David P. Goldberg

Evidence for an iron(III)-indolenylperoxo (OOIn–) complex, [FeIII(OOIn)(TPP)(OCH3)]− (TPP = 5,10,15,20-tetraphenylporphyrinato2–) trapped at −78 °C, was obtained. The formation of this species was initiated by reaction of either FeIII(TPP)(Cl) in the presence of excess O2, OCH3– as axial ligand and base, and 3-methylindole, or from reaction of preformed [FeIII(O2•–)(TPP)(OCH3)]− with 3-methylindole under the same basic conditions. The new species was characterized by UV–vis, X-band EPR, and Mössbauer spectroscopies. Interestingly, the EPR spectra of [FeIII(OOIn)(TPP)(OCH3)]− exhibited two overlapping low-spin (S = 1/2) rhombic signals (A: g = [2.31, 2.20, 1.93]; B: g = [2.24, 2.15, 1.96]), whose ratios are sensitive to the amount of MeOH in the solvent mixture MeOH/toluene. The two sets of EPR signals (A and B) were assigned as arising from the presence or absence of hydrogen bonding between the OCH3– axial ligand and the solvent MeOH. This assignment was supported by analysis of ligand field splitting parameters derived from the EPR data. Addition of 1-methylimidazole (1-MeIm) to [FeIII(OOIn)(TPP)(OCH3)]− at −78 °C leads to conversion of the two overlapping rhombic EPR signals into a new, single S = 1/2 rhombic spectrum with g = [2.31, 2.18, 1.94] and a sharper Mössbauer spectrum. These data are consistent with substitution of OCH3– axial ligand by 1-MeIm to give FeIII(OOIn)(TPP)(1-MeIm). Thermal decay of the iron(III)-indolenylperoxo complex gives the ring-opened, dioxygenated product N-(2-acetylphenyl)formamide (75% by GC-MS). The capability of [FeIII(OOIn)(TPP)(OCH3)]− to convert into dioxygenated product indicates that iron indolenylperoxide is a possible intermediate of the indole dioxygenation process. This work has implications for the proposed mechanisms of tryptophan/indoleamine 2,3-dioxygenase (TDO/IDO) and demonstrates a feasible pathway for dioxygenation mediated by a single iron porphyrin complex.

Cleavage and polyadenylation specificity factor 30 (CPSF30) is a zinc finger protein that plays a key role in pre-mRNA processing by recognizing specific AU-rich sequence elements to facilitate polyadenylation. CPSF30 contains five highly conserved domains made up of three cysteines and a single histidine residue (CCCH, where C = cysteine; H = histidine). These domains coordinate both Zn and an essential 2Fe-2S cluster required for high-affinity RNA binding. The location of the 2Fe-2S cluster within the five CCCH domains and its function have proven elusive. Here, we apply metal-catalyzed oxidation mass spectrometry (MCO-MS) to identify the 2Fe-2S cluster site within CPSF30. By first determining its redox properties and then initiating Fenton chemistry, we localized the Fe–S cluster to the second CCCH domain. The effect of redox state on RNA binding was then assessed, and it was determined that the Fe–S site is a structural domain. The effect of redox status in THP-1 cells on CPSF30 was then investigated, and the redox properties of the cluster were linked to protein abundance under hypoxic and normoxic stress. Together, this work describes a new approach to identify Fe–S sites in complex metalloproteins that house multiple metal cofactors, suggests a mechanism for metal-mediated RNA recognition by CPSF30, and reveals redox-mediated control of CPSF30 in cells.

The synthesis and characterization of a series of nonheme Fe(II), Mn(II), and Co(II) complexes, MII(BNPAPh2O)(Cl) (M = Fe, Mn, Co), are reported. These complexes were characterized using single-crystal X-ray crystallography, 1H NMR spectroscopy, and ATR-FTIR spectroscopy to establish their structural and electronic properties. Their reactivity with dioxygen revealed distinct metal-dependent pathways. The Mn(II) complex undergoes ligand-based C–N bond cleavage, forming a pentanuclear cluster, whereas the Fe(II) complex reacts with O2 to generate a well-defined FeIII(BNPAPh2O)(OH)(Cl) species, relevant to the rebound intermediate in nonheme iron halogenases. In contrast, the Co(II) complex exhibits no detectable reactivity toward O2. These differences illuminate the intrinsic metal-dependent factors that govern O2 activation and underscore the central role of metal identity in tuning reactivity and selectivity in bioinorganic oxidation chemistry.

High-valent metal–nitrido species are powerful nitrogen-atom transfer intermediates but remain difficult to access and control due to intrinsic instability and bimolecular N–N coupling pathways. Herein, we report the first formation of a high-valent Mn(V)–nitrido complex within a de novo designed protein scaffold and demonstrate that a reactive precursor to this species can be catalytically intercepted for enantioselective aziridination. A Mn(V)≡N unit derived from an abiological diphenyl porphyrin is confined within a designed helical bundle protein, where the protein environment suppresses bimolecular decay and enables detailed spectroscopic characterization. Electron paramagnetic resonance, resonance Raman, and circular dichroism spectroscopies confirm formation of a low-spin Mn(V)–nitrido species that is stable for weeks at room temperature and exhibits minimal perturbation of the Mn≡N unit upon modulation of the axial histidine ligand, while catalytic activity and stereochemical outcome are sensitive to its presence. Mechanistic studies identify monochloramine (NH₂Cl) as the operative nitrogen-atom donor and support the involvement of a transient Mn-bound N-transfer intermediate en route to nitrido formation. Under catalytic conditions, this intermediate is intercepted to perform aziridination with TON ≈ 180 and an enantiomeric ratio of 65:35. Together, these results establish de novo protein design as a platform for stabilizing high-valent metal–nitrido species and harnessing their reactivity for nitrogen-atom transfer chemistry beyond the limits of natural metalloenzymes and small-molecule catalysts.

Persulfides (RSSH) have been proposed as key players in biochemical transformations that often involve iron, including iron–sulfur cluster assembly, H₂S regulation, post translational modifications, and mitochondrial sulfur oxidation. An example of the latter is found in the O₂-mediated oxidation of glutathione persulfide to sulfite dianion (SO₃^2–) catalyzed by ETHE1, a nonheme iron persulfide dioxygenase (PDO). The iron-mediated mechanism of persulfide oxidation by PDOs remains poorly understood, and there are no synthetic analogues to date. Herein, we report the synthesis, characterization, and O₂ reactivity of a rare iron(II)-alkylpersulfide complex. The adamantyl persulfide anion (AdSS-) was isolated and characterized by X-ray diffraction as a complex with potassium 18-crown-6 [K(18-crown-6)][AdSS], and employed in the synthesis of a new dinuclear iron(II) complex, [(Fe^II(Me₃TACN))₂(μ₂-SSAd)₃][OTf] (1). Complex 1 was characterized by single crystal X-ray diffraction (XRD), UV–vis, ¹H/¹⁹F NMR, and ⁵⁷Fe Mössbauer spectroscopy. Reaction of 1 with O₂ in CH₃CN affords a diiron(III) oxo-bridged complex [(Fe^III(Me₃TACN))₂(μ-O)(μ₂-SO₄)(μ₂-SO₃Ad)][OTf] (2) identified by XRD, and SO₃^2– (∼0.5 equiv per Fe₂). Isotopic labeling studies using ¹⁸O₂ and H₂¹⁸O, supported by control experiments and ESI-MS analysis, indicate that SO₃^2– production proceeds via an iron-centered S-oxygenation mechanism similar to that proposed for persulfide dioxygenases.

A new pentadentate-fluorinated N₄S(thiolate) ligand was synthesized. Reaction with Fe(BF₄)₂·6H₂O gives a new thioether complex, [Fe^II(CH₃CN)(N3Py^pFSEtCN)][BF₄]₂ (1), and on-metal deprotection gives the thiolate complex, [Fe^II(CH₃CN)(N3Py^pFS)][BF₄] (2). Reaction of 2 with NO forms a low-spin ground state (S = 1/2) {FeNO}⁷ complex (3). Chemical reduction of 3 with cobaltocene gives a metastable intermediate spin S = 1 {FeNO}⁸ complex (4). Protonation of 4 releases nitroxyl (HNO), as observed by ESI-MS and ³¹P NMR trapping experiments with PPh₃. Complexes 1 and 2 were characterized by single-crystal X-ray crystallography, complexes 2-4 were characterized by EPR and FT-IR spectroscopies, and all iron complexes were characterized by ¹⁹F NMR, UV-vis, and ⁵⁷Fe Mössbauer spectroscopies. These results show that a nonheme iron complex can generate and release HNO, suggesting that nonheme iron centers could be endogenous or exogenous sources of HNO in biological systems. Additionally, the fluorine-substituted N₄S(thiolate) ligand provides a unique spectroscopic handle to monitor the reactivity of the iron center several bonds away from the fluorine substituent.

Mixed-valence coordination polymers (CPs) can exhibit enhanced and tunable conductivity and stimulus-driven phase transitions, making them promising new electronic materials. However, the mechanisms of the electron transfer processes that underlie these properties in the solid state merit further study. Here, we report the synthesis of a new mixed-valence CP, Fe^III₂Fe^IIO(OAc)₆(bpy)₂ (OAc = acetate, bpy = 4,4'-bipyridine), which is obtained from the self-assembly of Fe₃O(OAc)₆ clusters and bpy linkers. Notably, the CP is charge-neutral in its mixed-valence form, making it one of the few established intrinsically mixed-valence CPs. Detailed characterization of the valence and spin states of the constituent Fe ions in the CP via variable-temperature Mössbauer spectroscopy, single-crystal X-ray diffraction, and magnetic susceptibility measurements reveals the occurrence of thermally activated electron transfer (i.e., valence detrapping) and antiferromagnetic exchange between Fe^II and Fe^III ions. Intriguingly, valence-detrapping phenomena are confined to distinct regions of the CP and proceed to varying degrees of completion depending on the solid-state environment of the participating Fe ions. This study presents a convenient strategy for the direct synthesis of intrinsically mixed-valence coordination polymers and highlights the important role of solid-state structural order in manipulating electron transfer mechanisms in Class II Robin-Day mixed-valence materials.

The nonheme iron(II) complexes containing a fluoride anion, Fe^II(BNPA^Ph2O)(F) (1) and [Fe^II(BNPA^Ph2OH)(F)(THF)](BF₄) (2), were synthesized and structurally characterized. Addition of dioxygen to either 1 or 2 led to the formation of a fluoride-bridged, dinuclear iron(III) complex [Fe₂^III(BNPA^Ph2O)₂(F)₂(μ-F)]⁺ (4), which was characterized by single-crystal X-ray diffraction, ¹H NMR, and elemental analysis. An iron(II)(iodide) complex, Fe^II(BNPA^Ph2O)(I) (3), was prepared and reacted with O₂ to give the mononuclear complex cis-Fe^III(BNPA^Ph2O)(OH)(I) (5). Addition of excess fluoride to 5 led to the formation of the oxo-bridged, dinuclear iron(III) complex [Fe₂^III(BNPA^Ph2O)₂(F)₂(μ-O)] (6), while the mononuclear iron(III)(fluoride) complex cis-Fe^III(BNPA^Ph2O)(F)(Cl) (7) was prepared from the addition of excess F^- to Fe^III(BNPA^Ph2O)Cl₂. The dinuclear complexes 4 and 6 were unreactive to fluorine radical transfer, but mononuclear 7 reacts with the radical substrate (p-MeO-C₆H₄)₃C^• to give the fluorine radical transfer products Fe^II(BNPA^Ph2O)(Cl) and (p-OMe-C₆H₄)₃CF. These results show that a mononuclear Fe^III(F) complex is capable of mediating fluorine radical transfer, even in the presence of second coordination sphere hydrogen bonds to the F^- ligand. These findings are placed in context with what is known about the nonheme iron halogenases and related synthetic catalysts regarding their ability, or lack thereof, to mediate fluorine radical transfer reactions.