Anex Jose

Traditional electron‐transfer catalysis frequently requires complex procedures to separate the catalyst from the reaction mixture. In contrast, a concept of a gas‐mediated redox process may offer unique advantages, including its facile removal from the reaction medium. However, such a concept has remained unknown. Addressing this gap, we report the use of the SO ₂ gas molecule as an electron‐transfer mediator by generating the sulfur dioxide radical anion (SO ₂ ^•− ) under ambient and chemical conditions. Such SO ₂ ^•− enabled chemoselective, controlled, and scalable multi‐electron reductions (2e ⁻ /2H ⁺ , 4e ⁻ /4H ⁺ , 6e ⁻ /6H ⁺ ) of diverse nitrogen‐containing substrates. Furthermore, the method was successfully applied to the synthesis of clinically active drugs on a multi‐gram scale. Therefore, this work establishes a new paradigm in redox chemistry, demonstrating that a gas molecule can act as an electron‐transfer catalyst, capable of performing reactions that typically require transition metals.

Traditional electron‐transfer catalysis frequently requires complex procedures to separate the catalyst from the reaction mixture. In contrast, a concept of a gas‐mediated redox process may offer unique advantages, including its facile removal from the reaction medium. However, such a concept has remained unknown. Addressing this gap, we report the use of the SO ₂ gas molecule as an electron‐transfer mediator by generating the sulfur dioxide radical anion (SO ₂ ^•− ) under ambient and chemical conditions. Such SO ₂ ^•− enabled chemoselective, controlled, and scalable multi‐electron reductions (2e ⁻ /2H ⁺ , 4e ⁻ /4H ⁺ , 6e ⁻ /6H ⁺ ) of diverse nitrogen‐containing substrates. Furthermore, the method was successfully applied to the synthesis of clinically active drugs on a multi‐gram scale. Therefore, this work establishes a new paradigm in redox chemistry, demonstrating that a gas molecule can act as an electron‐transfer catalyst, capable of performing reactions that typically require transition metals.

Heme–copper oxidases, the terminal respiratory complex in the electron transport chain, harness the energy from the reduction of dioxygen to water to pump protons across mitochondrial or bacterial membranes against a gradient to power ATP synthesis. While proton pumping in heme–copper oxidases was discovered more than four decades ago, a molecular-level understanding of the proton pumping mechanism remains elusive. Particularly, the role of the heme–copper active site, including a unique tyrosine residue covalently crosslinked to a copper ligand, remained inaccessible due to intense overlapping spectroscopic features from other redox centers in these enzymes. Here, by leveraging site-selective spectroscopic methods, we show that the active site copper and its crosslinked tyrosine directly control the proton pumping, providing the molecular mechanism underlying this process. This was achieved by experimental elucidation of the key intermediate F, formed in the first proton pumping step in heme–copper oxidases. By performing variable-temperature, variable-field magnetic circular dichroism spectroscopy on the oxo-heme center and K-edge X-ray absorption spectroscopy on the copper center of F, we find that the iron(IV)-oxo in F is ferromagnetically coupled to an electron-delocalized copper/tyrosine radical. These results show that the copper(I)-tyrosyl radical character, triggered by protonation of the heme–copper center, enables proton pumping. Furthermore, we find that the copper-tyrosyl radical character is regenerated in all four proton pumping intermediates, completing the molecular mechanism for proton pumping by the respiratory oxidase family of enzymes.

The valorization of greenhouse gases CO₂ and N₂O into value-added chemicals has recently become a critical area of research. While the utilization of CO₂ gives quick access to important carboxylic acid building blocks, N₂O is able to act as an oxygen-transfer reagent that allows the formation of carbon-oxygen and heteroatom-oxygen bonds. No metal-free catalytic system has yet been described that is able to react with both gases. Additionally, the metal-free catalytic activation of N₂O is unprecedented in the literature. Relying on our previously established multi-PET catalysis that makes use of a BOIMPY dye, we were able to identify a single catalytic platform that allows reactions of both gases under super-reducing photochemical conditions. In this work, we report reactions between either CO₂ or N₂O and (poly)arenes, aryl halides, olefins, sulfides, and phosphines and present a thorough mechanistic investigation to understand the pathways leading to the described products. We found that N₂O is indeed catalytically activated by a nonmetal catalyst for the first time employing our system. We mention that the enclosed methodology can be utilized to react with abundant CO₂ or N₂O; however, it will not mitigate climate change.

High-valent Fe ^IV =O species are common intermediates in biological and artificial catalysts. Heme and nonheme S=1 Fe ^IV =O sites have been synthesized and studied for decades but little quantitative experimental comparison of their electronic structures has been available, due to the lack of direct methods focused on the iron. This study allows a rigorous determination of the electronic structure of a nonheme Fe ^IV =O center and its comparison to an Fe ^IV =O heme site using 1s2p resonant inelastic X-ray scattering (RIXS) and Fe L-edge X-ray absorption spectroscopy (XAS). Further, variable temperature magnetic circular dichroism (VT-MCD) of the ligand field transitions, combined with nuclear resonance vibrational spectroscopy of the two S=1 Fe ^IV =O systems show that the equatorial ligand field decreases from a nonheme to a heme Fe ^IV =O site. Alternatively, RIXS and Fe L-edge XAS combined with MCD show that the Fe d π orbitals are unperturbed in the Fe ^IV =O heme relative to the nonheme site because the strong axial Fe-O bond uncouples the Fe d π orbitals from the porphyrin π -system. As a consequence, the thermodynamics and kinetics of the H-atom abstraction reactions are actually very similar for heme compound II and nonheme Fe ^IV =O active sites.

Synthetic side-on peroxide-bound dicopper(II) (^SP) complexes are important for understanding the active site structure/function of many copper-containing enzymes. This work highlights the formation of new {Cu^II(μ-η²:η²-O₂^2–)Cu^II} complexes (with electronic absorption and resonance Raman (rR) spectroscopic characterization) using tripodal N₃ArOH ligands at −135 °C, which spontaneously participate in intramolecular phenolic H-atom abstraction (HAA). This results in the generation of bis(phenoxyl radical)bis(μ-OH)dicopper(II) intermediates, substantiated by their EPR/UV–vis/rR spectroscopic signatures and crystal structural determination of a diphenoquinone dicopper(I) complex derived from ligand para-C═C coupling. The newly observed chemistry in these ligand–Cu systems is discussed with respect to (a) our Cu-MeAN (tridentate N,N,N′,N′,N″-pentamethyldipropylenetriamine)-derived model ^SP species, which was unreactive toward exogenous monophenol addition (J. Am. Chem. Soc. 2012, 134, 8513–8524), emphasizing the impact of intramolecularly tethered ArOH groups, and (b) recent advances in understanding the mechanism of action of the tyrosinase (Ty) enzyme.

Copper ion is a versatile and ubiquitous facilitator of redox chemical and biochemical processes. These include the binding of molecular oxygen to copper(I) complexes where it undergoes stepwise reduction-protonation. A detailed understanding of thermodynamic relationships between such reduced/protonated states is key to elucidate the fundamentals of the chemical/biochemical processes involved. The dicopper(I) complex [Cu^I₂(BPMPO^-)]¹⁺ {BPMPOH = 2,6-bis{[(bis(2-pyridylmethyl)amino]methyl}-4-methylphenol)} undergoes cryogenic dioxygen addition; further manipulations in 2-methyltetrahydrofuran generate dicopper(II) peroxo [Cu^II₂(BPMPO^-)(O₂^2-)]¹⁺, hydroperoxo [Cu^II₂(BPMPO^-)(^-OOH)]²⁺, and superoxo [Cu^II₂(BPMPO^-)(O₂^•-)]²⁺ species, characterized by UV-vis, resonance Raman and electron paramagnetic resonance (EPR) spectroscopies, and cold spray ionization mass spectrometry. An unexpected EPR spectrum for [Cu^II₂(BPMPO^-)(O₂^•-)]²⁺ is explained by the analysis of its exchange-coupled three-spin frustrated system and DFT calculations. A redox equilibrium, [Cu^II₂(BPMPO^-)(O₂^2-)]¹⁺ ⇄ [Cu^II₂(BPMPO^-)(O₂^•-)]²⁺, is established utilizing Me₈Fc⁺/Cr(η⁶-C₆H₆)₂, allowing for [Cu^II₂(BPMPO^-)(O₂^•-)]²⁺/[Cu^II₂(BPMPO^-)(O₂^2-)]¹⁺ reduction potential calculation, E°' = -0.44 ± 0.01 V vs Fc^+/0, also confirmed by cryoelectrochemical measurements (E°' = -0.40 ± 0.01 V). 2,6-Lutidinium triflate addition to [Cu^II₂(BPMPO^-)(O₂^2-)]¹⁺ produces [Cu^II₂(BPMPO^-)(^-OOH)]²⁺; using a phosphazene base, an acid-base equilibrium was achieved, pK_a = 22.3 ± 0.7 for [Cu^II₂(BPMPO^-)(^-OOH)]²⁺. The BDFE_OO-H = 80.3 ± 1.2 kcal/mol, as calculated for [Cu^II₂(BPMPO^-)(^-OOH)]²⁺; this is further substantiated by H atom abstraction from O-H substrates by [Cu^II₂(BPMPO^-)(O₂^•-)]²⁺ forming [Cu^II₂(BPMPO^-)(^-OOH)]²⁺. In comparison to known analogues, the thermodynamic and spectroscopic properties of [Cu^II₂(BPMPO^-)] O₂-derived adducts can be accounted for based on chelate ring size variations built into the BPMPO^- framework and the resulting enhanced Cu^II-ion Lewis acidity.

An extended class of organic multi‐redox systems was derived from bicyclic(alkyl)amino carbenes (BICAACs). The highly‐conjugated system undergoes a total of 4 redox events spanning a 1.8 V redox range. These organic compounds exhibited four different stable redox states (dication, radical cation, neutral and radical anion), and all of them were characterized either by single crystal X‐ray study and/or various spectroscopic studies. Three of the four redox states are stable to air and moisture. The availability of stable multiple redox states demonstrated promise towards their efficacy in the symmetric H‐cell charge/discharge cycling. Among various redox states, the dication/neutral state works efficiently and continuously for 1500 cycles in 2e⁻ charge/discharge process outside glovebox in commercially available DMF with minimum capacity loss (retaining nearly 90 % Coulombic efficiency). Surprisingly, the efficiency of the redox cycle was retained even if the system was exposed to air for 30 days when it slowly regenerated to the initial deep blue radical cation, and it exhibited another 100 charge/discharge cycles with a minimal capacity loss. Such a stable H‐cell cycling ability is not well known among organic molecule‐based systems.

Much progress has been made in understanding the roles of the secondary coordination sphere (SCS) in tuning redox potentials of metalloproteins. In contrast, the impact of SCS on reactivity is much less understood. A primary example is how copper proteins can promote S-nitrosylation (SNO), which is one of the most important dynamic post-translational modifications, and is crucial in regulating nitric oxide storage and transportation. Specifically, the factors that instill Cu^II with S-nitrosylating capabilities and modulate activity are not well understood. To address this issue, we investigated the influence of the primary and secondary coordination sphere on Cu^II-catalyzed S-nitrosylation by developing a series of azurin variants with varying catalytic capabilities. We have employed a multidimensional approach involving electronic absorption, S and Cu K-edge XAS, EPR, and resonance Raman spectroscopies together with QM/MM computational analysis to examine the relationships between structure and molecular mechanism in this reaction. Our findings have revealed that kinetic competency is correlated with three balancing factors, namely Cu-S bond strength, Cu spin localization, and relative S(p_s) vs S(p_p) contributions to the ground state. Together, these results support a reaction pathway that proceeds through the attack of the Cu-S bond rather than electrophilic addition to Cu^II or radical attack of S_Cys. The insights gained from this work provide not only a deeper understanding of SNO in biology but also a basis for designing artificial and tunable SNO enzymes to regulate NO and prevent diseases due to SNO dysregulation.

Thirteen boronated cyanometallates [M(CN-BR₃)₆]^3/4/5- [M = Cr, Mn, Fe, Ru, Os; BR₃ = BPh₃, B(2,4,6,-F₃C₆H₂)₃, B(C₆F₅)₃] and one metalloboratonitrile [Cr(NC-BPh₃)₆]^3- have been characterized by X-ray crystallography and spectroscopy [UV-vis-near-IR, NMR, IR, spectroelectrochemistry, and magnetic circular dichroism (MCD)]; CASSCF+NEVPT2 methods were employed in calculations of electronic structures. For (t_2g)⁵ electronic configurations, the lowest-energy ligand-to-metal charge-transfer (LMCT) absorptions and MCD C-terms in the spectra of boronated species have been assigned to transitions from cyanide π + B-C borane σ orbitals. CASSCF+NEVPT2 calculations including t_1u and t_2u orbitals reproduced t_1u/t_2u → t_2g excitation energies. Many [M(CN-BR₃)₆]^3/4- complexes exhibited highly electrochemically reversible redox couples. Notably, the reduction formal potentials of all five [M(CN-B(C₆F₅)₃)₆]^3- anions scale with the LMCT energies, and Mn(I) and Cr(II) compounds, [K(18-crown-6)]₅[Mn(CN-B(C₆F₅)₃)₆] and [K(18-crown-6)]₄[Cr(CN-B(C₆F₅)₃)₆], are surprisingly stable. Continuous-wave and pulsed electron paramagnetic resonance (EPR; hyperfine sublevel correlation) spectra were collected for all Cr(III) complexes; as expected, ¹⁴N hyperfine splittings are greater for (Ph₄As)₃[Cr(NC-BPh₃)₆] than for (Ph₄As)₃[Cr(CN-BPh₃)₆].