title: Modeling the interplay of inter- and intramolecular hydrogen bonding in conformational polymorphs.
abstract: The predicted stability differences of the conformational polymorphs of oxalyl dihydrazide and ortho-acetamidobenzamide are unrealistically large when the modeling of intermolecular energies is solely based on the isolated-molecule charge density, neglecting charge density polarization. Ab initio calculated crystal electron densities showed qualitative differences depending on the spatial arrangement of molecules in the lattice with the greatest variations observed for polymorphs that differ in the extent of inter- and intramolecular hydrogen bonding. We show that accounting for induction dramatically alters the calculated stability order of the polymorphs and reduces their predicted stability differences to be in better agreement with experiment. Given the challenges in modeling conformational polymorphs with marked differences in hydrogen bonding geometries, we performed an extensive periodic density functional study with a range of exchange-correlation functionals using both atomic and plane wave basis sets. Although such electronic structure methods model the electrostatic and polarization contributions well, the underestimation of dispersion interactions by current exchange-correlation functionals limits their applicability. The use of an empirical dispersion-corrected density functional method consistently reduces the structural deviations between the experimental and energy minimized crystal structures and achieves plausible stability differences. Thus, we have established which types of models may give worthwhile relative energies for crystal structures and other condensed phases of flexible molecules with intra- and intermolecular hydrogen bonding capabilities, advancing the possibility of simulation studies on polymorphic pharmaceuticals.
authors.affiliation: Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, United Kingdom. p.karamertzanis@imperial.ac.uk
authors.forename: Panagiotis G
authors.initials: PG
authors.lastname: Karamertzanis
authors.forename: Graeme M
authors.initials: GM
authors.lastname: Day
authors.forename: Gareth W A
authors.initials: GW
authors.lastname: Welch
authors.forename: John
authors.initials: J
authors.lastname: Kendrick
authors.forename: Frank J J
authors.initials: FJ
authors.lastname: Leusen
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Neumann
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Price
mesh_terms: D003198:Computer Simulation; D003460:Crystallization; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D009930:Organic Chemicals / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry
chemical_list: D009930:Organic Chemicals; D004364:Pharmaceutical Preparations