Investigation of the Anomalous Solvation Free Energies of Amides and Amines: FEP Calculations in Cyclohexane and PS-GVB Calculations on Amide−Water Complexes

Free energy perturbation (FEP) calculations of acetamide, N -methylacetamide, N, N -dimethylacetamide, ammonia, and methylamine in cyclohexane were performed to help rationalize their counterintuitive experimental free energies of solvation in water (i.e., N -methylacetamide is more favorably solvated than acetamide, and methylamine is more favorably solvated than ammonia). Analogously to the aqueous FEP calculations in water carried out previously, the calculations in cyclohexane find an approximately additive methyl substitution effect for both the amides and amines, with, in this case, the most highly methylated molecule most favorably solvated in cyclohexane. PS-GVB calculations at the LMP2/cc-pVDZ level were also performed on the amides and suggest that their anomalous experimental aqueous solvation free energies could be due to differences in their hydrated gas-phase structures.