Spontaneous Resolution of Enantiomers by Crystallization: Insights from Computed Crystal Energy Landscapes

We used crystal structure prediction methods to generate racemic and homochiral crystal structures of benzo(c)phenanthrene, 3,4-dehydroproline anhydride, and 2,6-dimethylglycoluril, which are all known to spontaneously resolve. The known homochiral crystal structures were found at or near the global minimum in lattice energy; however, in all three cases there were hypothetical racemic crystal structures within a few kJ mol(-1) in energy. The comparison of hypothetical racemic structures with the known homochiral crystal structures showed structural similarities, despite the symmetry differences, suggesting that most molecules are very unlikely to crystallize in a chiral crystal structure that is markedly more stable than any racemic crystal. Thus the experimentally observed asymmetry in the thermodynamic favorability of racemic and homochiral crystal structures is not due to experimental bias; that is, any thermodynamic drive for spontaneous resolution is genuinely small. Hence, whereas the formation of a racemic crystal can have a significant enthalpic stability advantage over all possible homochiral crystal structures and be more readily predicted, spontaneous resolution cannot be predicted without careful consideration of entropic effects and accurate computational models.