Accounts of Chemical Research最新文献

{"title":"Cross-Couplings via Electroreductive C–F, C–O, and C–S Bond Cleavage and Radical-Polar Crossover Mechanisms","authors":"Luca Massaro, Helena Lundberg","doi":"10.1021/acs.accounts.6c00486","DOIUrl":"10.1021/acs.accounts.6c00486","url":null,"abstract":"<p>Electrochemical synthesis hasemerged as a powerful platform forgenerating reactive intermediates under conditions that are difficultto achieve with conventional chemical reductants or oxidants. In particular,cathodic electron transfer to polarized C–X bonds can providedirect access to carbon-centered radicals, while a second electrontransfer enables radical-polar crossover to carbanions that can beintercepted by suitable electrophiles. This umpolung sequence offersan attractive alternative to classical organometallic chemistry, allowingnucleophilic carbon intermediates to be generated without pyrophoricmetals or strong bases. The apparent simplicity of this process, however,masks several selectivity challenges. Productive reactivity requiresthe substrate to be reduced and undergo mesolytic bond cleavage beforethe solvent, supporting electrolyte, electrophile, or product is consumedat the cathode. The resulting carbon-centered radical must thereafteraccept a second electron faster than it undergoes hydrogen atom transfer,dimerization, or unproductive addition reactions. The resulting carbanionmust subsequently be trapped within the same strongly reducing environment.Electrode materials, the anodic counter reaction, and concentrationof the different species influence the kinetics and thermodynamicsof electroreductive radical-polar crossover, requiring the matchingof every component of the electrochemical setup rather than considerationof the substrate reduction potential alone. This Account describesour recent advances in addressing these challenges for electroreductiveactivation of C–F, C–O, and C–S bonds. In thecontext of C–F cleavage, trifluoromethyl arenes were convertedinto hydroxymethylated difluoromethyl arenes through selective monodefluorinationfollowed by trapping with <em>N,N</em>-dimethylformamide.Mechanistic and electroanalytical studies revealed the privilegedrole of DMF and rationalized the high selectivity against over-reduction.In the context of C–O bond cleavage, deoxygenative strategiesfrom alcohols and alcohol derivatives were explored. Under operationallysimple galvanostatic conditions, benzylic and propargylic alcoholsunderwent hydrodeoxygenation and, in some cases, C–C bond formationwith CO<sub>2</sub> without prior derivatization. The reaction designwas extended to deoxygenative C–Si bond formation in whichhydrosilanes serve a dual function as activating agents and electrophilicreaction partners. Finally, aryl alkyl thioethers were developed astunable alkyl radical precursors with the S-aryl group acting as anelectroauxiliary that modulates the reduction potential and selectivityof bond cleavage. Depending on the reaction conditions and trappingpartner, the resulting radical or carbanion intermediates provideaccess to C–H, C–D, C–C, and C–B bonds.For several of the protocols, borohydride oxidation was employed asan anodic counter reaction with a similar performance as the use ofsacrificial metal anodes. Together, the high","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 19","pages":"3179–3195"},"PeriodicalIF":18.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148973727","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":"Programmable Tethered Small-Molecule Acceptors for Efficient, Stable, and Stretchable Polymer Solar Cells","authors":"Yang Bai, Hongru Chen, Zhengkai Li, Zhi-Guo Zhang","doi":"10.1021/acs.accounts.6c00487","DOIUrl":"10.1021/acs.accounts.6c00487","url":null,"abstract":"<p>Recently, intensive research on donor–acceptorstructuredlow-bandgap small-molecule acceptors (SMAs) has enabled power conversionefficiencies (PCEs) exceeding 21% in polymer solar cells (PSCs), arecord-breaking milestone for the field. This success stems from theirbroad light absorption and minimized energy losses. For practicalapplication, however, further progress requires simultaneous advancesin efficiency, operational stability, and mechanical robustness. InPSCs, SMAs are blended with polymer donors to form a bulk-heterojunction(BHJ) morphology featuring finely mixed domains that facilitate excitondissociation and efficient charge collection. However, the lower glasstransition temperature of SMAs (<em>T</em><sub>g</sub> <100 °C) compared to that of polymer donors raises concerns abouttheir thermodynamic relaxation and crystallization within the mixeddomains, which can drive progressive phase separation and morphologicaldegradation, posing critical challenges for long-term operationalstability. Moreover, the high rigidity and crystalline nature of state-of-the-artSMAs that benefit charge transport often embrittle the BHJ film, creatinga bottleneck for stretchable device applications. Therefore, a fundamentalchallenge lies in simultaneously maximizing the PCE while ensuringlong-term morphological stability and mechanical flexibility in PSCs.</p><p>To address these challenges, our research program recently transitionedfrom individual SMAs to discrete tethered SMAs. In this moleculararchitecture, two or more SMA subunits are covalently attached viaflexible spacers to an aromatic core. This modular design permitsindependent programming of each component, offering a powerful meansto modulate aggregation behavior in both solution and thin films relativeto free SMA subunits. Current designs have evolved from simple dimericstructures to more complex topologies including three-dimensionaltetramers, dendritic hexamers, and star-shaped dodecamers. Importantly,such designs retain the synthetic precision and batch-to-batch reproducibilityof small molecules while introducing polymer-like attributes, includingan elevated <em>T</em><sub>g</sub>, suppressed molecular diffusion,and enhanced intermolecular entanglement.</p><p>In this Account, weprovide an overview of our efforts to designprogrammable tethered SMAs. We illustrate how modular control of the aromatic-core structure,spacer length, and subunit electronic structure enables precise manipulationof the molecular geometry, self-assembly, and intramolecular entanglementfor achieving high PCEs while ensuring the morphological stabilityand mechanical flexibility of PSCs. These factors lead to acceptorsdelivering high device efficiencies (e.g., 20.2% PCE in a binary device),long operational lifetimes (e.g., <em>T</em><sub>80</sub> ≈35,000 h), and superior mechanical flexibility (e.g., 150% enhancementin crack onset strain). Finally, we outline current challenges andfuture directions for the tethered appr","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 19","pages":"3152–3165"},"PeriodicalIF":18.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148821779","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":"Decoding the Biological Function of Bile Acids for Drug Discovery","authors":"Jun Yang, Xiaoguang Lei","doi":"10.1021/acs.accounts.6c00477","DOIUrl":"10.1021/acs.accounts.6c00477","url":null,"abstract":"<p>Bile acids are a class of cholesterol-derivedmetabolites thathave long been recognized for their essential roles in dietary lipidabsorption and cholesterol homeostasis. Over the past two decades,however, bile acids have emerged as crucial signaling molecules thatregulate diverse physiological and pathological processes, includingmetabolism, inflammation, immunity, host–microbiota interactions,and liver diseases. Dysregulation of bile acid homeostasis has beenimplicated in a broad spectrum of human disorders, making bile acidsignaling pathways attractive targets for therapeutic intervention.Despite substantial progress in identifying bile acid receptors andtransporters, a fundamental challenge remains: how can we systematicallydecode the biological functions of structurally diverse bile acidsand translate the knowledge into therapeutic opportunities?</p><p>In this Account, we summarize our 10-year mechanism-driven researcheffort to address this challenge through an integrated translationalchemical biology strategy that combines chemoproteomics, metabolomics,structural biology, and medicinal chemistry. We first developed chemoproteomicplatforms to globally profile bile-acid-interacting proteins in mammaliancells and bacteria, revealing an extensive bile-acid interactome thatextends beyond canonical receptors and transporters. These studiesuncovered hundreds of candidate interactors and identified previouslyunrecognized bile-acid-sensing mechanisms in host cells and gut microbes,providing a systems-level framework for understanding bile acid biology.</p><p>Building upon these discoveries, we focused on elucidating themolecular basis of cholestatic itch, a debilitating symptom frequentlyassociated with liver diseases. We identified the G-protein-coupledreceptor MRGPRX4 (hX4) as a human bile acid receptor mediating cholestaticpruritus and demonstrated that sulfated bile acids are key endogenouspruritogens that accumulate in patients with cholestasis. Throughcryo-electron microscopy (cryo-EM), we determined the structure ofhX4 in complex with a bile acid agonist and elucidated the molecularmechanism underlying receptor activation. These mechanistic insightsrevealed the critical role of the bile acid 3-hydroxyl group in receptorrecognition and signaling.</p><p>Importantly, a mechanistic understandingof bile acid signalingenabled the rational design of therapeutics. Guided by structuralinformation, we developed a modified bile acid derivative that retainstherapeutic efficacy for liver diseases while minimizing itch-relatedside effects. Furthermore, through high-throughput screening, medicinalchemistry optimization, structural analysis, and preclinical evaluation,we discovered HEP-50768, a potent inverse agonist of hX4 that hasadvanced toward clinical development for cholestatic itch. In parallel,we determined the cryo-EM structure of the bile acid transporter OSTα/βand uncovered its transport mechanism, providing new insights intothe regulation of bil","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 19","pages":"3134–3151"},"PeriodicalIF":18.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148973726","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":"Strain-Release Driven, Lewis Acid-Catalyzed, and Hexafluoroisopropanol-Mediated Reactions of Bicyclo[1.1.0]butanes","authors":"Shiksha Deswal, Rohan Chandra Das, Akkattu T. Biju","doi":"10.1021/acs.accounts.6c00497","DOIUrl":"10.1021/acs.accounts.6c00497","url":null,"abstract":"<p>Strain-releasedriven transformations of bicyclo[1.1.0]butanes(BCBs) have emerged as a powerful strategy for rapidly constructingfunctionalized cyclobutanes and complex bicyclic architectures throughradical, nucleophilic, and electrophilic pathways. Owing to theirunique reactivity and medicinal relevance, this Account highlightsrecent advances in exploiting BCBs for the synthesis of diverse bioisostericbicyclic scaffolds and cyclobutanes.</p><p>In 2023, we reported aLewis acid-catalyzed, diastereoselectivering-opening of BCBs with β-naphthols, providing trisubstitutedcyclobutane derivatives. Subsequently, thioindolinones were employedas nucleophilic partnersin a diastereoselective formal ene reaction of mono-substituted BCBs,affording disubstituted cyclobutanes. Interestingly, replacing mono-substitutedBCBs with disubstituted analogues resulted in a distinct reactionpathway, leading to the formation of trisubstituted cyclobutanethiols.Successively, we developed the Lewis acid-catalyzed annulation strategiesinvolving BCBs for the construction of diverse bicyclic frameworks.The (3+2) annulation of BCBs with ynamides provided efficient accessto bicyclo[2.1.1]hexene derivatives. Building on this, a (3+3) annulationwith isatogens enabled the synthesis of bicyclo[3.1.1]heptane scaffolds.Furthermore, the use of <em>para</em>-quinone methides ascoupling partners in a (4+3) annulation furnished bicyclo[4.1.1]octanederivatives, further showcasing the versatility of BCBs in strain-releaseannulation chemistry.</p><p>We recently realized that BCBs can beactivated in the presenceof hexafluoroisopropanol (HFIP) via hydrogen bonding. In this context,the HFIP-mediated diastereoselective ring-opening of BCBs using peroxidesfurnished cyclobutane scaffolds. Additionally, a spiro-annulationof BCBs with α-halo hydroxamates, where HFIP enables simultaneousactivation of BCBs and stabilization of the azaoxyallyl cation generatedin situ from α-halo hydroxamates, affording functionalized spirocyclobuteneshas been disclosed. Subsequently, the HFIP-mediated divergent reactivityof indolyl alcohols with BCBs where <em>N</em>-protected indolylalcohols undergo (3+3) annulation and <em>N</em>-unprotectedanalogues favor (3+2) spiro-annulation has been uncovered. Mechanisticstudies were conducted to elucidate the origin of this divergence.Further, we realized the strain-release driven hydroxy transfer toBCBs using diphenyl phosphine oxide for the diastereodivergent synthesisof cyclobutanol derivatives. Mechanistic studies have been carriedout to understand the reaction mechanism and the origin of the diastereodivergentoutcome.</p><p>The strain-release driven transformations using BCBsare poisedto continue flourishing, opening new avenues for reaction discoveryand molecular construction. Future efforts are likely to focus ondeveloping strategies to access tailor-made BCBs that can providea direct route to three-dimensional drug-like molecules and extendenantioselective transformat","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 19","pages":"3196–3210"},"PeriodicalIF":18.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003569","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":"Selectivity in CO2 Reduction: Beyond Two Electrons","authors":"Suman Patra,&nbsp;Soumili Ghosh,&nbsp;Abhijit Nayek,&nbsp;Abhishek Dey","doi":"10.1021/acs.accounts.6c00546","DOIUrl":"10.1021/acs.accounts.6c00546","url":null,"abstract":"<p>The development of catalystsfor the reduction of CO₂ to value-added chemicals is amajor contemporary global effort.A consistent problem in the reduction of CO₂ is selectivity.While two-electron reduction products such as CO and HCOOH have beenextensively investigated, achieving selective multielectron, multiprotonreduction to more reduced C₁ products, including HCHO,CH₃OH, and CH₄, as well as C₂+ products,remains significantly more difficult due to the involvement of multipleproton- and electron-transfer steps and competing reaction pathways.Molecular catalysts provide fertile ground for investigating the reactionmechanism of CO₂ reduction and determine the chemical stepsresponsible for the selectivity of CO₂ reduction. Ironporphyrins are attractive choices as catalysts to navigate the CO₂ reduction landscape because they not only are efficient catalystsfor the reduction of CO₂ to CO but also provide a versatilecanvas for catalyst design due to their synthetic amenability andbecause they are very suitable for spectroscopic investigations. Ina previous Account, the factors that determine the selectivity betweenCO and HCOOH, both 2e^–/2H⁺ reductionproducts of CO₂, had been discussed [<em>Acc. Chem. Res.</em> <strong>2022</strong>, <em>55</em> (2), 134–144].In this Account, we focus on the latest development of the mechanisticprinciples that enable selective CO₂ reduction beyond twoelectrons. The key to achieving further reduction of CO₂ is stabilization of the reduced carbonyl species by hydrogen bonding.The further reduction of CO₂ proceeds through intermediates,better described as branching points, where the site of protonationdetermines if partially reduced CO₂ species like the 4e^–/4H⁺ reduced HCHO or the 6e^–/6H⁺ reduced CH₃OH is released or if the CO₂ is reduced completely by 8e^–/8H⁺ to produce CH₄. The site of protonation appears to begoverned by the spin state of these intermediates. This reaction landscapecan be navigated by ligand design, which includes second-sphere hydrogenbonding/proton transfer residues and rates of electron transfer tothe catalytic site. The knowledge of the intermediates allows theiralternative uses including the formation of C–C bonds in amonometallic active site using a concept of “parking space”.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 19","pages":"3245–3255"},"PeriodicalIF":18.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003567","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":"Discovery, Design, and Evaluation of Nanomolar to Picomolar Inhibitors of Human Pancreatic α-Amylase for Control of Postprandial Blood Glucose Levels","authors":"Yuqing Tian,&nbsp;Rajneesh Bains,&nbsp;Stephen G Withers","doi":"10.1021/acs.accounts.6c00510","DOIUrl":"10.1021/acs.accounts.6c00510","url":null,"abstract":"&lt;p&gt;Type 2 diabetes is a diseasethat is rapidlyexpanding across theworld with global cases quadrupling since 1990 and now comprisingover 800 million people, the majority of whom are in low- and middle-incomecountries (Zhou et al.&lt;span&gt;&lt;span&gt;&lt;/span&gt;&lt;span&gt;Lancet&lt;/span&gt;&lt;span&gt;2024&lt;/span&gt;, &lt;span&gt;404&lt;/span&gt;, &lt;span&gt;2077&lt;/span&gt;–&lt;span&gt;2093&lt;/span&gt;.&lt;/span&gt;). The poor control of blood glucose levelsthat lies at the heart of this disease leads to debilitating complicationssuch as renal failure, vision loss, and amputations and has associationswith heart disease and a host of other conditions. Oral drugs thatcontrol blood glucose levels and can slow disease progression andreduce the risks are available. Among these are the α-glucosidaseinhibitors acarbose and miglitol that function in the gut to slowthe breakdown of starch and of oligosaccharides such as sucrose. However,gastrointestinal side effects such as discomfort and diarrhea frequentlycause patients to discontinue treatment, highlighting the need forimproved, cost-effective alternatives. Our approach has been to developselective inhibitors of human pancreatic α-amylase (HPA) thatshut down digestion of starch while sparing oligosaccharide breakdown,thereby lowering blood glucose without causing gastrointestinal discomfort.&lt;/p&gt;&lt;p&gt;In this Account, we present the approaches we have taken to identifypotent and selective inhibitors of HPA based upon our earlier determinationsof the three-dimensional structure and catalytic mechanism of thiskey digestive enzyme. Our screens of natural product extract librariesproduced two particularly interesting hits. One is the natural productMontbretin A (MbA) isolated from the corms of the common &lt;em&gt;Crocosmia&lt;/em&gt; garden flower. Through a series of fragmentation studies, in conjunctionwith X-ray crystallographic analysis of complexes of MbA with HPA,we identified the core inhibitory component of this (&lt;em&gt;K&lt;/em&gt;&lt;sub&gt;i&lt;/sub&gt; = 8 nM) glycosylated acyl flavonoid comprising a pairof π-stacked phenolic moieties that engage the essential activesite carboxylic acids in HPA. Animal studies have shown the efficacyand safety of MbA, and human clinical trials are underway. Based uponthis information, simpler inhibitors that retain nanomolar potencyhave been designed and synthesized.&lt;/p&gt;&lt;p&gt;Through a separate screenof marine natural product extracts, weidentified helianthamide, from the Caribbean sea anemone &lt;em&gt;Stichodactyla helianthus&lt;/em&gt;, as a particularly potent (&lt;em&gt;K&lt;/em&gt;&lt;sub&gt;i&lt;/sub&gt; = 10 pM) and stable 44 amino acid peptidic inhibitor of HPA.The structure of its complex with the highly similar porcine pancreaticα-amylase (PPA) shows it blocking the active site, using twotyrosines and a histidine to engage the catalytic residues, reminiscentof the “phenol sandwich” found with MbA while derivingconsiderable additional affinity from the burial of surface area.&lt;/p&gt;&lt;p&gt;Finally, we used mRNA display methods to screen large cyclic peptidelibraries using the RaPID (Random nonstandard Pe","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 19","pages":"3235–3244"},"PeriodicalIF":18.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003570","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":"Illuminating the Disease Landscape: Human Oxidoreductase-Targeted Imaging and Quantification Agents for Precision Imaging and Activity Determination","authors":"Nasim Akhtar,&nbsp;Stephy Jomy,&nbsp;Shibalik Mukherjee,&nbsp;Robin L. McCarley","doi":"10.1021/acs.accounts.6c00462","DOIUrl":"10.1021/acs.accounts.6c00462","url":null,"abstract":"&lt;p&gt;Electron-specific reductionreactions afforded by quinone oxidoreductaseshave long been recognized as essential for safeguarding &lt;em&gt;healthy&lt;/em&gt; mammalian cells against oxidative stress induced by environmentalinsults. The presence of reactive oxygen species (ROS) initiates theupregulation of intracellular redox enzyme activities used to battlethe effects of ROS in healthy cells. At the same time, &lt;em&gt;diseased&lt;/em&gt; human cells hijack the pathways of certain oxidoreductases, suchas the two-electron-specific human NAD(P)H:quinone oxidoreductaseisozyme 1 (hNQO1), and use the overexpressed enzymes as standaloneweapons or in concert with other proteins as an arsenal to advancedisease progression and defeat therapies. Fortunately, in numerouscancers, inherent overexpression of hNQO1 activity is successfullytargeted to trigger quinone-bearing, pro-therapeutic agents whosehNQO1 reduction yields cytotoxic agents only within hNQO1 activity-overexpressingcells. Furthermore, the development of diverse new approaches forcontrolling and leveraging expression of intracellular hNQO1 activityfor disease treatment is being propelled by the growing evidence aboutthe significant role of hNQO1 in cardiovascular diseases, centralnervous system disorders, and autoimmune conditions.&lt;/p&gt;&lt;p&gt;While oxidoreductaseslike hNQO1 are pivotal in many diseases andtheir development, there is a limited toolset for nonintrusive, selective,and low-limit-of-detection determination and quantification of enzymeactivity in human tissue or mammalian models of disease. Our researchteam used tailored design criteria and computational routes to developfluorescence-based molecular probes for highly selective, rapid measurementand visualization of hNQO1 activity through the latter’s catalyzedproduction of reporters that are spectrally distinct from their parentprobes. In this Account, we report on low- and tunable-brightnessprobes designed to be straightforwardly made and offer rapid intracellularaccessibility to and fast activation by target enzymes with high selectivityto generate high-brightness reporters having large Stokes shifts.The probe/reporter pairs exhibit high photophysical, chemical, andenvironmental stabilities, low cellular toxicities, and emission energiesthat enable mucosal/epithelial and subsurface tissue imaging. Theseoff–on and on–on probe–reporter pairs afforddetermination of intracellular enzyme presence and activity in simplecell cultures, complex tumor mimics, and an animal model of humancancer. These approaches offer unparalleled image contrast (target-to-backgroundratio, TBR), dynamic range, and limit of detection. The pivotal resultspresented in this Account stem from the focused development of fluorogenicmolecular probes designed to assess hNQO1 activity across diversecellular structures. The generalizable strategies for probe developmentdescribed herein have broad implications for chemical biology anddiagnostic/theranostic imaging with significant translational po","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 19","pages":"3118–3133"},"PeriodicalIF":18.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049452","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":"Solid-State Lithium Batteries with In Situ Polymerized Electrolytes: Interphase Chemistry, Solvation Structure, and Practical Cell Design","authors":"Hongtao Zhang,&nbsp;Peiran Bian,&nbsp;Xingchen Song,&nbsp;Yanhong Lu,&nbsp;Yongsheng Chen","doi":"10.1021/acs.accounts.6c00431","DOIUrl":"10.1021/acs.accounts.6c00431","url":null,"abstract":"&lt;p&gt;Solid-state lithium metal batterieshold immense promise for next-generationenergy storage devices because they can potentially combine the highenergy density of lithium metal anodes (LMAs) and high-voltage cathodeswith the improved safety of nonleaking solid electrolytes. In practice,these merits are difficult to achieve simultaneously. High energydensity requires high-voltage cathode operation, high cathode loading,thin lithium, lean electrolyte, and improved practical cell formats,whereas high safety requires suppressed dendrite growth, stable electrode/electrolyteinterphases, reduced volatility and flammability, and resistance tocell-level abuse. In situ polymerization has emerged as a powerfulstrategy to address these coupled demands by converting liquid precursorsinto polymer networks directly inside the cell. Early systems, largelybased on homopolymerized or weakly cross-linked polymers, preservedelectrode wetting but offered limited control over interphase formation,Li&lt;sup&gt;+&lt;/sup&gt; desolvation, solvation-shell composition, and high-voltagestability, thereby restricting their applications in high-energy-densityand high-safety batteries.&lt;/p&gt;&lt;p&gt;In this Account, we summarize ourrecent endeavors in evolvingin situ polymerization from a simple liquid-to-solid processing stepinto a highly tunable platform for interphase chemistry, solvation-structureregulation, and practical cell design. We first show how in situ gelationand interfacial additives improve electrode wetting and stabilizethe solid electrolyte interphase (SEI) on lithium metal. We then describehow three-dimensional cross-linked networks regulate solvent uptake,Li&lt;sup&gt;+&lt;/sup&gt; desolvation, and Li deposition, thereby transformingpolymer topology from a mechanical descriptor into a transport andinterphase parameter. These advances provide the interfacial foundationrequired for long-cycling lithium metal batteries.&lt;/p&gt;&lt;p&gt;We next discusshow high-voltage stability can be encoded throughprogressively deeper chemical design. Fluorinated monomers, fluorine/phosphorus-containingmultifunctional cross-linkers, and main-chain fluorinated polymerbackbones successively improve oxidative stability while preservinglithium compatibility. These designs promote anion-involved solvationand inorganic-rich SEI/CEI formation, enabling lithium metal batterieswith practical operation at 4.5–4.9 V, long cycling with Ni-richand high-voltage cathodes, ultrahigh-loading electrodes up to 70 mgcm&lt;sup&gt;–2&lt;/sup&gt;, and pouch-cell energy densities up to 405.3Wh kg&lt;sup&gt;–1&lt;/sup&gt;. We further show that polymer matrices canactively regulate local solvation structure. Localized high-concentrationgel polymer electrolytes (GPEs) and silsesquioxane-based GPEs demonstratethat polymer skeletons can host and reshape anion-rich Li&lt;sup&gt;+&lt;/sup&gt; solvation sheaths, accelerate Li&lt;sup&gt;+&lt;/sup&gt; desolvation, and stabilizeboth cathode and anode interphases. This strategy enables 4.7 V solid-state18650 lithium metal batteries, 4.6 V industrial","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 18","pages":"2914–2925"},"PeriodicalIF":18.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885343","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 Synthesis and Transformation of Heteroaromatic Compounds via Mediated Electrolysis","authors":"Eisuke Sato,&nbsp;Koichi Mitsudo,&nbsp;Seiji Suga","doi":"10.1021/acs.accounts.6c00488","DOIUrl":"10.1021/acs.accounts.6c00488","url":null,"abstract":"&lt;p&gt;Heteroaromatic compounds areubiquitous structural motifs in pharmaceuticals,natural products, and functional materials. Accordingly, the developmentof efficient methods for their construction, functionalization, andskeletal transformation has attracted considerable attention. Amongthe available approaches, electrochemical synthesis has emerged asa sustainable platform that enables the generation of highly reactiveintermediates through an electrode-driven electron transfer. Despitethese advantages, direct electrolysis often provides limited controlover reactivity, because electron transfer occurs directly betweenthe substrate and the electrode surface. To address this limitation,indirect electrolysis employing redox mediators has emerged as a versatilestrategy for generating reactive intermediates and expanding the scopeof the electrochemical synthesis. Building on these principles, wehave developed a range of electrochemical transformations of heteroaromaticcompounds that exploit the distinctive reactivity of mediator-derivedintermediates. Using both halogen-based and non-halogen mediators,these methods enable the efficient synthesis and skeletal transformationof diverse heteroaromatic frameworks under mild conditions.&lt;/p&gt;&lt;p&gt;In this Account, we describe our studies on mediator-controlledelectrochemical transformations of heteroaromatic compounds, focusingon halogen-mediated oxidative cyclizations and skeletal transformationsas well as DABCO-mediated radical processes. Particular emphasis isplaced on the design of reactive intermediates and the mechanisticprinciples that govern their reactivities.&lt;/p&gt;&lt;p&gt;The first sectionfocuses on bromide-mediated electrochemical C–Sbond formation for the synthesis of thienoacenes. Electrogeneratedelectrophilic bromenium ion species, represented as [Br&lt;sup&gt;+&lt;/sup&gt;] equivalents, activate sulfur atoms to form a bromosulfonium intermediate,thereby enabling oxidative cyclization. We then discuss halogen-mediatedelectrochemical transformations of indole derivatives. Electrophilic[Br&lt;sup&gt;+&lt;/sup&gt;] species selectively activate the C3 position of theindole framework. Furthermore, structurally complex natural productframeworks were accessed through mediator-controlled cyclization reactions,in which the choice of mediator dramatically influenced the reactionpathway and product architecture. In the final section, we describethe DABCO-mediated electrochemical synthesis of benzophosphole oxides.Electrochemically generated DABCO radical cations (DABCO&lt;sup&gt;•+&lt;/sup&gt;) promote hydrogen-atom transfer (HAT) from P–H bonds to generatephosphorus-centered radicals. These reactive intermediates subsequentlyundergo annulation reactions, providing efficient access to phosphorus-containingheteroaromatic compounds.&lt;/p&gt;&lt;p&gt;These studies illustrate how redoxmediators can control activationmodes under electrochemical conditions and, thereby, unlock distinctreaction pathways. A detailed understanding of the structures andreactivities of electro","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 18","pages":"2948–2961"},"PeriodicalIF":18.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148821780","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":"Norcorrole: A Stable Porphyrinoid for Exploration of Antiaromaticity","authors":"Norihito Fukui,&nbsp;Hiroshi Shinokubo","doi":"10.1021/acs.accounts.6c00503","DOIUrl":"10.1021/acs.accounts.6c00503","url":null,"abstract":"<p>Antiaromatic molecules are generallyreactive and unstable dueto their high highest occupied molecular orbital (HOMO) and low lowestunoccupied molecular orbital (LUMO) energy levels, which hinder theirhandling under ambient conditions and their use in functional materials.Nevertheless, antiaromatic molecules possess unique electronic features,including narrow HOMO–LUMO gaps, stable redox behavior, anddistinctive magnetic properties, making them attractive building blocksfor advanced functional materials. In this regard, the developmentof stable antiaromatic π-conjugated molecules is therefore animportant challenge in contemporary molecular science. Norcorroleis a porphyrin analogue that lacks two bridging carbon atoms betweenthe pyrrole subunits. Recent advances in norcorrole synthesis haveestablished norcorroles as a unique platform for exploring antiaromaticity.Despite their pronounced antiaromatic character, norcorroles exhibitsufficient stability under ambient conditions and display a rangeof unusual properties that are different from conventional porphyrins.</p><p>This Account details the development of the chemistry of norcorroles,focusing mainly on our research journey, covering the synthesis, structuralcharacteristics, electronic properties, reactivity, and emerging functionsof norcorrole derivatives. These include stacked-ring aromaticityarising from closely π-stacked architectures, reversible redoxbehavior for rechargeable batteries, intense near-infrared absorptionfor efficient photothermal conversion, high single-molecule conductivity,and the ability to form well-defined supramolecular assemblies. Throughthese investigations, norcorrole derivatives have evolved from fundamentaltargets in the chemistry of antiaromatic compounds into versatilefunctional materials for future applications.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 18","pages":"2962–2976"},"PeriodicalIF":18.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148858332","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}