Spectroscopic, X-ray Diffraction and Density Functional Theory Study of Intra- and Intermolecular Hydrogen Bonds in Ortho-(4-tolylsulfonamido)benzamides

Abstract

The conformations of the title compounds were determined in solution (NMR and UV-Vis spectroscopy) and in the solid state (FT-IR and XRD), complemented with density functional theory (DFT) in the gas phase. The nonequivalence of the amide protons of these compounds due to the hindered rotation of the C(O)–NH2 single bond resulted in two distinct resonances of different chemical shift values in the aromatic region of their 1H-NMR spectra. Intramolecular hydrogen bonding interactions between the carbonyl oxygen and the sulfonamide hydrogen atom were observed in the solution phase and solid state. XRD confirmed the ability of the amide moiety of this class of compounds to function as a hydrogen bond acceptor to form a six-membered hydrogen bonded ring and a donor simultaneously to form intermolecular hydrogen bonded complexes of the type N–H···O=S. The distorted tetrahedral geometry of the sulfur atom resulted in a deviation of the sulfonamide moiety from co-planarity of the anthranilamide scaffold, and this geometry enabled oxygen atoms to form hydrogen bonds in higher dimensions.

In Vitro Enzymatic and Kinetic Studies, and In Silico Drug-Receptor Interactions, and Drug-Like Profiling of the 5-Styrylbenzamide Derivatives as Potential Cholinesterase and β-Secretase Inhibitors with Antioxidant Properties

“…A singlet for NH of the 4-methylphenylsulfonamido group of derivatives 3 resonates significantly downfield due to the de-shielding effect of the S=O bonds. The downfield shift of this signal of the N 2 -sulfonamide derivatives is also consistent with the presence of an intramolecular hydrogen bond between this hydrogen and the carbonyl oxygen, as previously observed for the ortho-(4-tolylsulfonamido)benzamides [31]. Conformational restriction of small drug molecules due to intramolecular hydrogen bonding has been found to increase their lipophilicity, passive membrane permeability, and, therefore, brain penetration, as well as pharmacological activity due to favourable alignment with the protein pocket, which results in increased ligand-receptor interactions [32].…”