Lipophilicity and Substituent Effects

Every substituent has a particular steric and electronic influence on its scaffolding main structure. These substituent effects can be condensed into a set of physicochemical terms. The most important of these translate the steric interaction of the substituent with its immediate environment [8], its interaction with different types of solvent system (the lipophilicity log P or it describe the distribution in an w-octanol/water system) [9], and its electronic influence on the reactivity (o ) of the basic structure into the quantitative language of thermodynamics. 

The Hammett constant, r, can describe the influence of a functional group on the acidity or basicity of a neighboring site, as already discussed in Section 1.4.2. It determines the distribution of partial charges over the surface of a biologically active molecule, modulating its binding behavior toward a target structure. 

In addition, substituent properties can be used systematically to find quantitative structure-activity relationships (QSAR) during lead optimization in structures of pharmaceutical interest [10, 11]. 

Even if it might superficially seem logical, it cannot be concluded that fluorinated substituents always increase the lipophilicity of organic compounds. This is only true for fluorine itself and for perfluorinated groups in which the local carbon-fluorine dipole moments mostly compensate each other (e. g. CFj, C2F5). Accordingly, lipophilicity is increased by aromatic fluorination, by fluorination adjacent to atoms engaged in electron systems, and by perfluorination of alkyl chains [15]. 

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