Simultaneous determination of intermolecular and intramolecular 13C and 2H kinetic isotope effects at natural abundance
Simultaneous determination of intermolecular and intramolecular 13C and 2H kinetic isotope effects at natural abundance
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DOI：
10.1021/ja992016z
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发表时间：
1999-10-13
影响因子：
15
通讯作者：
Szymanski, MJ
中科院分区：
文献类型：
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作者：
Singleton, DA;Szymanski, MJ
动力学同位素效应（KIEs）是一种独特而有力的反应机制探针。大多数测量的KIEs提供分子间效应的限速步骤的反应。无论在绝对动力学还是在竞争反应中，无论何时对标记材料和未标记材料的速率进行比较，都是如此。因此，大多数同位素效应测定只探测速率限制步骤，而不能提供关于机制其余部分的直接信息。利用分子内同位素效应来克服这一限制是由Dolbier2开创的，Stevenson对此进行了详细阐述。3当一个部分标记的分子致力于反应（已经通过了限速过渡态）时，仍然具有立体化学或区域化学的活性同位素选择，产物分布反映了决定产物步骤的KIE。在许多情况下，对这些分子内的ky的研究已被用于获得有关限速步骤后中间体的其他罕见信息。4此外，比较分子间和分子内的KIEs有助于区分单步机制和多步机制。这种分子内/分子间同位素效应的研究面临一些困难和限制。分子间和分子内的KIE必须可靠地区分，因为它们具有不同的值，这要么需要非常精确的KIE测定，要么需要较大的KIE。在实践中，这些研究通常局限于涉及大一级H/D KIEs的反应，分子间和分子内13C KIEs的比较根本没有报道。此外，部分标记材料和完全标记底物所需的区域或立体特异性合成可能是艰巨的，通常是令人望而却步的。我们在这里描述了克服这些问题的简单方法，并允许在自然丰度下从单个实验中同时测量分子内和分子间的2H和13C KIEs。该方法的测试反应是环己酮的Baeyer-Villiger氧化制ϵ-caprolactone。相当多的证据支持Baeyer-Villiger反应的Criegee两步机制，包括半缩醛（例如，1）作为关键中间体。6,7机理研究一般集中在第一步或第二步是否限速以及烷基迁移步骤的性质。在许多反应条件下，第二步已被确定为速率限制，以及物理有机探针的全部曲目，包括动力学同位素
Kinetic isotope effects (KIEs) are a uniquely powerful probe of reaction mechanisms. Most measurements of KIEs provide intermolecular effects on the rate-limiting step for a reaction. This is true whenever the rates of labeled versus unlabeled materials are compared, whether by absolute kinetics or in competition reactions. 1 As such, most isotope effect determinations probe only the rate-limiting step and provide no direct information about the rest of a mechanism. The elegant use of intramolecular isotope effects to overcome this limitation was pioneered by Dolbier2 and elaborated by Stevenson. 3 When a partially labeled molecule that is committed to react (having passed through the rate-limiting transition state) still has a stereochemical or regiochemical choice of reactive isotopes, the product distribution reflects the KIE for the product-determining step. Studies of these intramolecular KIEs have been used in numerous cases to obtain otherwise rare information about intermediates after the rate-limiting step. 4 In addition, comparisons of intermolecular and intramolecular KIEs are useful for distinguishing single-step from multi-step mechanisms. 5Such studies of intramolecular/intermolecular isotope effects face several difficulties and limitations. The intermolecular and intramolecular KIEs must be reliably distinguished as having different values, requiring either very precise KIE determinations or the presence of large KIEs. In practice, these studies are often limited to reactions involving large primary H/D KIEs, and comparisons of intermolecular and intramolecular 13C KIEs have not been reported at all. In addition, the required regio-or stereospecific synthesis of partially labeled materials as well as fully labeled substrates can be arduous, often prohibitively so. We describe here simple methodology that overcomes these problems and allows the simultaneous measurement of the intramolecular and intermolecular 2H and 13C KIEs from a single experiment at natural abundance. The test reaction for the methodology was the Baeyer-Villiger oxidation of cyclohexanone to ϵ-caprolactone. Considerable evidence supports the Criegee two-step mechanism for the Baeyer-Villiger reaction, involving hemiperacetals (eg, 1) as key intermediates. 6, 7 Mechanistic study has generally focused on whether the first or second step is rate limiting and the nature of the alkyl migration step. Under many reaction conditions the second step has been established as rate limiting, and the full repertoire of physical organic probes, including kinetic isotope