Brighton A. Skeel

Iron-sulfur proteins perform a wide variety of reactions central to the metabolisms of all living organisms. Foundational to their reaction chemistry are the rich electronic structures of their constituent Fe-S clusters, which differ in important ways from the active sites of mononuclear Fe enzymes. In this perspective, we summarize the essential electronic structure features that make Fe-S clusters unique, and point to the need for studies aimed at understanding the electronic basis for their reactivity under physiological conditions. Specifically, at ambient temperature, both the ground state and a large number of excited states are thermally populated, and thus a complete understanding of Fe-S cluster reactivity must take into account the properties, energies, and reactivity patterns of these excited states. We highlight prior research toward characterizing the low-energy excited states of Fe-S clusters that has established what is now a consensus model of these excited state manifolds and the bonding interactions that give rise to them. In particular, we discuss the low-energy alternate spin states and valence electron configurations that occur in Fe-S clusters of varying nuclearities, and finally suggest that there may be unrecognized functional roles for these states. Graphical abstract

Cuboidal [Fe₄S₄] clusters are ubiquitous cofactors in biological redox chemistry. In the [Fe₄S₄]¹⁺ state, pairwise spin coupling gives rise to six arrangements of the Fe valences ("valence isomers") among the four Fe centers. Because of the magnetic complexity of these systems, it has been challenging to understand how a protein's active site dictates both the arrangement of the valences in the ground state as well as the population of excited-state valence isomers. Here, we show that the ground-state valence isomer landscape can be simplified from a six-level system in an asymmetric protein environment to a two-level system by studying the problem in synthetic [Fe₄S₄]¹⁺ clusters with solution C_3v symmetry. This simplification allows for the energy differences between valence isomers to be quantified (in some cases with a resolution of 3Fe₄S₄-X/L]ⁿ, (SIMes = 1,3-dimesityl-imidazol-4,5-dihydro-2-ylidene; n = 0 for anionic, X-type ligands and n = +1 for neutral, L-type ligands) and find that a single ligand substitution can alter the relative ground-state energies of valence isomers by at least 10³ cm^-1. On this basis, we suggest that one result of "non-canonical" amino acid ligation in Fe-S proteins is the redistribution of the valence electrons in the manifold of thermally populated excited states.

Nature employs weak-field metalloclusters to support a wide range of biological processes. The most ubiquitous metalloclusters are the cuboidal Fe–S clusters, which are comprised of Fe sites with locally high-spin electronic configurations. Such configurations enhance rates of ligand exchange and imbue the clusters with a degree of structural plasticity that is increasingly thought to be functionally relevant. Here, we examine this phenomenon using isotope tracing experiments. Specifically, we demonstrate that synthetic [Fe ₄ S ₄ ] and [MoFe ₃ S ₄ ] clusters exchange their Fe atoms with Fe ²⁺ ions dissolved in solution, a process that involves the reversible cleavage and reformation of every Fe–S bond in the cluster core. This exchange is facile—in most cases occurring at room temperature on the timescale of minutes—and documented over a range of cluster core oxidation states and terminal ligation patterns. In addition to suggesting a highly dynamic picture of cluster structure, these results provide a method for isotopically labeling pre-formed clusters with spin-active nuclei, such as ⁵⁷ Fe. Such a protocol is demonstrated for the radical S -adenosyl- l -methionine enzyme, RlmN.

Chemical oxidation with hydroxyl radical (HO^•) and sulfate radical (SO₄^•–) is often used to treat water contaminated with aromatic compounds. Although oxidation of aromatics by these radicals has been studied for decades, the commonly accepted transformation pathway—sequential hydroxylation of the ring followed by ring cleavage and mineralization of the resulting products—does not account for the loss of the parent compound observed during the initial phase of the process. To assess the importance of pathways for aromatic compound oxidation that do not result in ring hydroxylation, we identified products formed after the initial reaction between HO^• or SO₄^•– and benzene, toluene, ethylbenzene, and (BTEX) xylene isomers. We quantified products of ring hydroxylation and oxidation of alkyl substituents as well as a suite of ring-cleavage products, including acetaldehyde, formic acid, 6-, 7-, or 8-carbon oxoenals and oxodials. Other ring-cleavage products, which were most likely aldehydes and organic acids, were observed but not quantified. When SO₄^•– was used as the oxidant, aromatic organosulfates also were formed. Our results indicated that the initial phase of the oxidation process involves radical addition, hydrogen abstraction, or one-electron transfer to the ring followed by reaction with O₂. The hydroxycyclohexadienylperoxy radical produced in this reaction can eliminate hydroperoxyl radical (HO₂^•) to produce a phenolic compound or it can rearrange to form a bicyclic peroxy intermediate that subsequently undergoes ring cleavage. Hydroxylation of the ring and oxidation of the alkyl substituent accounted for approximately 15–40% of the reacted mass of the parent compound. Ring-cleavage products for which quantification was possible accounted for approximately 2 to 10% of the reacted mass. Our results raise concerns about the formation of toxic ring-cleavage products during the initial stage of oxidation whenever HO^• or SO₄^•– is used for the treatment of water containing benzene or alkylbenzenes.

Addition of the potassium salt of the bulky tetra(isopropyl)cyclopentadienyl (Cp^iPr4) ligand to UI₃(1,4-dioxane)_1.5 results in the formation of the bent metallocene uranium(III) complex (Cp^iPr4)₂UI (1), which is then used to obtain the uranium(IV) and uranium(III) dihalides (Cp^iPr4)₂U^IVX₂ (2-X) and [cation][(Cp^iPr4)₂U^IIIX₂] (3-X, [cation]⁺ = [Cp*₂Co]⁺, [Et₄N]⁺, or [Me₄N]⁺) as mononuclear, donor-free complexes, for X^– = F^–, Cl^–, Br^–, and I^–. Interestingly, reaction of 1 with chloride and cyanide salts of alkali metal ions leads to isolation of the chloride- and cyanide-bridged coordination solids [(Cp^iPr4)₂U(μ-Cl)₂Cs]_n (4-Cl) and [(Cp^iPr4)₂U(μ-CN)₂Na(OEt₂)₂]_n (4-CN). Abstraction of the iodide ligand from 1 further enables isolation of the “base-free” metallocenium cation salt [(Cp^iPr4)₂U][B(C₆F₅)₄] (5) and its DME adduct [(Cp^iPr4)₂U(DME)][B(C₆F₅)₄] (5-DME). Solid-state structures of all of the compounds, determined by X-ray crystallography, facilitate a detailed analysis of the effect of changing oxidation state or halide ligand on the molecular structure. NMR spectroscopy, X-ray crystallography, cyclic voltammetry, and UV–visible spectroscopy studies of 2-X and 3-X further reveal that the difluoride species in both series exhibit properties that differ significantly from trends observed among the other dihalides, such as a substantial negative shift in the potential of the [(Cp^iPr4)₂UX₂] uranium(III/IV) redox couple. Magnetic characterization of 1 and 5 reveals that both compounds exhibit slow magnetic relaxation of molecular origin under applied magnetic fields; this process is dominated by a Raman relaxation mechanism.

Straightforward syntheses are provided for the m-terphenyl dithiocarboxylic acid 2,6-(C₆H₄-4-^tBu)₂C₆H₃CS₂H (TerphCS₂H, 2) and its lithium and potassium salts, TerphCS₂Li(Et₂O)₂ and TerphCS₂K (1·Et₂O and 4, respectively). These compounds can be isolated in good yields on multi-gram scales starting from Terph–I without isolating intermediates. Salt metathesis and protonolysis reactions provided access to the homoleptic actinide(IV) complexes (TerphCS₂)₄An (An = Th (5) and U (6)). Electrochemical and reactivity studies revealed that the dithiocarboxylate ligand is incompatible with U(III). The homoleptic lanthanum(III) complex (TerphCS₂)₃La and its η⁶-toluene adduct (7 and 7·tol, respectively) were also structurally characterized. Binding of toluene to 7 was shown to displace intramolecular La–C_arene close contacts that are facilitated by a distortion from the usual geometry of bound dithiocarboxylate ligands.