HYDROPHOBIC EFFECT - 3 - A KEY INGREDIENT IN PREDICTING N-OCTANOL-WATER PARTITION-COEFFICIENTS

The quantitative development of the mobile order theory in H-bonded li quids is extended to predict the n-octanol/water partition coefficient (P). The log P predictive equation strictly issued from a thermodynam ic treatment reduces to a simple linear volume-log P relationship whos e intercept and slope encode, respectively, the solvation and entropy effects. For noncomplexing substances, the partition coefficient value s result from two volume-dependent entropic contributions reflecting ( a) the difference in the exchange entropy between the solute and solve nt molecules in the n-octanol and water phases, and (b) the propensity difference between the two H-bonded solvents to induce a hydrophobic effect toward the solute. Although both effects increase, although wit h opposite signs, compared with the growing molar volume of the partit ioned compound, the hydrophobic contribution always predominates favor ing the transfer of the solute into the organic phase and hence increa sing its partition coefficient. When dealing with complexing chemicals , the hydrophobic effect-related term, though remaining the dominant f actor in most cases, is more or less counterbalanced by the formation of H-bonds between the interacting sites of the solute and the n-octan ol and water solvent molecules. The log P, corrected for the substanti al content of water into n-octanol, is estimated for a number of compo unds of environmental and pharmaceutical interest. The extent to which the entropic and enthalpic factors affect the overall partition coeff icient value is analyzed.