Synthetic Pathway of Nonpsychoactive Cannabidiol from Psychoactive Tetrahydrocannabinol: A DFT Guide

In this study, a reaction pathway for converting the psychoactive compound Δ⁹-THC into the nonpsychoactive cannabidiol (CBD) was proposed. Related cannabinoids, including Δ⁸-THC and cannabinol (CBN), were also examined. The transformation proceeds via two key steps: (i) hydrogen elimination and cyclic ether ring cleavage, and (ii) hydrolysis to form hydroxyl groups, facilitated by boron trichloride (BCl₃) as a Lewis acid and 2,6-di-tert-butyl-4-methylpyridine as a selective base. Energy calculations indicate that TS_4-5 is the rate-determining transition state for Δ⁹-THC, Δ⁸-THC, and CBN, with corresponding activation free energies of 49.4, 50.3, and 54.1 kcal mol^-1, respectively. The overall reaction is highly exergonic (ΔG_rxn = -33.9 to -32.9 kcal mol^-1), indicating spontaneous conversion under mild conditions. These results provide a foundation for developing efficient and scalable production of nonpsychoactive cannabinoids, supporting the development of safe and commercially viable therapeutic applications.