Stereochemistry of β-deuterium isotope effects on amine basicity

Secondary beta-deuterium isotope effects on amine basicities are measured using a remarkably precise NMR titration method. Deuteration is found to increase the basicity of methylamine, dimethylamine, benzylamine, N,N-dimethylaniline, 2-methyl-2-azanorbornane, and pyrrolizidine. The increase in dimethylamine arises entirely from enthalpy, contrary to a previous report. The method permits a determination of intramolecular isotope effects in 1-benzyl-4-methylpiperidine and 2-benzyl-2-azanorbornane. It is found that deuteration has a larger isotope effect when either antiperiplanar or synperiplanar to a lone pair, but the synperiplanar effect is smaller, as confirmed by computations. The isotope effect is attributed to a lowered zero-point energy of a C-H bond adjacent to an amine nitrogen, arising from delocalization of either a syn or an anti lone pair, and with no detectable angle-independent inductive effect.