Modulating Twisted Amide Geometry and Reactivity Through Remote Substituent Effects

IF 15.6 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Mizhi Xu, McKinley K. Paul, Krista K. Bullard, Christopher DuPre, Will R. Gutekunst*
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引用次数: 1

Abstract

The unusual reactivity of twisted amides has long been associated with the degree of amide distortion, though classical bridged bicyclic amides offer limited methods to further modify these parameters. Here, we report that the geometry and reactivity of a single twisted amide scaffold can be significantly modulated through remote substituent effects. Guided by calculated ground state geometries, a library of twisted amide derivatives was efficiently prepared through a divergent synthetic strategy. Kinetic and mechanistic investigations of these amides in the alkylation/halide-rebound ring-opening reaction with alkyl halides show a strong positive correlation between the electron donating ability of the substituent and distortion of the amide bond, leading to rates of nucleophilic substitution spanning nearly 2 orders of magnitude. The rate limiting step of the cascade sequence is found to be dependent on the nature of the substituent, and additional studies highlight the role of solvent polarity and halide ion on reaction pathway and efficiency.

Abstract Image

通过远端取代基效应调制扭曲酰胺的几何形状和反应性
扭曲酰胺的异常反应性长期以来一直与酰胺的扭曲程度有关,尽管经典的桥联双环酰胺提供了有限的方法来进一步修改这些参数。在这里,我们报告了单个扭曲酰胺支架的几何形状和反应性可以通过远程取代基效应显着调节。在基态几何计算的指导下,通过发散合成策略有效地制备了扭曲酰胺衍生物库。这些酰胺类化合物在烷基化/卤化物-反跳开环反应中的动力学和机理研究表明,取代基的给电子能力与酰胺键的畸变之间存在很强的正相关关系,导致亲核取代率跨越近2个数量级。发现级联序列的限速步骤取决于取代基的性质,另外的研究强调了溶剂极性和卤化物离子对反应途径和效率的作用。
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来源期刊
CiteScore
24.40
自引率
6.00%
发文量
2398
审稿时长
1.6 months
期刊介绍: The flagship journal of the American Chemical Society, known as the Journal of the American Chemical Society (JACS), has been a prestigious publication since its establishment in 1879. It holds a preeminent position in the field of chemistry and related interdisciplinary sciences. JACS is committed to disseminating cutting-edge research papers, covering a wide range of topics, and encompasses approximately 19,000 pages of Articles, Communications, and Perspectives annually. With a weekly publication frequency, JACS plays a vital role in advancing the field of chemistry by providing essential research.
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