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Synthetic iron-sulfur cubanes are models for biological cofactors, which are essential to delineate oxidation states in the more complex enzymatic systems. However, a complete series of [Fe₄S₄]ⁿ complexes spanning all redox states accessible by 1-electron transformations of the individual iron atoms (n = 0–4+) has never been prepared, deterring the methodical comparison of structure and spectroscopic signature. Here, we demonstrate that the use of a bulky arylthiolate ligand promoting the encapsulation of alkali-metal cations in the vicinity of the cubane enables the synthesis of such a series. Characterization by EPR, 57Fe Mössbauer spectroscopy, UV-visible electronic absorption, variable-temperature X-ray diffraction analysis, and cyclic voltammetry reveals key trends for the geometry of the Fe₄S₄ core as well as for the Mössbauer isomer shift, which both correlate systematically with oxidation state. Furthermore, we confirm the S = 4 electronic ground state of the most reduced member of the series, [Fe₄S₄]⁰, and provide electrochemical evidence that it is accessible within 0.82 V from the [Fe₄S₄]2+ state, highlighting its relevance as a mimic of the nitrogenase iron protein cluster.

The replacement of benzene rings with sp 3 -hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity 1 – 5 . Rigid, strained frameworks such as bicyclo[1.1.1]pentane and cubane are particularly well suited as the ring strain imparts high bond strength and thus metabolic stability on their C–H bonds. Cubane is the ideal bioisostere as it provides the closest geometric match to benzene 6 , 7 . At present, however, all cubanes in drug design, like almost all benzene bioisosteres, act solely as substitutes for mono- or para -substituted benzene rings 1 – 7 . This is owing to the difficulty of accessing 1,3- and 1,2-disubstituted cubane precursors. The adoption of cubane in drug design has been further hindered by the poor compatibility of cross-coupling reactions with the cubane scaffold, owing to a competing metal-catalysed valence isomerization 8 – 11 . Here we report expedient routes to 1,3- and 1,2-disubstituted cubane building blocks using a convenient cyclobutadiene precursor and a photolytic C–H carboxylation reaction, respectively. Moreover, we leverage the slow oxidative addition and rapid reductive elimination of copper to develop C–N, C–C( sp 3 ), C–C( sp 2 ) and C–CF 3 cross-coupling protocols 12 , 13 . Our research enables facile elaboration of all cubane isomers into drug candidates, thus enabling ideal bioisosteric replacement of ortho -, meta - and para -substituted benzenes. The synthesis of 1,3- and 1,2-disubstituted cubanes is achieved using a cyclobutadiene precursor and a photolytic carboxylation reaction, respectively, and copper-catalysed amination, arylation, alkylation and trifluoromethylation reactions have been developed enabling the use of cubanes as bioisosteres of benzenes in drug design.

Photosynthetic water oxidation is catalyzed by the Mn₄CaO₅ cluster of photosystem II (PSII) with linear progression through five S-state intermediates (S₀ to S₄). To reveal the mechanism of water oxidation, we analyzed structures of PSII in the S₁, S₂, and S₃ states by x-ray free-electron laser serial crystallography. No insertion of water was found in S₂, but flipping of D1 Glu189 upon transition to S₃ leads to the opening of a water channel and provides a space for incorporation of an additional oxygen ligand, resulting in an open cubane Mn₄CaO₆ cluster with an oxyl/oxo bridge. Structural changes of PSII between the different S states reveal cooperative action of substrate water access, proton release, and dioxygen formation in photosynthetic water oxidation.

Molybdenum-dependent nitrogenases catalyze the transformation of dinitrogen into ammonia under ambient conditions. The active site (FeMo cofactor) is the structurally and electronically complex weak-field metal cluster [MoFe₇S₉C] built of Fe₄S₃ and MoFe₃S₃C portions connected by three sulfur bridges and containing an interstitial carbon atom centered in an Fe₆ trigonal prism. Chemical synthesis of this cluster is a major challenge in biomimetic inorganic chemistry. One synthetic approach of core ligand metathesis has been developed based on the design and synthesis of unprecedented incomplete ([(Tp*)WFe₂S₃Q₃]⁻) and complete ([(Tp*)WFe₃S₃Q₄]2−) cubane-type clusters containing bridging halide (Q = halide). These clusters are achieved by template-assisted assembly in the presence of sodium benzophenone ketyl reductant; products are controlled by reaction stoichiometry. Incomplete cubane clusters are subject to a variety ofmetathesis reactions resulting in substitution of a μ₂-bridging ligand with other bridges such as N₃⁻, MeO⁻, and EtS⁻. Reactions of complete cubanes with Me₃SiN₃ and S₈ undergo a redox metathesis process and lead to core ligand displacement and formation of [(Tp*)WFe₃S₃(μ₃-Q)Cl₃]⁻ (Q = Me₃SiN2−, S2−). This work affords entry to a wide variety of heteroleptic clusters derivable from incomplete and complete cubanes; examples are provided. Among these is the cluster [(Tp*)WFe₃S₃(μ₃-NSiMe₃)Cl₃]⁻, one of the very few instances of a synthetic Fe–S cluster containing a light atom (C, N, O) in the core, which constitutes a close mimic of the [MoFe₃S₃C] fragment in FeMo cofactor. Superposition of them and comparison of metric information disclose a clear structural relationship [Tp* = tris(3,5-dimethyl-1-pyrazolyl)hydroborate(1−)].

Electron transfers coupled to the hydrolysis of ATP allow various metalloenzymes to catalyze reductions at very negative reduction potentials. The double-cubane cluster protein (DCCP) catalyzes the reduction of small molecules, such as acetylene and hydrazine, with electrons provided by its cognate ATP-hydrolyzing reductase (DCCP-R). How ATP-driven electron transfer occurs is not known. To resolve the structural basis for ATP-driven electron transfer, we solved the structures of the DCCP:DCCP-R complex in three different states. The structures show that the DCCP-R homodimer is covalently bridged by a [4Fe4S] cluster that is aligned with the twofold axis of the DCCP homodimer, positioning the [4Fe4S] cluster to enable electron transfer to both double-cubane clusters in the DCCP dimer. DCCP and DCCP-R form stable complexes independent of oxidation state or nucleotides present, and electron transfer requires the hydrolysis of ATP. Electron transfer appears to be additionally driven by modulating the angle between the helices binding the [4Fe4S] cluster. We observed hydrogen bond networks running from the ATP binding site via the [4Fe4S] cluster in DCCP-R to the double-cubane cluster in DCCP, allowing the propagation of conformational changes. Remarkable similarities between the DCCP:DCCP-R complex and the nonhomologous nitrogenases suggest a convergent evolution of catalytic strategies to achieve ATP-driven electron transfers between iron–sulfur clusters.

The phenyl ring is a basic structural element in chemistry. Here, we show the design, synthesis, and validation of its new saturated bioisostere with improved physicochemical properties − 2-oxabicyclo[2.2.2]octane. The design of the structure is based on the analysis of the advantages and disadvantages of the previously used bioisosteres: bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, and cubane. The key synthesis step is the iodocyclization of cyclohexane-containing alkenyl alcohols with molecular iodine in acetonitrile. 2-Oxabicyclo[2.2.2]octane core is incorporated into the structure of Imatinib and Vorinostat (SAHA) drugs instead of the phenyl ring. In Imatinib, such replacement leads to improvement of physicochemical properties: increased water solubility, enhanced metabolic stability, and reduced lipophilicity. In Vorinostat, such replacement results in a new bioactive analog of the drug. This study enhances the repertoire of available saturated bioisosteres of (hetero)aromatic rings for the use in drug discovery projects. The phenyl ring is a basic structural element in chemistry. Here, the authors show the design, synthesis, and validation of 2-oxabicyclo[2.2.2]octane as a new saturated bioisostere with improved physicochemical properties

In an attempt to isolate boron-containing tri-niobium polychalcogenide species, we have carried out prolonged thermolysis reactions of [Cp*NbCl4] (Cp* = ɳ5-C5Me5) with four equivalents of Li[BH2E3] (E = Se or S). In the case of the heavier chalcogen (Se), the reaction led to the isolation of the tri-niobium cubane-like cluster [(NbCp*)3(μ3-Se)3(BH)(μ-Se)3] (1) and the homocubane-like cluster [(NbCp*)3(μ3-Se)3(μ-Se)3(BH)(μ-Se)] (2). Interestingly, the tri-niobium framework of 1 stabilizes a selenaborate Se3BH− ligand. A selenium atom is further introduced between boron and one of the selenium atoms of 1 to yield cluster 2. On the other hand, the reaction with the sulfur-containing borate adduct [LiBH2S3] afforded the trimetallic clusters [(NbCp*)3(μ-S)4μ-S2(BH)] (3) and [(NbCp*)3(μ-S)4μ-S2(S)] (4). Both clusters 3 and 4 have an Nb3S6 core, which further stabilizes BH and mono-sulfur units, respectively, through bi-chalcogen coordination. All of these species were characterized by 11B1H, 1H, and 13C1H NMR spectroscopy, mass spectrometry, infrared (IR) spectroscopy, and single-crystal X-ray crystallography. Moreover, theoretical investigations revealed that the triangular Nb3 framework is aromatic in nature and plays a vital role in the stabilization of the borate, borane, and chalcogen units.

A cubane-type Cu 4 I 4 cluster 3-PhPy 4 Cu 4 I 4 ( 1 ) was designed and synthesized (3-PhPy = 3-phenylpyridine). The cluster was characterized by elemental analysis, X-ray diffraction, FTIR and UV-Vis spectroscopic analysis. Single-crystal X-ray diffraction revealed that cluster 1 presents a supramolecular interlocking chain structure. Similar cluster 4-PhPy 4 Cu 4 I 4 ( 2 ) was also prepared and re-determined. The TD-DFT calculations reveal that their UV-Vis absorption and luminescence originate from the hybrid [(X + M)LCT] excited states. Based on the cluster 1 , a paper-based sensor ( 1) was prepared through a composite process, it shows a remarkable PL quenching response for pyridine (Py) / cyclohexylamine (CYA) detection with good selectivity. Using this sensor, an amazing sensing speed of T 90  = 5 s was achieved for the detection of Py and T 90  = 10 s for CYA. In the fluorescence sensing response of these two volatile organic compounds, their maximum fluorescence quenching efficiency reached outstanding 98%. The sensor ( 2 ) based on cluster 2 also demonstrated similar fluorescence sensing performance for selective detection of Py or CYA.

The Mn 4 CaO 5(6) cluster in photosystem II catalyzes water splitting through the S i state cycle ( i  = 0–4). Molecular O 2 is formed and the natural catalyst is reset during the final S 3  → (S 4 ) → S 0 transition. Only recently experimental breakthroughs have emerged for this transition but without explicit information on the S 0 -state reconstitution, thus the progression after O 2 release remains elusive. In this report, our molecular dynamics simulations combined with density functional calculations suggest a likely missing link for closing the cycle, i.e., restoring the first catalytic state. Specifically, the formation of closed-cubane intermediates with all hexa-coordinate Mn is observed, which would undergo proton release, water dissociation, and ligand transfer to produce the open-cubane structure of the S 0 state. Thereby, we theoretically identify the previously unknown structural isomerism in the S 0 state that acts as the origin of the proposed structural flexibility prevailing in the cycle, which may be functionally important for nature’s water oxidation catalysis. The Kok cycle describes the mechanism by which water is oxidized through a 5-step process. Here authors use theoretical calculations to reveal how the natural water oxidation catalyst “Mn 4 CaO 5 cluster” is reconstituted after O 2 release during photosynthesis and discover the structural isomerism in the first state of Kok’s cycle.

Exploration of efficient molecular water oxidation catalysts for long-term application remains a key challenge for the conversion of renewable energy sources into fuels. Cuboidal Co4O4 complexes keep attracting interest as molecular water oxidation catalysts as they combine features of both heterogeneous and homogeneous catalysis with bio-inspired motifs. However, the application of many cluster-based catalysts for the oxygen evolution reaction still requires new stabilization strategies. Drawing inspiration from the stabilizing effects of natural polymers, we introduce a conductive polymer-hybrid approach to covalently immobilize Co4O4 cubane oxo clusters as oxygen evolution catalysts. Polypyrrole is applied as an efficient p-type conducting polymer that promotes hole transfer during the oxygen evolution reaction, resulting in higher turnover frequency compared to the pristine Co4O4 oxo cluster and heterogeneous Co-oxide benchmarks. The asymmetric coordination of Co4O4 not only mitigates catalyst decomposition pathways, but also increases the catalytic efficiency by exposing a directed cofacial dihydroxide motif during catalysis.Cuboidal Co4O4 complexes are attractive molecular water oxidation catalysts as they combine features of both heterogeneous and homogeneous catalysis with bio-inspired motifs, but their application requires stabilization strategies. Here, the authors introduce a conductive polymer-hybrid approach to covalently immobilize Co4O4 clusters.