Polymorphism of methyl 4-amino-3-phenylisothiazole-5-carboxylate: an experimental and theoretical study.

Being a close analogue of amflutizole, methyl 4-amino-3-phenylisothiazole-5-carboxylate (CHNOS) was assumed to be capable of forming polymorphic structures. Noncentrosymmetric and centrosymmetric polymorphs have been obtained by crystallization from a series of more volatile solvents and from denser tetrachloromethane, respectively. Identical conformations of the molecule are found in both structures. The two polymorphs differ mainly in the intermolecular interactions formed by the amino group and in the type of stacking interactions between the π-systems. The most effective method for revealing packing motifs in structures with intermolecular interactions of different types (hydrogen bonding, stacking, dispersion, etc.) is to study the pairwise interaction energies using quantum chemical calculations. Molecules form a column as the primary basic structural motif due to stacking interactions in both polymorphic structures under study. The character of a column (straight or zigzag) is determined by the orientations of the stacked molecules (in a head-to-head' or head-to-tail' manner). Columns bound by intermolecular N-H...O and N-H...N hydrogen bonds form a double column as the main structural motif in the noncentrosymmetric structure. Double columns in the noncentrosymmetric structure and columns in the centrosymmetric structure interact strongly within the ab crystallographic plane, forming a layer as a secondary basic structural motif. The noncentrosymmetric structure has a lower density and a lower (by 0.59 kJ mol) lattice energy, calculated using periodic calculations, compared to the centrosymmetric structure.