Structural and energetic aspects of the differences between real and predicted polymorphs

In crystal structure prediction simulations based on lattice energy minimization, usually hundreds of structures within a reasonable range of lattice energy and density are found, whereas in practice, it is very rare to find more than a few polymorphs of the same compound. In the work presented here, this discrepancy is investigated from a structural and energetic point of view. 56 crystal structures of 26 polymorphic mono- and disubstituted aromatic compounds, extracted from the Cambridge Structural Database, have been analysed with respect to inter-polymorphic structural similarity. For comparison, potential crystal packing arrangements of the substances have been predicted with molecular mechanics simulations using a generic force field. The predicted structures are analysed with respect to structural features and similarity, and with respect to the number of structures and their lattice energy. It is found that the real polymorphs studied in this work tend to be structurally quite dissimilar with regard to hydrogen bonding and spatial packing of structural motifs, while many of the predicted structures of a given compound are very similar to each other. The results suggest that structure and lattice energy alone cannot explain why so few polymorphs are found in practice compared to the very large numbers predicted in simulations.