Gas phase versus solution chemistry: on the reversal of regiochemistry of methylation of sp2- and sp3-nitrogens

The nicotine analogue 3-(N,N-dimethylaminomethyl)pyridine 2, which reacts with methyl iodide in acetonitrile exclusively on the sp3-nitrogen, methylates exclusively on the pyridine nitrogen with trimethyloxonium in the gas phase. Calculations at the RHF/6-31G**//6-31G** level suggest that there is an interaction between the side chain nitrogen and hydrogens on the aromatic ring. This interaction affects both the conformation of 2 as well as the relative basicity of its two nitrogens. Calculations also indicate that, in the gas phase, the pyridine methylated product (no counterion) is more stable than the pyrrolidine methylated product.