Development of a generally applicable catalytic direct amidation reaction

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.

The synthesis of amides is commonplace throughout all areas of organic chemistry and the synthesis of amides from carboxylic acids and amines is perhaps the most commonly used organic chemical reaction in both academic and industrial laboratories. Furthermore, it has been identified as one of the most common reactions used in the large-scale synthesis of active pharmaceutical intermediates; amides are also ubiquitous in many other industrially important chemicals including agrochemicals, fine chemicals and organic polymers. Nevertheless, current methods for amide synthesis are inherently inefficient, relying on the use of stoichiometric reagents to mediate the loss of water from the reaction, and consequently leading to the production of large quantities of waste products. A practical catalytic method for amide synthesis could render the reaction highly efficient with water as the only byproduct. Whilst catalytic methods for amide synthesis do exist, they have failed to become widely adopted. This is largely a consequence of the poor scope of these reactions, but it is also due to the fact that they are often less efficient than reagent-based methods. In this proposal, we will address these issues by developing highly effective amidation catalysts which can be applied to a wide range of substrates. We have recently reported the most efficient catalytic amidation reaction yet developed, and in this project we will develop a detailed mechanistic understanding of the reaction to enable the design of more reactive catalysts that can be applied to almost any amidation process. By developing efficient and widely applicable catalytic amidation reactions, and crucially, by promoting their widespread adoption throughout the chemistry community, we will significantly reduce the waste produced by this common everyday chemical transformation. This will lead to efficiency savings in the preparation of molecules in the laboratory, but also to highly significant gains in the production of industrially important chemical products. This will have considerable environmental benefits by reducing the quantity of hazardous chemical waste produced, increasing the sustainability of the processes and reducing the associated carbon emissions. This will provide economic and environmental benefits to the UK, providing important efficiencies in a major UK industry and contributing to a reduction in greenhouse gas emissions.
The industrial relevance of the proposed research is evidenced by the inclusion of two major UK pharmaceutical companies and one major agrochemical company as project partners. They will provide useful scientific input into the research in terms of identifying industrially relevant targets and/or structural motifs which cannot currently be made using efficient catalytic amidation methods, enabling us to challenge the new methodologies developed in this project. This will help ensure rapid impact of the work through uptake of the new catalytic amidation processes in industries of high importance to the UK economy.