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Pre-Nucleation Clusters Predict Crystal Structures in Models of Chiral Molecules

Abstract

Kinetics can play an important role in the crystallization of molecules and give rise to polymorphism, the prevalent ability of molecules to form more than one crystal structure. Current computational methods of crystal structure prediction, however, focus almost exclusively on identifying the thermodynamically stable polymorph. Kinetic factors of nucleation and growth are often neglected because the underlying microscopic processes are thought to be complex and accurate rate calculations are numerically cumbersome. In this work, we use molecular dynamics computer simulations to study a simple molecular model that reproduces the crystallization behavior of real chiral molecules, including the formation of enantiopure and racemic crystals, as well as polymorphism. We show that in many cases, the crystal that robustly forms in simulations is not the one with the lowest free energy. We demonstrate that at high supersaturation the prevailing polymorph can be accurately predicted by considering the similarities between prevalent oligomeric species in solution and molecular motifs in the crystal structure. For the case of racemic mixtures, we even find that knowledge of crystal free energies is not necessary and kinetic considerations are sufficient to determine if the system will undergo spontaneous chiral separation. Our results suggest conceptually simple ways of improving current crystal structure prediction methods.

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