New thermodynamic model for the estimation of partition coefficients

Part 1 Weakly hydrogen-bonded solutes

Abstract

Solvent–solvent hydrogen-bond interactions (self-association), acting against cavity formation by an essentially entropic effect, generate a solute-rejecting process in the solvent medium (the solvophobic effect). In a partition, this effect results in greater affinity of the solute for one phase rather than the other. Instead of the usual methods of evaluating solute affinity, it is possible to make a direct evaluation of the solvophobic effect by using an enthalpic energy term based on mobile order theory which, together with expressions for the different mixing enthalpic and entropic contributions, enables us to develop a predictive and interpretive model for calculating lipophilicity. This is applied here to solutes that are non-H-bonded or weakly H-bonded to the solvent. The predictive quality of the model was verified for an octanol–water system for 75 solid, liquid, and gaseous solutes over a wide lipophilic range. A comparison is made with other empirical, semi-empirical and thermodynamic models.