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Issue 35, 2020
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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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Abstract

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 (ΔG0) and ΔrG° 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 (ΔG) 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-alkylation 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 ΔrG° to the activation barrier in this case, while O-alkylation of 3 is favoured due to the dominant contribution of the intrinsic barrier (ΔG0) for this process. These results are of profound significance in understanding the outcomes of reactions of ambident reactants in general.

Graphical abstract: 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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Supplementary files

Article information


Submitted
19 May 2020
Accepted
23 Jul 2020
First published
23 Jul 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020,11, 9630-9647
Article type
Edge Article

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

K. J. Sheehy, L. M. Bateman, N. T. Flosbach, M. Breugst and P. A. Byrne, Chem. Sci., 2020, 11, 9630
DOI: 10.1039/D0SC02834G

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