N Nature Chemistry · Dec 05, 2025 Revealing the impact of microenvironment on gold-catalysed CO2electroreduction via Marcus–Hush–Chidsey kinetics The microenvironment at electrochemical interfaces plays a crucial role in governing electrode-mediated electron transfer processes. However, elucidating the complex effects of the microenvironment remains challenging. The Butler–Volmer equation has been used in deducing reaction mechanisms and identifying rate-determining steps, but its empirical nature makes it challenging to deduce the molecular-level picture of interfacial electron transfer processes. By contrast, the application of the Marcus–Hush–Chidsey (MHC) electron transfer theory has been constrained by its tenuous connection to experimentally measurable parameters beyond reaction rates. Here we develop a mechanistic framework based on the MHC theory to systematically analyse the cation effect on the Au-catalysed CO2reduction reaction using experimentally accessible variables. Our analysis reveals consistent trends for both inorganic and organic cations through thermodynamic and kinetic parameters derived from the MHC theory, with potential applications for probing ionomer–electrode interface microenvironments. This study establishes a universal strategy for investigating interfacial microenvironments in electron transfer processes by bridging theoretical parameters with experimental descriptors. Chemical engineering Electrocatalysis
N Nature Chemistry · Dec 02, 2025 Iridium(III)-catalysed ionic hydrogenation of pyridines to multisubstituted piperidines Piperidine and pyridine are nitrogen heterocyclic motifs prominently used in pharmaceuticals and consequently of great importance. The direct reduction of planar pyridines into piperidines with highsp3-carbon content is highly attractive as this offers a route to producing high-value products and broadening the structural space. However, direct hydrogenation of pyridines with homogeneous catalysts is challenging due to their aromatic stability and catalyst-poisoning abilities. Here we describe a robust and selective iridium(III)-catalysed ionic hydrogenation of pyridines to corresponding functionalized piperidines. Important highly reduction-sensitive groups, including nitro, azido, bromo, alkenyl and alkynyl, are inert, enabling access to a broad range of multisubstituted piperidines in high yields, substantially expanding the available chemical space for this relevant scaffold. The method requires low catalyst loadings, is scalable to decagrams and delivers the most synthetically valuable free secondary amines as easily isolable and stable piperidinium salts. Applied in a complex late-stage setting, the pyridine motif in several FDA-approved drugs was successfully and selectively hydrogenated. Homogeneous catalysis Synthetic chemistry methodology Stereochemistry
N Nature Chemistry · Nov 28, 2025 Conformational preorganization of neighbouring groups modulates and expedites polymer self-deconstruction Controlling the rate at which polymers break down is essential for developing sustainable materials. Conventional approaches—which rely on introducing labile and cleavable bonds—often face an inherent trade-off between stability and ease of deconstruction. Inspired by self-deconstruction mechanisms in biomacromolecules, we leverage conformational preorganization of neighbouring groups to modulate and expedite polymer self-deconstruction. Here we show that precise spatial alignment of nucleophilic groups relative to labile bonds regulates the cleavage kinetics by shifting the conformational ensemble towards reactive geometries. This strategy enables programmable deconstruction of both linear polymers and bulk thermosetting networks under ambient conditions, with rates tunable across several orders of magnitude—without altering the chemical identity of the cleavable bond or compromising the polymers’ physical properties. Furthermore, even distal intramolecular functionalities can be harnessed to dynamically control bond cleavability through metal-induced polymer folding, enabling reversible activation and deactivation of self-deconstruction. This work establishes conformational control as a powerful strategy for fine-tuning polymer deconstruction. Polymer synthesis Polymers biology
N Nature Chemistry · Nov 26, 2025 Activation of alcohols as sulfonium salts in the photocatalytic hetero-difunctionalization of alkenes Motifs related to 1,2-diols and 1,2-amino alcohols are found widely in bioactive natural products, drugs and agrochemicals. These highly sought-after substructures would ideally be constructed by the direct addition of alcohols to the C=C bond of alkenes, both common substrate classes in chemical synthesis. However, their direct union is only possible if one of the pair can be rendered electron-deficient through derivatization; such approaches typically require stoichiometric amounts of strong oxidants and often lack generality. Here we describe a straightforward process in which both simple and complex alcohols can be converted under photocatalytic conditions to the corresponding alkoxy radicals—via the formation of alkoxy sulfonium salts—that react with alkenes en route to 1,2-diol and 1,2-amino-alcohol derivatives. The method can be easily adapted from laboratory to industrial, kilogram scale using a photoflow system. Spectroscopic analysis and control experiments have been used to probe the underpinning mechanism. Synthetic chemistry methodology Photocatalysis
N Nature Chemistry · Nov 25, 2025 Carbonate anions and radicals induce interfacial water ordering in CO2electroreduction on gold Interfacial hydration layers critically determine energy and chemical conversion processes, notably influencing the kinetics of electrocatalytic reactions. Fundamental mechanisms of reactions such as CO2electroreduction and hydrogen evolution remain controversial due to the challenge of in situ deciphering of hydration structures alongside reaction intermediates and products. Here, by using vibrational and electrochemical spectroscopy paired with theory we reveal how carbonates structure interfacial water, affecting CO2electroreduction and hydrogen evolution reactions on gold electrocatalysts in bicarbonate electrolytes. High cathodic potentials accelerate hydrogen evolution reactions by rapid proton delivery from ordered interfacial hydration networks, induced by carbonate molecules in equilibrium with their anion radicals. These radicals can serve, in addition to CO2, as a carbon source for CO and aldehyde production. Moreover we show water to be the primary proton donor for CO2electroreduction and hydrogen evolution reactions, with bicarbonate mostly participating in the Heyrovsky step. Our molecular-level insights are relevant to rationalizing and optimizing electrochemical interfaces. Catalytic mechanisms Electrocatalysis
N Nature Chemistry · Nov 24, 2025 An isolable germa-isonitrile featuring a terminal nitrogen–germanium triple bond Isonitriles (R–N≡C), first discovered by Lieke in 1859, are well-established functional molecules in organic and organometallic chemistry. By contrast, the synthesis and investigation of tetrela-isonitriles (R–N≡E, E = Si, Ge, Sn or Pb), their heavier group 14 analogues, remain challenging due to their high reactivity. The characterization of such species has largely relied on spectroscopic data collected at cryogenic temperatures or under gas-phase conditions. Here we report the synthesis and characterization of a germa-isonitrile (Ar–N≡Ge) stabilized by a bulky aryl ligand. This compound, which features a terminal N≡Ge triple bond with a Ge‒N bond length of 1.6395(19) Å, has been characterized through X-ray crystallographic, solid-state ¹⁵N nuclear magnetic resonance spectroscopic and computational studies. The highly polarized N≡Ge moiety exhibits versatile reactivity towards organic substrates and transition metal precursors, underscoring its potential use in synthetic chemistry. Coordination chemistry Inorganic chemistry
N Nature Chemistry · Nov 21, 2025 Programmable fluorescent aptamer-based RNA switches for rapid identification of point mutations The ability to detect single nucleotide polymorphisms (SNPs) is critical for identifying genetic disorders, assessing pathogen drug resistance and preventing infection transmission. Achieving a delicate balance across sequence-specific recognition, RNA structural stability and functional efficacy based on SNP-induced changes is crucial for precise genotyping using RNA-based probes. Here we report on in silico-designed aptamer-based RNA switches, referred to as ‘fast aptamer-based reporters for single-nucleotide-specific identification and genotyping through hybridization’ (FARSIGHTs), that enable rapid, low-leakage and multiplexed identification of virtually any target sequence with single-nucleotide specificity. Activation of the FARSIGHT probe can occur in as little as 5 min, separate from upstream amplification. Coupling FARSIGHTs with isothermal amplification enables the robust detection of single nucleotide mutations at attomolar concentrations through strong fluorescence output. We have demonstrated this by distinguishing the SARS-CoV-2 Omicron variant from Alpha, Beta and Gamma with 100% accuracy in RNA from clinical saliva samples. FARSIGHTs can be easily reprogrammed for genotyping emerging pathogens, with potential uses in point-of-care infectious disease monitoring and personalized healthcare applications. Biosensors RNA Synthetic biology biology
N Nature Chemistry · Nov 18, 2025 Developing design guidelines for controlling charge transport in DNA Conceptual frameworks that describe the electronic structure of molecules are an integral part of understanding chemical structures and reaction mechanisms and designing organic compounds. Here we develop a preliminary set of design guidelines for controlling the electronic structure of DNA. Recent work indicates that charge delocalization occurs over several bases and results in coherence lengths greater than a single base pair. To examine the interactions between bases and their effects on delocalization, this study investigates the influence of nearest-neighbour base pair interactions on the charge transport properties of DNA duplexes that are predominantly composed of guanine–cytosine base pairs. Results show that, by manipulating the sequence, the conductance can be substantially modified without altering the molecular composition. The electronic density of states are then analysed to deduce a set of design guidelines aimed at maintaining high conductance values in long duplexes. Utilizing these rules, we demonstrate that 20-base-pair DNA sequences can exhibit conductance values surpassing 1 × 10−3G0. Electronic properties and materials Molecular electronics
N Nature Chemistry · Nov 18, 2025 Computational design of superstable proteins through maximized hydrogen bonding Hydrogen bonds are fundamental chemical interactions that stabilize protein structures, particularly in β sheets, enabling resistance to mechanical stress and environmental extremes. Here, inspired by natural mechanostable proteins with shearing hydrogen bonds, such as titin and silk fibroin, we de novo designed superstable proteins by maximizing hydrogen-bond networks within force-bearing β strands. Using a computational framework combining artificial intelligence-guided structure and sequence design with all-atom molecular dynamics MD simulations, we systematically expanded protein architecture, increasing the number of backbone hydrogen bonds from 4 to 33. The resulting proteins exhibited unfolding forces exceeding 1,000 pN, about 400% stronger than the natural titin immunoglobulin domain, and retained structural integrity after exposure to 150 °C. This molecular-level stability translated directly to macroscopic properties, as demonstrated by the formation of thermally stable hydrogels. Our work introduces a scalable and efficient computational strategy for engineering robust proteins, offering a generalizable approach for the rational design of resilient protein systems for extreme environments. Protein design Single-molecule biophysics
N Nature Chemistry · Nov 17, 2025 Dearomativesyn-1,4-hydroalkylation and C(sp2)−H alkylation of arenes controlled by chemoselective electrolysis Dearomative functionalization of arenes represents a powerful synthetic strategy for the rapid assembly of complex chemical architectures. A significant challenge in this process is overcoming the inherent aromaticity of arenes. Here, leveraging the potential of organic electrolysis, we show the development of a dearomativesyn-1,4-hydroalkylation reaction targeting electron-deficient arenes and heteroarenes. This electrochemical approach, conducted under mild, operationally straightforward and scalable conditions, facilitates the synthesis of alkylatedsyn-1,4-cyclohexadienes with high chemoselectivity, regioselectivity and stereoselectivity. In addition, this alkylation protocol is controllable and switchable. By employing a niobium plate as the anode andnBu4NBr as the supporting electrolyte, our method enables thepara-selective C(sp2)–H alkylation of (hetero)arenes via electrolysis. Both reactions exhibit broad substrate scope and demonstrate excellent compatibility with various electron-deficient arenes and alkyl bromides. Furthermore, preliminary mechanistic studies and density functional theory calculations have been performed to elucidate the reaction mechanism and to rationalize the observed chemoselectivity, regioselectivity and stereoselectivity. Synthetic chemistry methodology
N Nature Chemistry · Nov 14, 2025 Tetrafunctional cyclobutanes tune toughness via network strand continuity Customizing the toughness of polymer networks independently of their chemical composition and topology remains an unsolved challenge. Traditionally, polymer network toughening is achieved by using specialized monomers or solvents or adding secondary networks/fillers that substantially alter the composition and may limit applications. Here we report a class of force-responsive molecules—tetrafunctional cyclobutanes (TCBs)—that enable the synthesis of single-network end-linked gels with substantially decreased or increased toughness, including unusually high toughness for dilute end-linked gels, with no other changes to network composition. This behaviour arises from stress-selective force-coupled TCB reactivity when stress is imparted from multiple directions simultaneously, which traditional bifunctional mechanophores cannot access. This molecular-scale mechanoreactivity translates to bulk toughness through a topological descriptor, network strand continuity, that describes the effect of TCB reactivity on the consequent local network topology. TCB mechanophores and the corresponding concepts of stress-selective force-coupled reactivity and strand continuity offer design principles for tuning the toughness of simple yet commonly used single-network gels. Gels and hydrogels Polymer synthesis
N Nature Chemistry · Nov 14, 2025 Construction of sulfur stereocentres by asymmetric geminate recasting Radical pairs generated by light-induced or heat-induced bond cleavage play a central role in biochemical transformations and the synthesis of pharmaceuticals, polymers and industrial chemicals. When such cleavage occurs at a stereocentre in chiral molecules, recombination of the produced radicals can lead to either enantiomer, typically resulting in racemization. Achieving selective conversion of racemic mixtures into single enantiomers is highly desirable yet challenging due to the uncontrolled behaviour of free radicals. Here we show that stereocontrol over these reactions can be achieved through asymmetric geminate recasting: a process in which homolysis and recombination occur within a solvent cage under the influence of a chiral photocatalyst. This strategy enabled the selective construction of chiral sulfur stereocentres via deracemization of sulfinamides, providing access to valuable sulfur-containing building blocks. The approach opens unexplored possibilities for controlling stereochemistry in radical reactions and may inspire broader applications in asymmetric synthesis, medicinal chemistry and materials development. Synthetic chemistry methodology Stereochemistry
N Nature Chemistry · Nov 14, 2025 Metal-hydroxyls mediate intramolecular proton transfer in heterogeneous O–O bond formation Metal (hydro)oxides are among the most effective heterogeneous water oxidation catalysts. Elucidating the interactions between oxygen-bridged metal sites at a molecular level is essential for developing high-performing electrocatalysts. Here we demonstrate that adjacent metal-hydroxyl groups function as intramolecular proton–electron transfer relays to enhance water oxidation kinetics. We achieved this using a well-defined molecular platform with an aza-fusedπ-conjugated microporous polymer that coordinates molecular Ni or Ni–Fe sites that emulate the structure of the most active edge sites in Ni–Fe materials for studying the heterogeneous water oxidation mechanism. We combine experimental and computational results to reveal the origin of pH-dependent reaction kinetics for O–O bond formation. We find both the anions in solution and the adjacent Ni3+–OH site act as proton transfer relays, facilitating O–O bond formation and leading to pH-dependent water oxidation kinetics. This study provides significant insights into the critical role of electrolyte pH in water oxidation electrocatalysis and enhancement of water oxidation activity in Ni–Fe systems. Catalytic mechanisms Electrocatalysis Heterogeneous catalysis
N Nature Chemistry · Nov 13, 2025 Transient Au–Cl adlayers modulate the surface chemistry of gold nanoparticles during redox reactions Controlling surface chemistry at the nanoscale is essential for stabilizing structure and tuning function in plasmonic, catalytic and sensing systems, where even trace ligands or ions can reshape surface charge and reactivity. However, probing such dynamic interfaces under operando conditions remains challenging, limiting efforts to engineer nanomaterials with precision. Here, using in situ surface-enhanced Raman spectroscopy, we identify a transient Au–Cl adlayer that forms during electrochemical cycling at gold interfaces. The adlayer exhibits significant charge transfer between gold and chlorine, generating an outward-facing dipole that polarizes neighbouring atoms and modulates the local potential. This dipole stabilizes nanogap interfaces and directs oriented ligand rebinding, enabling reversible reconstruction of subnanometre architectures. It also alters interfacial charge distributions and mediates electron transfer between gold oxidation states, acting as a redox-active intermediate. These findings show how transient surface species shape nanoscale reactivity and stability, offering strategies for designing catalysts, sensors and nanomaterials. Organic–inorganic nanostructures SERS Surface assembly
N Nature Chemistry · Nov 12, 2025 Compact RNA sensors for increasingly complex functions of multiple inputs Designing single molecules that compute general functions of input molecular partners is a major unsolved challenge in molecular design. Here we demonstrate that high-throughput, iterative experimental testing of diverse RNA designs crowdsourced from the online game Eterna yields sensors of increasingly complex functions of input oligonucleotide concentrations. After designing single-input RNA sensors with activation ratios beyond our detection limits, we created logic gates, including challenging XOR and XNOR gates, and sensors that respond to the ratio of two inputs. Finally, we describe the OpenTB challenge, which elicited 85-nucleotide sensors that compute a score for diagnosing active tuberculosis based on the ratio of products of three gene segments. Building on OpenTB design strategies, we created an algorithm, Nucleologic, that produces similarly compact sensors for the three-gene score based on RNA and DNA. These results expand the possibilities for using compact, single-molecule sensors in a range of applications previously constrained by design complexity. Biosensors RNA nanotechnology Synthetic biology
N Nature Chemistry · Nov 12, 2025 Stereodivergent construction of non-adjacent stereocentres via migratory functionalization of alkenes Stereodivergent construction of multiple stereocentres is one of the most essential tasks in asymmetric synthesis. However, strategies for assembling all possible stereoisomers of optically active compounds bearing non-adjacent stereocentres remain scarce and suffer from certain limitations in terms of reaction types and chemical space. Here we succeed in utilizing the chain walking strategy to realize the simultaneous construction of acyclic 1,n-non-adjacent (n= 3 or 4) stereocentres via Ni-catalysed migratory hydroalkylation of trisubstituted alkenes in an enantioselective and diastereodivergent manner. A series of alkyl units can be site-selectively installed at α-C(sp3)–H sites adjacent to nitrogen, affording chiral amines bearing an α-stereogenic centre and a remote (γ- or δ-) all-alkyl-substituted stereocentre. All four stereoisomers can be accessed using a single catalyst via an appropriate selection of the olefin geometry and ligand configuration, with exceptional control of stereochemistry. This simple and mild platform offers opportunities for the streamlined synthesis of complex bioactive molecules and medicinally relevant scaffolds. Asymmetric synthesis Synthetic chemistry methodology Stereochemistry
N Nature Chemistry · Nov 11, 2025 Triply convergent Ni-electrocatalytic assembly of 1,1-diaryl cyclobutanes, azetidines and oxetanes The pursuit of increasingly complex, three-dimensional molecules is pushing the boundaries of modern organic synthesis, particularly in drug discovery where rigid, saturated scaffolds such as cyclobutanes, azetidines and oxetanes are in high demand. Here we outline a modular, scalable, chemoselective approach to solve this problem using simple α-bromoacids and aryl halides as intuitive starting materials. As demonstrated herein, a sequential series of nickel-electrocatalytic cross-couplings can be enlisted to enable rapid access to such structures, many of which have been nearly impossible to access before without recourse to time-consuming polar bond disconnections that are inherently limiting in terms of accessible chemical space. The scalability of this new reaction sequence is demonstrated, alongside direct applications to known patented structures. A simple user guide is also presented to accelerate adoption of this strategy in medicinal chemistry and related fields. Electrocatalysis Synthetic chemistry methodology
N Nature Chemistry · Nov 06, 2025 Electroactive ferrocene/ferrocenium redox coupling for shuttle-free aqueous zinc–iodine pouch cells Aqueous zinc–iodine batteries are attractive for grid-scale energy storage because of their high safety and rate capability. However, conventional hosts for iodine cathodes are often electrochemically inactive and show weak interaction with polyiodides, which not only compromises the battery energy density, but also fails to eliminate shuttle effects. Here we report an electroactive redox coupling strategy to enhance energy density and suppress shuttle effects of zinc–iodine batteries by incorporating ferrocene in cathodes. The ferrocene enables a reversible ferrocene/ferrocenium redox conversion that couples with polyiodides to form insoluble ferrocenium–polyiodide complexes, thereby suppressing shuttle effects. Moreover, this redox elevates the overall discharge capacity of cathodes to 160.5 mAh gcathode−1and Coulombic efficiency to over 99.5% at 1 C in coin-cell configurations. A 1.2 ampere-hour pouch cell with high-area-capacity cathodes of 8.4 mAh cm−2sustains 600 stable cycles at 0.5 C with an average Coulombic efficiency of 99.8%. This finding provides a strategy to address both shuttle effects and host-derived energy density loss for battery applications. Batteries Chemical engineering
N Nature Chemistry · Nov 04, 2025 Co-electroreduction of CO and glyoxal promotes C3products The conversion of CO2and CO using electricity offers a promising, sustainable approach to achieve valuable products. Although CO electroreduction to C1and C2products has seen rapid progress in efficiency and production rate, C3synthesis remains a major challenge. Here we show that C3products lie along the ethylene pathway by using a probe reactant and isotope-labelled CO. We find that glyoxal addition promotes C3formation while suppressing acetate/ethanol production, while itself scarcely being consumed. Spectroscopy reveals lower CO* coverage in the presence of glyoxal. Reaction-order experiments show higher coverages of CO* and of OH−species linked to suppressing ethylene in favour of C3. By combining both strategies to suppress ethylene formation with an abundance of OH−and blocking acetate/ethanol formation with glyoxal, we report a high selectivity for C3products, including a 53% Faradaic efficiency. These insights aid the design of future catalysts for C3production. Catalysis Electrochemistry Nanoparticles
N Nature Chemistry · Nov 04, 2025 Non-ribosomal peptide cyclase-directed chemoenzymatic synthesis of lariat lipopeptides Lariat-shaped lipopeptides are important antimicrobial agents; however, their complex structures pose synthetic challenges that hamper efficient structural diversification. Here we report a new chemoenzymatic approach that facilitates access to lariat-shaped macrocycles. Unprotected, branched peptides bearing multiple nucleophiles, including a native amino terminus and a pseudo-amino terminus, were site-selectively cyclized using versatile non-ribosomal peptide cyclases, generating an array of lariat peptides with diverse sequences and ring sizes. The generality of this strategy was demonstrated using two penicillin-binding protein-type thioesterases, SurE and WolJ, as well as one type-I thioesterase, TycC thioesterase. Furthermore, the remaining nucleophile, which was not involved in the cyclization process, was exploited as a reactive handle for subsequent diversification via a site-selective acylation reaction (that is, Ser/Thr ligation). The tandem cyclization–acylation strategy enabled the one-pot, modular synthesis of lariat-shaped lipopeptides equipped with various acyl groups. Biological screening revealed that the site-selective acylation endowed the macrocyclic scaffolds with antimycobacterial activity and led to the identification of lipopeptides that inhibit 50% of growth at concentrations of 8–16 µg ml−1. Biocatalysis Biosynthesis
N Nature Chemistry · Oct 31, 2025 Discovery of highly fluorescent covalent organic frameworks through AI-assisted iterative experiment–learning cycles The development of porous crystalline materials with targeted properties remains challenging owing to the vast chemical design space and the high cost of experimental screening. Here we develop an artificial-intelligence-assisted interactive experiment–learning evolution approach to accelerate the discovery of highly fluorescent covalent organic frameworks (COFs). This approach integrates model recommendation, experimental validation and active learning in an iterative refinement cycle, allowing the artificial intelligence model to evolve along the process. Among the 520 possible combinations derived from a library of 20 amine and 26 aldehyde building blocks, we needed to experimentally evaluate only 11 COFs to identify one with a remarkable photoluminescence quantum yield of 41.3%. By embedding electronic configuration and quantum-level insights into the learning process, this approach transcends intuition based on statistical analysis intuition to enable material discovery driven by chemical knowledge, enhancing prediction reliability and interpretability. We also reveal the fluorescence mechanism of these COFs and outline the critical role of HOMO–LUMO alignment and excited-state charge distribution. Computational chemistry Fluorescence imaging Metal–organic frameworks
N Nature Chemistry · Oct 30, 2025 Profiling the proteome-wide selectivity of diverse electrophiles Covalent inhibitors that do not rely on hijacking enzymatic activity have mainly been limited to those targeting cysteine residues. The development of such cysteine-directed covalent inhibitors has greatly profited from the use of competitive residue-specific proteomics to determine their proteome-wide selectivity. Several probes have been developed to monitor other amino acids using this technology, and many more electrophiles exist to modify proteins. Nevertheless, there has been a lack of direct, proteome-wide comparisons of the selectivity of diverse electrophiles. Here we developed an unbiased workflow to analyse electrophile selectivity proteome-wide and used it to directly compare 56 alkyne probes containing diverse reactive groups. In this way, we verified and identified probes to monitor a total of nine different amino acids, as well as the protein amino terminus, across the proteome. Mass spectrometry Proteomics Screening Target identification
N Nature Chemistry · Oct 21, 2025 Azetidine amino acid biosynthesis by non-haem iron-dependent enzymes Azetidine, a four-membered aza-cycle, is a crucial structure in many bioactive compounds and drugs. However, their biosynthesis is frequently enigmatic. Here we report the mechanism of azetidine amino acid (polyoximic acid) biosynthesis in the polyoxin antifungal pathway. Genetic, enzymological and structural experiments revealed that PolF is a member of haem-oxygenase-like dimetal oxidase and/or oxygenase (HDO) superfamily, and this enzyme alone is sufficient for the transformation ofl-isoleucine (l-Ile) andl-valine to their azetidine derivatives via a 3,4-desaturated intermediate. Mechanistic studies of PolF suggested that a μ-peroxo-Fe(III)2intermediate is directly responsible for the unactivated C–H bond cleavage, and the post-H-abstraction reactions, including the C–N bond formation, probably proceed through radical mechanisms. We also found that PolE, a member of the DUF6421 family, is an Fe and pterin-dependent oxidase that catalyses the desaturation ofl-Ile, assisting PolF by increasing the flux ofl-Ile desaturation. The results provide important insights into azetidine biosynthesis and the catalytic mechanisms of HDO enzymes in general. Biocatalysis Biosynthesis Enzyme mechanisms
N Nature Chemistry · Oct 20, 2025 Copper-catalysed asymmetric cross-coupling reactions tolerant of highly reactive radicals Achieving high enantioselectivity in asymmetric catalysis, especially with very reactive species such as radicals, often comes at the expense of generality. Radicals with exceptionally high reactivity are typically unsuitable for existing asymmetric methodologies. Here we present a general catalytic approach to asymmetric radical cross-coupling that combines copper-catalysed enantioselective stereocentre resolution or formation with copper-mediated, chirality-transferring radical substitution. This sequential strategy enables the efficient coupling of over 50 distinct carbon-, nitrogen-, oxygen-, sulfur- and phosphorus-centred radicals, including highly reactive methyl,tert-butoxyl and phenyl radicals, yielding structurally diverse C-, P- and S-chiral compounds with outstanding enantioselectivity. Our method thus provides a unified platform for the synthesis of carbon, phosphorus and sulfur stereocentres, with important implications for the preparation of chiral molecules relevant to medicinal chemistry and related disciplines. Furthermore, this sequential stereodiscrimination and chirality transfer strategy offers a promising blueprint for the development of highly enantioselective methodologies applicable to other classes of highly reactive species beyond radicals. Asymmetric catalysis Homogeneous catalysis Synthetic chemistry methodology Stereochemistry
N Nature Chemistry · Oct 17, 2025 A recursive enzymatic competition network capable of multitask molecular information processing Living cells understand their environment by combining, integrating and interpreting chemical and physical stimuli. Despite considerable advances in the design of enzymatic reaction networks that mimic hallmarks of living systems, these approaches lack the complexity to fully capture biological information processing. Here we introduce a scalable approach to design complex enzymatic reaction networks capable of reservoir computation based on recursive competition of substrates. This protease-based network can perform a broad range of classification tasks based on peptide and physicochemical inputs and can simultaneously perform an extensive set of discrete and continuous information processing tasks. The enzymatic reservoir can act as a temperature sensor from 25 °C to 55 °C with 1.3 °C accuracy, and performs decision-making, activation and tuning tasks common to neurological systems. We show a possible route to temporal information processing and a direct interface with optical systems by demonstrating the extension of the network to incorporate sensitivity to light pulses. Our results show a class of competition-based molecular systems capable of increasingly powerful information-processing tasks. Cheminformatics Supramolecular chemistry
N Nature Chemistry · Oct 15, 2025 Water-detected NMR allows dynamic observations of repeat-expansion RNA condensates RNA condensation is implicated in the formation of neurotoxic RNA foci in cells affected by genomic expansions of trinucleotide or hexanucleotide repeats. However, the biophysical properties of repeat-expansion RNA condensates are poorly understood. Using CAG repeat-expansion RNA as a model system, we show that these RNA condensates cannot be observed with conventional nuclear magnetic resonance techniques. Therefore, we developed a nuclear magnetic resonance approach, based on water-detected semi-solid magnetization transfer, to detect and characterize RNA condensates in vitro. Our method, termed condensate detection by semi-solid magnetization transfer (CONDENSE-MT), is broadly applicable, highly sensitive and does not require direct observation of the biomolecules of interest. Using CONDENSE-MT, we could obtain dynamic information about RNA condensates, such as the relative amount and the tumbling rate of condensed RNA, the proton–solvent exchange kinetics and the amount of water molecules transiently bound in the condensate. We find that phase separation dramatically decreases molecular tumbling and is driven by heterotypic interactions between RNA and Mg2+. We further show that increasing CAG repeats decreases condensate hydration. Biophysical chemistry RNA Solution-state NMR
N Nature Chemistry · Oct 14, 2025 Selective CO2uptake mimics dissolution in highly fluorinated non-porous crystalline materials Separation of CO2from gas mixtures is important in applications such as CH4gas purification and blue hydrogen production. Here we report selective CO2uptake by a family of flexible silver coordination polymers (AgCPs) that are ostensibly non-porous but exhibit latent porosity to CO2above a gate pressure, through a mechanism akin to dissolution in fluoroalkanes. The CO2sorption properties are rationally modified by changing the perfluoroalkyl chain length of the constituent perfluorocarboxylate ligands. The AgCPs do not take up CH4owing to failure of the dissolution mechanism, consistent with alkane–perfluoroalkane immiscibility. In situ single-crystal and powder X-ray diffraction enable direct visualization of the CO2molecule binding domains. These techniques also reveal associated structural changes in the AgCPs and confirm the gating mechanism of CO2uptake. The combination of perfluoroalkylcarboxylate ligands with the flexible silver(I) coordination sphere generates highly fluorinated but mobile regions of the crystals that play an integral role in the selective uptake of CO2over CH4. Metal–organic frameworks Solid-state chemistry Supramolecular chemistry
N Nature Chemistry · Oct 09, 2025 Thermochemical heterolytic hydrogenation catalysis proceeds through polarization-driven hydride transfer Heterolytic hydrogenations, which split H2across a hydride acceptor and proton acceptor, comprise a key reaction class that spans the chemical value chain, including CO2hydrogenation to formate and NADH regeneration from nicotinamide adenine dinucleotide (NAD+). The dominant mechanistic models for heterogeneous catalysis of these reactions invoke classical surface reaction steps, largely ignoring the role of interfacial charge separation. Here we quantify the electrochemical potential of the catalyst during turnover and uncover evidence supporting an interfacial electrochemical hydride transfer mechanism for this overall thermochemical reaction class. We find that the proton acceptor induces spontaneous electrochemical polarization of the metal catalyst surface, thereby controlling the thermodynamic hydricity of the surface M–H intermediates and driving rate-determining electrochemical hydride transfer to the hydride acceptor substrate. This mechanistic framework, which applies across diverse reaction media and for the hydrogenation of CO2to formate and NAD+to NADH, enables the determination of intrinsic reaction kinetics and exposes design principles for the future development of sustainable hydrogenation reactivity. Catalytic mechanisms Electrocatalysis Heterogeneous catalysis
N Nature Chemistry · Oct 09, 2025 Core diversification using 1,2-oxaborines as a versatile molecular platform In drug discovery processes, changing the core structures of lead compounds to a variety of other ring systems is often needed, which typically requires laborious de novo syntheses of individual analogues. Here we report a conceptually different approach that allows rapid access to diverse core structures from a common intermediate using 1,2-oxaborines as a versatile molecular platform. A soft enolization/6π-electrocyclization strategy has been developed to efficiently synthesize 1,2-oxaborines from readily available enones or enals. Taking advantage of their multifaceted reactivities, 1,2-oxaborines can undergo further C−H functionalization and be transformed into a diverse range of arenes, heteroarenes and non-aromatic heterocycles. Finally, late-stage preparations of a suite of analogues that contain Lipitor substituents but with different aromatic cores are demonstrated using the 1,2-oxaborine-based core diversification strategy. Synthetic chemistry methodology
N Nature Chemistry · Oct 07, 2025 Covalent organic frameworks as infinite building units for metal–organic frameworks with compartmentalized pores Metal–organic frameworks typically rely on discrete molecules as building units, and creating frameworks featuring continuous organic or inorganic subnet moieties, such as chains and layers, is challenging. While all-inorganic subnets have been used as units with infinite connectivity, the intrinsic disorder in organic chains and layers hinders their role as well-defined building blocks for reticular materials. Here we report the one-pot synthesis of a series of Zr6O8-based or Hf6O8-based metal–organic frameworks that feature boroxine-based one-dimensional and two-dimensional covalent organic frameworks—chains with diverse conformations and layers with specific topology, respectively—as the organic components. The spatial compatibility between the constituents locks the infinite organic units into patterned arrangements and thus generates metal–organic frameworks with distinct structural entities and pore environments in separate sections along specific directions. The coexistence of extended covalent organic frameworks and discrete inorganic units, side by side and yet independent of each other, leads to high structural compartmentalization in space. Metal–organic frameworks are typically assembled using discrete organic linkers and inorganic nodes. Now it has been shown that combining covalent organic chains and layers as infinite building units with metal clusters results in compartmentalized frameworks with well-defined pores. Coordination chemistry Metal–organic frameworks
N Nature Chemistry · Oct 06, 2025 Unlocking red-to-near-infrared luminescence via ion-pair assembly in carbodicarbene borenium ions Achieving efficient red and near-infrared (NIR) emission in boron cation-based emitters remains challenging owing to their intrinsic instability, strong electrophilicity of the boron centre and pronounced non-radiative decay governed by the energy gap law. Here we report a family of air- and moisture-stable carbodicarbene (CDC)-borabenzo[c]anthanthrenium ions exhibiting solid-state red-to-NIR luminescence (maximum emission wavelength up to 730 nm) with competitive quantum yields. Crystallographic, photophysical and computational analyses reveal that the CDC ligand plays a dual role by electronically stabilizing the boron centre and directing ion-pair assembly via charge localization, thereby modulating exciton coupling and aggregate-state emission. These cationic π-extended boron frameworks represent rare examples of monoboron-doped luminophores displaying deep-red-to-NIR emission. Our findings highlight that the combination of π-extension, a charge-directing CDC ligand and ion-pair assembly constitutes an effective strategy to access efficient red/NIR emitters, providing guiding principles for the design of functional long-wavelength emitting main-group materials. Coordination chemistry Inorganic chemistry
N Nature Chemistry · Oct 06, 2025 Triplet state reactivity of iminium ions in organocatalytic asymmetric [2 + 2] photocycloadditions Organic transformations mediated by the transient formation of iminium ions have shown remarkable synthetic potential for the construction of enantioenriched molecules. The possibility to access their first singlet excited state (S1) under light irradiation has led to the development of previously inaccessible transformations. However, the triplet state (T1) reactivity remains limited and typically requires external photosensitizers. Here we show that structurally modified chiral iminium ions, integrated into extended π-systems, directly engage in T1reactivity. This modified conjugated architecture was designed to overcome the intrinsic photophysical limitations of conventional iminium ion chemistry, enabling access to previously inaccessible excited-state reaction manifolds. The resulting system allows organocatalytic enantioselective [2 + 2] photocycloadditions without the need for external sensitizers. Mechanistic studies, involving spectroscopic techniques and computational methods, elucidate the role of the T1intermediate as the key reactive intermediate. Synthetic chemistry methodology Photocatalysis
N Nature Chemistry · Oct 06, 2025 Enantioconvergent radical addition of racemic alkyl halides to access vicinal stereocentres The development of synthetic methods that convert readily accessible chemicals into highly valuable small organic molecules, especially those with enantioenriched three-dimensional structures, holds substantial importance in organic synthesis. Alkyl halides are pivotal substrates for generating chiral C(sp3)–C(sp3) bonds. However, constructing modular vicinal stereogenic carbon centres from racemic alkyl halides, especially those bearing the sterically bulky quaternary carbon stereocentres frequently found in natural products, remains a daunting challenge. Here we report cobalt-catalysed enantioconvergent reductive addition of racemic alkyl halides with imines, allowing for efficient construction of various contiguous stereogenic centres, including tertiary–tertiary, tertiary–quaternary and quaternary–quaternary stereocentres with high diastereo- and enantioselectivities. The mild reaction conditions circumvent the use of organometallic reagents, ensuring broad functional group compatibility and enabling the formation of valuable chiral organic motifs such as amino acids, organophosphorus compounds, amino alcohols and γ-lactams. This reductive radical addition protocol also enables the stereoselective construction ofC-glycosyl amino acids. Asymmetric catalysis Synthetic chemistry methodology
N Nature Chemistry · Oct 03, 2025 Divergent access toE- orZ-trisubstituted medium-sized cycloalkenes by Pd-catalysed cycloaddition Despite their significance in nature, medium-sized rings (particularly 9–11 membered ones) are non-existent in commercial small-molecule drugs largely due to the lack of efficient syntheses. Even with the widespread presence of macrocyclic alkenes in therapeutic agents, stereoselective access to eitherE- orZ-alkenes remains a formidable challenge. The few available methods for stereoselective macrocyclic alkene synthesis necessitate the use of geometrically pureE- orZ-alkene starting materials. Here we report the construction of 11-membered heterocyclic alkenes through Pd-catalysed formal cycloaddition of two readily available building blocks. This catalytic method also achieves a ligand-induced catalytic divergent preparation of eitherE- orZ-trisubstituted cycloalkenes starting from common terminal alkene substrates. Density functional theory calculations establish that the key alkoxide-chelated Pd-π-allyl intermediate adopts η1or η3coordination depending on the ligand used. This leads to allylic substitution using opposite π-allyl faces and in turnE- orZ-geometry in the cycloalkene products. Asymmetric catalysis Synthetic chemistry methodology
N Nature Chemistry · Oct 03, 2025 Leveraging electron donor–acceptor complexes for kinetic resolution in catalytic asymmetric photochemical synthesis The formation of electron donor–acceptor (EDA) complexes has emerged as a powerful strategy for accessing valuable molecules. However, protocols for constructing enantio-enriched molecules are limited, typically relying on EDA complex formation between a substrate and an intermediate generated from a chiral catalyst along with another substrate. This approach facilitates the coupling of the resulting radical species, thereby enabling the controlled enantioselective formation of stereocentres. Here we introduce a kinetic resolution strategy that harnesses the formation of EDA complexes between a chiral catalyst and racemic feedstock. The key lies in the thermodynamic disparity of the chiral catalyst’s interaction with the two enantiomers of the substrate, which is critical for enabling subsequent transformations under a kinetic control. We demonstrate that photochemical reactions involving racemic azaarene-functionalized tertiary alcohols and amines, together with a chiral phosphoric acid, yield enantio-enriched derivatives containing tertiary carbon stereocentres. The utility of this approach is further exemplified by synthesizing important azaarene variants featuring tertiary or secondary C–F bonds, as well as ethylene oxides. Asymmetric catalysis Synthetic chemistry methodology Organocatalysis Photocatalysis
N Nature Chemistry · Oct 03, 2025 Selective arylation of atypical C–F bonds in polyfluoroarenes with aryl chlorides Selective activation of specific C–F bonds in polyfluoroarenes represents a challenge in transition metal catalysis. Here we report a photoexcited nickel-catalysed cross-electrophile coupling between polyfluoroarenes and aryl chlorides, achieving highly selective arylation at atypical C–F sites of fluoroarenes, facilitated by a synergistic lithium salt effect. A wide range of structurally diverse fluorine-containing biaryls are obtained in 33−94% yields with satisfying C–F regioselectivity. Notably, the observed regioselectivity is atypical and complements existing methodologies, such as palladium-catalysed and visible-light photoredox-catalysed defluorinative functionalization reactions. Our mechanistic studies and theoretical calculations suggest that the lithium salt could interact with both pentafluorobenzene and the Ni catalyst, effectively lowering the energy barrier and modulating the regioselectivity. The synthetic versatility of our approach is underscored by late-stage synthetic application and sequential functionalization of multiple C–F bonds, which further demonstrates its robust utility in concisely constructing partially fluorinated and biologically interesting compounds. Homogeneous catalysis Synthetic chemistry methodology
N Nature Chemistry · Oct 03, 2025 Bottom-up approach to making larger hydrocarbon molecules capable of optical cycling Molecules capable of repeatable, narrow-band spontaneous photon scattering are prized for direct laser cooling and quantum state detection. Recently, large molecules incorporating phenyl rings have been shown to exhibit a high probability of returning to the same vibrational state after photon emission, a behaviour previously observed in small molecules, although it is not yet known if the high vibrational-mode density of even larger species will eventually compromise optical cycling. Here we systematically increase the size of hydrocarbon ligands attached to single alkaline-earth phenoxides from –H to –C14H19while measuring the vibrational branching fractions of the optical transition. We find that varying the ligand size from one to more than 30 atoms does not systematically reduce the cycle closure, which remains around 90%. Theoretical extensions to larger diamondoids and diamond surfaces suggest that alkaline-earth phenoxides may maintain their desirable scattering behaviour as the system size grows further, with no indication of an upper limit. Chemical physics Fluorescence spectroscopy
N Nature Chemistry · Oct 02, 2025 Pseudokinases can catalyse peptide cyclization through thioether crosslinking The protein-kinase-like superfamily proteins are crucial and generally catalyse substrate phosphorylation using adenosine 5′-triphosphate. Pseudokinases are non-canonical protein-kinase-like members deficient in kinase activity, and few of them are known to be enzymatically active and to have catalytic ability rather than phosphorylation. Based on biosynthetic investigations into thioamitides and lanthipeptides—two different families of ribosomally synthesized and post-translationally modified peptides—we here report a peptide cyclization activity of pseudokinases (TvaE and SacE) that enables (ene)thioether residue formation. We determine the dedicated cyclase activity in unsaturated 2-aminovinyl-cysteine formation and mine for similar activity in saturated lanthionine formation. Biochemical characterization, heterologous expression, co-crystallization, computational analysis, genome mining, isotope labelling and site-specific mutagenesis rationalize the commonality in catalysis, demonstrating that a protein-kinase fold can be repurposed for unexpected utilities. Related cyclases differ from known enzymatically active pseudokinases that resemble canonical protein-kinase-like proteins in mechanism and function. Instead, they catalyse Michael addition for (ene)thioether crosslinking through a sandwich-like substrate-assisted process. Biosynthesis Enzyme mechanisms
N Nature Chemistry · Sep 30, 2025 Dual dynamic helical poly(disulfide)s with conformational adaptivity and configurational recyclability The structural dynamics of biopolymers, such as proteins and DNA, feature the unique combination of simultaneous conformational adaptivity and configurational reversibility. However, it remains challenging to design a synthetic system featuring dynamic covalent bonds with secondary structural folding and full recycling capabilities. Here we present a synthetic covalent polymer, constructed from biologically relevant units (amino acids and disulfides), that can reversibly adapt between disordered and helical conformations and can recycle itself to the original small molecules. This dual dynamic feature arises from the subtle synergy of noncovalent bonds (H bonds) and dynamic covalent bonds within a coupled chemical equilibrium, of which thermodynamics is found to follow a nonlinear van’t Hoff equation with nonzero heat capacity change. The covalent polymers show conformational dynamics between structured helices and disordered coils and the ability to convert back to the original monomers. This system demonstrates how dual dynamic function can control helical and recyclable polymer formation. Supramolecular chemistry Supramolecular polymers
N Nature Chemistry · Sep 30, 2025 A two-metalloenzyme cascade constructs the azetidine-containing pharmacophore Azetidine is a prominent pharmacophore present in dozens of drug-related molecules of both natural and synthetic origins. But how nature builds this moiety has long remained enigmatic. Here we address the full deciphering of a two-metalloenzyme cascade leading to polyoximic acid, an azetidine-containing moiety of the fungicide polyoxin. We demonstrate that the PolE enzyme functions as an Fe2+/pterin-dependentl-isoleucine desaturase. Moreover we illustrate that PolF is a new member of the emerging haem-oxygenase-like diiron oxidases, converting the desaturatedl-isoleucine to polyoximic acid via an intramolecular C–N cyclization. Remarkably, we also establish that PolF exhibits dual functionality, orchestrating the sequential desaturation and cyclization withl-isoleucine as the initial substrate. Finally, our combined structural and quantum-mechanics/molecular-mechanics studies show that the PolF enzyme employs an extraordinary mechanism for the construction of the azetidine-containing moiety. These findings expand our knowledge on the catalysis of metalloenzymes and open the way for rational access of more azetidine-related molecules. Biocatalysis Oxidoreductases
N Nature Chemistry · Sep 26, 2025 Tunable cobalt-catalysed hydrogenation of allenes enabled by multiple metal–ligand cooperative functionalities Catalytic hydrogenation is essential in synthetic chemistry, with ongoing innovations aimed at enhancing the selectivity and efficiency of these reactions. The hydrogenation of multisubstituted allenes, however, presents a long-standing challenge due to the difficulty of controlling multiple selectivity factors simultaneously. Here we introduce a series of chiral pincer cobalt catalysts featuring multiple metal–ligand cooperative functionalities. These catalysts feature an ‘N–H’ moiety as an outer-sphere binding site and an N-heterocycle group as a hemilabile basic site, enabling the use of structurally diverse tridentate ligands for selective hydrogenation of functionalized allenes. This design liberates a coordination site for H2activation and enhances selectivity control through the structural tuning of the N-heterocycle group. The catalysts exhibit exceptional chemo-, regio-, enantio- andZ/E-selectivities, along with broad functional group tolerance, enabling access to all possible semihydrogenation products of multisubstituted allenes. Mechanistic studies uncover a distinctive redox-neutral Co(I) catalytic cycle that facilitates heterolytic cleavage of H2, assisted by the basic N-heterocycle on the ligand. Homogeneous catalysis Synthetic chemistry methodology
N Nature Chemistry · Sep 26, 2025 Live-cell imaging with fluorogenic radical-trapping antioxidant probes reveals the onset and progression of ferroptosis Ferroptosis is a form of cell death involving the formation of lipid peroxyl radicals, with potential therapeutic applications. Sensitivity to ferroptosis is expected to vary in different organelles. To monitor in real time the onset and progression of lipid peroxidation in ferroptosis, here we report lipophilic fluorogenic radical-trapping antioxidants, embedding in endoplasmic reticulum, lysosomes, mitochondria and plasma membrane. We show that endoplasmic reticulum- and lysosome-embedding fluorogenic radical-trapping antioxidants are most effective in protecting from cell death. The onset of lipid peroxidation happens in the endoplasmic reticulum, with lipid hydroperoxide accumulating in Golgi-associated vesicles. Disintegration of these structures spreads lipid hydroperoxide intracellularly, acting as ‘free radical embers’. Outwards migration of oxidized lipids to plasma membrane, the ultimate sink for oxidized lipids, was recorded. Our results underscore Golgi-associated structures as a site to regulate ferroptosis progression. The work further positions fluorogenic radical-trapping antioxidants as valuable tools for unravelling the dynamic subcellular progression of ferroptosis. Chemical tools Membranes
N Nature Chemistry · Sep 25, 2025 A pyridoxal radical carboligase and imine reductase photobiocatalytic cascade for stereoselective synthesis of unnatural prolines Cooperative photobiocatalysis is a useful strategy for achieving stereoselective intermolecular radical reactions that are not known in either biology or chemistry. The diastereoselective and enantioselective synthesis of cyclic non-canonical amino acids remains challenging using established methods. Here we report a multienzyme photobiocatalytic cascade to stereoselectively prepare polysubstituted unnatural prolines. We engineered an underexploited class of pyridoxal 5′-phosphate aldolases as new-to-nature radical carboligases to catalyse the decarboxylative C–C coupling of aspartic acid, furnishing imine-containing azacyclic non-canonical amino acids. High-throughput screening of metagenomic imine reductases led to the development of diastereoselective biocatalytic reduction and dynamic kinetic asymmetric transformation of cyclic imines, providing optically pure unnatural prolines featuring an elusive 2,5-anti stereochemistry with up to three stereocentres. Beyond its synthetic utility, this study established a new mode of radical pyridoxal enzymology by leveraging open-shell enamine catalysis, opening up avenues for developing new free radical reactions. Visible-light-driven pyridoxal radical biocatalysis offers a promising approach for developing stereoselective intermolecular radical reactions that have no known precedent in biology or chemistry. Now, building on the engineering of pyridoxal-dependent carboligases, a multienzyme photobiocatalytic cascade enables the stereoselective synthesis of polysubstituted unnatural prolines, including 2,5-anti-stereoisomers that remain challenging to access by other methods. Biocatalysis
N Nature Chemistry · Sep 24, 2025 Quantification of enantiomorphs in chiral crystalline powders through three-dimensional electron diffraction Chirality in crystalline materials is a fundamental feature that has a dramatic influence on their properties. Yet, the quantitative determination of the ratio between two enantiomorphic crystals in chiral solids remains challenging. Here we present the quantitative analysis of chiral nanocrystals through a method based on three-dimensional electron diffraction. We developed a dual tilt-scan protocol for tomography data collection in both real and reciprocal space, determining the absolute structure and estimating the crystal volume. Combined with automated serial data collection from hundreds of nanocrystals, this strategy allows high-throughput chirality determination, as well as the overall enantiomorphic excess. The successful application of this method to chiral inorganic nanocrystals reveals the role of chiral ligands in the bias of two enantiomorphic structures. We further demonstrated the robustness of this method on one chiral drug, cinchonine, offering a transformative approach to studying chiral organic materials when they are not enantiopure. Nanoparticles Solid-state chemistry Transmission electron microscopy
N Nature Chemistry · Sep 22, 2025 Bulk water redox chemistry enables radical-mediated C–C coupling in CO2electroreduction Electrocatalysis has long been viewed as an interfacial process, so the role of bulk water redox chemistry remains largely unexplored. Here we demonstrate that electrolyte-induced water redox radicals activate reactants in bulk solution for electrocatalysis at electrified interfaces. Using formate as a model electrolyte, we show that hydrogen-bond disruption in bulk water generates redox radicals, which oxidize formate to generate C1intermediates, as revealed by electron paramagnetic resonance, high-resolution mass spectrometry and Raman spectroscopy. Formate concentration-dependent hydrogen-bond restructuring drives the sequential generation of water-derived radicals and reactive intermediates, establishing bulk water as an active redox mediator rather than a passive solvent. In situ electrochemical studies demonstrate that these C1intermediates migrate to the Cu cathode surface, enabling C–C coupling via radical-mediated pathways. This work challenges the conventional view of electrocatalysis as solely an interfacial process and offers an alternative design principle for efficient electrochemical synthesis through tailored electrolyte engineering. Electrocatalysis
N Nature Chemistry · Sep 22, 2025 Electrifying industrial hydrogen peroxide production via soft interfacial molecular mediation Hydrogen peroxide is manufactured industrially via the anthraquinone autoxidation process—a typical thermocatalytic non-aqueous method. Despite a high interest in using renewable electricity to drive such processes, electrifying non-aqueous syntheses remains a substantial challenge. Here we present a multi-phase electrochemical anthraquinone autoxidation process that leverages an aqueous–non-aqueous interfacial proton-coupled electron transfer method facilitated by heterogeneous molecular mediation. This design enables the reduction of aqueous anthraquinones with high efficiency at high current densities, using only carbon electrodes. The method operates with high selectivity through a quinhydrone intermediate and prevents the over-reduction of aromatics during thermocatalytic hydrogenation. This approach combines the benefits of aqueous electrochemistry with those of the traditional non-aqueous process to achieve high current density electrochemistry with rapid kinetics and mass transport, while avoiding unwanted electrolyte in the hydrogen peroxide product. This strategy bridges aqueous electrochemistry with non-aqueous chemistry and establishes a framework for the electrification and decentralization of other non-aqueous chemical processes. Chemical engineering Electrochemistry Flow chemistry Synthetic chemistry methodology Sustainability
N Nature Chemistry · Sep 19, 2025 Olefin π-coordination chemistry at low-oxidation-state boron The coordination and substitution of hydrocarbon substrates is common for transition metals, and has been demonstrated in a handful of cases with molecules based on heavierp-block elements. By contrast, this behaviour is uncommon for the first-rowp-block elements, probably due to the generally irreversible nature of their covalent bond formation. Boranes can loosely bind and, in cooperation with strong Lewis donors, covalently bind and functionalize olefins. However, the single-site reversible coordination and functionalization of olefins by first-rowp-block elements remains elusive. Here we present a monovalent boron system able to coordinate olefins and mediate their liberation and functionalization, based on stable and well-defined borylene–olefin π complexes. These molecules are shown to be distinct from their conventional covalently bound form—boriranes—instead better resembling borylenes with π-bound olefins. The high π-complex character of these species suggests a rationale for their unique ability to reversibly bind and functionalize olefins. Chemical bonding
N Nature Chemistry · Sep 17, 2025 Chemical and ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines Potent peptide ligands for therapeutically relevant targets are regularly returned from screening trillion-member libraries of ribosomally synthesized peptides containing non-canonical amino acids and macrocyclic architectures. Yet the chemical space explored by these peptides is a fraction of that embodied by natural products and pharmaceuticals, and most peptide leads require exhaustive medicinal chemistry optimization to improve potency and physicochemistry. To address the need for strategies to introduce chemical complexity and conformational control into peptide macrocycles, we report here that linear peptides with a reactive N-terminal β-keto or γ-keto amide can be synthesized ribosomally. Subsequent Friedländer reactions generate quinoline–peptide hybrids, some of which contain stable biaryl atropisomeric axes. We also demonstrate intramolecular Friedländer macrocyclization reactions—sufficiently mild to be employed on unprotected and in vitro-translated peptides—that embed a quinoline pharmacophore directly within the peptide backbone. The introduction of N-terminal ketone motifs into genetically encoded materials and their post-translational derivatization provides a paradigm for the programmed synthesis of peptide-derived materials that more closely resemble complex natural products. Synthetic chemistry methodology Peptides
N Nature Chemistry · Sep 17, 2025 Diastereo- and enantioselective 1,3-hydrofunctionalization of trisubstituted alkenes by a directing relay Catalytic alkene hydrofunctionalization is arguably one of the most fundamentally important methodologies to construct diverse C–X bonds with concomitant creation of stereogenic centres. While most catalytic hydrofunctionalization methodologies create a single stereocentre or vicinal stereocentres through 1,2-addition, channelling hydrofunctionalization to 1,3-addition mode to create non-adjacent stereocentres with simultaneous controls of both relative and absolute configurations represents a notable challenge. Here we report a catalytic 1,3-hydrofunctionalization of unactivated trisubstituted alkenes to generate enantiopure products containing α and γ stereocentres. An amide group on the alkene first directs the catalyst to cleave the methylene C–H bond enantioselectively, delivering an allylic stereocentre through C–H transposition. The amide remains bound to the metal centre, subsequently directing the catalyst to hydrofunctionalize the resulting alkene with high regiochemical and stereochemical controls. The separate stereocontrols in this ‘directing relay’ enables stereodivergent access to 1,3-hydroalkynylation products, in which all four possible stereoisomers are obtained with excellent diastereoselectivities and enantioselectivities. Asymmetric catalysis Synthetic chemistry methodology
N Nature Chemistry · Sep 17, 2025 Energy-transfer photoproximity labelling in live cells using an organic cofactor Photocatalytic proximity labelling has emerged as a powerful tool to resolve a variety of biomolecular and cellular interactions. Although the use of high-resolution probes, such as diazirines, enables cell-surface protein labelling with nanometre precision, intracellular applications are limited by either the intrinsic toxicity of metal-based photocatalysts or by the lower resolution when long-lived reactive intermediates are used. Here we describe the discovery, characterization and application of an organic flavin cofactor derivative, deazaflavin, that activates diazirine to generate carbenes via triplet energy transfer and offers excellent biocompatibility. We demonstrate deazaflavin–diazirine energy-transfer labelling (DarT labelling) for cell surfaceome mapping and, most importantly, for intracellular interactome mapping as exemplified for cell-penetrating peptides. We successfully map the localization of linear and cyclic polyarginine cell-penetrating peptides, identifying putative membrane interactors. Furthermore, we show the applicability of DarT labelling over an extended time period by mapping the intracellular trafficking of a stable cyclic derivative to reveal its eventual exocytosis from the cell. We anticipate that DarT labelling could be used to profile intracellular dynamics across diverse biological systems with high spatio-temporal control. Chemical modification Chemical tools Peptides Photocatalysis Target identification
N Nature Chemistry · Sep 16, 2025 Photocatalytic labelling-enabled subcellular-resolved RNA profiling and synchronous multi-omics investigation Understanding cellular functions in health and disease requires dissecting spatiotemporal variations in the subcellular transcriptome. Existing methods for mitochondrial RNA profiling suffer from limitations, including low resolution, contamination and dependence on genetic manipulation. Here we present a bioorthogonal photocatalytic labelling and sequencing strategy (CAT-seq) that enables high-resolution, in situ profiling of mitochondrial RNA in living cells without genetic manipulation. We identified a quinone methide probe for efficient RNA labelling. Rigorous validation and optimization enabled CAT-seq to successfully profile mitochondrial RNA and track RNA dynamics in HeLa cells. We further applied CAT-seq to the challenging RAW 264.7 macrophages, revealing an underlying mitochondrial translational remodelling pathway. By leveraging the chemistry of quinone methide warheads, we established an orthogonal labelling system enabling synchronous RNA and protein multi-omics profiling within the same sample. Together, assisted by bioorthogonal photocatalytic chemistry, CAT-seq offers a general, non-genetic and well-compatible approach for subcellular-resolved RNA and multi-omics investigations, particularly in studies of intact primary living samples that are otherwise challenging to access. Chemical tools Proteomics RNA
N Nature Chemistry · Sep 16, 2025 Tumour-specific STING agonist synthesis via a two-component prodrug system Pharmacological activation of STING holds promise in cancer treatment. A recent trend is the development of tumour-specific or conditionally activated STING agonists for enhanced safety and efficacy. Here we explore an unconventional prodrug activation strategy for on-tumour synthesis of a potent agonist. Leveraging the unique mechanism of MSA2, a small-molecule agonist that dimerizes non-covalently before binding to STING, we showed that its analogues bearing reactive functional groups readily and selectively form covalent dimers under mild conditions and in complex environments. We identified a reacting pair that led to a thioether-linked dimer with submicromolar potency in cell-based assays. Caging one of the reactants with a self-immolative β-glucuronide moiety resulted in a two-component prodrug system that near-exclusively formed the active compounds in tumours overexpressing β-glucuronidase. These results exemplify the use of small-molecule recognition for on-site generation of active compounds from benign precursors. Drug delivery Small molecules
N Nature Chemistry · Sep 16, 2025 Colorimetric indication of hidden catalysis Hidden catalysis occurs when an impurity or species generated in situ facilitates the reaction instead of the intended catalyst. This pervasive issue plagues reaction development and fundamental understanding, with prominent examples including trace metal contamination, ‘metal-free’ reactivity, hidden (Brønsted) acid catalysis and hidden borane catalysis. Current methods to identify hidden catalysis are hindered by time-consuming and labour-intensive mechanistic analyses, limiting their practicality and widespread adoption. We introduce a transformative, colorimetric indicator that enables rapid, visual detection of hidden borane catalysis. The colorimetric test was successfully used for reaction sampling, in situ testing, reagent quality control and even test strip analyses. This rapid, visual detection method removes the necessity for laborious and costly mechanistic analyses and offers a powerful tool for chemists to quickly identify and mitigate hidden catalytic effects. This method holds the potential to substantially accelerate discovery and optimization in chemical synthesis by clarifying mechanistic understanding at the outset. Catalytic mechanisms Inorganic chemistry Reaction mechanisms
N Nature Chemistry · Sep 15, 2025 Reserved charges in a long-lived NiOOH phase drive catalytic water oxidation Although NiOOH has been widely studied as a water oxidation catalyst, its active structure and catalytic mechanism under operating conditions remain unclear. Isolating the true active phase is of great significance for further exploring the oxygen evolution reaction mechanisms in depth. Here we successfully isolated a long-lived active NiOOH phase with abundant Ni4+and detected the presence of a stable Ni–O–O–Ni2phase in the bulk during the electrochemical oxygen evolution reaction. This phase spontaneously and continuously evolves oxygen in pure water at room temperature for several minutes without requiring an applied potential. Through online mass spectrometry, we demonstrate that spontaneous oxygen evolution proceeds via initial lattice oxygen coupling followed by continuous water oxidation at active sites. By studying this process, we show that the charges stored by the Ni4+in NiOOH bulk can continuously migrate to the surface active sites to drive water oxidation. This offers guidance for the design of more advanced water oxidation catalysts and provides insights at the molecular level. Electrocatalysis
N Nature Chemistry · Sep 09, 2025 Isotope-dependent Tafel analysis probes proton transfer kinetics during electrocatalytic water splitting Proton transfer plays an important role in both hydrogen and oxygen evolution reactions during electrocatalytic water splitting to produce green hydrogen. However, directly adapting the conventional proton/deuterium kinetic isotope effect to study proton transfer in heterogeneous electrocatalytic processes is challenging. Here we propose using the shift in the Tafel slope between protic and deuteric electrolytes, or the Tafel slope isotope effect, as an effective probe of proton transfer characteristics. Comparison of the Tafel slope isotope effect for diverse hydrogen and oxygen evolution reaction electrocatalysts in different pH environments reveals that proton transfer is both pH and structure dependent. Using ruthenium oxide as an example, we show that local structure modification can change the rate-determining step from an electrochemical, concerted proton–electron transfer step to a chemical step and improve the oxygen evolution activity in acid. The isotope-dependent Tafel analysis will facilitate a better understanding of the proton transfer behaviours during electrocatalytic processes and provide guidance for designing efficient electrocatalysts. Electrocatalysis Energy Heterogeneous catalysis
N Nature Chemistry · Sep 09, 2025 Organocatalysed three-component modular synthesis of BN isosteres and BN-2,1-azaboranaphthalenes via Wolff-type rearrangement [2,1]-Azaboranaphthalenes represent unique boron–nitrogen (BN) isosteres of naphthalenes, attracting interest for the development of molecules with enhanced therapeutic potency. The existing synthetic strategies are generally two-component reactions with harsh conditions. Here we report an organocatalysed three-component modular synthesis of ring-fused BN isosteres and BN-2,1-azaboranaphthalenes following ring expansion of unstrained cyclic ketones (n=4–8) via Wolff-type rearrangement. The strategy used 2-formylarylboronic acid as a C–B surrogate and TMSN3as an exogenous single nitrogen source, allowing the de novo rapid synthesis of BN isosteres by forging C–C, C–N and B–N bonds under a single operation. The developed method proved to be compatible with a broad substrate scope (58 examples), including cyclic ketones and diverse heterocycles, which afforded 1C ring-expanded [2,1]-azaborines.The reaction was also effective with acyclic ketones, yielding BN naphthalene isosteres. Control experiments and density functional theory study dictate the plausible reaction pathways following [1,2]-C–C/C–H shift, analogous to Wolff rearrangement. Synthetic chemistry methodology
N Nature Chemistry · Sep 03, 2025 A label-free method for measuring the composition of multicomponent biomolecular condensates Many subcellular compartments are biomolecular condensates made of multiple components, often including several distinct proteins and nucleic acids. However, current tools to measure condensate composition are limited and cannot capture this complexity quantitatively because they either require fluorescent labels, which can perturb composition, or can distinguish only one or two components. Here we describe a label-free method based on quantitative phase imaging and analysis of tie-lines and refractive index to measure the composition of reconstituted condensates with multiple components. We first validate the method empirically in binary mixtures, revealing sequence-encoded density variation and complex ageing dynamics for condensates composed of full-length proteins. We then use analysis of tie-lines and refractive index to simultaneously resolve the concentrations of five macromolecular solutes in multicomponent condensates containing RNA and constructs of multiple RNA-binding proteins. Our measurements reveal an unexpected decoupling of density and composition, highlighting the need to determine molecular stoichiometry in multicomponent condensates. We foresee this approach enabling the study of compositional regulation of condensate properties and function. Bioanalytical chemistry Organelles Phase-contrast microscopy RNA-binding proteins Thermodynamics
N Nature Chemistry · Sep 03, 2025 Interfacial solvation pre-organizes the transition state of the oxygen evolution reaction The sluggish kinetics of the oxygen evolution reaction are an energetic bottleneck for green hydrogen production via water electrolysis. The reaction proceeds over a surface that undergoes (frustrated) phase transitions to accommodate bias-dependent excess charge. Here we perform Arrhenius analysis of common catalysts and correlate the activation energy and pre-exponential factor with the oxide’s structural adaptation via operando X-ray absorption spectroscopy and high-energy X-ray diffraction. We observe that the kinetics switch from a regime that is probably dominated by interfacial solvation to one where the surface energetics take over. This happens right at a transition potential between the α or β phases into the γ-crystal structure of Ni (oxy)hydroxides and when spectroscopic fingerprints of key intermediates emerge. Importantly, this turning potential is independent of the loading or the surface area and informs on the intrinsic catalyst activity. These results suggest that the catalyst activity is intrinsically linked to the initial interfacial solvation (pre-)step. Electrocatalysis Electrochemistry
N Nature Chemistry · Aug 28, 2025 Reversible self-assembly of small molecules for recyclable solid-state battery electrolytes Performance often overshadows recyclability in contemporary battery designs, leading to sustainability challenges. Preemptive strategies integrating recyclable chemistry from the outset are thus increasingly critical for addressing the complexities in conventional recycling. Here we harness bio-inspired molecular self-assembly to create inherently recyclable battery materials. We use aramid amphiphiles that self-assemble in water through strong, collective hydrogen bonding and π–π stacking, forming air-stable, high-aspect-ratio nanoribbons with gigapascal-level stiffness. When processed into bulk solid-state electrolytes, these nanoribbons retain their ordered molecular arrangement and exhibit total conductivities of 1.6 × 10−4S cm−1at 50 °C, Young’s moduli of 70 MPa and toughness values of 1 MJ m−3, despite being stabilized solely by reversible non-covalent bonds. We further demonstrate clean separation of battery components by exposing used cells to an organic solvent, which disrupts the non-covalent cohesion and reverts all battery components to their original forms. This study underscores the potential of molecular self-assembly for specialized recyclable designs in energy storage applications. Batteries Self-assembly
N Nature Chemistry · Aug 28, 2025 De novo design of light-responsive protein–protein interactions enables reversible formation of protein assemblies Light-responsive proteins play an essential role in all domains of life by sensing and responding to environmental light signals. However, the de novo design of light-responsive proteins with precisely defined structures and reversible responsive behaviours is an unmet challenge. Here we describe a computational approach to design protein–protein interactions regulated by non-canonical amino acids, focusing on the light-responsive phenylalanine-4′-azobenzene (AzoF). Using this approach, we designed light-responsive cyclic homo-oligomers and heterodimers, which only assemble in AzoF’stransconfiguration and disassemble when AzoF photoisomerizes to thecisconfiguration. Biophysical characterization confirms the light-responsive assembly and disassembly of these complexes, and the crystal structures match the design models with atomic accuracy. We demonstrate the applicability of these light-responsive proteins in constructing light-responsive hydrogels and engineering synthetic ligand receptors to optocontrol cell signalling in mammalian cells. Our approach opens avenues for designing environmentally responsive protein structures and broadens the toolkit for optogenetics and optochemistry. Protein design
N Nature Chemistry · Aug 27, 2025 Chemical tuning of quantum spin–electric coupling in molecular magnets Molecular magnets may serve as engineerable spin qubit candidates for quantum information science; however, the magnetic fields often used for control can be challenging to confine. Now, it has been shown that well-designed mononuclear Mn(II) complexes demonstrate enhanced spin–electric coupling, providing guidance for electrically controllable molecular spin qubits.
N Nature Chemistry · Aug 27, 2025 Head–tail carboboration of multisubstituted alkenes enabled by chain recognition The intricate, three-dimensional chain-walking of tertiary metal species has stood as a barrier to precision in migratory difunctionalization of multisubstituted alkenes. Now a sterically controlled chain recognition paradigm has been established, enabling highly selective head–tail carboboration and offering a streamlined route to natural products and functional materials.
N Nature Chemistry · Aug 27, 2025 Electrostatic atlas of non-covalent interactions built into metal–organic frameworks Non-covalent interactions are very diverse, and they are generally difficult to investigate through experimental methods. Here tailored metal–organic frameworks serve as a platform for the systematic generation of a variety of non-covalent interactions, which can be studied through the electric fields produced by the charges and dipoles involved in the interactions.
N Nature Chemistry · Aug 27, 2025 Magnetic activation of spherical nucleic acids enables the remote control of synthetic cells The programmability of synthetic cells, comprising lipid vesicles that are capable of imitating the structure and function of living cells, facilitates their application as drug delivery devices. Now, magnetic hyperthermia has been used to control the on-demand synthesis and release of biomolecules from within synthetic cells.
N Nature Chemistry · Aug 27, 2025 Carbon-to-nitrogen atom swap enables direct access to benzimidazoles from drug-like indoles Underexplored atom swap reactions offer the opportunity to selectively edit organic molecules and to streamline lead discovery and optimization in the pharmaceutical and agrochemical industry. Now it has been shown that benzimidazoles can be accessed from indoles via C-to-N atom swap. The method was applied to 15 drug-like indoles.
N Nature Chemistry · Aug 27, 2025 Stable single-site organonickel catalyst preferentially hydrogenolyses branched polyolefin C–C bonds Selective chemical upcycling of polyolefin mixtures remains challenging due to the structural similarity of their backbones. Now it has been shown that a single-site nickel catalyst can preferentially and efficiently cleave branched C–C bonds, enabling the hydrogenolytic separation of isotactic polypropylene from mixtures containing both isotactic polypropylene and polyethylene.
N Nature Chemistry · Aug 26, 2025 Unlocking azole chemical space via modular and regioselectiveN-alkylation Azoles are important synthetic targets due to their diverse applications in areas ranging from human health to food security. Accordingly, access toN-functionalized azoles is an essential goal in modern synthetic chemistry. Surprisingly, however, the relied-upon azoleN-alkylation strategies fundamentally limit the structural diversity of these important compounds that can be synthesized and studied. Here we introduce an approach to prepare a broad array of important but difficult-to-accessN-alkyl azole compounds. We accomplish this through the introduction of a base-catalysed hydroazolation of readily accessible alkenylthianthrenium electrophiles. This strategy circumvents the classical challenge of azole alkylation regiocontrol through an unusual reversible C–N-bond-forming step that exploits the thermodynamic differences between azoleN-alkylation isomers. This reaction furnishes a class of versatile azolothianthrenium building blocks that provides a general platform to investigate diverseN-alkyl azole molecules. More broadly, the distinctive approach outlined through this project is poised to impact the design and development of diverse regioselective alkylation reactions. Chemistry Synthetic chemistry methodology Organic chemistry
N Nature Chemistry · Aug 21, 2025 Zigzag graphene nanoribbons with periodic porphyrin edge extensions Graphene nanoribbons (GNRs) with zigzag edges are promising materials for spintronic devices due to tunable bandgaps and spin-polarized edge states. Porphyrins offer complementary benefits such as desirable optoelectronic properties. Here we combine these features in a hybrid system by means of the on-surface synthesis of zigzag-edge GNRs embedded with porphyrins laterally fused along the ribbon backbone. Using scanning probe methods, we show that this design achieves strong electronic coupling between the porphyrin and the GNR. For transition metal porphyrins, pronounced exchange coupling between distant metal centres is mediated by theπ-electron system. Such a hybriddandπelectron ribbon system introduces spin–orbit coupling and magnetic anisotropy to carbon nanomaterials, and holds great promise for coherent electrical control of electron spins. Magnetic materials Scanning probe microscopy Synthesis of graphene
N Nature Chemistry · Aug 20, 2025 Stepwise and reversible assembly of [2Fe–2S] rhombs to [8Fe–8S] clusters and their topological interconversions Among all enzymatic metallocofactors, those found in nitrogenases, the P and L or M clusters, stand out for their intricate structures. They are assembled by proteins of the Nif gene cluster from Fe2S2rhombs—the smallest building blocks in FeS cluster chemistry—through a sequence of reactions constructing a Fe8S8precursor. To advance our understanding of how enzymes selectively build such elaborate inorganic molecules, here we parallel the biosynthetic pathway by reporting the rational stepwise assembly of [Fe8S8]m+(m= 2, 4, 6) clusters from [Fe2S2]2+rhombs within an extensive cyclic synthetic network. A [Fe8S8]4+cluster of unique topology is identified, for which we coin the term ‘interlocked’ double cubane. As a molecular analogue of the NifB K cluster, a proposed precursor to both the P and L or M clusters, its preparation and the characterization of all related intermediates, offers fundamental insights into the molecular mechanisms governing the assembly of both biogenic and synthetic FeS clusters. Coordination chemistry Inorganic chemistry
N Nature Chemistry · Aug 20, 2025 Nucleoside diphosphate kinase A (NME1) catalyses its own oligophosphorylation Protein phosphorylation is a central signalling mechanism in eukaryotic cells. The scope of this post-translational modification includes protein pyro- and polyphosphorylation. Here we report the discovery of another mode of phosphorylation: protein oligophosphorylation. Using site-specifically phosphorylated and pyrophosphorylated nucleoside diphosphate kinase A (NME1), the effects of these modifications on enzyme activity were investigated. Phosphorylation, and more so pyrophosphorylation, on Thr94 reduced the nucleoside diphosphate kinase activity. Nevertheless, both phosphoprotein and pyrophosphoprotein catalysed their own oligophosphorylation—up to the formation of a hexaphosphate chain—using ATP as a cofactor. Oligophosphorylation was critically dependent on the catalytic histidine residue His118, and cryogenic electron microscopy analysis of the modified proteins suggests an intramolecular phosphoryl transfer mechanism. Oligophosphorylation of NME1 in biochemical samples, and in cell lysates, was further confirmed using mass spectrometry, and was found to promote a new set of protein interactions. Our results highlight the complex nature of phosphoregulation, and the methods described here provide the opportunity to investigate the impact of this unusual modification in the future. Cryoelectron microscopy Phosphorylation Proteomic analysis
N Nature Chemistry · Aug 20, 2025 An unnatural base pair for the detection of epigenetic cytosine modifications in DNA Natural, covalently modified cytosine bases within genomic DNA function as important epigenetic markers. Approaches for single-base-resolution sequencing of cytosine modifications typically deploy chemistry for modification-selective C-to-T code conversion and can require error-prone subtractive analysis of complex data. Here we report the sequencing of an epigenetic base by exploiting an unnatural base pair system. This approach relies on hydrogen-bonding complementarity between a malononitrile adduct of 5-formylcytosine and protonated 3,7-dideazaadenine. The specificity of this unnatural base pair was studied by biophysical DNA thermal melting analysis and by template-directed incorporation by DNA polymerase enzymes. Base pair selectivity was enhanced by controlling the protonation state of 3,7-dideazaadenine. We exemplify use of this unnatural base pair to sequence 5-formylcytosine in a DNA template using a Sanger-type format. There is scope for this base pair and the general concept to be implemented on further sequencing platforms that exploit Watson–Crick base pairing to directly identify epigenetic bases. DNA DNA sequencing Methylation analysis Nucleic acids
N Nature Chemistry · Aug 20, 2025 Vibronic coupling-driven symmetry breaking and solvation in the photoexcited dynamics of quadrupolar dyes Quadrupolar dyes, such as acceptor–donor–acceptor molecules, are highly relevant for applications in nonlinear optics and photovoltaics. They are also versatile models for exploring photoinduced charge-transfer dynamics. The interplay between electronic and vibronic couplings in these molecules may break excited-state symmetry, resulting in intramolecular charge separation and pronounced solvatochromism. Experimentally, distinguishing the roles of intramolecular vibronic coupling and solvent reorganization for the initial charge-transfer dynamics has been challenging so far. Here we investigate a prototypical quadrupolar dye in polar and non-polar solvents using ultrafast pump–probe and two-dimensional electronic spectroscopy. Our results reveal that vibronic couplings initiate excited-state symmetry breaking during the first ~50 fs of the photoinduced charge transfer, whereas solvent-induced charge localization sets in at later times. Quantum dynamics and electronic structure simulations support our experimental findings. Our results reveal the details of solvation dynamics in photoexcited molecules and suggest strategies for their manipulation through vibronic couplings. Excited states Nanoscale materials
N Nature Chemistry · Aug 19, 2025 Ultrafast charging of two-dimensional polymer cathodes enabled by cross-flow structure design While ultrafast charging and discharging is highly desired for energy storage, the densely packed crystalline inorganic electrodes suffer from sluggish ion transport that limits this capability. Here we report two-dimensional vertical ladder polymer cathode materials that feature layered nanosheets with rich intralayer pores and structural defects alongside weak interlayer interactions. This structural design allows lithium ions to migrate vertically across the intrinsic pores and/or defects accompanied by horizontal intercalation, thus establishing a cross-flow pathway for lithium storage. Such an effective ion-transport method enables flash charging of an ultrahigh-power polymer cathode to ~70% state-of-charge within 30 s at a high current density. Even operated at −50 °C, the polymer cathode achieves 3-min charging to ~55% state-of-charge. Furthermore, we propose an organic–inorganic hybrid strategy that overall improves the electrode-level specific energy at high rates for meeting practical metrics. This work demonstrates the potential of organic electrodes for high-power output under extreme operational conditions. Batteries Polymer chemistry Two-dimensional materials
N Nature Chemistry · Aug 18, 2025 Lattice O–O ligands in Fe-incorporated hydroxides enhance water oxidation electrocatalysis Understanding the structural dynamics of ligands and their interaction with catalytic centres under reaction conditions remains a fundamental challenge, yet it is essential for catalyst design. Here we reveal an in situ transformation of Ni–Fe hydroxide into a stable superoxo-hydroxide phase, which is accompanied by the formation of lattice O–O (Olatt–Olatt) ligands, as demonstrated using operando18O-labelling spectroelectrochemistry and machine-learning-assisted global optimization. By correlating the intrinsic activity of Fe with the Olatt–Olattconcentration across a series of Fe-incorporated transition-metal hydroxides and oxides, we demonstrate that Olatt–Olatttriggers Fe activation for oxygen evolution electrocatalysis—a finding further supported by first-principles calculations. Oxygen production proceeds via an adsorbate evolution mechanism, and the enhanced reaction kinetics stem from the lowered activation energy at surface Fe sites in the newly formed superoxo-hydroxide structure. This work offers a strategic framework for designing high-performance Fe-incorporated electrocatalysts and underscores the pivotal role of ligand dynamics in activating catalytic centres. Electrocatalysis
N Nature Chemistry · Aug 18, 2025 Magnetically induced convection enhances water electrolysis in microgravity Since the early days of space exploration, the efficient production of oxygen and hydrogen via water electrolysis has been a central task for regenerative life-support systems. Water electrolysers are, however, challenged by the near-absence of buoyancy in microgravity, resulting in hindered gas bubble detachment from electrodes and diminished electrolysis efficiencies. Here we show that a commercial neodymium magnet enhances water electrolysis with current density improvements of up to 240% in microgravity by exploiting the magnetic polarization of the electrolyte and the magnetohydrodynamic force. We demonstrate that these interactions enhance gas bubble detachment and displacement through magnetic convection and achieve passive gas–liquid phase separation. Two model magnetoelectrolytic cells, a proton-exchange membrane electrolyser and a magnetohydrodynamic drive, were designed to leverage these forces and produce oxygen and hydrogen at near-terrestrial efficiencies in microgravity. Overall, this work highlights achievable, lightweight, low-maintenance and energy-efficient phase separation and electrolyser technologies to support future human spaceflight architectures. Chemical engineering Electrochemistry Nanoscale materials
