Proton activating factors and keto–enol-zwitterion tautomerism of 2-, 3- and 4-phenylacetylpyridines

Abstract

Equilibrium constants for keto–enol tautomerism of 2-, 3- and 4-phenylacetylpyridines in aqueous solution at 25 °C have been measured as pK_T^E = 3.35, 4.2 and 3.1 respectively (K_T^E = [enol]/[ketone], pK_T^E = –log K_T^E). Corresponding values for the N-protonated ketones are 1.64, 2.80 and 1.54. These enol contents are consistently higher than those of the isomeric phenacylpyridines, except in the case of the (unprotonated) 2-isomer where the greater enol content of the latter (pK_T^E = 2.0) can be attributed to more effective stabilization by hydrogen-bonding to the pyridyl nitrogen in a six- than five-membered ring. The tautomeric constants were obtained by combining rate constants for enolisation, measured by halogen trapping, with rate constants for relaxation of the enol tautomer (generated by quenching the enolate anion into acid or acidic buffers) to its more stable keto isomer. Approximate tautomeric constants for zwitterion formation (pK_T^Z = 4.6, 7.4 and 6.1 for 2-, 3- and 4-isomers respectively) are inferred from measurements of ionisation constants and keto–enol tautomeric constants for N-methylated ketones by taking the N-methylated enolate anions as models for the zwitterions and correcting for the substituent effect of the methyl group. The tautomerism is discussed in terms of the relationship pK_T = ΔpK_ab + log PAF which dissects tautomeric constants into contributions from (a) a difference in pK_as of non-interacting acidic and basic tautomeric sites (ΔpK_ab) and (b) a mutual stabilisation of these sites from conjugative, inductive or hydrogen-bonded interactions between them. This stabilisation is described by a proton activating factor (PAF ) measuring the effect of protonation at one tautomeric site upon the ionisation constant at the other.

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