Authors
Patrick de L Barbosa, Felipe Lopes N da Silva, Diogo R Ramos, João G H Rosa, Rodrigo O M A de Souza, Rodolfo G Fiorot
Published in
Organic & biomolecular chemistry. Jul 20, 2026. Epub Jul 20, 2026.
Abstract
Cannabis sativa is a major source of phytocannabinoids, with cannabidiol (Δ9-CBD) serving as a key precursor to THC-type cannabinoids through acid-catalyzed intramolecular cyclization. However, the origin of regioselectivity under different conditions remains unclear. Herein, combined experimental and theoretical approaches were employed to elucidate the pathways leading to Δ9-THC, Δ8-THC, and iso-Δ8-THC under Brønsted (p-TsOH) and Lewis (BF3) acid catalysis in batch and continuous-flow systems, respectively. Experimentally, product distribution is strongly temperature-dependent. Under both catalytic conditions, lower temperatures favor Δ9-THC formation. Under p-TsOH, harsher conditions promote Δ9-THC/Δ8-THC interconversion and enrichment of Δ8-THC, whereas BF3 favored formation of iso-Δ8-THC at higher temperatures and longer reaction times. Computational simulations reveal that BF3 promotes parallel cyclization pathways leading to Δ9-THC and iso-Δ8-THC, whereas p-TsOH follows a sequential mechanism involving cyclization followed by double-bond isomerization. The calculations further indicate that Δ9-THC is the kinetic product, formed through lower activation barriers (ΔG‡), whereas Δ8-THC and iso-Δ8-THC are thermodynamically favored under Brønsted and Lewis conditions, respectively, displaying lower final free energies (ΔG). Overall, regioselectivity emerges from the interplay between temperature and catalyst type, with dual Lewis-Brønsted activation by BF3 driving rapid cyclization and suppressing isomerization pathways, as supported by DFT calculations.
PMID:
42475118
Bibliographic data and abstract were imported from PubMed on 20 Jul 2026.
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