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

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Sheehy, Kevin
Bateman, Lorraine M.
Flosbach, Niko T.
Breugst, Martin
Byrne, Peter A.
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Royal Society of Chemistry
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The preferred site of alkylation of diazine N-oxides by representative hard and soft alkylating agents was established conclusively using the 1H-15N HMBC NMR technique in combination with other NMR spectroscopic methods. Alkylation of pyrazine N-oxides (1 and 2) occurs preferentially on nitrogen regardless of the alkylating agent employed, while O-methylation of pyrimidine N-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 (∆G0‡) and ∆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 of 1 and 3 by MeI and MeOTf, and used to derive Gibbs energies of activation (∆G‡) for the processes of N- and O-methylation, respectively. These values, as well as those derived directly from the DFT calculations, closely reproduce the observed experimental N vs O selectivities for methylation reactions of 1 and 3, 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 N-alkylation of 1 is favoured due to the dominant contribution of ∆rG° to the activation barrier in this case, while O-alkylation of 3 is favoured due to the dominant contribution of the intrinsic barrier (∆G0‡) for this process. These results are of profound significance in understanding the outcomes of reactions of ambident reactants in general.
Diazine N-oxides , Marcus theory , Alkylation
Sheehy, K., Bateman, L. M., Flosbach, N. T., Breugst, M. and Byrne, P. (2020) 'Competition Between N and O: Use of Diazine N-Oxides as a Test Case for the Marcus Theory Rationale for Ambident Reactivity', Chemical Science, doi: 10.1039/D0SC02834G