Revealing Mechanisms of Spontaneous Chiral Resolution with Molecular Models

The separation of racemates is an essential step in the development of many bioactive organic compounds. Current methods of separation, however, can be costly and inefficient. For a small subset of chiral compounds, separation of enantiomers happens conveniently through spontaneous enantiopure crystallization. Despite computational and experimental efforts to understand this phenomenon, little is known about its driving forces and mechanisms.

To shed light on the aspects of molecular shape and interactions that drive spontaneous chiral resolution, we have developed a family of simple models of chiral molecules. Functional groups of molecules are treated schematically and interact through short-ranged pair potentials that include solvent effects implicitly. The simplicity of this model allows us to simulate the crystallization dynamics of a large number of different chiral molecules. Consistent with experiment, these simulations show a strong preference for racemic structure formation. To reveal thermodynamic driving forces for crystallization, we have developed an algorithm that can enumerate all polymorphs of a given molecule. Results of these calculations reveal intriguing correlations between the thermodynamics of crystal polymorphs and crystallization kinetics.