Model solvent systems for QSAR. Part 2. Fragment values (‘f-values’) for the ‘critical quartet’

Abstract

A data matrix has been prepared of log P values for 103 compounds distributed across four highly contrasted solvent–water partitioning systems: the ‘critical quartet’ of octanol (amphiprotic), alkane (inert), chloroform (proton donor) and propylene glycol dipelargonate (PGDP; proton acceptor). Here ‘alkane’ is defined as the straight-chain sequence from hexane to octane and (possibly) higher; it is shown that cyclohexane is out of line. In principle, these log P values can now be used to construct a comparative table of fragment values (f-values) for all four systems. In practice, those for non-polar substituents must first be established. Here the key quantity is f(CH₂). This has been re-determined, and in the process its variability rationalised, for 24 water-saturated solvent systems; here the key factors (dry solvents are different) turn out to be the molarity, in the organic phase, of water and the solvent's own functional group. There results an almost complete data matrix of 82 f-values for all four solvents, about 25% of which are derived from the linear solvation energy relationship (LSER) equations of Part 3.⁷ It is shown that these four sets are very distinct, a fact that misleading statistical treatments can easily disguise. How the medicinal chemist might use these contrasting data sets is critically discussed, with particular reference to the rationalisation of biological selectivity.