Catalytically Generated Amidyl Radicals for Site-Selective Intermolecular C-H Functionalization

项目摘要 C-H键的选择性活化和功能化是其中最重要和最具挑战性的一个 化学转化激活给定分子中任何目标C-H键的能力将极大地 扩大了合成可及化学转化的范围，将是一种强有力的方法， 复杂分子如药物、天然产物和日用化学品的分阶段功能化。 此外，使用丰富的无毒催化剂和可再生能源进行这些反应 (e.g.,太阳能）对可持续化学工艺的发展至关重要。实现C-选择性 H活化通常是困难的，因为在给定的分子中存在许多类似强度的C-H键。 更具有挑战性的是有区别地官能化接近较弱C-H键的强C-H键。 C-H活化的选择性通常由底物的性质决定，并且在这种情况下，反应性可以 仅限于最弱或最酸性的C-H键。然而，选择性的催化剂控制，其中结构 的H原子提取器决定选择性，提供了一个强大的方法，可预测地引入化学 来自碳氢化合物原料的多样性。酰胺基自由基是强有力的H-原子夺取剂（BDE（N-H）> 100 kcal mol-1），但它们在分子间C-H活化中的应用 反应通常依赖于预官能化的酰胺基源，使它们成为化学计量试剂。直接 活化酰胺N-H键以产生酰胺基自由基将为这些反应性化合物提供催化途径。 中间体，并且将显著提高它们在C-H官能化反应中的效用。这一拟议 研究战略旨在开发新的直接N-H键活化的电和光催化方法， 质子偶联电子转移以产生用于选择性C-H活化的酰胺基自由基。通过利用这些 在空间屏蔽的酰胺催化剂中，N-H键活化的模式， 自由基可以决定位点选择性。结合电化学动力学和电化学物理研究， 包括时间分辨瞬态吸收光谱和光晶体学，将用于 描述了决定选择性的关键结构和电子特征。总的来说，这些研究将扩大我们的 使用可持续能源进行催化、位点选择性C-H官能化反应的能力。

Project Summary The selective activation and functionalization of C–H bonds is one of the most important and challenging chemical transformations. The ability to activate any targeted C–H bond in a given molecule would immensely expand the scope of synthetically accessible chemical transformations and would be a powerful method of late- stage functionalization of complex molecules such pharmaceuticals, natural products, and commodity chemicals. Furthermore, carrying out these reactions using abundant, non-toxic catalysts and renewable energy sources (e.g., solar energy) is critical for the development of sustainable chemical processes. Achieving selectivity in C– H activation is often difficult due to the presence of numerous C–H bonds of similar strength in a given molecule. Even more challenging is discriminately functionalizing strong C–H bonds in proximity to weaker C–H bonds. Selectivity for C–H activation is often dictated by properties of the substrate, and in such cases, reactivity may be limited to the weakest or most acidic C–H bond. However, catalyst-control of selectivity, wherein the structure of the H-atom abstractor dictates selectivity, offers a powerful method of predictably introducing chemical diversity from hydrocarbon feedstocks. Amidyl radicals are potent H-atom abstractors (BDE(N–H) > 100 kcal mol-1) that are capable of cleaving strong C–H bonds, but their applications in intermolecular C–H activation reactions often rely on pre-functionalized amidyl sources, rendering them stoichiometric reagents. The direct activation of amide N–H bonds to generate amidyl radicals would provide catalytic access to these reactive intermediates and would dramatically improve their utility in C–H functionalization reactions. This proposed research strategy aims to develop new electro- and photocatalytic methods for direct N–H bond activation via proton-coupled electron transfer to generate amidyl radicals for selective C–H activation. By exploiting these modes of N–H bond activation in sterically shielded amide catalysts, the steric pressures imposed the amidyl radicals can dictate site-selectivity. A combination of electrochemical kinetics and photophysical studies, including time-resolved transient absorption spectroscopy and photocrystallography, will be employed to delineate the key structural and electronic features that govern selectivity. Overall, these studies will expand our ability to perform catalytic, site-selective C–H functionalization reactivity using sustainable energy sources.