Indian Journal of ChemistryVol. 28A, July 1989, pp. 606-608

Application of the Fujita-Ban model in theprediction of dissociation constants of

benzoic acids

B K Mishra, S C Dash & G B Behera*Department of Chemistry, Sambalpur University,

Jyotivihar 768 019

Received 25 April 1988; accepted 12 July 1988

C:rhe Fujita-Ban model has been used to predict thedissociation constants of substituted benzoic acids; forthis purpose the position dependent group contributionconstants have been evaluated. The predictability of thismodel has been compared with the models of Williamsand Norrington.

For the quantitative description of structure-activityrelations (QSAR), different de novo mathematicalmodels have been proposed of which the Free-Wil-son model I is one. It is based on the assumption thateach substituent makes an additive and constantcontribution to the activity regardless of the structu-ral variation in the rest of the molecule. Purcell?used this model in correlating butyryl-cholinester-ase inhibitory potencies of twelve alkyl substituted3-carbamoylpiperidines and the activities of twentysix other congeners were predicted. Later on one ofthese predicted derivatives was synthesised. Its bio-logical activity- supported the applicability of Free-Wilson model. Since then, few other successful ap-plications of this model have been reportedv". Sub-sequently two different modifications of the Free-Wilson model based on its additivity concept weredeveloped by Cammaratat" (Eq. 1) and Fujita andBans (Eq. 2). In Eqs (1) and (2) aij is the activity con-tribution of the substituent Xi in position j: Xij = 1 ifthe substituent Xi is in position j; otherwise Xij = O.In Eq. (1) fiH is the observed biological activity valueof the unsubstituted compound whereas in Eq. (2)fio is the predicted activity value of the unsubstitut-ed compound (Xi = H).

Biological activity = I aijXij + fiHij

... (l)

= I aijXij + fioij

... (2)

A comparison of different Free-Wilson modelsalongwith their applications in QSAR studies wasundertaken by Kubinyi II. He concluded that the Fu-

t)Ot)·

Notes

jita-Ban model is the most simple and suitable ap-proach.

Herein we report for the first time the use of Fuji-ta-Ban model to predict the dissociation constantsof substituted benzoic acids.

Results and discussionThe observed pKa values'? of twenty two disub-

stituted benzoic acids represented in the form of astructural matrix (Table 1) have been subjected toFujita-Ban analysis" (Eq. 2). The a; values for ninedifferent substituents (Table 2) and fio were ob-tained by multiple regression analysis of the inputequations obtained from Table 1at 98% confidencelevel (r= 0.976, s = 0.295 and F= 29.50) the fio va-lue being 4.279.

As the a, values for different substituents are ex-pected to depend on the field, resonance and stericeffects, an additive mode113.14 is proposed to ac-count for the contribution of these various individu-al effects. The a, values of nine substituents havebeen fitted toEq. (3), where F, and R, refer to thefield and resonance parameters 15 of substituent k, fjand r are the substituent independent positional

Lweightage factors 16 for position j and SDk is the ster-ic density parameter 'V'". The values of the regres-sion coefficients, b., b2 and b, have been deter-mined and the corresponding equation (Eq, 4) is ob-tained.

... (3)

a, = - 0.708 (± 0.156)flk - 0.661 (± 0.3S5)rjRk

- 0.272 (± 0.070)SDk ... (4)

(n = 9, r= 0.973, s = 0.180, F= 30.04)

From the student's t-test, it is noted that the reson-ance term (t = 0.16) is not significant. To this effect,Williams and Norrington 16 have explained that theortho-substituents render the dissociation of ben-zoic acids independent of resonance effect becausethe ortho-substituents 'perturb the co-planarity ofthe phenyl and carboxyl groups and thereby inhibitthe conjugation between their respective pi-electrons. Therefore, the resonance term is neglect-ed and the regression of a, values with field and ster-ic parameters has been made which gives rise toEq. (5)a, = - 0.723 (± 0.114 )flk - 0.264 (± 0.053)SDk

... (5)(11 = 9, r= O.~73, s = 0.165, F = 53.79)

NOTES

Table l=-Structural matrix of disubstituted benzoic acids with their observed and calculated pKa values

Substituents Obs o-Me o-OH o-N02 o-Ci m-Me m-OH m-N02 p-Me p-N02 CalculatedpKa pKa

(Eq.6)

3,4-Me2 4.41 I 4.47

3,5-Me2 4.30 2 4.29

3,5-(OHh 4.02 2 4.01

3,4~(N02h 2.82 1 2.50

3,5~(N02h 2.82 2 2.69

2,1-Me2 4.18 3.79

2,5-Me2 3.98 3.93

2,5-(OHh 2.95 2.992-0H,4-N02 2.23 2.332-0H,5-N02 2.12 2.14

2,4-(N02)2 1.42 1.72

2,5-~N02h 1.62 1.91

2-Ci,4-N02 1.96 1 1 2.062-CI,5-N02 2.17 1 2.252,6-CI2 1.59 2 1.80

2,6-Me2 3.25 2 3.572,6-(N02h 1.15 2 1.12

2-CI,6-N02 1.34 1 1.46

2,6-(OH)2 1.08 2 1.97

2-OH,6-N02 2.24 1 1.55

2-OH,6-Cl 2.63 1 1.892-0H,6-Me 3.32 1 2.78

Table 2-Group contribution values of Substituents Table 3- Prediction of pKa of polysubstituted benzoic acids

Substituent a; Substituent a; using Eq. (6) and a, values from Table 2.

Evaluated from Training Set Evaluated from Eq. (5) Substituent pKa Differenceo-Me -0.352 o-Br -1.974o-OH - 1.152 m-OMe - 0.293 Obs. Calc. Present Ref. 13 Ref. 16

o-N02 - 1.577 m-Ci -0.489o-Ci - 1.237 m-Br -0.515 3,4-(OHh 4.13 3.79 0.34 0.78 0.24

m-Me 0.005 p-OMe - 0.299 2,3-(OH)2 2.91 2.99 0.08 0.00 1.20

m-OH -0.132 p-OH - 0.352 2,4-(OHh 3.22 2.77 {).45 0.23 1.23

m-N02 - 0.796 p-Ci -0.499 2-Cl,3-N02 2.02 2.25 0.23 0.12 1.02

p-Me 0.189 p-l.Bu -0.075 2,4-CI2 2.68 2.54 0.14 0.27 0.77

p-No2 -0.983 2,5-Ci2 2.47 2.55 0.08 0.07 0.912-0H,5-Ci 2.63 2.64 om 0.13 1.232-0H,5-Br 2.61 2.61 0.00 0.13 1.24

The group contribution (a.) values of other substi- 2,3-Me2 3.74 3.93 0.19 0.21 0.62

tuents have been calculated using Eq. (5) and are 2,3-(N02)2 1.85 1.91 0.06 0.10 0.66

listed in Table 2. All a, values, thus obtained, can be 2-Br,6-N02 1.37 0.73 0.64 0.01 1.41

utilised to predict the pKa of polysubstituted ben- 3,4,5-(OMe)2 4.13 3.67 Q.46 0.57 0.05

zoic acids using Eq. (6) where 4.279 is the evaluated 2-0H,3-N02 1.87 2.33 0.74 0.62 1.663,6-Me2,4-CMe] 3.44 3.65 0.21 0.36 1.16

pK a = 4.279 + I Xa, ... (6)2-0H,3,5-(N02h 0.70 1.54 0.84 1.15 2.122,4,6-Me] 3.44 3.76 0.32 0.33 1.324-Me,3,5-(N02)2 2.97 2.88 0.09 0.10 0.08

pKa value of unsubstituted benzoic acid (observed 2,4,6-(N02h 0.65 0.14 0.51 0.45 0.81value = 4.203). Using this model the pentanitroben-

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INDIAN J CHEM, SEe. A. JULY 1l)~l)

zoic acid is found to have the maximum acidity inpolysubstituted benzoic acids (pKa = - 1.45).Some more predicted pK a values of polysubstitutedbenzoic acids are given in Table 3.

ReferencesI Free S M & Wilson J w.} med Chern, 7 (1964) 395.2 Purcell W P, Biochirn Biophys Acta, 105 (1965) 20l.3 Beasly J G & Purcell W P. Biochirn Biophys Acta, 178

(1969) 175.4 Smithfield & Purcell W P,} pharrn Sci, 56 (1967) 577.5 Purcell W P & Clayton J M, } rned Chern, II (1968) 199.

608

6 Ban T & Fujita T,} rned Chern, 12 (1969) 353.7 Hudson D R, Bass G E & Purcell W P, } med Chern, 13

(1970) 111l4.8 Fujita T & Ban T,} med Chern, 14 (1971) 148.9 Cammarata A & Yau S J,} med Chern, 13 (1970) 93.

10 Cammarata A.} rned Chern, IS (1972) 573.II Kubinyi H & Kehrhahn 0 H,} med Chern, 19 (1976) 578.12 Barlin G & Perrin D D, Quart Rev chern Soc, 20 (1966 )75.13 Dash S C & Behera G B. Indian J Chern, 19A (1980) 541.14 Dash S C & Behera G B.} Indian chern Soc. 57 (1980) 542.IS Swain C G & Lupton E C,} Am chem Soc, 90 (1968)4328.16 Williams S G & Norrington F E,) Am chem Soc, 98 (1976)

508.