Hansch substituent coefficients

J. Iwasa, T. Fujita, C. Hansch, Substituent Constants For Aliphatic Functions Obtained From Partition Coefficients,/. Med. Chem. 1965, 56, 150-3. 

The above equation can be rewritten as logPx = logPH + 7tx-Thus the logP of a compound is equal to the logP of the parent compound plus the Hansch partition coefficient of the substituent. Alternatively, the partition coefficient can be viewed as being equivalent to the sum of the contributions from all of the various groups from which it is comprised. Therefore,... 

T Fujita, J Iwasa, C Hansch. A new substituent constant, 7i, derived from partition coefficients. J Am Chem Soc 86 5175-5180, 1964. 

Several Hansch-Leo n substituent parameters denved from octanol-water partition coefficients (P), = log p (ce sX) - log P (C H ), are hsted m Table 9... 

In these equations, Dmax is the larger of the summed values of STERIMOL parameters, Bj, for the opposite pair 68). It expresses the maximum total width of substituents. The coefficients of the ct° terms in Eqs. 37 to 39 were virtually equal to that in Eq. 40. This means that the a° terms essentially represent the hydrolytic reactivity of an ester itself and are virtually independent of cyclodextrin catalysis. The catalytic effect of cyclodextrin is only involved in the Dmax term. Interestingly, the coefficient of Draax was negative in Eq. 37 and positive in Eq. 38. This fact indicates that bulky substituents at the meta position are favorable, while those at the para position unfavorable, for the rate acceleration in the (S-cyclodextrin catalysis. Similar results have been obtained for a-cyclodextrin catalysis, but not for (S-cyclodextrin catalysis, by Silipo and Hansch described above. Equation 39 suggests the existence of an optimum diameter for the proper fit of m-substituents in the cavity of a-cyclodextrin. The optimum Dmax value was estimated from Eq. 39 as 4.4 A, which is approximately equivalent to the diameter of the a-cyclodextrin cavity. The situation is shown in Fig. 8. A similar parabolic relationship would be obtained for (5-cyclodextrin catalysis, too, if the correlation analysis involved phenyl acetates with such bulky substituents that they cannot be included within the (5-cyclodextrin cavity. 

The first attempt for calculating logP was proposed by Hansch and Fujita [189] who considered partition coefficients as an additive-constitutive property. This means that lipophilicity of a given compound is given by that of the unsubstituted parent compound plus a 7T term representing the difference in partition coefficient between a particular substituent X and the hydrogen atom which it replaces ... 

Iwasa, I., Fujita, T., Hansch, C. (1965) Substituent constants for aliphatic functions obtained from partition coefficients. J. Med. Chem. 8, 150-153. 

Every component of an organic compound has a defined lipophilicity and calculation of partition coefficient can be performed from a designated structure. Likewise, the effect on log P of the introduction of a substituent group into a compound can be predicted by a number of methods as pioneered by Hansch [5-8] (k values), Rekker [9-10] (fvalues) and Leo/Hansch [5-7, 11-12] (f values). 

Hansch C., P.P. Maloney, T. Fujita, and R.M. Muir (1962). Correlation of biological activity of phenoxyacetic acids with Hammett substituent constants and partition coefficients. Nature (London) 194 178-180. 

Statistical and computational methods have been used to quantify structure-activi relationships leading to quantitative structure-activity relationships (QSAR). The concqpt of QSAR can be dated back to the work of Crum, Brown and Fraser from 1868 to 1869, and Richardson, also in 1869. Many notable papers were published in the period leading up to the twentieth century by men such as Berthelot and Jungfleisch in 1872, Nemst in 1891, Ov ton in 1897 and Meyer in 1899 (7). Professor Corwin Hansch is now regarded by many as the father of QSAR, because of his work in the development of new and innovative techniques for QSAR. He and his co-woikers produced a paper that was to be known as the birtii of QSAR, and was oititled "Correlation of biological activity of phenoxyacetic acids with Hammett substituent constants and partition coefficients" (2). 

The octanol-water (pH 5) partition coefficients of 1,2,3,4-tetrahydro-and 1,2,3,4,6,7,8,9-octahydro-llH-pyrido[2,l-Z>]quinazolin-l 1-ones and their 6-, 7-, 8-, and 9-methyl derivatives were determined and the Hansch it values of the methyl substituents were also calculated (84MI5). The oc-tahydro derivatives were more hydrophilic than the tetrahydro compounds. 

The octanol-water (pH 5) partition coefficients of alkyl-substituted 4H-pyrido[l,2-a]pyrimidines-4-ones 10 and 11, 3-phenyl and 3-ester derivatives (R2 = Ph, COOEt), and some tetra- and hexahydro derivatives were determined by the classical shake-flask technique at ambient temperature (81MI4 82MI9). Hansch-type 7r values of the substituent (R-R2) were also calculated. The apparent octanol-water partition coefficients of seg-anserine 6 and its 7-methyl derivative were measured (88MI14). The pAa values and apparent octanol-water partition coefficients (at pH 7.4) of risperidone 7 (92MI20, 92MI30), its 9-hydroxy derivative (92MI30), and ocaperidone 8 were reported (92MI20). 

A partition coefficient is a property of a whole molecule. To define 7tr, a substituent property, Hansch compared the partition coefficient of a substituted compound with an unsubstituted compound (Equation 12.13). 

Hansch equation A Hansch equation is a linear free-energy relationship that correlates biological activity (log 1/C) to molecular and substituent parameters. The parameters describe properties such as sterics, lipophilicity, and electronic effects, and the coefficients on the parameters determine the relative importance of each parameter. 

Lipophilic substituent constants are also known as hydrophobic substituent constants. They represent the contribution that a group makes to the partition coefficient and were defined by Hansch and co-workers by the equation ... 

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