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Chemoselectivity in the Oxidation of Cycloalkenes with a Non-Heme Iron(IV)-Oxo-Chloride Complex: Epoxidation vs. Hydroxylation Selectivity.

ABSTRACT: We report and analyze chemoselectivity in the gas phase reactions of cycloalkenes (cyclohexene, cycloheptene, cis-cyclooctene, 1,4-cyclohexadiene) with a non-heme iron(IV)-oxo complex [(PyTACN)Fe(O)(Cl)]+, which models the active species in iron-dependent halogenases. Unlike in the halogenases, we did not observe any chlorination of the substrate. However, we observed two other reaction pathways: allylic hydrogen atom transfer (HAT) and alkene epoxidation. The HAT is clearly preferred in the case of 1,4-cyclohexadiene, both pathways have comparable reaction rates in reaction with cyclohexene, and epoxidation is strongly favored in reactions with cycloheptene and cis-cyclooctene. This preference for epoxidation differs from the reactivity of iron(IV)-oxo complexes in the condensed phase, where HAT usually prevails. To understand the observed selectivity, we analyze effects of the substrate, spin state, and solvation. Our DFT and CASPT2 calculations suggest that all the reactions occur on the quintet potential energy surface. The DFT-calculated energies of the transition states for the epoxidation and hydroxylation pathways explain the observed chemoselectivity. The SMD implicit solvation model predicts the relative increase of the epoxidation barriers with solvent polarity, which explains the clear preference of HAT in the condensed phase.

SUBMITTER: Terencio T

PROVIDER: S-EPMC6805805 | biostudies-other | 2019 Oct

REPOSITORIES: biostudies-other

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Chemoselectivity in the Oxidation of Cycloalkenes with a Non-Heme Iron(IV)-Oxo-Chloride Complex: Epoxidation vs. Hydroxylation Selectivity.

Terencio Thibault T Andris Erik E Gamba Ilaria I Srnec Martin M Costas Miquel M Roithová Jana J

Journal of the American Society for Mass Spectrometry 20190809 10

We report and analyze chemoselectivity in the gas phase reactions of cycloalkenes (cyclohexene, cycloheptene, cis-cyclooctene, 1,4-cyclohexadiene) with a non-heme iron(IV)-oxo complex [(PyTACN)Fe(O)(Cl)]<sup>+</sup>, which models the active species in iron-dependent halogenases. Unlike in the halogenases, we did not observe any chlorination of the substrate. However, we observed two other reaction pathways: allylic hydrogen atom transfer (HAT) and alkene epoxidation. The HAT is clearly preferred ...[more]

PMID: 31399940

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Project description: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.

Project description:Cytochrome P450 enzymes are heme based monoxygenases that catalyse a range of oxygen atom transfer reactions with various substrates, including aliphatic and aromatic hydroxylation as well as epoxidation reactions. The active species is short-lived and difficult to trap and characterize experimentally, moreover, it reacts in a regioselective manner with substrates leading to aliphatic hydroxylation and epoxidation products, but the origin of this regioselectivity is poorly understood. We have synthesized a model complex and studied it with low-pressure Fourier transform-ion cyclotron resonance (FT-ICR) mass spectrometry (MS). A novel approach was devised using the reaction of [FeIII(TPFPP)]+ (TPFPP = meso-tetrakis(pentafluorophenyl)porphinato dianion) with iodosylbenzene as a terminal oxidant which leads to the production of ions corresponding to [FeIV(O)(TPFPP+?)]+. This species was isolated in the gas-phase and studied in its reactivity with a variety of olefins. Product patterns and rate constants under Ideal Gas conditions were determined by FT-ICR MS. All substrates react with [FeIV(O)(TPFPP+?)]+ by a more or less efficient oxygen atom transfer process. In addition, substrates with low ionization energies react by a charge-transfer channel, which enabled us to determine the electron affinity of [FeIV(O)(TPFPP+?)]+ for the first time. Interestingly, no hydrogen atom abstraction pathways are observed for the reaction of [FeIV(O)(TPFPP+?)]+ with prototypical olefins such as propene, cyclohexene and cyclohexadiene and also no kinetic isotope effect in the reaction rate is found, which suggests that the competition between epoxidation and hydroxylation - in the gas-phase - is in favour of substrate epoxidation. This notion further implies that P450 enzymes will need to adapt their substrate binding pocket, in order to enable favourable aliphatic hydroxylation over double bond epoxidation pathways. The MS studies yield a large test-set of experimental reaction rates of iron(iv)-oxo porphyrin cation radical complexes, so far unprecedented in the gas-phase, providing a benchmark for calibration studies using computational techniques. Preliminary computational results presented here confirm the observed trends excellently and rationalize the reactivities within the framework of thermochemical considerations and valence bond schemes.

Dataset Information

Chemoselectivity in the Oxidation of Cycloalkenes with a Non-Heme Iron(IV)-Oxo-Chloride Complex: Epoxidation vs. Hydroxylation Selectivity.

Publications

Chemoselectivity in the Oxidation of Cycloalkenes with a Non-Heme Iron(IV)-Oxo-Chloride Complex: Epoxidation vs. Hydroxylation Selectivity.

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