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. 2018 Aug 15;9(40):7843-7858.
doi: 10.1039/c8sc02053a. eCollection 2018 Oct 28.

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

Sujoy Rana  1 , Jyoti Prasad Biswas  1 , Asmita Sen  1 , Martin Clémancey  2 , Geneviève Blondin  2 , Jean-Marc Latour  2 , Gopalan Rajaraman  1 , Debabrata Maiti  1
Affiliations

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

Sujoy Rana et al. Chem Sci. .

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.

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Figures

Fig. 1
Fig. 1. sp3-C–H halogenation by non-heme complexes.
Fig. 2
Fig. 2. ORTEP diagram of the triflate anion coordinated iron(ii)-complex 1 (CCDC ; 1505984), the DFT optimized structure of iron(iv)-oxo 2, [FeIV(2PyN2Q)(O)]2+, and the ORTEP diagram of iron(ii)-halide complexes 3 (; 1505989) and 4 (; 1505986).
Fig. 3
Fig. 3. (a) Mössbauer spectra recorded at 80 K and 60 mT top and (b) at 5.5 K and 7 T (bottom). Experimental spectra: hatched bars; solid black line: simulation; colored lines: contributions of species A (red), B (blue) and C (green).
Fig. 4
Fig. 4. (a) UV-vis change during C–H oxidation of ethylbenzene, (b) time trace of 2 at 770 nm, (c) bond dissociation energy (BDE) correlation plot: Bell–Evans–Polyani plot during C–H oxidation by 2 and (d) kinetic isotope effect study (kinetic studies were carried out under a N2 atmosphere at 25 °C).
Fig. 5
Fig. 5. C–H oxidation by [FeIV(2PyN2Q)(O)]2+, 2 (reactions were carried out under a N2 atmosphere inside a glove box at 25 °C).
Fig. 6
Fig. 6. Plausible mechanism of C–H halogenation by iron(iv)-oxo, 2 in the presence of iron(ii)-halide complexes 3 or 4.
Fig. 7
Fig. 7. EPR spectrum showing one electron oxidation of 6 using 0.5 of mCPBA (temperature 4 K, X-band frequency 9.376 GHz, modulation amplitude 4G, modulation frequency 100 kHz, and attenuation 22 dB).
Fig. 8
Fig. 8. (a) UV-vis change during the bromination of toluene, (b) inset 770 nm decay plot of 2 during the bromination of toluene, (c) kinetic isotope effect study during the bromination reaction (kinetic studies were carried out under a N2 atmosphere at 25 °C).
Fig. 9
Fig. 9. (a) Important structural parameters and (b) spin densities of B3LYP-D2 optimized structures of [FeIV(2PyN2Q)(O)]2+, and (c) key orbitals of 3K.
Fig. 10
Fig. 10. Adopted mechanism for the DFT calculation for the halogenation/hydroxylation of cyclohexane by the putative Fe(iv)–O species.
Fig. 11
Fig. 11. (a) Important structural parameters of the B3LYP-D2 optimized structures of the ts1 and (b) spin densities of B3LYP-D2 computed 5ts1.
Fig. 12
Fig. 12. (a) Orbital occupancy diagrams for the H-abstraction process and (b) corresponding orbital selection rules for predicting transition-state structures.
Fig. 13
Fig. 13. Depiction of the B3LYP-D2-computed potential energy surface (ΔG in kJ mol–1) for the C–H activation followed by (a) the O–H rebound process and (b) the cage escape and subsequent halogenation pathway. Horizontal lines represent the spin state: high spin by green color, low spin state by blue and the intermediate state by red. The C–H bond activation pathway is shown in black, with the –OH rebound leading to hydroxylation in pink and –Cl rebound leading to the halogenation pathway in orange.
Fig. 14
Fig. 14. B3LYP-D2-optimized structures with selected structural parameters: (a) 5,5,3int1, (b) 2,4,6int2, (c) 3,5,7ts2, (d) 1,3,5P + POH, (e) 2,4,6int3, (f) 3,5,7int4, (g) 3,5,7ts3, and (h) 1,3,5P + PCl.
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