Preferential protonation and methylation at the nitrogen atoms of N , N ‐dimethylamino derivatives of pyridine

The relative reactivity toward protonation and methylation of the two nitrogen atoms in N , N ‐dimethylaminopyridines has been examined by 1 H NMR. The ring position of the dimethylamino group has no influence on protonation, which occurs in all the derivatives at the heterocyclic nitrogen. The N ‐methylation reaction does not follow a homogeneous behaviour, occurring at the exocyclic nitrogen in the 2‐substituted dimethylamino derivative. The electronic characteristics of the molecules, determined by MO calculations at a semi‐empirical level, indicate that both protonation and methylation should occur at the heterocyclic nitrogen; the calculated relative stabilites, however, of the N ‐protonated and N ‐methylated forms are in full agreement with the experimental results, and it appears that the anomalous behaviour of 2‐dimethylaminopyridine in the N ‐methylation reaction is caused by steric factors.