Accounts of Chemical Research最新文献

{"title":"<i>N</i>-Boryl Pyridyl Anion Chemistry.","authors":"Li Zhang, Fei-Yu Zhou, Lei Jiao","doi":"10.1021/acs.accounts.5c00024","DOIUrl":"10.1021/acs.accounts.5c00024","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusPyridine is a crucial heterocyclic compound in organic chemistry. Typically, the pyridine motif behaves as an N-nucleophile and an electron-deficient aromatic ring. Transforming the pyridine ring into an electron-rich system that exhibits reactivity contrary to classical expectations could unveil new opportunities in pyridine chemistry. This Account describes an approach to the umpolung reactivity of the pyridine ring through the formation of an unprecedented &lt;i&gt;N&lt;/i&gt;-boryl pyridyl anion (&lt;i&gt;N&lt;/i&gt;-BPA) intermediate that enables new catalysis and transformations.In 2017, we discovered that 4-phenylpyridine acts as an efficient catalyst for the borylation of iodo- and bromoarenes using diboron(4) compounds. Mechanistic studies revealed that the &lt;i&gt;in situ&lt;/i&gt; formation of an &lt;i&gt;N&lt;/i&gt;-BPA intermediate in the pyridine/diboron(4)/methoxide reaction system is a pivotal step in this transformation. Further investigations showed that &lt;i&gt;N&lt;/i&gt;-BPA exhibits dual reactivities as both a strong electron donor and a potent nucleophile. This unique reactivity profile has unveiled novel pathways for redox catalysis, pyridine derivatizations, and umpolung transformations.Based on the electron-donor characteristic of the &lt;i&gt;N&lt;/i&gt;-boryl pyridyl anion, we have developed a redox catalytic system mediated by a pyridine catalyst. In the pyridine/diboron(4)/base reaction system, the &lt;i&gt;in situ&lt;/i&gt; formation of &lt;i&gt;N&lt;/i&gt;-BPA followed by single electron transfer (SET) to a substrate with regeneration of the pyridine molecule establishes a redox catalytic cycle. This approach enables the single-electron reduction of a variety of substrates employing 4-phenylpyridine as a catalyst and diboron(4) as the electron source. Upon visible-light excitation, this intermediate transitions into its excited state, exhibiting significantly enhanced reductivity. This enables the establishment of a modular photoredox system consisting of various pyridine/diboron(4)/base combinations that allow for fine-tuning of its redox property. Using this strategy, we performed a series of challenging single-electron reduction reactions, including the single -electron reduction of nonactivated chloro- and fluoroarenes, and Birch reduction of arenes.The nucleophilic character of the &lt;i&gt;N&lt;/i&gt;-boryl pyridyl anion was effectively harnessed to facilitate pyridine derivatization and umpolung transformations. By directly quenching the &lt;i&gt;in situ&lt;/i&gt;-generated &lt;i&gt;N&lt;/i&gt;-BPA with a proton source, we developed a practical approach to &lt;i&gt;N&lt;/i&gt;-H-1,4-dihydropyridines (DHPs). Bimolecular nucleophilic substitution reaction between &lt;i&gt;N&lt;/i&gt;-BPA and an alkyl bromide produced a 4-alkyl-1,4-DHP, which subsequently releases an alkyl radical under photoredox conditions. This process enabled a catalytic transformation of alkyl bromides into alkyl radicals. Employing 4-trifluoromethylpyridine in this chemistry, the resulting &lt;i&gt;N&lt;/i&gt;-BPA intermediate undergoes elimination of fluoride to yield a 4-pyridyldiflu","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"1023-1035"},"PeriodicalIF":16.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522069","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":"E. B. Hershberg Award: Taming Inflammation by Tuning Purinergic Signaling.","authors":"Kenneth A Jacobson","doi":"10.1021/acs.accounts.5c00011","DOIUrl":"10.1021/acs.accounts.5c00011","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The author presents his personal story from early contributions in purinergic receptor research to present-day structure-guided medicinal chemistry. Modulating purinergic signaling (encompassing pyrimidine nucleotides as well) and other nucleoside targets with small molecules is fruitful for identifying new directions for therapeutic intervention. Purinergic signaling encompasses four adenosine receptors, eight P2Y receptors that respond to various extracellular nucleotides, and trimeric P2X receptors that respond mainly to ATP. Each organ and tissue in the body expresses some combination of this family of cell-surface receptors, along with the enzymes and transporters that form, degrade, and process the native nucleoside and nucleotide agonists. The purinergic signaling system responds to physiological stress to an organ, for example by increasing the energy supply or decreasing the energy demand. The receptors are widespread on immune cells, such that P2Y and P2X receptor activation boosts the immune response when and where it is needed, for example to repel infection. In contrast, the adenosine receptors, which are activated later in the process─as stress-elevated ATP is hydrolyzed locally to adenosine by ectonucleotidases─tend to put the brakes on inflammation and can be used to correct an imbalance in pro- versus anti-inflammatory signals, such as in chronic pain. Hypoxia activates the immunosuppressive extracellular adenosine-A&lt;sub&gt;2A&lt;/sub&gt; adenosine receptor axis, as originally formulated by Sitkovsky, which suppresses the immune response in the tumor microenvironment to make a cancer more aggressive. Conversely, the anti-inflammatory effects of adenosine receptor agonists have numerous therapeutic applications. Modulators of P2Y receptors, which respond to extracellular nucleotides, also show promise for treating chronic pain, metabolic disorders, and inflammation. Thus, control of this signaling system can be harnessed for treating a wide range of conditions, from cancer and neurodegeneration to autoimmune inflammatory diseases to ischemia of the brain or heart. The author's receiving the American Chemical Society's top award for medicinal chemistry in 2023 provides an opportunity to summarize these developments from their origins in empirical probing of receptor-ligand structure-activity relationship (SAR) to the current structure-based approaches, including conformational control of selectivity toward purinergic signaling. The work on each target receptor began either before or soon after it was cloned, and the initial focus was an academic exercise to use organic chemistry to develop a SAR for each target. The Jacobson lab has introduced chemical probes for 17 of the purinergic receptors as well as for associated regulators. Furthermore, surprisingly, some of the conformationally constrained nucleoside analogues can be designed to inhibit non-purinergic targets selectively, such as opioid and serotonin receptors and monoamine tr","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"958-970"},"PeriodicalIF":16.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transition Metal-Catalyzed Nitrogen Atom Insertion into Carbocycles.","authors":"Hong Lu, Jie Chang, Hao Wei","doi":"10.1021/acs.accounts.4c00854","DOIUrl":"10.1021/acs.accounts.4c00854","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Conspectus&lt;i&gt;N&lt;/i&gt;-Heterocycles are essential in pharmaceutical engineering, materials science, and synthetic chemistry. Recently, skeletal editing, which involves making specific point changes to the core of a molecule through single-atom insertion, deletion, or transmutation, has gained attention for its potential to modify complex substrates. In this context, the insertion of nitrogen atoms into carbocycles to form &lt;i&gt;N&lt;/i&gt;-heterocycles has emerged as a significant research focus in modern synthetic chemistry owing to its novel synthetic logic. This distinctive retrosynthetic approach enables late-stage modification of molecular skeletons and provides a different pathway for synthesizing multiply substituted &lt;i&gt;N&lt;/i&gt;-heterocycles. Nevertheless, nitrogen atom insertion into carbocycles has proven challenging because of the inherent inertness of carbon-based skeletons and difficulty in cleaving C-C bonds. Therefore, selective insertion of nitrogen atoms for skeletal editing remains a challenging and growing field in synthetic chemistry. This Account primarily highlights the contributions of our laboratory to this active field and acknowledges the key contributions from other researchers. It is organized into two sections based on the type of the carbocycle. The first section explores the insertion of nitrogen atoms into cycloalkenes. Recent Co-catalyzed oxidative azidation strategies have enabled nitrogen atom insertion into cyclobutenes, cyclopentenes, and cyclohexenes, facilitating the synthesis of polysubstituted pyridines, which has been conventionally challenging through pyridine cross-coupling. The subsequent section highlights our discovery in the realm of nitrogen atom insertion into arenes. The site-selective skeletal editing of stable arenes is challenging in synthetic chemistry. We developed a method for the intramolecular insertion of nitrogen atoms into the benzene rings of 2-amino biaryls by suppressing the competing C-H insertion process by using a paddlewheel dirhodium catalyst. In addition, to address the challenging site-selective issues in nitrogen atom insertion, we employed arenols as substrates, which could act as selective controlling elements in site-selective skeletal editing. We reported a Cu-catalyzed nitrogen atom insertion into arenols, which proceeds through a dearomative azidation/aryl migration process, enabling the site-selective incorporation of nitrogen atoms into arenes. Inspired by this result, we recently extended the reaction model by using a Fe-catalyst to facilitate the ring contraction of the nitrogen-inserted product, achieving the carbon-to-nitrogen transmutation of arenols. Various complex polyaromatic arenols could effectively undergo the desired atom's transmutation, presenting considerable potential for various applications in materials chemistry. In this Account, we present an overview of our achievements in nitrogen atom insertion reactions, with a focus on the reaction scopes, mechanistic ","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"933-946"},"PeriodicalIF":16.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497457","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":"Cobalt(III)-Catalyzed Enantioselective C-H Functionalization: Ligand Innovation and Reaction Development.","authors":"Qi-Jun Yao, Bing-Feng Shi","doi":"10.1021/acs.accounts.5c00013","DOIUrl":"10.1021/acs.accounts.5c00013","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusIn contrast to precious transition metals, such as palladium and rhodium, the development of novel chiral ligands for enantioselective C-H functionalizations catalyzed by earth-abundant, cost-effective, and environmentally friendly 3d metals poses substantial challenges, primarily due to the variable oxidation states, intricate coordination patterns, and limited mechanistic insights. In this Account, we summarize our research endeavors in the development of three novel types of Co(III) catalysis: pseudotetrahedral achiral Cp*Co(III)/chiral carbonyl acid (CCA) catalysis, &lt;i&gt;in situ&lt;/i&gt;-generated chiral octahedral cobalt(III) via cobalt/salicyloxazoline (Salox) catalysis, and Co(II)/chiral phosphoric acid (CPA) cooperative catalysis, achieved through strategic chiral ligand design. Our initial objective was to achieve enantioselective C-H functionalization catalyzed by achiral Cp*Co(III) catalysts with external chiral ligands, aiming to circumvent the laborious preparation of chiral Cp&lt;sup&gt;&lt;i&gt;x&lt;/i&gt;&lt;/sup&gt;Co(III) complexes. To this end, we developed several CCA ligands, incorporating non-covalent interactions (NCIs) as a crucial design element. Next, to address the limitations associated with the lengthy synthesis of Cp-ligated Co(III) complexes and the difficulties of modification, we explored the concept of the &lt;i&gt;in situ&lt;/i&gt; generation of Co(III) catalysis using commercially available cobalt(II) salts with tailor-made chiral ligands. This exploration led to the development of two innovative catalytic systems, namely, Co(II)/Salox catalysis and Co(II)/CCA sequential catalysis. The Co(II)/Salox catalysis emerged as a versatile strategy, demonstrating excellent enantioselectivities across a range of asymmetric C-H functionalization reactions to construct various chiral molecules with central, axial, planar, and inherent chirality. The facile synthesis in a single step, along with ease of modification, further enhances the versatility and applicability of this approach. Moreover, we successfully applied cobalt/Salox catalysis in electro- and photochemical-catalyzed enantioselective C-H functionalization, using electrons or oxygen as traceless oxidant, thereby eliminating the need for stoichiometric chemical oxidants. Through mechanistic studies and reaction developments, we elucidated the detailed ligand structure-enantioselectivity relationships in cobalt/Salox catalysis, which are expected to inform future research endeavors. Finally, the Co(II)/CPA cooperative catalysis enabled the synthesis of chiral spiro-γ-lactams through sequential C-H olefination/asymmetric [4 + 1] spirocyclization. Mechanistically, the establishment of stereochemistry occurs during the cyclization step, where the CPA ligand serves as both a neutral ligand and a chiral Brønsted acid, with stereoinduction independent of the C-H cleavage step. We anticipate that the insights and advancements detailed in this Account will inspire further innovations in ligand deve","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"971-990"},"PeriodicalIF":16.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497453","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":"Postsynthetic Modification of Metal-Organic Layers.","authors":"Zhiye Wang, Lingyun Cao, Huihui Hu, Cheng Wang","doi":"10.1021/acs.accounts.4c00726","DOIUrl":"10.1021/acs.accounts.4c00726","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusMetal-organic layers (MOLs), as a subclass of two-dimensional (2D) metal-organic frameworks (MOFs), have gained prominence in materials science by combining the structural versatility of MOFs with the unique physical and chemical properties of 2D materials. MOLs consist of metal oxide clusters connected by organic ligands, forming periodically extended 2D architectures with tunable properties and large surface areas. These characteristics endow MOLs with significant potential for applications in catalysis, sensing, energy storage, and biomedicine.The synthesis of MOLs predominantly follows two key pathways: top-down exfoliation of bulk layered MOFs and bottom-up assembly from molecular building units. The exfoliation method allows for the isolation of ultrathin MOL sheets from bulk precursors, but scalability and structural defects present ongoing challenges. In contrast, the bottom-up assembly offers more precise control over structural design, enabling the formation of MOLs with tailored chemical functionalities and morphologies. By carefully selecting linkers and synthetic conditions, researchers have successfully constructed MOLs with diverse geometric configurations including linear, triangular, and rectangular ligand motifs. Nevertheless, achieving consistent monolayer formation and controlling lateral dimensions remain critical challenges for the widespread application of these materials.A defining advantage of MOLs is their exceptional amenability to postsynthetic modification (PSM). PSM strategies enable fine-tuning of MOL properties and the introduction of novel functionalities without compromising the integrity of the underlying framework. Four principal approaches to PSM have been established: (1) linker modification, where additional coordination sites facilitate selective metalation or functional group incorporation; (2) secondary building unit (SBU) modification, using replaceable sites perpendicular to the MOL plane for targeted functionalization; (3) dual modification, integrating linker and SBU functionalization to achieve complex multifunctional platforms; and (4) multilevel assembly, incorporating MOLs into larger hierarchical architectures such as biomimetic systems and composite materials.These versatile modification strategies have unlocked novel applications of MOLs, including single-site catalysis, photocatalysis, and artificial photosynthetic systems. For instance, MOLs functionalized with transition metal complexes have more accessible reactive sites than conventional MOFs for faster substrate transport. Additionally, MOLs interfaced with biomimetic systems, such as liposomes and proteins, have demonstrated significant promise in photochemical energy conversion and selective oxidation processes.Despite these advancements, several key obstacles persist. Achieving uniform monolayer thickness while preventing multilayer aggregation remains a formidable task, necessitating deeper insights into the thermodyna","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"812-823"},"PeriodicalIF":16.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565523","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":"Dirhodium-Catalyzed Asymmetric Transformations of Alkynes via Carbene Intermediates.","authors":"Rui Wu, Zurong Xu, Dong Zhu, Shifa Zhu","doi":"10.1021/acs.accounts.4c00715","DOIUrl":"10.1021/acs.accounts.4c00715","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusFunctionalization of alkynes is an established cornerstone of organic synthesis. While numerous transition metals exhibit promising activities in the transformations of alkynes via π-insertion or oxidative cyclometalation, Lewis π-acids offer a different approach. By coordinating with alkynes through π-bonding, Lewis π-acids facilitate nucleophilic addition, leading to the formation of alkenyl metal species. These species can undergo electron rearrangement to generate metal carbenes, which are crucial intermediates for subsequent carbene transfer reactions. This reaction pathway provides a versatile route for alkyne functionalization, especially in an asymmetric manner. Although the Lewis π-acid, gold(I), pioneered this reaction mode, the development of asymmetric variants remains challenging due to the linear coordination of gold(I). Therefore, expanding the range of catalysts beyond gold(I) complexes to other metal catalysts would facilitate further advances in chiral molecule construction and the exploration of novel reaction modes.In this Account, we present a concise review of alkyne multifunctionalization via dirhodium-catalyzed asymmetric transformations, providing the development of the modulation strategies and substrates and plausible reaction mechanisms. In the aromatization-driven strategy, the furanyl dirhodium carbene is generated from an enynone, which is terminated by enantioselective intramolecular C-H insertion, cyclopropanation, aromatic substitution, or the Büchner reaction, giving chiral dihydroindoles, dihydrobenzofurans, cyclopropane-fused tetrahydroquinolines, fluorenes, or cyclohepta[&lt;i&gt;b&lt;/i&gt;]benzofurans. The cap-tether modulation strategy was developed in a subsequent study to balance the reactivity and selectivity of an azo-enyne. This strategy gave the first catalytic asymmetric cycloisomerization of azo-enyne, affording centrally and axially chiral isoindazole derivatives. The synergistic activation strategy, i.e., EWG activation and C-H···O interaction, was introduced to achieve the first dirhodium-catalyzed asymmetric cycloisomerization of enynes, providing a range of chiral cyclopropane-annulated bicyclic systems from enynals. Benefiting from these successes, difluoromethyl-substituted enynes were designed and proven to be effective substrates. With the corresponding benzo-1,6-enynes as the substrates, the enantioselective biscyclopropanation and the cascaded cyclopropanation/cyclopropenation were achieved using alkynes as dicarbene equivalents. Additionally, benzo-1,5-enynal generated vinyl dirhodium carbene, which reacted with a variety of alkenes via [2 + 1] cycloaddition, [4 + 3] cycloaddition, or formal allylation, giving spiro and fused polycyclic heterocycles. Coupling the synergistic activation strategy with desymmetrization, we further successfully achieved the asymmetric cycloisomerization of diynals, constructing furan-fused dihydropiperidines with an alkyne-substituted aza-quaternary ste","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"799-811"},"PeriodicalIF":16.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062100","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":"Fluorescent Metallacycles via Coordination-Driven Self-Assembly: Preparation, Regulation, and Applications","authors":"Wei-Tao Dou,&nbsp;Hai-Bo Yang* and Lin Xu*,&nbsp;","doi":"10.1021/acs.accounts.5c0004310.1021/acs.accounts.5c00043","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00043https://doi.org/10.1021/acs.accounts.5c00043","url":null,"abstract":"&lt;p &gt;Fluorescence by small molecular dyes is renowned for its real-time, dynamic, and noninvasive nature. It has become indispensable across scientific domains, including information storage, optoelectronic materials, biosensing, and both diagnosing and treating diseases. Despite their widespread use, these molecular dyes suffer from several limitations due to the sensitivity of their photophysical properties to environmental factors, such as concentration, solvent composition, and polarity. These challenges become particularly prominent when assembling or aggregating fluorescent molecules; their optical characteristics often become unpredictable or uncontrollable. Alternative strategies to stabilize and tune fluorescence during preparation are therefore crucial.&lt;/p&gt;&lt;p &gt;Metal coordination, a classical approach in supramolecular chemistry, offers a promising solution. Coordinating fluorescent dyes to metals precisely directs self-assembly, ensuring defined stoichiometries, geometries, and reversibility. The resulting multifunctional metallacycles combine the advantages inherent to molecular design and fluorescence, pushing the boundaries of fluorescence-based assemblies. We present a modular, directional, and controllable strategy for the self-assembly of supramolecular metallacycles with well-defined geometries, providing a new avenue to address the limitations of traditional small molecular dyes.&lt;/p&gt;&lt;p &gt;A key innovation in this research lies in the incorporation of photochromic units into the metallacycles, tuning their photophysical properties reversibly under external illumination. Their emission wavelengths, chiralities, and circularly polarized luminescence (CPL) signals can all be modulated dynamically. These characteristics offer the potential for holographic imaging, where fine control of fluorescence behavior is crucial. We introduce a novel multistep Förster resonance energy transfer (FRET) strategy that enables real-time monitoring of the metallacycle assembly dynamics. Our FRET approach has been employed to develop photosensitized oxygenation reactions and highly efficient light-harvesting systems, highlighting its versatility. The unique photophysical properties of our fluorescent metallacycles have been applied successfully in several fields. They detect heparin quantitatively, showcasing their potential in biosensing. They have been integrated into nanoagents for photothermal, photodynamic, and chemotherapeutic therapies guided by imaging, offering a multimodal approach to therapeutic intervention. Such precise control over fluorescence, energy transfer, and assembly dynamics not only opens new avenues in materials design but also underscores supramolecular metallacycles’ potential for advancing fluorescence technologies. Integrating metal coordination into fluorescence represents a significant step in the design and application of functional fluorescent metallacycles. This design strategy both advances fundamental supramolecular ch","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 7","pages":"1151–1167 1151–1167"},"PeriodicalIF":16.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737466","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":"Structural and Mechanistic Advances in the Chemistry of Methyl-Coenzyme M Reductase (MCR).","authors":"Bojana Ginovska, Simone Raugei, Stephen W Ragsdale, Christopher Ohmer, Ritimukta Sarangi","doi":"10.1021/acs.accounts.4c00730","DOIUrl":"10.1021/acs.accounts.4c00730","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Methane represents 34% of U.S. energy consumption and is a major greenhouse gas related to the global carbon cycle and energy production. However, current industrial practices significantly increase atmospheric methane levels, necessitating a deeper understanding of its biosynthesis and oxidation. Methyl-coenzyme M reductase (MCR) is central to biological methane metabolism, catalyzing the final step of methanogenesis and the first step in anaerobic methane oxidation. It is also a key target for strategies to capture and transform methane into value-added chemicals. The active site of MCR is a buried Ni-based cofactor only accessible by the substrates via a 50 Å long tunnel. Although the Ni(I) state is required to initiate catalysis, capturing this state remains a challenge for the current structural techniques. Recent advances in structural biology using X-ray Free-Electron Laser serial crystallography have provided insights into MCR's inactive Ni(II) state at room temperature and show promise for capturing its active Ni(I) form. Our team has established several critical aspects of the MCR mechanism using a combination of experimental and computational studies. MCR uses CH&lt;sub&gt;3&lt;/sub&gt;-SCoM and CoBSH as substrates, producing methane and a disulfide product CoMSSCoB. Kinetic analysis showed that productive substrate binding requires CH&lt;sub&gt;3&lt;/sub&gt;-SCoM to bind first, inducing conformational changes that optimize the active site for subsequent CoBSH binding. Following substrate binding, four proposed methane production/oxidation mechanisms were examined, establishing whether the reaction proceeds through an organometallic methyl-nickel(III), methyl anion ion, or methyl radical intermediate. Experimental measurements using CoBSH analogs successfully slowed the reaction, allowing for mechanistic insight that demonstrated the methyl radical pathway, where the initial interactions involve homolytic cleavage of the methyl-sulfur bond, generating a methyl radical that quickly abstracts the thiol hydrogen atom of CoBSH to form methane. Computational studies further confirmed that, compared to other mechanisms, the methyl radical mechanism is thermodynamically more favorable and accessible under physiological conditions.Spectroscopic and computational studies challenged the conventional understanding of substrate binding in MCR by proposing an alternative positioning of CH&lt;sub&gt;3&lt;/sub&gt;-SCoM and CoMSSCoB in the active site pocket. The research suggested that CH&lt;sub&gt;3&lt;/sub&gt;-SCoM (substrate) and CoMSSCoB (product) bind via their sulfonate groups to the Ni(I) center of cofactor F&lt;sub&gt;430&lt;/sub&gt;. This binding allows for the reaction without substrate reorganization in the pocket but would require a long-range electron transfer.Overall, the work summarized in this review reflects our current understanding of the enzyme's catalytic mechanism and structural dynamics. This is essential for developing efficient methane conversion technologies that could mitigate","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"824-833"},"PeriodicalIF":16.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555261","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":"Single-Electron-Transfer-Mediated Carbonylation Reactions.","authors":"Le-Cheng Wang, Xiao-Feng Wu","doi":"10.1021/acs.accounts.5c00039","DOIUrl":"10.1021/acs.accounts.5c00039","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusTransition-metal-catalyzed carbonylation coupling methods have been accepted as an essential tool for producing carbonylated products over the past few decades. Despite its long-standing history and widespread industrial applications, several challenges remain in carbonylation chemistry. These include reliance on precious metal catalysts, the need of high-energy radiation, difficulties in carbonylation of unactivated chemical bonds, etc. As an alternative to classic two-electron transfer process, single-electron-transfer (SET)-mediated carbonylation has emerged as a powerful tool to achieve elusive carbonylation transformations. Over the past few years, carbonylation of commonly available functional handles, such as alkenes and alkyl halides, via the single-electron pathway has emerged as a valuable area of research.Our team has been dedicated to developing new carbonylation reactions using bulk chemicals to construct high-value carbonylated products. These reactions have broad synthetic and industrial applications, motivating us to explore SET-mediated carbonylation transformations for two key classes of bulk chemicals: alkanes and alkyl halides. Specifically, our work has centered on two main approaches: (1) Single-electron reduction of C(sp&lt;sup&gt;3&lt;/sup&gt;)-X bonds: this strategy leverages single-electron reduction to activate C(sp&lt;sup&gt;3&lt;/sup&gt;)-X bonds, promoting the formation of carbon radicals, which in turn promotes subsequent addition to metals or CO. However, a significant challenge lies in the highly negative reduction potential of certain substrates [E&lt;sub&gt;red&lt;/sub&gt; &lt; -2 V compared to the saturated calomel electrode (SCE) for unactivated alkyl iodides]. Despite these challenges, the intrinsic reducibility of CO and the reactivity of various carbonyl-metal intermediates facilitate smooth reaction progress. (2) Single-electron oxidative of C(sp&lt;sup&gt;3&lt;/sup&gt;)-H bonds: this strategy emphasizes efficiency, high atomic utilization, and minimal waste by bypassing traditional preactivation methods. Using 3d metal catalysts, we have successfully performed aminocarbonylation and alkoxycarbonylation on a wide range of C(sp&lt;sup&gt;3&lt;/sup&gt;)-H bonds (such as those in aliphatic alkanes, ethers, amines, etc.). The above two approaches also enabled radical relay carbonylation of alkenes, allowing precise control over reaction intermediates and pathways. Such control improves both reaction efficiency and selectivity. These advancements have enabled transition metal or photoredox catalysis to facilitate radical relay carbonylation of unactivated alkenes, resulting in transformations such as oxyalkylative carbonylation, aminoalkylative carbonylation, fluoroalkylative carbonylation, double carbonylation, and rearrangement carbonylation.SET-mediated carbonylation significantly enhances the sustainability and scalability of the carbonylation process by reducing reliance on precious metal catalysts and enabling milder reaction conditions. Additionally,","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"1036-1050"},"PeriodicalIF":16.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Illuminating Palladium Catalysis.","authors":"Kelvin Pak Shing Cheung, Vladimir Gevorgyan","doi":"10.1021/acs.accounts.4c00815","DOIUrl":"10.1021/acs.accounts.4c00815","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusThe past decade has witnessed significant advancements of visible-light-induced photocatalysis, establishing it as a powerful and versatile tool in organic synthesis. The major focus of this field has centered on the development of methodologies that either rely solely on photocatalysts or combine photocatalysis with other catalytic methods, such as transition metal catalysis, to address a broader and more diverse array of transformations. Within this rapidly evolving area, a subfield that we refer to as transition metal photocatalysis has garnered significant attention due to its growing impact and mechanistic uniqueness. A distinguishing feature of this subfield is the dual functionality of a single transition metal complex, which not only acts as a photocatalyst to initiate photochemical processes but also functions as a traditional catalyst, facilitating key bond-breaking and bond-forming events. As such, an exogenous photocatalyst is not required in transition metal photocatalysis. However, the implications of harnessing both the excited- and ground-state reactivities of the transition metal complex can extend beyond this simplification. One of the most compelling aspects of this area is that photoexcited transition metal complexes can exhibit unique reactivities inaccessible through conventional thermal or dual photocatalytic approaches. These distinct reactivities can be leveraged to accomplish novel transformations either by engaging an entirely different substrate pool or by unlocking new reactivities of known substrates.In 2016, our group pioneered the use of phosphine-ligated palladium catalysts that can be photoexcited upon visible-light irradiation to engage diverse substrates in radical reactions. In our initial discovery, we showed that photoexcitation can redirect the well-established oxidative addition of a Pd(0) complex into aryl iodides toward an unprecedented radical process, generating hybrid aryl Pd(I) radical species. We subsequently extended this novel strategy to the formation of alkyl radicals from alkyl halides. These reactive radical intermediates have been harnessed in a wide variety of transformations, including desaturation, alkyl Heck reactions, and alkene difunctionalization cascades, among others.Seeking to further expand this new avenue, we achieved the first example of asymmetric palladium photocatalysis in the context of allylic C-H amination, where the palladium catalyst now plays triple duty by additionally controlling the stereochemical outcome of the reaction. In parallel to reaction discovery, we have also established that diazo compounds, strained molecules, and electron-deficient alkenes can serve as alkyl radical precursors beyond organic halides and redox-active esters. Notably, the engagement of electron-deficient alkenes has been made possible by the photoinduced hydricity enhancement of Pd-H species, representing a new mode of photoexcited reactivity.This Account presents our discov","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"861-876"},"PeriodicalIF":16.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513978","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}