E/Z Energetics for Molecular Modeling and Design

Thermochemical data have been obtained from G3B3 quantum mechanical calculations for 18 prototypical organic molecules, which exhibit E/Z conformational equilibria. The results are fundamentally important for molecular design including evaluation of structures from protein-ligand docking. For the 18 E/Z pairs, relative energies, enthalpies, free energies, and dipole moments are reported; the E - Z free-energy differences at 298 K range from +8.2 kcal/mol for 1,3-dimethyl carbamate to -6.4 kcal/mol for acetone oxime. A combination of steric and electronic effects can rationalize the variations. Free energies of hydration were also estimated using the GB/SA continuum solvent model. These results indicate that differential hydration is unlikely to qualitatively change the preferred direction of the E/Z equilibria, though further study with free-energy methods using explicit solvent is desirable.