Polymorphism in two biologically active dihydropyrimidinium hydrochloride derivatives: quantitative inputs towards the energetics associated with crystal packing

A new polymorph belonging to the tetrahydropyrimidinium class of compounds, namely 6-(4-chlorophenyl)-5-(methoxycarbonyl)-4-methyl-2-(3-(trifluoromethylthio) phenylamino)-3,6- dihydropyrimidin-1-ium chloride, and a hydrate of 2-(3-bromophenylamino)- 6-(4-chlorophenyl)-5-(methoxycarbonyl)- 4-methyl-3,6-dihydropyrimidin-1-ium chloride, have been isolated and characterized using single-crystal X-ray diffraction (XRD). A detailed comprehensive analysis of the crystal packing in terms of the associated intermolecular interactions and a quantification of their interaction energies have been performed for both forms of the two different organic salts (A and B) using X-ray crystallography and computational methods such as density functional theory (DFT) quantum mechanical calculations, PIXEL lattice-energy calculations (with decomposition of total lattice energy into the Coulombic, polarization, dispersion and repulsion contribution), the calculation of the Madelung constant (the EUGEN method), Hirshfeld and two-dimensional fingerprint plots. The presence of ionic [N-H](+)center dot center dot center dot Cl- and [C-H](+)center dot center dot center dot Cl- hydrogen bonds mainly stabilizes the crystal packing in both forms A and B, while in the case of B center dot H2O [N-H](+)center dot center dot center dot O-water and O-water-H center dot center dot center dot Cl- hydrogen bonds along with [N-H](+)center dot center dot center dot Cl- and [C-H](+)center dot center dot center dot Cl- provide stability to the crystal packing. The lattice-energy calculations from both PIXEL and EUGEN methods revealed that in the case of A, form (I) (monoclinic) is more stable whereas for B it is the anhydrous form that is more stable. The analysis of the 'Madelung mode' of crystal packing of two forms of A and B and its hydrates suggest that differences exist in the position of the charged ions/atoms in the organic solid state. The R/E (distance-energy) plots for all the crystal structures show that the molecular pairs in their crystal packing are connected with either highly stabilizing (due to the presence of organic R+ and Cl-) or highly destabilizing Coulombic contacts. The difference in crystal packing and associated intermolecular interactions between polymorphs (in the case of A) or the hydrates (in the case of B) have been clearly elucidated by the analysis of Hirshfeld surfaces and two-dimensional fingerprint plots. The relative contributions of the various interactions to the Hirshfeld surface for the cationic (dihydropyrimidinium) part and anionic (chloride ion) part for the two forms of A and B and its hydrate were observed to be different.