Probing the Free Energy Landscape of Organophotoredox-Catalyzed Anti-Markovnikov Hydrofunctionalization of Alkenes.
Probing the Free Energy Landscape of Organophotoredox-Catalyzed Anti-Markovnikov Hydrofunctionalization of Alkenes.
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DOI：
10.1021/jacs.2c07807
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发表时间：
2022-09-28
影响因子：
15
通讯作者：
Hirschi, Jennifer S.
中科院分区：
文献类型：
--
作者：
Mallojjala, Sharath Chandra;Nyagilo, Victor O.;Corio, Stephanie A.;Adili, Alafate;Dagar, Anuradha;Loyer, Kimberly A.;Seidel, Daniel;Hirschi, Jennifer S.
实验性 13C 动力学同位素效应 (KIE) 为有机光氧化还原催化下的三种分子间反马尔可夫尼科夫烯烃氢官能化反应（加氢酯化、加氢胺化和加氢醚化）提供了前所未有的机制见解。发现所有三个反应都是通过模型烯烃的初始氧化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以产生氢官能化产物。经历亲核攻击的烯属碳上的正常 13C KIE 为所有三个反应中的限速亲核攻击提供了定性证据。与从该步骤的密度泛函理论 (DFT) 计算获得的预测 13C KIE 值进行比较表明，烯烃氧化在加氢酯化和加氢胺化反应中具有部分限速影响，而亲核攻击在加氢醚化反应中仅具有限速作用。碱性添加剂（2,6-二甲基吡啶）通过去质子化激活亲核试剂，并且是对自由基阳离子进行亲核攻击的过渡态的组成部分，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表现出显着的速率增强。
Experimental 13C 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 13C KIE on the olefinic carbon that undergoes nucleophilic attack provides qualitative evidence for rate-limiting nucleophilic attack in all three reactions. Comparison to predicted 13C 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.
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