Exploring the multi-minima behavior of small molecule crystal polymorphs at finite temperature

Abstract

The predicted ambient-temperature crystal structures of organic small molecules are often represented by a single energy-minimized configuration at zero Kelvin. This procedure effectively collapses the ensemble of configurations that would be present at ambient temperature into a single representative structure. This simplification is likely to break down if the crystal structure has multiple different lattice energy minima within the ambient temperature ensemble. In this paper, we explore the existence of multiple minima within finite-temperature crystal basins by sampling crystals at a range of temperatures followed by rapidly quenching the configurations. We then observe whether each crystal returns to the original minimum or to an ensemble of minima on the lattice energy landscape. Eight of the twelve compounds examined in this work have at least one polymorph with multi-minima behavior. These multi-minima basins have implications for crystal structure prediction studies, and it is therefore important to understand the factors that lead a crystal structure to have multiple minima. We find that in general, the existence of multiple minima within a crystal basin is more likely for the compounds that are larger and have more flexibility. We find that the number of minima found tends to increase with the sampling temperature, and the lattice energy of minima found from the same finite-temperature trajectory can vary by > 2.0 kJ/mol. Finally, we show that the lattice energy minima contained within a single ambient temperature basin can have different space groups and numbers of molecules in the asymmetric unit. Overall, the data suggest that many experimental crystal polymorphs are highly likely to have multi-minima behavior and are best described by an ensemble of structures encompassing many minima rather than by a single lattice-energy minimum.

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ORCID for Graeme M. Day: orcid.org/0000-0001-8396-2771

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