The Relationship Between Chemical Structure and the Logarithm of the Partition Coefficient

Abstract

The relationship between chemical structure of a solute and the logarithm of its partition coefficient (log P) between the aqueous and a nonpolar phase is poorly understood. We have recently shown that the variation in log P data for 50 low molecular‐weight organic solutes in 6 aqueous‐non‐polar solvents is a function of two structural features. The main feature accounts for ≈︁60% of the variation in the log P data, and is uniformly weighted in all 6 nonpolar solvent systems. This suggests that it is related to the aqueous solution properties of the solute. The first feature is termed the isotropic surface area, or the surface area associated with the nonpolar portion of the solute when the solute is considered to be a hydrated complex. The hydrated solute complex is termed a supermolecule with waters of hydration occupying hydrogen bonding sites on the functional groups of the solute. Empirical rules for formation of the super molecule are discussed. In this report the analysis is extended to log P data for 72 solutes in the 6 nonpolar solvent systems. The results of the analysis are essentially unchanged for this more extended data set and the second factor is tentatively identified. The second structural feature accounted for ≈︁35% of the variation in the log P data was not equally weighted in all solvents and is difficult to interpret structurally.

Multivariate analysis of hydrophobic descriptors

“…Thus, PCA of log Pvalues again results in a two-component model as in the case of the previous analyses [15,16,17,18]. The loadings a ik (Table 2) represent correlation coefficients between log P from solvent i and scores t k (Table 1).…”

“… from 28 solutes [16], 50 solutes [17], and 69 solutes [18], respectively, in six solvent-water systems (n-octanol, diethylether, chloroform, carbon tetrachloride, benzene, n-hexane)…”

“…Whereas Dove et al [15] applied the standard PCA method, diagonalization of the correlation matrix, the results of the group of Bill Dunn [16,17,18] were based on diagonalizing the matrix of cross products implied in the SIMCA software pocket.…”

“…The series is a subset of the solutes analyzed by Koehler et al [18], the number of solvents was extended to eight (by toluene and cyclohexane). Data, either taken from ref.…”

“…Data, either taken from ref. [18] or from the tables of Hansch and Leo [5,6], are presented in Table 2 shows PCA results with respect to the solvents as well as the means and variances of the solvent columns which had to be additionally considered since merely the correlation structure of the data was analyzed by our PCA. Thus, log P scales from water soluble solvents capabable of forming hydrogen bonds show higher means and lower variances compared to log P scales from nonpolar solvents.…”