Toward an Understanding of the Propensity for Crystalline Hydrate Formation by Molecular Compounds. Part 2
Rana Sanii, Ewa Patyk‐Kaźmierczak, Carol Hua, Shaza Darwish, Tony Pham, Katherine A. Forrest, Brian Space, Michael J. Zaworotko
Abstract
The propensity of molecular organic compounds to form\nstoichiometric or nonstoichiometric crystalline hydrates remains a challenging\naspect of crystal engineering and is of practical relevance to fields such as\npharmaceutical science. In this work, we address the propensity for hydrate\nformation of a library of eight compounds comprised of 5- and 6-membered N-heterocyclic aromatics classified into three subgroups: linear dipyridyls, substituted\nSchiff bases, and tripodal molecules. Each molecular compound studied possesses\nstrong hydrogen bond acceptors and is devoid of strong hydrogen bond donors.\nFour methods were used to screen for hydrate propensity using the anhydrate\nforms of the molecular compounds in our library: water slurry under ambient\nconditions, exposure to humidity, aqueous solvent drop grinding (SDG), and\ndynamic water vapor sorption (DVS). In addition, crystallization from mixed\nsolvents was studied. Water slurry, aqueous SDG, and exposure to humidity were found to be the most effective methods for hydrate\nscreening. Our study also involved a structural analysis using the Cambridge Structural Database, electrostatic potential (ESP) maps,\nfull interaction maps (FIMs), and crystal packing motifs. The hydrate propensity of each compound studied was compared to a\ncompound of the same type known to form a hydrate through a previous study of ours. Out of the eight newly studied compounds\n(herein numbered 4−11), three Schiff bases were observed to form hydrates. Three crystal structures (two hydrates and one\nanhydrate) were determined. Compound 6 crystallized as an isolated site hydrate in the monoclinic space group P21/a, while 7 and\n10 crystallized in the monoclinic space group P21/c as a channel tetrahydrate and an anhydrate, respectively. Whereas we did not\nfind any direct correlation between the number of H−bond acceptors and either hydrate propensity or the stoichiometry of the\nresulting hydrates, analysis of FIMs suggested that hydrates tend to form when the corresponding anhydrate structure does not\nfacilitate intermolecular interactions.