Mechanistic Studies at the Frontiers of Catalysis

催化前沿的机理研究

• 批准号: 10406643
• 负责人: Mathew J Vetticatt
• 金额: $ 20.77万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406643
• 关键词: Address; Area; Carbon; Catalysis; Chemistry; Coupling; Environment; Funding; Goals; Hydrogen Bonding; Isotopes; Kinetics; Ligands; Metals; Methodology; Methods; Minor; Modernization; Nickel; Organic Synthesis; Palladium; Pathway interactions; Pharmaceutical Chemistry; Reaction; Research; Resolution; Time; United States National Institutes of Health; Vision; design; frontier; improved; insight; novel; programs; rational design; tool

Project Summary: Our research program investigates reaction mechanisms in asymmetric organocatalysis and palladium catalyzed cross-coupling reactions. We utilize 13C and 2H kinetic isotope effects (KIEs) in combination with theoretical calculations as design tools to evaluate fine details of the transition state (TS) of the rate-determining step (RDS) under unmodified reaction conditions. Our studies in the area of asymmetric organocatalysis (2013-present) have resolved long-standing debates, uncovered novel mechanistic pathways, and probed origins of enantioselectivity in a wide variety of reaction types. In 2018, NIH funding enabled us to expand our research program to the study of palladium catalyzed cross-coupling reactions – an area of catalysis that is central to medicinal chemistry. We have discovered that the magnitude of 13C KIE is highly sensitive to minor changes in the carbon-palladium distance at the TS of the RDS – allowing us to distinguish between competing pathways and probe the ligand environment at the metal center, all under catalytic conditions. Finally, we have developed a novel methodology that utilizes symmetric reactants to obtain this information at a fraction of the time and effort of traditional KIE approaches. This MIRA proposal seeks to further expand our research program to include new modes of catalysis at the frontier of modern-day organic synthesis: (a) palladium catalyzed C-H bond-activation and functionalization, and (b) nickel metallophotoredox catalysis. Over the next five years, our goal is to establish our combined experimental and theoretical approach as the state-of-the-art to gain atomistic understanding of the mechanistic underpinnings of these reactions. We chose these two areas to expand our research program for two reasons – (a) new reaction discovery has far outpaced mechanistic understanding of these reactions, and (b) our discoveries in palladium catalyzed cross- coupling chemistry strongly indicate that our approach is ideally suited to resolve key mechanistic questions in these contemporary areas of catalysis. The overall vision of our research program is to develop probes that can rapidly evaluate the mechanism of catalytic reactions. We seek to change the paradigm that rigorous mechanistic understanding follows new reaction discovery. We envision that the high-resolution mechanistic insight that is delivered by our studies will inspire the discovery of new and more robust catalytic methods that will enable organic synthesis.

项目概述：我们的研究计划研究不对称的反应机理 有机催化和钯催化的交叉偶联反应。我们利用13 C和2 H动力学同位素 的影响（KIE）结合理论计算作为设计工具，以评估的细节， 在未改性的反应条件下的速率决定步骤（RDS）的过渡态（TS）。我们 不对称有机催化领域的研究（2013年至今）解决了长期存在的争论， 发现了新的机制途径，并探讨了各种各样的对映体选择性的起源。 反应类型2018年，NIH的资助使我们能够将研究计划扩展到研究 钯催化的交叉偶联反应--一个对医药研究至关重要的催化领域 化学.我们已经发现，13 C KIE的大小对环境中的微小变化非常敏感。 在RDS的TS处的碳-钯距离-允许我们区分竞争的 途径和探测金属中心的配体环境，所有这些都在催化条件下进行。最后， 我们已经开发了一种新的方法，利用对称反应物，以获得这种信息， 传统KIE方法的时间和精力的一小部分。 这项MIRA提案旨在进一步扩大我们的研究计划，包括新的模式， 现代有机合成前沿的催化：（a）钯催化的C-H键活化 和功能化;（B）镍金属光氧化还原催化。未来五年，我们的目标是 建立我们的实验和理论相结合的方法，作为最先进的获得原子 理解这些反应的机械基础。我们选择了这两个领域， 扩大我们的研究计划有两个原因-（a）新的反应发现已经远远超过 这些反应的机理的理解，和（B）我们的发现，在钯催化的交叉- 耦合化学强烈表明，我们的方法是理想的适合解决关键的机制， 这些当代催化领域的问题。 我们研究计划的总体愿景是开发能够快速评估 催化反应机理。我们寻求改变严格机械化的范式， 新的反应发现之后才有理解。我们设想高分辨率的机械洞察力 我们的研究所提供的信息将激发新的和更强大的催化方法的发现， 可以进行有机合成。