Model Systems for C-H Bond Transformations through Multiple-Site Concerted Proton-Electron Transfer

项目摘要/摘要 C-H键转换是多种代谢途径的核心。 生物圈。氧化还原酶以有限的自由操控强的X-H键(X=C，N，O 通过称为多位协同质子-电子转移过程的能量消耗 (MS-CPET)是光合作用、呼吸作用和复杂生物分子合成的基础。在……里面 在许多这样的反应中，质子转移坐标是由预先对准的氢引导的 成键相互作用，没有C-H键。因此，许多人的机制 CH-CH氧化还原酶的酶反应目前尚不清楚，尽管有大量依赖于 远距离电子转移协因数。因此，MS-CPET背后涉及C-H的推导原理 键将为揭示大量酶的功能提供极大的信息。 在生物圈里。 在这个提议中，我们试图理解质子转移坐标是如何支配C-H键的 使用分子模型通过MS-CPET进行反应。具体地说，我们将探索关键方面 如质子转移预对准和质子隧穿距离影响C-H键断裂 通过结构变化。我们还将推导出还原的基本热化学原理。 C-H键在稳定的自由基体系中形成，发展了动力学自由能关系。最后， 我们将在这些动力学和热化学模型的基础上评估还原的 以厌氧微生物代谢为中心的芳香族底物加氢机理。我们的 目标是在我们的模型系统中发展对具有C-H键的MS-CPET的机理的理解 阐明未知的CH-CH氧化还原酶活性。这项研究将有助于阐明 酶执行困难的C-H键转换并引导合成化学家走向新的 操纵强势债券的方法。 我在梅耶尔小组的博士后培训将通过学习扩大我的研究技能 机械和动力学研究，以及允许我磨练我的导师，写作和 展示技能。重要的是，这次培训将教会我新的思维方式和科学方法 这些问题使我能够扩大我未来独立研究的范围 职业生涯。耶鲁大学以其卓越的设施营造了培养我的理想环境， 研讨会和教学机会，以及著名的合成有机专家教员， 理论化学和生物化学。我相信我所受的训练足以使我成为一名领导者 未来在学术机构担任独立研究员和教师。

Project Summary/Abstract C–H bond transformations lie at the heart of numerous metabolic pathways throughout the biosphere. Oxidoreductase enzymes manipulate strong X–H bonds (X = C, N, O) with limited free energy expenditure through a process known as multiple-site concerted proton-electron transfer (MS-CPET) which underlies photosynthesis, respiration, and complex biomolecule synthesis. In many of these reactions, the proton transfer coordinate is guided by pre-aligned hydrogen bonding interactions, which are absent with C–H bonds. Consequently, the mechanisms of many CH-CH oxidoreductase enzymatic reactions are not known despite the large number that rely on distant electron transfer cofactors. Therefore, deriving principles behind MS-CPET involving C–H bonds would be immensely informative to unveiling how a significant amount of enzymes function in the biosphere. In this proposal, we seek to understand how the proton transfer coordinate governs C–H bond reactivity through MS-CPET using molecular models. Specifically, we will probe how key aspects such as proton transfer pre-alignment and proton tunneling distance affect C–H bond cleavage through structural variation. We will also derive essential thermochemical principles for reductive C–H bond formation in a stable radical system to develop kinetic free energy relationships. Finally, we will build upon these kinetic and thermochemical models to assess the reductive hydrogenation mechanism of aromatic substrates central to anaerobic microbe metabolism. Our goal is to develop a mechanistic understanding of MS-CPET with C-H bonds in our model systems to illuminate unknown CH-CH oxidoreductase reactivity. This research will help elucidate how enzymes perform difficult C–H bond transformations and guide synthetic chemists towards new approaches for manipulating strong bonds. My postdoctoral training in the Mayer group will expand my research skillset through learning mechanistic and kinetic studies as well as allowing me to hone my mentorship, writing, and presenting skills. Importantly, this training will teach me new ways to think and approach scientific problems allowing me to expand the scope of research I can address in my future independent career. Yale University fosters an ideal environment to train me with its exceptional facilities, seminar and teaching opportunities, and prominent faculty who are experts in synthetic organic, theoretical, and biological chemistry. I believe my training will sufficiently equip me to be a leading independent researcher and teacher at an academic institution in the future.