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Issue 40, 2018
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Selective C–H halogenation over hydroxylation by non-heme iron(iv)-oxo

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Abstract

Non-heme iron based halogenase enzymes promote selective halogenation of the sp3-C–H bond through iron(IV)-oxo-halide active species. During halogenation, competitive hydroxylation can be prevented completely in enzymatic systems. However, synthetic iron(IV)-oxo-halide intermediates often result in a mixture of halogenation and hydroxylation products. In this report, we have developed a new synthetic strategy by employing non-heme iron based complexes for selective sp3-C–H halogenation by overriding hydroxylation. A room temperature stable, iron(IV)-oxo complex, [Fe(2PyN2Q)(O)]2+ was directed for hydrogen atom abstraction (HAA) from aliphatic substrates and the iron(II)-halide [FeII(2PyN2Q)(X)]+ (X, halogen) was exploited in conjunction to deliver the halogen atom to the ensuing carbon centered radical. Despite iron(IV)-oxo being an effective promoter of hydroxylation of aliphatic substrates, the perfect interplay of HAA and halogen atom transfer in this work leads to the halogenation product selectively by diverting the hydroxylation pathway. Experimental studies outline the mechanistic details of the iron(IV)-oxo mediated halogenation reactions. A kinetic isotope study between PhCH3 and C6D5CD3 showed a value of 13.5 that supports the initial HAA step as the RDS during halogenation. Successful implementation of this new strategy led to the establishment of a functional mimic of non-heme halogenase enzymes with an excellent selectivity for halogenation over hydroxylation. Detailed theoretical studies based on density functional methods reveal how the small difference in the ligand design leads to a large difference in the electronic structure of the [Fe(2PyN2Q)(O)]2+ species. Both experimental and computational studies suggest that the halide rebound process of the cage escaped radical with iron(III)-halide is energetically favorable compared to iron(III)-hydroxide and it brings in selective formation of halogenation products over hydroxylation.

Graphical abstract: Selective C–H halogenation over hydroxylation by non-heme iron(iv)-oxo

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Publication details

The article was received on 07 May 2018, accepted on 14 Aug 2018 and first published on 15 Aug 2018


Article type: Edge Article
DOI: 10.1039/C8SC02053A
Chem. Sci., 2018,9, 7843-7858
  • Open access: Creative Commons BY-NC license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    Selective C–H halogenation over hydroxylation by non-heme iron(IV)-oxo

    S. Rana, J. P. Biswas, A. Sen, M. Clémancey, G. Blondin, J. Latour, G. Rajaraman and D. Maiti, Chem. Sci., 2018, 9, 7843
    DOI: 10.1039/C8SC02053A

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