Underpinning Mechanistic Studies of NHC-Organocatalysis: A Breslow Intermediate Reactivity Scale

仿生化学涵盖了广泛的研究领域，这些领域的灵感来自于自然的不同方面。有机催化是有机化学的一个领域，其重点是设计有机小分子来模拟自然产生的‘酶’催化剂，形成‘仿生化学’的一个分支。酶是相对复杂的大分子，可以作为多种化学转化的高度特异性催化剂，对大多数生物过程都是必不可少的。尽管效率很高，但酶反应通常需要另一种称为辅助因子的分子来促进特定的转化。这一提议旨在对一类特定的简单有机分子，即N-杂环卡宾(NHCS)如何能够催化广泛的化学转化有一个基本的了解。自然界在几种生物转化中使用卡宾当量作为辅助因子，然而，有机催化领域最近的发展看到了一系列合成辅助因子类似物的设计，从而使人们能够获得更广泛的化学反应。通过了解基于NHC的过程中每一步的工作原理，以及了解每一步的速率如何随着催化剂结构的变化而变化，我们希望了解是什么控制了产品的形成类型。归根结底，对产品设计的控制对于允许合成获得化工和制药行业所需的各种支架至关重要。“有机催化”方法的主要优点之一是，典型的转化可以在相对温和、“更绿色”的条件下进行，从而提供可持续发展的好处。相比之下，使用金属进行催化通常需要更严格的条件，包括严格排除水分和氧气，以及使用通常昂贵且往往有毒的金属系统。然而，金属衍生催化剂体系的性能仍然远远优于有机催化类似物，在大多数有机催化反应中，高催化剂负载量仍然是必要的。因此，尽管有机催化方法具有明显的“绿色”优势，但到目前为止，有机催化方法在工业环境中的应用有限。特别是，对控制产品选择性的因素缺乏了解是有限的。更详细、更定量地了解催化剂结构和产品之间的相互关系，对于提高有机催化性能，从而形成具有竞争力的技术至关重要。这项提议将通过首次定义NHC的反应性范围，并将所开发的知识应用于一系列过程，从而对NHC中的关键成分--催化--即所谓的“布雷斯洛中间体”--有一个基本的定量了解。

Biomimetic chemistry encompasses a broad range of research areas which take inspiration from different aspects of Nature. Organocatalysis is an area of organic chemistry focused on the design of small organic molecules to mimic naturally occurring 'enzyme' catalysts and forms one branch of 'Biomimetic Chemistry'. Enzymes are relatively complex, large molecules that can be highly specific catalysts for a multitude of chemical transformations and are essential for most biological processes. Although efficient, enzyme reactions often need another molecule, known as a co-factor, to promote specific transformations. This proposal aims to develop a fundamental understanding of how one particular class of simple organic molecules, known as N-heterocyclic carbenes (NHCs), is able to catalyse a wide range of chemical transformations. Nature uses a carbene equivalent as a co-factor in several biological transformations, however, recent developments in organocatalysis have seen the design of a wide range of synthetic co-factor analogues thus allowing access to a broader range of chemical reactivities. By understanding how each step along an NHC-based process works, and by comprehending how the rate of each step changes with a change in catalyst structure, we hope to understand what controls the type of product formed. Ultimately, control over product design is essential to allow synthetic access to the vast range of scaffolds required by the chemical and pharmaceutical industries. One of the main advantages of the 'Organocatalysis' approach is that typical transformations may be performed under relatively mild, 'greener' conditions thus it offers sustainability benefits. By contrast, catalysis using metals usually requires more stringent conditions, including the rigorous exclusion of moisture and oxygen, as well as the use of typically expensive and frequently toxic metal systems. However, metal-derived catalyst systems still substantially outperform organocatalytic analogues and high catalyst loadings are still necessary in most organocatalytic reactions. As a result, there has been limited uptake to date of organocatalytic approaches in industry settings despite the clear 'green' advantages. In particular, the lack of understanding of factors controlling product selectivity is limiting. A more detailed, quantitative mechanistic understanding of the inter-relation between catalyst structure and product is essential to deliver enhanced organocatalytic performance and thus a competitive technology. This proposal will provide a fundamental quantitative understanding of a key component in NHC-catalysis - that of a so called "Breslow Intermediate" - by defining its reactivity scale for the first time, and applying the knowledge developed to a range of processes.