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

In this study, a reaction pathway for converting the psychoactive compound Δ 9 -THC into the nonpsychoactive cannabidiol (CBD) was proposed. Related cannabinoids, including Δ 8 -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 (BCl 3 ) 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 Δ 9 -THC, Δ 8 -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 (Δ G 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.