On the Interpretation of Deuterium Kinetic Isotope Effects in C?H Bond Functionalizations by Transition-Metal Complexes
On the Interpretation of Deuterium Kinetic Isotope Effects in C?H Bond Functionalizations by Transition-Metal Complexes
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DOI：
10.1002/anie.201107334
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Hartwig, John F.
中科院分区：
文献类型：
--
作者：
Simmons, Eric M.;Hartwig, John F.
对化学反应进行机理的详细了解使人们能够控制和改进给定的合成过程。只有了解控制转化的速度和选择性的因素，才能通过设计催化剂、试剂和条件来精确地调节反应的结果。[1]历史上，物理有机化学领域诞生于对了解有机分子反应的密切细节的渴望，从这项工作中产生的原理对合成有机化学的发展至关重要。[1]研究反应机理的最强大和最常见的技术之一是测量动力学同位素效应(Kie)。[1-3]所有物理有机化学课程都讲授这样的实验，任何有机化学家都应该熟悉。如果操作得当，这些实验可以提供关于在反应的不同阶段哪些键被断裂或形成的重要信息，在某些情况下，关于这些键被裂解的过渡态的性质。[4]在过去的几十年里，人们致力于开发基于金属介导的C？H键功能化的合成方法。[5]因为根据定义，这种转化涉及C？H键的断裂，所以这些过程的机理细节可以通过测量由C？H键的反应速率与类似的C？D键的反应速率的差异而导致的Kie来潜在地揭示。这种Kie实验特别适合于C±H键功能化的机理研究，因为C±H键通常在没有外部试剂或催化剂的情况下不发生交换(与N±H键和O±H键相反)，并且因为可以通过各种合成方法引入碳结合的氚标记。然而，对Kie的解释并不像Kie的测量那么简单。KIE测量的选择和KIE数据的解释必须谨慎，以避免得出不被现有数据支持的机械性结论。最近的一些出版物描述了涉及C？H键官能化的合成方法，其中包括旨在探索这些转化发生机制的KIE实验。这样的实验现在是例行公事，这一趋势应该有助于推动C±H键功能化领域的发展。然而，最近对KIE数据的许多讨论得出结论，在无法从实验数据中得出这样的结论的情况下，C±H键断裂发生在“速率决定步骤”[7]中。为了响应这一增长趋势，我们在本文中简要概述和分析了三种最常见的KIE实验类型，这些实验涉及含氢的底物。随后，我们说明了在涉及C±H键官能化的合成过程中常见的一些机械性情景下，每个实验与预期Kie之间的联系。本报告的目的是减少未来C？H键断裂被认为是反应的速率决定步骤(RDS)的情况[7]，当数据不支持这样的结论时。首先应该强调的是，本文中没有提出任何新的信息或概念。相反，我们只提醒人们一些最常见的KIE实验的局限性，以及实验与评估过程的速率决定步骤是否涉及C？H键和…的相关性
A detailed understanding of the mechanism by which a chemical reaction proceeds enables one to control and improve a given synthetic process. Only by understanding the factors that govern the rate and selectivity of a transformation can the outcome of the reaction be precisely modulated through design of the catalyst, reagents, and conditions.[1] Historically, the field of physical organic chemistry was born from the desire to understand the intimate details of the reactions of organic molecules, and the principles that have emerged from this work have been vital to the development of synthetic organic chemistry.[1] One of the most powerful and common techniques for studying reaction mechanisms is the measurement of kinetic isotope effects (KIEs).[1–3] Such experiments are taught in all physical organic chemistry courses and should be familiar to any organic chemist. When conducted appropriately, these experiments can provide important information about which bonds are broken or formed at different stages of a reaction, and, in some cases, about the properties of the transition state through which these bonds are cleaved.[4] Over the past several decades, considerable effort has been devoted to the development of synthetic methods based on metal-mediated CÀH bond functionalization.[5] Because such transformations, by definition, involve the cleavage of a CÀH bond, the mechanistic details of these processes can potentially be revealed through the measurement of KIEs that result from differences in the rate for reaction at a CÀH bond versus the analogous CÀD bond.[6] In fact, such KIE experiments are especially well suited for mechanistic studies of CÀH bond functionalization because CÀH bonds do not generally undergo exchange in the absence of an external reagent or catalyst (in contrast to NÀH and OÀH bonds), and because carbon-bound deuterium labels can be introduced by a variety of synthetic methods. However, the interpretation of a KIE is not as simple as the measurement of a KIE. The choice of KIE measurement and interpretation of KIE data must be done carefully in order to avoid drawing mechanistic conclusions that are unsupported by the available data. A number of recent publications describing synthetic methods involving CÀH bond functionalization have included KIE experiments designed to probe the mechanism by which these transformations occur. Such experiments are now being undertaken routinely, and this trend should help to advance the field of CÀH bond functionalization. However, many recent discussions of KIE data have concluded that CÀH bond cleavage occurs during the “rate-determining step”[7] in cases when such a conclusion cannot be drawn from the experimental data.In response to this growing trend, we provide in this essay a brief overview and analysis of three of the most common types of KIE experiments involving substrates containing deuterium. We subsequently illustrate the connection between each experiment and the expected KIE under a number of mechanistic scenarios that commonly occur in synthetic processes involving CÀH bond functionalization. The purpose of this presentation is to diminish the number of future instances in which CÀH bond cleavage is stated to be the ratedetermining step (RDS)[7] of a reaction when the data do not support such a conclusion. It should be emphasized at the outset that no new information or concepts are presented in this essay. Rather, we provide only a reminder of the limitations of some of the most common KIE experiments and the relevance of an experiment to assessing whether the rate-determining step of a process involves CÀH bond …