Competition between N and O: use of diazine -oxides as a test case for the Marcus theory rationale for ambident reactivity.

The preferred site of alkylation of diazine -oxides by representative hard and soft alkylating agents was established conclusively using the H-N HMBC NMR technique in combination with other NMR spectroscopic methods. Alkylation of pyrazine -oxides ( and ) occurs preferentially on nitrogen regardless of the alkylating agent employed, while -methylation of pyrimidine -oxide () is favoured in its reaction with MeOTf. As these outcomes cannot be explained in the context of the hard/soft acid/base (HSAB) principle, we have instead turned to Marcus theory to rationalise these results. Marcus intrinsic barriers (Δ ) and Δ ° values were calculated at the DLPNO-CCSD(T)/def2-TZVPPD/SMD//M06-2X-D3/6-311+G(d,p)/SMD level of theory for methylation reactions of and by MeI and MeOTf, and used to derive Gibbs energies of activation (Δ ) for the processes of - and -methylation, respectively. These values, as well as those derived directly from the DFT calculations, closely reproduce the observed experimental - vs. -alkylation selectivities for methylation reactions of and , indicating that Marcus theory can be used in a semi-quantitative manner to understand how the activation barriers for these reactions are constructed. It was found that -alkylation of is favoured due to the dominant contribution of Δ ° to the activation barrier in this case, while -alkylation of is favoured due to the dominant contribution of the intrinsic barrier (Δ ) for this process. These results are of profound significance in understanding the outcomes of reactions of ambident reactants in general.