Pub Date : 2026-10-20Epub Date: 2026-10-08DOI: 10.1021/acs.accounts.6c00547
Yi-Zhou Sun, Shuo-Qing Zhang, Xin Hong
Understanding how molecularstructure determines reaction performanceis a central objective of physical organic chemistry and an increasinglyimportant challenge in data-driven organic synthesis. As the frontiersof synthetic chemistry continue to advance, predictive structure–performancerelationship modeling is expected not only to reproduce known reactionoutcomes but also to guide new chemical design. In this Account, wesummarize our efforts to integrate mechanistic insight with machinelearning across data construction, model development, and discoveryapplications. At the data level, mechanistic understanding can helpdefine reaction spaces and learning targets, allowing automated densityfunctional theory calculations and literature-derived databases tobecome chemically consistent learning resources. This idea is illustratedby computed selectivity data sets for radical C–H functionalizationand Cu(II)-mediated radical bond formation as well as literature databasesfor asymmetric hydrogenation of olefins and N,N′-dioxide/metal-catalyzedMichael additions. At the modeling level, mechanistic knowledge canbe embedded into reaction representations and model architectures.Transition-state-based reaction encoding introduces pathway-specificstereochemical information into enantioselectivity prediction, whilesteric- and electronics-embedded molecular graphs incorporate physicalorganic effects directly into molecular deep learning. At the discoverylevel, mechanistic relatedness provides a basis for selecting historicaldata and transferring structure–performance relationships intolow-data chemical space. This mechanism-guided transfer learning formalizeshow chemists reuse related precedents, enabling few-shot catalystligand discovery for Ni-catalyzed atroposelective Suzuki–Miyauracoupling. A central lesson from these studies is that mechanisticinsight is not a replacement for machine learning but the chemicalfoundation that makes it more reliable, interpretable, and extrapolative.By translating mechanistic understanding into data boundaries, reactionrepresentations, and transfer strategies, machine learning can movebeyond retrospective fitting and become a chemically grounded frameworkfor predicting and discovering new organic reactions.
{"title":"Leveraging the Synergy between Mechanistic Insight and Machine Learning for Predictive Structure–Performance Relationships in Organic Synthesis","authors":"Yi-Zhou Sun, Shuo-Qing Zhang, Xin Hong","doi":"10.1021/acs.accounts.6c00547","DOIUrl":"10.1021/acs.accounts.6c00547","url":null,"abstract":"<p>Understanding how molecularstructure determines reaction performanceis a central objective of physical organic chemistry and an increasinglyimportant challenge in data-driven organic synthesis. As the frontiersof synthetic chemistry continue to advance, predictive structure–performancerelationship modeling is expected not only to reproduce known reactionoutcomes but also to guide new chemical design. In this Account, wesummarize our efforts to integrate mechanistic insight with machinelearning across data construction, model development, and discoveryapplications. At the data level, mechanistic understanding can helpdefine reaction spaces and learning targets, allowing automated densityfunctional theory calculations and literature-derived databases tobecome chemically consistent learning resources. This idea is illustratedby computed selectivity data sets for radical C–H functionalizationand Cu(II)-mediated radical bond formation as well as literature databasesfor asymmetric hydrogenation of olefins and N,N′-dioxide/metal-catalyzedMichael additions. At the modeling level, mechanistic knowledge canbe embedded into reaction representations and model architectures.Transition-state-based reaction encoding introduces pathway-specificstereochemical information into enantioselectivity prediction, whilesteric- and electronics-embedded molecular graphs incorporate physicalorganic effects directly into molecular deep learning. At the discoverylevel, mechanistic relatedness provides a basis for selecting historicaldata and transferring structure–performance relationships intolow-data chemical space. This mechanism-guided transfer learning formalizeshow chemists reuse related precedents, enabling few-shot catalystligand discovery for Ni-catalyzed atroposelective Suzuki–Miyauracoupling. A central lesson from these studies is that mechanisticinsight is not a replacement for machine learning but the chemicalfoundation that makes it more reliable, interpretable, and extrapolative.By translating mechanistic understanding into data boundaries, reactionrepresentations, and transfer strategies, machine learning can movebeyond retrospective fitting and become a chemically grounded frameworkfor predicting and discovering new organic reactions.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 20","pages":"3400–3412"},"PeriodicalIF":18.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149150814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-20Epub Date: 2026-09-30DOI: 10.1021/acs.accounts.6c00516
Hanqi Zhou, He Chen, Christopher J. Teskey
<p>First row transition metalssuch as iron, cobalt and manganesewith weak-field ligands are able to form metal hydride species insitu which have a weak M–H bond. In these cases, the formaladdition of a hydrogen atom to an olefin is thermodynamically favored.The high regio and chemoselectivity of this process, termed metalhydride hydrogen-atom-transfer (MHAT) catalysis, together with thebroad availability of olefins and the divergent reaction pathwaysfrom the carbon centered radical that is formed, has resulted in awide range of radical hydrofunctionalization strategies that havebeen used extensively in complex synthetic settings.</p><p>Until around5 years ago, a typical catalytic cycle for formingthe metal hydride relied on oxidation as a first step, followed byreaction with a hydride equivalent. The requirement to find compatibleoxidant/reductant pairs defined and limited the scope of this chemistry.However, several groups including our own recognized that it wouldinstead be possible to first <em>reduce</em> the metal andthen protonate the low-valent form to yield the same metal hydridespecies. This net reductive approach would unlock new avenues foronward reactivity, circumventing the compatibility issues associatedwith the reagents used previously.</p><p>A number of different approachesto this reductive MHAT paradigmhave been reported, using chemical reductants, electrochemistry orphotochemistry. Our group has focused on the merger of cobalt catalysisand photocatalysis to enable new hydrofunctionalization reactivity.Under reductive reaction conditions, it is possible to simultaneouslyform a persistent radical via single electron reduction and couplethis with the radical formed from the alkene. We have used this conceptto couple alkenes with cyanoarenes, pyridyl phosphonium salts, ketonesand imines.</p><p>Radical rearrangements, initiated by MHAT, can takeplace thatwere previously inefficient or not possible under oxidative MHAT conditions.We have used this to promote aryl migration reactions, building newC–C bonds with sterically demanding aromatic groups. And mostrecently, we have reported the combination of MHAT catalysis withreductive radical polar crossover, a new type of reactivity that enablesthe use of an electrophile as a coupling partner, contrasting withthe commonly reported oxidative radical polar crossover pathway wherehydrofunctionalization takes place with nucleophiles.</p><p>In summary,the reductive MHAT concept has reinvigorated interestin radical hydrofunctionalization reactions. Here, we present ourjourney in uncovering new reactivities accessible only through thiscatalytic paradigm, enabled by photochemistry. We are confident thatboth the synthetic utility and the broader appeal of this modern approachto classical MHAT reactivity will continue to increase in the comingyears, driven by the growing demand for catalytic systems that employearth-abundant transition metals and which enable direct functionalizationof native olefin
{"title":"Radical Hydrofunctionalization Using Light Driven, Reductive Cobalt Hydride Catalysis","authors":"Hanqi Zhou, He Chen, Christopher J. Teskey","doi":"10.1021/acs.accounts.6c00516","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00516","url":null,"abstract":"<p>First row transition metalssuch as iron, cobalt and manganesewith weak-field ligands are able to form metal hydride species insitu which have a weak M–H bond. In these cases, the formaladdition of a hydrogen atom to an olefin is thermodynamically favored.The high regio and chemoselectivity of this process, termed metalhydride hydrogen-atom-transfer (MHAT) catalysis, together with thebroad availability of olefins and the divergent reaction pathwaysfrom the carbon centered radical that is formed, has resulted in awide range of radical hydrofunctionalization strategies that havebeen used extensively in complex synthetic settings.</p><p>Until around5 years ago, a typical catalytic cycle for formingthe metal hydride relied on oxidation as a first step, followed byreaction with a hydride equivalent. The requirement to find compatibleoxidant/reductant pairs defined and limited the scope of this chemistry.However, several groups including our own recognized that it wouldinstead be possible to first <em>reduce</em> the metal andthen protonate the low-valent form to yield the same metal hydridespecies. This net reductive approach would unlock new avenues foronward reactivity, circumventing the compatibility issues associatedwith the reagents used previously.</p><p>A number of different approachesto this reductive MHAT paradigmhave been reported, using chemical reductants, electrochemistry orphotochemistry. Our group has focused on the merger of cobalt catalysisand photocatalysis to enable new hydrofunctionalization reactivity.Under reductive reaction conditions, it is possible to simultaneouslyform a persistent radical via single electron reduction and couplethis with the radical formed from the alkene. We have used this conceptto couple alkenes with cyanoarenes, pyridyl phosphonium salts, ketonesand imines.</p><p>Radical rearrangements, initiated by MHAT, can takeplace thatwere previously inefficient or not possible under oxidative MHAT conditions.We have used this to promote aryl migration reactions, building newC–C bonds with sterically demanding aromatic groups. And mostrecently, we have reported the combination of MHAT catalysis withreductive radical polar crossover, a new type of reactivity that enablesthe use of an electrophile as a coupling partner, contrasting withthe commonly reported oxidative radical polar crossover pathway wherehydrofunctionalization takes place with nucleophiles.</p><p>In summary,the reductive MHAT concept has reinvigorated interestin radical hydrofunctionalization reactions. Here, we present ourjourney in uncovering new reactivities accessible only through thiscatalytic paradigm, enabled by photochemistry. We are confident thatboth the synthetic utility and the broader appeal of this modern approachto classical MHAT reactivity will continue to increase in the comingyears, driven by the growing demand for catalytic systems that employearth-abundant transition metals and which enable direct functionalizationof native olefin","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 20","pages":"3375–3386"},"PeriodicalIF":18.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-20Epub Date: 2026-10-01DOI: 10.1021/acs.accounts.6c00598
Michał Terlecki, Iwona Justyniak, Krzysztof Budny-Godlewski, Janusz Lewiński
<p>Organometallic reactivity is traditionally rationalizedin termsof well-defined molecular structures. In this Account, we argue thatfor organozinc compounds, this picture is incomplete: their reactivityis governed not by isolated molecules but by dynamic speciation landscapes─equilibratingLewis acid–base adducts, interconverting aggregates, speciesgenerated by Schlenk redistribution, transient intermediates, andphase-confined assemblies whose composition evolves throughout a reaction.Drawing on more than two decades of our group’s work, we showthat reaction outcomes emerge from the identity and evolution of thesereactive ensembles rather than from any single species that can becrystallized and assigned a formula. Moving from static structuresto reactive landscapes, we first consider molecular complexes as programmablereactive platforms, in which aggregation and donor coordination generatefamilies of interconverting species that can be deliberately tuned.We then recast Schlenk equilibria, long regarded as a passive redistributionnuisance, as an active determinant of reactivity: by continuouslyreshaping the pool of available reagents, they define which speciesare present when the reaction occurs and thereby redirect its course.</p><p>Asymmetric catalysis puts the ensemble picture to its sharpesttest. For example, chiral amplification in the dialkylzinc additionto aldehydes is classically explained by an equilibrium between catalyticallyactive and dormant aggregates, a two-level picture of the reactiveensemble. Our work on bifunctional alcohols indicates that this ensembleis richer: we isolated an unprecedented tetranuclear zinc aggregate,pointing to higher-nuclearity species as possible sources of the catalyticallycompetent centers. The unexpected incorporation of the solvent intoone such species further showed that even the reaction medium participatesin shaping the ensemble. Conversely, where the ensemble proved simpleenough to define─as in the epoxidation of enones by zinc alkylperoxides─itbecame a design tool: systematic ligand modification delivered enantioselectivitiesreaching 91% <em>ee</em>. Speciation control overturns aneven longer-standing assumption. The reaction of organozinc compoundswith O<sub>2</sub>, long treated as an uncontrolled radical process,emerges instead as a sequence of elementary steps governed by latentLewis acidity, inner-sphere electron transfer (ISET), and productinhibition─steps that allow reactive intermediates to be intercepted,giving controlled access to alkylzinc alkylperoxides and related oxygenatedspecies.</p><p>Beyond homogeneous solution, we show how phase-dependentspeciationmodulates reactivity in the solid state: mechanochemical and phase-confinedenvironments, together with supramolecular self-assembly, stabilizeensembles and open pathways─and give access to functional materials─inaccessiblein solution, establishing a continuum linking molecular speciationto materials formation.</p><p>Across these system
{"title":"Dynamic Speciation as a Hidden Driver of Reactivity: Lessons from Organozinc Chemistry","authors":"Michał Terlecki, Iwona Justyniak, Krzysztof Budny-Godlewski, Janusz Lewiński","doi":"10.1021/acs.accounts.6c00598","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00598","url":null,"abstract":"<p>Organometallic reactivity is traditionally rationalizedin termsof well-defined molecular structures. In this Account, we argue thatfor organozinc compounds, this picture is incomplete: their reactivityis governed not by isolated molecules but by dynamic speciation landscapes─equilibratingLewis acid–base adducts, interconverting aggregates, speciesgenerated by Schlenk redistribution, transient intermediates, andphase-confined assemblies whose composition evolves throughout a reaction.Drawing on more than two decades of our group’s work, we showthat reaction outcomes emerge from the identity and evolution of thesereactive ensembles rather than from any single species that can becrystallized and assigned a formula. Moving from static structuresto reactive landscapes, we first consider molecular complexes as programmablereactive platforms, in which aggregation and donor coordination generatefamilies of interconverting species that can be deliberately tuned.We then recast Schlenk equilibria, long regarded as a passive redistributionnuisance, as an active determinant of reactivity: by continuouslyreshaping the pool of available reagents, they define which speciesare present when the reaction occurs and thereby redirect its course.</p><p>Asymmetric catalysis puts the ensemble picture to its sharpesttest. For example, chiral amplification in the dialkylzinc additionto aldehydes is classically explained by an equilibrium between catalyticallyactive and dormant aggregates, a two-level picture of the reactiveensemble. Our work on bifunctional alcohols indicates that this ensembleis richer: we isolated an unprecedented tetranuclear zinc aggregate,pointing to higher-nuclearity species as possible sources of the catalyticallycompetent centers. The unexpected incorporation of the solvent intoone such species further showed that even the reaction medium participatesin shaping the ensemble. Conversely, where the ensemble proved simpleenough to define─as in the epoxidation of enones by zinc alkylperoxides─itbecame a design tool: systematic ligand modification delivered enantioselectivitiesreaching 91% <em>ee</em>. Speciation control overturns aneven longer-standing assumption. The reaction of organozinc compoundswith O<sub>2</sub>, long treated as an uncontrolled radical process,emerges instead as a sequence of elementary steps governed by latentLewis acidity, inner-sphere electron transfer (ISET), and productinhibition─steps that allow reactive intermediates to be intercepted,giving controlled access to alkylzinc alkylperoxides and related oxygenatedspecies.</p><p>Beyond homogeneous solution, we show how phase-dependentspeciationmodulates reactivity in the solid state: mechanochemical and phase-confinedenvironments, together with supramolecular self-assembly, stabilizeensembles and open pathways─and give access to functional materials─inaccessiblein solution, establishing a continuum linking molecular speciationto materials formation.</p><p>Across these system","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 20","pages":"3545–3559"},"PeriodicalIF":18.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-16DOI: 10.1021/acs.accounts.6c00544
Christian Santiago Strong,Peng-Jui Chen,Alexander Q. Cusumano,William A. Goddard,Brian M. Stoltz
Conspectus The enantioselective Pd-catalyzed allylic alkylation reaction has proven to be an incredibly powerful and versatile methodology for the construction of stereoenriched building blocks bearing all-carbon quaternary centers. We have contributed to this field by investigating the application of chiral phosphinooxazoline (PHOX) palladium catalysts in the context of asymmetric alkylations of unstabilized nucleophiles toward a diverse array of products. In the course of our computational and mechanistic investigations, we have uncovered an oxygen-bound Pd enolate intermediate that is proposed to undergo an inner-sphere pericyclic reductive elimination. This mechanistic hypothesis stands in contrast to the outer-sphere and charge-separated mechanisms proposed for many other Pd-catalyzed allylic alkylation reactions. Intercepting this chiral enolate with other electrophiles beyond an allyl group would allow more diverse chemical space to be accessible using this platform. This Account describes several distinct approaches toward this end that are enabled by joint computational and experimental mechanistic studies. To begin, we discuss our early efforts to intercept Pd enolates using exogeneous electrophiles such as acidic protons and benzylidene malononitriles. Through these approaches, we discovered that strongly activated and polarized external electrophiles were the most successful substrates in the context of selective asymmetric transformations. We have expanded this scope to weaker carbon electrophiles by intramolecularly tethering these groups to our Pd enolate precursors alongside the application of exogeneous allyl scavengers. These strategies allow the formation of products that do not bear an allyl substituent. This development enabled construction of a library of chiral spirocycles, motifs that are prevalent in bioactive molecules. In order to extend the range of electrophiles compatible with this chemistry, we have identified the use of terminally substituted allyl groups to be important for the formation of stereotriads and -tetrads. Exploring these reactions experimentally and computationally has suggested new possible turnover mechanisms and stereochemical considerations that have informed further design iterations.
{"title":"Enantioselective\u0000Reactions of Palladium Enolate Intermediates:\u0000Beyond Allylic Alkylation","authors":"Christian Santiago Strong,Peng-Jui Chen,Alexander Q. Cusumano,William A. Goddard,Brian M. Stoltz","doi":"10.1021/acs.accounts.6c00544","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00544","url":null,"abstract":"Conspectus The enantioselective Pd-catalyzed allylic alkylation reaction has proven to be an incredibly powerful and versatile methodology for the construction of stereoenriched building blocks bearing all-carbon quaternary centers. We have contributed to this field by investigating the application of chiral phosphinooxazoline (PHOX) palladium catalysts in the context of asymmetric alkylations of unstabilized nucleophiles toward a diverse array of products. In the course of our computational and mechanistic investigations, we have uncovered an oxygen-bound Pd enolate intermediate that is proposed to undergo an inner-sphere pericyclic reductive elimination. This mechanistic hypothesis stands in contrast to the outer-sphere and charge-separated mechanisms proposed for many other Pd-catalyzed allylic alkylation reactions. Intercepting this chiral enolate with other electrophiles beyond an allyl group would allow more diverse chemical space to be accessible using this platform. This Account describes several distinct approaches toward this end that are enabled by joint computational and experimental mechanistic studies. To begin, we discuss our early efforts to intercept Pd enolates using exogeneous electrophiles such as acidic protons and benzylidene malononitriles. Through these approaches, we discovered that strongly activated and polarized external electrophiles were the most successful substrates in the context of selective asymmetric transformations. We have expanded this scope to weaker carbon electrophiles by intramolecularly tethering these groups to our Pd enolate precursors alongside the application of exogeneous allyl scavengers. These strategies allow the formation of products that do not bear an allyl substituent. This development enabled construction of a library of chiral spirocycles, motifs that are prevalent in bioactive molecules. In order to extend the range of electrophiles compatible with this chemistry, we have identified the use of terminally substituted allyl groups to be important for the formation of stereotriads and -tetrads. Exploring these reactions experimentally and computationally has suggested new possible turnover mechanisms and stereochemical considerations that have informed further design iterations.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"89 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-16DOI: 10.1021/acs.accounts.6c00501
Kan Li,Hiwot A Demssie,Guangjin Fan,Jun Wang
Conspectus In this Account, we describe our efforts to establish enteroviral 2C as a tractable target for antiviral drug discovery by integrating medicinal chemistry, molecular pharmacology, resistance profiling, structural modeling, and assay development. Rather than relying solely on conventional phenotypic high-throughput screening, our initial studies focused on the rational optimization of reported 2C inhibitors identified from a drug-repurposing campaign. This strategy led to quinoline-based antivirals with substantially improved potency and selectivity against enterovirus D68 (EV-D68), providing early medicinal chemistry insights into ligand recognition by enteroviral 2C and supporting the feasibility of chemically targeting this protein. Building on these findings, we subsequently developed pyrazolopyridine-based inhibitors, which evolved into one of the most potent classes of enteroviral 2C inhibitors reported to date. Mechanistic studies combining differential scanning fluorimetry (DSF), serial viral passage, reverse genetics, and molecular modeling supported direct engagement of a conserved allosteric pocket corresponding to the previously defined (S)-fluoxetine binding site. Structure-guided optimization led to Jun6504, a rationally designed 2C inhibitor with improved metabolic stability, favorable pharmacokinetic properties, and robust in vivo efficacy in a neonatal mouse model of EV-D68-induced paralysis. Collectively, these studies provided strong pharmacological validation of 2C as a therapeutically actionable antiviral target. In parallel, we recognized that the absence of direct, scalable biochemical assays was a major impediment to 2C-targeted antiviral discovery. To address this bottleneck, we developed a fluorescence polarization-based binding assay that monitors ligand engagement of the conserved allosteric pocket in enteroviral 2C proteins. Using Jun14157, a fluorescent probe derived from the pyrazolopyridine inhibitor series, this platform enabled direct, quantitative, and high-throughput characterization of ligand–2C interactions across EV-D68, EV-A71, and CVB3. Coupling this assay with structure-based virtual screening further enabled the identification of new allosteric inhibitor scaffolds and established a generalizable discovery platform for enteroviral 2C inhibitors. Together, these studies define an integrated framework for enteroviral 2C antiviral discovery, spanning hit-to-lead optimization, mechanism of action studies, resistance mapping, pharmacological validation, and assay innovation. Continued advances in inhibitor-bound structural elucidation, broad-spectrum inhibitor design, and next-generation therapeutic strategies should further accelerate the development of clinically useful antivirals targeting enteroviral 2C proteins.
{"title":"Enterovirus\u00002C Protein Drug Design, Assay Development,\u0000and Drug Resistance Studies","authors":"Kan Li,Hiwot A Demssie,Guangjin Fan,Jun Wang","doi":"10.1021/acs.accounts.6c00501","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00501","url":null,"abstract":"Conspectus In this Account, we describe our efforts to establish enteroviral 2C as a tractable target for antiviral drug discovery by integrating medicinal chemistry, molecular pharmacology, resistance profiling, structural modeling, and assay development. Rather than relying solely on conventional phenotypic high-throughput screening, our initial studies focused on the rational optimization of reported 2C inhibitors identified from a drug-repurposing campaign. This strategy led to quinoline-based antivirals with substantially improved potency and selectivity against enterovirus D68 (EV-D68), providing early medicinal chemistry insights into ligand recognition by enteroviral 2C and supporting the feasibility of chemically targeting this protein. Building on these findings, we subsequently developed pyrazolopyridine-based inhibitors, which evolved into one of the most potent classes of enteroviral 2C inhibitors reported to date. Mechanistic studies combining differential scanning fluorimetry (DSF), serial viral passage, reverse genetics, and molecular modeling supported direct engagement of a conserved allosteric pocket corresponding to the previously defined (S)-fluoxetine binding site. Structure-guided optimization led to Jun6504, a rationally designed 2C inhibitor with improved metabolic stability, favorable pharmacokinetic properties, and robust in vivo efficacy in a neonatal mouse model of EV-D68-induced paralysis. Collectively, these studies provided strong pharmacological validation of 2C as a therapeutically actionable antiviral target. In parallel, we recognized that the absence of direct, scalable biochemical assays was a major impediment to 2C-targeted antiviral discovery. To address this bottleneck, we developed a fluorescence polarization-based binding assay that monitors ligand engagement of the conserved allosteric pocket in enteroviral 2C proteins. Using Jun14157, a fluorescent probe derived from the pyrazolopyridine inhibitor series, this platform enabled direct, quantitative, and high-throughput characterization of ligand–2C interactions across EV-D68, EV-A71, and CVB3. Coupling this assay with structure-based virtual screening further enabled the identification of new allosteric inhibitor scaffolds and established a generalizable discovery platform for enteroviral 2C inhibitors. Together, these studies define an integrated framework for enteroviral 2C antiviral discovery, spanning hit-to-lead optimization, mechanism of action studies, resistance mapping, pharmacological validation, and assay innovation. Continued advances in inhibitor-bound structural elucidation, broad-spectrum inhibitor design, and next-generation therapeutic strategies should further accelerate the development of clinically useful antivirals targeting enteroviral 2C proteins.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"39 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-16DOI: 10.1021/acs.accounts.6c00576
SangHyun Lee,Trung-Kien H. Nguyen,Griffin Stewart,Christian A. Malapit
Conspectus Aromatic amination has long been a reaction of interest in organic synthesis, and aromatic amines themselves are prized for their bioactivity and their usefulness in the synthesis of organic materials. However, traditional syntheses have struggled to directly access aryl amines, going through sequences of aromatic prefunctionalization followed by reduction or cross-coupling. Modern advances in the control of radical chemistry have reopened the avenue of aromatic C–H functionalization based on electrophilic radical(s) (cations). However, radical C–H amination methods have struggled with generality in aromatic substrate, being unable to access electron poor arenes in a selective manner. Further challenges present themselves in the fundamental reactivities of amino radical(s) (cations), due to their tendency to undergo alpha elimination in oxidizing conditions, forcing the field to access such radicals reductively through activated, electrophilic precursors. Bicyclic amino radical cations, however, have proven more robust, due to their constrained geometry. In this Account, we present our efforts to broaden the utility of radical aromatic C–H amination using bicyclic amino radical cations generated via electrochemistry. We first recount the synthetic results of accessing these radicals reductively, showing selective radical amination. Computational studies help to illuminate the chemoselectivity of the amination reaction compared to other known reactivities of N-radical cations, such as hydrogen atom transfer (HAT). Next, we flipped the polarity of N-radical cation generation to oxidative, utilizing the bicyclic amine itself as an oxidizable radical cation precursor. By leveraging both electrophilicity-enhancing conditions and the inherent recyclability of bicyclic amines in anodic electrochemical systems, we were successfully able to broaden the scope of aromatic C–H amination to highly electron deficient arenes. The broader scope of the reaction was able to shed more light on the regioselectivity, showing that positional electron density is not the only determining factor in radical C–H amination. Photoelectrochemical studies revealed that arene oxidation mechanisms were operative for electron-rich arenes, explaining their preservation and efficient amination in a system otherwise expected to be too oxidizing. Lastly, we showcased that the resulting aryl-ammonium salts can (1) be transformed into an array of aryl piperazine derivatives through substitution/elimination and (2) act as synthetically useful aryl radical precursors in C–C, C–B, and C–P bond formations. We anticipate that the direct comparison between our two systems can help future synthetic efforts parse between reductive or oxidative strategies when targeting new electrophilic radicals, recognizing inherent advantages of each approach.
{"title":"Electrochemical\u0000Site-Selective Aromatic C–H\u0000Amination via Bicyclic N-Radical Cations","authors":"SangHyun Lee,Trung-Kien H. Nguyen,Griffin Stewart,Christian A. Malapit","doi":"10.1021/acs.accounts.6c00576","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00576","url":null,"abstract":"Conspectus Aromatic amination has long been a reaction of interest in organic synthesis, and aromatic amines themselves are prized for their bioactivity and their usefulness in the synthesis of organic materials. However, traditional syntheses have struggled to directly access aryl amines, going through sequences of aromatic prefunctionalization followed by reduction or cross-coupling. Modern advances in the control of radical chemistry have reopened the avenue of aromatic C–H functionalization based on electrophilic radical(s) (cations). However, radical C–H amination methods have struggled with generality in aromatic substrate, being unable to access electron poor arenes in a selective manner. Further challenges present themselves in the fundamental reactivities of amino radical(s) (cations), due to their tendency to undergo alpha elimination in oxidizing conditions, forcing the field to access such radicals reductively through activated, electrophilic precursors. Bicyclic amino radical cations, however, have proven more robust, due to their constrained geometry. In this Account, we present our efforts to broaden the utility of radical aromatic C–H amination using bicyclic amino radical cations generated via electrochemistry. We first recount the synthetic results of accessing these radicals reductively, showing selective radical amination. Computational studies help to illuminate the chemoselectivity of the amination reaction compared to other known reactivities of N-radical cations, such as hydrogen atom transfer (HAT). Next, we flipped the polarity of N-radical cation generation to oxidative, utilizing the bicyclic amine itself as an oxidizable radical cation precursor. By leveraging both electrophilicity-enhancing conditions and the inherent recyclability of bicyclic amines in anodic electrochemical systems, we were successfully able to broaden the scope of aromatic C–H amination to highly electron deficient arenes. The broader scope of the reaction was able to shed more light on the regioselectivity, showing that positional electron density is not the only determining factor in radical C–H amination. Photoelectrochemical studies revealed that arene oxidation mechanisms were operative for electron-rich arenes, explaining their preservation and efficient amination in a system otherwise expected to be too oxidizing. Lastly, we showcased that the resulting aryl-ammonium salts can (1) be transformed into an array of aryl piperazine derivatives through substitution/elimination and (2) act as synthetically useful aryl radical precursors in C–C, C–B, and C–P bond formations. We anticipate that the direct comparison between our two systems can help future synthetic efforts parse between reductive or oxidative strategies when targeting new electrophilic radicals, recognizing inherent advantages of each approach.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"12 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-12DOI: 10.1021/acs.accounts.6c00633
Haifeng Chen,Magnus Rueping
Organogermanium compounds have attracted growing interest in materials science, medicinal chemistry, and catalysis because of their distinctive electronic properties, tunable steric environments, high chemical stability, and emerging utility as bioisosteric motifs. Despite these attractive features, the development of general and modular methods for carbon–germanium (C–Ge) bond formation has lagged that of silicon and tin. Conventional approaches frequently rely on preformed organometallic reagents, hydrogermanes, or stoichiometric chemical reductants, thereby limiting functional-group compatibility and the direct use of readily available organic electrophiles. Electrochemical synthesis offers an alternative strategy in which electron transfer can be regulated through electrode potential, current, catalyst identity, and cell configuration. In this context, chlorogermanes are particularly attractive germylating reagents because they are readily accessible, bench-stable, and structurally tunable. Their combination with electrochemical activation enables the controlled generation of low-valent metal species, carbon-centered radicals, metal-germyl intermediates, or nucleophilic germanium species, depending on the catalyst and electrochemical regime. This mechanistic flexibility provides opportunities to construct C–Ge bonds without the prior preparation of organogermanium nucleophiles. In this Account, we describe our efforts to establish chlorogermane-based electrochemical germylation as a modular platform for C(sp3)–Ge, C(sp2)–Ge, and C(sp)–Ge bond formation, as well as for multicomponent group 14 functionalization. Cobalt electrocatalysis enables the cross-electrophile coupling of chlorogermanes with alkyl, aryl, and alkenyl halides, providing access to alkyl-, aryl-, and alkenylgermanes under mild conditions. Nickel electrocatalysis extends this strategy to regioselective allylic substitution and three-component difunctionalization of 1,3-enynes. Iron electrocatalysis enables the coupling of alkynyl chlorides with chlorogermanes, furnishing structurally diverse alkynylgermanes while suppressing competing homocoupling. We also discuss switchable transformations of nitrile-containing substrates, in which changes in electrochemical conditions and catalyst participation result in either decyanative germylation or anodic C–H germylation. Mechanistic studies involving cyclic voltammetry, radical-probe experiments, electrolysis controls, and density functional theory calculations reveal several recurring design principles. These include catalyst-centered reduction before direct substrate reduction, selective activation of Ge–Cl and C–X bonds, controlled interception of carbon-centered radicals, and electrochemical modulation of radical, organometallic, and radical–polar pathways. Rather than proceeding through a single universal catalytic cycle, these transformations operate through distinct but related mechanistic pathways that can be selected and adju
{"title":"From Chlorogermanes to Carbon–Germanium Bonds: Electrochemical Strategies for Modular Germylation","authors":"Haifeng Chen,Magnus Rueping","doi":"10.1021/acs.accounts.6c00633","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00633","url":null,"abstract":"Organogermanium compounds have attracted growing interest in materials science, medicinal chemistry, and catalysis because of their distinctive electronic properties, tunable steric environments, high chemical stability, and emerging utility as bioisosteric motifs. Despite these attractive features, the development of general and modular methods for carbon–germanium (C–Ge) bond formation has lagged that of silicon and tin. Conventional approaches frequently rely on preformed organometallic reagents, hydrogermanes, or stoichiometric chemical reductants, thereby limiting functional-group compatibility and the direct use of readily available organic electrophiles.\u0000Electrochemical synthesis offers an alternative strategy in which electron transfer can be regulated through electrode potential, current, catalyst identity, and cell configuration. In this context, chlorogermanes are particularly attractive germylating reagents because they are readily accessible, bench-stable, and structurally tunable. Their combination with electrochemical activation enables the controlled generation of low-valent metal species, carbon-centered radicals, metal-germyl intermediates, or nucleophilic germanium species, depending on the catalyst and electrochemical regime. This mechanistic flexibility provides opportunities to construct C–Ge bonds without the prior preparation of organogermanium nucleophiles.\u0000In this Account, we describe our efforts to establish chlorogermane-based electrochemical germylation as a modular platform for C(sp3)–Ge, C(sp2)–Ge, and C(sp)–Ge bond formation, as well as for multicomponent group 14 functionalization. Cobalt electrocatalysis enables the cross-electrophile coupling of chlorogermanes with alkyl, aryl, and alkenyl halides, providing access to alkyl-, aryl-, and alkenylgermanes under mild conditions. Nickel electrocatalysis extends this strategy to regioselective allylic substitution and three-component difunctionalization of 1,3-enynes. Iron electrocatalysis enables the coupling of alkynyl chlorides with chlorogermanes, furnishing structurally diverse alkynylgermanes while suppressing competing homocoupling. We also discuss switchable transformations of nitrile-containing substrates, in which changes in electrochemical conditions and catalyst participation result in either decyanative germylation or anodic C–H germylation.\u0000Mechanistic studies involving cyclic voltammetry, radical-probe experiments, electrolysis controls, and density functional theory calculations reveal several recurring design principles. These include catalyst-centered reduction before direct substrate reduction, selective activation of Ge–Cl and C–X bonds, controlled interception of carbon-centered radicals, and electrochemical modulation of radical, organometallic, and radical–polar pathways. Rather than proceeding through a single universal catalytic cycle, these transformations operate through distinct but related mechanistic pathways that can be selected and adju","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"9 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-06Epub Date: 2026-09-25DOI: 10.1021/acs.accounts.6c00616
Shi-Yu Chen, Jun Li, Ye Liu
<p>Commercial polyolefin plasticsare indispensable to modern society;however, their chemical inertness renders them environmentally persistent,thereby contributing to severe plastic pollution and ecological challenges.Accordingly, the development of commercially viable degradable materialswith performance comparable to or even superior to that of conventionalpolyolefins has received substantial interest. Polyketones representa compelling alternative: they are synthesized from commercially availableolefin feedstocks and low-cost carbon monoxide (CO) and exhibit excellentmechanical strength, high thermal stability, superior barrier properties,and inherent photodegradability arising from their regularly spacedin-chain carbonyls. Despite the industrialization of palladium-catalyzedcarbonylative polymerization, this reaction remains largely undeveloped,constrained by the reliance on a precious palladium catalyst, thepoisoning effect of CO on transition metals, and the kinetic preferencefor CO insertion, which results in limited polymer compositions andsequence structures.</p><p>This Account summarizes our systematicresearch progress in catalystdesign, structural regulation, and material properties for carbonylativepolymerization. Building on the fundamental mechanistic differencebetween olefin homopolymerization and olefin/CO copolymerization,we have custom-designed and developed three classes of [P,O]-typeligand platforms: diphosphazane monoxide (PNPO), phosphine-sulfonate(PSO), and bisphosphine monoxide (BPMO). Their applications in Earth-abundantnickel-catalyzed carbonylative polymerization of ethylene reveal thatthe electron-donating ability of the ligands, rather than steric hindrance,could alleviate CO poisoning to the metal center and exert a dominanteffect on catalytic activity and polymer molecular weight. To addressthe limitation in polymer composition, we have realized the firstnickel-catalyzed carbonylative copolymerization of ethylene and propylene.Further extension to diverse <em>α</em>-olefins andpolar monomers has greatly expanded the accessible polymer compositions,enabling the resulting polyketones to evolve from conventional resinsand fibers into ultrastrong hot-melt adhesives and elastomers. Modulationof electronic asymmetry in [P,O]-Pd catalyst systems has enabled chainsequence control through nonalternating copolymerization to overcomethe kinetic preference for CO insertion, yielding precisely tunablecarbonyl content and uniform distribution along the polymer backbone.This nonalternating copolymerization produces a unique multiblockarchitecture integrating short polar segments and extended nonpolarmethylene sequences. Such a multiblock copolymer could act as a robustcompatibilizer for polyethylene/nylon blends, converting inherentlybrittle materials into mechanically tough composites. The introductionof true phosphorus chirality afforded a series of <em>P</em>-chirogenic palladium catalysts, which exhibited unprecedented enantios
商品聚烯烃塑料是现代社会不可缺少的；然而，它们的化学惰性使它们具有环境持久性，从而造成严重的塑料污染和生态挑战。因此，开发与传统聚烯烃性能相当甚至优于传统聚烯烃的商业上可行的可降解材料已经引起了极大的兴趣。聚酮代表了一种令人信服的替代方案：它们由市售的烯烃原料和低成本的一氧化碳（CO）合成，具有优异的机械强度、高热稳定性、优越的阻隔性能，以及由于其排列有序的链内羰基而产生的固有的光降解性。尽管钯催化羰基聚合已实现工业化，但由于对贵金属钯催化剂的依赖、CO对过渡金属的中毒作用以及CO插入的动力学偏好，导致聚合物组成和序列结构有限，该反应在很大程度上仍未得到发展。本文综述了羰基聚合催化剂设计、结构调控、材料性能等方面的系统研究进展。基于烯烃均聚和烯烃/CO共聚的基本机理差异，我们定制设计并开发了三类[P，O]型配体平台：一氧化二磷（PNPO）、膦磺酸盐（PSO）和一氧化二磷（BPMO）。它们在地球富集镍催化乙烯羰基聚合中的应用表明，配体的供电子能力，而不是位阻，可以减轻CO对金属中心的毒害，并对催化活性和聚合物分子量起主导作用。为了解决聚合物组成的限制，我们首次实现了镍催化乙烯和丙烯的羰基共聚。进一步扩展到不同的α-烯烃和极性单体，大大扩展了可接触的聚合物成分，使聚酮从传统的树脂和纤维演变成超强热熔胶和弹性体。[P，O]-Pd催化剂体系中电子不对称的调制使得通过非交替共聚控制链序列成为可能，从而克服CO插入的动力学偏好，从而产生精确可调的羰基含量和沿聚合物主链的均匀分布。这种非交替共聚产生了一种独特的多嵌段结构，集成了短极性段和扩展的非极性亚甲基序列。这种多嵌段共聚物可以作为聚乙烯/尼龙共混物的增容剂，将固有的脆性材料转化为机械韧性的复合材料。真磷手性的引入提供了一系列p -致氮钯催化剂，这些催化剂在各种乙烯基芳烃的羰基聚合中表现出前所未有的对映选择性和活性。这种方法产生一系列功能化聚酮产品，其等规性高达99%，分子量达到289 kg mol-1。值得注意的是，对映纯含氟聚酮薄膜对l-和d-氨基酸表现出意想不到的手性识别性能。总的来说，我们已经通过电子调制实现了高效的后过渡金属催化的各种烯烃羰基化聚合。本工作不仅建立了该聚合中催化剂设计的理论框架，而且大大扩展了聚酮材料的应用范围，为其未来的发展指明了一条有希望的途径。
{"title":"Harnessing Composition and Sequence in Carbonylative Polymerization of Olefin for Tailored Material Properties","authors":"Shi-Yu Chen, Jun Li, Ye Liu","doi":"10.1021/acs.accounts.6c00616","DOIUrl":"10.1021/acs.accounts.6c00616","url":null,"abstract":"<p>Commercial polyolefin plasticsare indispensable to modern society;however, their chemical inertness renders them environmentally persistent,thereby contributing to severe plastic pollution and ecological challenges.Accordingly, the development of commercially viable degradable materialswith performance comparable to or even superior to that of conventionalpolyolefins has received substantial interest. Polyketones representa compelling alternative: they are synthesized from commercially availableolefin feedstocks and low-cost carbon monoxide (CO) and exhibit excellentmechanical strength, high thermal stability, superior barrier properties,and inherent photodegradability arising from their regularly spacedin-chain carbonyls. Despite the industrialization of palladium-catalyzedcarbonylative polymerization, this reaction remains largely undeveloped,constrained by the reliance on a precious palladium catalyst, thepoisoning effect of CO on transition metals, and the kinetic preferencefor CO insertion, which results in limited polymer compositions andsequence structures.</p><p>This Account summarizes our systematicresearch progress in catalystdesign, structural regulation, and material properties for carbonylativepolymerization. Building on the fundamental mechanistic differencebetween olefin homopolymerization and olefin/CO copolymerization,we have custom-designed and developed three classes of [P,O]-typeligand platforms: diphosphazane monoxide (PNPO), phosphine-sulfonate(PSO), and bisphosphine monoxide (BPMO). Their applications in Earth-abundantnickel-catalyzed carbonylative polymerization of ethylene reveal thatthe electron-donating ability of the ligands, rather than steric hindrance,could alleviate CO poisoning to the metal center and exert a dominanteffect on catalytic activity and polymer molecular weight. To addressthe limitation in polymer composition, we have realized the firstnickel-catalyzed carbonylative copolymerization of ethylene and propylene.Further extension to diverse <em>α</em>-olefins andpolar monomers has greatly expanded the accessible polymer compositions,enabling the resulting polyketones to evolve from conventional resinsand fibers into ultrastrong hot-melt adhesives and elastomers. Modulationof electronic asymmetry in [P,O]-Pd catalyst systems has enabled chainsequence control through nonalternating copolymerization to overcomethe kinetic preference for CO insertion, yielding precisely tunablecarbonyl content and uniform distribution along the polymer backbone.This nonalternating copolymerization produces a unique multiblockarchitecture integrating short polar segments and extended nonpolarmethylene sequences. Such a multiblock copolymer could act as a robustcompatibilizer for polyethylene/nylon blends, converting inherentlybrittle materials into mechanically tough composites. The introductionof true phosphorus chirality afforded a series of <em>P</em>-chirogenic palladium catalysts, which exhibited unprecedented enantios","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 19","pages":"3267–3281"},"PeriodicalIF":18.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149050303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-06Epub Date: 2026-09-04DOI: 10.1021/acs.accounts.6c00489
Yugo Shimizu, Naoki Shida, Mahito Atobe
<p>Organic electrosynthesis has re-emerged as anattractive strategyfor electrifying chemical industries without stoichiometric redoxreagents. However, the practical value of an electrochemical transformationis not determined by yield and selectivity alone. Energy consumption,supporting-electrolyte removal, and downstream separation must alsobe considered when translating laboratory-scale reactions into chemicalproduction. Solid polymer electrolyte (SPE) electrolyzers, which havebeen developed extensively in fuel cells and water electrolysis, offera promising architecture for addressing these practical requirementsin organic electrosynthesis.</p><p>In an SPE electrolyzer, an ion-exchangemembrane is sandwichedbetween electrodes to form a membrane electrode assembly with a zero-gapconfiguration. This structure shortens the ion-conduction path, lowersohmic losses, and eliminates the need for dissolved supporting electrolytes.Within the electrode, the electrocatalyst, ionomer, and organic phaseform a triple-phase boundary where electron transfer, ion transport,substrate adsorption, and chemical conversion occur in close proximity.Thus, the SPE architecture provides not only energetic and processadvantages but also a platform for engineering the local environmentin which electrosynthesis takes place.</p><p>This Account is organizedaround three general advances enabledby this architecture. First, the zero-gap configuration can lowercell resistance, while supporting-electrolyte-free operation can simplifyproduct isolation. Second, integration of the electrocatalyst andionomer converts the triple-phase boundary into a tunable interfacialreaction field. The electrocatalyst controls substrate adsorptionand the formation and reactivity of surface intermediates, whereasthe ionomer governs the local ionic environment. Membrane selectionis also important for broadening the range of compatible substratesand electrocatalysts. Together, the ionomer, electrocatalyst, andmembrane provide complementary means of controlling activity and selectivity.Third, SPE electrolyzers offer a useful platform for operando characterizationbecause the working ionomer-catalyst interface can be retained duringspectroscopic measurements. Operando infrared and X-ray absorptionspectroscopies reveal adsorbed hydrogen species, substrate adsorptiongeometries, and catalyst oxidation states that cannot be reliablyinferred from ex situ characterization alone. These observations showthat the catalytically relevant interface is dynamic and that rationalcatalyst and ionomer design must be based on the states present underoperating conditions.</p><p>After outlining the energetic basis andhistorical developmentof SPE electrosynthesis, we discuss representative hydrogenation andoxidation studies that establish these design principles. By integratinglow-voltage and supporting-electrolyte-free operation with interfacialreaction engineering and operando mechanistic analysis, SPE electrolyzersprovide a
{"title":"Organic Electrosynthesis in Solid Polymer Electrolyte Electrolyzers: Interfacial Reaction Engineering and Operando Analysis","authors":"Yugo Shimizu, Naoki Shida, Mahito Atobe","doi":"10.1021/acs.accounts.6c00489","DOIUrl":"10.1021/acs.accounts.6c00489","url":null,"abstract":"<p>Organic electrosynthesis has re-emerged as anattractive strategyfor electrifying chemical industries without stoichiometric redoxreagents. However, the practical value of an electrochemical transformationis not determined by yield and selectivity alone. Energy consumption,supporting-electrolyte removal, and downstream separation must alsobe considered when translating laboratory-scale reactions into chemicalproduction. Solid polymer electrolyte (SPE) electrolyzers, which havebeen developed extensively in fuel cells and water electrolysis, offera promising architecture for addressing these practical requirementsin organic electrosynthesis.</p><p>In an SPE electrolyzer, an ion-exchangemembrane is sandwichedbetween electrodes to form a membrane electrode assembly with a zero-gapconfiguration. This structure shortens the ion-conduction path, lowersohmic losses, and eliminates the need for dissolved supporting electrolytes.Within the electrode, the electrocatalyst, ionomer, and organic phaseform a triple-phase boundary where electron transfer, ion transport,substrate adsorption, and chemical conversion occur in close proximity.Thus, the SPE architecture provides not only energetic and processadvantages but also a platform for engineering the local environmentin which electrosynthesis takes place.</p><p>This Account is organizedaround three general advances enabledby this architecture. First, the zero-gap configuration can lowercell resistance, while supporting-electrolyte-free operation can simplifyproduct isolation. Second, integration of the electrocatalyst andionomer converts the triple-phase boundary into a tunable interfacialreaction field. The electrocatalyst controls substrate adsorptionand the formation and reactivity of surface intermediates, whereasthe ionomer governs the local ionic environment. Membrane selectionis also important for broadening the range of compatible substratesand electrocatalysts. Together, the ionomer, electrocatalyst, andmembrane provide complementary means of controlling activity and selectivity.Third, SPE electrolyzers offer a useful platform for operando characterizationbecause the working ionomer-catalyst interface can be retained duringspectroscopic measurements. Operando infrared and X-ray absorptionspectroscopies reveal adsorbed hydrogen species, substrate adsorptiongeometries, and catalyst oxidation states that cannot be reliablyinferred from ex situ characterization alone. These observations showthat the catalytically relevant interface is dynamic and that rationalcatalyst and ionomer design must be based on the states present underoperating conditions.</p><p>After outlining the energetic basis andhistorical developmentof SPE electrosynthesis, we discuss representative hydrogenation andoxidation studies that establish these design principles. By integratinglow-voltage and supporting-electrolyte-free operation with interfacialreaction engineering and operando mechanistic analysis, SPE electrolyzersprovide a ","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 19","pages":"3166–3178"},"PeriodicalIF":18.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148894889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-06Epub Date: 2026-09-15DOI: 10.1021/acs.accounts.6c00324
Namrata Sharma, Louis Godeffroy, Tristan Petit
<p>Chemical imaging combines microscopy with spectroscopy to achievea chemical contrast, enabling the identification of different chemicalspecies with high spatial resolution. This capability is particularlyvaluable for the characterization of composite and heterogeneous materials,as well as for probing chemical reactions that are spatially segregatedat the micro- or nanoscale. Representative examples include catalyticprocesses that locally modify the state of a catalyst, or batteryparticles that charge nonuniformly during cycling.</p><p>Chemicalimaging can be implemented using scanning probe, optical,electron, or X-ray spectromicroscopy techniques, each providing distinctforms of chemical contrast. Scanning probe and optical methods primarilyprobe valence electrons or vibrational modes, offering high chemicalsensitivity, whereas electron and X-ray techniques typically probecore-level excitations, providing element-specific information. Thelatter also enable higher spatial resolution, as electrons and X-rayshave much shorter wavelengths than visible light (typically <10nm versus ∼400 nm).</p><p>Among these approaches, X-ray-basedmethods are particularly powerfulfor direct, label-free chemical imaging due to their high elementaland site specificity. They are also significantly less invasive thanelectron-beam techniques. The soft X-ray range (ca. 100–2000eV) is especially relevant, as it enables the selective excitationof the K-edge of light elements such as carbon, oxygen, and nitrogen,as well as the L- or M-edge of transition metals. Despite these relativelylow photon energies, spatial resolutions down to ∼10 nm canbe routinely achieved using standard X-ray optics.Moreover, the informationdepth can be tuned through the detection mode. For instance, photoemission-basedtechniques such as X-ray photoemission electron microscopy (X-PEEM)provide high surface sensitivity, whereas transmission-based methodssuch as scanning transmission X-ray microscopy (STXM) probe the bulkof the material that is though limited to thin samples. Finally, thecomparatively large penetration depth of X-rays, relative to electrons,enables the use of <em>in situ</em> cells to investigate chemicalprocesses under realistic conditions.</p><p>In this Account, we presentrecent advances in X-ray chemical imaging,highlighting our work on two-dimensional transition-metal carbidesknown as MXenes. These materials are particularly well-suited forsuch approaches due to their rich surface chemistry, flat geometry,and micrometer-sized flakes. MXenes have attracted growing interestacross a wide range of applications, including electromagnetic interferenceshielding, sensing, and energy storage. They adopt a M<sub>n+1</sub>X<sub>n</sub>T<sub><em>x</em></sub> layered structure, whereM is a transition metal, X is carbon and/or nitrogen, and T<sub><em>x</em></sub> denotes mixed surface terminations, which can beselectively imaged by (soft) X-ray techniques. This account focusesmainly on Ti<su
{"title":"Chemical Imaging of MXenes with X-ray Microscopy","authors":"Namrata Sharma, Louis Godeffroy, Tristan Petit","doi":"10.1021/acs.accounts.6c00324","DOIUrl":"10.1021/acs.accounts.6c00324","url":null,"abstract":"<p>Chemical imaging combines microscopy with spectroscopy to achievea chemical contrast, enabling the identification of different chemicalspecies with high spatial resolution. This capability is particularlyvaluable for the characterization of composite and heterogeneous materials,as well as for probing chemical reactions that are spatially segregatedat the micro- or nanoscale. Representative examples include catalyticprocesses that locally modify the state of a catalyst, or batteryparticles that charge nonuniformly during cycling.</p><p>Chemicalimaging can be implemented using scanning probe, optical,electron, or X-ray spectromicroscopy techniques, each providing distinctforms of chemical contrast. Scanning probe and optical methods primarilyprobe valence electrons or vibrational modes, offering high chemicalsensitivity, whereas electron and X-ray techniques typically probecore-level excitations, providing element-specific information. Thelatter also enable higher spatial resolution, as electrons and X-rayshave much shorter wavelengths than visible light (typically <10nm versus ∼400 nm).</p><p>Among these approaches, X-ray-basedmethods are particularly powerfulfor direct, label-free chemical imaging due to their high elementaland site specificity. They are also significantly less invasive thanelectron-beam techniques. The soft X-ray range (ca. 100–2000eV) is especially relevant, as it enables the selective excitationof the K-edge of light elements such as carbon, oxygen, and nitrogen,as well as the L- or M-edge of transition metals. Despite these relativelylow photon energies, spatial resolutions down to ∼10 nm canbe routinely achieved using standard X-ray optics.Moreover, the informationdepth can be tuned through the detection mode. For instance, photoemission-basedtechniques such as X-ray photoemission electron microscopy (X-PEEM)provide high surface sensitivity, whereas transmission-based methodssuch as scanning transmission X-ray microscopy (STXM) probe the bulkof the material that is though limited to thin samples. Finally, thecomparatively large penetration depth of X-rays, relative to electrons,enables the use of <em>in situ</em> cells to investigate chemicalprocesses under realistic conditions.</p><p>In this Account, we presentrecent advances in X-ray chemical imaging,highlighting our work on two-dimensional transition-metal carbidesknown as MXenes. These materials are particularly well-suited forsuch approaches due to their rich surface chemistry, flat geometry,and micrometer-sized flakes. MXenes have attracted growing interestacross a wide range of applications, including electromagnetic interferenceshielding, sensing, and energy storage. They adopt a M<sub>n+1</sub>X<sub>n</sub>T<sub><em>x</em></sub> layered structure, whereM is a transition metal, X is carbon and/or nitrogen, and T<sub><em>x</em></sub> denotes mixed surface terminations, which can beselectively imaged by (soft) X-ray techniques. This account focusesmainly on Ti<su","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 19","pages":"3023–3035"},"PeriodicalIF":18.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148973729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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