doi: 10.1021/jacs.1c11981.
- PMID: 35451301
- DOI: 10.1021/jacs.1c11981
Abstract
Quantum tunneling is computed for a reaction sequence that models the conversion of the ortho-quinone methide of cannabigerolic acid 1 to the decarboxylated product (-)-trans-Δ9-tetrahydrocannabinol (THC, 3). This calculation is the first to evaluate multidimensional tunneling in this sequence. Computations were carried out with POLYRATE and GAUSSRATE using B3LYP/6-31G(d,p) to examine the mechanism of THC 3 formation. The pentyl chain on THC 3 and its precursors were replaced with a methyl group to compute tunneling contributions to the rates of four separate steps: (i) initial Diels-Alder reaction of the quinone methide with the trisubstituted alkene end-group of the geranyl 1Z-CH3 to give 2Z-CH3, (ii) acid-catalyzed keto-enol tautomerization, which converts 2rZ-CH3 to 4rZ-CH3, (iii) carboxyl rotamerization converting 4rZ-CH3 to 4E-CH3, and (iv) decarboxylation that converts 4E-CH3 to 3-CH3. Tunneling contributions to the rate constants of steps (i)-(iv) are between 19 and 76% at 293 K. In step (ii), nonuniform changes in the zero-point vibrational energy along the reaction path created a shallow minimum in the 0 K free energy. It is a hidden intermediate because it is not a minimum on the potential energy surface and is detectable only when zero-point energy is taken into account along the reaction path. Predicted kinetic isotope effects would be experimentally observable at temperatures that are convenient to use. This is particularly relevant in the decarboxylation stage of the reaction sequence and has important implications because of its role in THC 3 formation.
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.1c11981.
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Calculated structures and energies of species involved in reported reactions, reaction energetics written by POLYRATE for each step 1–4, transmission coefficients κZCT(T) and κSCT(T), rate constants, half-lives for each step 1–4, Arrhenius plots for each step 1–4, tunneling paths (vibrationally adiabatic ground–state curve, VaG) and tunneling contributions to the SCT transmission coefficient κSCT for formic acid-catalyzed tautomerization of 2Z-CH3-HCOOH at 383 K, results of benchmarking DFT calculations, scalar curvature analysis for formic acid-catalyzed tautomerization of 2rZ-CH3-HCOOH, and sample input files for POLYRATE calculations (PDF)
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