A Molecular Modeling Study into Brønsted and Lewis Acid Catalyzed Conversion of CBD into Other Cannabinoids

There is a continuous interest in cannabinoids like Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Previous experimental research has described the conversion of CBD to either Δ8-THC or Δ9-THC, depending on the acid catalyst applied. The use of para-toluene sulfonic acid (pTSA) has led to the formation of Δ8-THC, while boron trifluoride etherate (BF3·Et2O) has mainly yielded Δ9-THC. The enormous difference in product selectivity between these two catalysts was investigated with Molecular Modeling, applying quantum chemical density functional theory. It was found that pTSA leads to fast isomerization of Δ9-CBD to Δ8-CBD and subsequent ring closure to Δ8-THC. BF3·Et2O catalysis leads to the formation of tertiary carbenium ions in the transition states, which yield Δ9-THC and some iso THC. Under dry conditions in refluxing toluene, it was found that pTSA is predominantly present as a dimer, and only a small fraction is available as monomeric catalyst. Applying the computationally derived activation barriers in transition state theory yielded reaction rates that predicted the amounts of cannabinoids that are in close agreement with the experimental findings from the previous literature.