Accounts of Chemical Research最新文献

{"title":"Enterovirus 2C Protein Drug Design, Assay Development, and Drug Resistance Studies","authors":"Kan Li,&nbsp;Hiwot A Demssie,&nbsp;Guangjin Fan,&nbsp;Jun Wang","doi":"10.1021/acs.accounts.6c00501","DOIUrl":"10.1021/acs.accounts.6c00501","url":null,"abstract":"<p>In this Account, we describeour efforts to establish enteroviral2C as a tractable target for antiviral drug discovery by integratingmedicinal chemistry, molecular pharmacology, resistance profiling,structural modeling, and assay development. Rather than relying solelyon conventional phenotypic high-throughput screening, our initialstudies focused on the rational optimization of reported 2C inhibitorsidentified from a drug-repurposing campaign. This strategy led toquinoline-based antivirals with substantially improved potency andselectivity against enterovirus D68 (EV-D68), providing early medicinalchemistry insights into ligand recognition by enteroviral 2C and supportingthe feasibility of chemically targeting this protein.</p><p>Buildingon these findings, we subsequently developed pyrazolopyridine-basedinhibitors, which evolved into one of the most potent classes of enteroviral2C inhibitors reported to date. Mechanistic studies combining differentialscanning fluorimetry (DSF), serial viral passage, reverse genetics,and molecular modeling supported direct engagement of a conservedallosteric pocket corresponding to the previously defined (<em>S</em>)-fluoxetine binding site. Structure-guided optimizationled to <strong>Jun6504</strong>, a rationally designed 2C inhibitor withimproved metabolic stability, favorable pharmacokinetic properties,and robust in vivo efficacy in a neonatal mouse model of EV-D68-inducedparalysis. Collectively, these studies provided strong pharmacologicalvalidation of 2C as a therapeutically actionable antiviral target.</p><p>In parallel, we recognized that the absence of direct, scalablebiochemical assays was a major impediment to 2C-targeted antiviraldiscovery. To address this bottleneck, we developed a fluorescencepolarization-based binding assay that monitors ligand engagement ofthe conserved allosteric pocket in enteroviral 2C proteins. Using <strong>Jun14157</strong>, a fluorescent probe derived from the pyrazolopyridineinhibitor series, this platform enabled direct, quantitative, andhigh-throughput characterization of ligand–2C interactionsacross EV-D68, EV-A71, and CVB3. Coupling this assay with structure-basedvirtual screening further enabled the identification of new allostericinhibitor scaffolds and established a generalizable discovery platformfor enteroviral 2C inhibitors.</p><p>Together, these studies definean integrated framework for enteroviral2C antiviral discovery, spanning hit-to-lead optimization, mechanismof action studies, resistance mapping, pharmacological validation,and assay innovation. Continued advances in inhibitor-bound structuralelucidation, broad-spectrum inhibitor design, and next-generationtherapeutic strategies should further accelerate the development ofclinically useful antivirals targeting enteroviral 2C proteins.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 21","pages":"3619–3630"},"PeriodicalIF":18.0,"publicationDate":"2026-11-03","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}

{"title":"From Anti-Sintering to Anti-Dispersion: Preserving Reactive Metallic Pt Ensembles in Light-Alkane Oxidation","authors":"Xuan Tang,&nbsp;Lide Yang,&nbsp;Sheng Dai,&nbsp;Yun Guo","doi":"10.1021/acs.accounts.6c00721","DOIUrl":"10.1021/acs.accounts.6c00721","url":null,"abstract":"&lt;p&gt;A long-standing principle in supported noble-metalcatalysis isto maximize metal dispersion and prevent nanoparticle sintering. Thisdispersion-centered, anti-sintering paradigm is rational because highlydispersed species increase apparent metal utilization and often exposelow-coordinated sites with distinct electronic structures. For low-temperatureoxidation of C&lt;sub&gt;2+&lt;/sub&gt; light alkanes, however, dispersion alonedoes not define the working catalyst. Propane is considered here asa representative model because its complete oxidation couples initialalkane adsorption and C–H activation with subsequent dehydrogenation,C–C bond cleavage, and deep oxidation of C&lt;sub&gt;&lt;em&gt;x&lt;/em&gt;&lt;/sub&gt; intermediates. These functions require a balance between alkane-accessiblemetallic Pt ensembles and oxygen or interfacial functions that sustaincomplete oxidation. Excessive dispersion can disrupt this balanceby promoting Pt oxidation, strong oxygen binding, or stabilizationof isolated species, whereas less-dispersed Pt can preserve the contiguousmetallic sites needed for alkane activation under suitable reactionconditions.&lt;/p&gt;&lt;p&gt;In this Account, we propose anti-dispersion as adesign conceptfor constructing and preserving the appropriate working Pt ensemble.Pt dispersion is treated not as a monotonic activity descriptor butas a reaction-dependent variable coupled to metallic character, ensembleavailability, oxygen coverage, accessible-site density, and supportanchoring. Anti-dispersion therefore encompasses both controlled restructuringof over-dispersed Pt into reactive metallic ensembles and preventionof their subsequent fragmentation under working conditions. Our studiesreveal these two complementary dimensions. Size-controlled Pt/CeO&lt;sub&gt;2&lt;/sub&gt; model catalysts show that increasing Pt size can enhancemetallic character and intrinsic activity for propane oxidation, whilethe overall rate reflects a trade-off between ensemble reactivityand exposed-site density. Controlled sintering of Pt on MgAl&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;4&lt;/sub&gt; further demonstrates that lower dispersion can be beneficialwhen it generates metallic surfaces that remain alkane-accessiblewithin the relevant oxygen-coverage window. Conversely, active metallicPt ensembles on CeO&lt;sub&gt;2&lt;/sub&gt; can fragment during propane oxidationand become stabilized as isolated Pt spectators. Selective blockingof the corresponding atom-trapping sites suppresses this reaction-inducedredispersion and preserves metallic Pt ensembles. Extending this conceptacross oxide supports shows that anti-dispersion must be adapted tothe dominant anchoring environment. Depending on the support, therelevant strategy may involve blocking support-templated Pt oxideformation, moderating acid-site-mediated anchoring, or competitivelyoccupying hydroxyl sites that otherwise over-disperse Pt. The unifyingobjective is to regulate the anchoring landscape selectively whileretaining useful interfacial functions for oxygen management, C&lt;sub&gt;&lt;em&gt;x&lt;/em&gt;&lt;/sub&gt;-inter","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 21","pages":"3681–3692"},"PeriodicalIF":18.0,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221797","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}

{"title":"Electrochemical Site-Selective Aromatic C–H Amination via Bicyclic N-Radical Cations","authors":"SangHyun Lee,&nbsp;Trung-Kien H. Nguyen,&nbsp;Griffin Stewart,&nbsp;Christian A. Malapit","doi":"10.1021/acs.accounts.6c00576","DOIUrl":"10.1021/acs.accounts.6c00576","url":null,"abstract":"<p>Aromatic amination has longbeen a reaction of interest in organicsynthesis, and aromatic amines themselves are prized for their bioactivityand their usefulness in the synthesis of organic materials. However,traditional syntheses have struggled to directly access aryl amines,going through sequences of aromatic prefunctionalization followedby reduction or cross-coupling. Modern advances in the control ofradical chemistry have reopened the avenue of aromatic C–Hfunctionalization based on electrophilic radical(s) (cations). However,radical C–H amination methods have struggled with generalityin aromatic substrate, being unable to access electron poor arenesin a selective manner. Further challenges present themselves in thefundamental reactivities of amino radical(s) (cations), due to theirtendency to undergo alpha elimination in oxidizing conditions, forcingthe field to access such radicals reductively through activated, electrophilicprecursors. Bicyclic amino radical cations, however, have proven morerobust, due to their constrained geometry. In this Account, we presentour efforts to broaden the utility of radical aromatic C–Hamination using bicyclic amino radical cations generated via electrochemistry.We first recount the synthetic results of accessing these radicalsreductively, showing selective radical amination. Computational studieshelp to illuminate the chemoselectivity of the amination reactioncompared to other known reactivities of <em>N</em>-radicalcations, such as hydrogen atom transfer (HAT). Next, we flipped thepolarity of <em>N</em>-radical cation generation to oxidative,utilizing the bicyclic amine itself as an oxidizable radical cationprecursor. By leveraging both electrophilicity-enhancing conditionsand the inherent recyclability of bicyclic amines in anodic electrochemicalsystems, we were successfully able to broaden the scope of aromaticC–H amination to highly electron deficient arenes. The broaderscope of the reaction was able to shed more light on the regioselectivity,showing that positional electron density is not the only determiningfactor in radical C–H amination. Photoelectrochemical studiesrevealed that arene oxidation mechanisms were operative for electron-richarenes, explaining their preservation and efficient amination in asystem otherwise expected to be too oxidizing. Lastly, we showcasedthat the resulting aryl-ammonium salts can (1) be transformed intoan array of aryl piperazine derivatives through substitution/eliminationand (2) act as synthetically useful aryl radical precursors in C–C,C–B, and C–P bond formations. We anticipate that thedirect comparison between our two systems can help future syntheticefforts parse between reductive or oxidative strategies when targetingnew electrophilic radicals, recognizing inherent advantages of eachapproach.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 21","pages":"3642–3653"},"PeriodicalIF":18.0,"publicationDate":"2026-11-03","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}

{"title":"Negative Photochromism of Biaryl-Bridged Imidazole Dimers: Designing Biradical-Mediated Reaction Networks","authors":"Jiro Abe","doi":"10.1021/acs.accounts.6c00693","DOIUrl":"10.1021/acs.accounts.6c00693","url":null,"abstract":"&lt;p&gt;Negative photochromism reversesthe usual behavior of T-type photochromicmolecules: a thermally stable colored state is converted by lightinto a less absorbing metastable state and subsequently recovers thermally.Because the photoproduct attenuates excitation light less strongly,negative photochromism is attractive for optically dense materialsand systems requiring an intrinsic thermal reset. The challenge isto combine long-wavelength excitation, efficient photoconversion,controllable state populations and thermal lifetimes, and adaptationto different operating environments. Our studies of biaryl-bridgedimidazole dimers originated from efforts to accelerate radical recombinationin hexaarylbiimidazole (HABI) photochromes by covalently bridgingthe two imidazole units and suppressing diffusional separation ofthe photogenerated radicals. Introduction of a 1,1′-binaphthylbridge unexpectedly produced negative photochromism. In the resulting1,1′-binaphthyl-bridged imidazole dimer (BN-ImD), the thermodynamicallystable colored state (5MR) contains a diazafulvene chromophore absentfrom conventional HABI photochromes. Visible-light excitation cleavesa C–N bond to generate a short-lived biradical intermediate(BR), which recombines either to regenerate 5MR or to form the metastablecolorless state (6MR). Thermal cleavage of the interimidazole C–Cbond of 6MR regenerates BR, completing a thermally resettable 5MR–BR–6MRnetwork. This behavior revealed that molecular bridging can controlnot only radical proximity but also the covalent states and reactionpathways accessible through BR. This reaction-network perspectiveprovides several design coordinates. Extension of the π-conjugatedbridge and donor substitution enable long-wavelength excitation, whereasdifferential tuning of 5MR and 6MR absorptions can produce large spectralseparation and wavelength-selective bidirectional switching. Molecularasymmetry can bias BR recombination among competing covalent products,and excitation intensity can open nonlinear pathways to alternativestates. Conformational restriction alters activation barriers andthermal recovery, while transient spectroscopy and global kineticanalysis separate BR formation, product branching, and thermal regenerationas distinct contributions. Structural modification can also open accessto 7MR and 8MR states and generate kinetic hierarchies spanning rapidradical recombination, seconds-scale switching, and hours-to-daysthermal equilibration. The 5MR/6MR contrast can also be translatedinto function, including turn-on fluorescence, four-photon-like fluorescenceresponses under two-photon excitation, operation in polar and aqueousmedia, and light-driven reorganization of lyotropic and chiral nematicliquid crystals. This Account organizes these developments aroundfour interdependent design principles─spectral control, kineticcontrol, branching selectivity, and environmental integration. Thecentral message is that negative photochromism in this family is best","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 21","pages":"3668–3680"},"PeriodicalIF":18.0,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149226115","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}

{"title":"The Long and Lucky Road to Continuous Molecular Monitoring: A Personal History of Electrochemical Aptamer-Based Sensors","authors":"Kevin W. Plaxco","doi":"10.1021/acs.accounts.6c00684","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00684","url":null,"abstract":"“Continuous molecular monitoring”, the ability to measure specific molecules in vivo, in real time, and at high frequency, could transform biomedical science and clinical practice. It could, for example, expose physiological dynamics that current “sample-then-analyze” paradigms obscure and improve the personalization of medical treatment, such as via feedback-controlled dosing that responds automatically to a patient’s changing physiology.\u0000Unlocking the full potential of continuous molecular monitoring requires a reagentless, reversible sensing mechanism both selective enough to deploy in the body and general enough to detect almost any analyte, a combination that had long proven elusive. Enzymatic sensors, for example, including the continuous glucose monitor, often work well in vivo but are limited to the small number of analytes for which suitably transforming enzymes exist. “Affinity biosensors”, in contrast, do not require the chemical transformation of their target, rendering them far more general. However, these have historically relied on adsorption to generate a signal (e.g., binding-induced changes in mass), a mechanism that performs poorly in unprocessed biofluids in vitro, much less in vivo.\u0000In this Account, I describe the near-30-year effort required to create and bring to clinical trials the first affinity biosensor architecture that performs well in vivo: electrochemical aptamer-based (EAB) sensors. To achieve this, EAB sensors use the binding-induced folding of an electrode-attached aptamer to alter the electron transfer kinetics of an attached redox reporter, a biomimetic signaling mechanism that is reagentless, spontaneously reversible, highly selective, and thus supports the real-time, in vivo measurement of almost any analyte for which a suitable aptamer is available.\u0000The road to EAB sensors began in the late 1990s with coincidentally convergent evidence suggesting that binding-induced folding is a near-universal property of destabilized proteins. Through the years-long contributions of many creative collaborators, this ultimately evolved into a nucleic acid-based, electrochemical biosensor architecture of broad utility. However, while even the first examples worked well in blood serum in vitro, EAB sensors drift when placed in the body, a problem ultimately solved by an engineering insight: the strongly frequency-dependent signaling of EAB sensors makes it possible to use them as their own drift-correcting reference. Leveraging this, in 2017, we demonstrated the first real-time, multihour in vivo monitoring of circulating drugs, an advance since extended to a wide range of analytes, to week-long in vivo operation and to feedback-controlled drug delivery.\u0000Given these unique measurement and control capabilities, EAB sensors can answer scientific questions and solve clinical problems that other technologies cannot. Seconds-resolved EAB sensor measurements are beginning to reveal, for example, previously unrecognized regulatory a","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"8 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305300","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}

{"title":"Toward Sustainable Production of Reduced Phosphorus Compounds","authors":"Pawel Löwe,Christopher C. Cummins","doi":"10.1021/acs.accounts.6c00639","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00639","url":null,"abstract":"Although phosphate is the thermodynamically stable and overwhelmingly abundant form of phosphorus in Nature, the modern phosphorus chemicals industry still relies heavily on white phosphorus (P4) as its central feedstock. In the thermal process, phosphate rock is reduced with coke and silica at temperatures around 1500 °C to produce P4, which is then converted to intermediates such as PCl3 before further conversion to value-added phosphorus compounds. This reaction sequence is effective, but involves the reduction of phosphate under high temperature, followed by additional redox and functionalization steps before many target phosphorus compounds are obtained. We therefore asked whether phosphate-derived feedstocks could be converted more directly into reduced phosphorus compounds, making the production of P4 as an intermediate unnecessary while retaining the synthetic flexibility needed for producing a large variety of phosphorus compounds.\u0000That question led to three areas of investigation. The first exploits the strong thermodynamic driving force of Si–O bond formation to achieve oxygen-abstraction reduction of phosphate-derived substrates. This led to the discovery of the bis(trichlorosilyl)phosphide anion, [P(SiCl3)2]− ⁠, a previously unknown P(−3) synthon that can now be accessed from trimetaphosphate, orthophosphate salts, and phosphoric acid. It can be further converted to value-added phosphorus compounds, such as phosphines, hexafluorophosphate, or phosphonium salts. Protonation of [P(SiCl3)2]− gives bis(trichlorosilyl)phosphine, HP(SiCl3)2 ⁠, which undergoes selective radical hydrophosphination and gives synthetic access to primary phosphines, chlorophosphines, phosphinic acids, phosphonic acids, and phosphonium salts. The second strategy uses mechanochemistry to convert condensed phosphates directly to phosphite through hydride phosphorylation. Ball milling with alkali-metal hydrides provides a solvent-free route to a P(III) product while retaining the PO3 framework of the starting material. This route also works with biologically recovered polyphosphate feedstocks, which is important for the recycling of sewage sludge. The same mechanochemical platform further proved useful for the analogous redox-neutral phosphorylation of acetylides, giving alkynyl phosphonates directly from condensed phosphates. Finally, strongly reducing mechanochemical conditions based on supported alkali-metal dispersions gave access to ortho-phosphite, PO33− ⁠, a previously “missing” phosphorus oxoanion. This new anion can be converted further to phosphite salts, tris(trimethylsilyl) phosphite, and alkyl phosphonates.\u0000Taken together, these studies show that condensed phosphates and phosphoric acid can be directly used as feedstocks for synthetic phosphorus chemistry, without relying on P4 as an intermediate. This approach enables the identification of reactions that preserve P–O bonds where desirable and creates new opportunities to link phosphorus recovery from ","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"7 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149304477","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}

{"title":"Covalent Organic Pillars: Programmable Nanotubular Cavitands","authors":"Hongliang Ye,Xuming Sha,Yiqiu Sun,Andrew C.-H. Sue","doi":"10.1021/acs.accounts.6c00513","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00513","url":null,"abstract":"For more than half a century, the construction of molecular host compounds has emerged as a central theme in supramolecular chemistry, driven by the promise of controlling molecular recognition, transport, and reactivity. While a wide variety of macrocyclic hosts have been developed, achieving deep-cavity cavitands with confined inner spaces extending over several nanometers has remained challenging. This limitation has hindered systematic investigations of how confinement governs molecular behavior within the so-called “inner phase”, as originally articulated by Cram. Motivated by these challenges, our laboratory has pursued the design and synthesis of a family of covalent organic pillars (COPs)─single-molecule nanotubular architectures assembled through dynamic covalent imine condensation of aldehyde-functionalized paracyclophane building blocks with diamine linkers. In this Account, we summarize our efforts to establish COPs as a versatile class of open-ended nanotubular cavitands, offering highly preorganized one-dimensional cavities with lengths exceeding 2 nm that encapsulate guests with complementary size and surface properties. By adopting an isoreticular design strategy, we demonstrate that systematic variation of linker structure and length enables the construction of a series of COPs with precisely tunable cavity length, sidewall composition, and effective channel width. This modularity provides a rare opportunity to correlate host geometry with recognition behavior in a quantitative and predictive manner. Beyond host–guest chemistry, we show that COPs also provide a powerful platform for exploring dynamic stereochemical phenomena during self-assembly from inherently chiral yet stereolabile macrocyclic building blocks. Whereas COPs constructed from rigid diamine spacers undergo exclusive narcissistic chiral self-sorting, yielding pairs of enantiomeric nanotubular structures, incorporation of flexible aliphatic diamine spacers leads to pronounced odd–even effects in chiral self-sorting, giving either racemic mixtures of chiral COPs or achiral meso-COPs, depending on linker parity. This conformational flexibility further endows COPs with adaptive host–guest recognition behavior, enabling cooperative accommodation of guests through a balance of host deformation and guest distortion. A distinctive feature of our work is that the molecular structures of essentially all COPs and their key host–guest complexes are elucidated by single-crystal X-ray crystallography, providing a rigorous structural foundation that remains rare for deep-cavity molecular hosts. Overall, our studies establish COPs as a precision design paradigm for nanotubular cavitands that bridge the gap between discrete macrocycles and extended porous frameworks, thereby opening a new regime of molecular control in supramolecular chemistry.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"7 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149304475","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}

{"title":"Cross-Electrophile Coupling through Direct Electrolysis","authors":"Nicholas I. Cemalovic,Bofei Wang,Song Lin","doi":"10.1021/acs.accounts.6c00618","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00618","url":null,"abstract":"Electrochemical reduction is a powerful means of generating reactive radical and anionic species with a degree of modularity and versatility that rivals other traditional chemical and photochemical reduction approaches. Our group has been motivated by the goal of using electrolysis as an enabling tool to develop reactivity and selectivity that are inaccessible using traditional reductants. In particular, we have leveraged the characteristics of direct electrolysis to promote sequential electron-transfer events that enable net-reductive radical-polar crossover, generating nucleophilic anionic intermediates from electrophilic reactants that undergo umpolung reactions with additional electrophiles. Guided further by physical organic principles, we identified systems that selectively activate a variety of common electrophiles to engage in a diverse array of formal cross-electrophile coupling (XEC) reactions.\u0000In this Account, we first describe the development of electroreductive cross-coupling of alkyl halides and its extension to silicon–silicon bond formation. This mechanistic framework was then applied to three-component dialkylation of alkenes using two distinct alkyl halides with high site- and chemoselectivity. Beyond alkyl halides, we further expanded the scope of electroreductive XEC to the deoxygenative functionalization of alcohols with a collection of heteroatom-based electrophiles. These transformations were enabled by in situ activation strategies that convert alcohols into reductively active intermediates, allowing them to behave analogously to alkyl halides and undergo borylation, silylation, and related coupling reactions. Finally, we recognized that an analogous activation logic could also enable the reductive functionalization of carbonyl compounds including ketones, aldehydes, and esters, which remains a major synthetic challenge that cannot be readily resolved by direct cathodic reduction. The continued evolution of activation methods ultimately enabled the formal geminal difunctionalization of electronically unbiased aldehydes and ketones that would otherwise require strongly reducing potentials to activate. These methods provided efficient access to densely functionalized sp3-carbon centers while demonstrating that product selectivity can be regulated through Faradaic control, a unique feature of electrochemistry.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"13 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2026-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149304135","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}

{"title":"Quantitative Determination of the Hydration Shell, Counterion Association and Intermolecular Distances in Nanoscale Macroionic Solutions and Their Correlations to the Self-Assembly Behaviors and Phase Transitions of Macroions","authors":"Xiaohan Xu,Kexing Xiao,Tianbo Liu","doi":"10.1021/acs.accounts.6c00613","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00613","url":null,"abstract":"Hydrophilic macroions with characteristic sizes of 1–6 nm represent a unique transition stage between simple ions and large colloidal particles. Typical macroions include well-defined molecular clusters, metal–organic cages (MOCs), small nanoparticles, and biomacromolecules such as globular proteins. In this regime, classic Debye–Hückel limiting theory is inapplicable due to the large sizes of macroions, while DLVO theory is also inadequate because macroionic solutions remain thermodynamically stable, with negligible van der Waals attractions compared to colloids.\u0000In the past two decades, our group has been devoted to understanding the behavior of macroionic solutions. We discovered the assembly behavior (formation of hollow, spherical, single-layered blackberry-type structures) and new phases (gelation and coacervation) in dilute macroionic solutions. However, it was not until recently that we were able to quantitatively determine the molecular-level interactions in macroionic solutions, clarifying the origin of these phenomena and leading us to discover more phase transitions and outline a whole picture of macroionic solutions. This fundamental progress will help scientists deal with more complex macroionic solutions, such as the poorly understood polyelectrolyte and biomolecular solutions.\u0000In this Account, we highlight how modern techniques enable the quantitative determination of intermolecular interactions in macroionic solutions and how these interactions dictate the self-assembly and macrophase transitions, summarized as follows: (1) Determination of the hydration shell thicknesses of metal-oxide molecular clusters in solution, achieved for the first time by using the analytical ultracentrifugation (AUC) technique and correlating this value with the macroionic charge density. (2) Determination of the number of associated counterions and their average distances to the central macroion for different metal counterions by using the anomalous synchrotron small-angle X-ray scattering (ASAXS) technique. (3) Determination of the intermolecular distances between macroions in their dimeric state with different counterions. The gradual decrease in the intermolecular distance reveals the increasing strength of counterion-mediated attraction. (4) Successful correlation of the change of intermolecular distance in the dimers with the self-assembly (into blackberry structures of different sizes) and macrophase transitions (gelation, coacervation, and crystallization) in macroionic solution. (5) Correlation of the delicate difference in intermolecular interactions/distance to the intriguing self-recognition and chiral recognition features of macroions, which we reported earlier.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"9 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2026-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149304134","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}

{"title":"Beyond Long-Term Protection by Intelligent Poly(lactic acid) Nanofibers: Structuring Multiscale Hierarchies for Passive Sensing","authors":"Shao-Zhen Wang,Xinjian He,Jia-Lian Gao,Chang-Wei Zhang,Hao-Ran Yang,Long Zhang,Zhengyan Wu,Liang Wang,Bingyou Jiang,Liang Yuan,Yuzhen Hou,Weiqing Kong,Huan Xu","doi":"10.1021/acs.accounts.6c00652","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00652","url":null,"abstract":"Recent advances in electrospun biodegradable polymer nanofibrous membranes (NFMs) are reshaping the design of functional materials from passive morphological optimization toward programmed charge regulation and function-oriented structural engineering. Extending this concept to biobased poly(lactic acid) (PLA), however, remains challenging because PLA exhibits weak cooperative alignment of ester dipoles, a low dielectric response, and a limited number of highly polar or ionizable groups. These molecular characteristics give rise to shallow charge traps, insufficient interfacial polarization, and rapid charge dissipation across crystalline–amorphous regions. Therefore, the key scientific issue is not only how to fabricate porous PLA membranes but also how to organize their molecular conformations, crystalline domains, filler interfaces, and fibrous networks into a multiscale charge-regulation system.\u0000Electrospinning provides an effective route for addressing this issue because electric-field stretching, jet elongation, solvent evaporation, and phase separation can simultaneously regulate PLA chain orientation, crystalline morphology, fiber assembly, and pore architecture without altering the chemical structure of PLA chains. On this basis, research has progressed from single-parameter optimization toward multidimensional structural regulation. First, tuning electrospinning parameters, including voltage, collection distance, solution viscosity, and collector motion, promotes axial chain orientation and cooperative ester-dipole alignment. This oriented conformation enhances crystalline ordering, enriches crystalline–amorphous interfaces, and creates favorable charge-trapping domains, while more ordered fiber assembly narrows pore-size distributions and improves airflow continuity. Second, stereocomplexation between poly(l-lactide) and poly(d-lactide) introduces tightly packed stereocomplex crystallites through stereospecific interchain interactions. These ordered crystallites intensify dipolar polarization, deepen trap energy levels, and improve charge-storage stability, thereby mitigating the poor electret durability of pristine PLA. Third, nanoscale filler interfacial engineering with electroactive porous or dielectric fillers, such as metal–organic frameworks and titanium dioxide, introduces dielectric heterogeneity, defect-rich interfaces, unsaturated coordination sites, and high-surface-area contact domains. These features enrich multilevel charge-trapping sites, promote interfacial polarization, facilitate localized charge regeneration, and impart additional functions, including adsorption, antibacterial activity, humidity tolerance, and photothermal or optical regulation.\u0000An increasingly systematic understanding of the processing–structure–electroactivity–function relationship is accelerating the transition of PLA NFMs from mechanistic studies to engineering applications. The coordinated regulation of fiber orientation, stereocomplex crystall","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"282 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149272069","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}