Elucidation of Active Iron Species and Mechanism in Simple Iron Salt and Iron-N-Heterocyclic Carbene Catalyzed C-C Cross-Couplings

C-C键的选择性形成在药物合成中具有根本的重要性， 天然产物和生物活性分子，用于健康相关研究和临床应用。铁催化 C-C交叉偶联已经成为传统贵金属催化的非常有前途的替代方案， 提供降低的成本、低毒性和新颖的反应性。尽管最近在这方面取得了许多成就， 虽然这些方法还没有发展出有效的铁催化的C-C交叉偶联，但这些方法仅仅开始解决了 铁基催化剂的潜力以及许多挑战和需要显著改进的领域仍然存在。 实例包括目前在许多铁盐中需要大量的有毒NMP共溶剂 催化的交叉偶联，缺乏广泛适用的立体选择性交叉偶联方法， 铁，以及需要扩大范围的亲核和亲电试剂，可以交叉偶联 （包括用于烷基-烷基交叉偶联反应）。提出研究的动机来自于 假设对活性催化剂结构和机理的详细了解可以提供基础 为改进目前的催化系统，以及灵感的发展，新的 催化剂和方法，这将大大扩大范围和利用铁在C-C交叉偶联。 我提出的项目的目标是利用一种新的实验方法， 光谱、密度泛函理论和合成结合动力学研究， 从分子水平深入了解活性催化剂结构。这将有助于阐明 目前前沿的铁催化的C-C交叉偶联反应涉及简单的铁盐催化剂， 简单铁盐和NHC配体添加剂的组合。根据Neidig先前的研究， 在FeMe4-的分离和表征方面，我将研究在FeMe4-中形成的还原铁物种。 简单铁盐与甲基和乙基格氏试剂反应，以鉴定活性铁物种 和交叉偶联催化的潜在机制。更多的研究将把这项工作扩展到 NMP和β-氢的存在（即在EtMgBr中）对原位形成的铁物种的影响， 与简单铁盐的交叉偶联机制。在铁-NHC催化的碳-碳交叉反应领域， 偶联，我将评估活性催化剂物种，催化机理和NHC的影响 结构对芳基-芳基和芳基-烷基与铁-NHC交叉偶联反应性的影响。研究将包括 原位形成的铁物种的光谱鉴定，其结构表征和详细的 评价它们与亲电试剂的反应。拟议工作的预期成果是 了解活性铁催化剂的结构和反应机理，在前沿铁十字， 耦合系统，将促进和启发新的反应方法的发展， 这个基本的洞察力。

The selective formation of C-C bonds is of fundamental importance in the synthesis of pharmaceuticals, natural products and bio-active molecules for both health related research and clinical use. Iron-catalyzed C-C cross-coupling has emerged as a highly promising alternative to traditional precious metal catalysis, offering reduced cost, low toxicity and novel reactivities. Despite many recent achievements in the development of effective iron-catalyzed C-C cross-couplings, these methods only begin to address the potential of iron-based catalysts, and numerous challenges and areas for significant improvement remain. Examples include the current requirements for large amounts of toxic NMP co-solvent in many ferric salt catalyzed cross-couplings, the lack of broadly applicable methods for stereoselective cross-coupling with iron, and the need to broaden the scope of the nucleophiles and electrophiles that can be cross-coupled (including for alkyl-alkyl cross-coupling reactions). Motivation for the proposed research derives from the hypothesis that a detailed understanding of active catalyst structure and mechanism can provide the basis for improvements in current catalytic systems, as well as the inspiration for the development of new catalysts and methodologies that will greatly expand the scope and utility of iron in C-C cross-coupling. The objective of my proposed project is to utilize a novel experimental approach combining inorganic spectroscopies, density functional theory and synthesis combined with kinetic studies to develop molecular-level insight into active catalyst structure. This will shed light on the mechanisms involved in current leading edge iron-catalyzed C-C cross-coupling reactions involving simple ferric salt catalysts and combinations of simple ferric salts and NHC ligand additives. Building upon previous studies by the Neidig group on the isolation and characterization of FeMe4-, I will investigate the reduced iron species formed in reactions of simple ferric salts and methyl and ethyl Grignards in order to identify the active iron species and mechanisms underlying cross-coupling catalysis. Additional studies will extend this work to the effects of NMP and the presence of β-hydrogens (i.e. in EtMgBr) on the in-situ formed iron species and mechanism in cross-couplings with simple ferric salts. In the area of iron-NHC catalyzed C-C cross- couplings, I will evaluate the active catalyst species, mechanisms of catalysis and the effects of NHC structure on reactivity in aryl-aryl and aryl-alkyl cross-coupling with iron-NHCs. Studies will include the spectroscopic identification of the in-situ formed iron species, their structural characterization and detailed evaluation of their reactions with electrophiles. The expected outcome of the proposed work is a detailed understanding of active iron catalyst structures and reaction mechanisms in leading edge iron cross- coupling systems that will facilitate and inspire the development of novel reaction methodologies based upon this fundamental insight.