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

项目概要/摘要 C-H键转化位于整个代谢过程中许多代谢途径的核心。 生物圈氧化还原酶操纵强X-H键（X = C、N、O）， 通过一个称为多位点协同质子-电子转移的过程消耗能量 （MS-CPET），其是光合作用、呼吸作用和复杂生物分子合成的基础。在 在许多这些反应中，质子转移坐标由预先排列的氢引导 键合相互作用，这是不存在的C-H键。因此，许多机制 CH-CH氧化还原酶的酶促反应是未知的，尽管大量依赖于 远距离电子转移辅因子。因此，推导涉及C-H的MS-CPET背后的原理 这些化学键将为揭示大量酶的功能提供大量信息 in the biosphere生物圈. 在这个提议中，我们试图了解质子转移坐标如何控制C-H键 反应性通过MS-CPET使用分子模型。具体来说，我们将探讨如何关键方面 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反应的基本热化学原理。 在稳定的自由基体系中C-H键的形成，以发展动力学自由能关系。最后， 我们将建立在这些动力学和热化学模型，以评估还原 厌氧微生物代谢中芳香底物的氢化机理。我们 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的机理理解 以阐明未知的CH-CH氧化还原酶反应性。这项研究将有助于阐明 酶执行困难的C-H键转换，并指导合成化学家开发新的 操纵强键的方法。 我在Mayer集团的博士后培训将通过学习扩展我的研究技能 机械和动力学研究，以及让我磨练我的导师、写作和 展示技能。重要的是，这次培训将教会我新的方式来思考和接近科学 这些问题使我能够扩大研究范围，我可以在我未来的独立研究中解决这些问题。 事业耶鲁大学培养了一个理想的环境，以其卓越的设施来培养我， 研讨会和教学机会，以及杰出的教师谁是合成有机， 理论和生物化学。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.