Computational insight into the antioxidant activity of thymol in diverse solvent environments: a DFT approach

Natural phenolic compounds are a good source of antioxidant. Thymol, a naturally occurring substance containing a phenolic OH group and non-phenolic CHₓ (x = 1, 3) groups, are expectedly reported to possess antioxidant activity. In this study, its antioxidant potential was systematically studied using DFT along with the B3LYP hybrid functional and 6-311G ++ (d,p) basis set in gas and several variable solvent media. The major antioxidant mechanisms (HAT, SPLET, and SETPT) were calculated. Frontier molecular orbitals, energy gap, physico-chemical reactivity descriptors, Fukui functions, MEP surfaces, spin density, and TD-DFT analysis were examined. Furthermore, changes of enthalpy (ΔH) and free energy (ΔG) were calculated from the DFT computed results for scavenging of OH^● and DPPH radicals. The results confirm thymol as an efficient antiradical molecule, with radical scavenging preferentially occurring at the phenolic OH site followed by the 3-CH group, where the HAT mechanism is the most favorable pathway. CONTEXT: Natural phenolic compounds play a crucial role as antioxidants due to their ability to neutralize reactive free radicals. Thymol, a naturally occurring monoterpenoid phenol, contains both a phenolic hydroxyl (O-H) group and non-phenolic CHₓ (x = 1, 3) groups, which are believed to contribute to its antioxidant activity. Although thymol is widely recognized for its strong radical scavenging ability and biological significance, a comprehensive theoretical understanding of its antioxidant mechanisms particularly the relative contributions of O-H and CHₓ sites under different solvent environments remains limited. This study aims to provide a detailed computational investigation of thymol's antioxidant behavior by exploring its thermodynamic, electronic, and mechanistic properties in gas and solvent phases. METHODS: Density functional theory (DFT) calculations were performed using the B3LYP hybrid functional with the 6-311 ++ G(d,p) basis set as implemented in Gaussian 16. The geometries of thymol and its corresponding radical, cationic, and anionic species were fully optimized in the gas phase and in various solvent media (water, DMSO, methanol, ethanol, dichloromethane, chloroform, benzene, and cyclohexane) using the IEFPCM solvation model. Vibrational frequency analyses confirmed all structures as true minima. Antioxidant mechanisms were investigated through hydrogen atom transfer (HAT), single electron transfer-proton transfer (SETPT), and sequential proton loss-electron transfer (SPLET) pathways by calculating key thermodynamic parameters, including bond dissociation energy (BDE), ionization potential (IP), proton dissociation energy (PDE), proton affinity (PA), and electron transfer energy (ETE). Additional electronic structures analyses included frontier molecular orbitals (HOMO-LUMO), global reactivity descriptors, Fukui functions, molecular electrostatic potential (MEP), spin density distribution, and time-dependent DFT (TD-DFT). The enthalpy (ΔH) and Gibbs free energy (ΔG) changes were also computed for hydroxyl (HO•) and DPPH radical scavenging reactions.