Isostructural Series of a Cyclometalated Iron Complex in Three Oxidation States.

An isostructural series of FeII, FeIII, and FeIV complexes [Fe(ImP)2]0/+/2+ utilizing the ImP 1,1'-(1,3-phenylene)bis(3-methyl-1-imidazol-2-ylidene) ligand, combining N-heterocyclic carbenes and cyclometalating functions, is presented. The strong donor motif stabilizes the high-valent FeIV oxidation state yet keeps the FeII oxidation state accessible from the parent FeIII compound. Chemical oxidation of [Fe(ImP)2]+ yields stable [FeIV(ImP)2]2+. In contrast, [FeII(ImP)2]0, obtained by reduction, is highly sensitive toward oxygen. Exhaustive ground state characterization by single-crystal X-ray diffraction, 1H NMR, Mössbauer spectroscopy, temperature-dependent magnetic measurements, a combination of X-ray absorption near edge structure and valence-to-core, as well as core-to-core X-ray emission spectroscopy, complemented by detailed density functional theory (DFT) analysis, reveals that the three complexes [Fe(ImP)2]0/+/2+ can be unequivocally attributed to low-spin d6, d5, and d4 complexes. The excited state landscape of the FeII and FeIV complexes is characterized by short-lived 3MLCT and 3LMCT states, with lifetimes of 5.1 and 1.4 ps, respectively. In the FeII-compound, an energetically low-lying MC state leads to fast deactivation of the MLCT state. The distorted square-pyramidal state, where one carbene is dissociated, can not only relax into the ground state, but also into a singlet dissociated state. Its formation was investigated with time-dependent optical spectroscopy, while insights into its structure were gained by NMR spectroscopy.

Transferrin Receptor-Mediated Cellular Uptake of Fluorinated Chlorido[N,N'-bis(salicylidene)-1,2-phenylenediamine]iron(III) Complexes.

Fluorinated chlorido[salophene]iron(III) complexes (salophene = N,N'-bis(salicylidene)-1,2-phenylenediamine) are promising anticancer agents. Apoptosis and necrosis induction have already been described as part of their mode of action. However, the involvement of ferroptosis in cell death induction, as confirmed for other chlorido[salophene]iron(III) complexes, has not yet been investigated. Furthermore, the mechanism of cellular uptake of these compounds is unknown. Therefore, the biological activity of the fluorescent chlorido[salophene]iron(III) complexes with a fluorine substituent at positions 3, 4, 5, or 6 at the salicylidene moieties (C1-C4) was evaluated in malignant and nonmalignant cell lines with focus on the involvement of the transferrin receptor-1 (TfR-1) in cellular uptake, the influence of the complexes on mitochondrial function, and the analysis of the molecular mechanism of cell death. All complexes significantly decreased the metabolic activity in the tested ovarian cancer (A2780, A2780cis), breast cancer (MDA-MB 231), and leukemia (HL-60) cell lines, while the nonmalignant human stroma cell line HS-5 at a concentration of 0.5 µM, which represents the IC50 of the complexes in most of the used tumorigenic cell lines, was not affected. The mitochondrial function was impaired, as evidenced by a reduced mitochondrial membrane potential ΔΨm and decreased mitochondrial activity. Besides apoptosis and necroptosis, ferroptosis was identified as part of the mode of action. It was further demonstrated for the first time that fluorinated chlorido[salophene]iron(III) complexes downregulate TfR-1 expression, comparable to ferristatin II, an iron transport inhibitor that acts via TfR-1 degradation. FerroOrange staining further indicated that the complexes strongly increased the intracellular iron(II) level as a driving force to induce ferroptosis. In conclusion, these fluorinated chlorido[salophene]iron(III) complexes are potent, tumor cell-specific chemotherapeutic agents, with the potential to treat various types of cancers.

Design, synthesis, and biological evaluation of novel halogenated chlorido[N,N'-bis(salicylidene)-1,2-bis(3-methoxyphenyl)ethylenediamine]iron(III) complexes as anticancer agents.

Iron(III) complexes based on N,N´-bis(salicylidene)ethylenediamine (salene) scaffolds have demonstrated promising anticancer features like induction of ferroptosis, an iron dependent cell death. Since poor cellular uptake limits their therapeutical potential, this study aimed to enhance the lipophilic character of chlorido[N,N'-bis(salicylidene)-1,2-bis(3-methoxyphenyl)ethylenediamine]iron(III) complexes by introducing lipophilicity improving ligands such as fluorine (X1), chlorine (X2) and bromine (X3) in 5-position in the salicylidene moieties. After detailed characterization the binding to nucleophiles, logP values and cellular uptake were determined. The complexes were further evaluated regarding their biological activity on MDA-MB 231 mammary carcinoma, the non-tumorous SV-80 fibroblast, HS-5 stroma and MCF-10A mammary gland cell lines. Stability of the complexes in aqueous and biological environments was proven by the lack of interactions with amino acids and glutathione. Cellular uptake was positively correlated with the logP values, indicating that higher lipophilicity enhanced cellular uptake. The complexes induced strong antiproliferative and antimetabolic effects on MDA-MB 231 cells, but were inactive on all non-malignant cells tested. Generation of mitochondrial reactive oxygen species, increase of lipid peroxidation and induction of both ferroptosis and necroptosis were identified as mechanisms of action. In conclusion, halogenation of chlorido[N,N'-bis(salicylidene)-1,2-bis(3-methoxyphenyl)ethylenediamine]iron(III) complexes raises their lipophilic character resulting in improved cellular uptake.

Iron(III)-salophene catalyzes redox cycles that induce phospholipid peroxidation and deplete cancer cells of ferroptosis-protecting cofactors.

Ferroptosis, a lipid peroxidation-driven cell death program kept in check by glutathione peroxidase 4 and endogenous redox cycles, promises access to novel strategies for treating therapy-resistant cancers. Chlorido [N,N'-disalicylidene-1,2-phenylenediamine]iron (III) complexes (SCs) have potent anti-cancer properties by inducing ferroptosis, apoptosis, or necroptosis through still poorly understood molecular mechanisms. Here, we show that SCs preferentially induce ferroptosis over other cell death programs in triple-negative breast cancer cells (LC50 ≥ 0.07 µM) and are particularly effective against cell lines with acquired invasiveness, chemo- or radioresistance. Redox lipidomics reveals that initiation of cell death is associated with extensive (hydroper)oxidation of arachidonic acid and adrenic acid in membrane phospholipids, specifically phosphatidylethanolamines and phosphatidylinositols, with SCs outperforming established ferroptosis inducers. Mechanistically, SCs effectively catalyze one-electron transfer reactions, likely via a redox cycle involving the reduction of Fe(III) to Fe(II) species and reversible formation of oxo-bridged dimeric complexes, as supported by cyclic voltammetry. As a result, SCs can use hydrogen peroxide to generate organic radicals but not hydroxyl radicals and oxidize membrane phospholipids and (membrane-)protective factors such as NADPH, which is depleted from cells. We conclude that SCs catalyze specific redox reactions that drive membrane peroxidation while interfering with the ability of cells, including therapy-resistant cancer cells, to detoxify phospholipid hydroperoxides.

A mesoionic carbene stabilized nickel(II) hydroxide complex: a facile precursor for C-H activation chemistry.

We report the synthesis of a new nickel(II) hydroxide complex 2 supported by a rigid, tridentate triazolylidene-carbazolid ligand. The complex can be accessed in high yields following a simple and stepwise extraction protocol using dichloromethane and aqueous ammonium chloride followed by aqeous sodium hydroxide solution. We found that complex 2 is highly basic, undergoing various deprotonation/desilylation reactions with E-H and C-H acidic and silylated compounds. In this context we synthesized a variety of novel, functionalized nickel(II) complexes with trimethylsilylolate (3), trityl sulfide (4), tosyl amide (5), azido (6), pyridine (7), acetylide (8, 9), fluoroarene (10 & 11) and enolate (12) ligands. We furthermore found that 2 reacts with malonic acid dimethyl ester in a knoevennagel-type condensation reaction, giving access to a new enolate ligand in complex 13, consisting of two malonic acid units. Furthermore, complex 2 reacts with acetonitrile to form the cyanido complex 14. The formation of complexes 13 and 14 is particularly interesting, as they underline the potential of complex 2 in both C-C bond formation and cleavage reactions.

Design, Synthesis, Electrochemical, and Biological Evaluation of Fluorescent Chlorido[N,N'-bis(methoxy/hydroxy)salicylidene-1,2-bis(4-methoxyphenyl)ethylenediamine]iron(III) Complexes as Anticancer Agents.

The impact of methoxy and hydroxyl groups at the salicylidene moiety of chlorido[N,N'-bis(methoxy/hydroxy)salicylidene-1,2-bis(4-methoxyphenyl)ethylenediamine]iron(III) complexes was evaluated on human MDA-MB 231 breast cancer and HL-60 leukemia cells. Methoxylated complexes (C1-C3) inhibited proliferation, migration, and metabolic activity in a concentration-dependent manner following the rank order: C2 > C3 > C1. In particular, C2 was highly cytotoxic with an IC50 of 4.2 µM which was 6.6-fold lower than that of cisplatin (IC50 of 27.9 µM). In contrast, hydroxylated complexes C4-C6 were almost inactive up to the highest concentration tested due to lack of cellular uptake. C2 caused a dual mode of cell death, ferroptosis, and necroptosis, whereby at higher concentrations, ferroptosis was the preferred form. Ferroptotic morphology and the presence of ferrous iron and lipid reactive oxygen species proved the involvement of ferroptosis. C2 was identified as a promising lead compound for the design of drug candidates inducing ferroptosis.

Expanding the Utility of ß-Diketiminate Ligands in Heavy Group VI Chemistry of Molybdenum and Tungsten.

We report the synthesis of 17 molybdenum and tungsten complexes supported by the ubiquitous BDI ligand framework (BDI = ß-diketiminate). The focal entry point is the synthesis of four molybdenum and tungsten(V) BDI complexes of the general formula [MO(BDIR)Cl2] [M = Mo, R = Dipp (1); M = W, R = Dipp (2); M = Mo, R = Mes (3); M = W, R = Mes (4)] synthesized by the reaction between MoOCl3(THF)2 or WOCl3(THF)2 and LiBDIR. Reactivity studies show that the BDIDipp complexes are excellent precursors toward adduct formation, reacting smoothly with dimethylaminopyridine (DMAP) and triethylphosphine oxide (OPEt3). No reaction with small phosphines has been observed, strongly contrasting the chemistry of previously reported rhenium(V) complexes. Additionally, the complexes 1 and 2 are good precursors for salt metathesis reactions. While 1 can be chemically reduced to the first stable example of a Mo(IV) BDI complex 15, reduction of 2 resulted in degradation of the BDI ligand via a nitrene transfer reaction, leading to MAD (4-((2,6-diisopropylphenyl)imino)pent-2-enide) supported tungsten(V) and tungsten(VI) complexes 16 and 17. All reported complexes have been thoroughly studied by VT-NMR and (heteronuclear) NMR spectroscopy, as well as UV-vis and EPR spectroscopy, IR spectroscopy, and X-ray diffraction analysis.

Curious Case of Cobaltocenium Carbaldehyde.

Cobaltocenium carbaldehyde (formylcobaltocenium) hexafluoridophosphate, a long sought-after functionalized cobaltocenium salt, is accessible from cobaltocenium carboxylic acid by a three-step synthetic sequence involving (i) chlorination to the acid chloride, (ii) copper-borohydride reduction to the hydroxymethyl derivative, and (iii) Dess-Martin oxidation to the title compound. Due to the strongly electron-withdrawing cationic cobaltocenium moiety, no standard aldehyde reactivity is observed. Instead, nucleophilic addition followed by haloform-type cleavage prevails, thereby ruling out common useful aldehyde derivatization. One-electron reduction of cobaltocenium carbaldehyde hexafluoridophosphate affords the deep-blue, isolable cobaltocene carbaldehyde 19-valence-electron radical whose spin density is located fully at cobalt and not at the formyl carbon atom. 1H/13C NMR, IR, EPR spectroscopy, high-resolution mass spectrometry, cyclic voltammetry, single crystal structure analysis (XRD), and density functional theory are applied to characterize these unusual formyl-cobaltocenium/cobaltocene compounds.

Janus-type emission from a cyclometalated iron(III) complex.

Although iron is a dream candidate to substitute noble metals in photoactive complexes, realization of emissive and photoactive iron compounds is demanding due to the fast deactivation of their charge-transfer states. Emissive iron compounds are scarce and dual emission has not been observed before. Here we report the FeIII complex [Fe(ImP)2][PF6] (HImP = 1,1'-(1,3-phenylene)bis(3-methyl-1-imidazol-2-ylidene)), showing a Janus-type dual emission from ligand-to-metal charge transfer (LMCT)- and metal-to-ligand charge transfer (MLCT)-dominated states. This behaviour is achieved by a ligand design that combines four N-heterocyclic carbenes with two cyclometalating aryl units. The low-lying π* levels of the cyclometalating units lead to energetically accessible MLCT states that cannot evolve into LMCT states. With a lifetime of 4.6 ns, the strongly reducing and oxidizing MLCT-dominated state can initiate electron transfer reactions, which could constitute a basis for future applications of iron in photoredox catalysis.

Correction: Distinct photodynamics of κ-N and κ-C pseudoisomeric iron(II) complexes.

Correction for 'Distinct photodynamics of κ-N and κ-C pseudoisomeric iron(II) complexes' by Philipp Dierks et al., Chem. Commun., 2021, 57, 6640-6643, https://doi.org/10.1039/D1CC01716K.

Reactivity and Structure of a Bis-phenolate Niobium NHC Complex.

We report the facile synthesis of a rare niobium(V) imido NHC complex with a dianionic OCO-pincer benzimidazolylidene ligand (L 1 ) with the general formula [NbL 1 (N t Bu)PyCl] 1-Py. We achieved this by in situ deprotonation of the corresponding azolium salt [H 3 L 1 ][Cl] and subsequent reaction with [Nb(N t Bu)Py 2 Cl 3 ]. The pyridine ligand in 1-Py can be removed by the addition of B(C6F5)3 as a strong Lewis acid leading to the formation of the pyridine-free complex 1. In contrast to similar vanadium(V) complexes, complex 1-Py was found to be a good precursor for various salt metathesis reactions, yielding a series of chalcogenido and pnictogenido complexes with the general formula [ NbL 1 (N t Bu)Py(EMes)] (E = O (2), S (3), NH (4), and PH (5)). Furthermore, complex 1-Py can be converted to alkyl complex (6) with 1 equiv of neosilyl lithium as a transmetallation agent. Addition of a second equivalent yields a new trianionic supporting ligand on the niobium center (7) in which the benzimidazolylidene ligand is alkylated at the former carbene carbon atom. The latter is an interesting chemically "noninnocent" feature of the benzimidazolylidene ligand potentially useful in catalysis and atom transfer reactions. Addition of mesityl lithium to 1-Py gives the pyridine-free aryl complex 8, which is stable toward "overarylation" by an additional equivalent of mesityl lithium. Electrochemical investigation revealed that complexes 1-Py and 1 are inert toward reduction in dichloromethane but show two irreversible reduction processes in tetrahydrofuran as a solvent. However, using standard reduction agents, e.g., KC8, K-mirror, and Na/Napht, no reduced products could be isolated. All complexes have been thoroughly studied by various techniques, including 1H-, 13C{1H}-, and 1H-15N HMBC NMR spectroscopy, IR spectroscopy, and X-ray diffraction analysis.

Imidazolyl-Substituted Benzo- and Naphthodithiophenes as Precursors for the Synthesis of Transient Open-Shell Quinoids.

The synthesis of three novel imidazolyl-substituted sulfur-containing heteroacenes is reported. These heteroacenes consisting of annelated benzo- and naphthothiophenes serve as precursors for the generation of open-shell quinoid heteroacenes by oxidation with alkaline ferric cyanide. Spectroscopic and computational experiments support the formation of reactive open-shell quinoids, which, however, quickly produce paramagnetic polymeric material.

Clathrochelate Complexes Containing Axial Cymantrene and Tromancenium Moieties.

New clathrochelate complexes of manganese, iron and cobalt containing peripheral organometallic manganese moieties cymantrene or tromancenium were synthesized via self-assembly from di/tri-topic dioximes, metal templates and cymantrene/tromancenium boronic acid pinacol esters. These air-stable, highly colored, oligometallic complexes are composed of various combinations of MnIFeIIMnI, MnICoIIMnI, MnIMnIIMnIIMnI and MnICoIICoIIMnI metal assemblies with corresponding complicated magnetic and electrochemical properties. Full spectroscopic and structural characterization by 1H/11B/13C NMR, HRMS, IR, UV-vis, single crystal XRD and CV (cyclic voltammetry) is provided. Tetrametallic complexes containing tromanceniumyl substituents with two CoII or MnII central metals exhibit promising anticancer properties against different tumor cell lines.

Borylated Cymantrenes and Tromancenium Salts with Unusual Reactivity.

In continuation of our study of the chemistry of cationic (cycloheptatrienyl)(cyclopentadienyl)manganese(I) sandwich complexes, so-called "tromancenium" salts, we report here on their boron-substituted derivatives focusing on useful boron-mediated synthetic applications. Transmetalation of lithiated tricarbonyl(cyclopentadienyl)manganese ("cymantrene") with boric or diboronic esters affords monoborylated cymantrenes that are converted by advanced high-power LED photosynthesis followed by oxidation with tritylium to their 8-boron-substituted tromancenium complexes. These new functionalized tromancenium salts are fully characterized by 1H/11B/13C/19F/55Mn NMR, IR, UV-vis, HRMS spectroscopy, single-crystal structure analysis (XRD) and cyclic voltammetry (CV). IR spectra were thoroughly analyzed by density functional theory (DFT) on the harmonic approximation in qualitative agreement of calculated vibrations with experimental values. Uncommon chemical reactivity of these borylated tromancenium salts is observed, due to the strongly electron-withdrawing cationic tromancenium moiety. No Suzuki-type cross-coupling reactions proved so far achievable, but unusual copper-promoted amination with sodium azide under microwave irradiation is possible. Diazoniation of aminotromancenium affords an extremely reactive dicationic tromanceniumdiazonium salt, which is too labile for standard Sandmeyer reactions, in contrast to analogous chemistry of cobaltocenium salts. Overall, borylated tromancenium salts display unexpected and intriguing chemical properties with the potential for novel synthetic applications in future work.

A mesoionic carbene complex of manganese in five oxidation states.

Reaction between a carbazole-based mesoionic carbene ligand and manganese(II) iodide results in the formation of a rare air-stable manganese(IV) complex after aerobic workup. Cyclic voltammetry reveals the complex to be stable in five oxidation states. The electronic structure of all five oxidation states is elucidated chemically, spectroscopically (NMR, high-frequency EPR, UV-Vis, MCD), magnetically, and computationally (DFT, CASSCF).

Supramolecular networks by imine halogen bonding.

Halogen bonding of neutral donors using imine groups of porous organic cage compounds as acceptors leads to the formation of halogen-bonded frameworks. We report the use of two different imine cages, in combination with three electron-poor halogen bond donors. Four resulting solid-state structures elucidated by single-crystal X-ray analysis are presented and analysed for the first time by plane-wave DFT calculations and QTAIM-analyses of the entire unit cells, demonstrating the formation of halogen bonds within the networks. The supramolecular frameworks can be obtained either from solution or mechanochemically by liquid-assisted grinding.

Coupling of CO2 and epoxides catalysed by novel N-fused mesoionic carbene complexes of nickel(II).

We report the syntheses of two rigid mesoionic carbene (MIC) ligands with a carbazole backbone via an intramolecular Finkelstein-cyclisation cascade and investigate their coordination behavior towards nickel(II) acetate. Despite the nickel(II) carbene complexes 4a,b showing only minor differences in their chemical composition, they display curious differences in their chemical properties, e.g. solubility. Furthermore, the potential of these novel MIC complexes in the coupling of carbon dioxide and epoxides as well as the differences in reactivity compared to classical NHC-derived complexes are evaluated.

Rhodocenium Functionalization Enabled by Half-Sandwich Capping, Zincke Reaction, Diazoniation and Sandmeyer Chemistry.

In continuation of our exploration of metallocenium chemistry we report here on innovative ways toward monofunctionalized rhodocenium salts applying half-sandwich capping reactions of cyclopentadienyl rhodium(III) halide synthons with cyclopentadienyl ylides containing pyridine, phosphine or dinitrogen leaving groups, followed by Zincke and Sandmeyer reactions. Thereby amino, diazonio, bromo, azido and iodo rhodocenium salts containing valuable functional groups are accessible for the first time. Target compounds were characterized by spectroscopic (1H/13C/103Rh-NMR, IR, HR-MS), structural (single crystal XRD) and electrochemical (CV) methods and their properties were compared to those of isoelectronic cobaltocenium compounds. These new functionalized rhodocenium complexes significantly expand the so far extremely limited chemical space of rhodocenium salts with promising options for the future development in the area of rhodocenium chemistry.

Mesoionic Carbenes in Low- to High-Valent Vanadium Chemistry.

We report the synthesis of vanadium(V) oxo complex 1 with a pincer-type dianionic mesoionic carbene (MIC) ligand L1 and the general formula [VOCl(L1)]. A comparison of the structural (SC-XRD), electronic (UV-vis), and electrochemical (cyclic voltammetry) properties of 1 with the benzimidazolinylidene congener 2 (general formula [VOCl(L2)]) shows that the MIC is a stronger donor also for early transition metals with low d-electron population. Since electrochemical studies revealed both complexes to be reversibly reduced, the stronger donor character of MICs was not only demonstrated for the vanadium(V) but also for the vanadium(IV) oxidation state by isolating the reduced vanadium(IV) complexes [Co(Cp*)2][1] and [Co(Cp*)2][2] ([Co(Cp*)2] = decamethylcobaltocenium). The electronic structures of the compounds were investigated by computational methods. Complex 1 was found to be a moderate precursor for salt metathesis reactions, showing selective reactivity toward phenolates or secondary amides, but not toward primary amides and phosphides, thiophenols, or aryls/alkyls donors. Deoxygenation with electron-rich phosphines failed to give the desired vanadium(III) complex. However, treatment of the deprotonated ligand precursor with vanadium(III) trichloride resulted in the clean formation of the corresponding MIC vanadium(III) complex 6, which undergoes a clean two-electron oxidation with organic azides yielding the corresponding imido complexes. The reaction with TMS-N3 did not afford a nitrido complex, but instead the imido complex 10. This study reveals that, contrary to popular belief, MICs are capable of supporting early transition-metal complexes in a variety of oxidation states, thus making them promising candidates for the activation of small molecules and redox catalysis.

Bright luminescent lithium and magnesium carbene complexes.

We report on the convenient synthesis of a CNC pincer ligand composed of carbazole and two mesoionic carbenes, as well as the corresponding lithium- and magnesium complexes. Mono-deprotonation affords a rare "naked" amide anion. In contrast to the proligand and its mono-deprotonated form, tri-deprotonated s-block complexes show bright luminescence, and their photophysical properties were therefore investigated by absorption- and luminescence spectroscopy. They reveal a quantum yield of 16% in solution at ambient temperature. Detailed quantum-chemical calculations assist in rationalizing the emissive properties based on an Intra-Ligand-Charge-Transfer (ILCT) between the carbazolido- and mesoionic carbene ligands. (Earth-)alkali metals prevent the distortion of the ligand following excitation and, thus, by avoiding non-radiative deactivation support bright luminescence.