Manganese(III) Nitrate Complexes as Bench-Stable Powerful Oxidants.

We report herein a convenient one-pot synthesis for the shelf-stable molecular complex [Mn(NO3)3(OPPh3)2] (2) and describe the properties that make it a powerful and selective one-electron oxidation (deelectronation) reagent. 2 has a high reduction potential of 1.02 V versus ferrocene (MeCN) (1.65 vs normal hydrogen electrode), which is one the highest known among readily available redox agents used in chemical synthesis. 2 exhibits stability toward air in the solid state, can be handled with relative ease, and is soluble in most common laboratory solvents such as MeCN, dichloromethane, and fluorobenzene. 2 is substitutionally labile with respect to the coordinated (pseudo)halide ions enabling the synthesis of other new Mn(III) nitrato complexes also with high reduction potentials ranging from 0.6 to 1.0 V versus ferrocene.

Alkaline earth metal-assisted dinitrogen activation at nickel.

Rare examples of trinuclear [Ni-N2-M-N2-Ni] core (M = Ca, Mg) with linear bridged dinitrogen ligands are reported in this work. The reduction of [iPr2NN]Ni(µ-Br)2Li(thf)2 (1) (iPr2NN = 2,4-bis-(2,6-diisopropylphenylimido)pentyl) with elemental Mg or Ca in THF under an atmosphere of dinitrogen yields the complex {iPr2NNNi(µ-N2)}2M (thf)4 (M = Mg, complex 2 and M = Ca, complex 3). The bridging end-on (µ-N2)2M(thf)4 moiety connects the two [iPr2NNNi]- nickelate fragments. A combination of X-ray crystallography, solution and solid-state spectroscopy have been applied to characterize complexes 2 and 3, and DFT studies have been used to help explain the bonding and electronic structure in these unique Ni-N2-Mg and Ni-N2-Ca complexes.

Tellurolate: an effective Te-atom transfer reagent to prepare the triad of group 5 metal bis(tellurides).

We show in this work how lithium tellurolate Li(X)nTeCH2SiMe3 (X = THF, n = 1, 1; X = 12-crown-4, n = 2, 2), can serve as an effective Te-atom transfer reagent to all group 5 transition metal halide precursors irrespective of the oxidation state. Mononuclear and bis(telluride) complexes, namely (PNP)M(Te)2 (M = V; Nb, 3; Ta, 4; PNP- = N[2-PiPr2-4-methylphenyl]2), are reported herein including structural and spectroscopic data. Whereas the known complex (PNP)V(Te)2 can be readily prepared from the trivalent precursor (PNP)VCl2, two equiv. of tellurolate, and elemental Te partially solubilized with PMe3, complex 3 can also be similarly obtained following the same procedure but with or without a reductant, Na/NaCl. Complex 4 on the other hand is formed from the addition of four equiv. of tellurolate to (PNP)TaF4. Having access to a triad of (PNP)M(Te)2 systems for group 5 metals has allowed us to compare them using a combination of theory and spectroscopy including Te-L1 edge XANES data.

Benzimidazole-diamide (bida) Pincer Chromium Complexes: Structures and Reactivity.

Serendipitous discovery of bida (i.e., N1-Ar-N2-((1-Ar-1-benzo[d]imidazol-2-yl)methyl)benzene-1,2-diamide; Ar = 2,6-iPr-C6H3), a potentially redox noninnocent, hemilabile pincer ligand with a methylene group that may facilitate proton/H atom reactivity, prompted its investigation. Chromium was chosen for study due to its multiple stable oxidation states. Disodium salt (bida)Na2(THF)n was prepared by thermal rearrangement of (dadi)Na2(THF)4 (i.e., (N,N'-di-2-(2,6-diisopropylphenylamine)phenylglyoxaldiimine)-Na2(THF)4). Salt metathesis of (bida)Na2(THF)n (generated in situ) with CrCl3(THF)3 or Cl3V═NAr (Ar = 2,6-iPr2C6H3) afforded (bida)CrCl(THF) (1-THF) and (bida)ClV═NAr, respectively. Substitutions provided (bida)CrCl(PMe2Ph) (1-PMe2Ph) and (bida)CrR(THF) (2-R, where R = Me, CH2CMe2Ph (Nph)). Oxidation of 1-THF with ArN3 (Ar = 2,6-iPr2C6H3) or AdN3 (Ad = 1-adamantyl) generated (bida)ClCr═NAr (3═NAr) and (bida)ClCr═NAd (3═NAd) and subsequent alkylation converted these to (bida)R'Cr═NR (R' = Me, R = Ad, Ar, 5═NR; R' = CH2CMe2Ph (Nph), R = Ad, Ar, 6═NR). In contrast, the addition of AdN3 to 2-Nph gave the insertion product (bida)Cr(κ2-N,N-ArN3Nph) (7). Addition of N-chlorosuccinimide to 1-THF produced (bia)CrCl2(THF) (8), where bia is the pincer derived via hydrogen atom loss from bida methylene. A similar HAT afforded (bia)ClCr(CNAr')2 (9, Ar' = 2,6-Me2C6H3) when 3═NAd was exposed to Ar'NC. An empirical equation of charge was applied to each bida species, whose metric parameters are unchanging despite formal oxidation state conversions from Cr(III) to Cr(V). Calculations and Mulliken spin density assessments reveal several situations in which antiferromagnetic (AF) coupling and admixtures of integer ground states (GSs) describe a complicated electronic structure.

Experimental and Computational Determination of a M-Cl Homolytic Bond Dissociation Free Energy: Mn(III)Cl-Mediated C-H Cleavage and Chlorination.

This study confirms the hypothesis that [MnCl3(OPPh3)2] (1) and acetonitrile-solvated MnCl3 (i.e., [MnCl3(MeCN)x]) can be used as synthons to prepare Mn(III) chloride complexes with facially coordinating ligands. This was achieved through the preparation and characterization of six new {MnIIICl} complexes using anionic ligands TpH (tris(pyrazolyl)borate) and TpMe (tris(3,5-dimethylpyrazolyl)borate). The MnIII-chloride dissociation and association equilibria (Keq) and MnIII/II reduction potentials were quantified in DCM. These two thermochemical parameters (Keq and E1/2), in addition to the known Cl-atom reduction potential in DCM, enabled the quantification of the Mn-Cl bond dissociation (homolysis) free energy of 21 and 23 ± 7 kcal/mol at room temperature for R = H and Me, respectively. These are in reasonable agreement with the bond dissociation free energy (BDFEM-Cl) of 34 ± 6 kcal/mol calculated using density functional theory. The BDFEM-Cl of 1 was also calculated (25 ± 6 kcal/mol). These energies were used in predictive C-H bond reactivity.

High-Concentration Self-Assembly of Zirconium- and Hafnium-Based Metal-Organic Materials.

Metal-organic frameworks (MOFs) are crystalline, porous solids constructed from organic linkers and inorganic nodes that are promising for applications in chemical separations, gas storage, and catalysis, among many others. However, a major roadblock to the widespread implementation of MOFs, including highly tunable and hydrolytically stable Zr- and Hf-based frameworks, is their benchtop-scalable synthesis, as MOFs are typically prepared under highly dilute (≤0.01 M) solvothermal conditions. This necessitates the use of liters of organic solvent to prepare only a few grams of MOF. Herein, we demonstrate that Zr- and Hf-based frameworks (eight examples) can self-assemble at much higher reaction concentrations than are typically utilized, up to 1.00 M in many cases. Combining stoichiometric amounts of Zr or Hf precursors with organic linkers at high concentrations yields highly crystalline and porous MOFs, as confirmed by powder X-ray diffraction (PXRD) and 77 K N2 surface area measurements. Furthermore, the use of well-defined pivalate-capped cluster precursors avoids the formation of ordered defects and impurities that arise from standard metal chloride salts. These clusters also introduce pivalate defects that increase the exterior hydrophobicity of several MOFs, as confirmed by water contact angle measurements. Overall, our findings challenge the standard assumption that MOFs must be prepared under highly dilute solvothermal conditions for optimal results, paving the way for their scalable and user-friendly synthesis in the laboratory.

Scrutinizing formally NiIV centers through the lenses of core spectroscopy, molecular orbital theory, and valence bond theory.

Nickel K- and L2,3-edge X-ray absorption spectra (XAS) are discussed for 16 complexes and complex ions with nickel centers spanning a range of formal oxidation states from II to IV. K-edge XAS alone is shown to be an ambiguous metric of physical oxidation state for these Ni complexes. Meanwhile, L2,3-edge XAS reveals that the physical d-counts of the formally NiIV compounds measured lie well above the d6 count implied by the oxidation state formalism. The generality of this phenomenon is explored computationally by scrutinizing 8 additional complexes. The extreme case of NiF62- is considered using high-level molecular orbital approaches as well as advanced valence bond methods. The emergent electronic structure picture reveals that even highly electronegative F-donors are incapable of supporting a physical d6 NiIV center. The reactivity of NiIV complexes is then discussed, highlighting the dominant role of the ligands in this chemistry over that of the metal centers.

Regioselective Radical Alkylation of Arenes Using Evolved Photoenzymes.

Substituted arenes are ubiquitous in molecules with medicinal functions, making their synthesis a critical consideration when designing synthetic routes. Regioselective C-H functionalization reactions are attractive for preparing alkylated arenes; however, the selectivity of existing methods is modest and primarily governed by the substrate's electronic properties. Here, we demonstrate a biocatalyst-controlled method for the regioselective alkylation of electron-rich and electron-deficient heteroarenes. Starting from an unselective "ene"-reductase (ERED) (GluER-T36A), we evolved a variant that selectively alkylates the C4 position of indole, an elusive position using prior technologies. Mechanistic studies across the evolutionary series indicate that changes to the protein active site alter the electronic character of the charge transfer (CT) complex responsible for radical formation. This resulted in a variant with a significant degree of ground-state CT in the CT complex. Mechanistic studies on a C2-selective ERED suggest that the evolution of GluER-T36A helps disfavor a competing mechanistic pathway. Additional protein engineering campaigns were carried out for a C8-selective quinoline alkylation. This study highlights the opportunity to use enzymes for regioselective radical reactions, where small molecule catalysts struggle to alter selectivity.

Regioselective Radical Alkylation of Arenes Using Evolved Photoenzymes.

Substituted arenes are ubiquitous in molecules with medicinal functions, making their synthesis a critical consideration when designing synthetic routes. 1,2 Regioselective C-H functionalization reactions are attractive for preparing alkylated arenes, 3-5 however, the selectivity of existing methods is modest and primarily governed by substrate electronic properties. 6,7 Here, we demonstrate a biocatalyst-controlled method for the regioselective alkylation of electron-rich and electron-deficient heteroarenes. Starting from an unselective 'ene'-reductase (ERED) (GluER-T36A), we evolved a variant that selectively alkylates the C4 position of indole, an elusive position using prior technologies. Mechanistic studies across the evolutionary series indicate that changes to the protein active site alter the electronic character of the charge transfer (CT) complex responsible for radical formation. This resulted in a variant with a significant degree of ground state change transfer in the CT complex. Mechanistic studies on a C2 selective ERED suggest that the evolution of GluER-T36A helps disfavor a competing mechanistic pathway. Additional protein engineering campaigns were carried out for a C8 selective quinoline alkylation. This study highlights the opportunity to use enzymes for regioselective reactions where small molecule catalysts struggle to alter selectivity.

Asymmetric C-Alkylation of Nitroalkanes via Enzymatic Photoredox Catalysis.

Tertiary nitroalkanes and the corresponding α-tertiary amines represent important motifs in bioactive molecules and natural products. The C-alkylation of secondary nitroalkanes with electrophiles is a straightforward strategy for constructing tertiary nitroalkanes; however, controlling the stereoselectivity of this type of reaction remains challenging. Here, we report a highly chemo- and stereoselective C-alkylation of nitroalkanes with alkyl halides catalyzed by an engineered flavin-dependent "ene"-reductase (ERED). Directed evolution of the old yellow enzyme from Geobacillus kaustophilus provided a triple mutant, GkOYE-G7, capable of synthesizing tertiary nitroalkanes in high yield and enantioselectivity. Mechanistic studies indicate that the excitation of an enzyme-templated charge-transfer complex formed between the substrates and cofactor is responsible for radical initiation. Moreover, a single-enzyme two-mechanism cascade reaction was developed to prepare tertiary nitroalkanes from simple nitroalkenes, highlighting the potential to use one enzyme for two mechanistically distinct reactions.

A Fluorogenic Inhibitor of the Mitochondrial Calcium Uniporter.

Inhibitors of the mitochondrial calcium uniporter (MCU) are valuable tools for studying the role of mitochondrial Ca2+ in various pathophysiological conditions. In this study, a new fluorogenic MCU inhibitor, RuOCou, is presented. This compound is an analogue of the known MCU inhibitor Ru265 that contains fluorescent axial coumarin carboxylate ligands. Upon aquation of RuOCou and release of the axial coumarin ligands, a simultaneous increase in its MCU-inhibitory activity and fluorescence intensity is observed. The fluorescence response of this compound enabled its aquation to be monitored in both HeLa cell lysates and live HeLa cells. This fluorogenic prodrug represents a potential theranostic MCU inhibitor that can be leveraged for the treatment of human diseases related to MCU activity.

Altering the solubility of metal-organic polyhedra via pendant functionalization of Cp3Zr3O(OH)3 nodes.

The chemistry of zirconium-based metal-organic polyhedra (ZrMOPs) is often limited by their poor solubilities. Despite their attractive features-including high yielding and facile syntheses, predictable topologies, high stability, and tunability-problematic solubilities have caused ZrMOPs to be under-studied and under-applied. Although these cages have been synthesized with a wide variety of carboxylate-based bridging ligands, we explored a new method for ZrMOP functionalization via node-modification, which we hypothesized could influence solubility. Herein, we report ZrMOPs with benzyl-, vinylbenzyl-, and trifluoromethylbenzyl-pendant groups decorating cyclopentadienyl moieties. The series was characterized by 1H/19F NMR, high-resolution mass spectrometry, infrared spectroscopy, and single-crystal X-ray diffraction. The effects of node functionalities on ZrMOP solubility were quantified using inductively coupled plasma mass spectrometry. Substitution caused a decrease in water solubility, but for certain organic solvents, e.g. DMF, solubility could be enhanced by ∼20×, from 16 µM for the unfunctionalized cage to 310 µM for the vinylbenzyl- and trifluoromethylbenzyl-cages.

Lowering the Symmetry of Cofacial Porphyrin Prisms for Selective Oxygen Reduction Electrocatalysis.

Cofacial porphyrin catalysts for the Oxygen Reduction Reaction (ORR) formed via coordination-driven self-assembly have so far been limited to designs with fourfold symmetry, where four molecular clips bridge two porphyrin sites. We have synthesized six PynPhm (Py = pyridyl, Ph = phenyl) metalloporphyrin prisms (Co2+, Zn2+) bridged by molecular clips containing two Rh3+ centers. Four of these structures are lower symmetry, with the Py3Ph and Py2Ph2 prisms containing three and two molecular clips, respectively. The Co2+ species were evaluated for their ORR activity. Cyclic and hydrodynamic voltammetry studies of heterogeneous catalyst inks in aqueous media revealed marked differences in selectivity from ∼5% (Py3Ph) to ∼37% (Py2Ph2) for the formation of H2O2. The single-crystal X-ray structure of the Zn2 Py2Ph2 prism shows an offset between the porphyrin faces. This structural feature may be responsible for the change in selectivity, consistent with previous studies of covalently tethered cofacial porphyrins that have shown that geometry is a critical determinant of two-electron/two-proton versus four-electron/four-proton pathways. Extraction of standard rate constants ks for the ORR revealed a cofacial enhancement of ∼2 orders of magnitude over mononuclear Co2+ tetrapyridyl porphyrin. Even though all the prisms described here use the same molecular clip, the resultant structures, and thus the reactivity for the ORR, differ significantly based on the number and orientation of pyridyl donor groups on the porphyrins, highlighting how coordination-driven self-assembly can be used to rapidly tune dinuclear catalysts.

Synthesis and crystallographic characterization of 6-hydroxy-1,2-dihydropyridin-2-one.

The title compound, C5H5NO2, is a hy-droxy-lated pyridine ring that has been studied for its involvement in microbial degradation of nicotinic acid. Here we describe its synthesis as a formic acid salt, rather than the standard hydro-chloride salt that is commercially available, and its spectroscopic and crystallographic characterization.

Lithiated Oppolzer Enolates: Solution Structures, Mechanism of Alkylation, and Origin of Stereoselectivity.

Camphorsultam-based lithium enolates referred to colloquially as Oppolzer enolates are examined spectroscopically, crystallographically, kinetically, and computationally to ascertain the mechanism of alkylation and the origin of the stereoselectivity. Solvent- and substrate-dependent structures include tetramers for alkyl-substituted enolates in toluene, unsymmetric dimers for aryl-substituted enolates in toluene, substrate-independent symmetric dimers in THF and THF/toluene mixtures, HMPA-bridged trisolvated dimers at low HMPA concentrations, and disolvated monomers for the aryl-substituted enolates at elevated HMPA concentrations. Extensive analyses of the stereochemistry of aggregation are included. Rate studies for reaction with allyl bromide implicate an HMPA-solvated ion pair with a +Li(HMPA)4 counterion. Dependencies on toluene and THF are attributed to exclusively secondary-shell (medium) effects. Aided by density functional theory (DFT) computations, a stereochemical model is presented in which neither chelates nor the lithium gegenion serves roles. The stereoselectivity stems from the chirality within the sultam ring and not the camphor skeletal core.

Examining the Alkaline Stability of Tris(dialkylamino)sulfoniums and Sulfoxoniums.

Herein, a synthetic method was developed to prepare a series of tris(dialkylamino)sulfonium and sulfoxonium cations from sulfur monochloride. Alkaline stability studies of these two cation families in 2 M KOH/CD3OH solution at 80 °C revealed how degradation pathways change as a function of the oxidation state of the S center, as determined by 1H NMR spectroscopy. The sulfonium cations (+S(NR2)3) typically degrade by nucleophilic attack at the sulfur atom with loss of an amino group and a proton transfer reaction to produce sulfoxides, while the sulfoxoniums (+O═S(NR2)3) tend to degrade by loss of an R group to form sulfoximines. From the group of sulfoniums and sulfoxoniums explored in this work, the tris(piperidino)sulfoxonium cation was noted to have excellent alkaline stability. This sulfoxonium should be suitable for future examination as a tethered cation in anion-exchange membranes (AEMs), or as a phase-transfer catalyst in biphasic reactions.

Carboxylate-Capped Analogues of Ru265 Are MCU Inhibitor Prodrugs.

The mitochondrial calcium uniporter (MCU) is a transmembrane protein that resides on the inner membrane of the mitochondria and mediates calcium uptake into this organelle. Given the critical role of mitochondrial calcium trafficking in cellular function, inhibitors of this channel have arisen as tools for studying the biological relevance of this process and as potential therapeutic agents. In this study, four new analogues of the previously reported Ru-based MCU inhibitor [ClRu(NH3)4(µ-N)Ru(NH3)4Cl]Cl3 (Ru265) are reported. These compounds, which bear axial carboxylate ligands, are of the general formula [(RCO2)Ru(NH3)4(µ-N)Ru(NH3)4(O2CR)]X3, where X = NO3- or CF3SO3- and R = H (1), CH3 (2), CH2CH3 (3), and (CH2)2CH3 (4). These complexes were fully characterized by IR spectroscopy, NMR spectroscopy, and elemental analysis. X-ray crystal structures of 1 and 3 were obtained, revealing the expected presence of both the linear Ru(µ-N)Ru core and axial formate and propionate ligands. The axial carboxylate ligands of complexes 1-4 are displaced by water in buffered aqueous solution to give the aquated compound Ru265'. The kinetics of these processes were measured by 1H NMR spectroscopy, revealing half-lives that span 5.9-9.9 h at 37 °C. Complex 1 with axial formate ligands underwent aquation approximately twice as fast as the other compounds. In vitro cytotoxicity and mitochondrial membrane potential measurements carried out in HeLa and HEK293T cells demonstrated that none of these four complexes negatively affects cell viability or mitochondrial function. The abilities of 1-4 to inhibit mitochondrial calcium uptake in permeabilized HEK293T cells were assessed and compared to that of Ru265. Fresh solutions of 1-4 are approximately 2-fold less potent than Ru265 with IC50 values in the range of 14.7-19.1 nM. Preincubating 1-4 in aqueous buffers for longer time periods to allow for the aquation reactions to proceed increases their potency of mitochondrial uptake inhibition to match that of Ru265. This result indicates that 1-4 are aquation-activated prodrugs of Ru265'. Finally, 1-4 were shown to inhibit mitochondrial calcium uptake in intact, nonpermeabilized cells, revealing their value as tools and potential therapeutic agents for mitochondrial calcium-related disorders.

Synthesis of a Bench-Stable Manganese(III) Chloride Compound: Coordination Chemistry and Alkene Dichlorination.

The complex [MnCl3(OPPh3)2] (1) is a bench-stable and easily prepared source of MnCl3. It is prepared by treating acetonitrile solvated MnCl3 (2) with Ph3PO and collecting the resulting blue precipitate. 1 is useful in coordination reactions by virtue of the labile Ph3PO ligands, and this is demonstrated through the synthesis of {Tpm*}MnCl3 (3). In addition, methodologies in synthesis that rely on difficult or cumbersome to prepare solutions of reactive MnCl3 can be accomplished using 1 instead. This is demonstrated through alkene dichlorinations in a wide range of solvents, open to air, and with good substrate scope. Light-accelerated halogenation and radical sensitive experiments support a radical mechanism involving stepwise Cl-atom transfer(s) from 1.

An aryl diimine cobalt(I) catalyst for carbonyl hydrosilylation.

Through the application of a redox-innocent aryl diimine chelate, the discovery and utilization of a cobalt catalyst, (Ph2PPrADI)Co, that exhibits carbonyl hydrosilylation turnover frequencies of up to 330 s-1 is described. This activity is believed to be the highest ever reported for metal-catalyzed carbonyl hydrosilylation.

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.