Synthesis of phenazone based carboxamide under thiourea reaction conditions. Molecular and crystal structure, Hirshfeld surface analysis and intermolecular interaction energies

KHURSHID, ASMA; SAEED, AAMER; SHABIR, GHULAM; GIL, DIEGO M.; BOLTE, MICHAEL; ERBEN, MAURICIO FEDERICO

JOURNAL OF MOLECULAR STRUCTURE

ELSEVIER SCIENCE BV

Año: 2023 vol. 1278

0022-2860

Considering the added advantage of active pyrazolone pharmacophore and phenazone drug itself with associated medicinal applications, we herein aim to derivatize this potent active non-steroidal anti-inflammatory drug (NSAID) to its thiourea derivative for enhanced biological potential. Thiourea reaction conditions were utilized to make use of active amino group of phenazone drug in reaction with furan-2-carbonyl isothiocyanate for formation of corresponding aroyl thiourea derivative. However, on detailed single crystal XRD, spectroscopic and analytical investigations, it become apparent the formation of phenazone-carbonothioyl carboxamide rearranged product. The novel compound was characterized by spectroscopic methods and its crystal structure was determined by single-crystal X-ray diffraction. In the solid, the pseudo-syn conformation is observed for the amide/thioamide groups, with the C=O and C=S double bonds oriented mutually parallel, favoring the occurrence of intramolecular O2···S1 chalcogen bond, as characterized by Atoms in Molecules (AIM) topological analysis. According to quantum chemical calculations, the pyrazolone group favors the formation of a dimer (Etot = -56.7 kJ/mol) which is mainly stabilized by C-H···O hydrogen bonds and π···π stacking interactions between the pyrazole and furan rings. The solid-state structure was analyzed through Hirshfeld surface analysis, including the evaluation of the different energy frameworks, indicating that H···O hydrogen bonds and H···S/S···H contacts are the main electrostatic interactions. These studies are complemented with DFT calculations (B3LYP-D3/def2-TZVP) and a combination of QTAIM/NCIplot analyses disclosing that the H-bonding and π···π stacking interactions dominate the crystal packing.