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

NHC 有机催化的基础机制研究：Breslow 中级反应量表

• 批准号: EP/S020713/1
• 负责人: AnnMarie O'Donoghue
• 金额: $ 55.55万
• 依托单位: Durham University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FS020713%2F1
• 关键词: Underpinning; Mechanistic; Studies; NHC; Organocatalysis

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.

仿生化学涵盖了广泛的研究领域，从自然的不同方面汲取灵感。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天然存在的“酶”催化剂，并形成“仿生化学”的分支。酶是相对复杂的大分子，可以是许多化学转化的高度特异性催化剂，并且是大多数生物过程所必需的。虽然酶反应是有效的，但通常需要另一种分子，称为辅因子，以促进特定的转化。该提案旨在从根本上了解一类特殊的简单有机分子，称为N-杂环卡宾（NHC），如何能够催化广泛的化学转化。自然界使用卡宾等价物作为几种生物转化中的辅因子，然而，有机催化的最新发展已经看到了广泛的合成辅因子类似物的设计，从而允许获得更广泛的化学反应性。通过了解NHC工艺的每一个沿着步骤是如何工作的，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所形成的产品类型。最终，对产品设计的控制对于允许合成获得化学和制药工业所需的大量支架至关重要。“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，“绿色”的条件下进行，因此它提供了可持续性的好处。相比之下，使用金属的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经常有毒的金属系统。然而，金属衍生的催化剂体系仍然显著优于有机催化类似物，并且在大多数有机催化反应中仍然需要高催化剂负载。因此，尽管有机催化方法具有明显的“绿色”优势，但迄今为止在工业环境中的吸收有限。特别是，对控制产品选择性的因素缺乏了解是限制性的。对催化剂结构和产物之间的相互关系的更详细、定量的机理理解对于提供增强的有机催化性能和因此具有竞争力的技术是必不可少的。该提案将提供一个基本的定量理解的关键组成部分NHC催化-即所谓的“Breslow中间体”-通过定义其反应性规模的第一次，并应用知识开发的一系列过程。

项目成果

Triazolium Salt Organocatalysis: Mechanistic Evaluation of Unusual Ortho-Substituent Effects on Deprotonation

• DOI: 10.3390/catal11091055
• 发表时间: 2021-08
• 期刊: Catalysts
• 影响因子: 3.9
• 作者: P. Quinn;Matthew S. Smith;Jiayun Zhu;David R. W. Hodgson;A. O’Donoghue

Cover Feature: Kinetic and Structure-Activity Studies of the Triazolium Ion- Catalyzed Intramolecular Stetter Reaction (26/2021)

封面专题：三唑离子催化分子内 Stetter 反应的动力学和构效研究 (26/2021)

• DOI: 10.1002/ejoc.202100644
• 发表时间: 2021
• 期刊: European Journal of Organic Chemistry
• 影响因子: 2.8
• 作者: Collett C

Kinetic and Structure-Activity Studies of the Triazolium Ion- Catalyzed Intramolecular Stetter Reaction

• DOI: 10.1002/ejoc.202100384
• 发表时间: 2021-05-31
• 期刊: EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
• 影响因子: 2.8
• 作者: Collett, Christopher J.;Young, Claire M.;Smith, Andrew D.
• 通讯作者: Smith, Andrew D.

Rate and equilibrium constants for the addition of triazolium salt derived N-heterocyclic carbenes to heteroaromatic aldehydes.

• DOI: 10.1039/d2sc05704b
• 发表时间: 2022-12-21
• 期刊: Chemical science
• 影响因子: 8.4

The Role of the Fused Ring in Bicyclic Triazolium Organocatalysts: Kinetic, X-ray, and DFT Insights.

• DOI: 10.1021/acs.joc.1c03073
• 发表时间: 2022-03-18
• 期刊: The Journal of organic chemistry
• 作者: Zhu J;Moreno I;Quinn P;Yufit DS;Song L;Young CM;Duan Z;Tyler AR;Waddell PG;Hall MJ;Probert MR;Smith AD;O'Donoghue AC
• 通讯作者: O'Donoghue AC