Despite recent progress in electrocatalytic CO2 and CO conversion, improvement in the generation of high-value multi-carbon products is required for practical sustainability goals. Here we report a plasma–electrocatalysis platform that delivers non-thermal plasma-activated CO2 or CO to a Cu gas diffusion electrode, enabling electrocatalytic conversion of plasma species while avoiding quenching in the electrolyte. Co-feeding CO2 and CO enhances C3+ and alcohol productivities by 3.3 and 1.5 times, respectively, compared with electrocatalysis alone. In addition, plasma activation unlocks the formation of chemicals that are not generated through electrocatalytic-only pathways, including methanol, acetylene, ethane, propane, butane and butanol. Plasma simulation, experimental evidence and in situ analysis suggest that vibrationally excited molecules and carbon suboxide can lead to the emergence and enrichment of certain reaction intermediates on Cu, accounting for the effects of the plasma activation on the electrocatalysis. The synergistic plasma–electrocatalytic conversion provides pathways towards the electrosynthesis of high-value chemicals and fuels at elevated production rates. Achieving efficient electrocatalytic conversion of CO2 and CO to high-value multi-carbon products remains a major challenge. Now, plasma activation is coupled with electrocatalysis on copper to enable unexplored reaction pathways, enhancing the production rates of C3+ hydrocarbons and oxygenates.
5-Azacytidine is a cytidine-mimic nucleoside containing the 1,3,5-triazine base 5-azacytosine and is currently used to treat myelodysplastic syndrome, a group of blood cancers. 5-Azacytidine was initially reported as a synthetic cytidine analogue before its isolation as a natural product in 1966. Since then, its biosynthesis has remained unexplored, probably because it was regarded as a synthetic analogue. Here we identified the 5-azacytidine biosynthetic gene cluster and revealed unusual catalytic reactions underlying 5-azacytosine biosynthesis through biochemical, structural and density functional theory analyses. AzcE, a guanosine triphosphate (GTP) cyclohydrolase, converts GTP to 2,5,6-triaminopyrimidin-4(1H)-one; AzcA, a cupin domain-containing enzyme, remodels the carbon–nitrogen framework of the pyrimidine into 6-amino-4-oxo-1,4-dihydro-1,3,5-triazine-2-carboxylic acid through selective cleavage and reassembly of the heterocyclic skeleton; and AzcB/C catalyses an unusual thiamine pyrophosphate-dependent decarboxylation at the α‑imino carboxylic acid moiety of the AzcA product to complete 5‑azacytosine biosynthesis. This work uncovers intriguing enzymatic chemistry in the biosynthesis of a long-known therapeutic natural product, highlighting opportunities for discovering enzymatic diversity. Despite decades of clinical use, the biosynthetic origin of 5-azacytidine remained unknown. Now the responsible gene cluster is identified, revealing enzymes that convert guanosine triphosphate into a triazine nucleobase through rare skeletal editing and unconventional thiamine-dependent chemistry.
Frontier molecular orbital engineering provides a powerful means to control chemical reactivity and unlock new catalytic functions in main-group compounds. However, prevailing approaches largely rely on geometric distortion, a design principle that has proven highly successful for multivalent p-block centres, but remains poorly suited to divalent chalcogen systems owing to its element-specific nature. Here we introduce a conceptually distinct strategy that exploits through-space orbital interactions to tailor electronic structure in divalent organosulfur compounds. By anchoring four sulfur atoms to a single carbon centre, a spirocyclic scaffold enforces spatial overlap between sulfur p orbitals, giving rise to a four-centred highest-occupied molecular orbital of elevated energy. This design unveils a multicentred main-group catalyst that enables electrophilic arene halogenation with pronounced reactivity, distinguishing it from prototypical organosulfur compounds. Mechanistic studies reveal that multi-atom cooperativity co-localizes enhanced nucleophilicity in the sulfide state with unusual halogen-transfer capability in the corresponding sulfonium state. This catalytic platform is compatible with complex arenes that are otherwise difficult to functionalize and expands the toolkit for late-stage modification of drug-like scaffolds. Geometric distortions are the prevailing approaches for engineering frontier molecular orbitals and chemical reactivity in p-block elements. Here the authors show a spirocyclic structure that exploits through-space orbital interactions in sulfur atoms to engineer highest-occupied molecular orbitals with elevated energies.
Cations play a critical role in electrochemical CO2 reduction, yet the mechanisms underlying their influence remain incompletely understood owing to limited knowledge of their solvation structures and interfacial interactions under operating conditions. Here we combine surface-sensitive total electron yield X-ray absorption spectroscopy, surface-enhanced infrared absorption spectroscopy and density functional theory calculations to determine the solvation environment of caesium ions near a ligand-modified silver nanocatalyst under CO2-reducing conditions. We find that desolvated Cs+ ions, confined between a detached ligand layer and the silver surface, enable CO2 activation at potentials as high as 0.4 V versus reversible hydrogen electrode—reducing the overpotential for CO2-to-CO conversion by 250 mV compared with a bare Ag film. Our results further reveal partial covalent character in Cs–intermediate interactions, which directly accounts for the enhanced catalytic activity. These findings provide multimodal spectroscopic evidence that cations can modulate reaction kinetics beyond purely electrostatic effects. The mechanism of cation enhancement in electrocatalytic CO2 reduction has been widely debated but spectroscopic evidence under operating conditions is lacking. Now operando X-ray and surface-enhanced infrared spectroscopy are combined with theory to reveal that desolvated Cs+ cations enable CO2 activation at substantially reduced overpotentials through partial covalent interactions.
Selectively producing multicarbon alcohols such as ethanol via CO2 electroreduction remains challenging due to inefficient C–C coupling and competing C–O bond cleavage. Here we report a nanoconfined catalytic reactor design that integrates structural confinement with localized CO2 supersaturation to enhance ethanol selectivity. Specifically, a cavity-engineered copper catalyst (CuCav-CH3@C) was developed to enrich CO2 concentrations ([CO2]) beyond their saturation limit by leveraging confined gas–liquid domains. Under these conditions, the catalyst achieves an ethanol Faradaic efficiency of 70.3% ± 3.5% and an ethanol partial current density of 245.9 ± 4.2 mA cm−2. In situ spectroscopic analysis and theoretical simulations reveal that local CO2 enrichment stabilizes the ethoxy intermediates and modulates C–O bond configurations, thereby suppressing ethylene formation and promoting ethanol selectivity. This work demonstrates how nanoconfinement and local molecular regulation can be synergistically used to tailor the microenvironment and unlock efficient pathways for producing oxygenated C2+ products. Achieving a high selectivity for multicarbon alcohols via electrocatalytic CO2 reduction on copper has proved challenging. Here a nanoconfined catalytic reactor strategy integrates localized CO2 supersaturation, leading to the stabilization of ethoxy intermediates and a 70.3% Faradaic efficiency for ethanol at practical current densities.
The active phase for the partial oxidation of methane (POM) to syngas on Ni catalysts has been attributed to metallic nanoparticles, with high Ni loadings (~10 wt%) considered essential. Here we show, on NiO surfaces, that in situ-generated [Ni1O1Ni4] motifs, where one Ni atom sits on an oxygen atom that bridges four surrounding Ni atoms, drive POM with promising efficiency. A Ni/Al2O3-ME catalyst with Ni loading of 0.8 wt% fabricated via deposition of preformed Ni nanoparticles onto Al2O3 achieves 92.0% CH4 conversion and 87.0% CO/H2 selectivity at 650 °C for POM, maintaining a stable H2/CO ratio of 2.0. Operando spectroscopy and environmental microscopy confirm the oxidation of metallic Ni to NiO during POM. The results of operando high-resolution annular bright-field imaging, combined with density functional theory calculations, suggest that the [Ni1O1Ni4] structure formed on the NiO(100) surface reduces the C–H activation barrier to 12.5 kcal mol−1. Thus, metallic Ni nanoparticles with high metal loadings may not be strictly required for efficient POM. The partial oxidation of methane to syngas on Ni is commonly attributed to its metallic phase. Now, by combining in situ spectroscopy and microscopy, as well as density functional theory calculations, specific Ni–O motifs are identified as the active sites on Ni/Al2O3.
Most of the current photocatalytic methodologies for the generation of reactive radical intermediates have limited redox windows and can operate within a single redox manifold. Here, to overcome these constraints, we report a purely organic photocatalyst that operates via a two-photon excitation mechanism, enabling both oxidative and reductive transformations within a unified platform. Upon visible-light irradiation, the molecule undergoes reversible fragmentation into three reactive subunits spanning a 5.7 V redox window. These fragments orchestrate an unusual consecutive light-induced electron-transfer mechanism that enables the orthogonal activation of thermodynamically challenging substrates. The mechanistic scenario is revealed through a combination of spectroscopic and optical techniques, supported by quantum calculations. Selectivity is mainly governed by the activity of a transiently generated catalytic species, whose presence prevents the need for external radical-sorting agents. Finally, the generality of this light-driven radical-coupling reactivity is demonstrated across a broad range of structurally diverse substrates. Photocatalysts can generate radical species from substrates following light excitation. Here the authors report a two-photon bimodal catalysis approach in which the light-activated photocatalyst generates reactive intermediates at opposite redox scales, expanding the accessible redox window.
Bulk measurements obscure critical microscopic variations, limiting the mechanistic understanding of complex electrocatalyst interfaces central to sustainability technologies. Although emerging single-particle techniques address ensemble averaging, they focus on catalyst structure, reactant adsorption or special model reactions, and cannot quantify turnover rates of practical electrocatalytic reactions. Here we report domino-reaction-enabled label-free imaging for nanoscopic electrocatalysis (DELINE), enabling subparticle, single-turnover imaging of surface water dissociation under operando conditions. DELINE decouples size–structure effects in electrocatalysts, reveals unexpected heterogeneity in Volmer transition states and uncovers strong coupling between charge-transfer coefficient and exchange velocity. Using DELINE imaging, we provide evidence of a compensation rule in electrocatalysis, akin to Meyer–Neldel behaviour. Cost-effective and high-throughput, DELINE quantifies key activity descriptors at single-particle/subparticle levels under realistic conditions, bridging the theory–experiment gap and accelerating catalyst screening. Understanding nanoscale heterogeneity in electrocatalytic reactions is critical for advancing catalyst design and performance. Now, a single-turnover imaging technique with subparticle resolution, DELINE, is introduced, which enables the mapping of electrocatalytic reactions and is used to probe surface water dissociation.
Carbonyl–ene-type reactions are recognized by chemists for their ability to form carbon–carbon bonds between aldehydes and alkenes, both abundantly available early-stage chemicals. However, despite remarkable progress with intramolecular variants, intermolecular carbonyl–ene-type reactions in which unactivated aldehydes react with unactivated alkenes are underexplored and, to the best of our knowledge, catalytic enantioselective versions have not yet been described. Here we report a solution to this problem that enables a variety of unactivated aromatic and aliphatic aldehydes to be united with alkenes, furnishing highly enantioenriched homoallylic alcohols. The method benefits from the high reactivity of confined silylium ion-based organic Lewis acid catalysts, which, according to computational studies, mediate a cationic Prins-type pathway. Intermolecular asymmetric carbonyl–ene-type reactions of unactivated aldehydes and alkenes remain largely unexplored. Now this transformation is achieved by combining confined imidodiphosphorimidate catalysts with an external silicon source to deliver enantioenriched homoallylic alcohols.
Impurities are usually blamed for irreproducible catalysis, but what if, in electrochemistry, they are part of the active material? It is now shown that, in CO2 electroreduction on oxide-derived copper, an uninvited ingredient from a standard bicarbonate electrolyte, Na+, can be incorporated into nanoscale, defect-rich microstructures during the oxide-to-metal transformation. This incorporation tracks with enhanced CO2 reduction activity, suggesting that trace electrolyte ions can become an integral (and previously hidden) part of the catalyst’s working state.
Phosphorothioate oligonucleotides (PS-ODNs) and cyclic dinucleotides are important therapeutic agents whose activity depends critically on phosphorus stereochemistry. However, existing strategies largely rely on chiral auxiliaries that require multistep installation and removal. Although chiral phosphoric acid catalysis enables diastereoselective synthesis of P-stereogenic dinucleotides via P(III)-phosphoramidite chemistry, this approach fails to access long-chain stereodefined PS-ODNs. Here we report a catalytic asymmetric P(V)-based strategy that enables stereocontrolled synthesis of PS-ODNs and cyclic dinucleotides using chiral organocatalysts. This platform integrates a catalyst-controlled nucleoside loading step with a stereospecific coupling process under mild, redox-neutral conditions. The method exhibits broad substrate scope, enabling efficient construction of diverse P–O, P–S, P–C and P–N linkages with high stereochemical fidelity. Notably, the method enables the stereocontrolled synthesis of PS-ODNs under both 5′ → 3′ and standard 3′ → 5′ solid-phase oligonucleotide synthesis workflows. Mechanistic studies support a cooperative activation mode involving hydrogen bonding, nucleophilic activation and general base catalysis. Existing methodologies for the stereocontrolled synthesis of phosphorothioate oligonucleotides and cyclic dinucleotides generally rely on chiral auxiliaries and are not catalytic. This study reports a catalytic asymmetric P(V)-based strategy, enabled by a C2-symmetric multifunctional chiral bis(amidine) organocatalyst, for the stereoselective synthesis of these classes of compounds.
Phosphorothioate modifications are central to oligonucleotide medicines, but their stereocontrolled syntheses has proven challenging. A catalyst-controlled loading strategy now delivers stereodefined building blocks for oligonucleotides and cyclic dinucleotides.
Understanding catalysis at its core requires more than the concept of the active site: it demands situating the active site within the reaction environment that ultimately governs its behaviour. Progress in catalysis science and engineering will increasingly depend on treating the active site and its environment as inseparable components, enabling a holistic and predictive framework for designing catalytic technologies.
Chemoenzymatic peptide functionalization requires potent biocatalysts. Now, a rapid screening platform is developed to expand the underexplored diversity of the enzyme family of prenyltransferases, providing a broadly feasible approach to facilitating the discovery of biocatalysts.
Lithium-mediated nitrogen reduction offers a unique route to ammonia synthesis, but its performance depends strongly on the reactive solid-electrolyte interphase. Operando Raman spectroscopy now reveals how salt chemistry and ethanol can construct this interphase to control nitrogen transport, lithium reactivity and ammonia formation.
DNA-encoded chemical library (DEL) technology is a powerful tool in early-stage drug discovery. Although widely applied in industry and academia, challenges persist in generating DELs with high quality and chemical diversity. Low yields in building-block incorporation, limited selectivity and, most importantly, DNA damage from harsh reaction conditions compromise library quality, reduce signal-to-noise in affinity selections and ultimately hinder drug discovery. Here we show that tailored enzymes can be harnessed for the effective construction of molecular diversity on DNA under mild conditions. Targeting amide bond formation, we designed a cascade of complementary coenzyme A ligases and rationally tailored N-acyltransferases to access a broad amide scope on-DNA (>120 examples), identifying structural elements that optimize the biocatalysts' DNA compatibility in the process. Integrating the enzymatic cascade with chemical synthesis led to the construction of a diverse DEL without damage to the DNA barcode, highlighting the biocatalysts' applicability for early scaffold construction and late-stage functionalization.
Electrocatalysts often undergo dynamic phase transitions during electrochemical operation, which introduce structural and chemical complexities that obscure the fundamental origins of their catalytic performance. Oxide-derived Cu (OD-Cu), produced by the electrochemical reduction of Cu oxide, exemplifies this challenge and continues to prompt debate regarding the nature of its high activity in CO2 electrolysis. Here, using cryogenic atom probe tomography, we show the formation of nanoscale Na+-containing microstructures within OD-Cu, originating from phase transitions of Cu oxide in a NaHCO3 electrolyte. Comparative studies with Na+-free OD-Cu and pulsed electrolysis identify a strong correlation between Na+ impurity incorporation and enhanced CO2 electrolysis activity. Complementary in situ Raman spectroscopy studies further confirm that these extrinsic impurities stabilize labile yet catalytically active Cu+ species. Overall, our findings elucidate the pivotal role of Na+ impurities and provide mechanistic insights to guide the rational design of synthetic and operational strategies for more efficient CO2 valorization.
Rational design of electrode-electrolyte interfaces is central to achieving an efficient oxygen reduction reaction (ORR) in proton-exchange membrane fuel cells. Here we demonstrate that 7-alkyltheophyllines are a group of bifunctional molecular additives capable of enhancing ORR activity on Pt(111) in the presence of strongly binding anions, for example, sulfonate in Nafion and phosphate, by enhancing intrinsic ORR kinetics and suppressing the specific adsorption of anions. Single-crystal voltammetric analysis and computational investigations reveal that the enhanced intrinsic ORR kinetics by adsorbed 7-alkyltheophyllines stems from facilitating the reduction of *O to *OH, which is a kinetically important step in the ORR on Pt surfaces. Mechanistic insights regarding the molecular additives gained on Pt(111) are shown to be valid on polycrystalline Pt. Finally, the practical relevance of this discovery is demonstrated by substantial performance enhancements in proton-exchange membrane fuel cells with Pt/C catalysts modified by 7-ethyltheophylline, highlighting the transferability of fundamental insights.
