Khan Shahriar N, Hymel John H, Pederson John P, McDaniel Jesse G
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, United States.
J Org Chem. 2024 Dec 20;89(24):18353-18369. doi: 10.1021/acs.joc.4c02227. Epub 2024 Dec 3.
In anodic electrosynthesis, cation radicals are often key intermediates that can be highly susceptible to nucleophilic attack and/or deprotonation, with the selectivity of competing pathways dictating product yield. In this work, we computationally investigate the role of methanol in alcohol trapping of enol ether cation radicals for which substantial modulation of the reaction yield by the solvent environment was previously observed. Reaction free energies computed for intramolecular coupling unequivocally demonstrate that the key intramolecular alcohol attack on the oxidized enol ether group is catalyzed by methanol, proceeding through overall second-order kinetics. Methanol complexation with the formed oxonium ion group gives rise to a "Zundel-like", shared proton conformation, providing a critical driving force for the intramolecular alcohol attack. Free energies computed for methanol solvent attack of enol ether cation radicals demonstrate an analogous mechanism and overall third-order kinetics, due to similar complexation from a secondary methanol molecule to form the "Zundel-like", shared proton conformation. As catalyzed by methanol, both intramolecular alcohol attack and methanol attack on the oxidized enol ether group are barrierless or low-barrier reactions, with kinetic competition dictated by the conformational free energy profile of the cation radical substrate and the difference in reaction rate orders.
在阳极电合成中，阳离子自由基通常是关键中间体，极易受到亲核攻击和/或去质子化作用的影响，竞争途径的选择性决定了产物产率。在这项工作中，我们通过计算研究了甲醇在烯醇醚阳离子自由基的醇捕获反应中的作用，此前已观察到溶剂环境对该反应产率有显著调节作用。为分子内偶联计算的反应自由能明确表明，甲醇催化了对氧化烯醇醚基团的关键分子内醇攻击，反应遵循整体二级动力学。甲醇与形成的氧鎓离子基团络合产生了一种“类尊德尔”的共享质子构象，为分子内醇攻击提供了关键驱动力。为烯醇醚阳离子自由基的甲醇溶剂攻击计算的自由能表明了类似的机制和整体三级动力学，这是由于来自第二个甲醇分子的类似络合作用形成了“类尊德尔”的共享质子构象。在甲醇的催化下，分子内醇攻击和甲醇对氧化烯醇醚基团的攻击都是无势垒或低势垒反应，动力学竞争由阳离子自由基底物的构象自由能分布和反应速率级数的差异决定。
