Ortho-substituent effects in NHC-catalysis

Abstract

N-Heterocyclic carbenes (NHCs) are extensively used in contemporary organocatalysis in diverse C-C bond forming reactions. Although successful, high catalyst loadings are typically required and chemoselectivity highly depends on catalyst type and structure. Catalysts are commonly selected by screening based approaches because it is not entirely clear how the structures of both the N-aryl ring and aldehyde substrate affect reactivity. In particular, ortho-substituents on both the NHC and aryl aldehyde have been found to display enhanced rate and equilibrium constants for deprotonation and hydroxyaryl adduct formation, however, the mechanistic reason is unclear.
Chapter 2 describes the synthesis, kinetic evaluation and structural analysis using X-ray crystallography and DFT calculations of a range of triazolium salts, which are precursors to triazolyl NHCs. The findings from this chapter suggest that large dihedral angles between the triazolium and N-aryl ring, which are found in ortho-substituted systems, lead to relatively fast proton transfer from the triazolium salts. This is attributed to a ground state destabilisation of the cationic starting material through reduced inter-ring conjugation.
Chapter 3 describes the kinetic studies aimed at investigating ortho-substituent effects on both the catalyst and aldehyde substrate on the intial hydroxyaryl adduct forming equilibrium. Ortho-substituted NHCs result in relatively fast rates and large equilibrium constants for hydroxyaryl adduct formation. This may be attributed to the relatively large dihedral angle between the triazolyl and N-aryl rings. Approach of the incoming electrophile requires the N-aryl ring to rotate out of plane of the triazolyl ring, which results in an energetic penalty for non-ortho-substituted NHCs. An ortho-alkoxy substituent on the aryl aldehyde have also been found to lead to enhanced rate and equilibrium constants for formation relative to unsubstitued aryl aldehyde. These findings are rationalised in terms of the formation of an increasingly optimal intramolecular H-bond in the transition state for hydroxyaryl adduct formation.
Chapter 4 describes the attempts to determine a pKa for the conjugate acid of the Breslow intermediate based on the triazolyl scaffold. Methylated analogues were prepared and the kinetics of deprotonation by NMR and stopped flow UV-vis spectrophotometry are in agreement and suggest that a small proportion of O-methylated BI is observable in aqueous solution. Attempts were also made to reprotonate the BI to determine a pKa value in aqueous solution.