Electronic structure, NBO, and radical stability analyses of thymol and carvacrol along metabolic transformation pathways: a DFT study

Abstract Understanding the proposed reaction mechanisms and radical stabilization processes leading to the formation of the two bioactive monoterpenes, thymol and carvacrol, remains challenging because of complex reaction networks, tautomeric interconversions, and electron delocalization effects. In this study, density functional theory (DFT) calculations were performed at the B3LYP/6-311 + G(d) level using Gaussian 09 software. Ten proposed reaction pathways and twenty transition states were identified and analyzed, including key tautomeric transformations and intermediate rearrangements. Activation energies and Gibbs free energies were evaluated to assess the feasibility of the proposed reaction routes. To gain deeper mechanistic insight, molecular electrostatic potential (MEP), Natural Bond Orbital (NBO), and spin density analyses were performed for selected intermediates, transition states, and radical species. MEP analysis revealed notable changes in charge distribution during tautomeric interconversions, while NBO analysis indicated strong donor–acceptor interactions and extensive π-electron delocalization within the aromatic framework. Spin density analysis confirmed resonance-assisted delocalization of the unpaired electron following hydrogen abstraction, supporting the stabilization of the corresponding phenoxy radicals. Comparative analysis revealed slightly greater electronic delocalization in thymol than in carvacrol. Overall, the present computational results provide molecular-level insight into the proposed reaction mechanisms, electronic structure evolution, and radical stabilization behavior associated with the formation of thymol and carvacrol.