Catalytic Ambiphilic C-H Activation: Mechanism and Exploitation

C-C和C-Y(Y=O，N)键的形成方法是合成新分子的关键。在过去的20年里，钯催化的交叉偶联反应取得了巨大的进展，这一点在2011年的诺贝尔奖中得到了认可。这些反应包括将两个有机分子连接在一起，其中一个具有碳和卤素之间的键(C-X键)，而另一个偶联伙伴可能具有非碳中心，如锡、硼或锌(C-M键)。这两个伙伴的偶联通常涉及到钯催化剂，以获得新的C-C键。后来的版本涉及形成C-N或C-O键。这种耦合反应通常效果良好，然而，这一单独步骤的效率掩盖了大量时间和精力的浪费以及环境可持续性的问题。这些问题的出现是因为两个偶联伙伴最终都来自只包含C-H键的前体，因此需要事先合成，这通常涉及几个步骤，每个步骤都有昂贵的能量和纯化影响。此外，最终的偶合过程本身消除了在处置之前必须首先从反应产物中分离出来的盐(进一步的昂贵和昂贵的过程)，这往往会对环境产生重大影响。更可取的办法是直接使用未活化的含有C-H的前体作为偶联伙伴。这种化合物很容易买到，而且很便宜。这种方法将避免制造C-X和M-C物种所需的昂贵和浪费的预活化，以及M-X副产品的后处理清理。直到最近，这种方法才被采用，因为基于C-H的前体通常在化学上是相当惰性的。然而，基于这种C-H物种的催化(催化C-H活化)现在是可以实现的，这主要是因为最近的进展，人们已经了解了用过渡金属催化剂激活C-H键的方法。C-H活化的一个关键点是在原料分子上的其他地方有一个导向基团，这样它就可以与金属催化剂相互作用，从而使C-H键足够接近，从而进行反应。这样形成的M-C键然后可以与其他底物反应以产生所需的C-C、C-N或C-O键。此外，如果相反，这种新的键与同一分子中的另一个原子形成，那么就形成了一个环。这种含有N或O原子的环状化合物是杂环化合物，它们作为药物和农用化学品的主要成分发挥着关键作用。此外，它们本身往往具有有趣的光学和电学特性，这些特性在一系列技术应用中都很重要。因此，尽可能有效地合成杂环化合物是至关重要的；此外，对具有不同性质的广泛杂环的需求取决于为它们的合成开发新的、有效的方法。在科学文献中，这种类型的催化C-H活化有几个先例，然而，到目前为止，关于是什么控制这种反应活性的了解很少。因此，可以制备的物种范围有限，催化效率还不高，对反应的选择性也知之甚少。要改善这种情况，需要更深入地了解这些系统是如何工作的。我们的目标是通过实验研究和计算建模相结合的方式来提供这一点。通过了解控制反应活性和选择性的因素，我们将能够设计新的、更有效的催化剂，并扩大催化C-H活化方法的范围。最终目的是提供一套灵活有效的合成工具，化学家将能够使用这些工具以环境可持续的方式制造各种重要的杂环。

Methods for the formation of C-C and C-Y (Y = O, N) bonds are crucial for the synthesis of new molecules. In the last 20 years there have been huge advances in Pd-catalysed cross-coupling reactions and this was recognized in the award of the 2011 Nobel Prize. These reactions involve joining together two organic molecules, one of which features a bond between carbon and a halogen (a C-X bond) while the other coupling partner may feature a non-carbon centre such as tin, boron or zinc (a C-M bond). The coupling of these two partners to give a new C-C bond usually involves a palladium catalyst. Later versions involved forming C-N or C-O bonds. This coupling reaction generally works well, however the efficiency of this individual step masks significant waste of time and energy as well problems with environmental sustainability. These problems arise because both coupling partners ultimately derive from precursors that only contain C-H bonds and therefore require prior synthesis that usually involves several steps each with costly energy and purification implications. Moreover the final coupling process itself eliminates salts that must first of all be separated from the reaction products (a further costly and expensive process) before disposal, often with significant environmental impact. A far more desirable approach would be to use the unactivated C-H containing precursors directly as the coupling partners. Such compounds are readily available and cheap. This approach would circumvent the need for the costly and wasteful preactivation that is required to make C-X and M-C species, as well as the post processing clean up of M-X by-products. Until very recently this approach has not been adopted as C-H based precursors are usually rather chemically inert. However, catalysis based on such C-H species (catalytic C-H activation) is now within reach, mainly due to recent advances where the means to activate the C-H bond with a transition metal catalyst have been understood. A key point in C-H activation is to have a directing group elsewhere on the feedstock molecule so that it can interact with the metal catalyst and so bring the C-H bond close enough to react. The M-C bond that is thus formed can then undergo reactions with other substrates to produce the desired C-C, C-N or C-O bond. Moreover, if instead this new bond is formed with another atom in the same molecule then a ring is formed. Such cyclic compounds containing an N or O atom are heterocyclic compounds and these play a key role as major constituents of pharmaceuticals and agrochemicals. In addition they often have interesting optical and electrical properties in their own right that are important in a range of technological applications. It is therefore crucial that the synthesis of heterocyclic compounds is as efficient as possible; moreover the need for a wide range of heterocycles with different properties depends upon the development of new, efficient methods for their synthesis.There are several precedents for this type of catalytic C-H activation in the scientific literature, however to date there is little understanding of what controls this reactivity. Thus the range of species that can be made is limited, the catalysis is not yet efficient and the selectivity of the reaction is poorly understood. To improve this situation requires a deeper understanding of how these systems work. We aim to provide this here through a combination of experimental studies and computational modeling. By understanding the factors that control reactivity and selectivity we will be able to design new, more efficient catalysts and also to widen the scope of the catalytic C-H activation methodology. The ultimate aim is to provide a flexible set of efficient synthetic tools that chemists will be able to use to make a wide range of important heterocycles in an environmentally sustainable manner.