Iron-Catalyzed Carbon-Carbon and Carbon-Heteroatom Bond Forming Reactions

过渡金属催化已解决了全合成、药物化学和生物化学中的许多问题。 精细化学品的生产。虽然这些反应传统上是使用铂进行的 族金属(PGM)，最近一直在推动开发方法，以避免需要 贵金属催化剂价格昂贵且有毒。越来越多的研究表明，铁可以 一种出色的催化剂，可用于各种有机转化，包括已证实的反应 高活性的烷基卤化物和格氏试剂的交叉偶联 选择性。而铁催化的C-C交叉偶联和烯烃氨基官能化提供了巨大的 有机合成中选择性C-C和C-N键形成的可持续、低成本方法的潜力 在分子水平上对这些系统的详细了解仍然难以捉摸，因此阻碍了合理的催化剂 发展。这一局限性与钯化学形成了鲜明对比，在钯化学中，对活性的详细研究 催化剂的结构和机理为催化剂的继续设计和开发提供了基础 具有新的和/或改进的催化性能的催化剂。我们的长期目标是开发铁催化的 碳-碳和碳-杂原子键的形成反应达到目前的理解水平 对于钯，从而允许在所需的C-C光谱上合理地发展铁化学， C-N和C-X(X=B、F等)键形成反应。在拟议的拨款中，一种新的实验方法 结合无机光谱、密度泛函理论、合成和动力学研究 从分子水平深入了解铁的活性催化剂和反应机理-- 催化C-C交叉偶联和烯烃氨基官能化。这些见解可以用来激励和 促进具有更高催化性能的新催化剂和反应方法的开发。 继我们在前一批赠款期间的成功工作之后，该提案的具体目标是：(1)扩大 铁配体中活性铁催化剂及其反应机理的分子水平理解 催化C-C交叉偶联，(2)扩大对活性铁催化剂的分子水平的了解，以及 C-C与简单铁盐的交叉偶联反应机理，以及(3)发展分子水平 了解铁催化烯烃中存在的活性铁催化剂和反应机理 氨基功能化。这项研究具有创新性，因为它涉及到一种新的物理-无机方法来 研究铁催化的有机反应，促进我们对活性铁物种和 参与催化的机制，以激励和促进改进方法学的发展。这个 拟议中的研究具有重要意义，因为它有望扩大可以制造的分子的数量 使用低成本、可持续的铁催化剂。从长远来看，这种合成方法的扩展将使 对人类健康有直接影响的分子生物学和药理学的发现。

Transition metal catalysis has solved countless problems in total synthesis, pharmaceutical chemistry, and the production of fine chemicals. While these reactions have traditionally been performed using platinum group metals (PGMs), there has been a recent push to develop methods that circumvent the need for expensive and toxic precious metal catalysts. A growing body of research has demonstrated that iron can be an excellent catalyst across a wide variety of organic transformations, including reactions that have proven difficult for PGMs, such as the cross-coupling of alkyl halides and Grignard reagents with both high activity and selectivity. While iron-catalyzed C-C cross-couplings and olefin aminofunctionalizations offer tremendous potential for sustainable, low-cost methods for selective C-C and C-N bond formation in organic synthesis, a detailed molecular-level understanding of these systems has remained elusive, thus, hindering rational catalyst development. This limitation is in stark contrast to palladium chemistry, where detailed studies of active catalyst structure and mechanism have provided the foundation for the continued design and development of catalysts with novel and/or improved catalytic performance. Our long-term goal is to develop iron-catalyzed carbon-carbon and carbon-heteroatom bond forming reactions to the level of understanding currently present for palladium, thus permitting the rational development of iron chemistry across the spectrum of desired C-C, C-N and C-X (X = B, F, etc.) bond forming reactions. In the proposed grant, a novel experimental approach combining inorganic spectroscopies, density functional theory, synthesis and kinetic studies will be utilized to provide molecular-level insight into the active iron catalysts and reaction mechanisms involved in iron- catalyzed C-C cross-coupling and olefin aminofunctionalization. These insights can be utilized to inspire and facilitate the development of new catalysts and reaction methodologies with improved catalytic performance. Following our successful work in the prior grant period, the specific aims of the proposal are to: (1) expand molecular-level understanding of the active iron catalysts and reaction mechanisms present in iron-ligand catalyzed C-C cross-coupling, (2) expand molecular-level understanding of the active iron catalysts and reaction mechanisms present in C-C cross-couplings with simple ferric salts, and (3) develop molecular-level understanding of the active iron catalysts and reaction mechanisms present in iron-catalyzed olefin aminofunctionalizations. The research is innovative because it involves a novel physical-inorganic approach to study iron-catalyzed organic reactions and advances our understanding of the active iron species and mechanisms involved in catalysis to inspire and facilitate the development of improved methodologies. The proposed research is significant because it is expected to expand the number of molecules that can be made using low-cost, sustainable iron catalysis. Long term, this expansion of synthetic methods will enable discoveries in molecular biology and pharmacology of direct impact to human health.