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

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.

This project involves fundamental research focused on a topical area of international attention. Our proposed research will establish an underpinning understanding of the reactivity of the archetypal "Breslow intermediate", which is the linch pin of the state-of-the-art area of synthetic catalysis research, that of carbene-based organocatalytic reactions. This project will provide impact in the following areas:

1. Knowledge: This project will deliver fundamental and innovative knowledge advances, contributing to our understanding of NHC-based catalytic reaction processes that to date have relied upon empirical observations to guide reaction development and understanding. The new BI Reactivity Scale will be used broadly by synthetic chemists in many research areas who utilise the unique organic chemistry enabled by NHC/BAC catalysis, thus fostering broader research development. The application of the new quantitative data to developing reaction understanding and optimisation will be showcased by specifically addressing key mechanistic and chemoselectivity anomalies.

2. People: As identified by a consortium of key industrialists in a 2017 'RSC Chemistry World' article, there has emerged a skills shortage in the pharmaceutical and agrochemical industries of synthetic chemists trained with a quantitative mindset. This involves the abilities to break complex reactions into individual parts, gather data from application of different methods to inform mechanism and the collective usage of this information to make quantitative predictions to inform process development. The PDRAs trained on this project will specifically meet this skills shortage thus making them highly competitive in industrial as well as the academic jobs markets. Through working both individually and as a team the PDRAs will also be endowed with a valuable set of general transferable and employment-related skills always demanded by employers.

3. Knowledge Transfer: Organocatalysis offers significant potential to industry, however, is under-utilised largely owing to a lack of fundamental quantitative understanding. Our quantitative study of 'real substrates and catalysts' in NHC and BAC organocatalysis will address this gap. To aid knowledge transfer we will (i) hold a specific workshop targeting early to mid-career scientists to showcase the power of cutting-edge mechanistic and kinetic analysis of catalytic reactions targeted at users within the UK and internationally. This will develop a network of UK-based researchers, from academia and industry, with interests in using kinetic analysis of mechanism for reaction understanding, and promote transfer of knowledge in this area; (ii) promote knowledge transfer through CDT engagement; and (iii) demonstrate impact through knowledge translation through Durham Research and Innovation Services (RIS) and the Knowledge Transfer Centre (KTC) at St Andrews.

4. Society and Economy: Catalysis plays a key role in society; it currently contributes over £50 billion per year to the UK economy and is a key enabling technology. The development of a fundamental understanding of catalytic processes leads to more effective procedures that minimise waste. The increasing popularity of organocatalysis stems in part from sustainable chemistry advantages. With no requirement for expensive, sensitive metal-based catalysts, organocatalytic processes generally operate in more user-friendly, 'green' conditions. Although it is hard to predict where the specific developments in this project will have direct societal and economic impact, it is clear that any major advances in catalysis will broadly benefit society in terms of health and quality of life. We will also diversify impact through public engagement and outreach channels to the broader public.