Catalytic generation and harnessing of reactive intermediates

反应性化学中间体是短寿命和高能量的分子。虽然利用这些物种的高水平反应性本身就要求很高，但潜在的好处是引人注目的。提供了巨大的机会来进行强大的新的化学和生物过程，在医学和材料开发等应用。本提案的目标是提供新的方法来利用活性中间体，从而促进具有巨大效用的反应。我们将重点关注被称为芳炔的中间体，其中苯环上的三个碳-碳（C-C）双键之一被C-C三键取代的分子。这个三键的断裂导致环变得高度紧张，因此具有高度反应性。芳基炔是非常有用的，因为它们能够快速生成在药物、农用化学品、材料和染料中常见的复杂的含苯环的产物。尽管最近取得了进展，但使用催化剂制备芳炔的理想方案的方法-少量促进反应但不消耗并因此可以回收的物质-非常罕见，并且不存在通用程序。因此，我们的长期目标将是开发一个通用的战略，催化芳炔合成，也利用丰富的化学品。从开发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，这有无数潜在的好处。（一个苯环与氧原子连接），与60，000商业上可用的类似物也提供了巨大的潜力，结构多样化。通过将活化基团连接到氧上，我们将研究能够将催化剂近端加成到苯环上的策略。然后，该催化剂可以与相邻的活化基团相互作用，以帮助从环上消除两种物质，产生芳炔。然后，催化剂将自由地添加到另一个活化的酚环上，从而建立循环。我们还将期待随后在要求苛刻的反应中利用芳炔的反应性，例如操纵无处不在的碳氢（C-H）键。打破一个特定的C-H键并用另一个原子取代氢是非常可取的，因为这意味着有价值的化合物可以直接从廉价的碳氢化合物材料中制备。然而，由于C-H键的强度，该过程非常困难，并且已经使用可能昂贵且有毒的金属催化剂取得了大多数进展。在这里，我们将利用高反应性的芳炔开发新的互补的无金属的方法，选择性的C-H键断裂，涉及初始氢离子转移从烃化合物上的芳炔。这个新的过程导致两个带相反电荷的分子，我们提出，通过这些电荷的重组，一个新的C-C键将被制成。对氢离子转移到芳炔上的研究将从两种组分在同一分子中的系统开始，它们紧密地结合在一起以帮助反应。随着我们的理解的增加，我们将看到它们是否可以成为不同分子的一部分，预计这将更具挑战性。最重要的是，我们已经有了初步的结果来支持这个独特的概念，之所以选择这个研究领域，是因为芳炔可以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，染料和农用化学品化合物，甚至可能制备目前无法获得的分子。这些进步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来造福更广泛的社会。

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.