Exploring the Multi-minima Behavior of Small Molecule Crystal Polymorphs at Finite Temperature

The predicted ambient-temperature
crystal structures of organic
small molecules are often represented by a single energy-minimized
configuration at 0 K. 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 work, 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 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.