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

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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.