ConspectusThe manipulation of strained rings is a powerful strategy for accessing the valuable chemical frameworks present in natural products and active pharmaceutical ingredients. Aziridines, the smallest N-containing heterocycles, have long served as building blocks for constructing more complex amine-containing scaffolds. Traditionally, the reactivity of typical aziridines has been focused on ring-opening by nucleophiles or the formation of 1,3-dipoles. However, over the past decade, our group has pioneered highly chemo-, site-, and stereoselective Ag- and Rh-catalyzed nitrene transfer (NT) reactions of allenes and alkenes to furnish unusual, or "anomalous", aziridines. The unique features of these aziridines, coupled with our ability to control the fate of strained intermediates resulting from diverse reactions of these precursors, allow for their transformation to densely substituted, stereochemically complex N-heterocyclic structures that would otherwise be difficult to access using conventional strategies. Our research is driven by a keen interest in versatile synthetic approaches that explore high Fsp (the fraction of sp carbons relative to the total number of carbons in a molecule) amine chemical space, which holds promise for uncovering novel bioactivity toward challenging protein targets. We begin by outlining the design and synthesis of selected anomalous aziridines and highlighting the key features that are pertinent to their versatility as synthetic intermediates. We detail chemo-, site-, and stereoselective Rh-catalyzed NT of homoallenic sulfamates leading to the key ()-methyleneaziridines (MAs) and the development of new Ag catalysts to achieve chemo- and enantioselective aziridinations of homoallenic and homoallylic carbamates/carbamimidates to yield bicyclic (methylene)aziridines. The chemoselective Ag-catalyzed NT of carbamimidates to accomplish intramolecular aza-Büchner reactions via polycyclic aziridine intermediates is also highlighted. Next, we focus on unlocking several modes of reactivity of our anomalous aziridines. These include regioselective ring-opening with nucleophiles and subsequent functionalization to afford amine stereotriads, the stereocontrolled formation and reaction of 2-amidoallyl cations, and alkene oxidation of endo- and exocyclic MAs. Additionally, due to the unusual molecular geometry of bicyclic (methylene)aziridines, the nitrogen lone pair can react with carbenes to generate aziridinium ylides that can be diverted along multiple pathways. From only a handful of anomalous aziridines, our chemistry is capable of delivering amine stereotriads, azetidines, azetidinones, piperidines, aminated cyclopentanes and cycloheptanes, azepines, and azepanes. Finally, we discuss our efforts to leverage this chemistry to explore the complex amine chemical space relevant to the natural products jogyamycin and methyl detoxinine. Ultimately, our goal is to use these methods to generate DNA-encoded libraries of high Fsp compounds with potential activity against difficult-to-target proteins.

ConspectusColloidal nanocrystals are an interesting platform for studying the surface chemistry of materials due to their high surface area/volume ratios, which results in a large fraction of surface atoms. As synthesized, the surfaces of many colloidal nanocrystals are capped by organic ligands that help control their size and shape. While these organic ligands are necessary in synthesis, it is often desirable to replace them with other molecules to enhance their properties or to integrate them into devices. Traditionally, these ligand exchanges have been studied using H NMR. Recently, isothermal titration calorimetry has proven itself to be a highly versatile measurement technique, yielding insights into the thermodynamics of the reaction, including the enthalpy and entropy of the reaction, that are inaccessible via H NMR. The most common technique for analyzing ligand exchange reactions has been to model these data with one-site and two-site Langmuir isotherm models. Unfortunately, a detailed analysis of H NMR and isothermal titration calorimetry data simultaneously demonstrates that these simple models are inadequate for understanding ligand reactions on the surfaces of colloidal nanocrystals.In this Account, we illustrate that the collective effects of the aliphatic chains of the organic ligands on the surfaces of colloidal nanocrystals dictate much of the reaction thermodynamics and how we have manipulated the thermodynamics of ligand exchange reactions by modulating the geometry and length of the organic ligands, the shape of the underlying nanocrystal, and the size of the nanocrystal. One of the main contributions of our body of work is the implementation of a modified Ising model, which accounts for nearest neighbor interactions, or collective effects, between the surface ligands and can be used to fit self-consistent thermodynamic parameters to describe the ligand exchange reactions. Using this model, we reveal the entropic and enthalpic factors of both the head binding group and the tail group that drive exchange reactions. In particular, we demonstrate the significant interligand interactions and the effect that ligand geometry and length have on these interactions. Further, we have shown that as the size of the nanocrystal increases, the interactions between the organic ligands become much stronger, and we have provided evidence that structural differences are present in the solvated ligand shell based on the ligand length. We also demonstrate in the case of ligand exchanges on cadmium selenide quantum dots that the crystal facet has very little impact on the thermodynamics of the ligand exchange using (100) and (111) faceted quantum dots. These findings rely critically on using a composition dependent model. We believe that this model or another accounting for these collective effects is critical for accurately analyzing the thermodynamics of the organic ligand shells for the field moving forward.

ConspectusThe advancement of synthetic methodologies is fundamentally driven by a deeper understanding of the structure-reactivity relationships of reactive key intermediates. Carbyne anions are compounds featuring a monovalent anionic carbon possessing four nonbonding valence electrons, which were historically confined to theoretical constructs or observed solely within the environment of gas-phase studies. These species possess potential for applications across diverse domains of synthetic chemistry and ancillary fields. This Account details our focused efforts to isolate singlet carbyne anions and explores our isolation of a range of related low-valent carbon species. Our achievements include the synthesis and characterization, under normal laboratory conditions, of gold-substituted free carbenes, copper carbyne anion complexes, ketenyl anions, keteniminyl anions, and a free stannyne. These have been accomplished using a bulky cyclic phosphino substituent, which effectively stabilizes these reactive species.Our journey commenced with the isolation of gold-substituted phosphinocarbenes, characterized by a robust carbon-gold covalent single bond, and progressed to the isolation of copper carbyne anion complexes featuring a carbon-copper ionic bond. This was realized through the synergistic combination of a bulky cyclic phosphino group and a closed-shell electron-rich late transition metal. The robustness of the carbon-gold bond contrasts markedly with the susceptibility of the carbon-copper bond, which imparts to the copper complexes the behavior characteristic of a phosphinocarbyne anion within the coordination sphere of copper, thereby enabling unique carbyne anion transfer reactions. The tri-active ambiphilic nature of the anionic carbon in these copper carbyne complexes enables the formation of three chemical bonds at the carbon center through one-pot reactions. Subsequent investigations unveiled ligand exchange reactions at the carbyne anion site, leading to the generation of stable crystalline ketenyl and keteniminyl anions. These species emerge as potent synthons capable of producing a diverse array of derivatives. In addition, we isolated a free phosphinostannyne, a rare species featuring a carbon-tin multiple bond and two adjacent ambiphilic centers. Collectively, these compounds have demonstrated a remarkable propensity for engaging in a spectrum of unique reactions, underscoring their versatility and confirming their utility in synthesizing uncharted, unique main group species.The methodologies and insights derived from our research contribute to the broader understanding of low-valent carbon species and may provide a platform for future innovations in synthetic chemistry, catalytic processes, and novel materials. As we continue to explore and develop this area of study, we hope that these low-valent carbon species might follow in the footsteps of stable singlet carbenes, potentially finding applications across various fields in the future.

ConspectusUnderstanding f element-ligand covalency is at the center of efforts to design new separations schemes for spent nuclear fuel, and is therefore of signficant fundamental and practical importance. Considerable effort has been invested into quantifying covalency in f element-ligand bonding. Over the past decade, numerous studies have employed a variety of techniques to study covalency, including XANES, EPR, and optical spectroscopies, as well as X-ray crystallography. NMR spectroscopy is another widely available spectroscopic technique that is complementary to these more established methods; however, its use for measuring 4f/5f covalency is still in its infancy. This Account describes efforts in the authors' laboratories to develop and validate multinuclear NMR spectroscopy as a tool for studying metal-ligand covalency in the actinides and selected lanthanide complexes. Thus far, we have quantified M-L covalency for a variety of ligand types, including chalcogenides, carbenes, alkyls, acetylides, amides, and nitrides, and for a variety of isotopes, including C, N, Se, and Te. Using NMR spectroscopy to probe M-C and M-N covalency is particularly attractive because of the ready availability of theC and N isotopes (both = 1/2), and also because these elements are found in some of the most important f element ligand classes, including alkyls, carbenes, polypyridines, amides, imidos, and nitrides.The covalency analysis is based on the chemical shift (δ) and corresponding nuclear shielding constant (σ) of the metal-bound nucleus. The diamagnetic (σ), paramagnetic (σ), and spin-orbit contributions (σ) to σ can be obtained and analyzed by relativistic density functional theory (DFT). Of particular importance is σ, which arises from the combination of spin-orbit coupling, the magnetic field, and chemical bonding. Its magnitude correlates with the amount of ligand s-character and metal f (and (+1)d) character in the M-L bond. In practice, Δ, the total difference between calculated chemical shift for the ligand nucleus including vs excluding SO effects, provides a more convenient metric for analysis. For the examples discussed herein, Δ accounts primarily for σ in an f-element complex, but also includes minor SO effects on the other shielding mechanisms and (usually) minor SO effects on the reference shielding. Δ can be very large, as in the case of [U(CHSiMe)] (348 ppm), which is not surprising as the An-C bonds in this example exhibits a high degree of covalency (e.g., 20% 5f character). However, even small values of Δ can indicate profound bonding effects, as shown by our analysis of [La(CCl)]. In this case, Δ is only 9 ppm, consistent with a highly ionic La-C bond (e.g., <1% 4f character). Nonetheless, the inclusion of SO effects in the calculation are necessary to achieve good agreement between the predicted and experimentally determined chemical shifts. Overall, the examples discussed herein highlight the exquisite sensitivity of this method to unravel electronic structure in f element complexes.

ConspectusWhile photochromic natural sodalites, an aluminosilicate mineral, were originally considered as curiosities, articles published in the past ten years have radically changed this perspective. It has been proven that their artificial synthesis was easy and allowed compositional tuning. Combined with simulations, it has been shown that a wide range of photochromic properties were achievable for synthetic sodalites (color, activation energy, reversibility, etc.), making them interesting as alternatives to organic photochromes but with the stability offered only by inorganic materials.The photochromism in this mineral originates from a photoinduced electron transfer from a sulfur based impurity toward a chlorine vacancy generating a trapped electron called an F-center. This F-center gives the color of the mineral. To investigate further the mechanism of the coloration and design artificial forms of these minerals, we built a multidisciplinary international consortium (Finland, Norway, United Kingdom, Belgium, and France). By combining experimental and computational characterizations, specifically designed for these minerals, we discovered that the stability of the F-center is due to the motion of a single sodium atom, able to move by more than 1 Å inside the structure to stabilize the trapped electron.Our international consortium, combining expertise in geology, material science, spectroscopy, and computational chemistry, has leveraged this understanding to design artificial sodalites for targeted applications. By adjusting their chemical composition, we can now fine-tune their photochromic properties (activation energy, color, thermal stability, etc.). As a result, photochromic sodalites have emerged as a highly promising platform for inorganic photonics, inspiring exciting new research directions. Notably, we have already demonstrated proof-of-concept applications as detectors and sensors for UV, X-ray, and α-, β-, or γ-irradiation. The first tests to use them as photosensitive films toward visible light and X-rays have also been performed to open the way of new imaging technologies.Beyond the development of technological applications for synthetic sodalites, their investigation was a driving force in the design of new experimental and computational techniques to study photochromism in the solid state. For instance, the "thermotenebrescence" technique was formulated to extract the stabilization energy of the F-center, and a methodology to compute excited states by quantum chemistry based on a multilayer electrostatic embedding was conceived for these systems. The latter has already been applied to understand other optical properties in other minerals, such as the photochromism in scapolite and tugtupite, the polychromism of cordierite and alexandrite, or the persistent luminescence in sodalites.This Account highlights the strength of a multidisciplinary approach to tackle the investigation of complex phenomena.

ConspectusSkeletal editing, which involves adding, deleting, or substituting single or multiple atoms within ring systems, has emerged as a transformative approach in modern synthetic chemistry. This innovative strategy addresses the ever-present demand for developing new drugs and advanced materials by enabling precise modifications of molecular frameworks without disrupting essential functional complexities. Ideally performed at late stages of synthesis, skeletal editing minimizes the need for the cost- and labor-intensive processes often associated with synthesis, thus accelerating the discovery and optimization of complex molecular architectures. While current efforts in skeletal editing predominantly focus on monatomic-scale modifications, editing molecules through cycloaddition followed by cycloreversion offers a unique strategy to manipulate molecular frameworks on a double-atomic scale. This introduces new possibilities for chemical transformations and enables transformations such as double-atom transmutation, formal single-atom transmutation, and atom insertion. Early examples of such skeletal editing processes often relied on the inherent high reactivity of the substrates, which needed to be sufficiently active to undergo cycloaddition and possess good leaving groups for the subsequent fragmentation (cycloreversion) step. Recently, however, the structural editing of relatively inert substrates has become achievable through substrate activation strategies designed to enhance either the cycloaddition or subsequent cycloreversion step.Along these lines, we recently developed a dearomative process for activating pyridines. In a simple high-yielding chemical operation, oxazinopyridines are readily obtained as activated dearomatized isolable intermediates. This method enabled us to achieve the transformation of pyridines into benzenes and naphthalenes through a cycloaddition/cycloreversion sequence. In this Account, related recent contributions from other research groups are highlighted as well, alongside early examples involving tetrazines, triazines, diazines, and other similar heterocycles as cycloaddition reaction partners. By offering a streamlined route to modify molecular structures, these approaches have demonstrated their ability to interconvert arenes and heteroarenes and have shown significant potential for late-stage editing applications as well as advancing drug discovery and the synthesis of bioactive molecules.In the future, these approaches will undoubtedly see broader development in the field of skeletal editing. New strategies for substrate activation should be devised to enable not only the incorporation of nitrogen and other heteroatoms into rings─rather than their deletion─but also to achieve ring contraction and expand the application of this strategy to non-aromatic rings. We hope that the advancements summarized in this Account will inspire chemists to explore and expand skeletal editing methodologies. By pushing the boundaries of these approaches, researchers can unlock new opportunities for constructing and modifying complex molecular frameworks, eventually paving the way for innovative applications in chemistry, biology, and materials science.

ConspectusLithium-ion batteries are recognized as an important electrochemical energy storage technology due to their superior volumetric and gravimetric energy densities. Graphite is widely used as the negative electrode, and its adoption enabled much of the modern portable electronics technology landscape. However, developing markets, such as electric vehicles and grid-scale storage, have increased demands, including higher energy content and a diverse materials supply chain. Alternatives that provide the opportunity to increase capacity and address supply chain concerns are of interest.Understanding the fundamental mechanisms that govern battery function is crucial to driving further improvements in the field. Advanced characterization techniques, such as those enabled by synchrotron light sources and high-resolution electron microscopes, that can uncover these mechanisms have become a necessity for elucidating structural evolution upon electrochemical conversion at the nano- to mesoscales. Performing these experiments with relevant electrochemistry using and experiments imparts the ability to identify critical reaction pathways and capture intermediate (dis)charge products not discernible by traditional experiments.This Account describes a series of recent studies focused on the advanced characterization of spinel-type iron oxide-based anode materials. These studies begin with magnetite (FeO), a low cost iron oxide which, when synthesized with appropriate coprecipitation based crystallite size control, provides opportunity to realize eight electrons per formula unit via electrochemical reduction. We then transition to bi- and trimetallic ferrites (such as ZnFeO and CoMnFeO) and conclude with high-entropy spinel ferrite oxides (HEOs) that contain at least 5 transition metals. For each material type, a variety of characterization techniques are utilized to describe the fundamental reaction mechanisms and rationalize electrochemical behavior. X-ray absorption spectroscopy (XAS) is featured prominently, as it allows for element specific analysis of electronic structure and local atomic environments, including nanocrystalline products of electrochemical conversion. Combining XAS-based techniques with diffraction and microscopy, the transition of iron oxide-type electrodes from spinel to rock-salt to metal nanoparticles upon full lithiation can be deciphered. For magnetite and its bi- and trimetallic ferrite analogues, delithiation results in return to a highly disordered network of FeO-like domains. Notably, while magnetite and the bi- and trimetallic ferrites appear to be limited to reoxidation of Fe to the 2+ state, through introduction of entropy-induced structural stability, higher Fe oxidation states (up to 2.6+) can be accessed upon electrochemical oxidation. These materials may hold promise as alternatives to traditional graphite electrodes where their combination of high capacity and compositional flexibility provides an avenue toward low-cost, sustainable energy storage.

ConspectusThe Mannich reaction, involving the nucleophilic addition of an enol(ate) intermediate to an imine or iminium ion, is one of the most widely used synthetic methods for the synthesis of β-amino carbonyl compounds. Nevertheless, the homo-Mannich reaction, which utilizes a homoenolate intermediate as the nucleophilic partner and provides straightforward access to the valuable γ-amino carbonyl compounds, remains underexplored. This can be largely attributed to the difficulties in generation and manipulation of the homoenolate species, despite various homoenolate equivalents that have been developed. Among the homoenolate equivalents developed, cyclopropanol stands out due to its intriguing reactivities endowed by the highly strained cyclopropane. Upon activation by a metal, cyclopropyl alcohol is prone to undergo an endocyclic C(sp)-C(sp) bond cleavage to give a homoenolate intermediate or a β-keto radical intermediate, which sets the stage for a diverse range of transformations. This account outlines our recent progress in the development of homo-Mannich reaction of cyclopropanol and its applications in natural product total synthesis. This new methodology can be classified into two subtypes: 1) the homo-Mannich reaction of cyclopropanol with imines or iminium ions and 2) the homo-Mannich-type reaction of cyclopropanol with heteroarenes. Through different ways to generate imines or iminium ions, tandem or sequential reactions of C-H oxidation/homo-Mannich, Bischler-Napieralski/homo-Mannich, and asymmetric allylation/homo-Mannich have been developed, leading to the rapid assembly of core scaffolds of sarpagine, koumine, ibophyllidine, , , and alkaloids. Besides the reactions with imines or iminium ions, cyclopropyl alcohol can undergo ring-opening addition to indole and pyrrole rings to deliver core scaffolds of schizozygane and indolizidine alkaloids. Based on these methodology advancements, we have accomplished the asymmetric synthesis of 29 alkaloids belonging to 8 families. In this Account, we present a complete picture of our works concerning synthetic design, method development, and applications in natural product total synthesis. It is anticipated that the development of new methodologies of cyclopropyl alcohol will find broad applications in the realm of natural product synthesis.

ConspectusIn the search for efficient and selective electrocatalysts capable of converting greenhouse gases to value-added products, enzymes found in naturally existing bacteria provide the basis for most approaches toward electrocatalyst design. Ni,Fe-carbon monoxide dehydrogenase (Ni,Fe-CODH) is one such enzyme, with a nickel-iron-sulfur cluster named the C-cluster, where CO binds and is converted to CO at high rates near the thermodynamic potential. In this Account, we divide the enzyme's catalytic contributions into three categories based on location and function. We also discuss how computational techniques provide crucial insight into implementing these findings in homogeneous CO reduction electrocatalysis design principles. The CO binding sites (e.g., Ni and "unique" Fe ion) along with the ligands that support it (e.g., iron-sulfur cluster) form the primary coordination sphere. This is replicated in molecular electrocatalysts via the metal center and ligand framework where the substrate binds. This coordination sphere has a direct impact on the electronic configuration of the catalyst. By computationally modeling a series of Ni and Co complexes with bipyridyl--heterocyclic carbene ligand frameworks of varying degrees of planarity, we were able to closely examine how the primary coordination sphere controls the product distribution between CO and H for these catalysts. The secondary coordination sphere (SCS) of Ni,Fe-CODH contains residues proximal to the active site pocket that provide hydrogen-bonding stabilizations necessary for the reaction to proceed. Enhancing the SCS when synthesizing new catalysts involves substituting functional groups onto the ligand for direct interaction with the substrate. To analyze the endless possible substitutions, computational techniques are ideal for deciphering the intricacies of substituent effects, as we demonstrated with an array of imidazolium-functionalized Mn and Re bipyridyl tricarbonyl complexes. By examining how the electrostatic interactions between the ligand, substrate, and proton source lowered activation energy barriers, we determined how best to pinpoint the SCS additions. The outer coordination sphere comprises the remaining parts of Ni,Fe-CODH, such as the elaborate protein matrix, solvent interactions, and remote metalloclusters. The challenge in elucidating and replicating the role of the vast protein matrix has understandably led to a localized focus on the primary and secondary coordination spheres. However, certain portions of Ni,Fe-CODH's expansive protein scaffold are suggested to be catalytically relevant despite considerable distance from the active site. Closer studies of these relatively overlooked areas of nature's exceptionally proficient catalysts may be crucial to continually improve upon electrocatalysis protocols. Mechanistic analysis of cobalt phthalocyanines (CoPc) immobilized onto carbon nanotubes (CoPc/CNT) reveals how the active site microenvironment and outer coordination sphere effects unlock the CoPc molecule's previously inaccessible intrinsic catalytic ability to convert CO to MeOH. Our research suggests that incorporating the three coordination spheres in a holistic approach may be vital for advancing electrocatalysis toward viability in mitigating climate disruption. Computational methods allow us to closely examine transition states and determine how to minimize key activation energy barriers.

ConspectusLithium-ion batteries (LIBs) based on graphite anodes are a widely used state-of-the-art battery technology, but their energy density is approaching theoretical limits, prompting interest in lithium-metal batteries (LMBs) that can achieve higher energy density. In addition, the limited availability of lithium reserves raises supply concerns; therefore, research on postlithium metal batteries is underway. A major issue with these metal anodes, including lithium, is dendritic formation and insufficient reversibility, which leads to safety risks due to short circuits and the use of flammable electrolytes.Ionic liquid electrolytes (ILEs), composed of metal salts and ionic liquids, offer a safer alternative due to their nonflammable nature and high thermal stability. Moreover, they can enable high Coulombic efficiency (CE) for lithium metal anodes (LMAs) and allow reversible stripping/plating of various post-lithium metals for battery application, e.g., aluminum metal batteries (AMBs). Despite these advantages, ILEs suffer from high viscosity, which impairs ion transport and wettability. To resolve these challenges, researchers have developed locally concentrated ionic liquid electrolytes (LCILEs) by adding low-viscosity nonsolvating cosolvents, e.g., hydrofluoroether, to ILEs. These cosolvents do not coordinate with cationic charge carriers, thereby reducing viscosity and improving ion transport without compromising the compatibility of electrolytes with metal anodes. However, due to the inherent difference of molecular organic solvents and ionic liquids full of charged species, the most used nonsolvating cosolvents, i.e., hydrofluoroether, are less effective for ILEs with respect to concentrated electrolytes based on conventional organic solvents. Moreover, hydrofluoroether contains environmentally problematic -CF and/or -CF- groups, i.e., per- and polyfluoroalkyl substances (PFAS), with their use subject to restrictions.In this Account, we provide an overview of the endeavors of our research group on the development of PFAS-free LCILEs for high-energy LMBs and AMBs. First, aromatic organic cations and aromatic less/nonfluorinated cosolvents are proposed to weaken the organic cation-anion interaction and strengthen the organic cation-cosolvent interaction, respectively. This is with consideration of the uncovered phase nanosegregation structure of LCILEs that effectively reduces the viscosity and promotes the Li transport ability with respect to the conventional nonaromatic organic cations and highly fluorinated PFAS cosolvents. Then, the effect of electrolyte components that do not coordinate to Li, including organic cations and nonsolvating cosolvents, on the SEI composition and LMA reversibility is presented, which confirms the feasibility of reaching a high lithium stripping/plating CE up to 99.7% in the developed PFAS-free LCILEs. In the subsequent discussion on cathode compatibility, we present that in addition to LiFePO with high cyclability but inferior energy density, nickel-rich layered oxide and sulfurized polyacrylonitrile (SPAN) can be employed to construct high-energy LMBs for PFAS-free LCILEs with different anodic stability. Additionally, the feasible application of the LCILE strategy to promote the kinetics of AMBs relying on a different anode chemistry is demonstrated. Lastly, future research directions with an emphasis on nonsolvating component optimization, electrolyte dynamics, and electrode/electrolyte interphase formation are provided.

ConspectusSymmetry is a pervasive phenomenon spanning diverse fields, from art and architecture to mathematics and science. In the scientific realms, symmetry reveals fundamental laws, while symmetry breaking─the collapse of certain symmetry─is the underlying cause of phenomena. Research on symmetry and symmetry breaking consistently provides valuable insights across disciplines, from parity violation in physics to the origin of homochirality in biology. Chemistry is particularly rich in symmetry breaking studies, encompassing areas such as asymmetric synthesis, chiral resolution, chiral structure assembly, and so on. Across different disciplines, a well-defined methodology is fundamental and necessary to analyze the symmetry or symmetry breaking nature behind the phenomenon, enabling researchers to uncover the underlying principles and mechanisms. Basically, three key points underpin symmetry-related research: the scale-dependency of symmetry/symmetry breaking, the driving force behind symmetry breaking phenomena, and the properties arising from symmetry breaking.This Account will focus on the three aforementioned key points elucidated with organic cages as proof-of-concept models, as organic cages exhibit shape-persistent 3D molecular frameworks, well-defined molecular motion, and a high propensity for crystallization.First, we examine racemization processes of organic cages with dynamic molecular motions to illustrate that symmetry and symmetry breaking are time-scale-dependent. Specifically, the racemization, driven by molecular motion, is influenced by hydrogen bonding and the rigidity of the cage framework, which may or may not be observable within the experimental temporal scale. This determines whether the enantiomeric excess system, namely, the symmetry broken system, can be detected experimentally. We also investigate the hierarchical structures self-assembled by racemic organic cages, demonstrating that symmetry and asymmetry manifest differently across spatial scales, from molecular to supramolecular and macroscopic levels. Second, we discuss the driving force behind spontaneous chiral resolution─a classic symmetry-breaking event during crystallization─from a thermodynamic perspective. We suggest that racemic compounds, compared to conglomerates, are more entropy-favored, explaining their greater prevalence in nature. Spontaneous chiral resolution can take place only when a favorable enthalpy compensates for unfavorable entropy. In conglomerates composed of organic cages, strong intermolecular interactions along the screw axes provide the necessary compensation. Finally, we explore the unique properties that emerge from symmetry-broken molecular packing within crystals of cage racemates, such as second-harmonic generation and piezoelectricity. It turns out that the symmetry operation in molecular packing plays a critical role in determining material properties. By comprehensively analyzing symmetry and symmetry-breaking in organic cage racemates, this Account provides insights into symmetry-related phenomena across scientific disciplines. It also paves the way for designing novel materials with tailored properties for applications in optics, electronics, and beyond.

ConspectusThe discovery of reversible hydrogenation using metal-free phosphoborate species in 2006 marked the official advent of frustrated Lewis pair (FLP) chemistry. This breakthrough revolutionized homogeneous catalysis approaches and paved the way for innovative catalytic strategies. The unique reactivity of FLPs is attributed to the Lewis base (LB) and Lewis acid (LA) sites either in spatial separation or in equilibrium, which actively react with molecules. Since 2010, heterogeneous FLP catalysts have gained increasing attention for their ability to enhance catalytic performance through tailored surface designs and improved recyclability, making them promising for industrial applications. Over the past 5 years, our group has focused on investigating and strategically modifying various types of solid catalysts with FLPs that are unique from classic solid FLPs. We have explored systematic characterization techniques to unravel the underlying mechanisms between the active sites and reactants. Additionally, we have demonstrated the critical role of catalysts' intrinsic electronic and geometric properties in promoting FLP formation and stimulating synergistic effects. The characterization of FLP catalysts has been greatly enhanced by the use of advanced techniques such as synchrotron X-ray diffraction, neutron powder diffraction, X-ray photoelectron spectroscopy, extended X-ray absorption fine structure, elemental mapping in scanning transmission electron microscopy, electron paramagnetic resonance spectroscopy, diffuse-reflectance infrared Fourier transform spectroscopy, and solid-state nuclear magnetic resonance spectroscopy. These techniques have provided deeper insights into the structural and electronic properties of FLP systems for the future design of catalysts.Understanding electron distribution in the overlapping orbitals of LA and LB pairs is essential for inducing FLPs in operando in heterogeneous catalysts through target electron reallocation by external stimuli. For instance, in silicoaluminophosphate-type zeolites with weak orbital overlap, the adsorption of polar gas molecules leads to heterolytic cleavage of the Al-O bond, creating unquenched LA-LB pairs. In a Ru-doped metal-organic framework, the Ru-N bond can be polarized through metal-ligand charge transfer under light, forming Ru-N pairs. This activation of FLP sites from the framework represents a groundbreaking innovation that expands the catalytic potential of existing materials. For catalysts already employing FLP chemistry to dynamically generate products from substrates, a complete mechanistic interpretation requires a thorough examination of the surface electronic properties and the surrounding environment. The hydrogen spillover ability on the Ru-doped FLP surfaces improves conversion efficiency by suppressing hydrogen poisoning at metal sites. In situ H-HO conditions enable the production of organic chemicals with excellent activity and selectivity by creating new bifunctional sites via FLP chemistry. By highlighting the novel FLP systems featuring FLP induction and synergistic effects and the selection of advanced characterization techniques to elucidate reaction mechanisms, we hope that this Account will offer innovative strategies for designing and characterizing FLP chemistry in heterogeneous catalysts to the research community.

ConspectusIons are the crucial signaling components for living organisms. In cells, their transportation across pore-forming membrane proteins is vital for regulating physiological functions, such as generating ionic current signals in response to target molecule recognition. This ion transport is affected by confined interactions and local environments within the protein pore. Therefore, the pore-forming protein can efficiently transduce the characteristics of each target molecule into ion-transport-mediated signals with high sensitivity. Inspired by nature, various protein pores have been developed into high-throughput and label-free nanopore sensors for single-molecule detection, enabling rapid and accurate readouts. In particular, aerolysin, a key virulence factor of , exhibits a high sensitivity in generating ionic current fingerprints for detecting subtle differences in the sequence, conformation, and structure of DNA, proteins, polypeptides, oligosaccharides, and other molecules. Aerolysin features a cap that is approximately 14 nm wide on the side and a central pore that is about 10 nm long with a minimum diameter of around 1 nm. Its long lumen, with 11 charged rings at two entrances and neutral amino acids in between, facilitates the dwelling of the single analyte within the pore. This characteristic enables rich interactions between the well-defined residues within the pore and the analyte. As a result, the ionic current signal offers a unique molecular fingerprint, extending beyond the traditional volume exclusion model in nanopore sensing. In 2006, aerolysin was first reported to discriminate conformational differences of single peptides, opening the door for a rapidly growing field of aerolysin nanopore electrochemistry. Over the years, various mutant aerolysin nanopores have emerged, associated with advanced instrumentation and data analysis algorithms, enabling the simultaneous identification of over 30 targets with the number still increasing. Aerolysin nanopore electrochemistry in particular allows time-resolved qualitative and quantitative analysis ranging from DNA sequencing, proteomics, enzyme kinetics, and single-molecule reactions to potential clinical diagnostics. Especially, the feasibility of aerolysin nanopore electrochemistry in dynamic quantitative analysis would revolutionize omics studies at the single-molecule level, paving the way for the promising field of single-molecule temporal omics. Despite the success of this approach so far, it remains challenging to understand how confined interactions correlate to the distinguishable ionic signatures. Recent attempts have added correction terms to the volume exclusion model to account for variations in ion mobility within the nanopore caused by the confined interactions between the aerolysin and the analyte. Therefore, in this Account, we revisit the origin of the current blockade induced by target molecules inside the aerolysin nanopore. We highlight the contributions of the confined noncovalent interactions to the sensing ability of the aerolysin nanopore through the corrected conductance model. This Account then describes the design of interaction networks within the aerolysin nanopore, including electrostatic, hydrophobic, hydrogen-bonding, cation-π, and ion-charged amino acid interactions, for ultrasensitive biomolecular identification and quantification. Finally, we provide an outlook on further understanding the noncovalent interaction network inside the aerolysin nanopore, improving the manipulating and fine-tuning of confined electrochemistry toward a broad range of practical applications.

ConspectusCovalent triazine frameworks (CTFs) are a novel class of nitrogen-rich conjugated porous organic materials constructed by robust and functional triazine linkages, which possess unique structures and excellent physicochemical properties. They have demonstrated broad application prospects in gas/molecular adsorption and separation, catalysis, energy conversion and storage, etc. In particular, crystalline CTFs with well-defined periodic molecular network structures and regular pore channels can maximize the utilization of the features of CTFs and promote a deep understanding of the structure-property relationship. However, due to the poor reversibility of the basic reaction for constructing the triazine unit and the traditional harsh synthesis conditions, it remains a considerable challenge to synthesize crystalline CTFs with diverse molecular structures, and there is still a significant lack of understanding of their polymerization mechanism, which limits their precise structural design, large-scale preparation, and practical applications. As the basic building block of bulk crystalline CTFs, two-dimensional triazine polymers (2D-TPs) which ideally have single-atom thickness have also aroused intensive interest due to their ultrathin 2D sheet morphology with structural flexibility, a fully exposed molecular plane and active sites, and excellent dispersibility and processability. However, the efficient and scalable production of high-quality 2D-TPs and the investigation of their unique properties and functions remain largely unexplored.In this Account, we summarize our recent contributions to the synthesis and application exploration of crystalline CTFs and 2D-TPs. We first introduce the design, synthesis, and polymerization mechanism of the crystalline CTFs. In order to synthesize high-quality CTFs, we have successively used a series of new synthetic methods including a solution polymerization strategy, microwave-assisted superacid-catalyzed polymerization strategy, polyphosphoric acid-catalyzed polymerization strategy, and solvent-free FeCl-catalyzed polymerization strategy, achieving the production of highly crystalline layered CTFs from the gram level to the hundred-gram level and then to the kilogram level and realizing new CTF molecular structures. We also reveal a direct ordered 2D polymerization mechanism that provided meaningful guidance for the controllable preparation of functional CTFs. Next, we introduce the design, synthesis, and formation mechanism of 2D-TPs. We have developed effective bottom-up and top-down strategies to prepare 2D-TPs for different needs. On one hand, we have established the dynamic interface polymerization method, the monomer-dependent method, and the solvent-free salt-catalyzed polymerization strategy for the direct synthesis of ultrathin 2D-TPs with thickness down to the single-layer limit and provided important insights into the 2D polymerization mechanism. On the other hand, we have opened up the physical and chemical exfoliation of crystalline layered CTFs such as liquid sonication and ball milling exfoliation and covalent and noncovalent modification exfoliation for the large-scale production of 2D-TPs. Then, we present the application progress of crystalline CTFs and 2D-TPs in various batteries, photo/electrocatalysis, and adsorbents with an emphasis on their unique and outstanding performance and structure-property relationship. Lastly, the main challenges faced by crystalline CTFs and 2D-TPs in practical applications and future research directions are discussed in detail. We hope that this Account will provide valuable insights and practical strategies for promoting the development of functional organic framework materials and 2D polymer materials.

ConspectusIn recent years, our research group has dedicated significant effort to the field of asymmetric organometallic electrochemical synthesis (AOES), which integrates electrochemistry with asymmetric transition metal catalysis. On one hand, we have rationalized that organometallic compounds can serve as molecular electrocatalysts (mediators) to reduce overpotentials and enhance both the reactivity and selectivity of reactions. On the other hand, the conditions for asymmetric transition metal catalysis can be substantially improved through electrochemistry, enabling precise modulation of the transition metal's oxidation state by controlling electrochemical potentials and regulating the electron transfer rate via current adjustments. This synergistic approach addresses key challenges inherent in traditional asymmetric transition metal catalysis, particularly those related to the use of redox-active chemical reagents. Furthermore, the redox potentials of molecular electrocatalysts can be conveniently tuned by modifying their ligands, thereby governing the reaction regioselectivity and stereoselectivity. As a result, the AOES has emerged as a powerful and promising tool for the synthesis of chiral compounds.In this Account, we summarize and contextualize our recent efforts in the field of AOES. Our primary strategy involves leveraging the controllability of electrochemical potential and current to regulate the oxidation state of organometallics, thereby facilitating the desired reactions. An efficient asymmetric synthesis platform was established under mild conditions, significantly reducing the reliance on chemical redox reagents. Our research has been systematically categorized into three sections based on distinct electrolysis modes: asymmetric transition metal catalysis combined with anodic oxidation, cathodic reduction, and paired electrolysis. In each section, we highlight our innovative discoveries tailored to the unique characteristics of the respective electrolysis modes.In many transformations, transition metal-catalyzed reactions involving traditional chemical redox reagents and those utilizing electrochemistry exhibit similar reactivities. However, we also observed notable differences in certain cases. These findings include the following: (1) Enhanced efficiency in asymmetric electrochemical synthesis: for instance, the Rh-catalyzed enantioselective electrochemical functionalization of C-H bonds demonstrates superior efficiency. (2) Expanded scope of transformations: certain transformations, previously challenging in traditional transition metal catalysis, can be achieved through electrochemistry due to the tunability of redox potentials. A notable example is the enantioselective reductive coupling of aryl chlorides, which significantly expands the range of accessible transformations. Additionally, our mechanistic studies explore unique techniques intrinsic to electrochemistry, such as controlled potential electrolysis experiments, the impact of electrode materials on catalyst performance, and cyclic voltammetry studies. These investigations provide a more intuitive understanding of the behavior of metal catalysts through the study of electrochemical mechanisms, which can also guide the design of new catalytic systems.The advancements in this field offer a robust platform for environmentally friendly and sustainable selective asymmetric transformations. By integrating electrochemistry with transition metal catalysis, we have developed a versatile approach for organic synthesis that not only enhances the efficiency and selectivity of reactions but also reduces the environmental impact. We anticipate that this Account will stimulate further research and innovation in the realm of AOES, leading to the discovery of new catalytic systems and the development of more sustainable synthetic methodologies.

ConspectusChiral organosilicon compounds bearing a Si-stereogenic center have attracted increasing attention in various scientific communities and appear to be a topic of high current relevance in modern organic chemistry, given their versatile utility as chiral building blocks, chiral reagents, chiral auxiliaries, and chiral catalysts. Historically, access to these non-natural Si-stereogenic silanes mainly relies on resolution, whereas their asymmetric synthetic methods dramatically lagged compared to their carbon counterparts. Over the past two decades, transition-metal-catalyzed desymmetrization of prochiral organosilanes has emerged as an effective tool for the synthesis of enantioenriched Si-stereogenic silanes. Despite the progress, these catalytic reactions usually suffer from limited substrate scope, poor functional-group tolerance, and low enantioselectivity. The growing demand for Si-stereogenic silanes with structural diversity has continued to drive the development of new practical methods for the assembly of these chiral molecules.Five years ago, our research group embarked on a project aimed at developing a general catalytic approach that can unlock access to various functionalized Si-stereogenic organosilanes with high efficiency. This Account describes our laboratory's endeavor in the exploration and development of catalytic asymmetric dehydrogenative Si-H/X-H coupling toward Si-stereogenic silanes. This approach features (1) readily accessible dihydrosilane starting materials; (2) diverse X-H (X═C, N, O, etc.) coupling partners; (3) platform transformable Si-stereogenic monohydrosilane products; and (4) high efficiency and atomic economy.At the initial stage of the research, a biaryl dihydrosilane was selected as the model substrate to conduct an enantioselective intramolecular C-H/Si-H dehydrogenative coupling reaction. Rh/Josiphos catalytic system was found to be effective at the early stage of this process, while the final enantiocontrol was elusive. Mechanistic studies indicated that a rhodium silyl dihydride complex is the resting state in the catalytic cycle, which may undergo racemization of the Si-stereogenic center. Enlightened by the mechanistic investigations, two strategies, the tandem alkene hydrosilylation strategy and bulky alkene-assisted dehydrogenative strategy, were adopted to avoid racemization, delivering the corresponding Si-stereogenic 9-silafluorenes with excellent yields and enantioselectivities. Further enantioselective intramolecular C(sp)-H or C(sp)-H silylation gave access to a series of five-, six- and seven-membered Si-stereogenic heterocycles with high efficiency. Next, we extended the reaction to an intermolecular version, realizing asymmetric Si-H/C-H, Si-H/O-H, and Si-H/N-H dehydrogenative coupling reactions toward a variety of acyclic Si-stereogenic monohydrosilanes, silyl ethers, siloxanes, silanols, and silazanes. We also presented our endeavors to apply the resulting Si-stereogenic compounds, including further derivatization, polymerization, and chiroptical property investigations, which successfully introduced Si-stereocenters into bioactive molecules, polymers, and chiroptical materials. Lastly, based on the understanding of silyl metal species, we developed a new type of chiral silyl ligand that can be applied to enable an atroposelective intermolecular C-H/Si-H dehydrogenative coupling reaction. We anticipate that our research, including synthetic methodology, mechanistic insights, and property studies, will not only inspire the further development of chiral organosilicon chemistry but also contribute to the creation of novel chiral molecules to be applied in synthetic chemistry, medicinal chemistry, and materials science.

ConspectusThe electronic properties of atomically thin van der Waals (vdW) materials can be precisely manipulated by vertically stacking them with a controlled offset (for example, a rotational offset─i.e., twist─between the layers, or a small difference in lattice constant) to generate moiré superlattices. In recent years, the application of this "twistronics" concept to interfacial electrochemistry has unveiled unique pathways for tailoring the electrochemical reactivity. This Account provides an overview of our work that leveraged a suite of structural characterization methods, such as interferometric four-dimensional scanning transmission electron microscopy, dark-field transmission electron microscopy, and scanning tunneling microscopy, along with nanoscale electrochemical measurement techniques, namely, scanning electrochemical cell microscopy (SECCM), to uncover and dissect the profound impact of electrode electronic structure, controlled by interlayer twist, on interfacial electron transfer kinetics. At the heart of our findings is the discovery that moiré engineering enables the isolation of thermodynamically unfavorable stacking configurations, or topological defects, that substantially increase the standard electron transfer rate constant at the solid-liquid interface beyond what has been measured on conventional, nontwisted two-dimensional (2D) materials. This enhancement in interfacial reactivity can be attributed to the localization of a high density of electronic states within these particular sites in the superlattice, a similar effect to that which occurs upon incorporation of physical defects or vacancies in an electrode material but instead using an atomically pristine surface with a highly tunable structure. Throughout our studies, understanding the nuances of the relationship between the preimposed moiré twist angle and the observed electron transfer kinetics has heavily relied on the interrogation of additional factors such as spontaneous superlattice reconstruction and three-dimensional localization of electronic states, illustrating the importance of combining electrochemical measurements with both nanoscale structural probes and theoretical modeling for designing and optimizing moiré-engineered electrodes. The insight afforded by our efforts in this space continues to deepen our understanding of the fundamental mechanisms governing electron transfer at electrochemical interfaces at large and also points to the revolutionary prospect of twistronics for advancing electrochemical technologies. While our electrochemical studies have, so far, focused largely on graphene-based moiré materials, we also offer a perspective on the promise of transition metal dichalcogenide (TMD)-based moirés as candidates for highly versatile (photo)electrode surfaces. Accordingly, we provide a discussion of our studies on the structural relaxation observed in moiré superlattices of TMDs, and we summarize our work combining SECCM with field-effect electrostatic gating of TMDs to deconvolute the influences of material conductivity and intrinsic electron transfer kinetics from the overall electrochemical response of a semiconducting 2D material. Overall, this body of work establishes a distinctive foundation for the design of a wide range of materials with tailored properties that can provide crucial insights into interfacial charge transfer chemistry─potentially serving as platforms for sensing, energy conversion, and electrocatalysis─in addition to the emergent exotic correlated electron physics that originally ignited intense interest in moiré twistronics.

ConspectusA key challenge in modern chemistry research is to mimic life-like functions using simple molecular networks and the integration of such networks into the first functional artificial cell. Central to this endeavor is the development of signaling elements that can regulate the cell function in time and space by producing entities of code with specific information to induce downstream activity. Such artificial signaling motifs can emerge in nonequilibrium systems, exhibiting complex dynamic behavior like bistability, multistability, oscillations, and chaos. However, the , bottom-up design of such systems remains challenging, primarily because the kinetic characteristics and energy aspects yielding bifurcation have not yet been globally defined. We herein review our recent work that focuses on the design and functional analysis of peptide-based networks, propelled by replication reactions and exhibiting bistable behavior. Furthermore, we rationalize and discuss their exploitation and implementation as variable signaling motifs in homogeneous and heterogeneous environments.The bistable reactions constitute reversible second-order autocatalysis as positive feedback to generate two distinct product distributions at steady state (SS), the low-SS and high-SS. Quantitative analyses reveal that a phase transition from simple reversible equilibration dynamics into bistability takes place when the system is continuously fueled, using a reducing agent, to keep it far from equilibrium. In addition, an extensive set of experimental, theoretical, and simulation studies highlight a defined parameter space where bistability operates.Analogous to the arrangement of protein-based bistable motifs in intracellular signaling pathways, sequential concatenation of the synthetic bistable networks is used for signal processing in homogeneous media. The cascaded network output signals are switched and erased or transduced by manipulating the order of addition of the components, allowing it to reach "on demand" either the low-SS or high-SS. The pre-encoded bistable networks are also useful as a programming tool for the downstream regulation of nanoscale materials properties, bridging together the Systems Chemistry and Nanotechnology fields. In such heterogeneous cascade pathways, the outputs of the bistable network serve as input signals for consecutive nanoparticle formation reaction and growth processes, which-depending on the applied conditions-regulate various features of (Au) nanoparticle shape and assembly.Our work enables the design and production of various signaling apparatus that feature higher complexity than previously observed in chemical networks. Future studies, briefly discussed at the end of the Account, will be directed at the design and analysis of more elaborate functionality, such as bistability under flow conditions, multistability, and oscillations. We propose that a profound understanding of the design principles facilitating the replication-based bistability and related functions bear implications for exploring the origin of protein functionality prior to the highly evolved replication-translation-transcription machinery. The integration of our peptide-based signaling motifs within future synthetic cells seems to be a straightforward development of the two alternating states as memory and switch elements for controlling cell growth and division and even communication among different cells. We furthermore suggest that such systems can be introduced into living cells for various biotechnology applications, such as switches for cell temporal and spatial manipulations.

ConspectusFor chemical reactions with complex pathways, it is extremely difficult to adjust the catalytic performance. The previous strategies on this issue mainly focused on modifying the fine structures of the catalysts, including optimization of the geometric/electronic structure of the metal nanoparticles (NPs), regulation of the chemical composition/morphology of the supports, and/or adjustment of the metal-support interactions to modulate the reaction kinetics on the catalyst surface. Although significant advances have been achieved, the catalytic performance is still unsatisfactory.It is accepted that the chemical equilibrium of a reaction can be disturbed by changing the concentration of the reactants or products, and the equilibrium will shift to another side to offset the perturbation until a new equilibrium is established. This is known as Le Chatelier's principle. Following this understanding, we show that the catalytic performance can be significantly modulated by adjusting the molecular sorption equilibrium on the catalyst surface. For example, enriching the reactants and/or intermediates on the catalyst surface pushes the reaction forward, thus increasing the catalytic conversion; removing the product away from the catalyst surface improves the catalytic conversion and product selectivity; and inhibiting the side reactions enhances the product selectivity and catalyst durability. Using these strategies has successfully enhanced the catalytic performances in many challenging reactions, such as increasing HO concentration around the metal active sites to enhance methane oxidation, enriching olefin on the catalyst surface to boost hydroformylation, selective combustion of H to shift the reaction equilibrium and improve ethane conversion in ethane dehydrogenation, and removing water from the reaction system to enhance Fischer-Tropsch synthesis. The key to these successes is effectively shifting the molecular sorption equilibrium under the working conditions.In this Account, we briefly summarize recent advances in adjusting molecular sorption equilibrium for boosting catalysis, with a focus on the equilibrium shift for a desired pathway by the unique functions of zeolites and polymers such as silanol nests on zeolite for olefin adsorption, the "molecular fence" effect of zeolite for HO enrichment, MFI zeolite nanosheets for olefin diffusion, and the hydrophobic zeolite sheath and polymer for water separation/diffusion. We report the adjustment of the molecular sorption equilibrium on the catalyst surface via enriching the reactants and intermediates, removing the products, and inhibiting the side reactions to enhance the catalytic performance. As a result, high activity, excellent selectivity, and outstanding durability of the catalysts were achieved. In addition, current challenges and perspectives of applying this strategy to more important industrial reactions are discussed. Applications of advanced characterization tools, machine learning, and artificial intelligence for monitoring the dynamic structural changes of the catalyst and predicting the structural evolutions under working conditions are anticipated to continuously play important roles in catalyst design. We believe that this strategy will open a door for the development of highly efficient catalysts with potential applications in the future.

ConspectusZinc metal batteries (ZMBs) appear to be promising candidates to replace lithium-ion batteries owing to their higher safety and lower cost. Moreover, natural reserves of Zn are abundant, being approximately 300 times greater than those of Li. However, there are some typical issues impeding the wide application of ZMBs. Traditional inorganic cathodes exhibit an unsatisfactory cycling lifetime because of structure collapse and active materials dissolution. Apart from inorganic cathodes, organic materials are now gaining extensive attention as ZMBs cathodes because of their sustainability, high environmental friendliness, and tunable molecule structure which make them usually exhibit superior cycling life. Nevertheless, due to the inferior conductivity of organic materials, their mass loading and volumetric energy density still cannot meet our demands. In addition, the specific working mechanism of inorganic/organic cathodes also needs further investigation, necessitating the use of advanced in situ characterization technologies. Reversibility of metallic Zn anodes is also crucial in determining the overall cell performances. Like Li and Na anodes, uncontrolled dendrite growth is also an annoying problem for Zn anodes, which may penetrate the separator and cause inner short circuit. In aqueous electrolyte, highly reactive HO molecules easily attack metallic Zn anode, leading to undesired Zn corrosion. Furthermore, during cell operation, hydrogen evolution reaction (HER) occurs, which leads to continuous consumption of electrolytes and formation of insulating byproducts on Zn anodes. Although strategies like novel Zn anode design and artificial SEI layer construction are proposed to inhibit dendrites growth and protect Zn anodes from active HO attack, the corresponding manufacturing process remains complex. Modifying electrolyte components is relatively simple to implement and effectively stabilizes Zn anodes. However, HER cannot be completely eliminated when HO exists in the modified electrolytes. Under such conditions, nonaqueous electrolytes appear to be a promising solution for ZMBs in the future due to their aprotic nature and high stability with the Zn anodes. However, the ionic conductivity of nonaqueous electrolytes is relatively low compared to that of aqueous electrolytes. Most of the previous reviews focus only on the individual components of ZMBs. A review of ZMBs from a higher perspective, focusing on advanced ZMBs system design, is currently lacking.In this Account, we begin with a brief overview of ZMBs, highlighting their advantages and current challenges. Subsequently, we give a summary of the development of inorganic cathodes (such as MnO) for ZMBs. Specifically, development history and representative modification strategy of inorganic cathodes are illustrated. Following this, representative organic cathodes are discussed, along with introduction of novel modification strategies for organic cathodes. Afterward, Zn anode form design, additive selection and artificial solid electrolyte interface (SEI) layer are briefed for development of Zn anodes. Thereafter, formulation of electrolyte components is systematically discussed, highlighting potential future of nonaqueous electrolyte in ZMBs. Unlike other reviews giving very detailed information in one aspect, this Account offers an overview of current opportunities and challenges faced by ZMBs. We hope this Account can provide researchers with deeper insights into the evolution of ZMBs, encouraging them to devise effective and innovative strategies that will accelerate widespread application of ZMB technology.