Two-electron Oxidation Research Articles

Electrochemically driven nonheme iron complex-catalyzed oxidation reactions using water as an oxygen source

High-valent metal-oxo species have been invoked as key intermediates in enzymatic and biomimetic oxidation reactions. The generation of high-valent metal-oxo species using water (H2O) as an oxygen source represents one of the most environmentally friendly approaches in developing biologically inspired oxidation catalysis. Herein, we report the electrochemical oxidation of benzylic C−H bonds and alcohols utilizing a mononuclear nonheme iron(III)-monoamidate complex [FeIII(dpaq)(H2O)]2+ (dpaq = 2-[bis(pyridin-2-ylmethyl)]amino-N-quinolin-8-yl-acetamidate) as a catalyst and H2O as an oxygen source. Selective benzylic C−H bond oxidation of alkanes to ketones was achieved in 43–85 % yields, and primary and secondary alcohols were converted to the corresponding aldehydes and ketones, respectively, in 46–95 % yields. The generation of an iron(V)-oxo species [FeV(O)(dpaq)]2+ from proton-coupled electron-transfer (PCET) oxidation of the iron(III) aqua complex [FeIII(dpaq)(H2O)]2+ was evidenced by cyclic voltammetry analysis; the iron(V)-oxo species [FeV(O)(dpaq)]2+ was recently detected using transient absorption spectroscopy in water oxidation reactions. Mechanistic studies revealed that electrochemical oxidation of alcohols catalyzed by FeIII(dpaq) is a two-electron oxidation process, hydrogen-atom transfer (HAT) from the α-C−H bond of alcohols by iron(V)-oxo species is the rate-determining step, and there is a remarkable charge transfer from the highly electrophilic iron(V)-oxo species to the alcohols in the HAT step. This research paves a significant groundwork aimed at developing electrochemically driven biomimetic asymmetric oxidation reactions catalyzed by nonheme metal complexes supported by chiral ligands.

Dirhodium-Catalyzed [2 + 2 + 2] Cycloaddition of 1,6-Diynes and Alkynes.

A facile method for the construction of fused arenes has been developed through dirhodium-catalyzed [2 + 2 + 2] cycloaddition, which represents a new application of dirhodium complexes. This protocol is convenient to handle without the addition of extra ligands and reductants and tolerates a broad range of functional groups. Mechanistic studies revealed that the two-electron oxidation process, carboxylate ligand departure, and heteroatom coordination-promoted [2 + 2 + 2] cycloaddition were possibly involved.

ER Oxidoreductin 1-Like Activity of Cyclic Diselenides Drives Protein Disulfide Isomerase in an Electron Relay System.

Disulfide formation generally involves a two-electron oxidation reaction between cysteine residues. Additionally, disulfide formation is an essential post-translational modification for the structural maturation of proteins. This oxidative folding is precisely controlled by an electron relay network constructed by protein disulfide isomerase (PDI), with a CGHC sequence as the redox-active site, and its family enzymes. Creating reagents that mimic the functions of these enzymes facilitates folding during chemical protein synthesis. In this study, we aimed to imitate a biological electron relay system using cyclic diselenide compounds as surrogates for endoplasmic reticulum oxidoreductin 1 (Ero1), which is responsible for the re-oxidation of PDI. Oxidized PDI (PDIox) introduces disulfide bonds into substrate proteins, resulting in its conversion to reduced PDI (PDIred). The PDIred is then re-oxidized to PDIox by a coexisting cyclic diselenide compound, thereby restoring the function of PDI as a disulfide-forming agent. The produced diselenol state is readily oxidized to the original diselenide state with molecular oxygen, continuously sustaining the PDI catalytic cycle. This artificial electron relay system regulating enzymatic PDI function effectively promotes the oxidative folding of disulfide-containing proteins, such as insulin-a hypoglycemic formulation-by enhancing both yield and reaction velocity.

Membrane-free Electrolysis Production of Hydrogen Peroxide on Low-Cost Metal-Free Electrocatalysts for Dye Degradation.

The efficient production of hydrogen peroxide (H2O2) solution was achieved by combining cathodic two-electron oxygen reduction (2e- ORR) and anodic two-electron water oxidation (2e- WOR) in two half-reaction cells. h-BN loaded on carbon fibers (h-BN@C) is prepared and employed as an anode material to catalyze 2e- WOR, while sulfonated commercial BP-2000 carbons (BP-2000-SO3H) were prepared as the cathode materials for 2e- ORR. In a 2 M KHCO3 solution, an overall Faradaic efficiency of 97% and a total H2O2 production rate of 1872 mmol g-1 h-1 over metal-free electrodes were accomplished in a membrane-free flow cell. The dilute H2O2 solution could be directly used to degrade cationic Rhodamine B or methyl orange and anionic methylene blue dyes in water. This work proved low-cost production of dilute H2O2 solution in simple membrane-free flow cells with single electrolyte and on-site utilization for efficient dye degradation.

Al-N3 Bridge Site Enabling Interlayer Charge Transfer Boosts the Direct Photosynthesis of Hydrogen Peroxide from Water and Air.

Manipulating the electronic environment of the reactive center to lower the energy barrier of the rate-determining water oxidation step for boosting the direct generation of H2O2 from water, air, and sunlight is fascinating yet remains a grand challenge. Driven by a first-principles screening across a series of metal single atoms in carbon nitride, we report a class of an Al-N3 bridge site enabling interlayer charge transfer in carbon nitride nanotubes (CNNT-Al) for the highly efficient photosynthesis of H2O2 directly from water, oxygen, and sunlight. We demonstrate that the interlayered Al-N3 bridge site in CNNT-Al is able to activate the neighboring surface N atom for promoting the rate-determining step of the two-electron water oxidation to H2O2. It is also able to act as a bridge for enhancing the vertical interlaminar charge transfer due to the hybridization between the 3s and 3p states of the interstitial Al atom and the conduction band of two adjacent carbon nitride layers. Collectively, these factors lead to a highest photocatalytic mass activity of 1410.2 μmol g-1 h-1 (with a photocatalyst concentration of 1 g L-1) for direct photosynthesis of H2O2 out of all CN-based photocatalysts and a 7-fold higher solar-to-chemical conversion efficiency (0.73%) compared to that of the natural photosynthesis of typical plants (∼0.1%). Most importantly, the CNNT-Al-based flow reactor can steadily produce H2O2 for 200 h and be directly used for the on-site degradation of organic dye in water. The CNNT-Al-based flow reactor can also kill a 10 times higher concentration of bacteria in deionized water than that in natural water with 100% efficiency, which makes our design economically appealing for practical water treatment.

First oxidative coupling of cyclazine heterocycle via regioselective dimerization of 1,2-dicarbomethoxy-3-phenylcycl[3.2.2]azine: synthesis, theoretical aspects and physicochemical studies

The first covalently linked dimer has been prepared for cyclazine systems by regioselective oxidative homocoupling of 1,2-dicarbomethoxy-3-phenylcycl[3.2.2]azine. The regioselectivity of this reaction at 4-position, having been confirmed by X-ray diffraction analysis and NMR spectroscopy, has been also reliably predicted within the model of average local ionization energy on the molecular surface of the starting monomer at the BP86/def2-TZVP level of theory. Due to the planar π-π interaction of the cycl[3.2.2]azine subunits, the dimer is a green fluorophore (λem = 527 nm, toluene), characterized by a bathochromic shift of the main bands in the UV-vis and fluorescence spectra relative to the monomer by 41 and 71 nm, respectively. Furthermore, the dimer demonstrates an increased fluorescence quantum yield relative to the monomer (55% vs. 35% in toluene), and according to the data of X-ray diffraction analysis, DFT calculations and variable temperature 1D and 2D 1H NMR spectroscopy, is characterized by hindered rotation of the S1-state-involved cycl[3.2.2]azine cores along the C4-C4' bond axis. Such prerequisites determine good application potential of the 4-4' coupled cycl[3.2.2]azine derivatives as turn-on fluorescent, i.e. fluorogenic probes for advanced bioimaging in living systems. Finally, unlike the monomer, the dimer shows reversibility of both one- and two-electron reduction and oxidation processes, and therefore can become the basis of both n- and p-type semiconductors.

Advances in Two-Electron Water Oxidation Reaction for Hydrogen Peroxide Production: Catalyst Design and Interface Engineering.

Hydrogen peroxide (H2O2) is a versatile and zero-emission material that is widely used in the industrial, domestic, and healthcare sectors. It is clear that it plays a critical role in advancing environmental sustainability, acting as a green energy source, and protecting human health. Conventional production techniques focused on anthraquinone oxidation, however, electrocatalytic synthesis has arisen as a means of utilizing renewable energy sources in conjunction with available resources like oxygen and water. These strides represent a substantial change toward more environmentally and energy-friendly H2O2 manufacturing techniques that are in line with current environmental and energy goals. This work reviews recent advances in two-electron water oxidation reaction (2e-WOR) electrocatalysts, including design principles and reaction mechanisms, examines catalyst design alternatives and experimental characterization techniques, proposes standardized assessment criteria, investigates the impact of the interfacial milieu on the reaction, and discusses the value of in situ characterization and molecular dynamics simulations as a supplement to traditional experimental techniques and theoretical simulations, as shown in Figure 1. The review also emphasizes the importance of device design, interface, and surface engineering in improving the production of H2O2. Through adjustments to the chemical microenvironment, catalysts can demonstrate improved performance, opening the door for commercial applications that are scalable through tandem cell development.

Imidazolate-Stabilized Cu(III): Dioxygen to Oxides at Type 3 Copper Sites.

Imidazole ligation of metals through histidine is extensive among metalloproteins and enzymes, yet the role of the imidazolate conjugate base is often neglected, despite its potential accessibility when bonded to a highly oxidized metal center. Using synthetic models of oxygenated tyrosinase enzymes with exclusive monodentate imidazole ligation, we find that deprotonation of the μ2-η2:η2-peroxidodicopper(II) species triggers redox isomerization to an imidazolate-ligated bis(μ2-oxido)dicopper(III) species. Formal two-electron oxidation to Cu(III) remains unprecedented in biological systems, yet is effected readily by addition of base in these model systems. Spectrophotometric titrations by UV/visible/near-IR and copper K-edge X-ray absorption spectroscopies are interpreted most simply as two cooperative, 2H+ transformations in which the peroxide O-O is cleaved in the first step. Elaboration from simple imidazoles to a protected histidine extends this isomerization into an amino acid environment. The role of phenolate as a base suggests this four-electron reduction of O2 is energetically viable in a biological context and requires only two copper centers, which act as two-electron shuttles when imidazole deprotonation assists. This existential precedent of viable imidazolate intermediates invites speculation into an alternative mechanism for phenol hydroxylation not previously considered at Type 3 copper sites such a tyrosinases.

Thieno[3,2-b]thiophene Incorporated Redox Active 22π and 34π Core-Modified Expanded Isophlorinoids.

Incorporation of a thieno[3,2-b]thiophene into an isophlorinoid-like framework alters the aromaticity by extending the macrocyclic π-circuit. Their opto-electronic and aromatic properties significantly differ from other 22π and 34π porphyrinoids. Among the three different 34π hexaphyrins, furan based hexaphyrin adopts a non-aromatic 'figure-of-eight' conformation. Replacing all the furans either by thiophene or selenophene induces a planar conformation with aromatic characteristics. Spectro-electrochemical studies revealed reversible two-electron ring oxidation to yield their 4np dicationic species respectively.

De novo production of protoberberine and benzophenanthridine alkaloids through metabolic engineering of yeast

Protoberberine alkaloids and benzophenanthridine alkaloids (BZDAs) are subgroups of benzylisoquinoline alkaloids (BIAs), which represent a diverse class of plant-specialized natural metabolites with many pharmacological properties. Microbial biosynthesis has been allowed for accessibility and scalable production of high-value BIAs. Here, we engineer Saccharomyces cerevisiae to de novo produce a series of protoberberines and BZDAs, including palmatine, berberine, chelerythrine, sanguinarine and chelirubine. An ER compartmentalization strategy is developed to improve vacuole protein berberine bridge enzyme (BBE) activity, resulting in >200% increase on the production of the key intermediate (S)-scoulerine. Another promiscuous vacuole protein dihydrobenzophenanthridine oxidase (DBOX) has been identified to catalyze two-electron oxidation on various tetrahydroprotoberberines at N7-C8 position and dihydrobenzophenanthridine alkaloids. Furthermore, cytosolically expressed DBOX can alleviate the limitation on BBE. This study highlights the potential of microbial cell factories for the biosynthesis of a diverse group of BIAs through engineering of heterologous plant enzymes.

Self-Resistance Gene-Guided Discovery of the Molecular Basis for Biosynthesis of the Fatty Acid Synthase Inhibitor Cerulenin.

Cerulenin (1) is the first reported natural fatty acid synthase inhibitor and has been intensively researched for its antifungal, anticancer and anti-obesity properties. However, the molecular basis for its biosynthesis has remained a mystery for six decades. Here, we have identified the polyketide biosynthetic gene cluster (cer) responsible for the biosynthesis of 1 from two Sarocladium species using a self-resistance gene mining approach, which we validated via heterologous reconstitution of cer cluster in an Aspergillus nidulans host. Expression of various combinations of cer genes uncovered key pathway intermediates, electrocyclisation products derived from PKS-encoded polyenoic acids, and a suite of 13 new analogues of 1. This enabled us to establish a biosynthetic pathway to 1 that starts with a C12 polyketide precursor containing both E and Z double bonds and involves a complex series of epoxidations, double bond shifts, E/Z isomerisation and epoxide reduction. Using in vitro assays, we further validated the roles of amidotransferase CerD in amidation, and oxidase CerF and reductase CerE in the final two-electron oxidation and enone reduction steps towards 1. These findings expand our understanding of complex tailoring modifications in highly reducing PKS pathways and pave the way for the engineered biosynthesis of cerulenin analogues.

Novel electrocatalyst with abundant oxygen vacancies enabling efficient two-electron water oxidation reaction for H2O2 synthesis

In the realm of electrocatalytic two-electron water oxidation reaction, the quest for efficient and selective catalysts poses a significant challenge in balancing productivity and activity, hindering the decentralized generation of hydrogen peroxide (H2O2) through electrochemical means. Addressing this hurdle, our study introduces a novel approach to crafting an effective and stable electrocatalyst for the two-electron water oxidation reaction (2e-WOR). Through the synthesis of magnesium stannite tungstate from a mixture of MgSnO3 and WO3, the engineer of a material with abundant oxygen vacancies is crucial for catalytic activity. This catalyst demonstrates exceptional performance, ascribed to its distinctive oxygen vacancies proximal to the active center Sn and electronic modulation by tungsten. Notably, Mg1-xSnWO6-x700 exhibits a remarkably low overpotential of 70 mV at 10 mA cm−2, coupled with a high faradic efficiency of 84 % for 2e- WOR at 2.6 V vs. RHE, maintaining consistent performance over 35 h. Furthermore, the formation of oxygen vacancies and the associated electronic transfer underscore the novelty and promise of our material in advancing the field of two-electron WOR. In sum, our electrocatalyst presents a cost-efficient and selective solution for water oxidation, offering potential avenues for enhancing H2O2 production.

Pairing Oxygen Reduction and Water Oxidation for Dual-Pathway H2O2 Production.

Hydrogen peroxide (H2O2) is a crucial chemical applied in various industry sectors. However, the current industrial anthraquinone process for H2O2 synthesis is carbon-intensive. With sunlight and renewable electricity as energy inputs, photocatalysis and electrocatalysis have great potential for green H2O2 production from oxygen (O2) and water (H2O). Herein, we review the advances in pairing two-electron O2 reduction and two-electron H2O oxidation reactions for dual-pathway H2O2 synthesis. The basic principles, paired redox reactions, and catalytic device configurations are introduced initially. Aligning with the energy input, the latest photocatalysts, electrocatalysts, and photo-electrocatalysts for dual-pathway H2O2 production are discussed afterward. Finally, we outlook the research opportunities in the future. This minireview aims to provide insights and guidelines for the broad community who are interested in catalyst design and innovative technology for on-site H2O2 synthesis.

Photoelectrochemical Synthesis of Hydrogen Peroxide from Saline Water via the Two-Electron Water Oxidation Reaction.

Hydrogen peroxide (H2O2) production on the anode is more valuable than oxygen and chlorine evolution for photoelectrochemical saline water splitting. In this work, by the introduction of bicarbonate (HCO3-), H2O2 is produced from saline water (2 M KHCO3 + 0.5 M NaCl aqueous solution) via the two-electron water oxidation reaction by a photoanode of bismuth vanadate (BiVO4). Furthermore, the Faradaic efficiency (FE) and accumulation for H2O2 are improved by coating antimony tetroxide (Sb2O4) on BiVO4. A H2O2 FE of 26% at 1.54 V vs RHE is obtained by Sb2O4/BiVO4 and 49 ppm of H2O2 is accumulated after a 135 min chronoamperometry. Similar to that in KHCO3 pure water solution, infrared spectroscopy and electrochemical analysis confirm that HCO3- plays a surface-mediating role in the formation of H2O2 in KHCO3 saline water solution. The presence of HCO3- in the electrolyte is able to not only increase the photocurrent density but also effectively inhibit the chlorine evolution reaction.

Unbiased Photoelectrochemical H2O2 Coupled to H2 Production via Dual Sb2S3-Based Photoelectrodes with Ultralow Onset Potential.

The productions of hydrogen peroxide (H2O2) and hydrogen (H2) in a photoelectrochemical (PEC) water splitting cell suffer from an onset potential that limits solar conversion efficiencies. Moreover, the formation of H2O2 through two-electron PEC water oxidation reaction competes with four-electron oxidation evolution reaction. Herein, we developed the surface selenium doped antimony trisulfide photoelectrode with the integrated ruthenium cocatalyst (Ru/Sb2(S,Se)3) to achieve the low onset potential and high Faraday efficiency (FE) for selective H2O2 production. The photoanode exhibits an outstanding average FE of 85 % in the potential range of 0.4-1.6 VRHE and the H2O2 yield of 1.01 μmol cm-2 min-1 at 1.6 VRHE, especially at low potentials of 0.1-0.55 VRHE with 80.4 % FE. Impressively, an unassisted PEC system that employs light and electrolyte was constructed to simultaneously produce H2O2 and H2 production on both the Ru/Sb2(S,Se)3 photoanode and the Pt/TiO2/Sb2S3 photocathode. The integrated system enables the average PEC H2O2 production rate of 0.637 μmol cm-2 min-1 without applying any addition bias. To our knowledge, this is the first demonstration that Sb2S3-based photoelectrodes exhibit H2O2/H2 two-side production with a strict key factor of the system, which represents its powerful platform to achieve high efficiency and productivity and the feasibility to facilitate value-added products in neutral conditions.

Synthesis of Quinoline-Based Pt-Sb Complexes with L- or Z-Type Interaction: Ligand-Controlled Redox via Anion Transfer.

A series of Pt-Sb complexes with two or three L-type quinoline side arms were prepared and studied. Two ligands, tri(8-quinolinyl)stibane (SbQ3, Q = 8-quinolinyl, 1) and 8,8'-(phenylstibanediyl)diquinoline (SbQ2Ph, 2), were used to synthesize the PtII-SbIII complexes (SbQ3)PtCl2 (3) and (SbQ2Ph)PtCl2 (4). Chloride abstraction with AgOAc provided the bis-acetate complexes (SbQ3)Pt(OAc)2 (5) and (SbQ2Ph)Pt(OAc)2 (6). To better understand the electronic effects of the Sb moiety, analogous bis-chloride complexes were oxidized to an overall formal oxidation state of +7 (i.e., Pt + Sb formal oxidation states = 7) using dichloro(phenyl)-λ3-iodane (PhICl2) and 3,4,5,6-tetrachloro-1,2-dibenzoquinone (o-chloranil) as two-electron oxidants. Depending on the oxidant, different conformational changes occur within the coordination sphere of Pt as confirmed by single-crystal X-ray diffraction and NMR spectroscopy. In addition, the nature of Pt-Sb interactions was evaluated via molecular and localized orbital calculations.

Metal Supported Metal Oxide Catalysts for Hydrogen Peroxide Production Via Water Splitting

The two-electron water oxidation reaction (WOR) has drawn recent attention as an efficient, simple method of producing on-site hydrogen peroxide through electrochemical water splitting. However, finding electrocatalysts with high activity and stability in the reaction’s harsh oxidizing environment is challenging. This is made especially difficult due to the competing four-electron and one-electron WOR, which necessitate a catalyst material with high selectivity towards the hydrogen peroxide production pathway. Here, we utilize metal/metal oxide coupling interactions to tune metal oxide catalysts to be active for 2 e- WOR via the creation of a Mott-Schottky junction. Metal/metal oxide interactions have been well studied for supported metal catalysts, but their behavior has been less investigated for catalysts where the metal oxide provides the active sites, called inverse catalysts. In this case, the difference in work functions between the metal support and metal oxide semiconductor catalyst drives electron transfer between the two, facilitating electronic interactions which can modulate the binding energy of reaction intermediates at the interface and thus tune the catalytic ability of the metal oxide. In this work, we investigate a variety of metal oxide catalyst and metal support materials and find that a thin layer of indium tin oxide (ITO) supported by a layer of platinum (Pt) has excellent catalytic ability towards 2 e- WOR. The activity, selectivity, and stability of the ITO/Pt catalyst shows significant improvement over the unsupported ITO catalyst and yields hydrogen peroxide production rates greater than those reported in literature using other standard catalysts for this reaction. This method of catalyst engineering also provides a future pathway to create new catalysts for this electrochemical reaction. Figure 1

Enhancement of direct electron transfer by aromatic thiol modification with truncated d-fructose dehydrogenase

A heterotrimeric membrane-bound d-fructose dehydrogenase (FDH) from Gluconobacter japonicus, composed of subunits L, C, and S, shows strong direct electron transfer (DET)-type bioelectrocatalytic performance in the two-electron oxidation of d-fructose. The electrode-active site of the enzyme is the heme c moiety in the subunit C. A previous study reported the construction of the subunit L/S subcomplex (ΔC FDH) lacking the subunit C. In this work, we attempted to realize the DET-type reaction of ΔC FDH using porous gold electrodes functionalized with several thiols, and investigated the influence of the thiols on DET. Kinetic analysis of the steady-state catalytic waves revealed that the electrode-active site of ΔC FDH is the [3Fe-4S] iron-sulfur cluster in the L subunit. The experimental results demonstrated that uncharged aromatic thiols on the electrode enhance the DET-type reaction of ΔC FDH. Based on the pH-dependent profile of the DET-type activity and the surface conditions of the modified thiols evaluated by electrochemical reductive desorption, we suggest an enhancement mechanism for DET by aromatic thiols.

Octahedral Hexanuclear Rhenium Cluster Dimers Bridged by Pyrazine or 4,4'-Bipyridine with 23- and 24-Electron Configurations.

New pyrazine (pz)- and 4,4'-bipyridine (4,4'-bpy)-bridged octahedral hexanuclear rhenium(III) cluster dimers, [{Re6(μ3-S)8Cl5}2(μ-L)]6- (L = pz, [1]6-; L = 4,4'-bpy, [2]6-), with 2 × 24 d-electrons {Re6(24e)}2 were obtained in a single-step reaction via photoirradiation of [Re6(μ3-S)8Cl6]4- with L in a 2:1 ratio at room temperature. The {Re6(23e)}2 dimers, [{Re6(μ3-S)8Cl5}2(μ-L)]4- (L = pz, [1']4-; L = 4,4'-bpy, [2']4-), were synthesized through two-electron oxidation of [1]6- and [2]6-, respectively. The single-crystal X-ray structures of [1]6- and [1']4- were determined, revealing structural distortion of the Re6 core of [1']4- due to the Jahn-Teller effect. The cyclic voltammograms of [1]6- and [2]6- showed two steps of one-electron redox processes attributable to Re6(23e)Re6(24e)/{Re6(24e)}2 and {Re6(23e)}2/Re6(23e)Re6(24e), respectively. The separation between the two redox potentials is small (0.056 V for [1]6- and 0.039 V for [2]6-). The magnetic susceptibilities of [1']4- and [2']4- were almost temperature-independent, with values of 2.98 and 2.85 μB, respectively, indicating paramagnetism. These results suggest weak electronic interaction between two cluster units bridged by pz or 4,4'-bpy in the intercluster mixed valence state. The compounds [1]6- and [2]6- show photoluminescence in the near-infrared region at 296 K in the solid state.

Comparing thiol and selenol reactivity towards peroxynitrite by computer simulation

Peroxynitrite is a very reactive species implicated in a variety of pathophysiological cellular processes. Particularly, peroxynitrite-mediated oxidation of cellular thiol-containing compounds such as cysteine residues is a key process which has been extensively studied. Cysteine plays roles in many redox biochemistry pathways. In contrast, selenocysteine, the 21st amino acid, is only present in 25 human proteins. Investigating the molecular basis of selenocysteine's reactivity may provide insights into its unique role in these selenocysteine-containing proteins. The two-electron oxidation of thiols or selenols by peroxynitrite is a process that is carried out by the thiolate/selenate forms and peroxynitrous acid.In this work, we shed light on the molecular basis of the differential reactivity of both species towards peroxynitrite by means of state-of-the-art computer simulations. We performed electronic structure calculations of the reaction in the methanethiolate and methaneselenolate model systems with peroxynitrous acid at different levels of theory using an implicit solvent scheme. In addition, we employed a multi-scale quantum mechanics/molecular mechanics approach for obtaining free energy profiles of these chemical reactions in aqueous solution, which enabled the comparison between the simulations and the available experimental data. Our results suggest that the larger reactivity observed in the selenocysteine case at physiological pH is mainly due to the lower pKa, which affords a larger fraction of the reactive anionic species in these conditions, and in a second place to a slightly enhanced intrinsic reactivity of the selenate form due to its larger nucleophilicity.