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 Electrochemistry Marcus-Hush-Chidsey CO2 Reduction Catalysis
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 other
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 Drug Development Photocatalysis Organic Synthesis Mechanistic Study
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 Electrochemistry Spectroscopy Gold CO2 Reduction
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 Organometallic Chemistry X-ray Crystallography Germanium Synthetic 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 Genetics DNA Charge Transport Molecular Design
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 biology
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 Organic Chemistry Electrochemistry Dearomatization C-H Alkylation
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 other
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 other
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 Electrocatalysis Water Oxidation Ni-Fe Systems Proton Transfer
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 Surface Chemistry Nanoparticles Electrochemistry Catalysis
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 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 Drug Development Asymmetric Synthesis Catalysis Organic Chemistry
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 Drug Development Organic Synthesis Electrocatalysis Medicinal Chemistry
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 Battery Technology Redox Chemistry Energy Storage
