Intrinsic molecular volume as a measure of the cavity term in linear solvation energy relationships: octanol-water partition coefficients and aqueous solubilities.

A new, calculated value of the van der Waals or intrinsic molecular volume VI is shown to be at least as effective as molar volume, V (the molecular weight divided by the liquid density), as a measure of the cavity term in linear solvation energy relationships for octanol-water partition coefficients and aqueous solubilities. Use of VI obviates the need for the empirical 10-mL/mol correction factor for aromatic and alicyclic solutes which was previously required, and which is shown here to arise from an underestimate of the cavity term due to reduced free volume in the pure liquid. In addition, since VI is a calculated quantity, equations which contain this term can be extended to compounds that are solids or gases in the pure state. Octanol-water partition coefficients, log P, of gases and solids are predicted accurately by the equation: log P = 0.41 + 5.14 VI/100 - 0.29 mu - 3.58 beta, where mu is the dipole moment and beta is the hydrogen bond acceptor basicity. Aqueous solubilities of some solids are reasonably well predicted by the equation: log Sw = 0.19 - 5.79 VI/100 + 0.24 mu + 4.95 beta - 0.01 (mp - 25), where mp is the melting point. The same equation without the melting point term gives good estimates of the comparable solubility of some gases.