Mechanism-led development of catalytic C-H functionalisation

催化C-H功能化的机制主导发展

• 批准号: EP/J021709/1
• 负责人: David Davies
• 金额: $ 41.97万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FJ021709%2F1
• 关键词: Mechanism; led; development; catalytic; functionalisation

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 30 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. More recent versions have coupled C-N or C-O bonds. These coupling reactions generally work well, however the efficiency of this individual step masks significant waste of time and energy, as well as problems with environmental sustainability. These problems arise because both C-X and C-M coupling partners ultimately derive from precursors that only contain C-H bonds and therefore require prior synthesis. This preactivation usually involves several steps, each with costly energy and purification implications. Moreover, the final coupling process itself eliminates salts (M-X) that must first of all be separated from the reaction products before disposal. This is a further costly and expensive process that often has a 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 functionalisation) 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 functionalisation 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 called heterocyclic compounds and 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. Although there is precedent for this type of catalytic C-H functionalisation in the scientific literature, 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 functionalisation 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.

C-C键和C-Y（Y = O，N）键的形成方法对于新分子的合成至关重要。在过去的30年里，钯催化的交叉偶联反应取得了巨大的进展，这在2011年诺贝尔奖的颁奖典礼上得到了认可。这些反应涉及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），而另一个偶联配偶体可以具有非碳中心，如锡、硼或锌（C-M键）。这两个配偶体的偶联以产生新的C-C键通常涉及钯催化剂。最近的版本有耦合的C-N或C-O键。这些偶联反应通常效果良好，然而，该单个步骤的效率掩盖了时间和能量的显著浪费，以及环境可持续性的问题。这些问题的出现是因为C-X和C-M偶联配偶体最终都来源于仅含有C-H键的前体，因此需要预先合成。这种预活化通常涉及几个步骤，每个步骤都涉及昂贵的能量和净化问题。此外，最终的偶联过程本身消除了在处置之前必须首先从反应产物中分离的盐（M-X）。这是另一种昂贵且昂贵的方法，其通常具有显著的环境影响。更理想的方法是直接使用未活化的含C-H的前体作为偶联配偶体。这些化合物容易获得且便宜。这种方法将避免制造C-X和M-C物质所需的昂贵且浪费的预活化以及M-X副产物的后处理清除的需要。直到最近，这种方法还没有被采用，因为基于C-H的前体通常是相当化学惰性的。然而，基于这种C-H物质的催化（催化C-H官能化）现在是可以实现的，这主要是由于最近的进展，其中已经理解了用过渡金属催化剂活化C-H键的方法。C-H官能化的一个关键点是在原料分子上的其他地方具有导向基团，使得它可以与金属催化剂相互作用，从而使C-H键足够接近以进行反应。由此形成的M-C键然后可以与其他底物进行反应以产生所需的C-C、C-N或C-O键。此外，如果这个新键与同一分子中的另一个原子形成，则形成环。这种含有N或O原子的环状化合物被称为杂环化合物，作为药物和农用化学品的主要成分发挥着关键作用。此外，它们本身通常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非常重要。因此，至关重要的是，杂环化合物的合成是尽可能有效的;此外，对具有不同性质的广泛的杂环的需求取决于新的、有效的合成方法的开发。 虽然在科学文献中有这种类型的催化C-H官能化的先例，但到目前为止，对控制这种反应性的原因几乎没有了解。因此，可以制备的物质的范围是有限的，催化剂还不是有效的，并且对反应的选择性知之甚少。为了改善这种情况，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的结合来提供这一点。通过了解控制反应性和选择性的因素，我们将能够设计新的，更有效的催化剂，并扩大催化C-H官能化方法的范围。最终目标是提供一套灵活的高效合成工具，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。

项目成果

Tetraphenylcyclopentadienyl rhodium complexes in stoichiometric and catalytic CH functionalization

• DOI: 10.1016/j.jorganchem.2018.09.005
• 发表时间: 2019-01
• 期刊: Journal of Organometallic Chemistry
• 影响因子: 2.3
• 作者: D. Davies;Charles E. Ellul;Kuldip Singh

Steric effects on acetate-assisted cyclometallation of meta-substituted N-phenyl and N-benzyl imidazolium salts at [MCl2Cp*]2 (M = Ir, Rh).

间位取代的 N-苯基和 N-苄基咪唑鎓盐在 [MCl2Cp*]2 (M = Ir, Rh) 上的乙酸辅助环金属化的空间效应。

• DOI: 10.1039/d1dt02677a
• 发表时间: 2021
• 期刊: 2003)
• 作者: Davies DL

Combined experimental and computational investigations of rhodium-catalysed C - H functionalisation of pyrazoles with alkenes.

• DOI: 10.1002/chem.201405550
• 发表时间: 2015-02-09
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Algarra AG;Davies DL;Khamker Q;Macgregor SA;McMullin CL;Singh K;Villa-Marcos B
• 通讯作者: Villa-Marcos B