Theoretical and experimental analysis of the antioxidant features of substituted phenol and aniline model compounds

Although natural polyphenols have attracted extended attention as antioxidants, there is only limited information available on their structure-activity relationship (SAR). In addition, while often having significant antioxidant activity, amino group-containing compounds have only been sporadically studied. Often, the complex structure makes studying the individual contribution of aromatic OH or NH₂ groups on the activity of these antioxidants difficult. In this work, several substituted simple phenols and anilines were selected as model compounds. Both the experimental radical scavenging activity and major structural descriptors have been determined to gain more insights into the potential SAR. Physicochemical properties pertaining to energetic and structural parameters were determined and experimental data gathered from three antioxidant assays to identify fundamental features with reasonable effect on antioxidant activity. Density functional theory (DFT) calculations were carried out at the B3LYP/6-31G(d,p) level to determine the N–H and O–H bond distances, dipole moments, logP values, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) orbital energies, HOMO-LUMO gaps, radical spin densities, proton affinities, and ionization potentials. The compounds were screened for activity against the 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), 2,2-diphenyl-1picrylhydrazyl (DPPH), and peroxyl (ORAC assay) radicals. Based on the results, ABTS antioxidant activity was selected for further investigations to observe correlations with the calculated properties. The HOMO energies, bond-dissociation energy values, HOMO-LUMO gap energies, dipole moment, proton affinity, and the Hammett constants appear to show meaningful correlation with the experimental data.