Accounts of Chemical Research最新文献

In this Account, we discuss our group’s research over the past decade on a class of functionalized boron clusters with tunable chemical and physical properties, with an emphasis on accessing and controlling their redox behavior. These clusters can be thought of as three-dimensional aromatic systems that have distinct redox behavior and photophysical properties compared to their two-dimensional organic counterparts. Specifically, our lab has studied the highly tunable, multielectron redox behavior of B₁₂(OR)₁₂ clusters and applied these molecules in various settings. We first discuss the spectroscopic and electrochemical characterization of B₁₂(OR)₁₂ clusters in various oxidation states, followed by their use as catholytes and/or anolytes in redox flow batteries and chemical dopants in conjugated polymers. Additionally, the high oxidizing potential and visible light-absorbing nature of fluoroaryl-functionalized B₁₂(OR)₁₂ clusters have been leveraged by our group to generate weakly coordinating, photoexcitable species that can promote photooxidation chemistry.

We have further translated these solution-phase studies of B₁₂(OR)₁₂ clusters to the solid state by using the precursor [B₁₂(OH)₁₂]^2– cluster as a robust building block for hybrid metal oxide materials. Specifically, we have shown that the boron cluster can act as a thermally stable cross-linking material, which enhances electron transport between metal oxide nanoparticles. We applied this structural motif to create TiO₂- and WO₃-containing materials that showed promising properties as photocatalysts and electroactive materials for supercapacitors. Building on this concept, we later discovered that B₁₂(OCH₃)₁₂, the smallest of the B₁₂(OR)₁₂ family, could retain its redox behavior in the solid state, a previously unseen phenomenon. We successfully harnessed this unique behavior for solid-state energy storage by implementing this boron cluster as a cathode-active material in a Li-ion prototype cell device. Recently, our group has also explored how to tune the redox properties of clusters other than B₁₂(OR)₁₂ species by synthesizing a library of vertex-differentiated clusters containing both B-OR and B-halogen groups. Due to the additive qualities of different functional groups on the cluster, these species allow access to a region of electrochemical potentials previously inaccessible by fully substituted closo-dodecaborate alkoxy-based derivatives.

Lastly, we discuss our research into smaller-sized redox-active polyhedral boranes (B₆- and B₁₀-based cluster cores). Interestingly, these clusters show significantly less redox stability and reversibility than their dodecaborate-based counterparts. While exploring the functionalization o

Due to its importance for electrolyzers or metal–air batteries for energy conversion or storage, there is huge interest in the development of high-performance materials for the oxygen evolution reaction (OER). Theoretical investigations have aided the search for active material motifs through the construction of volcano plots for the kinetically sluggish OER, which involves the transfer of four proton–electron pairs to form a single oxygen molecule. The theory-driven volcano approach has gained unprecedented popularity in the catalysis and energy communities, largely due to its simplicity, as adsorption free energies can be used to approximate the electrocatalytic activity by heuristic descriptors.

In the last two decades, the binding-energy-based volcano method has witnessed a renaissance with special concepts being developed to incorporate missing factors into the analysis. To this end, this Account summarizes and discusses the different generations of volcano plots for the example of the OER. While first-generation methods relied on the assessment of the thermodynamic information for the OER reaction intermediates by means of scaling relations, the second and third generations developed strategies to include overpotential and kinetic effects into the analysis of activity trends. Finally, the fourth generation of volcano approaches allowed the incorporation of various mechanistic pathways into the volcano methodology, thus paving the path toward data- and mechanistic-driven volcano plots in electrocatalysis.

Although the concept of volcano plots has been significantly expanded in recent years, further research activities are discussed by challenging one of the main paradigms of the volcano concept. To date, the evaluation of activity trends relies on the assumption of proton-coupled electron transfer steps (CPET), even though there is experimental evidence of sequential proton–electron transfer (SPET) steps. While the computational assessment of SPET for solid-state electrodes is ambitious, it is strongly suggested to comprehend their importance in energy conversion and storage processes, including the OER. This can be achieved by knowledge transfer from homogeneous to heterogeneous electrocatalysis and by focusing on the material class of single-atom catalysts in which the active center is well defined. The derived concept of how to analyze the importance of SPET for mechanistic pathways in the OER over solid-state electrodes could further shape our understanding of the proton–electron transfer steps at electrified solid/liquid interfaces, which is crucial for further progress toward sustainable energy and climate neutrality.

Carbohydrates are called the third chain of life. Carbohydrates participate in many important biochemical functions in living species, and the biological information carried by them is several orders of magnitude larger than that of nucleic acids and proteins. However, due to the intrinsic complexity and heterogeneity of carbohydrate structures, furnishing pure and structurally well-defined glycans for functional studies is a formidable task, especially for homogeneous large-size glycans. To address this issue, we have developed a donor preactivation-based one-pot glycosylation strategy enabling multiple sequential glycosylations in a single reaction vessel.

The donor preactivation-based one-pot glycosylation refers to the strategy in which the glycosyl donor is activated in the absence of a glycosyl acceptor to generate a reactive intermediate. Subsequently, the glycosyl acceptor with the same anomeric leaving group is added, leading to a glycosyl coupling reaction, which is then iterated to rapidly achieve the desired glycan in the same reactor. The advantages of this strategy include the following: (1) unique chemoselectivity is obtained after preactivation; (2) it is independent of the reactivity of glycosyl donors; (3) multiple-step glycosylations are enabled without the need for intermediate purification; (4) only stoichiometric building blocks are required without complex protecting group manipulations. Using this protocol, a range of glycans including tumor-associated carbohydrate antigens, various glycosaminoglycans, complex N-glycans, and diverse bacterial glycans have been synthesized manually. Gratifyingly, the synthesis of mycobacterial arabinogalactan containing 92 monosaccharide units has been achieved, which created a precedent in the field of polysaccharide synthesis. Recently, the synthesis of a highly branched arabinogalactan from traditional Chinese medicine featuring 140 monosaccharide units has been also accomplished to evaluate its anti-pancreatic-cancer activity. In the spirit of green and sustainable chemistry, this strategy can also be applied to light-driven glycosylation reactions, where either UV or visible light can be used for the activation of glycosyl donors.

Automated synthesis is an advanced approach to the construction of complex glycans. Based on the two preactivation modes (general promoter activation mode and light-induced activation mode), a universal and highly efficient automated solution-phase synthesizer was further developed to drive glycan assembly from manual to automated synthesis. Using this synthesizer, a library of oligosaccharides covering various glycoforms and glycosidic linkages was assembled rapidly, either in a general promoter-activation mode or in a light-induced-activation mode. The automated synthesis of a fully protected fondaparinux pentasaccharide was realized on a gram scale. Furthermore, the automated synthesis of large-size polysaccharides was performed, a

In 1960, Weber prophesied that “There are many ways in which the properties of the excited state can be utilized to study points of ignorance of the structure and function of proteins”. This has been realized, illustrating that an intrinsic and highly responsive fluorophore such as tryptophan can alter the course of an entire scientific discipline. But what about RNA and DNA? Adapting Weber’s protein photophysics prophecy to nucleic acids requires the development of intrinsically emissive nucleoside surrogates as, unlike Trp, the canonical nucleobases display unusually low emission quantum yields, which render nucleosides, nucleotides, and oligonucleotides practically dark for most fluorescence-based applications.

Over the past decades, we have developed emissive nucleoside surrogates that facilitate the monitoring of nucleoside-, nucleotide-, and nucleic acid-based transformations at a nucleobase resolution in real time. The premise underlying our approach is the identification of minimal atomic/structural perturbations that endow the synthetic analogs with favorable photophysical features while maintaining native conformations and pairing. As illuminating probes, the photophysical parameters of such isomorphic nucleosides display sensitivity to microenvironmental factors. Responsive isomorphic analogs that function similarly to their native counterparts in biochemical contexts are defined as isofunctional.

Early analogs included pyrimidines substituted with five-membered aromatic heterocycles at their 5 position and have been used to assess the polarity of the major groove in duplexes. Polarized quinazolines have proven useful in assembling FRET pairs with established fluorophores and have been used to study RNA–protein and RNA–small-molecule binding. Completing a fluorescent ribonucleoside alphabet, composed of visibly emissive purine (^thA, ^thG) and pyrimidine (^thU, ^thC) analogs, all derived from thieno[3,4-d]pyrimidine as the heterocyclic nucleus, was a major breakthrough. To further augment functionality, a second-generation emissive RNA alphabet based on an isothiazolo[4,3-d]pyrimidine core (^thA, ^tzG, ^tzU, and ^tzC) was fabricated. This single-atom “mutagenesis” restored the basic/coordinating nitrogen corresponding to N7 in the purine skeleton and elevated biological recognition.

The isomorphic emissive nucleosides and nucleotides, particularly the purine analogs, serve as substrates for diverse enzymes. Beyond polymerases, we have challenged the emissive analogs with metabolic and catabolic enzymes, opening optical windows into the biochemistry of nucleosides and nucleotides as metabolites as well as coenzymes and second messengers. Real-time fluorescence-based assays for adenosine deaminase, guanine deaminase, and cytidine deaminase have been fabricated and used for inhibitor discovery. Emissive cofactors (e.g., S

Evolution of implantable neural interfaces is critical in addressing the challenges in understanding the fundamental working principles and therapeutic applications for central and peripheral nervous systems. Traditional approaches utilizing hermetically sealed, rigid electronics and detached electrodes face challenges in power supply, encapsulation, channel count, dispersed application location, and modality. Employing thin-film, wirelessly powered devices is promising to expand capabilities. Devices that forego bulky power supplies, favoring a configuration where electronics are integrated directly onto thin films, reduce displacement volumes for seamless, fully implantable interfaces with high energy availability and soft mechanics to conform to the neuronal target. We discuss 3 device architectures: (1) Highly miniaturized devices that merge electronics and neural interfaces into a single, injectable format; (2) Interfaces that consolidate power, computation, and neural connectivity on a thin sheet applied directly to the target area; (3) A spatially dislocated approach where power and computation are situated subdermally, connected via a thin interconnect to the neural interface.Each has advantages and constraints in terms of implantation invasiveness, power capturing efficiency, and directional sensitivity of power delivery. In powering these devices, near-field power delivery emerges as the most implemented technique. Key parameters are size and volume of primary and secondary antennas, which determine coupling efficiency and power delivery. Based on application requirements, ranging from small to large animal models, subjects require system level designs. Material strategies play a crucial role; monolithic designs, with materials like polyimide substrates, enable scalability with high performance. This contrasts with established hermetic encapsulation approaches that use a stainless steel or titanium box with passthroughs that result in large tissue displacements and prohibit intimate integration with target organ systems. Encapsulation, particularly with parylene, enables longevity and effectiveness; more research is needed to enable human lifetime operation. Implant-to-ambient device communication, focusing on strategies compatible with well-established standards and off-the-shelf electronics, is discussed with the goal of enabling seamless system integration, reliability, and scalability. The interface with the central nervous system is explored through various wireless, battery-free devices capable of both stimulation (electrical and optogenetic) and recording (photometric and electrochemical). These devices show advanced capabilities for chronic studies and insights into neural dynamics. In the peripheral nervous system, stimulation devices for applications, such as spinal and muscle stimulation, are discussed. The challenges lie in the mechanical and electrochemical durability. Examples that successfully navigate these challenge

London dispersion (LD) forces are ubiquitous in chemistry, playing a pivotal role in a wide range of chemical processes. For example, they influence the structure of molecular crystals, the selectivity of organocatalytic transformations, and the formation of biomolecular assemblies. Harnessing these forces for chemical applications requires consistent quantification of the LD energy across a broad and diverse spectrum of chemical scenarios. Despite the great progress made in recent years in the development of experimental strategies for LD quantification, quantum chemical methods remain one of the most useful tools in the hand of chemists for the study of these weak interactions. Unfortunately, the accurate quantification of LD effects in complex systems poses many challenges for electronic structure theories. One of the problems stems from the fact that LD forces originate from long-range electronic dynamic correlation, and hence, their rigorous description requires the use of complex, highly correlated wave function-based methods. These methods typically feature a steep scaling with the system size, limiting their applicability to small model systems. Another core challenge lies in disentangling short-range from long-range dynamic correlation, which from a rigorous quantum mechanical perspective is not possible.

In this Account, we describe our research endeavors in the development of broadly applicable computational methods for LD quantification in molecular chemistry as well as challenging applications of these schemes in various domains of chemical research. Our strategy lies in the use of local correlation theories to reduce the computational cost associated with complex electronic structure methods while providing at the same time a simple means of decomposition of dynamic correlation into its long-range and short-range components. In particular, the local energy decomposition (LED) scheme at the domain-based local pair natural orbital coupled cluster (DLPNO-CCSD(T)) level has emerged as a powerful tool in our research, offering a clear-cut quantitative definition of the LD energy that remains valid across a plethora of different chemical scenarios. Typical applications of this scheme are examined, encompassing protein–ligand interactions and reactivity studies involving many fragments and complex electronic structures. In addition, our research also involves the development of novel cost-effective methodologies, which exploit the LED definition of the LD energy, for LD energy quantification that are, in principle, applicable to systems with thousands of atoms. The Hartree–Fock plus London Dispersion (HFLD) scheme, correcting the HF interaction energy using an approximate CCSD(T)-based LD energy, is a useful, parameter-free electronic structure method for the study of LD effects in systems with hundreds of molecular fragments. However, the usefulness of the LED scheme reaches beyond providing an interpretation of the calculated

Cellular senescence can be defined as an irreversible stopping of cell proliferation that arises in response to various stress signals. Cellular senescence is involved in diverse physiological and pathological processes in different tissues, exerting effects on processes as differentiated as embryogenesis, tissue repair and remodeling, cancer, aging, and tissue fibrosis. In addition, the development of some pathologies, aging, cancer, and other age-related diseases has been related to senescent cell accumulation. Due to the complexity of the senescence phenotype, targeting senescent cells is not trivial, is challenging, and is especially relevant for in vivo detection in age-related diseases and tissue samples. Despite the elimination of senescent cells (senolysis) using specific drugs (senolytics) that have been shown to be effective in numerous preclinical disease models, the clinical translation is still limited due to the off-target effects of current senolytics and associated toxicities. Therefore, the development of new chemical strategies aimed at detecting and eliminating senescent cells for the prevention and selective treatment of senescence-associated diseases is of great interest. Such strategies not only will contribute to a deeper understanding of this rapidly evolving field but also will delineate and inspire new possibilities for future research.

In this Account, we report our recent research in the development of new chemical approaches for the detection and elimination of senescent cells based on new probes, nanoparticles, and prodrugs. The designed systems take advantage of the over-representation in senescent cells of certain biomarkers such as β-galactosidase and lipofuscin. One- and two-photon probes, for higher tissue penetration, have been developed. Moreover, we also present a renal clearable fluorogenic probe for the in vivo detection of the β-galactosidase activity, allowing for correlation with the senescent burden in living animals. Moreover, as an alternative to molecular-based probes, we also developed nanoparticles for senescence detection. Besides, we describe advances in new therapeutic agents to selectively eradicate senescent cells using β-galactosidase activity-sensitive gated nanoparticles loaded with cytotoxic or senolytic agents or new prodrugs aiming to increase the selectivity and reduction of off-target toxicities of current drugs. Moreover, new advances therapies have been applied in vitro and in vivo. Studies with the probes, nanoparticles, and prodrugs have been applied in several in vitro and in vivo models of cancer, fibrosis, aging, and drug-induced cardiotoxicity in which senescence plays an important role. We discuss the benefits of these chemical strategies toward the development of more specific and sophisticated probes, nanoparticles, and prodrugs targeting senescent cells.

Enzymes are desired catalysts for chemical synthesis, because they can be engineered to provide unparalleled levels of efficiency and selectivity. Yet, despite the astonishing array of reactions catalyzed by natural enzymes, many reactivity patterns found in small molecule catalysts have no counterpart in the living world. With a detailed understanding of the mechanisms utilized by small molecule catalysts, we can identify existing enzymes with the potential to catalyze reactions that are currently unknown in nature. Over the past eight years, our group has demonstrated that flavin-dependent “ene”-reductases (EREDs) can catalyze various radical-mediated reactions with unparalleled levels of selectivity, solving long-standing challenges in asymmetric synthesis.

This Account presents our development of EREDs as general catalysts for asymmetric radical reactions. While we have developed multiple mechanisms for generating radicals within protein active sites, this account will focus on examples where flavin mononucleotide hydroquinone (FMN_hq) serves as an electron transfer radical initiator. While our initial mechanistic hypotheses were rooted in electron-transfer-based radical initiation mechanisms commonly used by synthetic organic chemists, we ultimately uncovered emergent mechanisms of radical initiation that are unique to the protein active site. We will begin by covering intramolecular reactions and discussing how the protein activates the substrate for reduction by altering the redox-potential of alkyl halides and templating the charge transfer complex between the substrate and flavin-cofactor. Protein engineering has been used to modify the fundamental photophysics of these reactions, highlighting the opportunity to tune these systems further by using directed evolution. This section highlights the range of coupling partners and radical termination mechanisms available to intramolecular reactions.

The next section will focus on intermolecular reactions and the role of enzyme-templated ternary charge transfer complexes among the cofactor, alkyl halide, and coupling partner in gating electron transfer to ensure that it only occurs when both substrates are bound within the protein active site. We will highlight the synthetic applications available to this activation mode, including olefin hydroalkylation, carbohydroxylation, arene functionalization, and nitronate alkylation. This section also discusses how the protein can favor mechanistic steps that are elusive in solution for the asymmetric reductive coupling of alkyl halides and nitroalkanes. We are aware of several recent EREDs-catalyzed photoenzymatic transformations from other groups. We will discuss results from these papers in the context of understanding the nuances of radical initiation with various substrates.

These biocatalytic asymmetric radical reactions often complement the state-of-the-art small-molecule-catalyzed reactions, making EREDs a val

The development of an advanced energy conversion system for water electrolysis with high efficiency and durability is of great significance for a hydrogen-powered society. This progress relies on the fabrication of electrocatalysts with superior electrochemical performance. Despite decades of advancements in exploring high-performance noble and non-noble metal electrocatalysts, several challenges persist at both the micro- and macrolevels in the field of water electrolysis.

At the microlevel, which encompasses electrocatalyst synthesis and characterization, design strategies for high-performance electrocatalysts have primarily focused on interface chemical engineering. However, comprehensive understanding and investigation of interface chemical engineering across various length scales, from micrometers to atomic scales, are still lacking. This deficiency hampers the rational design of catalysts with optimal performance. Under harsh reaction conditions, such as high bias potential and highly acidic or alkaline media, the surface of catalyst materials is susceptible to undergoing “reconstruction”, deviating from what is observed through ex situ characterization techniques postsynthesis. Conventional ex situ characterization methods do not provide an accurate depiction of the catalyst’s structural evolution during the electrocatalytic reaction, hindering the exploration of the catalytic mechanism.

At the macrolevel, pertaining to catalysis-performance evaluation systems and devices, traditional laboratory settings employ a conventional three-electrode or two-electrode system to assess the catalytic performance of electrocatalysts. However, this approach does not accurately simulate hydrogen production under realistic industrial conditions, such as elevated temperatures (60–70 °C), high current densities exceeding 0.5 A cm^–2, and flowing electrolytes. To address this limitation, it is crucial to develop testing equipment and methodologies that replicate the actual industrial conditions.

In this Account, we propose a multiscale research framework for water electrolysis, spanning from microscale synthesis to macroscale scaled reactor design. Our approach focuses on the design and evaluation of high-performance HER/OER (hydrogen evolution reaction/oxygen evolution reaction) electrocatalysts, incorporating the following strategies: Leveraging principles of interface chemical engineering across various length scales (micrometers, nanometers, and atoms) enables the design of catalyst materials that enhance both activity and durability. This approach provides a comprehensive understanding of the intricate interplay between the catalyst structure and activity, implementing in situ/operando characterization techniques to monitor dynamic interfacial reactions and surface reconstruction processes. This facilitates a profound exploration of catalytic reaction mechanisms, offering insights into the c

Zinc oxide (ZnO) is a multipurpose material and finds its applications in various fields such as rubber manufacturing, medicine, food additives, electronics, etc. It has also been intensively studied in photocatalysis due to its wide band gap and environmental compatibility. Recently, heterogeneous catalysts with supported ZnO_x species have attracted more and more attention for the dehydrogenation of propane (PDH) and isobutane (iBDH) present in shale/natural gas. The olefins formed in these reactions are key building blocks of the chemical industry. These reactions are also of academic importance for understanding the fundamentals of the selective activation of C–H bonds. Differently structured ZnO_x species supported on zeolites, SiO₂, and Al₂O₃ have been reported to be active for nonoxidative dehydrogenation reactions. However, the structure–activity–selectivity relationships for these catalysts remain elusive. The main difficulty stems from the preparation of catalysts containing only one kind of well-defined ZnO_x species.

In this Account, we describe the studies on PDH and iBDH over differently structured ZnO_x species and highlight our approaches to develop catalysts with controllable ZnO_x speciation relevant to their performance. Several methods, including (i) the in situ reaction of gas-phase metallic Zn atoms with OH groups on the surface of supports, (ii) one-pot hydrothermal synthesis, and (iii) impregnation/anchoring methods, have been developed/used for the tailored preparation of supported ZnO_x species. The first method allows precise control of the molecular structure of ZnO_x through the nature of the defective OH groups on the supports. Using this method, a series of ZnO_x species ranging from isolated, binuclear to nanosized ZnO_x have been successfully generated on different SiO₂-based or ZrO₂-based supports as demonstrated by complementary ex/in situ characterization techniques. Based on kinetic studies and detailed characterization results, the intrinsic activity (Zn-related turnover frequency) of ZnO_x was found to depend on its speciation. It increases with an increasing number of Zn atoms in a Zn_mO_n cluster from 1 to a few atoms (less than 10) and then decreases strongly for ZnO_x nanoparticles. The latter promote the formation of undesired C₁–C₂ hydrocarbons and coke, resulting in lower propene selectivity in comparison with the catalysts containing only ZnO_x species ranging from isolated to subnanometer Zn_mO_n clusters. In addition, the strategy for improving the thermal stability of ZnO_x species and the consequences of mass-transport limit