Computational Insights and Modeling of Metabolic Pathways of Thymol and Carvacrol Chemical Reactions: Predictive Modeling of Medicinal Plant Biosynthesis

Despite significant advances in plant biochemistry, the chemical reaction pathways of secondary metabolites remain poorly understood due to metabolic complexity and environmental influences. Here, we investigate the formation of thymol and carvacrol, two monoterpenoid phenols from <i>p</i>-cymene in medicinal plants, using density functional theory (DFT) calculations. Twenty possible metabolic pathways and 28 transition states were analyzed, encompassing hydroxyl radical addition and cytochrome P450-mediated epoxidation, epoxide intermediates (2A-2C), and keto-enol tautomerizations. In enzymatic epoxidation, the enzyme-substrate binding step was identified as rate-determining for 1A-1D formation, while transition states TS6 and TS9 exhibited the lowest activation barriers in subsequent rearrangements. Comparative analysis indicates that thymol formation is kinetically and thermodynamically favored over carvacrol due to the lower activation energy of TS12. Frontier molecular orbital and bond dissociation energy analyses further elucidate the electronic properties and the reactivity of the intermediate compounds, and this study provides a focused computational framework for understanding the chemical reactions of thymol and carvacrol in medicinal plants.