Department of Chemistry, Binghamton University, Binghamton, New York 13902, United States.
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States.
J Am Chem Soc. 2022 Sep 28;144(38):17692-17699. doi: 10.1021/jacs.2c07807. Epub 2022 Sep 16.
Experimental C kinetic isotope effects (KIEs) provide unprecedented mechanistic insight into three intermolecular anti-Markovnikov alkene hydrofunctionalization reactions─hydroesterification, hydroamination, and hydroetherification─enabled by organophotoredox catalysis. All three reactions are found to proceed via initial oxidation of the model alkenes to form a radical cation intermediate, followed by sequential nucleophilic attack and hydrogen-atom transfer to deliver the hydrofunctionalized product. A normal C KIE on the olefinic carbon that undergoes nucleophilic attack provides qualitative evidence for rate-limiting nucleophilic attack in all three reactions. Comparison to predicted C KIE values obtained from density functional theory (DFT) calculations for this step reveals that alkene oxidation has partial rate-limiting influence in hydroesterification and hydroamination, while the nucleophilic attack is solely rate-limiting in the hydroetherification reaction. The basic additive (2,6-lutidine) activates the nucleophile via deprotonation and is an integral part of the transition state for nucleophilic attack on the radical cation, providing an important design principle for the development of asymmetric versions of these reactions. A more electron-rich pyridine base (2,6-dimethoxypyridine) exhibits considerable rate enhancements in both inter- and intramolecular hydrofunctionalization reactions.
实验 C 动力学同位素效应（KIE）为通过有机光氧化还原催化实现的三种分子间反 Markovnikov 烯烃氢官能化反应——氢酯化、氢胺化和氢醚化——提供了前所未有的机理见解。所有这三个反应都被发现是通过初始氧化模型烯烃形成自由基阳离子中间体，然后进行连续的亲核攻击和氢原子转移来提供氢官能化产物。在经历亲核攻击的烯烃碳上的正常 C KIE 为所有三个反应中的限速亲核攻击提供了定性证据。与通过密度泛函理论（DFT）计算预测的该步骤的 C KIE 值进行比较表明，在氢酯化和氢胺化反应中，烯烃氧化具有部分限速影响，而在氢醚化反应中，亲核攻击是唯一的限速步骤。碱性添加剂（2,6- 二甲基吡啶）通过去质子化激活亲核试剂，并且是自由基阳离子亲核攻击过渡态的组成部分，为这些反应的不对称版本的开发提供了重要的设计原则。更富电子的吡啶碱（2,6-二甲氧基吡啶）在分子间和分子内氢官能化反应中都表现出相当大的速率增强。
