## Calculation of Lipophilicity 231 Substitution Method

The Hansch group were the first to point out [2] in their influential paper of 1964, that the octanol/water log/3 value of simple benzenoid derivatives could be calculated by a method bearing close analogy to the Hammett [22] treatment of chemical reactivity, including ionization, of substituted benzene derivatives. Hammett had shown in the 1930s that the equilibrium or rate constant of parent (unsubstituted) molecule, KH, and the equilibrium or rate constant for a substituted compound, Kx, could be correlated by

which could be rewritten as log K = gax + log /C„ (6)

The substituent constant crx refers to the electronic effect of the substituent and is a parameter applicable to many different reactions (characterized by different values of g) whose rate depends on the degree of electron release or withdrawal by the substituent. For the derivation of a constants, the ionization of benzoic acids was defined as the standard reaction for which g was set to unity. In analogous fashion to the Hammett treatment, Hansch defined substituent constants, n, by Eq. (7), choosing octanol/water as the standard system. Then, by analogy to Eq. (6) for reaction rates or equilibria, Eq. (8) could be used to calculate logP.

Just as Hammett had found that different o values were required for para- and for meta-substituents on a benzoic acid, because of differing contributions of field and resonance effects on reactivity, so the Hansch group immediately recognized that different it values would be required according to the environment of the substituent. Electronic effects in particular would alter the interaction of a polar substituent with the water phase: consider 4-nitrophenol, where neither the hydroxyl group nor the nitro group would behave towards water or towards octanol in like fashion to the hydroxyl or nitro group in phenol itself, or in nitrobenzene. It was rapidly appreciated that the lipophilicity parameter, logP, was only to a first approximation an additive property: it has considerable constitutive character. This at first proved to be a major difficulty for the calculation of lipophilicity, but in fact opened the way to using lipophilicity measurements to probe a variety of. intramolecular effects, including not only electronic but steric effects, so-called proximity effects when polar groups share a solvation shell, hydrogen bonding, and conformation (sometimes called folding effects, see chapter 4).

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