Experimental and theoretical structure characterization of two isoniazid derivatives: 2,4-Difluoro-N′-isonicotinoylbenzohydrazide and 2,4-dichloro-N′-isonicotinoylbenzohydrazide hydrochloride

An X-ray and a theoretical study of the structure of the isoniazid derivatives, 2,4-difluoro-N′-isonicotinoylbenzohydrazide, 3, and 2,4-dichloro-N′-isonicotinoylbenzohydrazide hydrochloride, [4H+, Cl−, 2(H2O)], are reported. Quantum chemical calculations as well as conformational analysis are presented with the isolated cations [3H+] and [4H+], where the former was protonated in silico to allow direct comparison of results. Supermolecule calculations were also carried out with the asymmetric unit of [4H+, Cl−, 2(H2O)], which is comprised of two independent cations (4H+), two chloride ions and four water molecules. Our results indicate that the crystal structures, although clearly representing accessible conformations, are highly distorted in comparison to the predicted lower energy conformers in the gas-phase. These distortions are most probably imposed by polar and electrostatic interactions within the crystal packing. In general, the calculated potential energy surfaces (PES) for both isoniazid derivatives are fairly flat, a feature confirmed by the low energetic difference calculated for several conformers corresponding to local minima in PES. Noteworthy, the fluorinated compound [3H+] shows an important additional energy barrier for rotation around the bond connecting the halogenated ring to the proximate carbonyl due to a strong internal hydrogen bond involving the fluorine atom.