The mechanism of imine–enamine tautomerism of 2- and 4-phenacylquinolines

Abstract

Isomerisations of 2- and 4-phenacylquinolines to their enaminone tautomers via 1,3 or 1,5 carbon–nitrogen hydrogen shifts occur by stepwise acid- or base-catalysed pathways similar to those for the enolisation of ketones. The reactions are observed as relaxations of the unstable to stable tautomers by stopped-flow spectrophotometry or, where the aromatic imine is the stable form, by trapping the enaminone with iodine in the reverse reaction. Evidence of mechanism comes from observations of general acid and general base catalysis, agreement between kinetically determined pK_a values and independently measured values, and comparisons between rate and equilibrium constants for protonation of the enaminone tautomers and their N-methyl derivatives. The reactions show a primary isotope effect and yield normal Brönsted plots with αca. 0.5. The kinetically determined pK_a values indicate N- rather than O-protonation of phenacylquinolines but for the enaminones O-protonation competes kinetically with the thermodynamically preferred C-protonation. Combination of pK_a values for C-, N-, and O-protonation leads to equilibrium constants K_T for enamine–imine and (protonated) keto–enol tautomerisation. The effect of 2- and 4-N-protonation (proton activating factors) upon rates and equilibria for ionisation of hydrogen from the methylene carbons is discussed and evidence of ‘imbalance’ in charge development on the carbon base in the transition state is noted. A concerted intramolecular 1,3-proton transfer is predicted but not observed.