Correlation of electronic effects in N-alkylnicotinamides with NMR chemical shifts and hydride transfer reactivity


Journal Article

The 13C and 15N NMR chemical shifts for ring atoms of a series of N-alkylnicotinamides are shown to be correlated with their reduction potentials and reactivities toward NaBH3CN. The nicotinamide compounds include N-ethyl-N-benzyl-N-[p-(trifluoromethyl)benzyl]-, N-(p-cyanobenzyl)-, N-(carbomethoxymethyl)-, and N-(cyanomethyl)nicotinamides. The values of δ13C for all the ring carbons increase with increasing electron-withdrawing power of the N-alkyl substituent. The value for C-4 increases the most, a range of 2.4 ppm in this series, whereas those for other atoms increase on the order of 1 ppm. The value of δ15N for N-1 decreases with increasing electron-withdrawing power over a range of 20 ppm. The NMR data indicate that inductive electron withdrawal by N-alkyl substituents polarizes the π-electron system to decrease electron density on ring carbons and increase electron density on the ring nitrogen. The values of log k (second order) for reduction of these compounds by NaBH3CN are proportional to the values of δ13C for C-4 and inversely proportional to δ15N for N-1. The reduction potentials are proportional to δ13C. The substituent effects are qualitatively similar to the substrate-induced electrostatic effects on the nicotinamide ring of NAD+ at the active site of UDP-galactose 4-epimerase (Burke, J. R.; Frey, P. A. Biochemistry 1993, 32, 13220-13230). However, they differ quantitatively in that the upfield perturbation at N-1 is smaller in the enzyme and the signal for C-6 is also shifted upfield. The substrate-induced enzymatic perturbation of electron density at C-4 of NAD+ quantitatively accounts for its increase in reactivity at the active site, but the perturbation at N-1 is less closely correlated with reactivity.

Cited Authors

  • Burke, JR; Frey, PA

Published Date

  • January 26, 1996

Published In

Volume / Issue

  • 61 / 2

Start / End Page

  • 530 - 533

International Standard Serial Number (ISSN)

  • 0022-3263

Citation Source

  • Scopus