The reduction of aryl trifluoromethyl ketones by N-carbamoylmethyl-1,4-dihydronicotinamide

Abstract

The reaction of 15 aryl trifluoromethyl ketones with N-carbamoylmethyl-1,4-dihydronicotinamide has been studied in aqueous sulfolane buffer. The unsubstituted ketone and those containing electron-withdrawing groups in the ring have the following reaction characteristics: (a) a high yield of alcohol is obtained, (b) the observed reaction rate is independent of ring substituent; however, when corrections are made for degree of hydration of the ketones the rate is correlated with Hammett σ values with a rho of +1.98, (c) a secondary isotope effect of approximately 1.08 and primary isotope effects of 1.45–1.62 are observed at 43.4 °C for the reaction of the dihydronicotinamide containing one or two atoms of deuterium at C-4, (d) ΔH≠ = 15.2 kcal mol−1, and ΔS≠ = −27.0 cal deg−1 mol−1 for the unsubstituted compound, uncorrected for ketone hydration; ΔS≠ for reaction of the unhydrated ketone and dihydronicotinamide is estimated to be −45 to −50 cal deg−1 mol−1. The mechanism for the reduction is consistent with hydride transfer from reductant to oxidant, very possibly accompanied by blind-alley formation of an adduct between ketone hydrate and dihydronicotinamide. Ketones containing electron-donating groups in the ring react with the dihydronicotinamide in some undetermined way, giving little or no alcohol as product.