Decarboxylation of Δ⁹-tetrahydrocannabinol: Kinetics and molecular modeling

Efficient tetrahydrocannabinol (Δ⁹-THC) production from cannabis is important for its medical application and as basis for the development of production routes of other drugs from plants. This work presents one of the steps of Δ⁹-THC production from cannabis plant material, the decarboxylation reaction, transforming the Δ⁹- THC-acid naturally present in the plant into the psychoactive Δ⁹-THC. Results of experiments showed pseudo-first order reaction kinetics, with an activation barrier of 85 kJ mol^-1 and a pre-exponential factor of 3.7 × 10⁸ s^-1. Using molecular modeling, two options were identified for an acid catalyzed β-keto acid type mechanism for the decarboxylation of Δ⁹- THC-acid. Each of these mechanisms might play a role, depending on the actual process conditions. Formic acid proved to be a good model for a catalyst of such a reaction. Also, the computational idea of catalysis by water to catalysis by an acid, put forward by Li and Brill, and Churchev and Belbruno was extended, and a new direct keto-enol route was found. A direct keto-enol mechanism catalyzed by formic acid seems to be the best explanation for the observed activation barrier and the pre-exponential factor of the decarboxylation of Δ⁹-THC-acid. Evidence for this was found by performing an extraction experiment with Cannabis Flos. It revealed the presence of short chain carboxylic acids supporting this hypothesis. The presented approach is important for the development of a sustainable production of Δ⁹-THC from the plant.