Development of a generally applicable catalytic direct amidation reaction

酰胺官能团的形成是在学术实验室和化学工业中合成有机分子的最常见的过程之一。虽然有许多有效的方法来进行该反应，但所有广泛使用的方法都需要使用低效的试剂，这些试剂会产生大量的废物，其中许多是危险的或有毒的。作为这些问题的结果，酰胺的形成是产生大量化学废物的原因。通常，酰胺化试剂提供了一种激活羧酸的方法，以便使其与胺充分反应以形成所需的酰胺。从理论上讲，同样的过程可以通过使用催化剂来实现，同时将水分子作为副产品进行去除。虽然在确定有效的酰胺合成催化剂方面取得了一些进展，但由于这些方法的效率往往低于现有的使用试剂的方法--通常是因为催化方法在反应和加工过程中都需要更多的溶剂，因此这些方法没有得到广泛采用。大多数酰胺化催化剂的另一个局限性是它们可以用来制备酰胺的范围相当有限。我们最近报道了迄今开发的最有效的催化酰胺化反应，并证明了它可以应用于一些工业相关分子的多克合成。本项目的目的是对该反应的机理有一个详细的了解，并以此为基础设计可应用于几乎任何酰胺合成的新型、易获得和有效的酰胺化催化剂。我们还将确定它们的有效使用程序，使它们能够在任何有机化学实验室中被广泛采用为制造酰胺的“首选”方法。我们将使用实验和计算方法来获得对催化酰胺化反应途径的详细机理了解，并利用这些了解来设计新的催化剂和程序。此外，我们将制定一份全面的催化酰胺化“用户指南”，使任何化学家都能迅速确定特定酰胺化反应的最佳催化剂和程序，促进这些反应在全球化学界的应用，并导致化学废物的大幅减少。

The formation of an amide functional group is one of the most common processes used in the synthesis of organic molecules both in academic labs and in the chemical industry. Whilst many effective methods exist for this reaction, all of the widely used approaches require the use of inefficient reagents which generate large quantities of waste products, many of which are hazardous or toxic. As a consequence of these issues, amide formation is responsible for the generation of large quantities of chemical waste.Commonly, amidation reagents provide a method for activating a carboxylic acid in order to make it sufficiently reactive towards an amine to form the desired amide. In theory, the same process can be achieved using a catalyst with removal of a molecule of water as a byproduct. Whilst some progress has been made on the identification of efficient catalysts for amide synthesis, such methods have failed to become widely adopted as a consequence of the fact that they are often less efficient than the existing approaches using reagents - usually because the catalytic methods require larger quantities of solvent in both the reaction and work-up procedure. A further limitation of most amidation catalysts is that they are fairly limited in scope in terms of the amides they can be used to prepare.We have recently reported the most efficient catalytic amidation reaction yet developed, and demonstrated that it can be applied to the multigram synthesis of some industrially relevant molecules. The aim of this project is to develop a detailed mechanistic understanding of this reaction, and to use that to design novel, readily accessible, and effective catalysts for amidation which can be applied in almost any amide synthesis. We will also identify efficient procedures for their use which can enable them to become widely adopted as the 'go to' method for making an amide in any organic chemistry laboratory. We will employ experimental and computational approaches to obtain a detailed mechanistic understanding of catalytic amidation reaction pathways, and use this understanding to design the new catalysts and procedures. Furthermore, we will develop a comprehensive 'user guide' to catalytic amidation which should enable any chemist to rapidly identify the best catalyst and procedure for a particular amidation reaction, facilitating the uptake of these reactions throughout the global chemistry community and leading to large reductions in chemical waste.