理论计算研究过渡金属-有机分子协同催化的酮的C-H或C-C键官能团化的催化机理及新催化体系的发展

C–H bond is ubiquitous in organic molecules. The construction of C–C and C–heteroatom bonds via directed C−H bond functionalization, which could offer an atom- and step-economic synthetic method to access complex molecules, is appreciated to be the “holy grail” in the area of transition metal (TM) catalysis, attracting extensive research effort. The addition of a C–H bond of ketone/aldehyde to olefin represents such a family of C–C bond forming reactions. Metal-organic cooperative catalysis (MOCC) which combines a TM catalyst and an organic cocatalyst to functionalize a C–H bond cooperatively is a conceptually new strategy proposed for aldehyde C(sp2)–H bond functionalization to avoid decarbonylation side reaction in hydroacylation of olefin and aldehyde. The strategy later on was also found to be effective in promoting ketone C-C bond activation/functionalization. Despite these early successes, the functionalization of less reactive C(sp3)–H bond of ketone remained to be a challenge for a relatively long period. Recently, Dong et al. have advanced the strategy greatly. By elaborating the two components of MOCC systems, they accomplished the challenging C(sp3)–H bond functionalization of ketone, achieving Cα-alkylation of ketones with simple olefins, and synthesized bridged ring systems from cyclobutanones and olefins via MOCC-mediated C–C bond activation of ketone. Although the MOCC strategy has demonstrated its power in organic synthesis, relatively less attention has been paid to this strategy, leaving room for further development. Herein we propose using computational chemistry to deeply understand the mechanisms of MOCC strategy by choosing experimentally realized MOCC-based catalytic reactions as representatives, including ketone Cα-alkylation with olefins via directed C(sp3)–H bond functionalization and the catalytic reactions via activating ketone C–C bond. In addition to understanding the mechanisms of MOCC, the computed mechanism will be used to solve experimental puzzles and to serve as a base for mechanism-based development. After deeply understanding the mechanisms, we will use computation as an “experimental” mean to explore new MOCC chemistry: designing new organic cocatalysts, expanding the hitherto sole use of rhodium metal to other TMs such as cobalt and nickel, expanding the hitherto exclusive use of the Rh(I)/Rh(III) redox cycling to other redox cycling of TMs such as Co(0)/Co(II), Ni(0)/Ni(II), and Ni(II)/Ni(IV) manifolds. On the basis of the above studies, we will ultimately challenge the C(sp3)–H bond functionalization of more general ketone (such as linear ketones and cyclohexanone) which have been attempted experimentally but are not efficient and develop new MOCC systems to carry out asymmetric ketone C-C bond activation based transformations with higher yield and enantiomeic selectivity. We expect that these studies will promote the enrichment and development of MOCC chemistry.

选择性催化活化C-H生成新的C-X(X=C或杂原子)提供一种“原子经济”、简捷的合成方法。醛/酮的C-H与烯烃的加成反应属于这类反应。早期提出的金属-有机分子协同催化(MOCC)策略能有效地实现醛的C(sp2)–H官能团化和基于C-C活化的酮与烯烃的反应, 但不能完成酮的C(sp3)–H官能团化。基于MOCC, 实验近来实现了酮与烯烃的α-C(sp3)–H烷基化和C–C活化的[4+2]偶联反应。虽然MOCC在合成化学中崭露头角，但没有得到深入研究和发展。我们拟用计算化学的方法深入研究实验实现的MOCC催化的C–H活化和C–C活化反应的机理，解释实验上的困惑。基于机理认识，我们将进一步以计算为“实验”手段设计新的有机共催化剂、拓展现在唯一使用的铑和铑(I)/铑(III)氧化还原循环到其它金属及氧化还原循环并探索实现更具挑战性酮的C(sp3)–H官能团化。该研究将促进MOCC化学的丰富和发展。

发展基于储存丰富的廉价过渡金属的催化反应是实现绿色化学重要策略。由于催化过程的复杂性及第一过渡金属络合物存在多个可能的自旋电子态, 实验难以对催化机理进行深刻认识, 理论计算可以弥补实验的不足甚至优于实验。根据研究计划, 开展过渡金属(主要是第一过渡金属)催化反应的机理研究, 主要工作如下: 1)研究仿生加氧酶钴(II)-O2过氧化物活化腈加氧酶的化学活性,发现类似[1,3]-sigmatropic重排反应机理断裂O-O键的新模式; 2)研究无外碱镍催化的酸氟Suzuki−Miyaura偶联反应, 发现新的分步转金属机理较传统的协同机理要有利得多, 计算预言加入CsF添加剂可能实现无外碱的酸氯或酸溴的Suzuki−Miyaura偶联反应; 3)研究[Ti(IV)]=NPh催化的偶氮苯与烯烃和炔烃的碳胺化反应, 发现钛以氧化还原中性(Ti(IV)/Ti(IV)实现催化循环, 而不是实验化学家设想的按Ti(IV)/Ti(II)催化循环进行。提出发展钛催化反应的策略。4)对比研究PNP-Mn/PNP-Ru螯合物催化的腈与一/二级醇烯基化反应, 发现活化腈和经过类似OR-阴离子活化C-H键的新模式, 提出统一机理, 深刻认识这两类反应的催化根源。5)研究在有氧条件下钯催化的杂环化合物与tBuNC发生C-H键官能团化反应, 揭示该策略能克服挑战性的”杂原子问题”的根源: 反应物中(PyCONHOMe)甲氧基酰胺容易被氧气氧化, 原位生成活性L2Pd(II)X2中间体, 避免金属与环内杂原子配位, 因此反应物(PyCONHOMe)可通过oxidase 机理进行反应, 阻止破坏性的oxygenase反应。(6)发展了一系列基于高价碘或高价硫的[3,3]-, [5,5]-sigmatropic 重排反应, 实现无催化剂的多种芳基官能团化反应。通过对上述反应的热力学和动力学进行计算, 得到反应的最佳通道, 通过对关键过渡态和中间体的几何结构和电子结构的分析, 认识化学键生成或断裂的根源, 从而发现新的催化模式, 帮助实验改进或发现新的催化系统。在化学类主流杂志发表论文22篇, 包括J. Am. Chem. Soc. (1篇), Angew. Chem. Int. Ed. (2篇), Chem. Sci. (1 篇), ACS catalysis (1 篇)。