Iron is an essential elementi nn onheme enzymes that plays ac rucial role in many vital oxidative transformations and metabolic reactions in the human body.M any of those reactions are regio-ands tereospecific and it is believed that the selectivity is guided by second-coordination sphere effects in the protein. Here, results are shown of a few engineered biomimetic ligand frameworks based on the N4Py (N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine) scaffold and the second-coordination sphere effects are studied. For the first time, selectives ubstitutions in the ligand framework have been shown to tune the catalytic properties of the iron(IV)-oxo complexes by regulating the steric and electronic factors. In particular,abetter positioning of the oxidant and substrate in the rate-determining transition state lowers the reactionb arriers. Therefore, an optimum balance between steric and electronic factors mediates the ideal positioning of oxidanta nd substrate in the rate-determining transition state that affects the reactivity of high-valent reaction intermediates.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.

Metrics & MoreArticle Recommendations CONSPECTUS: Non-heme iron dioxygenases catalyze vital processes for human health related to the biosynthesis of essential products and the biodegradation of toxic metabolites. Often the natural product biosyntheses by these non-heme iron dioxygenases is highly regio-and chemoselective, which are commonly assigned to tight substratebinding and positioning. However, recent high-level computational modeling has shown that substrate-binding and positioning is only part of the story and long-range electrostatic interactions can play a major additional role.In this Account, we review and summarize computational viewpoints on the high regioand chemoselectivity of α-ketoglutarate-dependent non-heme iron dioxygenases and how external perturbations affect the catalysis. In particular, studies from our groups have shown that often a regioselectivity in enzymes can be accomplished by stabilization of the rate-determining transition state for the reaction through external charges, electric dipole moments, or local electric field effects. Furthermore, bond dissociation energies in molecules are shown to be influenced by an electric field effect, and through targeting a specific bond in an electric field, this can lead to an unusually specific reaction. For instance, in the carbon-induced starvation protein, we studied two substrate-bound conformations and showed that regardless of what C−H bond of the substrate is closest to the iron(IV)-oxo oxidant, the lowest hydrogen atom abstraction barrier is always for the pro-S C 2 −H abstraction due to an induced dipole moment of the protein that weakens this bond. In another example of the hygromycin biosynthesis enzyme, an oxidative ring-closure reaction in the substrate forms an ortho-δ-ester ring. Calculations on this enzyme show that the selectivity is guided by a protonated lysine residue in the active site that, through its positive charge, triggers a low energy hydrogen atom abstraction barrier. A final set of examples in this Account discuss the viomycin biosynthesis enzyme and the 2-(trimethylammonio)ethylphosphonate dioxygenase (TmpA) enzyme.Both of these enzymes are shown to possess a significant local dipole moment and local electric field effect due to charged residues surrounding the substrate and oxidant binding pockets. The protein dipole moment and local electric field strength changes the C− H bond strengths of the substrate as compared to the gas-phase triggers the regioselectivity of substrate activation. In particular, we show that in the gas phase and in a protein environment C−H bond strengths are different due to local electric dipole moments and electric field strengths. These examples show that enzymes have an intricately designed structure that enables a chemical reaction under ambient conditions through the positioning of positively and negatively charged residues that influence and enhance reaction mechanisms. These computational insights create huge possibilities in bioengineering to apply local electric field and dip...

Oxygen atom transfer by high-valent enzymatic intermediates remains an enigma in chemical catalysis. In particular, manganese is an important first-row metal involved in key biochemical processes, including the biosynthesis of molecular oxygen (through the photosystem II complex) and biodegradation of toxic superoxide to hydrogen peroxide by superoxide dismutase. Biomimetic models of these biological systems have been developed to gain understanding on the structure and properties of short-lived intermediates but also with the aim to create environmentally benign oxidants. In this work, we report a combined spectroscopy, kinetics and computational study on aldehyde deformylation by two side-on manganese(III)-peroxo complexes with bispidine ligands. Both manganese(III)-peroxo complexes are characterized by UV-vis and mass spectrometry techniques, and their reactivity patterns with aldehydes was investigated. We find a novel mechanism for the reaction that is initiated by a hydrogen atom abstraction reaction, which enables a keto-enol tautomerization in the substrate. This is an essential step in the mechanism that makes an electrophilic attack on the olefin bond possible as the attack on the aldehyde carbonyl is too high in energy. Kinetics studies determine a large kinetic isotope effect for the replacement of the transferring hydrogen atom by deuterium, while replacing the transferring hydrogen atom by a methyl group makes the substrate inactive and hence confirm the hypothesized mechanism. Our new mechanism is confirmed with density functional theory modeling on the full mechanism and rationalized through valence bond and thermochemical cycles. Our unprecedented new mechanism may have relevance to biological and biomimetic chemistry processes in general and gives insight into the reactivity patterns of metal-peroxo and metal-hydroperoxo intermediates in general.

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The biodegradationo fc ompounds with CÀF bonds is challenging due to the fact that these bonds are stronger than the CÀHb ond in methane. In this work, results on the unprecedented reactivity of ab iomimetic model complex that contains an N-bridged diiron-phthalocyanine are presented;t his model complex is shown to react with perfluorinated arenes under addition of H 2 O 2 effectively.T o get mechanistic insighti nto this unusualr eactivity,d etailed densityf unctionalt heoryc alculations on the mechanism of C 6 F 6 activation by an iron(IV)-oxo active species of the Nbridgedd iiron phthalocyanine system were performed. Our studies showt hat the reaction proceeds through ar ate-determining electrophilic CÀOa ddition reactionf ollowed by a 1,2-fluoride shift to give the ketone product, which can further rearranget ot he phenol. At hermochemical analysis showst hat the weakestC ÀFb ond is the aliphatic CÀFb ond in the ketonei ntermediate.

Enzymes are highly efficient catalysts in Nature that often react with high stereo-, chemo-, and regioselectivity. Usually, enzymes achieve this selectivity through substrate binding and positioning in the active site. The second-coordination sphere effects (also called noncovalent interactions) position the substrate and oxidant in close vicinity, and their effects include electrostatic interactions, hydrogen-bonding interactions, salt-bridges, and also long-range charge-effects from bound cations and anions. Each of these environmental perturbations can affect the kinetics and selectivity of reactions differently. Over the past couple of years, a variety of biomimetic model complexes have been developed and designed that have a similar first-coordination sphere to mononuclear iron-containing enzymes. However, sometimes the reactivity patterns of the biomimetic models in solution are different from the analogous enzymatic systems, and often the selectivity of the reaction is lost. To understand the functional differences between enzymes and biomimetic models, large catalytic clusters have been developed that incorporate second-coordination sphere effects that influence spectroscopic features as well as reactivity patterns. In this Review, we summarize and highlight recent advances in biomimetic chemistry on the creation and design of iron catalysts and the insights that have been obtained when elaborate ligand features are added, which influence the substrate approach to the catalytic center. We start with a highlight of the axial and distal ligand effects of metal centers and how these can be perturbed by hydrogen bonding as well as steric restraints. The syntheses of the active oxidants through the addition of a proton-donating or -accepting groups to the structure have also been discussed in detail in this article. As shown in this work, second-coordination sphere effects can be useful not only to trap and characterize short-lived intermediates but also to enable high selectivity and specificity of a chemical reaction in analogy to enzymatic systems. These biomimetic models appear highly useful for biotechnological and engineering applications with reasonable turnover numbers and consequently have great potential for the future of stereo-and chemoselective synthetic catalytic reactions.

The reactivity and characterization of a novel iron(iv)-oxo species is reported that gives enhanced reactivity as a result of second-coordination sphere perturbations of the ligand system.