Tonglei Li1, Shaoxin Feng. 1. Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, USA. tonglei@uky.edu
Abstract
PURPOSE: Solid-state reactions are highly anisotropic. Different polymorphs of the same compound may have remarkably different chemical reactivities. It was reported that two polymorphs of indomethacin single crystals, alpha- and gamma-forms, reacted with ammonia gas at dramatically different rates. In this study, the effect of crystal packing on their difference in chemical reactivity was investigated by examining the electronic structures and properties of the crystal forms. METHODS: Ab initio methods, including density functional theory, were used to calculate electronic structures of the alpha- and gamma-forms of indomethacin. In particular, nuclear Fukui functions were obtained to elucidate how a molecule in a crystal may respond to an electronic perturbation that can be caused by a chemical reaction. RESULTS: Different conformers in the two polymorphs showed different electronic structures. The carboxylic group of one symmetrically different molecule in the alpha-form had significantly larger nuclear Fukui functions than those of other molecules of either the alpha- or gamma-form, supporting the experimental observation that the alpha-form was much more reactive with ammonia than the gamma-form. In addition, the large nuclear Fukui functions associated with atoms other than those from the carboxylic group were attributed to the tension of two dislodged aromatic rings. CONCLUSIONS: Electronic calculations were able to provide insightful glimpses into the effect of crystal packing on the solid-state reaction of indomethacin. The nuclear Fukui function, which characterizes the physical stress on an atom due to perturbation in electron density, may provide a powerful means of studying the solid-state reactions of organic crystals at the electronic level.
PURPOSE: Solid-state reactions are highly anisotropic. Different polymorphs of the same compound may have remarkably different chemical reactivities. It was reported that two polymorphs of indomethacin single crystals, alpha- and gamma-forms, reacted with ammonia gas at dramatically different rates. In this study, the effect of crystal packing on their difference in chemical reactivity was investigated by examining the electronic structures and properties of the crystal forms. METHODS: Ab initio methods, including density functional theory, were used to calculate electronic structures of the alpha- and gamma-forms of indomethacin. In particular, nuclear Fukui functions were obtained to elucidate how a molecule in a crystal may respond to an electronic perturbation that can be caused by a chemical reaction. RESULTS: Different conformers in the two polymorphs showed different electronic structures. The carboxylic group of one symmetrically different molecule in the alpha-form had significantly larger nuclear Fukui functions than those of other molecules of either the alpha- or gamma-form, supporting the experimental observation that the alpha-form was much more reactive with ammonia than the gamma-form. In addition, the large nuclear Fukui functions associated with atoms other than those from the carboxylic group were attributed to the tension of two dislodged aromatic rings. CONCLUSIONS: Electronic calculations were able to provide insightful glimpses into the effect of crystal packing on the solid-state reaction of indomethacin. The nuclear Fukui function, which characterizes the physical stress on an atom due to perturbation in electron density, may provide a powerful means of studying the solid-state reactions of organic crystals at the electronic level.