Underpinning mechanistic studies of NHC-organocatalysis

: towards a Breslow intermediate reactivity scale

Abstract

Despite many advances in synthetic organocatalysis using N-heterocyclic carbenes (NHCs), it is still not understood why product distributions for a given reaction often differ dramatically with variation of a catalyst scaffold and reactants. This thesis focuses on a kinetic and structural analysis of the origin of NHC-catalytic behaviour with a particular focus upon the reactions of NHCs that employ an initial nucleophilic addition to heteroaromatic (pyridyl) aldehydes as part of their reaction mechanism.

In Chapter 2, 15 bicyclic triazolium salts were synthesized via a three-step one-pot method. The addition of these NHCs to aldehydes results in stable isolable tetrahedral species; in total 12 triazolium adducts derived from benzaldehydes and 20 triazolium adducts derived from heteroaromatic aldehydes were isolated and purified.

Subsequent work measured the equilibrium constants for the addition of triazolium NHC precatalysts to benzaldehyde and 2-methoxybenzaldehyde. The result indicates the effect of the fused ring size in triazolium salts and 2-substituent benzaldehyde on equilibrium constants.

A thorough kinetic investigation between heteroaromatic aldehydes and NHC precatalysts was also studied. Nineteen sets of data have been determined. The obtained results demonstrated that nucleophilic addition into pyridyl aldehydes is fast compared with previous data for addition to benzaldehydes. Notably, the combined effect of an additional substituent and the heteroatom of the heterocyclic aldehyde both ortho to the aldehydic position leads to exceptionally large enhancements in equilibrium constants for tetrahedral adduct formation.

Lastly, a new kinetic method for quantifying the reactivity of various Michael acceptors in their reaction with the presumed N-C₆F₅ substituted triazolium salt derived Breslow Intermediate in the intermolecular Stetter reaction was developed. Forty-three pseudo first-order rate constants from Michael acceptors (predominantly (E)-chalcones) were measured and analyzed. Forty-six Stetter products were also isolated and fully characterized.

Date of Award	13 Jun 2024
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Andrew Smith (Supervisor)