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现成的起始材料中生成复杂分子的合成方法的发展有利于健康科学的许多领域，包括那些专注于阐明生化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解锁新的化学反应性提供了一种强有力的方法。利用这种催化反应性反过来又依赖于对转化机理方面的坚定理解。例如，过渡金属催化剂通常通过将芳烃与亲核试剂（如芳基硼酸）偶联来实现交叉偶联反应性。相反，金（III）催化剂为简单芳烃的直接碳氢活化提供了后续功能化的机会。然而，与其他促进C-H直接活化的过渡金属催化剂体系相比，金催化的途径提供了温和和高选择性的准选择性取代途径，但人们对其知之甚少。确定这一过程的基本机制对于充分利用金在芳基C-H活化中的催化潜力至关重要。重要的是，有限的实验证据支持芳基金（III）有机金属物种的明显中间作用。这种以金为中心的中间体是对其他过渡金属的有益补充，因为它可以通过对碳氢键活化直接与简单芳烃（如甲苯）结合，从而有可能获得各种对取代芳烃产品。通过发展甲苯的对芳基化，本研究计划的目标是分离和表征催化相关的芳基金中间体，并阐明其催化成键反应性的潜力。光谱学技术和x射线晶体学将用于阐明这种方法所涉及的机制过程。还将探讨配体和取代基效应，以确定初始化和随后的还原消除机制的动力学和热力学性质。芳基金中间体的反应性也将被研究，特别关注通过假定的AuI/AuIII氧化还原过程对甲苯的对芳基化。一组竞争实验也将旨在阐明在Au-C和C-C键形成过程中涉及的氧化和还原机制。这种基于芳基金（III）中间体分离和表征的策略，将为细致的金催化机理研究提供一种方便的方法，使简单芳烃成为芳基亲电试剂的通用前体成为可能。最终，这种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。具体来说，本提案中概述的对芳基化方法为探索自然界中蛋白质-蛋白质相互作用以及开发用于药物的互补和重要结构类分子提供了重要工具。

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.