Accounts of Chemical Research最新文献

ConspectusNeurotechnology has seen dramatic improvements in the last three decades. The major focus in the field has been to design electrical communication platforms with high spatial resolution, stability, and translatability for understanding and affecting neural pathways. The deployment of nanomaterials in bioelectronics has enhanced the capabilities of conventional approaches employing microelectrode arrays (MEAs) for electrical interfaces, allowing the construction of miniaturized, high-performance neuroelectronics (Garg, R.; et al. ACS Appl. Nano Mater. 2023, 6, 8495). While these advancements in the electrical neuronal interface have revolutionized neurotechnology both in scale and breadth, an in-depth understanding of neurons' interactions is challenging due to the complexity of the environments where the cells and tissues are laid. The activity of large, three-dimensional neuronal systems has proven difficult to accurately monitor and modulate, and chemical cell-cell communication is often completely neglected. Recent breakthroughs in nanotechnology have provided opportunities to use new nonelectric modes of communication with neurons and to significantly enhance electrical signal interface capabilities. The enhanced electrochemical activity and optical activity of nanomaterials owing to their nonbulk electronic properties and surface nanostructuring have seen extensive utilization. Nanomaterials' enhanced optical activity enables remote neural state modulation, whereas the defect-rich surfaces provide an enormous number of available electrocatalytic sites for neurochemical detection and electrochemical modulation of cell microenvironments through Faradaic processes. Such unique properties can allow multimodal neural interrogation toward generating closed-loop interfaces with access to more complete neural state descriptors. In this Account, we will review recent advances and our efforts spearheaded toward utilizing nanostructured electrodes for enhanced bidirectional interfaces with neurons, the application of unique hybrid nanomaterials for remote nongenetic optical stimulation of neurons, tunable nanomaterials for highly sensitive and selective neurotransmitter detection, and the utilization of nanomaterials as electrocatalysts toward electrochemically modulating cellular activity. We highlight applications of these technologies across cell types through nanomaterial engineering with a focus on multifunctional graphene nanostructures applied though several modes of neural modulation but also an exploration of broad material classes for maximizing the potency of closed-loop bioelectronics.

ConspectusBiological nitrogen fixation mediated by nitrogenases has garnered significant research interest due to its critical importance to the development of efficient catalysts for mild ammonia synthesis. Although the active center of the most studied FeMo-nitrogenases has been determined to be a complicated [Fe₇S₉MoC] hetero-multinuclear metal-sulfur cluster known as the FeMo-cofactor, the exact binding site and reduction pathway of N₂ remain a subject of debate. Over the past decades, the majority of studies have focused on mononuclear molybdenum or iron centers as potential reaction sites. In stark contrast, cooperative activation of N₂ through bi- or multimetallic centers has been largely overlooked and underexplored, despite the renewed interest sparked by recent biochemical and computational studies. Consequently, constructing bioinspired bi- or multinuclear metallic model complexes presents an intriguing yet challenging prospect. In this Account, we detail our long-standing research on the design and synthesis of novel thiolate-bridged diiron complexes as nitrogenase models and their application to chemical simulations of potential biological N₂ reduction pathways.Inspired by the structural and electronic features of the potential diiron active center in the belt region of the FeMo-cofactor, we have designed and synthesized a series of new thiolate-bridged diiron nitrogenase model complexes, wherein iron centers with +2 or +3 oxidation states are coordinated by Cp* as carbon-based donors and thiolate ligands as sulfur donors. Through the synergistic interaction between the two iron centers, unstable diazene (NH═NH) species can be trapped to generate the first example of a [Fe₂S₂]-type complex bearing a cis-μ-η¹:η¹-NH═NH subunit. Significantly, this species can not only catalyze the reductive N-N bond cleavage of hydrazine to ammonia but also trigger a stepwise reduction sequence NH═NH → [NH₂-NH]^- → [NH]^2-(+NH₃) → [NH₂]^- → NH₃. Furthermore, an unprecedented thiolate-bridged diiron μ-nitride featuring a bent Fe-N-Fe moiety was successfully isolated and structurally characterized. Importantly, this diiron μ-nitride can undergo successive proton-coupled electron transfer processes to efficiently release ammonia in the presence of separate protons and electrons and can even be directly hydrogenated using H₂ as a combination of protons and electrons for high-yield ammonia formation. Based on combined experimental and computational studies, we proposed two distinct reductive transformation sequences on the diiron centers, which involve a series of crucial N_xH_y intermediates. Moreover, we also achieved catalytic N₂ reduction to silylamines with [Fe₂S₂]-type complexes by ligand mod

ConspectusThe bis-tetrahydroisoquinoline (bis-THIQ) natural products represent a medicinally important class of isoquinoline alkaloids that exhibit broad biological activities with particularly potent antitumor properties, as exemplified by the two U.S. FDA approved molecules trabectidin and lurbinectedin. Accordingly, other members within the bis-THIQ family have emerged as prime targets for synthetic chemists, aiming to innovate an orthogonal chemical production of these compounds. With the ability of these complementary strategies to reliably and predictably manipulate molecular structures with atomic precision, this should allow the preparation of synthetic derivatives not existing in nature as new drug leads in the development of novel medicines with desired biological functions.Beyond the biological perspective, bis-THIQ natural products also possess intricate and unique structures, serving as a source of intellectual stimulation for synthetic organic chemists. Within our laboratory, we have developed an integrated program that combines reaction development and target-directed synthesis, leveraging the architecturally complex molecular framework of bis-THIQ natural products as a driving force for the advancement of novel reaction methodologies. In this Account, we unveil our synthetic efforts in a comprehensive story, describing how our synthetic strategy toward bis-THIQ natural products, specifically jorunnamycin A and jorumycin, has evolved over the course of our studies through our key transformations comprising (a) the direct functionalization of isoquinoline N-oxide to prepare the bis-isoquinoline (bis-IQ) intermediate, (b) the diastereoselective and enantioselective isoquinoline hydrogenation to forge the pentacyclic skeleton of the natural product, and (c) the late-stage oxygenation chemistry to adjust the oxidation states of the A- and E-rings. First, we detail our plan in utilizing the aryne annulation strategy to prepare isoquinoline fragments for the bis-THIQ molecules. Faced with unpromising results in the direct C-H functionalization of isoquinoline N-oxide, we lay out in this Account our rationale behind the design of each isoquinoline coupling partner to overcome these challenges. Additionally, we reveal the inspiration for our hydrogenation system, the setup of our pseudo-high-throughput screening, and the extension of the developed hydrogenation protocols to other simplified isoquinolines.In the context of non-natural bis-THIQ molecules, we have successfully adapted this tandem coupling/hydrogenation approach in the preparation of perfluorinated bis-THIQs, representing the first set of electron-deficient non-natural analogues. Finally, we include our unsuccessful late-stage oxygenation attempts prior to the discovery of the Pd-catalyzed C-O cross-coupling reaction. With this full disclosure of the chemistry developed for the syntheses of bis-THIQs, we hope our orthogonal synthetic tactics will provide us

ConspectusSophisticated genetic networks play a pivotal role in orchestrating cellular responses through intricate signaling pathways across diverse environmental conditions. Beyond the inherent complexity of natural cellular signaling networks, the construction of artificial signaling pathways (ASPs) introduces a vast array of possibilities for reshaping cellular responses, enabling programmable control of living organisms. ASPs can be integrated with existing cellular networks and redirect output responses as desired, allowing seamless communication and coordination with other cellular processes, thereby achieving designable transduction within cells. Among diversified ASPs, establishing connections between originally independent endogenous genes is of particular significance in modifying the genetic networks, so that cells can be endowed with new capabilities to sense and deal with abnormal factors related to differentiated gene expression (i.e., solve the issues of the aberrant gene expression induced by either external or internal stimuli). In a typical scenario, the two genes X and Y in the cell are originally expressed independently. After the introduction of an ASP, changes in the expression of gene X may exert a designed impact on gene Y, subsequently inducing the cellular response related to gene Y. If X represents a disease signal and Y serves as a therapeutic module, the introduction of the ASP empowers cells with a new spontaneous defense system to handle potential risks, which holds great potential for both fundamental and translational studies.In this Account, we primarily review our endeavors in the construction of RNA-mediated ASPs between endogenous genes that can respond to differentiated RNA expression. In contrast to other molecules that may be restricted to specific pathways, synthetic RNA circuits can be easily utilized and expanded as a general platform for constructing ASPs with a high degree of programmability and tunability for diversified functionalities through predictable Watson-Crick base pairing. We first provide an overview of recent advancements in RNA-based genetic circuits, encompassing but not limited to utilization of RNA toehold switches, siRNA and CRISPR systems. Despite notable progress, most reported RNA circuits have to contain at least one exogenous RNA X as input or one engineered RNA Y as a target, which is not suitable for establishing endogenous gene connections. While exogenous RNAs can be engineered and controlled as desired, constructing a general and efficient platform for manipulation of naturally occurring RNAs poses a formidable challenge, especially for the mammalian system. With a focus on this goal, we are devoted to developing efficient strategies to manipulate cell responses by establishing RNA-mediated ASPs between endogenous genes, particularly in mammalian cells. Our step-by-step progress in engineering customized cell signaling circuits, from bacterial cells to mammalian cells,

ConspectusChemists have long been inspired by biological photosynthesis, wherein a series of excited-state electron transfer (ET) events facilitate the conversion of low energy starting materials such as H₂O and CO₂ into higher energy products in the form of carbohydrates and O₂. While this model for utilizing light-driven charge transfer to drive catalytic reactions thermodynamically "uphill" has been extensively adapted for small molecule activation, molecular machines, photoswitches, and solar fuel chemistry, its application in organic synthesis has been less systematically developed. However, the potential benefits of these approaches are significant, both in enabling transformations that cannot be readily achieved using conventional thermal chemistry and in accessing distinct selectivity regimes that are uniquely enabled by excited-state mechanisms. In this Account, we present work from our group that highlights the ability of visible light photoredox catalysis to drive useful organic transformations away from their equilibrium positions, addressing a number of long-standing synthetic challenges.We first discuss how excited-state ET enabled the first general methods for the catalytic anti-Markovnikov hydroamination of unactivated alkenes with alkyl amines. In these reactions, an excited-state iridium(III) photocatalyst reversibly oxidizes secondary amine substrates to their corresponding aminium radical cations (ARCs). These electrophilic N-centered radicals can then react with olefins to furnish valuable tertiary amine products with complete anti-Markovnikov regioselectivity. Notably, some of these products are less thermodynamically stable than their corresponding amine and alkene starting materials. We next present a strategy for light-driven C-C bond cleavage within various aliphatic alcohols mediated by homolytic activation of alcohol O-H bonds by excited-state proton-coupled electron transfer (PCET). The resulting alkoxy radical intermediates then undergo C-C β-scission to ultimately provide isomeric linear carbonyl products that are often higher in energy than their cyclic alcohol precursors. Applications of this chemistry for the light-driven depolymerization of lignin biomass, commercial phenoxy resin, hydroxylated polyolefin derivatives, and thermoset polymers are presented as well. We then describe a method for the contrathermodynamic positional isomerization of highly substituted olefins by means of cooperative photoredox and chromium(II) catalysis. In this work, generation of an allylchromium(III) species that can undergo highly regioselective in situ protodemetalation enables access to a less substituted and thermodynamically less stable positional isomer. Product selectivity in this reaction is determined by the large differential in oxidation potentials between differently substituted olefin isomers. Lastly, we discuss a light-driven deracemization reaction developed in col

ConspectusKohn-Sham density functional theory (KS DFT) is arguably the most widely applied electronic-structure method with tens of thousands of publications each year in a wide variety of fields. Its importance and usefulness can thus hardly be overstated. The central quantity that determines the accuracy of KS DFT calculations is the exchange-correlation functional. Its exact form is unknown, or better "unknowable", and therefore the derivation of ever more accurate yet efficiently applicable approximate functionals is the "holy grail" in the field. In this context, the simultaneous minimization of so-called delocalization errors and static correlation errors is the greatest challenge that needs to be overcome as we move toward more accurate yet computationally efficient methods. In many cases, an improvement on one of these two aspects (also often termed fractional-charge and fractional-spin errors, respectively) generates a deterioration in the other one. Here we report on recent notable progress in escaping this so-called "zero-sum-game" by constructing new functionals based on the exact-exchange energy density. In particular, local hybrid and range-separated local hybrid functionals are discussed that incorporate additional terms that deal with static correlation as well as with delocalization errors. Taking hints from other coordinate-space models of nondynamical and strong electron correlations (the B13 and KP16/B13 models), position-dependent functions that cover these aspects in real space have been devised and incorporated into the local-mixing functions determining the position-dependence of exact-exchange admixture of local hybrids as well as into the treatment of range separation in range-separated local hybrids. While initial functionals followed closely the B13 and KP16/B13 frameworks, meanwhile simpler real-space functions based on ratios of semilocal and exact-exchange energy densities have been found, providing a basis for relatively simple and numerically convenient functionals. Notably, the correction terms can either increase or decrease exact-exchange admixture locally in real space (and in interelectronic-distance space), leading even to regions with negative admixture in cases of particularly strong static correlations. Efficient implementations into a fast computer code (Turbomole) using seminumerical integration techniques make such local hybrid and range-separated local hybrid functionals promising new tools for complicated composite systems in many research areas, where simultaneously small delocalization errors and static correlation errors are crucial. First real-world application examples of the new functionals are provided, including stretched bonds, symmetry-breaking and hyperfine coupling in open-shell transition-metal complexes, as well as a reduction of static correlation errors in the computation of nuclear shieldings and magnetizabilities. The newest versions of range-separated local hybrids (e.g., ωLH

ConspectusTransmembrane pores are currently at the forefront of nanobiotechnology, nanopore chemistry, and synthetic chemical biology research. Over the past few decades, significant studies in protein engineering have paved the way for redesigning membrane protein pores tailored for specific applications in nanobiotechnology. Most previous efforts predominantly centered on natural β-barrel pores designed with atomic precision for nucleic acid sequencing and sensing of biomacromolecules, including protein fragments. The requirement for a more efficient single-molecule detection system has driven the development of synthetic nanopores. For example, engineering channels to conduct ions and biomolecules selectively could lead to sophisticated nanopore sensors. Also, there has been an increased interest in synthetic pores, which can be fabricated to provide more control in designing architecture and diameter for single-molecule sensing of complex biomacromolecules. There have been impressive advancements in developing synthetic DNA-based pores, although their application in nanopore technology is limited. This has prompted a significant shift toward building synthetic transmembrane α-helical pores, a relatively underexplored field offering novel opportunities. Recently, computational tools have been employed to design and construct α-helical barrels of defined structure and functionality.We focus on building synthetic α-helical pores using naturally occurring transmembrane motifs of membrane protein pores. Our laboratory has developed synthetic α-helical transmembrane pores based on the natural porin PorACj (Porin A derived from Corynebacterium jeikeium) that function as nanopore sensors for single-molecule sensing of cationic cyclodextrins and polypeptides. Our breakthrough lies in being the first to create a functional and large stable synthetic transmembrane pore composed of short synthetic α-helical peptides. The key highlight of our work is that these pores can be synthesized using easy chemical synthesis, which permits its easy modification to include a variety of functional groups to build charge-selective sophisticated pores. Additionally, we have demonstrated that stable functional pores can be constructed from D-amino acid peptides. The analysis of pores composed of D- and L-amino acids in the presence of protease showed that only the D pores are highly functional and stable. The structural models of these pores revealed distinct surface charge conformation and geometry. These new classes of synthetic α-helical pores are highly original systems of general interest due to their unique architecture, functionality, and potential applications in nanopore technology and chemical biology. We emphasize that these simplified transmembrane pores have the potential to be components of functional nanodevices and therapeutic tools. We also suggest that such designed peptides might be valuable as antimicrobial agents and can be targeted to

ConspectusThe directed synthesis and functionalization of porous crystalline materials pose significant challenges for chemists. The synergistic integration of different functionalities within an ordered molecular material holds great significance for expanding its applications as functional materials. The presence of coordination bonds connected by inorganic and organic components in molecular materials can not only increase the structural diversity of materials but also modulate the electronic structure and band gap, which further regulates the physical and chemical properties of molecular materials. In fact, porous crystalline materials with coordination bonds, which inherit the merits of both organic and inorganic materials, already showcase their superior advantages in optical, electrical, and magnetic applications. In addition to the inorganic components that provide structural rigidity, organic ligands of various types serve as crucial connectors in the construction of functional porous crystalline materials. In addition, redox activity can endow organic linkers with electrochemical activity, thereby making them a perfect platform for the study of charge transfer with atom-resolved single-crystal structures, and they can additionally serve as stimuli-responsive sites in sensor devices and smart materials.In this Account, we introduce the synthesis, structural characteristics, and applications of porous crystalline materials based on the famous redox-active units, tetrathiafulvalene (TTF) and its analogues, by primarily focusing on metal-organic frameworks (MOFs) and covalent organic frameworks (COFs). TTF, a sulfur-rich conjugated molecule with two reversible and easily accessible oxidation states (i.e., radical TTF^•+ cation and TTF²⁺ dication), and its analogues boast special electrical characteristics that enable them to display switchable redox activity and stimuli-responsive properties. These inherent properties contribute to the enhancement of the optical, electrical, and magnetic characteristics of the resultant porous crystalline materials. Moreover, delving into the charge transfer phenomena, which is key for the electrochemical process within these materials, uncovers a myriad of potential functional applications. The Account is organized into five main sections that correspond to the different properties and applications of these materials: optical, electrical, and magnetic functionalities; energy storage and conversion; and catalysis. Each section provides detailed discussions of synthetic methods, structural characteristics, the physical and chemical properties, and the functional performances of highlighted examples. The Account also discusses future directions by emphasizing the exploration of novel organic units, the transformation between radical cation TTF^•+ and dication TTF²⁺, and the integration of multifunctionalities within these frameworks to foster the development of

ConspectusThe halogen-metal exchange reaction is a very powerful method for preparing functionalized organometallic reagents in the fields of organic and organometallic chemistry. Since its inception, significant interest has been directed toward the on-demand development of new halogen-metal exchange reactions, primarily through the upgrading of exchange reagents. The enduring quest for optimal reactivity, superior functional group compatibility, and innovative synthetic applications of exchange reagents remains a fundamental objective. In the past several years, the emergence of some significant discoveries in halogen-metal exchange reactions has proclaimed a renaissance to this field. This Account outlines the latest advances within the domain contributed by the Knochel group, including the main points as follows.The stereoretentive I/Li exchange on stereodefined secondary alkyl iodides was developed for the synthesis of nonstabilized chiral secondary alkyllithium reagents. This provided a straightforward method to access chiral organolithium reagents, which can be trapped by various electrophiles or transmetalated with other metals such as copper, zinc, and magnesium, thus enabling the stereoselective synthesis of a series of functionalized compounds and natural products.Faster halogen-magnesium and halogen-zinc exchanges in toluene were realized using a novel kind of exchange reagent complexed with lithium alkoxide. These highly efficient exchange reactions are much faster than traditional ones and performed in an industrially friendly solvent. These advantages are of great value in practical synthesis, paving the way for new developments in this evolving area.Halogen-lanthanide exchanges and their novel applications in organic synthesis were established. These new exchanges introduced the lanthanide metals into halogen-metal exchange reactions for the first time, thereby opening new avenues in synthetic chemistry. Building on these achievements, a comparative analysis of the exchange reaction rates by kinetic study has quantified the relationship between the electronegativity of metals and the rates of halogen-metal exchanges.Br/Na exchange in continuous flow was achieved using a hexane-soluble exchange reagent, 2-ethylhexylsodium. This approach effectively circumvented the poor solubility of the organosodium reagent, which has proven to be of significant practical value and greatly enhanced the synthetic utility of the organosodium reagent in organic synthesis.These remarkable breakthroughs as mentioned above are fueled mainly by upgrading the exchange reagents, resulting in the development of new halogen-metal exchange reactions and innovative applications in organic synthesis. Given the importance of halogen-metal exchanges in synthetic chemistry, the pursuit of other types of exchange reactions, particularly those involving new metals, will be in continuous demand. This Account provides a timely summary of recent progress and will

ConspectusMembranes are pivotal in a myriad of energy production processes and modern separation techniques. They are essential in devices for energy generation, facilities for extracting energy elements, and plants for wastewater treatment, each of which hinges on effective ion separation. While biological ion channels show exceptional permeability and selectivity, designing synthetic membranes with defined pore architecture and chemistry on the (sub)nanometer scale has been challenging. Consequently, a typical trade-off emerges: highly permeable membranes often sacrifice selectivity and vice versa. To tackle this dilemma, a comprehensive understanding and modeling of synthetic membranes across various scales is imperative. This lays the foundation for establishing design criteria for advanced membrane materials. Key attributes for such materials encompass appropriately sized pores, a narrow pore size distribution, and finely tuned interactions between desired permeants and the membrane. The advent of covalent-organic-framework (COF) membranes offers promising solutions to the challenges faced by conventional membranes in selective ion separation within the water-energy nexus. COFs are molecular Legos, facilitating the precise integration of small organic structs into extended, porous, crystalline architectures through covalent linkage. This unique molecular architecture allows for precise control over pore sizes, shapes, and distributions within the membrane. Additionally, COFs offer the flexibility to modify their pore spaces with distinct functionalities. This adaptability not only enhances their permeability but also facilitates tailored interactions with specific ions. As a result, COF membranes are positioned as prime candidates to achieve both superior permeability and selectivity in ion separation processes.In this Account, we delineate our endeavors aimed at leveraging the distinctive attributes of COFs to augment ion separation processes, tackling fundamental inquiries while identifying avenues for further exploration. Our strategies for fabricating COF membranes with enhanced ion selectivity encompass the following: (1) crafting (sub)nanoscale ion channels to enhance permselectivity, thereby amplifying energy production; (2) implementing a multivariate (MTV) synthesis method to control charge density within nanochannels, optimizing ion transport efficiency; (3) modifying the pore environment within confined mass transfer channels to establish distinct pathways for ion transport. For each strategy, we expound on its chemical foundations and offer illustrative examples that underscore fundamental principles. Our efforts have culminated in the creation of groundbreaking membrane materials that surpass traditional counterparts, propelling advancements in sustainable energy conversion, waste heat utilization, energy element extraction, and pollutant removal. These innovations are poised to redefine energy systems and industrial waste