A Nonheme Iron(III) Superoxide Complex Leads to Sulfur Oxygenation.

A new alkylthiolate-ligated nonheme iron complex, FeII(BNPAMe2S)Br (1), is reported. Reaction of 1 with O2 at -40 °C, or reaction of the ferric form with O2•- at -80 °C, gives a rare iron(III)-superoxide intermediate, [FeIII(O2)(BNPAMe2S)]+ (2), characterized by UV-vis, 57Fe Mössbauer, ATR-FTIR, EPR, and CSIMS. Metastable 2 then converts to an S-oxygenated FeII(sulfinate) product via a sequential O atom transfer mechanism involving an iron-sulfenate intermediate. These results provide evidence for the feasibility of proposed intermediates in thiol dioxygenases.

Selective Radical Transfer in a Series of Nonheme Iron(III) Complexes.

A series of nonheme iron complexes, FeIII(BNPAPh2O)(Lax)(Leq) (Lax/eq = N3-, NCS-, NCO-, and Cl-) have been synthesized using the previously reported BNPAPh2O- ligand. The ferrous analogs FeII(BNPAPh2O)(Lax) (Lax = N3-, NCS-, and NCO-) were also prepared. The complexes were structurally characterized using single crystal X-ray diffraction, which shows that all the FeIII complexes are six-coordinate, with one anionic ligand (Lax) in the H-bonding axial site and the other anionic ligand (Leq) in the equatorial plane, cis to the Lax ligand. The reaction of FeIII(BNPAPh2O-)(Lax)(Leq) with Ph3C• shows that one ligand is selectively transferred in each case. A selectivity trend emerges that shows •N3 is the most favored for transfer in each case to the carbon radical, whereas Cl• is the least favored. The NCO and NCS ligands showed an intermediate propensity for radical transfer, with NCS > NCO. The overall order of selectivity is N3 > NCS > NCO > Cl. In addition, we also demonstrated that H-bonding has a small effect on governing product selectivity by using a non-H-bonded ligand (DPAPh2O-). This study demonstrates the inherent radical transfer selectivity of nonhydroxo-ligated nonheme iron(III) complexes, which could be useful for efforts in synthetic and (bio)catalytic C-H functionalization.

Investigating Metal-Metal Bond Polarization in a Heteroleptic Tris-Ylide Diiron System.

This article describes the synthesis, characterization, and S-atom transfer reactivity of a series of C3v-symmetric diiron complexes. The iron centers in each complex are coordinated in distinct ligand environments, with one (FeN) bound in a pseudo-trigonal bipyramidal geometry by three phosphinimine nitrogens in the equatorial plane, a tertiary amine, and the second metal center (FeC). FeC is coordinated, in turn, by FeN, three ylidic carbons in a trigonal plane, and, in certain cases, by an axial oxygen donor. The three alkyl donors at FeC form through the reduction of the appended N═PMe3 arms of the monometallic parent complex. The complexes were studied crystallographically, spectroscopically (NMR, UV-vis, and Mössbauer), and computationally (DFT, CASSCF) and found to be high-spin throughout, with short Fe-Fe distances that belie weak orbital overlap between the two metals. Further, the redox nature of this series allowed for the determination that oxidation is localized to the FeC. S-atom transfer chemistry resulted in the formal insertion of a S atom into the Fe-Fe bond of the reduced diiron complex to form a mixture of Fe4S and Fe4S2 products.

Oxygen versus Sulfur Coordination in Cobalt Superoxo Complexes: Spectroscopic Properties, O2 Binding, and H-Atom Abstraction Reactivity.

A five-coordinate, disiloxide-ligated cobalt(II) (S = 3/2) complex (1) was prepared as an oxygen-ligated analogue to the previously reported silanedithiolate-ligated CoII(Me3TACN)(S2SiMe2) (J. Am. Chem. Soc., 2019, 141, 3641-3653). The structural and spectroscopic properties of 1 were analyzed by single-crystal X-ray diffraction, electron paramagnetic resonance (EPR), and NMR spectroscopies. The reactivity of 1 with dioxygen was examined, and it was shown to bind O2 reversibly in a range of solvents at low temperatures. A cobalt(III)-superoxo complex, CoIII(O2·-)(Me3TACN)((OSi2Ph)2O) (2), was generated, and was analyzed by UV-vis, EPR, and resonance Raman spectroscopies. Unlike its sulfur-ligated analogue, complex 2 can thermally release O2 to regenerate 1. Vibrational assignments for selective 18O isotopic labeling of both O2 and disiloxide ligands in 2 are consistent with a 6-coordinate, Co(η1-O2·-)("end-on") complex. Complex 2 reacts with the O-H bond of 4-methoxy-2,2,6,6-tetramethylpiperidin-1-ol (4-MeO-TEMPOH) via H-atom abstraction with a rate of 0.58(2) M-1 s-1 at -105 °C, but it is unable to oxidize phenol substrates. This bracketed reactivity suggests that the O-H bond being formed in the putative CoIII(OOH) product has a relatively weak O-H bond strength (BDFE ∼66-74 kcal mol-1). These thermodynamic and kinetic parameters are similar to those seen for the sulfur-ligated Co(O2)(Me3TACN)(S2SiMe2), indicating that the differences in the electronic structure for O versus S ligation do not have a large impact on H-atom abstraction reactivity.

Nonheme Iron(III) Azide and Iron(III) Isothiocyanate Complexes: Radical Rebound Reactivity, Selectivity, and Catalysis.

The new nonheme iron complexes FeII(BNPAPh2O)(N3) (1), FeIII(BNPAPh2O)(OH)(N3) (2), FeII(BNPAPh2O)(OH) (3), FeIII(BNPAPh2O)(OH)(NCS) (4), FeII(BNPAPh2O)(NCS) (5), FeIII(BNPAPh2O)(NCS)2 (6), and FeIII(BNPAPh2O)(N3)2 (7) (BNPAPh2O = 2-(bis((6-(neopentylamino)pyridin-2-yl) methyl)amino)-1,1-diphenylethanolate) were synthesized and characterized by single crystal X-ray diffraction (XRD), as well as by 1H NMR, 57Fe Mössbauer, and ATR-IR spectroscopies. Complex 2 was reacted with a series of carbon radicals, ArX3C· (ArX = p-X-C6H4), analogous to the proposed radical rebound step for nonheme iron hydroxylases and halogenases. The results show that for ArX3C· (X = Cl, H, tBu), only OH· transfer occurs to give ArX3COH. However, when X = OMe, a mixture of alcohol (ArX3COH) (30%) and azide (ArX3CN3) (40%) products was obtained. These data indicate that the rebound selectivity is influenced by the electron-rich nature of the carbon radicals for the azide complex. Reaction of 2 with Ph3C· in the presence of Sc3+ or H+ reverses the selectivity, giving only the azide product. In contrast to the mixed selectivity seen for 2, the reactivity of cis-FeIII(OH)(NCS) with the X = OMe radical derivative leads only to hydroxylation. Catalytic azidation was achieved with 1 as catalyst, λ3-azidoiodane as oxidant and azide source, and Ph3CH as test substrate, giving Ph3CN3 in 84% (TON = 8). These studies show that hydroxylation is favored over azidation for nonheme iron(III) complexes, but the nature of the carbon radical can alter this selectivity. If an OH· transfer pathway can be avoided, the FeIII(N3) complexes are capable of mediating both stoichiometric and catalytic azidation.

Iron Insertion at the Assembly Site of the ISCU Scaffold Protein Is a Conserved Process Initiating Fe-S Cluster Biosynthesis.

Iron-sulfur (Fe-S) clusters are prosthetic groups of proteins biosynthesized on scaffold proteins by highly conserved multi-protein machineries. Biosynthesis of Fe-S clusters into the ISCU scaffold protein is initiated by ferrous iron insertion, followed by sulfur acquisition, via a still elusive mechanism. Notably, whether iron initially binds to the ISCU cysteine-rich assembly site or to a cysteine-less auxiliary site via N/O ligands remains unclear. We show here by SEC, circular dichroism (CD), and Mössbauer spectroscopies that iron binds to the assembly site of the monomeric form of prokaryotic and eukaryotic ISCU proteins via either one or two cysteines, referred to the 1-Cys and 2-Cys forms, respectively. The latter predominated at pH 8.0 and correlated with the Fe-S cluster assembly activity, whereas the former increased at a more acidic pH, together with free iron, suggesting that it constitutes an intermediate of the iron insertion process. Iron not binding to the assembly site was non-specifically bound to the aggregated ISCU, ruling out the existence of a structurally defined auxiliary site in ISCU. Characterization of the 2-Cys form by site-directed mutagenesis, CD, NMR, X-ray absorption, Mössbauer, and electron paramagnetic resonance spectroscopies showed that the iron center is coordinated by four strictly conserved amino acids of the assembly site, Cys35, Asp37, Cys61, and His103, in a tetrahedral geometry. The sulfur receptor Cys104 was at a very close distance and apparently bound to the iron center when His103 was missing, which may enable iron-dependent sulfur acquisition. Altogether, these data provide the structural basis to elucidate the Fe-S cluster assembly process and establish that the initiation of Fe-S cluster biosynthesis by insertion of a ferrous iron in the assembly site of ISCU is a conserved mechanism.

Direct Reduction of NO to N2O by a Mononuclear Nonheme Thiolate Ligated Iron(II) Complex via Formation of a Metastable {FeNO}7 Complex.

Addition of NO to a nonheme dithiolate-ligated iron(II) complex, FeII(Me3TACN)(S2SiMe2) (1), results in the generation of N2O. Low-temperature spectroscopic studies reveal a metastable six-coordinate {FeNO}7 intermediate (S = 3/2) that was trapped at -135 °C and was characterized by low-temperature UV-vis, resonance Raman, EPR, Mössbauer, XAS, and DFT studies. Thermal decay of the {FeNO}7 species leads to the evolution of N2O, providing a rare example of a mononuclear thiolate-ligated {FeNO}7 that mediates NO reduction to N2O without the requirement of any exogenous electron or proton sources.

What Drives Radical Halogenation versus Hydroxylation in Mononuclear Nonheme Iron Complexes? A Combined Experimental and Computational Study.

Nonheme iron halogenases are unique enzymes in nature that selectively activate an aliphatic C-H bond of a substrate to convert it into C-X (X = Cl/Br, but not F/I). It is proposed that they generate an FeIII(OH)(X) intermediate in their catalytic cycle. The analogous FeIII(OH) intermediate in nonheme iron hydroxylases transfers OH• to give alcohol product, whereas the halogenases transfer X• to the carbon radical substrate. There remains significant debate regarding what factors control their remarkable selectivity of the halogenases. The reactivity of the complexes FeIII(BNPAPh2O)(OH)(X) (X = Cl, Br) with a secondary carbon radical (R•) is described. It is found that X• transfer occurs with a secondary carbon radical, as opposed to OH• transfer with tertiary radicals. Comprehensive computational studies involving density functional theory were carried out to examine the possible origins of this selectivity. The calculations reproduce the experimental findings, which indicate that halogen transfer is not observed for the tertiary radicals because of a nonproductive equilibrium that results from the endergonic nature of these reactions, despite a potentially lower reaction barrier for the halogenation pathway. In contrast, halogen transfer is favored for secondary carbon radicals, for which the halogenated product complex is thermodynamically more stable than the reactant complex. These results are rationalized by considering the relative strengths of the C-X bonds that are formed for tertiary versus secondary carbon centers. The computational analysis also shows that the reaction barrier for halogen transfer is significantly dependent on secondary coordination sphere effects, including steric and H-bonding interactions.

An Iron(III) Superoxide Corrole from Iron(II) and Dioxygen.

A new structurally characterized ferrous corrole [FeII (ttppc)]- (1) binds one equivalent of dioxygen to form [FeIII (O2-. )(ttppc)]- (2). This complex exhibits a 16/18 O2 -isotope sensitive ν(O-O) stretch at 1128 cm-1 concomitantly with a single ν(Fe-O2 ) at 555 cm-1 , indicating it is an η1 -superoxo ("end-on") iron(III) complex. Complex 2 is the first well characterized Fe-O2 corrole, and mediates the following biologically relevant oxidation reactions: dioxygenation of an indole derivative, and H-atom abstraction from an activated O-H bond.

A Reactive, Photogenerated High-Spin (S = 2) FeIV(O) Complex via O2 Activation.

Addition of dioxygen at low temperature to the non-heme ferrous complex FeII(Me3TACN)((OSiPh2)2O) (1) in 2-MeTHF produces a peroxo-bridged diferric complex Fe2III(µ-O2)(Me3TACN)2((OSiPh2)2O)2 (2), which was characterized by UV-vis, resonance Raman, and variable field Mössbauer spectroscopies. Illumination of a frozen solution of 2 in THF with white light leads to homolytic O-O bond cleavage and generation of a FeIV(O) complex 4 (ν(Fe=O) = 818 cm-1; δ = 0.22 mm s-1, ΔEQ = 0.23 mm s-1). Variable field Mössbauer spectroscopy measurements show that 4 is a rare example of a high-spin S = 2 FeIV(O) complex and the first synthetic example to be generated directly from O2. Complex 4 is highly reactive, as expected for a high-spin ferryl, and decays rapidly in fluid solution at cryogenic temperatures. This decay process in 2-MeTHF involves C-H cleavage of the solvent. However, the controlled photolysis of 2 in situ with visible light and excess phenol substrate leads to competitive phenol oxidation, via the proposed transient generation of 4 as the active oxidant.

Halogen Transfer to Carbon Radicals by High-Valent Iron Chloride and Iron Fluoride Corroles.

High-valent iron halide corroles were examined to determine their reactivity with carbon radicals and their ability to undergo radical rebound-like processes. Beginning with Fe(Cl)(ttppc) (1) (ttppc = 5,10,15-tris(2,4,6-triphenylphenyl)corrolato3-), the new iron corroles Fe(OTf)(ttppc) (2), Fe(OTf)(ttppc)(AgOTf) (3), and Fe(F)(ttppc) (4) were synthesized. Complexes 3 and 4 are the first iron triflate and iron fluoride corroles to be structurally characterized by single crystal X-ray diffraction. The structure of 3 reveals an AgI-pyrrole (η2-π) interaction. The Fe(Cl)(ttppc) and Fe(F)(ttppc) complexes undergo halogen transfer to triarylmethyl radicals, and kinetic analysis of the reaction between (p-OMe-C6H4)3C• and 1 gave k = 1.34(3) × 103 M-1 s-1 at 23 °C and 2.2(2) M-1 s-1 at -60 °C, ΔH⧧ = +9.8(3) kcal mol-1, and ΔS⧧ = -14(1) cal mol-1 K-1 through an Eyring analysis. Complex 4 is significantly more reactive, giving k = 1.16(6) × 105 M-1 s-1 at 23 °C. The data point to a concerted mechanism and show the trend X = F- > Cl- > OH- for Fe(X)(ttppc). This study provides mechanistic insights into halogen rebound for an iron porphyrinoid complex.

A Nonheme Mononuclear {FeNO}7 Complex that Produces N2 O in the Absence of an Exogenous Reductant.

A new nonheme iron(II) complex, FeII (Me3 TACN)((OSiPh2 )2 O) (1), is reported. Reaction of 1 with NO(g) gives a stable mononitrosyl complex Fe(NO)(Me3 TACN)((OSiPh2 )2 O) (2), which was characterized by Mössbauer (δ=0.52 mm s-1 , |ΔEQ |=0.80 mm s-1 ), EPR (S=3/2), resonance Raman (RR) and Fe K-edge X-ray absorption spectroscopies. The data show that 2 is an {FeNO}7 complex with an S=3/2 spin ground state. The RR spectrum (λexc =458 nm) of 2 combined with isotopic labeling (15 N, 18 O) reveals ν(N-O)=1680 cm-1 , which is highly activated, and is a nearly identical match to that seen for the reactive mononitrosyl intermediate in the nonheme iron enzyme FDPnor (ν(NO)=1681 cm-1 ). Complex 2 reacts rapidly with H2 O in THF to produce the N-N coupled product N2 O, providing the first example of a mononuclear nonheme iron complex that is capable of converting NO to N2 O in the absence of an exogenous reductant.

Proton-Coupled Electron-Transfer Reactivity Controls Iron versus Sulfur Oxidation in Nonheme Iron-Thiolate Complexes.

Reaction of the five-coordinate FeII(N4S) complexes, [FeII(iPr3TACN)(abtX)](OTf) (abt = aminobenzenethiolate, X = H, CF3), with a one-electron oxidant and an appropriate base leads to net H atom loss, generating new FeIII(iminobenzenethiolate) complexes that were characterized by single-crystal X-ray diffraction (XRD), as well as UV-vis, EPR, and Mössbauer spectroscopies. The spectroscopic data indicate that the iminobenzenethiolate complexes have S = 3/2 ground states. In the absence of a base, oxidation of the FeII(abt) complexes leads to disulfide formation instead of oxidation at the metal center. Bracketing studies with separated proton-coupled electron-transfer (PCET) reagents show that the FeII(aminobenzenethiolate) and FeIII(iminobenzenethiolate) forms are readily interconvertible by H+/e- transfer and provide a measure of the bond dissociation free energy (BDFE) for the coordinated N-H bond between 64 and 69 kcal mol-1. This work shows that coordination to the iron center causes a dramatic weakening of the N-H bond and that Fe- versus S-oxidation in a nonheme iron complex can be controlled by the protonation state of an ancillary amino donor.

Evaluation of the Physicochemical Properties of the Iron Nanoparticle Drug Products: Brand and Generic Sodium Ferric Gluconate.

Complex iron nanoparticle-based drugs are one of the oldest and most frequently administered classes of nanomedicines. In the US, there are seven FDA-approved iron nanoparticle reference drug products, of which one also has an approved generic drug product (i.e., sodium ferric gluconate (SFG)). These products are indicated for the treatment of iron deficiency anemia and are administered intravenously. On the molecular level, iron nanomedicines are colloids composed of an iron oxide core with a carbohydrate coating. This formulation makes nanomedicines more complex than conventional small molecule drugs. As such, these products are often referred to as nonbiological complex drugs (e.g., by the nonbiological complex drugs (NBCD) working group) or complex drug products (e.g., by the FDA). Herein, we report a comprehensive study of the physiochemical properties of the iron nanoparticle product SFG. SFG is the single drug for which both an innovator (Ferrlecit) and generic product are available in the US, allowing for comparative studies to be performed. Measurements focused on the iron core of SFG included optical spectroscopy, inductively coupled plasma mass spectrometry (ICP-MS), X-ray powder diffraction (XRPD), 57Fe Mössbauer spectroscopy, and X-ray absorbance spectroscopy (XAS). The analysis revealed similar ferric-iron-oxide structures. Measurements focused on the carbohydrate shell comprised of the gluconate ligands included forced acid degradation, dynamic light scattering (DLS), analytical ultracentrifugation (AUC), and gel permeation chromatography (GPC). Such analysis revealed differences in composition for the innovator versus the generic SFG. These studies have the potential to contribute to future quality assessment of iron complex products and will inform on a pharmacokinetic study of two therapeutically equivalent iron gluconate products.

Temperature-Dependent Reactivity of a Non-heme FeIII(OH)(SR) Complex: Relevance to Isopenicillin N Synthase.

Non-heme iron complexes with cis-FeIII(OH)(SAr/OAr) coordination were isolated and examined for their reactivity with a tertiary carbon radical. The sulfur-ligated complex shows a temperature dependence on •OH versus ArS• transfer, whereas the oxygen-ligated complex does not. These results provide the first working model for C-S bond formation in isopenicillin N synthase and indicate that kinetic control may be a key factor in the selectivity of non-heme iron "rebound" processes.

The Selective Monobromination of a Highly Sterically Encumbered Corrole: Structural and Spectroscopic Properties of Fe(Cl)(2-Bromo-5,10,15-tris(triphenyl)phenyl corrole).

The corrole ligand serves as a versatile tri-anionic, macrocyclic platform on which to model biological catalytic systems, as well as to effect mechanistically challenging chemical transformations. Here in we describe the synthesis, structure, and characterization of an isomerically pure corrole ligand, selectively mono-brominated at the ß-carbon position adjacent to the corrole C-C bond (2-C) and produced in relatively high yields, as well as its iron chloride complex. Analysis of the iron metalated complex by cyclic voltammetry shows that the bromine being present on the ligand resulted in anodic shifts of +93 and +63 mV for first oxidation and first reduction of the complex respectively. The Mossbauer spectrum of the iron metalated complex shows negligible change relative to the non-brominated analog, indicating the presence of the halide substituent predominantly effects the orbitals of the ligand rather than the metal.

Hydroxyl Transfer to Carbon Radicals by Mn(OH) vs Fe(OH) Corrole Complexes.

The transfer of •OH from metal-hydroxo species to carbon radicals (R•) to give hydroxylated products (ROH) is a fundamental process in metal-mediated heme and nonheme C-H bond oxidations. This step, often referred to as the hydroxyl "rebound" step, is typically very fast, making direct study of this process challenging if not impossible. In this report, we describe the reactions of the synthetic models M(OH)(ttppc) (M = Fe (1), Mn (3); ttppc = 5,10,15-tris(2,4,6-triphenyl)phenyl corrolato3-) with a series of triphenylmethyl carbon radical (R•) derivatives ((4-X-C6H4)3C•; X = OMe, tBu, Ph, Cl, CN) to give the one-electron reduced MIII(ttppc) complexes and ROH products. Rate constants for 3 for the different radicals ranged from 11.4(1) to 58.4(2) M-1 s-1, as compared to those for 1, which fall between 0.74(2) and 357(4) M-1 s-1. Linear correlations for Hammett and Marcus plots for both Mn and Fe were observed, and the small magnitudes of the slopes for both correlations imply a concerted •OH transfer reaction for both metals. Eyring analyses of reactions for 1 and 3 with (4-X-C6H4)3C• (X = tBu, CN) also give good linear correlations, and a comparison of the resulting activation parameters highlight the importance of entropy in these •OH transfer reactions. Density functional theory calculations of the reaction profiles show a concerted process with one transition state for all radicals investigated and help to explain the electronic features of the OH rebound process.

Determining the Inherent Selectivity for Carbon Radical Hydroxylation versus Halogenation with FeIII(OH)(X) Complexes: Relevance to the Rebound Step in Non-heme Iron Halogenases.

The first structural models of the proposed cis-FeIII(OH)(halide) intermediate in the non-heme iron halogenases were synthesized and examined for their inherent reactivity with tertiary carbon radicals. Selective hydroxylation occurs for these cis-FeIII(OH)(X) (X = Cl, Br) complexes in a radical rebound-like process. In contrast, a cis-FeIII(Cl)2 complex reacts with carbon radicals to give halogenation. These results are discussed in terms of the inherent reactivity of the analogous rebound intermediate in both enzymes and related catalysts.

Oxidation of an indole substrate by porphyrin iron(iii) superoxide: relevance to indoleamine and tryptophan 2,3-dioxygenases.

Reaction of FeIII(O2˙-)(TPP) with 2,3-dimethylindole at -40 °C gives the ring-opened, dioxygenated N-(2-acetyl-phenyl)-acetamide product. The reaction was monitored in situ by low-temperature UV-vis and 1H NMR spectroscopies. This work demonstrates that a discrete iron(iii)(superoxo) porphyrin is competent to carry out indole oxidation, as proposed for the tryptophan and indoleamine 2,3-dioxygenases.