Selectivity under microwave irradiation. Benzylation of 2-pyridone: an experimental and theoretical study

The reaction of 2-pyridone with benzyl bromide in the absence of base and under solvent-free conditions has been studied experimentally and by computational methods. This reaction was one of the first reported examples in which modification of selectivity under microwave irradiation was observed. C- and/or N-alkylations were obtained depending on the benzyl halide and the heating system. N-Alkylation through mechanism A (S_N2 mechanism) is kinetically favoured while C-alkylation through an S_N1-type mechanism is thermodynamically favoured and is observed under microwave irradiation. Two S_N1-type mechanisms (mechanisms B and C) have been calculated, mechanism C being a kind of S_Ni. The influence of the pyridone/benzyl bromide ratio was studied. A second molecule of pyridone stabilizes the transition state and assists the leaving of the bromide ion. The occurrence of C-alkylation under microwave irradiation is explained by the predominance of the thermodynamic control in these conditions. Under microwave irradiation N-alkylation through an S_N1-type mechanism (mechanism C) can also occur. The dependence of the outcome of N-alkylation on the benzyl bromide ratio has been explained by a shift in the mechanism from S_N2 to S_N1 under microwave irradiation. Computational calculations have shown to be a useful tool for determination of the origin of the selectivity under microwave irradiation.