Mechanistic Studies Yield Improved Protocols for Base-Catalyzed Anti-Markovnikov Alcohol Addition Reactions
Mechanistic Studies Yield Improved Protocols for Base-Catalyzed Anti-Markovnikov Alcohol Addition Reactions
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DOI：
10.1021/jacs.1c13397
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发表时间：
2022-06-08
影响因子：
15
通讯作者：
Bandar，Jeffrey S.
中科院分区：
文献类型：
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作者：
Luo，Chaosheng;V. Alegre-Requena，Juan;Bandar，Jeffrey S.
醇与单烯的催化反Markovnikov加成反应是一个长期存在的合成挑战。我们最近公开了有机超碱催化剂用于醇与活性苯乙烯衍生物的亲核加成反应。本文介绍了这一可逆反应的机理研究，包括热力学和动力学分析以及计算模型。我们的发现表明，加成的负熵被在非极性溶剂中最有利的热焓所抵消。然而，在这些条件下，较大的负醇率顺序表明，过量的酒精隔离了活性的醇氧离子对，减缓了反应速度。这些观察为一个热力学上具有挑战性的反应带来了意想不到的解决方案：使用更少的酒精可以更快地添加，这反过来又允许更低的反应温度来抵消Le Chatelier原理。因此，我们原来的方法得到了改进，新的方案不需要过量的酒精化学计量，能够扩大烯烃底物的范围，并允许使用更实用的催化剂系统。这一观点对其他具有挑战性的氢醚化反应的普遍性也通过新的烯醇环化和氧-迈克尔加成反应得到了证明。
The catalytic anti-Markovnikov addition of alcohols to simple alkenes is a longstanding synthetic challenge. We recently disclosed the use of organic superbase catalysis for the nucleophilic addition of alcohols to activated styrene derivatives. This article describes mechanistic studies on this reversible reaction, including thermodynamic and kinetic profiling as well as computational modeling. Our findings show the negative entropy of addition is counterbalanced by an enthalpy that is most favored in nonpolar solvents. However, a large negative alcohol rate order under these conditions indicates excess alcohol sequesters the active alkoxide ion pairs, slowing the reaction rate. These observations led to an unexpected solution to a thermodynamically challenging reaction: use of less alcohol enables faster addition, which in turn allows for lower reaction temperatures to counteract Le Chatelier’s principle. Thus, our original method has been improved with new protocols that do not require excess alcohol stoichiometry, enable an expanded alkene substrate scope, and allow for the use of more practical catalyst systems. The generality of this insight for other challenging hydroetherification reactions is also demonstrated through new alkenol cyclization and oxa-Michael addition reactions.