The Synergistic Effect of Substituents, Hydrogen Bonding, and Solvents on Antiradical Activity of Catechol Derivatives: Insights from Density Functional Theory

Abstract This study provides a detailed investigation into the synergistic effects of substituents, intramolecular hydrogen bonding (IHB), and solvent environments on the antiradical activity of catechol derivatives. The findings indicate that the ortho ‐1 conformer, stabilized by IHB, significantly influences several thermodynamic parameters, including bond dissociation enthalpy (BDE), proton affinity (PA), and ionization energy (IE). These effects are particularly pronounced in pentyl ethanoate solvent compared to water. Kinetic analyses reveal that catechols with electron‐donating groups (EDGs) outperform standard antioxidants in nonpolar solvents, such as ascorbic acid and Trolox. In aqueous environment, CN‐substituted catechol strongly prefers the formal hydrogen transfer (FHT) mechanism in its anionic state, achieving a high rate constant ( k app = 3.7 × 108 M⁻¹s⁻¹). In contrast, the neutral form shows slower reaction rates ( k app = 9.8 × 102–2.9 × 103 M⁻¹s⁻¹). CH3‐substituted derivatives follow mixed FHT and single electron transfer (SET) pathways. Overall, catechol derivatives exhibit significantly enhanced antioxidant activities ( k overall = 6.3 × 107–3.3 × 108 M⁻¹s⁻¹) in aqueous media, considerably exceeding the performance of Trolox ( k overall = 8.96 × 104 M⁻¹s⁻¹). These findings provide a strong basis for creating customized antioxidants with enhanced efficiency for diverse applications and offer practical guidelines for developing effective antioxidants.