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使健康科学的许多领域受益，包括那些侧重于阐明生化途径和发现新药物的领域。定义良好的有机金属络合物的催化作用为揭示新的化学反应活性提供了一种强有力的途径。这种催化反应性的利用反过来又取决于对转化的机械方面的坚定理解。例如，过渡金属催化剂通常通过将含有活化基团或离开基团的芳烃与芳基硼酸等亲核试剂偶联来实现交叉偶联反应。相反，金(III)催化剂提供了直接C-H活化简单芳烃的机会，以便随后的官能化。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对位选择性取代反应，但人们对此知之甚少。确定这一过程中涉及的基本机制对于充分利用金在芳基C-H活化中的催化潜力是至关重要的。重要的是，支持芳基金(III)有机金属物种的表面中间体的实验证据有限。这种以金为中心的中间体是对其他过渡金属中间体的有益补充，因为它可以通过对C-H活化直接进入甲苯等简单芳烃，从而有可能获得各种对位取代芳烃产品。通过开发甲苯的对位芳基化反应，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，并阐明它们催化成键反应的潜力。光谱技术和X射线结晶学将被用来阐明这种方法所涉及的机理过程。还将探讨配体和取代基的影响，以确定初始反应和随后的还原消除机理的动力学和热力学性质。还将研究芳基金中间体的反应性，特别是甲苯通过假定的AUI/AuIII氧化还原过程的对位芳基化反应。一系列竞争实验也将旨在阐明在连续的Au-C和C-C键形成中涉及的氧化和还原机制。这一策略基于芳基金(III)中间体的分离和表征，将为仔细研究金的催化机理提供一种方便的方法，使简单的芳烃能够用作芳基亲电体的通用前体。最终，这一过程代表了对其他催化C-H激活平台的补充，并提供了一系列新的生物相关结构的途径。具体地说，本提案中概述的对位芳基化方法为探索自然界中的蛋白质-蛋白质相互作用以及开发用于药物的补充和重要的结构类分子提供了重要的工具。

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.