Theoretical Determination of Partition Coefficients

The free energy perturbation method, implemented within a molecular dynamics framework, has been used to calculate differences in log Ps between methanol, ethanol, and propanol partitioned between water and carbon tetrachloride. The calculated results agree with experiment to within 0.45 log P unit or about 3 kJ mol⁻¹. The difference in log P between methanol and ethanol was determined relatively easily. However, difficulties were experienced in extending the calculations to include the more flexible propanol molecule. A systematic variation of parameters was performed which highlighted the reason for the poor results, namely, the failure of the atomic charges to give a good description of the electrostatics in all conformations. This problem was overcome by using charges derived from the molecular electrostatic potential (MEP) for each conformation, weighted according to the appropriate Bolzmann population. It is proposed that these multiple conformation MEP derived charges will be useful in many other applications.