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

通过多位点协同质子-电子转移进行 C-H 键转变的模型系统

• 批准号: 10453794
• 负责人: Scott Christopher Coste
• 金额: $ 5.74万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-05-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453794
• 关键词: Acids; Active Sites; Address; Affect; Alkenes; Amides; Anaerobic Bacteria; Betula Genus; Biochemical; Biochemical Reaction; Biochemistry; Biological; Biological Models; Carbon; Cell Respiration; Coenzyme A; Complex; Coupling; Dependence; Development; Distant; Educational process of instructing; Electron Transport; Energy Metabolism; Energy Transfer; Environment; Enzymes; Faculty; Fostering; Foundations; Free Energy; Future; Goals; Heart; Hydrogen Bonding; Hydrogenation; Institution; Kinetics; Learning; Measurement; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Microbe; Modeling; Oxidation-Reduction; Oxidoreductase; Pathway interactions; Photosynthesis; Process; Protons; Reaction; Research; Research Personnel; Respiration; Series; Site; Sulfonamides; System; Training; Universities; Variant; Writing; base; career; cofactor; cost; design; driving force; insight; kinetic model; methyl group; molecular modeling; morphogens; novel strategies; oxidation; post-doctoral training; reaction rate; skills; teacher; thioester; unsaturated bonds; Acids; Active Sites; Address; Affect; Alkenes; Amides; Anaerobic Bacteria; Betula Genus; Biochemical; Biochemical Reaction; Biochemistry; Biological; Biological Models; Carbon; Cell Respiration; Coenzyme A; Complex; Coupling; Dependence; Development; Distant; Educational process of instructing; Electron Transport; Energy Metabolism; Energy Transfer; Environment; Enzymes; Faculty; Fostering; Foundations; Free Energy; Future; Goals; Heart; Hydrogen Bonding; Hydrogenation; Institution; Kinetics; Learning; Measurement; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Microbe; Modeling; Oxidation-Reduction; Oxidoreductase; Pathway interactions; Photosynthesis; Process; Protons; Reaction; Research; Research Personnel; Respiration; Series; Site; Sulfonamides; System; Training; Universities; Variant; Writing; base; career; cofactor; cost; design; driving force; insight; kinetic model; methyl group; molecular modeling; morphogens; novel strategies; oxidation; post-doctoral training; reaction rate; skills; teacher; thioester; unsaturated bonds

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.

项目摘要/摘要 C – H键转换位于整个整个代谢途径的核心 生物圈。氧化酶酶操纵X – H键（X = C，N，O），有限 通过称为多站点协调的质子电子转移的过程的能量支出 （MS-CPET）是光合作用，呼吸和复杂生物分子合成的基础。在 这些反应中有许多，质子转移坐标由预先对准的氢引导 键相互作用，C – H键不存在。因此，许多机制 CH-CH氧化还原酶酶促反应尚不清楚 遥远的电子传递辅助因子。因此，得出涉及C – H的MS-CPET背后的原则 债券将非常有用，以揭示大量酶的功能如何 在生物圈中。 在此提案中，我们试图了解质子转移坐标如何管理C – H债券 使用分子模型通过MS-CET反应性。具体来说，我们将探讨如何关键方面 例如质子转移预先对齐和质子隧道距离会影响C – H键裂解 通过结构变化。我们还将得出减少的基本热化学原理 稳定的自由基系统中的C – H键形成，以发展动力学自由能力关系。最后， 我们将基于这些动力学和热化学模型来评估减少 芳香质微生物代谢中心的芳族底物的氢化机理。我们的 目标是在我们的模型系统中以C-H键对MS-CPET进行机械理解 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键转化，并指导合成化学家对新的 操纵牢固纽带的方法。 我在Mayer组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精神训练，写作和 呈现技巧。重要的是，这项培训将教会我思考和接近科学的新方法 问题使我扩大了我将来可以独立的研究范围 职业。耶鲁大学培养了一个理想的环境，以训练我的特殊设施， 开创性和教学机会，以及合成有机专家的著名教师， 理论和生物化学。我相信我的培训足以使我成为领先的 未来的学术机构的独立研究人员和老师。