Mechanistic Investigations of Gold-Catalyzed C-H Activation of Arenes

描述（由申请人提供）：以环境友好的方式从容易获得的起始材料生成复杂分子的合成方法的开发有益于健康科学的许多领域，包括那些专注于阐明生物化学途径和发现新药的领域。明确定义的有机金属配合物的催化作用为释放新的化学反应性提供了一种强有力的方法。这种催化反应性的利用反过来又依赖于对转化机制方面的坚定理解。例如，过渡金属催化剂通常通过将带有活化或离去基团的芳烃与亲核试剂如芳基硼酸偶联来实现交叉偶联反应性。相反，金（III）催化剂提供了简单芳烃的直接C-H活化以用于随后官能化的机会。然而，与促进直接C-H活化的其他过渡金属催化剂系统相比，金催化的途径提供了温和和高度选择性的对位选择性取代，但明显不太了解。定义在这样一个过程中所涉及的基本机制是必不可少的充分利用的催化潜力的金芳基C-H活化。重要的是，有有限的实验证据来支持arylgold（III）有机金属物种的明显中间性。这种以金为中心的中间体是对其他过渡金属的有用补充，因为它可以通过帕拉C-H活化直接获得简单的芳烃如甲苯，从而潜在地提供获得不同帕拉取代的芳烃产物的途径。 通过甲苯的对位芳基化的发展，本研究的目标是分离和表征催化相关的芳基金中间体，并阐明其潜在的催化成键反应。光谱技术和X射线晶体学将被用来阐明这种方法所涉及的机械过程。配体和取代基的影响也将被探测，以确定初始auration和随后的还原消除机制的动力学和热力学性质。的arylgold中间体的反应性也将进行研究，具体集中在甲苯的帕拉芳基化通过推定的AuI/AuIII氧化还原过程。一组竞争实验也将旨在阐明连续Au-C和C-C键形成所涉及的氧化和还原机制。 这种策略，基于芳基金（III）中间体的分离和表征，将提供一个方便的方法，仔细的金催化的机理研究，使使用简单的芳烃作为通用前体芳基亲电试剂。最终，这样的过程代表了对其他催化C-H活化平台的补充方法，并提供了一系列新的生物相关结构。具体而言，在本提案中概述的帕拉芳基化方法提供了一个重要的工具，用于探测蛋白质-蛋白质相互作用的性质和开发的互补和重要的结构类的分子用作药物。

DESCRIPTION (provided by applicant): The development of synthetic methods for the generation of complex molecules from readily available starting materials in an environmentally friendly manner benefits many areas of the health sciences, including those focused on the elucidation of biochemical pathways and the discovery of new pharmaceuticals. Catalysis by well-defined organometallic complexes offers a powerful approach to unlocking new chemical reactivity. The harnessing of this catalytic reactivity is in turn dependant on a firm understandin of the mechanistic aspects of a transformation. For example, transition metal catalysts often enable cross-coupilng reactivity by coupling arenes bearing activating or leaving groups with nucleophiles such as aryl boronic acids. Conversely, gold(III) catalysts offer the opportunity for direct C-H activation of simple arenes for subsequent functionalization. Compared to other transition metal catalyst systems that promote direct C-H activation however, the gold-catalyzed pathway offers mild and highly selective access to para-selective substitutions, but is significantly less understood. Defining the fundamental mechanisms involved in such a process is essential for fully harnessing the catalytic potential of gold in aryl C-H activation. Importanty, there is limited experimental evidence to support the apparent intermediacy of an arylgold(III) organometallic species. This gold-centered intermediate is a useful complement to that of other transition metals, as it can be accessed directly via para C-H activation to simple arenes such as toluene, potentially providing access to diverse para- substituted arene products. Through the development of a para-arylation of toluene, the goal of this research proposal is to isolate and characterize catalytically relevant arylgold intermediates and elucidate their potential for catalytic bond-forming reactivity. Spectroscopic techniques and x-ray crystallography will be used to elucidate the mechanistic processes involved in this approach. Ligand and substituent effects will also be probed to determine the kinetic and thermodynamic properties of the initial auration and subsequent reductive elimination mechanisms. The reactivity of the arylgold intermediate will also be investigated, with specific focus on the para arylation of toluene through a presumptive AuI/AuIII redox process. A set of competition experiments will also be aimed at elucidating the oxidative and reductive mechanisms involved in successive Au-C and C-C bond formation. This strategy, based on arylgold(III) intermediate isolation and characterization, will provide a convenient method for careful mechanistic study of gold catalysis, enabling the use of simple arenes as generic precursors to aryl electrophiles. Ultimately, such a process represents a complementary approach to other catalytic C-H activation platforms and offers access to a range of new, biologically relevant structures. Specifically, the para arylation method outlined in this proposal provides an important tool for probing protein-protein interactions in nature and for the development of a complementary and important structural class of molecules for use as medicines.