Development of a generally applicable catalytic direct amidation reaction

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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.