A computational study of the structure-activity relationships of some p-hydroxybenzoic acid antioxidants

Abstract: Equilibrium structures of all derivatized systems of p-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3-methoxy-4-hydroxybenzoic acid, and 3,5-dimethoxy-4-hydroxybenzoic acid and calculated structural and energetic molecular descriptors were determined at the B3LYP/6-31+G(d) density functional theoretical level in an attempt to study their structure-activity relationships (SAR). The theoretical antioxidant activity trend, derived in terms of hydrogen-donating capacity against radicals in lipid systems, is in excellent agreement with the experimental one. The lower antioxidant activity of benzoates, experimentally found relative to the homologous cinnamates, could be due to (i) their lower spin delocalization, (ii) their higher calculated heats of formation values in forming radicals (ΔHOF), and (iii) the much stronger electron-withdrawing effect of the-COOH group than-CH=CHCOOH. The low calculated dipole moment values of the global minimum structures of the antioxidants could facilitate their solubilities in nonpolar solvents, hence the ease of hydrogen abstraction. However, highest occupied molecular orbital (HOMO) eigenvalues can neither predict antioxidant activity nor differentiate the same activity between two series of structurally related compounds. Again, density functional theory calculations provide a good molecular descriptor, ΔHOF, to correlate with the antioxidant activity in molecules showing similar structural characteristics.