Department of Natural Sciences, Baruch College of the City University of New York, 17 Lexington Avenue, New York, New York 10010, United States.
Department of Chemistry and Graduate Center, Brooklyn College of the City University of New York, 2900 Bedford Avenue, Brooklyn, New York 11210, United States.
J Am Chem Soc. 2022 May 4;144(17):7646-7656. doi: 10.1021/jacs.1c11981. Epub 2022 Apr 22.
Quantum tunneling is computed for a reaction sequence that models the conversion of the -quinone methide of cannabigerolic acid to the decarboxylated product (-)--Δ-tetrahydrocannabinol (THC, ). 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 formation. The pentyl chain on THC 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 to give (ii) acid-catalyzed keto-enol tautomerization, which converts to , (iii) carboxyl rotamerization converting to , and (iv) decarboxylation that converts to . 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 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 formation.
量子隧穿计算用于模拟大麻萜酚 - 醌甲醚转化为脱羧产物（-）-Δ-四氢大麻酚（THC，）的反应序列。这是首次在该序列中评估多维隧穿。使用 POLYRATE 和 GAUSSRATE 并结合 B3LYP/6-31G(d,p)进行计算，以检查 THC 形成的机制。THC 及其前体的戊基链被甲基取代，以计算对四个单独步骤速率的隧穿贡献：（i）醌甲醚与香叶基的三取代烯烃末端基团的初始 Diels-Alder 反应，生成 （ii）酸催化的酮-烯醇互变异构，将 转化为 ，（iii）羧基构象旋转，将 转化为 ，以及（iv）脱羧，将 转化为 。在 293 K 时，步骤（i）-（iv）的隧穿对速率常数的贡献在 19%至 76%之间。在步骤（ii）中，反应路径上零点振动能的非均匀变化在 0 K 自由能中产生了一个浅的最小值。它是一个 ，因为它不是势能面上的最小值，并且只有在考虑反应路径上的零点能时才能检测到。预测的动力学同位素效应将在方便使用的温度下在实验中可观察到。这在反应序列的脱羧阶段尤其重要，因为它在 THC 形成中具有重要意义。
