Activation of a High-Valent Manganese–Oxo Complex by a Nonmetallic Lewis Acid

The reaction of a manganese­(V)–oxo porphyrinoid complex with the Lewis acid B­(C₆F₅)₃ leads to reversible stabilization of the valence tautomer Mn^IV(O)­(π-radical cation). The latter complex, in combination with B­(C₆F₅)₃, reacts with ArO–H substrates via formal hydrogen-atom transfer and exhibits dramatically increased reaction rates over the Mn^V(O) starting material

Aggregation of a Crown Ether Decorated Zinc–Phthalocyanine by Collision-Induced Desolvation of Electrospray Droplets

The aggregation of phthalocyanines is well-known in solution but has never before been studied in the gas phase. We investigated the tetra-[18]­crown-6 ether functionalized zinc–phthalocyanine (ZnPcTetCr, <b>M</b>) with electrospray ionization mass spectrometry (ESI-MS) in the absence of coordinating metal cations. Apart from the molecular ion <b>M</b>^+•, singly and multiply charged aggregates <b>M</b>_<i>n</i>^{<i>z</i>(+•)} were observed, bound together by electrostatic interactions, without alkali metal cations inside the crown ethers. Collision-induced dissociation (CID) experiments indicate that these clusters consist of stacked neutral <b>M</b> and radical cations <b>M</b>^+•. After the oxidation of individual molecules at the electrospray needle, the aggregation occurs during desolvation of the charged droplets created in the source. Complete evaporation of the solvent and detection of the aggregates was found to require an additional acceleration of the droplets in the transfer region of the instrument, the resulting collisions with neutral gas assisting the desolvation process

Redox Behavior of a Dinuclear Ruthenium(II) Complex Bearing an Uncommon Bridging Ligand: Insights from High-Pressure Electrochemistry

A dinuclear ruthenium complex bridged by 2,3,5,6-pyrazinetetracarboxylic acid (μ-LH₂^2–) was synthesized and characterized by X-ray crystallography, cyclic voltammetry under ambient and elevated pressures, electron paramagnetic resonance (EPR) and UV/vis-NIR (NIR = near-infrared) spectroelectrochemistry, pulse radiolysis, and computational methods. We probed for the first time in the field of mixed-valency the use of high-pressure electrochemical methods. The investigations were directed toward the influence of the protonation state of the bridging ligand on the electronic communication between the ruthenium ions, since such behavior is interesting in terms of modulating redox chemistry by pH. Starting from the [Ru^II(μ-LH₂^2–)­Ru^II]⁰ configuration, which shows an intense metal-to-ligand charge transfer absorption band at 600 nm, cyclic voltammetry revealed a pH-independent, reversible one-electron reduction and a protonation-state-dependent (proton coupled electron transfer, PCET) reversible oxidation. Deeper insight into the electrode reactions was provided by pressure-dependent cyclic voltammetry up to 150 MPa, providing insight into the conformational changes, the protonation state, and the environment of the molecule during the redox processes. Spectroelectrochemical investigations (EPR, UV/vis-NIR) of the respective redox reactions suggest a ligand-centered radical anion [Ru^II(μ-LH₂^•3–)­Ru^II]⁻ upon reduction (EPR Δ<i>g</i> = 0.042) and an ambiguous, EPR-silent one-electron oxidized state. In both cases, the absence of the otherwise typical broad intervalence charge transfer bands in the NIR region for mixed-valent complexes support the formulation as radical anionic bridged compound. However, on the basis of high-pressure electrochemical data and density functional theory calculations the one-electron oxidized form could be assigned as a charge-delocalized [Ru^II.5(μ-LH₂^2–)­Ru^II.5]⁺ valence tautomer rather than [Ru^III(μ-LH₂^•3–)­Ru^III]⁺. Deprotonation of the bridging ligand causes a severe shift of the redox potential for the metal-based oxidation toward lower potentials, yielding the charge-localized [Ru^III(μ-LH^3–)­Ru^II]⁰ complex. This PCET process is accompanied by large intrinsic volume changes. All findings are supported by computational methods (geometry optimization, spin population analysis). For all redox processes, valence alternatives are discussed

Copper Chloride Catalysis: Do μ₄‑Oxido Copper Clusters Play a Significant Role?

Copper chloride catalysis is a well-established field in organic and inorganic chemistry. However, in most cases a detailed mechanistic understanding of the individual reaction steps and identification of reactive intermediates are still missing. The present study reports the results of spectroscopic and spectrometric measurements that support formation of copper agglomerates during catalytic processes. The composition of CuCl₂·2H₂O in several coordinating solvents and the influence of basic coreagents such as NaO^<i>t</i>Bu and K₂CO₃ on the structure in the solid state as well as in solution were investigated. Several experiments involving crystal structure determination, IR spectroscopy, and ultra-high-resolution cryospray-ionization mass spectrometry were performed. The crystal structures of [CuCl₂­(H₂O)]·0.5­(CH₃)₂­CO (<b>1</b>), [Cu₂­(CH₃CN)₂­Cl₄] (<b>2</b>), [Cu₃­(CH₃CN)₃­Cl₆] (<b>3</b>), [Cu₃Cl₆­(THF)₄] (<b>4</b>), [Cu­(DMSO)₂­Cl₂] (<b>5</b>), (H₂N­(CH₃)₂)₂­[CuCl₃] (<b>6</b>), and [Cu₄OCl₆­(THF)­(urea)₃]·3THF·urea (<b>8</b>) are reported herein. It can be clearly demonstrated that μ₄-oxido copper clusters of the formula [Cu₄OCl₆­(solvent)₄] are the main product from the reactions of CuCl₂·2H₂O and basic coreagents. As a final result of these experiments, it can be stated that μ₄-oxido copper clusters most likely play an important role in the mechanism of copper chloride-catalyzed reactions

Nitrogen Oxide Atom-Transfer Redox Chemistry; Mechanism of NO_(g) to Nitrite Conversion Utilizing μ‑oxo Heme-Fe^III–O–Cu^II(L) Constructs

While nitric oxide (NO, nitrogen monoxide) is a critically important signaling agent, its cellular concentrations must be tightly controlled, generally through its oxidative conversion to nitrite (NO₂^–) where it is held in reserve to be reconverted as needed. In part, this reaction is mediated by the binuclear heme a₃/Cu_B active site of cytochrome <i>c</i> oxidase. In this report, the oxidation of NO_(g) to nitrite is shown to occur efficiently in new synthetic μ-oxo heme-Fe^III–O–Cu^II(L) constructs (L being a tridentate or tetradentate pyridyl/alkylamino ligand), and spectroscopic and kinetic investigations provide detailed mechanistic insights. Two new X-ray structures of μ-oxo complexes have been determined and compared to literature analogs. All μ-oxo complexes react with 2 mol equiv NO_(g) to give 1:1 mixtures of discrete [(L)­Cu^II(NO₂^–)]⁺ plus ferrous heme-nitrosyl compounds; when the first NO_(g) equiv reduces the heme center and itself is oxidized to nitrite, the second equiv of NO_(g) traps the ferrous heme thus formed. For one μ-oxo heme-Fe^III–O–Cu^II(L) compound, the reaction with NO_(g) reveals an intermediate species (“intermediate”), formally a bis-NO adduct, [(NO)­(porphyrinate)­Fe^II–(NO₂^–)–Cu^II(L)]⁺ (λ_max = 433 nm), confirmed by cryo-spray ionization mass spectrometry and EPR spectroscopy, along with the observation that cooling a 1:1 mixture of [(L)­Cu^II(NO₂^–)]⁺ and heme-Fe^II(NO) to −125 °C leads to association and generation of the key 433 nm UV–vis feature. Kinetic-thermodynamic parameters obtained from low-temperature stopped-flow measurements are in excellent agreement with DFT calculations carried out which describe the sequential addition of NO_(g) to the μ-oxo complex

Does Perthionitrite (SSNO^–) Account for Sustained Bioactivity of NO? A (Bio)chemical Characterization

Hydrogen sulfide (H₂S) and nitric oxide (NO) are important signaling molecules that regulate several physiological functions. Understanding the chemistry behind their interplay is important for explaining these functions. The reaction of H₂S with <i>S</i>-nitrosothiols to form the smallest <i>S</i>-nitrosothiol, thionitrous acid (HSNO), is one example of physiologically relevant cross-talk between H₂S and nitrogen species. Perthionitrite (SSNO^–) has recently been considered as an important biological source of NO that is far more stable and longer living than HSNO. In order to experimentally address this issue here, we prepared SSNO^– by two different approaches, which lead to two distinct species: SSNO^– and dithionitric acid [HON­(S)­S/HSN­(O)­S]. (H)­S₂NO species and their reactivity were studied by ¹⁵N NMR, IR, electron paramagnetic resonance and high-resolution electrospray ionization time-of-flight mass spectrometry, as well as by X-ray structure analysis and cyclic voltammetry. The obtained results pointed toward the inherent instability of SSNO^– in water solutions. SSNO^– decomposed readily in the presence of light, water, or acid, with concomitant formation of elemental sulfur and HNO. Furthermore, SSNO⁻ reacted with H₂S to generate HSNO. Computational studies on (H)­SSNO provided additional explanations for its instability. Thus, on the basis of our data, it seems to be less probable that SSNO^– can serve as a signaling molecule and biological source of NO. SSNO^– salts could, however, be used as fast generators of HNO in water solutions

Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3

In this work we report a design, synthesis, and detailed functional characterization of unique strongly biased allosteric agonists of CXCR3 that contain tetrahydroisoquinoline carboxamide cores. Compound <b>11</b> (FAUC1036) is the first strongly biased allosteric agonist of CXCR3 that selectively induces weak chemotaxis and leads to receptor internalization and the β-arrestin 2 recruitment with potency comparable to that of the chemokine CXCL11 without any activation of G proteins. A subtle structural change (addition of a methoxy group, <b>14</b> (FAUC1104)) led to a contrasting biased allosteric partial agonist that activated solely G proteins, induced chemotaxis, but failed to induce receptor internalization or β-arrestin 2 recruitment. Concomitant structure–activity relationship studies indicated very steep structure–activity relationships, which steer the ligand bias between the β-arrestin 2 and G protein pathway. Overall, the information presented provides a powerful platform for further development and rational design of strongly biased allosteric agonists of CXCR3

Photoinitiated Reactivity of a Thiolate-Ligated, Spin-Crossover Nonheme {FeNO}⁷ Complex with Dioxygen

The nonheme iron complex, [Fe­(NO)­(N3PyS)]­BF₄, is a rare example of an {FeNO}⁷ species that exhibits spin-crossover behavior. The comparison of X-ray crystallographic studies at low and high temperatures and variable-temperature magnetic susceptibility measurements show that a low-spin <i>S</i> = 1/2 ground state is populated at 0–150 K, while both low-spin <i>S</i> = 1/2 and high-spin <i>S</i> = 3/2 states are populated at <i>T</i> > 150 K. These results explain the observation of two N–O vibrational modes at 1737 and 1649 cm^–1 in CD₃CN for [Fe­(NO)­(N3PyS)]­BF₄ at room temperature. This {FeNO}⁷ complex reacts with dioxygen upon photoirradiation with visible light in acetonitrile to generate a thiolate-ligated, nonheme iron­(III)-nitro complex, [Fe^III(NO₂)­(N3PyS)]⁺, which was characterized by EPR, FTIR, UV–vis, and CSI-MS. Isotope labeling studies, coupled with FTIR and CSI-MS, show that one O atom from O₂ is incorporated in the Fe^III–NO₂ product. The O₂ reactivity of [Fe­(NO)­(N3PyS)]­BF₄ in methanol is dramatically different from CH₃CN, leading exclusively to sulfur-based oxidation, as opposed to NO· oxidation. A mechanism is proposed for the NO· oxidation reaction that involves formation of both Fe^III-superoxo and Fe^III-peroxynitrite intermediates and takes into account the experimental observations. The stability of the Fe^III-nitrite complex is limited, and decay of [Fe^III(NO₂)­(N3PyS)]⁺ leads to {FeNO}⁷ species and sulfur oxygenated products. This work demonstrates that a single mononuclear, thiolate-ligated nonheme {FeNO}⁷ complex can exhibit reactivity related to both nitric oxide dioxygenase (NOD) and nitrite reductase (NiR) activity. The presence of the thiolate donor is critical to both pathways, and mechanistic insights into these biologically relevant processes are presented

Aromatic C–F Hydroxylation by Nonheme Iron(IV)–Oxo Complexes: Structural, Spectroscopic, and Mechanistic Investigations

The synthesis and reactivity of a series of mononuclear nonheme iron complexes that carry out intramolecular aromatic C–F hydroxylation reactions is reported. The key intermediate prior to C–F hydroxylation, [Fe^IV(O)­(N4Py^2Ar₁)]­(BF₄)₂ (<b>1-O</b>, Ar₁ = −2,6-difluorophenyl), was characterized by single-crystal X-ray diffraction. The crystal structure revealed a nonbonding C–H···OFe interaction with a CH₃CN molecule. Variable-field Mössbauer spectroscopy of <b>1-O</b> indicates an intermediate-spin (<i>S</i> = 1) ground state. The Mössbauer parameters for <b>1-O</b> include an unusually small quadrupole splitting for a triplet Fe^IV(O) and are reproduced well by density functional theory calculations. With the aim of investigating the initial step for C–F hydroxylation, two new ligands were synthesized, N4Py^2Ar₂ (<b>L2</b>, Ar₂ = −2,6-difluoro-4-methoxyphenyl) and N4Py^2Ar₃ (<b>L3</b>, Ar₃ = −2,6-difluoro-3-methoxyphenyl), with −OMe substituents in the <i>meta</i> or <i>ortho</i>/<i>para</i> positions with respect to the C–F bonds. Fe^II complexes [Fe­(N4Py^2Ar₂)­(CH₃CN)]­(ClO₄)₂ (<b>2</b>) and [Fe­(N4Py^2Ar₃)­(CH₃CN)]­(ClO₄)₂ (<b>3</b>) reacted with isopropyl 2-iodoxybenzoate to give the C–F hydroxylated Fe^III–OAr products. The Fe^IV(O) intermediates <b>2-O</b> and <b>3-O</b> were trapped at low temperature and characterized. Complex <b>2-O</b> displayed a C–F hydroxylation rate similar to that of <b>1-O</b>. In contrast, the kinetics (via stopped-flow UV–vis) for complex <b>3-O</b> displayed a significant rate enhancement for C–F hydroxylation. Eyring analysis revealed the activation barriers for the C–F hydroxylation reaction for the three complexes, consistent with the observed difference in reactivity. A terminal Fe^II(OH) complex (<b>4</b>) was prepared independently to investigate the possibility of a nucleophilic aromatic substitution pathway, but the stability of <b>4</b> rules out this mechanism. Taken together the data fully support an electrophilic C–F hydroxylation mechanism

Switching between Inner- and Outer-Sphere PCET Mechanisms of Small-Molecule Activation: Superoxide Dismutation and Oxygen/Superoxide Reduction Reactivity Deriving from the Same Manganese Complex

Readily exchangeable water molecules are commonly found in the active sites of oxidoreductases, yet the overwhelming majority of studies on small-molecule mimics of these enzymes entirely ignores the contribution of water to the reactivity. Studies of how these enzymes can continue to function in spite of the presence of highly oxidizing species are likewise limited. The mononuclear Mn^II complex with the potentially hexadentate ligand <i>N</i>-(2-hydroxy-5-methylbenzyl)-<i>N</i>,<i>N</i>′,<i>N</i>′-tris­(2-pyridinylmethyl)-1,2-ethanediamine (L^OH) was previously found to act as both a H₂O₂-responsive MRI contrast agent and a mimic of superoxide dismutase (SOD). Here, we studied this complex in aqueous solutions at different pH values in order to determine its (i) acid–base equilibria, (ii) coordination equilibria, (iii) substitution lability and operative mechanisms for water exchange, (iv) redox behavior and ability to participate in proton-coupled electron transfer (PCET) reactions, (v) SOD activity and reductive activity toward both oxygen and superoxide, and (vi) mechanism for its transformation into the binuclear Mn^II complex with ^(H)OL–L^OH and its hydroxylated derivatives. The conclusions drawn from potentiometric titrations, low-temperature mass spectrometry, temperature- and pressure-dependent ¹⁷O NMR spectroscopy, electrochemistry, stopped-flow kinetic analyses, and EPR measurements were supported by the structural characterization and quantum chemical analysis of proposed intermediate species. These comprehensive studies enabled us to determine how transiently bound water molecules impact the rate and mechanism of SOD catalysis. Metal-bound water molecules facilitate the PCET necessary for outer-sphere SOD activity. The absence of the water ligand, conversely, enables the inner-sphere reduction of both superoxide and dioxygen. The L^OH complex maintains its SOD activity in the presence of ^•OH and Mn^IV-oxo species by channeling these oxidants toward the synthesis of a functionally equivalent binuclear Mn^II species