Development of a generally applicable catalytic direct amidation reaction

酰胺官能团的形成是学术实验室和化学工业中有机分子合成中最常见的过程之一。虽然存在许多用于该反应的有效方法，但所有广泛使用的方法都需要使用低效的试剂，这会产生大量的废物，其中许多是危险的或有毒的。通常，酰胺化试剂提供了一种活化羧酸的方法，以使其对胺具有足够的反应性，从而形成所需的酰胺。理论上，使用催化剂可以实现相同的过程，同时去除作为副产物的水分子。虽然在鉴定用于酰胺合成的有效催化剂方面已经取得了一些进展，但是由于这样的方法通常比使用试剂的现有方法效率更低的事实，这些方法未能被广泛采用-通常是因为催化方法在反应和后处理程序中都需要更大量的溶剂。大多数酰胺化催化剂的另一个限制是，它们在可用于制备酰胺的范围方面相当有限，我们最近报道了迄今为止开发的最有效的催化酰胺化反应，并证明它可以应用于一些工业相关分子的多克合成。该项目的目的是开发一个详细的机制理解这一反应，并使用它来设计新颖的，容易获得的，有效的催化剂酰胺化，可以应用于几乎任何酰胺合成。我们还将确定有效的程序，使他们能够成为广泛采用的'去'的方法，使酰胺在任何有机化学实验室。我们将采用实验和计算方法来获得催化酰胺化反应途径的详细机理理解，并使用这种理解来设计新的催化剂和程序。此外，我们将开发一个全面的催化酰胺化“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，促进全球化学界对这些反应的吸收，并导致大量减少化学废物。

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.