Conformational Change in Molecular Crystals: Impact of Solvate Formation and Importance of Conformational Free Energies

Abstract

Changes in molecular conformation and its relationship with crystal polymorphism have been well documented in previous work. To the best of our knowledge, however, the effect of solvate formation on molecular conformation has never been explored. Using the Cambridge Structural Database in combination with molecular modeling, we provide insights into the impact of solvate formation on the conformation adopted by a compound and whether such conformation is different to that found in its neat form(s). Typically, the more flexible a molecule is, the higher the chances that conformational change occurs upon solvate formation. There are no trends as to the relative stability of conformers and their likelihood to be observed in either the solvates or the neat forms. Typically, conformer energy differences in solvate-neat form pairs are small (<5 kJ/mol) and when larger energy differences are observed (>15 kJ/mol), these can be reduced significantly when both solvent and thermal effects are considered in the simulations. This highlights of the importance of computing thermal contributions in conformer energies as well as accounting for environmental effects. Overall, we find that conformational change in solvate-neat form pairs mirrors the behavior of conformational change in polymorphism.