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 TS4-5 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 (ΔGrxn = -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.