Catalytic generation and harnessing of reactive intermediates

活性化学中间体是寿命短、能量高的分子。虽然开发这些物种的高水平反应性本身就要求很高，但潜在的好处是令人信服的。在医药和材料开发等方面的应用，提供了进行强大的新的化学和生物工艺的巨大机会。这项建议的目标是提供新的方法来利用活性中间体，从而促进反应的巨大用途。我们将集中在被称为芳烃的中间体，即苯环上的三个碳-碳(C-C)双键中的一个被C-C三键取代的分子。加入这种三键会导致环变得高度紧张，从而具有高度的活性。芳烃非常有用，因为它们能够快速生成复杂的苯环产品，这些产品在制药、农用化学品、材料和染料中很常见。尽管最近取得了进展，但理想情况下使用催化剂制备芳烃的方法极其罕见，而且没有通用的程序。催化剂是一种少量的物质，可以促进反应，但不会被消耗，因此可以回收利用。因此，我们的长期目标将是开发一种通用的催化芳烃合成策略，同时也利用丰富的化学品。从开发应用于医疗保健和制造业的新化学反应，到减少废物产生和使用更丰富的起始材料的环境问题，有无数潜在的好处。这一过程的廉价大宗化学品的一个例子是苯酚(一个连接了氧原子的苯环)，60,000个商业上可用的类似物也提供了巨大的结构多样化潜力。通过将活化基团连接到氧上，我们将研究使催化剂能够近端添加到苯环上的策略。然后，该催化剂可以与相邻的活化基团相互作用，以帮助从环上消除这两种物种，生成芳烃。然后催化剂将自由地添加到另一个活化的苯酚环上，从而建立循环。我们还将寻求随后在要求苛刻的反应中利用芳烃的反应性，例如操纵普遍存在的碳-氢(C-H)键。打破特定的C-H键并用另一个原子取代氢原子是非常可取的，因为这意味着可以直接从廉价的碳氢化合物材料中制造出有价值的化合物。然而，由于C-H键的强度，这一过程非常困难，而且大多数进展是使用昂贵且有毒的金属催化剂取得的。在这里，我们将利用芳烃的高反应性来开发新的互补的无金属方法来选择性地打破C-H键，包括从烃类化合物到芳烃的初始氢离子转移。这一新的过程导致了两个相反电荷的分子，我们认为通过这些电荷的复合，将形成一个新的C-C键。氢离子转移到芳烃上的研究将从两个组分位于同一分子中的系统开始，它们紧密结合在一起以帮助反应。随着我们理解的加深，我们将看到它们是否可以是不同分子的一部分，这预计将是更具挑战性的。至关重要的是，我们有了支持这一独特概念的初步结果。之所以选择这个研究领域，是因为芳烃能够快速构建有用的复杂分子。开发这些新方法将使化学家能够更有效地制造药物、聚合物、染料和农用化合物，甚至可能制备目前无法获得的分子。这些进展可以通过开发治疗疾病的药物、除草剂和杀虫剂来改善全球粮食生产，并通过利用更可持续的化学原料，使更广泛的社会受益。

Reactive chemical intermediates are short-lived and high-energy molecules. Whilst it is inherently demanding to exploit the high levels of reactivity of these species, the potential benefits are compelling. Great opportunities are afforded to conduct powerful new chemical and biological processes, with applications in medicine and materials development amongst others. The goal of this proposal is to provide new methods to harness reactive intermediates and hence facilitate reactions of immense utility.We will focus on intermediates called arynes; molecules in which one of the three carbon-carbon (C-C) double bonds in a benzene ring has been replaced with a C-C triple bond. Incorporating this triple bond causes the ring to become highly strained and thus highly reactive. Arynes are extremely useful as they enable rapid generation of complex benzene ring-containing products that are common in pharmaceuticals, agrochemicals, materials and dyes. Despite recent advances, methods for an ideal scenario whereby arynes are prepared using a catalyst - a small amount of a substance that promotes a reaction but is not consumed and can thus be recycled - are extremely rare and no general procedure exists. As a result, our long term goal will be to develop a general strategy for catalytic aryne synthesis that also exploits abundant chemicals. There are myriad potential benefits, from the development of new chemical reactions for application in healthcare and manufacturing, to the environmental issues of reduced waste production and the use of more plentiful starting materials.One example of a cheap bulk chemical for this process is phenol (a benzene ring with an oxygen atom attached), with 60,000 commercially available analogues also offering great potential for structural diversification. By attaching an activating group to the oxygen, we will investigate strategies that enable the proximal addition of a catalyst onto the benzene ring. This catalyst can then interact with the adjacent activating group to aid elimination of the two species from the ring, producing an aryne. The catalyst will then be free to add to another activated phenol ring and thus the cycle is established.We will also look to subsequently exploit the reactivity of arynes in demanding reactions, such as manipulating the ubiquitous carbon-hydrogen (C-H) bond. Breaking a particular C-H bond and replacing that hydrogen with another atom is extremely desirable, as it means valuable compounds can be made directly from cheap hydrocarbon materials. However, this process is very difficult due to the strength of the C-H bond and most progress has been made using metal catalysts that can be expensive and toxic. Here we will utilise the high reactivity of arynes to develop new complementary metal-free methods for selective C-H bond breaking, involving an initial hydrogen ion transfer from the hydrocarbon compound onto the aryne. This novel process results in two oppositely charged molecules, and we propose that via the recombination of these charges, a new C-C bond will be made. Studies into hydrogen ion transfer onto an aryne will commence with systems where the two components are in the same molecule, tied together in close proximity to aid the reaction. As our understanding increases, we will see whether they can be part of different molecules, which is anticipated to be more challenging. Crucially, we have a preliminary result to support this unique concept.This research area has been chosen because arynes enable rapid construction of useful complex molecules. Developing these new methods will enable chemists to make drug, polymer, dye and agrochemical compounds more efficiently, and maybe even prepare molecules that are currently inaccessible. These advances can benefit wider society through the development of drugs to treat illnesses, herbicides and pesticides to improve global food production and by harnessing more sustainable chemical feedstocks.