Molecular Polarization Effects on the Relative Energies of the Real and Putative Crystal Structures of Valine

Abstract

The computer-generation of the crystal structures of the α-amino acid valine is used as a challenging test of lattice energy modeling methods for crystal structure prediction of flexible polar organic molecules and, specifically, to examine the importance of molecular polarization on calculated relative energies. Total calculated crystal energies, which combine atom-atom model potential calculations of intermolecular interactions with density functional theory intramolecular energies, do not effectively distinguish the real (known) crystal structures from the rest of the low energy computer-generated alternatives when the molecular electrostatic models are derived from isolated molecule calculations. However, we find that introducing a simple model for the bulk crystalline environment when calculating the molecular energy and electron density distribution leads to important changes in relative total crystal energies and correctly distinguishes the observed crystal structures from the set of computer-generated possibilities. This study highlights the importance of polarization of the molecular charge distribution in crystal structure prediction calculations, especially for polar flexible molecules, and suggests a computationally inexpensive approach to include its effect in lattice energy calculations.

Powder crystallography of pharmaceutical materials by combined crystal structure prediction and solid-state 1H NMR spectroscopy

“…Final energies of the lowest energy structures were calculated as a combination of a DFT (B3LYP/6-31G(d,p)) calculation for the intramolecular contribution and the exp-6 + atomic multipoles description for the intermolecular interactions. The influence of polarisation on the inter-and intra-molecular contributions to the relative crystal energies was approximated by performing the molecular calculations in a continuum dielectric ( = 3), as we have previously suggested for flexible molecule CSP 53 .…”

Effects of a More Accurate Polarizable Hamiltonian on Polymorph Free Energies Computed Efficiently by Reweighting Point-Charge Potentials

“…[54][55][56][57][58] The inclusion of polarization is likely to be even more important in periodic solids due to long-range electrostatic correla-3 tions, and numerous crystallographic studies based on lattice energies have emphasized the need for distributed multipoles or full polarization for proper polymorph prediction. 6,23,25,32,33,36,[59][60][61][62][63][64][65] For example, Williams and Weller modeled various azabenzene structures and concluded that no point-charge model will be able to reproduce the correct structures unless additional lone pair sites are included. 59 Reilly and Tkatchenko also showed that the stability of the observed form I of acetylsalycilic acid (aspirin) results from a coupling of the electronic fluctuations and lattice vibrations in higher level energy models rather than a mechanical instability of form II as previously proposed.…”

Prediction of the crystal structures of axitinib, a polymorphic pharmaceutical molecule

“…In order to analyze the impact of computational choices on the accuracy of reproduction of the experimental structures, CrystalOptimizer computations starting from the Stage 1 structures that best match the experimental structures and using different levels of theory were carried out. The approaches used, in addition to M06/6-31G(d,p), were HF, PBE0, B3LYP with a 6-31G (d,p) basis, and M06/6-31G(d,p) with the polarizable continuum model (PCM) with a dielectric constant of 3 (Cooper et al, 2008). The resulting rms 15 values were found to be similar or worse in all cases.…”