leading to a poly-linear freeenergy relationship. Thus, the variations, AT% in T W h y ) values caused ultimately by the electronic interactions between substituents have been shown to be well analyzed by a “bidirectional” Hammett-type procedure.2 For ortho X-c,H,-Y series of compounds, specificproximity electronic and steric interaction fadors between substituents also have to be considered. In principle, these proximity interaction factors are also separable bidirectionally and additive. Unfortunately, the number of systematically measured log P values of ortho-&substitutedcompoundshas been limited, so the previous analyses including the ortho .sr(x/phY)values have not accumulated as much as analyses for meta and para substituent values.“ In this study, we attempted to extend the procedure to additional disubstituted aromatic series as well as to substantiate the previous analyses using additional ortho .sr(x/phY) values. We also examined the applicability of the procedure in analyzing the “T (Xl, X.5’hYY as Alog P for di-ortho substitutions in 2,6-disubstitutedderivatives (2-X,6-&&&3-Y) in these series.

Experimental Section Data Sets and Compounds-Six series of solutes were studied: substituted phenols, phenyl acetates, methyl benzoates, acetanilides, benzamides, and benzoic acids. The analyses for substituted phenols, acetanilides, benzamides, and benzoic acids are extensions from our previous publications2.4 to include mmlues for di-ortho substitutions. Substituted phenyl acetates and methyl benzoates were studied for the first time. Meta- and para-substituent n-values (except for some in phenyl acetates, methyl benzoates, and acetanilides) and monoortho-substituent T values in phenols, phenyl acetates, and benzoic acids were taken from the literature (including our previous publications1.2.4W. Other values including mono-ortho-substituent values of methyl benzoates, acetanilides, and benzamides, and most of the di-ortho substitution values were newly measured with either synthesized or commercially obtained compounds. Phenyl acetates and acetanilides were synthesized from the corresponding phenols and anilines by reaction with acetyl chloride. The starting phenols and anilines were from commercial sources. Most of the ortho- and di-ortho-substituted benzamides were the same samples as synthesized in our previous work.6 Di-ortho-substituted benzoic acids were purchased from Tokyo Kasei Company (Tokyo) except for 2-chloro-6-nitrobenzoic acid, which was derived from the corresponding benzamide by hydrolysis with sodium nitrite in sulfuric acid.7 Methyl benzoates were from the corresponding benzoic acids, mostly via reactions of benzoyl chlorides with methanol in benzene. Newly synthesized compoundswere identified by elemental analysis (50.3% for C and H). All compounds, including those commercially obtained, were purified by recrystallization or silica gel column chromatography (or both) before use. OO22-3549/93/08OO-0776$02.50/0 0 ‘1993, American Pharmaceutical Association

*

Measurement of P-TheP value was measured at 25 1 "C by the usual flask-shaking method.' After partition equilibrium was reached, the concentration of the water phase was evaluated with a Shimadzu W 360 spectrophotometer.For the P value of phenols and benzoic acids, a small amount of concentrated hydrochloric acid was added to the octanol-saturated water before the shaking procedure to make its pH lower than each of their pyI (K,is the association constant) values by at least two logarithmic units.1 Procedure of Analyses-For meta- and pam-&substituted benzenes (X-C,H4-Y), actual examination of the applicability of eq 2 for the bidirectional Hammett relationships was based on eq 3, which was slightly modified from eq 2:

positions in eq 3. Each of the coefficients to the independent variable terms and intercept can be evaluated by regression analysis. For the series dealt with in this study, however, preliminary examinations showed that the $values as the regression coefficient of two px terms were either insigruficant statistically (in phenols and acetanilides)or else very close to each other, overlapping within 95% confidence intervals (in the four other series). Therefore, they were either neglected or combined as a single <&term. The 6value in this term as the regression coefficient represents an "averaged" backward electronic effect of the fixed Y substituent in the d scale. Thus, eq 3 can be simplified to eq 4:

.rr(X/Phy) = adx/"hH)

Here, r W h H ) is used as the independent variable. Although it should be close to unity, the slope a of r W h H ) term is not necessarily fixed to unity. The 8 values were used throughout this study instead of the regular u.We have previously examined which is best among various Hammett-type u parameters, and found that the d parameters works better than u-9 for r values from phenols and anilines.2~4Even r values from benzoic acids and benzamides were better corrected by d than r.2.4 The d parameter is that applicable when resonance interaction of the functional groups, but not the substituents, is not significant with the benzene ring.8 In the &a", term for the forward electronic effect of X substituents on the fixed substituent Y, a", is an independent variable. In the
+ p,.d + $&+ c

(4)

To avoid giving the unsubstituted solute excessive weight, an intercept term, c, which should be close to zero, is included. For mono-ortho-substituted compounds,4 the proximity effects of ortho X substituents on the relative solvation of the Y substituent should be considered in addition to the ordinary electronic effect, which is regarded as being equivalent to a", @am).lO In principle, the proximity effects between two neighboring ortho groups consist of inductive (field) electronic and steric components that can be expressed by HammettTaft parameters.4JO To represent the inductive electronic component of proximity effects, the Charton a,constant11 can be adopted. For the steric effect of ortho substituents, the Taft-Kutter-Hansch Esparameter,12 the reference of which is shifted to that of H,is used. The proximity effects, which are also bidirectional, can be expressed as a linear combination of uIand E, values of X and Y substituents. For a set of compounds including monoortho-substituted derivatives, eq 5 is formulated for when intramolecular hydrogen bonding does not occur+

The "regular" electronic effects working bidirectionally between

Table I-Physlcochemlcal Parameters Used In Analysls Substituent

H F CI Br I Me Et Pr kPr s-Bu t-BU CH,OH CH2COOH CF, Ac CONH, CN COOMe COOH OH OMe OEt 0-kPr OCONHMe OCH2COOH NH2 NMe, NHAc NO2 SMe a

r (X/PhH)"

4"

4"

P"

0.00

0.00

0.00

0.14 0.71 0.86 1.12 0.56 1.02 1.55 1.53 2.03 1.98 -1.03 -0.72

0.35 0.37 0.38 0.35 -0.07 -0.07 -0.07 -0.07

0.1 7 0.27 0.26 0.27 -0.12 -0.13 -0.13 -0.16 -0.16 -0.17 0.05 0.53 0.46 0.36 0.69 0.46 -0.13 -0.16 -0.14 -0.17

0.88 -0.55 -1.49 -0.57 -0.01 -0.32 -0.67 -0.02 0.38 0.68 -0.97 -0.87 -1.23 0.18 -0.97 -0.28 0.61

-

0.00 0.03 0.47 0.34 0.28 0.62 0.36 0.04 0.06 0.04

-

0.05 -0.14 -0.15

-

0.70 -

From refs 4 and 5. From refs 4 and 14. From ref 4.

-

-0.21 -0.38

-

0.03 0.82

0.08

qd

Es'

0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.49 0.29 0.00 0.16 0.45 0.00 -

0.00 0.54 0.47 0.47 0.40 -0.01 -0.01 -0.01 0.01 -0.01 -0.01 0.40 -

0.00 -0.46 -0.97 -1.16 -1.40 -1.24 -1.31 -1.60 -1.71 -2.37 -2.78

0.44

-

0.94 0.27 0.60 0.42 0.74 0.91 -0.14 0.00'

-

0.63

-

-

0.30 0.28 0.27 -

-

0.67 0.30

-

-2.40

-

-0.51 -

-

-0.55 -0.55 -0.55

-

-1.01 -1.07

From ref 11. 'From ref 12. 'Estimated.

Journal of Pharmaceutical Sciences I 7l7 Vol. 82, No. 8, August 1993

Table Il-Substltuent Substituent log Pnb

?r

Values Used In Analysls' Phenols (1.46)

Phenylacetates -(1.49)

Methylbenzoates (2.12)

Acetanilides (1.16) ~~

H 0.0 0.0 Nonhydrogen-bonding meta and para substituents mF (0.47) (0.25) PF (0.31) (0.83) ma (1 (0.93) PCI mBr (1.17) (1.13) PBr ml (1.47) PI (1.45) mMe (0.56) (0.60) PMe (0.48) (0.62) mEt (0.94) 0.96 PEt (1.07) pi-Pr pt-Bu mCF, (1.49) (1.14) FcF3 Hydrogen-bonding meta and para substituents mCN (0.22) (0.14) PCN mCH,OH (-1.02) (-1.10) pCH,OH mCH,COOH (-0.61) mAc (-0.07) (-0.11) (-0.20) PAC mCOOH (0.04) pCOOH (0.12) mCONH, (-1.07) pCONH, (-1.13) (-1.22) (- 1.29) mNH, (-1.63) PNH, mNO, (0.54) (0.50) 0.01 PNO, mNMe, (0.10) pNHAc mOH (-0.66) POH (-0.87) mOMe (0.12) 0.12 pOMe (-0.1 2) (0.05) mOEt 0.59 pOEt (0.46) mOCH,COOH (-0.70) pOCH,COOH (-0.81) pOCONHMe mOCONHMe Nonhydrogen-bondingmono-ortho substituents &F (0.25) (0.27) PCI (0.69) (0.69) PBr (0.89) (0.71) &I (1.19) (1.06) (0.51) (0.44 &Me &Et (1.01) (0.93) o+Pr (1.47) &i-Pr (1.42) (1.29) o-sBu (1.81) &Bu (135) &CF, (1.21) Hydrogen-accepting mono-ortho substituents (FCN &OMe (- 0.14) (-0.1 1) &OEt (0.22) eO-CPr (0.57) &NO, (0.33) (0.06) &Me Di-ortho substitutions with nonhydrogen bonders Z,6-F2 0.50 2,6-(CI), 1.48 1.45 1.90 2,6-(Br), 2,6-(Me), (0.90) 0.83 1.57 1.91 2,6-(Et),

.w

778 I Journal of Pharmaceutical Sciences Vol. 82, No. 8, August 1993

Benzoic Acids (1.87)

Benzamides

(0.64)

~~

0.0

0.0

0.0

0.0

-

(0.31) 0.96 1.15 (1.13)

(0.28) (0.19)

(0.27) (0.27) (0.87) (0.91) (1.01) (1.12) (1.35)

C

0.16 0.73 0.64 0.83

0.65 0.58

-

(1.30) 0.36

(0.83)

(0.78)

(0.99) (0.98) (1.28) (1.14) (0.52) (0.42)

(1.07) (-0.37) (-0.31) -

(-1.15) -

-0.23 -0.18

-

0.31 (0.50)

-

(-0.38) (-0.30) (0.14)

(-0.25) (- 0.16)

(-0.13)

(0.54) (1.50) (1.87) (1.07) (- 0.12) (-0.16) -

(-0.30) (-1.19) (-0.05) (0.02)

-

(0.54)

(0.08)

(-0.97) (-1.05) (0.13) (0.18) (-0.63) (-0.25) (-0.31) (0.21) (0.22)

(-0.62) (-0.70) -0.30 0.14 0.62 0.19

-0.13 (0.12) 0.18 0.46 -0.30 0.16

(-0.10) (0.18) (0.33) (0.53) (0.31)

-

-0.05 0.00 0.13 0.29 0.12 0.53

-

0.75

-

-

-

0.01

0.04

-0.08

-0.49 -

-0.46

-

-0.22 -

-0.16 0.67

-0.47 0.16 -

-

-

0.43

-

-

-

0.69

(-0.28) (-0.41) -

-0.64

-0.28 1.71 0.34 -

-0.39 0.13 0.36 0.26

-

-0.76 0.07

-

Table 11-Substltuent w Values Used In Analyslsa (Continued)

Substituent log PHb 2-CI-6-F 2-Br-6-F 2-Br-6-CI

Phenols (1.46)

-

Phenylacetates (1.49)

Methylbenzoates (2.12)

1.22 -

2-N02-6-OMe

-

-

(1.16)

Benzoic Acids (1.87)

Benzamides (0.64) -0.15

-0.01 0.36 0.25 -

2-CI-6-Me 1.34 2-Et-6-CPr Di-ortho substitutions including hydrogen acceptors 2,6-(OMe), -0.31 2-Me-6-NO2 2-CI-6-OMe 2-Br-6-NOZ 2-CI-6-NOZ

Acetanilides

-0.86 -0.54

-0.05

-

-0.36 -0.52 -0.90

-

~~~~~~~~

a

Unless in parentheses, values were newly measured; values in parentheses were taken from refs 1 , 4 ,or 5. * Figures in parentheses are the log

P values of unsubstituted parent compounds, H-CBH,-X. -, Not determined.

ortho X andY substituents are included in the second and third terms, with the assumption that a0 (ortho)= d (rx-wtd.10 The t e r n bracketed with “ortho” are for the bidirectional proximity effects, and 6 and 6 are independent variables representing the susceptibility of X substituents to inductive electronicand steric effects of the Y substituent. For the set of T values including ortho X substituents that are nonhydrogen-bondingor only weakly hydrogen-bonding,eq 5 reduces to eq 6:

(6) When the more complicated eq 5 is used, the 6 and 6” values as independent variables should be known in advance for each of the hydrogen-bondable ortho X substituents. These values could be estimated by a method similar to that used to estimate the px values. The and SYvaluesevaluated as regression coefficients in eq 6 should be equivalent to 6 and s” values when the hydrogen-bondable Y substituent appears as one of the variable X substituents in a system in which the other substituent is fixed. Unfortunately, the hydmgenbonding ortho X substituents are sometimes capable of chelating internally with the functional group Y, so that their behavior is not in accord with eq 5. One of the original purposes of this study was to include additional ortho TT values, but we limited the ortho substituents to nonhydrogen bonders as alkyls, halogens, and CF3 and hydrogen-bond acceptors as CN, NO,, SMe, and alkoxyls in each series. These hydrogen acceptors are shown to behave so that the internal hydrogen-bond formation is unlikely in ortho-substituted phenols at least in hydroxylic partitioning solvents.4 For these sets, the simpler eq 6 could be used. For 2,6-disubstituted analogues, the observed TT (XI, W h Y l was analyzed with the simple sum of each of the substituent parameters for X, and & as independent variables in eq 6. In some series, the analyses were made first without including substituents for which some of the parameter values were unavailable. After the observation that the terms for such parameters were insignificant, these substituents were included in the formulation of the final correlations. The relevant independent parameters used to derive final correlations are listed in Table I.

Results The substituents and the newly measured 7(X/PhY) and 7 (X,,X&’hY) values are listed in Table 11. Table I11 shows correlation. Because the number of mono- and di-orthosubstituted compounds was smaller than that of meta- and para-substituted isomers, the analysis was made by the consecutive addition of the mono- and di-ortho values to the meta plus para substituent set. For each series, the first equation (I)was formulated for the subset of metu andpara

substituents with eq 4. The second equation (11)for the subset of mono-ortho,meta, andpara substituents, the third equation (111)for the subset of metu, para, and di-ortho substituents, and the fourth equation (rV)for all substituents were derived with eq 6. For each equation, n is the total number of substituents, northois the number of mono- and di-ortho substituents (or both), s is the standard deviation, r is the correlation coefficient, and F is the ratio of regression and residual variances. Figures in parentheses are the 95% confidence intervals. In each equation, the unsubstituted compound was included as the reference. The parameter terms were not indicated unless they were significant above the 95% level in each of the equations for each series. For the set of meta andpara substituents, eq 4 was found to hold in each series, although the forward electronic effect in terms of py< in methyl benzoates (eq 9-1)and the backward effect in terms of
Table Ill-Correlatlon Equatlons'

0.983 0.993 (0.37) (0.099) 0.981 0.944 (0.027) (0.081) 0.957 0.968 (0.035) (0.100) 0.963 0.919 (0.028) (0.084) Phenyl acetates 0.945 0.259 (0.069) (0.152) 0.940 0.296 (0.060) (0.117) 0.960 0.260 (0.068) (0.136) 0.954 0.288 (0.064) (0.117) Methyl benzoates 0.906 (0.070) 0.880 (0.084) 0.869 (0.117) 0.858 (0.099) Acetanilides 0.990 0.869 (0.072) (0.714) 0.972 0.914 (0.069) (0.142) (0.965) 0.807 (0.076) (0.178) 0.960 0.865 (0.081) (0.169) Benzoic acids 0.999 0.419 (0.042) (0.095) 0.954 0.394 (0.060) (0.131) 0.989 0.381 (0.042) (0.090) 0.951 0.360 (0.053) (0.110) Benzamides 0.951 0.445 (0.054) (0.126) 0.921 0.411 (0.063) (0.141) 0.899 0.399 (0.057) (0.128) 0.893 0.397 (0.057) (0.127)

-b

-

-

-

-

-

-

-

-

-0.364 (0.140) -0.235 (0.117) -0.269 (0.096)

-

-

-

-

0.123 (0.061) 0.072 (0.055) 0.084 (0.052)

-

-

-

0.345 (0.120) 0.318 (0.153) 0.320 (0.211) 0.320 (0.188)

-

-

0.330 (0.088) 0.268 (0.077) 0.267 (0.071)

-

-

-

-

-

0.538 (0.078) 0.442 (0.064) 0.455 (0.067)

-0.333 (0.226) -0.703 (0.168) -0.620 (0.172)

-

-

0.262 (0.110) 0.324 (0.040) 0.303 (0.050)

-0.474 (0.239) -0.378 (0.085) -0.397 (0.106)

-

-

0.339 (0.067) 0.349 (0.059) 0.364 (0.051)

-0.670 (0.199) -0.645 (0.130) -0.622 (0.117)

-

0.383 (0.115) 0.296 (0.168) 0.347 (0.115) 0.270 (0.146) 0.284 (0.1 49) 0.223 (0.174) 0.170 (0.169) 0.178 (0.167)

-

a The coefficient of each term is listed; ?r(X/PhY) = a&rX + equationsare, I: H, meta,para, II: H, meta, para, mono-ortho,111:

0.032 (0.035) 0.045 (0.028) 0.031 (0.035) 0.044 (0.029)

35

-

0.082

0.996

1852.6

7-1

50

15

0.081

0.996

1870.1

7-11

42

7

0.095

0.995

1252.5

7-111

57

22

0.091

0.995

1757.0

7-IV

0.106 (0.051) 0.100 (0.045) 0.102 (0.052) 0.088 (0.049)

15

-

0.072

0.994

493.9

8-1

24

9

0.073

0.993

442.6

8-11

19

4

0.092

0.995

487.7

8-111

28

13

0.083

0.992

504.0

8-IV

13

-

0.053

0.996

580.6

9-1

19

6

0.079

0.988

207.0

9-11

18

5

0.101

0.981

118.3

9-111

24

11

0.103

0.976

135.2

9-IV

12

-

0.074

0.995

488.2

10-1

21

9

0.083

0.993

262.8

10-11

18

6

0.088

0.993

244.8

10-Ill

27

15

0.108

0.986

192.4

10-IV

22

-

0.049

0.998

1261.2

11-1

29

7

0.076

0.993

334.9

11-11

28

6

0.052

0.997

721.2

11-111

0.021 (0.051)

35

13

0.072

0.993

404.5

11-IV

0.085 (0.060) 0.108 (0.068) 0.123

24

-

0.068

0.997

9937.5

12-1

35

11

0.089

0.993

390.4

12-11

38

14

0.089

0.993

444.6

12-111

49

25

0.098

0.990

407.2

12-IV

+

+

0.063 (0.040) 0.058 (0.054) 0.055 (0.071) 0.039 (0.064) 0.010 (0.070) -0.002 (0.061) 0.034 (0.076) 0.018 (0.074) -0.019 (0.044) 0.008 (0.062) -0.006

(0.044)

(0.066) 0.115 [0.062)

term for phenols. On the other hand, the intercept tended to be slightly higher for phenols and benzamides. Ideally, the slopes of all terms should be unchanged and the intercept should not be significant in any series. This could be because the separation of forward and backward effects as well as proximity electronic and steric effects are still somewhat incomplete as far as the substituents examined and the procedure used here are concerned. Among the present results of six sets of T values, those for phenols, acetanilides, benzoic acids, and benzamides seemed to reinforce the previous analyses.2.4 With an additional number of substituents, including mono- and di-ortho substi-

700 1 Journal of Pharmaceutical Sciences Vol. 82, No. 8, August 1993

+

px dy Z+fi3qiOrmoc. Substituents included in each series 4+ meta, para, di-ortho,and IV: H, meta, para, mono-and di-ortho. -, Not determined.

tutions, these correlations should be taken to supersede the previous ones.2.4

Discussion The py value (the susceptibility to the electronic effect of X) for the hydrogen-acceptor OAc and COOMe groups was estimated here as 0.28 (2 0.02) and 0, respectively. As mentioned above, the p,, value for amphiprotic Y substituents agreed well with the value previously estimated. The size of the py value for hydrogen-accepting Y substituents was lower than that for amphiprotic Y substituents. This is in accord

Table IV-Coefflclent of the Terms for Proxlmlty Effects

Compound Phenols Phenyl acetates Methyl benzoates Acetanilides Benzoic acids Benzamides

6y a

0.08 0.27 0.46 0.30 0.36

P’

-0.27 -a -a

-0.62 -0.40 -0.62

* Insignificant, nearly zero. with the previous observation in which p (Ac) equaled 0.16 and p (CN) equaled 0.2,4 The py value for amphiprotic substituents seems to be related to the position of the “acidic” hydrogen relative to the benzene ring so that the closer to the ring, the larger is the value, as suggested previously.2.4 The substituent effect on the hydrogen-accepting solvation of the hydrogen-acceptorY substituent with 1-octanolmay be counteracted by that with water to a greater extent than the substituent effect on the hydrogen-donating solvations of amphiprotic Y substituents with 1-octanol and water. This is understandable because the hydrogen-bonding “acidity” scales are much closer than the hydrogen-bonding “basicity” scales between alkanols and water as solvents, as indicated by the solvatochromic scales defined by Kamlet, Taft, and coworkers.13 The “acidity” scale (Y of alkanols and water is -0.80 and 1.10, respectively, and the “basicity” scale p is -0.90 and 0.20.19 Table lV summarizes the susceptibility constants of Y substituents to the proximity effects of ortho substituents. The susceptibility constant 6y of the steric effect increases with increased congestion of substituents near the benzene ring. The 6y values for benzoyl substituents such as COOMe, COOH, and CONH, are all similar. That the SY value of NHAc is higher than that of OAc is understandable because the hydrogen-donating solvation is more sensitive to substituent variations than is the hydrogen-accepting solvation in the amphiprotic NHAc group. The 8 value (the susceptibility to the proximity inductive effect of ortho substituents) was insignificant for hydrogen-

accepting Y substituents like OAc and COOMe. This is in accord with the above arguments for the magnitude of the p value. The value was significant only for amphiprotic 3 substituents. If the proximity electronic effect operates through space, the effect of electron-withdrawing X substituents could be to prevent electron migration in the Y substituent toward the benzene ring, making the amphiprotic group less “acidic” than otherwise. The “regular” electronic effect represented in terms of #@ara) for ortho substituents would probably give a n overall electronic effect that is too high. The negative 84“h” term can be understood as the component compensating for this overestimation. In summary, the present correlation equations seemed to be useful for practical prediction of the unknown log P value of mono- and di-ortho-substituted derivatives, unless the substituents were hydrogen bondable. The simple summation of each of the “regular” # and the proximity effect parameters a, and E , gave the T (X,,XJPhY) value for 2,Bdi-orthosubstitutions, indicating that the procedure was suitable as a first approximation.

References and Notes 1. Fujita, T.;Iwasa, J.; Hansch, C. J. Am. Chem. Soc. 1964,86,5175. 2. Fujita, T.J. Pharm. Sci. 1983, 72, 285. 3. Leffler, J. E.; Grunwald, E. Rates and Equilibria of Organic Reactions; John Wiley and Sons: New York, 1963:pp 139-146. 4. Fujita, T.Progr. Phys. Org. Chem. 1983,14,75. 5. Hansch, C.; Leo, A. J. Substituent Constants for Correlation Analysis in Chemistry and Biology; Wiley: New York, 1979. 6. Nakagawa, Y.; Sotomatsu, T.;Irie, K.; Kitahara, T.;Iwamura, H.; Fujita, T.Pestic. Biochem. Physiol. 1987,27,143. 7. Mann, F. G.; Porter, J. W. G. J. Chem. SOC.1945,67,751. 8. Taft, R.W.J. Phys. Chem. 1960,64,751. 9. JaE6, H. H.Chem. Rev. 1958,53,191. 10. Fujita, T.;Nishioka, T.Progr. Phys. Org. Chem. 1976,12,49. 11. Charton, M.Progr. Phys. Org. Chem. 1981,13,119. 12. Kutter. E.: Hansch. C. J. Med. Chem. 1969.12. 647. 13. Kamlet, hi. J.; AbLud, J. L. M.; Taft, R. W. Progr. Phys. Org. Chem. 1981.13. 485. 14. Exner, 0.In Advances in Linear Free Ener Relationships; Charpman, N. B.; Shorter, J., Eds.; Plenum: Endon, 1972;pp 1-117.

Journal of Pharmaceutical Sciences I 701 Vol. 82,No. 8, August 1993