Mechanistic Studies of NHC Organocatalysis – Quantifying the Reactivity of the Breslow Intermediate

N-heterocyclic carbenes (NHCs) are the most versatile class of organocatalyst, allowing access to a variety of catalytic intermediates for the construction of complex targets from simple starting materials under mild conditions.

Despite many individual conceptual advances in this field, it is not understood (or even commonly acknowledged by practitioners) why product distributions of NHC-catalysed processes often differ dramatically with catalyst scaffold or with subtle substituent variation within an NHC-catalyst family.

Following the many synthetic innovations over the past decade, future transformative benefits will rely on the careful, quantitative and detailed analysis and understanding of all aspects of reactions mechanisms in order to make informed choice of catalyst for a given transformation, rather then relying on brute force screening.

To break from this traditional, time-intensive screening approach and fully realize the potential of NHCs, a quantitative mechanistic understanding is required.

Central to this state-of-the-art field is the catalytically competent “Breslow intermediate” (BI) that is regarded as the cornerstone of modern NHC-mediated catalysis. First characterised in 2012, its reactivity is key to a multitude of synthetic transformations.

Despite its importance, a quantitative understanding of the behaviour of this transiently formed species has yet to be defined.

This proposal will deliver quantitative underpinning knowledge of this key intermediate that will (i) be used to develop a fundamental scale to quantify BI reactivity with a range of electrophilic species and (ii) be applied to answer unresolved mechanistic and chemoselectivity questions in contemporary NHC-based catalysis.