Biomimetic Iron Research Articles

Construction of Hierarchically Biomimetic Iron Oxide Nanosystems for Macrophage Repolarization-Promoted Immune Checkpoint Blockade of Cancer Immunotherapy.

Cancer immunotherapy is developing as the mainstream strategy for treatment of cancer. However, the interaction between the programmed cell death protein-1 (PD-1) and the programmed death ligand 1 (PD-L1) restricts T cell proliferation, resulting in the immune escape of tumor cells. Recently, immune checkpoint inhibitor therapy has achieved clinical success in tumor treatment through blocking the PD-1/PD-L1 checkpoint pathway. However, the presence of M2 tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) will inhibit antitumor immune responses and facilitate tumor growth, which can weaken the effectiveness of immune checkpoint inhibitor therapy. The repolarization of M2 TAMs into M1 TAMs can induce the immune response to secrete proinflammatory factors and active T cells to attack tumor cells. Herein, hollow iron oxide (Fe3O4) nanoparticles (NPs) were prepared for reprogramming M2 TAMs into M1 TAMs. BMS-202, a small-molecule PD-1/PD-L1 inhibitor that has a lower price, higher stability, lower immunogenicity, and higher tumor penetration ability compared with antibodies, was loaded together with pH-sensitive NaHCO3 inside hollow Fe3O4 NPs, followed by wrapping with macrophage membranes. The formed biomimetic FBN@M could produce gaseous carbon dioxide (CO2) from NaHCO3 in response to the acidic TME, breaking up the macrophage membranes to release BMS-202. A series of in vitro and in vivo assessments revealed that FBN@M could reprogram M2 TAMs into M1 TAMs and block the PD-1/PD-L1 pathway, which eventually induced T cell activation and the secretion of TNF-α and IFN-γ to kill the tumor cells. FBN@M has shown a significant immunotherapeutic efficacy for tumor treatment.

Dearomative syn-Dihydroxylation of Naphthalenes with a Biomimetic Iron Catalyst.

Arenes are interesting feedstocks for organic synthesis because of their natural abundance. However, the stability conferred by aromaticity severely limits their reactivity, mostly to reactions where aromaticity is retained. Methods for oxidative dearomatization of unactivated arenes are exceedingly rare but particularly valuable because the introduction of Csp3-O bonds transforms the flat aromatic ring in 3D skeletons and confers the oxygenated molecules with a very rich chemistry suitable for diversification. Mimicking the activity of naphthalene dioxygenase (NDO), a non-heme iron-dependent bacterial enzyme, herein we describe the catalytic syn-dihydroxylation of naphthalenes with hydrogen peroxide, employing a sterically encumbered and exceedingly reactive yet chemoselective iron catalyst. The high electrophilicity of hypervalent iron oxo species is devised as a key to enabling overcoming the aromatically promoted kinetic stability. Interestingly, the first dihydroxylation of the arene renders a reactive olefinic site ready for further dihydroxylation. Sequential bis-dihydroxylation of a broad range of naphthalenes provides valuable tetrahydroxylated products in preparative yields, amenable for rapid diversification.

Single-atom catalysts-based catalytic ROS clearance for efficient psoriasis treatment and relapse prevention via restoring ESR1

Psoriasis is a common inflammatory disease of especially high recurrence rate (90%) which is suffered by approximately 3% of the world population. The overexpression of reactive oxygen species (ROS) plays a critical role in psoriasis progress. Here we show that biomimetic iron single-atom catalysts (FeN4O2-SACs) with broad-spectrum ROS scavenging capability can be used for psoriasis treatment and relapse prevention via related gene restoration. FeN4O2-SACs demonstrate attractive multiple enzyme-mimicking activities based on atomically dispersed Fe active structures, which are analogous to those of natural antioxidant enzymes, iron superoxide dismutase, human erythrocyte catalase, and ascorbate peroxidase. Further, in vitro and in vivo experiments show that FeN4O2-SACs can effectively ameliorate psoriasis-like symptoms and prevent the relapse with augmented efficacy compared with the clinical drug calcipotriol. Mechanistically, estrogen receptor 1 (ESR1) is identified as the core protein upregulated in psoriasis treatment through RNA sequencing and bioinformatic analysis. Together, this study provides a proof of concept of psoriasis catalytic therapy (PCT) and multienzyme-inspired bionics (MIB).

Reactivity Differences of Trigonal Pyramidal Nonheme Iron(IV)-Oxo and Iron(III)-Oxo Complexes: Experiment and Theory.

High-valent metal-oxo species play critical roles in enzymatic catalysis yet their properties are still poorly understood. In this work we report a combined experimental and computational study into biomimetic iron(IV)-oxo and iron(III)-oxo complexes with tight second-coordination sphere environments that restrict substrate access. The work shows that the second-coordination sphere slows the hydrogen atom abstraction step from toluene dramatically and the kinetics is zeroth order in substrate. However, the iron(II)-hydroxo that is formed has a low reduction potential and hence cannot do OH rebound favorably. The tolyl radical in solution then reacts further with alternative reaction partners. By contrast, the iron(IV)-oxo species reacts predominantly through OH rebound to form alcohol products. Our studies show that the oxidation state of the metal influences reactivities and selectivities with substrate dramatically and that enzymes will likely need an iron(IV) center to catalyze C-H hydroxylation reactions.

Cassia fistula nutrition rich flower tea derived biotic nanoparticles synthesis, characterization and their antioxidant and anti-hyperglycaemic properties.

Cassia fistula (CF) is a nutrient-rich flowering plant and it has been used to cure numerous human health problems including cardiac diseases, bacterial infection, and inflammation. The purpose of this study was to investigate the production and characterisation of biomimetic iron oxide nanoparticles (ICF) derived from CF flower tea as well as evaluate their antioxidant and anti-hyperglycemic properties. CF tea derived ICF synthesis and characterized by established physical-chemical methods. Moreover, this synthesized ICF were checked for their antioxidant and anti-hyperglycemic properties such as alpha-amylase, glucose intake, total antioxidant (TAA), ferrous reducing (FA), and radical scavenging (DPPH) properties. The synthesized ICF characterization and size were confirmed primarily by described physical and chemical methods. Our findings revealed that ICF have a powerful antihyperglycemic mechanism by involving alpha-amylase inhibition and enhanced glucose absorption. Meanwhile, this ICF exhibited distinguished antioxidant competence by improving TAA and free radical scavenging (TAA, DPPH) properties. Finally, this ICF has proven anti-hyperglycemic and antioxidant mechanisms due to their presence of nano-sized biomolecules. In this study, it might be concluded that the CF is the best source for iron oxide nanoparticles production with clarity, small size and high solidity. Moreover, this nanoparticle has proven in vitro anti-hyperglycemic and antioxidant mechanisms.

Which is the real oxidant in competitive ligand self-hydroxylation and substrate oxidation-a biomimetic iron(II)-hydroperoxo species or an oxo-iron(IV)-hydroxy one?

Nonheme iron(II)-hydroperoxo species (FeII-(η2-OOH)) 1 and the concomitant oxo-iron(IV)-hydroxyl one 2 are proposed as the key intermediates of a large class of 2-oxoglutarate dependent dioxygenases (e.g., isopenicillin N synthase). Extensive biomimetic experiments have been exerted to identify which one is the real oxidant and to reveal the structure-function relationship of them, whereas the mechanistic picture is still elusive. To this end, density functional theory (DFT) calculations were performed to systematically study the mechanistic details of ligand self-hydroxylation and competitive substrate oxidation by these two species supported by a tridentate ligand Fe(TpPh2)(benzilate) (TpPh2 = hydrotris(3,5-diphenylpyrazole-1-yl)borate). The calculated results revealed that the structure and the conversion of the FeII-(η2-OOH) complex 1 are obviously different from the ferric FeIII-OOH one. The orientation of the Fe-OOH moiety of 1 is side-on, while that of the ferric FeIII-OOH species is end-on. The conversion of 1 to the high-valent iron-oxo species is exothermic, while the conversion of the ferric FeIII-OOH species to the high-valent species is endothermic. Thus, the sluggish 1 does not act as the oxidant and readily decays to the robust 2. The activation energy of intramolecular ligand self-hydroxylation in 2 is 14.8 kcal mol-1 and intermolecular substrate oxidations (e.g., thioanisole sulfoxidation) with a lower barrier show a strong inhibiting ability toward ligand self-hydroxylation, while those with a higher barrier (e.g., cyclohexane hydroxylation) have no effect. Our theoretical results fit nicely with the experimental observations and will enrich the knowledge of the metal-oxygen intermediate and play a positive role in the rational design of new biomimetic catalysts.

Electrocatalytic alcohol oxidation by a molecular iron complex.

An efficient electrochemical method for the selective oxidation of alcohols to their corresponding aldehydes/ketones using a biomimetic iron complex, [(bTAML)FeIII-OH2]-, as the redox mediator in an undivided electrochemical cell with inexpensive carbon and nickel electrodes using water as an oxygen source is reported. The substrate scope also includes alcohols that contain O and N heteroatoms in the scaffold, which are well tolerated under these reaction conditions. Mechanistic studies show the involvement of a high-valent FeV(O) species, [(bTAML)FeV(O)]-, formed via PCET (overall 2H+/2e-) from [(bTAML)FeIII-OH2]- at 0.77 V (vs. Fc+/Fc). Moreover, electrokinetic studies of the oxidation of C-H bonds indicate a second-order reaction, with the C-H abstraction by FeV(O) being the rate-determining step. The overall mechanism, studied using linear free energy relationships and radical clocks, indicates a "net hydride" transfer, leading to the oxidation of the alcohol to the corresponding aldehyde or ketone. When the reaction was carried out at pH > 11, the reaction could be carried out at a ∼500 mV lower potential than that at pH 8, albeit with reduced reaction rates. The reactive intermediate involved at pH > 11 is the corresponding one-electron oxidized [(bTAML)FeIV(O)]2- species.

Cover Feature: TET‐Like Oxidation in 5‐Methylcytosine and Derivatives: A Computational and Experimental Study (ChemBioChem 23/2021)

The reactivity of a biomimetic iron (IV)-oxo complex (the sun) towards a number of methylated cytosine and uracil substrates (the orbiting planets) was investigated. The reaction rates (corresponding to the orbital periods) are in very good agreement with the calculated bond dissociation energies. 5mC, T and 5miC possess a different reactivity than the solely N-methylated compounds 1mC and 1mU or the dimethylated compounds 1,5dimC and 1,5dimU. The image was created by coauthor R. Janßen. More information can be found in the Full Paper by L. J. Daumann et al.

TET-Like Oxidation in 5-Methylcytosine and Derivatives: A Computational and Experimental Study.

The epigenetic marker 5‐methylcytosine (5mC) is an important factor in DNA modification and epigenetics. It can be modified through a three‐step oxidation performed by ten‐eleven‐translocation (TET) enzymes and we have previously reported that the iron(IV)‐oxo complex [Fe(O)(Py5Me2H)]2+ (1) can oxidize 5mC. Here, we report the reactivity of this iron(IV)‐oxo complex towards a wider scope of methylated cytosine and uracil derivatives relevant for synthetic DNA applications, such as 1‐methylcytosine (1mC), 5‐methyl‐iso‐cytosine (5miC) and thymine (T/5mU). The observed kinetic parameters are corroborated by calculation of the C−H bond energies at the reactive sites which was found to be an efficient tool for reaction rate prediction of 1 towards methylated DNA bases. We identified oxidation products of methylated cytosine derivatives using HPLC‐MS and GC‐MS. Thereby, we shed light on the impact of the methyl group position and resulting C−H bond dissociation energies on reactivity towards TET‐like oxidation.

Casey Wade

Angewandte ChemieVolume 133, Issue 41 p. 22282-22282 Introducing …Free Access Casey Wade First published: 31 August 2021 https://doi.org/10.1002/ange.202111108AboutSectionsPDF ToolsRequest permissionAdd to favorites ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract “Chemistry is fun because it allows you to use your imagination to solve problems and create something tangible … I advise my students to make the science engines run …” Find out more about Casey Wade in his Introducing … Profile. Casey R. Wade The author presented on this page has published his first article as a submitting corresponding author in Angewandte Chemie: “Direct NO Reduction by a Biomimetic Iron(II) Pyrazolate MOF”: Z. Cai, W. Tao, C. E. Moore, S. Zhang, C. R. Wade, Angew. Chem. Int. Ed. 2021, 60, doi.org/10.1002/anie.202108095; Angew. Chem. 2021, 133, doi.org/10.1002/ange.202108095. Position: Assistant Professor of Chemistry, The Ohio State University (USA) Homepage: https://u.osu.edu/wadelab ORCID: orcid.org/0000-0002-7044-9749 Education: 2006 B.S. in Chemistry, University of Nebraska–Lincoln (USA) 2011 Ph.D. with François Gabbaï, Texas A&M University (USA) 2011–2013 Postdoc with Mircea Dincă, Massachusetts Institute of Technology (USA) Research: metal–organic frameworks, organometallics, catalysis, gas separation Hobbies: fishing, cooking, American football, bourbon The biggest challenge facing scientists is public perception. We need to get out there and let everyone know about the exciting things we are doing! Chemistry is fun because it allows you to use your imagination to solve problems and create something tangible. It's like cooking without licking the spatula! The most exciting thing about my research is making a new molecule or material that no one has ever reported. I advise my students to make the science engines run. The best advice I have ever been given is don't send an email to someone who is just down the hall. Stimulating discussions with colleagues and students never happen via email. I lose track of time when I get to work in the lab. Just ask my wife! (Better yet, don't …) A good day at work starts with a new crystal structure or clean NMR spectrum. I can never resist good Texas BBQ. What I appreciate most about my friends is their upside down sense of humor. The most important quality of a mentor is patience and empathy. My favorite thing about my lab group is their infectious enthusiasm for science. My favorite reaction is the dissolution of gold metal in aqua regia. My favorite name theorem is Bercaw's Law of Initial Optimization. It holds true all too often … My favorite drink is Weller 12 Wheated Bourbon. My favorite song/piece of music is Pearl Snaps by Jason Boland and the Stragglers. Behind the Science References 1This project was led by an outstanding postdoc in my lab, Dr. Zhongzheng (Amy) Cai. She discovered the new MOF serendipitously, and as soon as we determined the structure, we knew we had stumbled onto something interesting. Our initial characterization and reactivity studies turned into a collaborative project after conversations with my colleague, Prof. Shiyu Zhang, who is an expert in NO chemistry. After a multitude of carefully planned experiments, COVID-related delays, Zoom meetings, and a new γ-ray source for our Mössbauer spectrometer, we're excited to share this work with the scientific community. Google Scholar Volume133, Issue41October 4, 2021Pages 22282-22282 This is the German version of Angewandte Chemie. Note for articles published since 1962: Do not cite this version alone. Take me to the International Edition version with citable page numbers, DOI, and citation export. We apologize for the inconvenience. ReferencesRelatedInformation

Direct NO Reduction by a Biomimetic Iron(II) Pyrazolate MOF.

A novel metal-organic framework (MOF) containing one-dimensional, Fe2+ chains bridged by dipyrazolate linkers and N,N-dimethylformamide (DMF) ligands has been synthesized. The unusual chain-type metal nodes feature accessible coordination sites on adjacent metal centers, resulting in motifs that are reminiscent of the active sites in non-heme diiron enzymes. The MOF facilitates direct reduction of nitric oxide (NO), producing nearly quantitative yields of nitrous oxide (N2 O) and emulating the reactivity of flavodiiron nitric oxide reductases (FNORs). The ferrous form of the MOF can be regenerated via a synthetic cycle involving reduction with cobaltocene (CoCp2 ) followed by reaction with trimethylsilyl triflate (TMSOTf).

Direct NO Reduction by a Biomimetic Iron(II) Pyrazolate MOF

AbstractA novel metal‐organic framework (MOF) containing one‐dimensional, Fe2+ chains bridged by dipyrazolate linkers and N,N‐dimethylformamide (DMF) ligands has been synthesized. The unusual chain‐type metal nodes feature accessible coordination sites on adjacent metal centers, resulting in motifs that are reminiscent of the active sites in non‐heme diiron enzymes. The MOF facilitates direct reduction of nitric oxide (NO), producing nearly quantitative yields of nitrous oxide (N2O) and emulating the reactivity of flavodiiron nitric oxide reductases (FNORs). The ferrous form of the MOF can be regenerated via a synthetic cycle involving reduction with cobaltocene (CoCp2) followed by reaction with trimethylsilyl triflate (TMSOTf).

Repurposed and artificial heme enzymes for cyclopropanation reactions

Heme enzymes are some of the most versatile catalysts in nature. In recent years it has been found that they can also catalyze reactions for which there are no equivalents in nature. This development has been driven by the abiological catalytic reactivity reported for bio-inspired and biomimetic iron porphyrin complexes. This review focuss es on heme enzymes for catalysis of cyclopropanation reactions. The two most important approaches used to create enzymes for cyclopropanation are repurposing of heme enzymes and the various strategies used to improve these enzymes such as mutagenesis and heme replacement, and artificial heme enzymes. These strategies are introduced and compared. Moreover, lessons learned with regard to mechanism and design principles are discussed.

Theoretical investigation on the elusive biomimetic iron(III)-iodosylarene chemistry: An unusual hydride transfer triggers the Ritter reaction

Introduction of iodosylarnes into biomimetic nonheme chemistry has made great achievement on identification of the subtle metal-oxygen reaction intermediates. However, after more than three decades of experimental and theoretical efforts the nature of the metal-iodosylarene adducts and the related dichotomous one-oxidant/multiple-oxident controversy have remained a matter of speculation. Herein, we report a theoretical study of the structure-activity relationship of the noted iron(III)-iodsylarene complex, FeIII(PhIO)(OTf)3 (1), in oxygenation of cyclohexene. The calculated results revealed that 1 behaves like a chameleon by adapting its roles as a 2e-oxidant or an oxygen donor, as a response to the regioselective attack of the C–H bond and the C=C bond. The oxidative C–H bond activation by 1 was found, for the first time, to proceed via a novel hydride transfer process to form a cyclohexene carbonium intermediate, such non-rebound step triggers the Ritter reaction to uptake an acetonitrile molecule to form the amide product, or proceeds with the rebound of the hydroxyl group return to the solvent cage to form the hydroxylated product. While in the C=C bond activation, 1 is a normal oxygen donor and shows two-state reactivity to present the epoxide product via a direct oxygen atom transfer mechanism. These mechanistic findings fit and explain the famous Valentine's experiments and enrich the non-rebound scenario in bioinorganic chemistry.

Probing the Mechanism for 2,4'-Dihydroxyacetophenone Dioxygenase Using Biomimetic Iron Complexes.

In this study, we report the synthesis and characterization of [Fe(T1Et4iPrIP)(2-OH-AP)(OTf)](OTf) (2), [Fe(T1Et4iPrIP)(2-O-AP)](OTf) (3), and [Fe(T1Et4iPrIP)(DMF)3](OTf)3 (4) (T1Et4iPrIP = tris(1-ethyl-4-isopropyl-imidazolyl)phosphine; 2-OH-AP = 2-hydroxyacetophenone, and 2-O-AP- = monodeprotonated 2-hydroxyacetophenone). Both 2 and 3 serve as model complexes for the enzyme-substrate adduct for the nonheme enzyme 2,4'-dihydroacetophenone (DHAP) dioxygenase or DAD, while 4 serves as a model for the ferric form of DAD. Complexes 2-4 have been characterized by X-ray crystallography which reveals T1Et4iPrIP to bind iron in a tridentate fashion. Complex 2 additionally contains a bidentate 2-OH-AP ligand and a monodentate triflate ligand yielding distorted octahedral geometry, while 3 possesses a bidentate 2-O-AP- ligand and exhibits distorted trigonal bipyramidal geometry (τ = 0.56). Complex 4 displays distorted octahedral geometry with 3 DMF ligands completing the ligand set. The UV-vis spectrum of 2 matches more closely to the DAD-substrate spectrum than 3, and therefore, it is believed that the substrate for DAD is bound in the protonated form. TD-DFT studies indicate that visible absorption bands for 2 and 3 are due to MLCT bands. Complexes 2 and 3 are capable of oxidizing the coordinated substrate mimics in a stoichiometric and catalytic fashion in the presence of O2. Complex 4 does not convert 2-OH-AP to products under the same catalytic conditions; however, it becomes anaerobically reduced in the presence of 2 equiv 2-OH-AP to 2.

The curious case of peptide-coordinated iron-sulfur clusters: prebiotic and biomimetic insights.

Iron-sulfur clusters are among the most ancient biological cofactors and are thought to have had an ancient role in mediating the chemical reactions that led to life. Two different, yet complementary approaches, based on bioinorganic chemistry and prebiotic chemistry, have already provided important clues for the formation and activity of biomimetic iron-sulfur analogues in aqueous solution. This frontier article discusses the efforts spent in the last 50 years in the context of peptide-coordinated iron-sulfur clusters, with a particular emphasis on insightful contributions from recent prebiotic chemistry research.

Facile approach to the solid support photografting coating of citric acid as a novel biomimetic iron chelator film

Herein, the facile photografting coating method was used to develop a novel metal biochelator film by covalent immobilization of citric acid (CA) onto polypropylene (PP) surface. First, PP film underwent a surface modification by UV-grafting of glycidyl methacrylate (GMA) in the presence of benzophenone (BP). The concentrations of GMA (bifunctional monomer) and BP (photoinitiator) were appropriately optimized to achieve the breath-figure-array structure and brush-like grafting configuration with a high availability of the reactive oxirane ring. Subsequently, CA was immobilized onto the PP-g-GMA surface via the ring-opening reaction to obtain the biochelator film (PP-g-GMA-g-CA). Fourier-transform infrared spectroscopy and solid state 13C nuclear magnetic resonance spectroscopy elucidated the chemical structure and grafting mechanism of grafted samples. X-ray photoelectron spectroscopy was used to detect the chemical composition of the surface of the grafted samples, by which the grafting density was relatively estimated. In addition, the uniformity of the grafting pattern and morphology of the grafting unit were observed using scanning electron microscopy and atomic force microscopy. Furthermore, the carboxylic acid density of the biochelator film (PP-g-GMA-g-CA) was quantified using a toluidine blue O assay, in which approximately 327 ± 58 nM carboxylic acid was detected per each film. The metal chelating activity of the film was also investigated using the colorimetric ferrozine assay, by which PP-g-GMA-g-CA film chelated approximately 215 ± 11 nM of Fe3+. Therefore, this newly developed system can be used as a versatile metal biochelator in a wide range of biomedical, cosmetic, and packaging applications.11Citric acid (CA), benzophenone (BP), glycidyl methacrylate (GMA), Fourier-transform infrared spectroscopy (FTIR), 13C nuclear magnetic resonance (13C NMR), X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM), atomic force microscopy (AFM), polypropylene (PP), toluidine blue O (TBO), breath figure array (BFA)

Computational Study on O–O Bond Formation on a Mononuclear Non‐Heme Iron Center

Cleavage and formation of the O–O bond in dioxygen is among the most important metal‐dependent processes in Nature. The former process has been mimicked structurally and functionaly with a number of biomimetic iron complexes. The reverse process, namely the dioxygen bond formation, however, appears unfavorable with iron. Over the years many attempts have been made to oxidize water on a mononuclear iron center through reactions with peroxide. In this work we present a computational study focused on the mechanism of dioxygen formation on two mononuclear non‐heme iron(IV)‐oxo species upon addition of peracid (m‐chloroperbenzoic acid, mCPBA). A range of test reactions and sequences are analyzed with thermochemical cycles with respect to the thermodynamic and kinetic feasibility of product formation. The work shows that iron‐borne O–O bond formation through peracid attack at FeIVO indeed is feasible through two competing pathways. These are initiated by homolytic inner‐sphere splitting of the RC(O)OO‐H and the RC(O)O‐OH bond in the peracid, respectively.

Oxoiron(v) mediated selective electrochemical oxygenation of unactivated C-H and C[double bond, length as m-dash]C bonds using water as the oxygen source.

An efficient electrochemical method for the selective oxidation of C–H bonds of unactivated alkanes (BDE ≤97 kcal mol−1) and CC bonds of alkenes using a biomimetic iron complex, [(bTAML)FeIII-OH2]−, as the redox mediator in an undivided electrochemical cell with inexpensive carbon and nickel electrodes is reported. The O-atom of water remains the source of O-incorporation in the product formed after oxidation. The products formed upon oxidation of C–H bonds display very high regioselectivity (75 : 1, 3° : 2° for adamantane) and stereo-retention (RC ∼99% for cyclohexane derivatives). The substrate scope includes natural products such as cedryl acetate and ambroxide. For alkenes, epoxides were obtained as the sole product. Mechanistic studies show the involvement of a high-valent oxoiron(v) species, [(bTAML)FeV(O)]− formed via PCET (overall 2H+/2e−) from [(bTAML)FeIII-OH2]− in CPE at 0.80 V (vs. Ag/AgNO3). Moreover, electrokinetic studies for the oxidation of C–H bonds indicate a second-order reaction with the C–H abstraction by oxoiron(v) being the rate-determining step.

Computational Investigations of Heme Carbenes and Heme Carbene Transfer Reactions.

Engineered heme proteins and biomimetic iron porphyrins have been found to possess excellent catalytic properties for numerous carbene transfer reactions. Computational studies, including the use of DFT calculations and molecular dynamics simulations, have been employed to help understand some important mechanistic aspects of heme carbene transfer reactions. This review summarizes advances in the computational results published in the following two areas: 1) the electronic and geometric structures of heme carbenes; spectroscopic properties; and effects of carbene substituent, porphyrin substituent, axial ligand, and spin state on heme carbene formation; and 2) mechanisms of heme carbenoid X-H (X=C, Si, B, N, S) insertions and cyclopropanation, including effects of heme carbene structural components and protein environment, as well as oxidation state and spin state. A brief outlook of future development is also addressed.