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

The preferred site of alkylation of diazineN-oxides by representative hard and soft alkylating agents was established conclusively using the¹H-¹⁵N HMBC NMR technique in combination with other NMR spectroscopic methods. Alkylation of pyrazineN-oxides (1and2) occurs preferentially on nitrogen regardless of the alkylating agent employed, whileO-methylation of pyrimidineN-oxide (3) 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 (ΔG‡0) and Δ_rG° 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 of1and3by MeI and MeOTf, and used to derive Gibbs energies of activation (ΔG^‡) for the processes ofN- andO-methylation, respectively. These values, as well as those derived directly from the DFT calculations, closely reproduce the observed experimentalN- vs.O-alkylation selectivities for methylation reactions of1and3, 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 thatN-alkylation of1is favoured due to the dominant contribution of Δ_rG° to the activation barrier in this case, whileO-alkylation of3is favoured due to the dominant contribution of the intrinsic barrier (ΔG‡0) for this process. These results are of profound significance in understanding the outcomes of reactions of ambident reactants in general.