Free energy calculations on the relative solvation free energies of benzene, anisole, and 1,2,3-trimethoxybenzene: theoretical and experimental analysis of aromatic methoxy solvation

We have carried out experimental determinations of the free energy of solvation of anisole, 1,2-dimethoxybenzene (DMB), and 1,2,3-trimethoxybenzene (TMB) in water and perturbation free energy calculations on the relative aqueous solvation free energies of benzene, anisole, and TMB. The measured differences between the relative experimental free energies of solvation of benzene, anisole, DMB, and TMB support the concept of near additivity of aromatic methoxy group contributions to such gas phase to water transfer free energies. Calculated differences in solvation free energies were shown to be sensitive to the choice of electrostatic charge distribution model. Quantum mechanical electrostatic potential fit charge models from STO-3G, 4-31G, and 6-31G* basis sets were compared for their ability to reproduce the relative free energies of solvation found experimentally. The 6-31G* charge model was the best in this regard and the STO-3G model was next in quality, but the 4-31G model significantly overestimated the effect of O-CH3 substitution on solvation free energies. Models based on scaled 4-31G charges also produced reasonable results.