Angewandte Chemie International Edition

Applications of the Wittig-Still rearrangement in organic synthesis ()
This review traces the discovery of the Wittig-Still rearrangement and its applications in organic synthesis. Its relationship to Wittig rearrangements is discussed along with detailed analysis of E/Z- and diastereoselectivity. Modifications of the products arising from the Wittig-Still rearrangement are reviewed in the context of increased complexity in intermediates potentially useful in target oriented synthesis. Early applications of the Wittig-Still rearrangement to modifications of steroids are reviewed as are applications to various terpene and alkaloid natural product targets and miscellaneous compounds. To the best of our knowledge, the literature is covered through December 2016.
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A Tale of Two Elements: The Lewis Acidity/Basicity Umpolung of Boron and Phosphorus ()
This mini-review focuses on the Lewis acidity/basicity "umpolung" of B-based nucleophiles and P-based electrophiles.
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New Modalities for Challenging Targets in Drug Discovery ()
An ever increasing understanding of biological systems is providing a range of exciting novel biological targets whose modulation may enable novel therapeutic options in many diseases. These targets include protein-protein and protein-nucleic acid interactions, which are, however, often refractory to classical small molecule approaches. Other types of molecules, or modalities, are therefore required to address these targets, which has led several academic research groups and pharmaceutical companies to increasingly use the concept of so-called 'New Modalities'. This review defines for the first time the scope of this term, which includes novel peptidic scaffolds, oligonucleotides, hybrids, molecular conjugates as well as new uses of classical small molecules. We provide herein a journey through the most representative examples of these modalities to target large binding surface areas such as those found in protein-protein interactions and for biological processes at the center of cell regulation.
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Advanced Biofuels and Beyond: Chemistry Solutions for Propulsion and Production ()
Sustainably produced biofuels are being discussed intensively as one possible component in the energy scenarios for future ground transportation, especially when they are derived from lignocellulosic biomass. Traditionally, research activities on their production focus on the synthesis process, while leaving their combustion properties to subsequent evaluation by a different community. The present article adopts an integrative view of engine combustion and fuel synthesis, focusing on the chemical aspects as the common denominator. We wish to demonstrate that fundamental understanding of the combustion process can be instrumental to derive design criteria for the molecular structure of fuel candidates that can then be targets for the analysis of synthetic pathways and the development of catalytic production routes. With such an integrative approach to fuel design, it will be possible to improve systematically the entire system, spanning biomass feedstock, conversion process, fuel, engine, and pollutants with a perspective to improve the carbon footprint, increase efficiency, and reduce emissions of the transportation sector along the whole value chain.
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Nanostructured Materials for Heterogeneous Electrocatalytic CO2 Reduction and Related Reaction Mechanisms ()
The gradually increased concentration of carbon dioxide (CO2) in the atmosphere has been recognized as the primary culprit for the raise of the global mean temperature, thus resulting in the aggravated desert formation and extinction of species. In recent years, development of the routes for highly efficient conversion of CO2 has received numerous attentions. Among them, the reduction of CO2 with electric power is an important transformation route with high application prospect, due to its high environmental compatibility and good combination with other renewable energy sources such as solar and wind energy. This review describes recent progress on the design and synthesis of solid state catalysts (i.e., heterogeneous catalysts) and their emerging catalytic performances in the CO2 reduction. The significance for catalytic conversion of CO2 and the advantages of CO2 electroreduction will be presented in the introduction section, followed by the general parameters for CO2 electroreduction and the summary of reaction apparatus. We also discuss various types of solid catalysts according to CO2 conversion mechanisms. Furthermore, we summarize the crucial factors (particle size, surface structure, composition and etc.) determining the performance for electroreduction. These studies in improvement of solid state catalysts for CO2 reduction offer numerous experiences for developing potential industrialized CO2 electroreduction catalysts in the future. Additionally, the abundant experience for controllable synthesis of solid state catalysts could effectively guide the rational design of catalysts for other electrocatalytic reactions.
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Catalytic Dearomatization of N-Heteroarenes with Silicon and Boron Compounds ()
Dearomatized N-heterocycles provide a class of structural motifs important in the fields of synthetic organic chemistry and chemical biology. The catalytic dearomative reduction of unactivated N-heteroarenes using silicon and/or boron-containing compounds as a reductant is one of the most straightforward alternatives to hydrogenation. However, scattered precedents on the catalytic reduction of N-heteroaromatics with silane or borane reducing agents have been reported thus far, and a handful of elegant catalytic procedures for the reduction of N-aromatics have emerged only recently as a viable tool in organic synthesis. This review presents recent advances in the catalytic reduction of unactivated N-heteroarenes using hydrosilanes, hydroboranes, silaboranes, and diboranes. The focus presents the general chemical behavior and selectivity of transition-metal or metal-free organocatalyst systems for the dearomative homogeneous reduction of N-heteroarenes. In addition, the working modes of these catalysis will be described particularly on the basis of the experimental mechanistic insights.
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Modern Inorganic Aerogels ()
Essentially, the term aerogel describes a special geometric structure of matter. It is neither limited to any material nor to any synthesis procedure. Hence, the possible variety of materials and therefore the multitude of their applications are almost unbounded. In fact, the same applies for nanoparticles. These are also just defined by their geometrical properties. In the past decades nano-sized materials were intensively studied and possible applications appeared in nearly all areas of natural sciences. To date a large variety of metal, semiconductor, oxide and other nanoparticles are available from colloidal synthesis. However, for many applications of these materials an assembly into macroscopic structures is needed. Here we present a comprehensive picture of the developments that enabled the fusion of the colloidal nanoparticle and the aerogel world. This became possible by the controlled destabilization of pre-formed nanoparticles, which leads to their assembly into three-dimensional macroscopic networks. This revolutionary approach makes it possible to use precisely controlled nanoparticles as building blocks for macroscopic porous structures with programmable properties.
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Uniform Supersonic Chemical Reactors: 30 Years of Astrochemical History and Future Challenges ()
The interstellar medium attracts our great attention, as the place where stars and planets are born and from where, probably, the molecular precursors of life have come to Earth. To understand the chemical pathways to the formation of stars, planets, and biological molecules, astronomical observations, astrochemical modelling, and laboratory astrochemistry should go hand in hand. In this paper we review the laboratory experiments devoted to investigations of the reaction dynamics of species of astrochemical interest at the temperatures of the interstellar medium and performed by using one of the most popular techniques in the field, CRESU. We discuss new technical developments and scientific ideas for CRESU, which, if realized, will bring us one more step closer to an understanding of the astrochemical history and future of our Universe.
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Luminescence, Plasmonic and Magnetic Properties of Doped Semiconductor Nanocrystals: Current Developments and Future Prospects ()
Introducing few atoms of impurities or dopants in semiconductor nanocrystals can drastically alter the existing or even introduce new properties. For example, mid-gap states created by doping tremendously affect photocatalytic activities and surface controlled redox reactions, generate new emission centres, show thermometric optical switching, make suitable FRET donors by enhancing the excited state lifetime and also create localized surface plasmon resonance induced low energy absorption. In addition, researchers have more recently started focusing their attention on doped nanocrystals as an important and alternative material for solar energy conversion in order to meet the current demand for renewable energy. Moreover, electrical as well as magnetic properties of the host are also strongly altered on doping. These dopant-induced beneficial changes in material properties suggest that doped nanocrystals with proper selections of dopant-host pairs may be helpful for generating designer materials for a wide range of current technological needs. Such exciting properties related to various aspects of doping a variety of semiconductor nanocrystals are summarized and reported in this mini review.
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Protein-templated fragment ligations - from molecular recognition to drug discovery ()
The understanding and manipulation of molecular recognition events is the key to modern approaches in drug discovery. Protein-templated fragment ligation is a novel concept to support drug discovery and can help to improve the efficacy of already existing protein ligands. Protein-templated fragment ligations are chemical reactions between small molecules ("fragments") that utilize a protein´s surface as a template to combine and to form a protein ligand with increased binding affinity. The approach exploits the molecular recognition of reactive small molecule fragments by proteins both for ligand assembly and for the identification of bioactive fragment combinations. Chemical synthesis and bioassay are thus integrated in one single step. In this article we portrait the biophysical basis of reversible and irreversible fragment ligations and the available methods to detect protein-templated ligation products. The scope of known chemical reactions providing templated ligation products is reviewed and the possibilities to extend the reaction portfolio are discussed. Selected recent applications of the method in protein ligand discovery are reported. Finally, the strengths and limitations of the concept are discussed and an outlook on the future impact of templated fragment ligations on the drug discovery process is given.
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Black Phosphorus Rediscovered: From Bulk to Monolayer ()
Phosphorus is a non-metal with several allotropes, from the highly reactive white phosphorus to the thermodynamically stable black phosphorus (BP) with a puckered orthorhombic layered structure. The bulk form of BP was synthesized for the first time more than a century ago, in 1914, not receiving much attention until very recently rediscovered, in 2014, joining the new wave of 2D layered nanomaterials. BP can be exfoliated to a single sheet structure with tunable direct band, semiconducting, high carrier mobility at room temperature and in-plane anisotropic layered structure. Surface chemistry degradation can still be a holdback for the advancement of BP applications, thus compelling efforts to achieve effective BP passivation are ongoing, such as its integration in van der Waals heterostructures. Currently, BP has been tested as a novel nanomaterial in batteries, transistors, sensors and photonics related fields. In this review we take a look back at BP origin story, taking the path from bulk to nowadays few/single layer. Physical and chemical properties are summarized, highlighting the state-of-the-art in BP applications.
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Xenobiology meets enzymology: Exploring the potential of unnatural building blocks in biocatalysis ()
Xenobiology (XB) aims to design biological systems endowed with unusual biochemistries, while enzymology concerns the study of enzymes, the workhorses of biocatalysis. Biocatalysis employs enzymes and organisms to perform useful biotransformations in synthetic chemistry and biotechnology. During the past years, the effects of incorporating noncanonical amino acids (ncAAs) into enzymes with potential applications in biocatalysis have been increasingly investigated. Here we provide an overview of the effects of new chemical functionalities that have been introduced into proteins to improve various facets of enzymatic catalysis. We also discuss future research avenues that will complement unnatural mutagenesis with the standard protein-engineering toolbox for producing novel and versatile biocatalysts with applications in synthetic organic chemistry and biotechnology.
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Carbon-Carbon Bond Formation in a Weak Ligand Field: Leveraging Open Shell First Row Transition Metal Catalysts ()
Unique features of Earth abundant transition metal catalysts are reviewed in the context of catalytic carbon-carbon bond forming reactions. Aryl-substituted bis(imino)pyridine iron and cobalt dihalide compounds, when activated with alkyl aluminum reagents, form highly active catalysts for the polymerization of ethylene. Open shell iron and cobalt alkyl complexes have been synthesized that serve as single component olefin polymerization catalysts. Reduced bis(imino)pyridine iron- and cobalt dinitrogen compounds have also been discovered that promote the unique [2+2] cycloaddition of unactivated terminal alkenes. Electronic structure studies support open shell intermediates, a deviation from traditional strong field organometallic compounds that promote catalytic C-C bond formation.
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Fullerenes in space ()
In 1985 the football structure of $\textrm{C}_{60}$, buckminsterfullerene was proposed and subsequently confirmed following its macroscopic synthesis in 1990. From the very beginning the role of $\textrm{C}_{60}$ and $\textrm{C}_{60}^{+}$ in space was considered, particularly in the context of the enigmatic diffuse interstellar bands. These are absorption features found in the spectra of reddened star light. The first astronomical observations were made around one hundred years ago and despite significant efforts none of the interstellar molecules responsible have been identified. The absorption spectrum of $\textrm{C}_{60}^{+}$ was measured in a $5\,\textrm{K}$ neon matrix in 1993 and two prominent bands near $9583\,\textrm{\AA}$ and $9645\,\textrm{\AA}$ were observed. On the basis of this data the likely wavelength range in which the gas phase $\textrm{C}_{60}^{+}$ absorptions should lie was predicted. In 1994 two diffuse interstellar bands were found in this spectral region and proposed to be due to $\textrm{C}_{60}^{+}$. It took over 20 years to measure the absorption spectrum of $\textrm{C}_{60}^{+}$ under conditions similar to those prevailing in diffuse clouds. In 2015, sophisticated laboratory experiments led to the confirmation that these two interstellar bands are indeed caused by $\textrm{C}_{60}^{+}$, providing the first answer to this century old puzzle. Here, we describe the experiments, concepts and astronomical observations that led to the detection of $\textrm{C}_{60}^{+}$ in interstellar space.
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From composition to cure: A systems engineering approach to anti-cancer drug carriers ()
The molecular complexity and heterogeneity of cancer has led to a persistent, and as yet unsolved, challenge of developing cures for this disease. Although the pharmaceutical industry focuses the bulk of its efforts on the development of new drugs, an alternative —and in many ways complementary— approach is the improvement of the delivery of existing drugs with drug carriers that can manipulate when, where, and how a drug exerts its therapeutic effect. For the treatment of solid tumors, systemically delivered drug carriers face significant challenges that are imposed by the pathophysiological barriers that lie between their site of administration and their site of therapeutic action in the tumor. Furthermore, drug carriers face additional challenges in their translation from pre-clinical validation to clinical approval and adoption. Addressing this diverse network of challenges requires a systems engineering approach to anti-cancer drug delivery. Such a perspective is needed to better enable the rational design of optimized vehicles that navigate the trade-offs of this complex system to create next generation anti-cancer drug carriers that have a realistic prospect for translation from the lab to the patient.
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Gaining Momentum: Sulfonimidamides in Medicinal- and Agrochemistry ()
Synthesis and evaluation of structural analogues and isosteres represent a cornerstone methodology among the practitioners of medicinal- and agrochemistry. The sulfonamide functional group represents one of the most important amide isosteres in contemporary drug design, with some 500 compounds that has overcome both the pharmacological and regulatory hurdles that precede studies in humans. We note that mono aza-analogues of sulfonamides, i.e. sulfonimidamides, are rapidly gaining popularity as a novel functional group among molecular architects involved in the design of biologically active compounds for both pharmaceutical- and agrochemical applications. Herein, we review these recent developments with the ambition to showcase the promise of this functional group to the wider chemical community.
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Methyltransferase directed labeling of biomolecules and its applications ()
Methyltransferases (MTases) compose a large family of enzymes which have the ability to methylate a diverse set of targets, ranging from the three major biopolymers DNA, RNA and protein to small molecules. Most of these MTases use the cofactor S-Adenosyl-L-Methionine (AdoMet) as their methyl source. Given the important biological role of methylation, e.g. in epigenetic regulation of gene activity and the vast potential of targeted functionalization in biology, diagnostics and nanotechnology, it should come as no surprise that recent years have seen significant efforts in the development of AdoMet analogues with the aim of transferring moieties other than simple methyl groups. Two major classes of AdoMet analogues currently exist- the doubly-activated and aziridine based molecules- each of which employs a different approach for transalkylation, as opposed to transmethylation, of the target molecule. In this review, we discuss the various strategies for labelling and functionalizing biomolecules using AdoMet-dependent MTases and AdoMet analogues. We cover the synthetic routes to AdoMet analogues, their stability in biological environments and their application in transalkylation reactions. Finally, some perspectives are presented for the potential use of AdoMet analogues in biology research, (epi)genetics and nanotechnology.
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Synthetic Biology - The Synthesis of Biology ()
Synthetic biology envisages the engineering of man-made living biomachines from standardized components that can perform pre-defined functions in a (self-)controlled manner. Different research strategies and interdisciplinary efforts are pursued to implement engineering principles to biology. The "top-down" strategy exploits nature's incredible diversity of existing, natural parts to construct synthetic compositions of genetic, metabolic or signalling networks with predictable and controllable properties. This mainly application-driven approach results in living factories that produce drugs, biofuels, biomaterials and fine chemicals and results in living pills that are based on engineered cells with the capacity to autonomously detect and treat disease states in vivo. In contrast, the "bottom-up" strategy seeks to be independent of existing living systems by designing biological systems from scratch and synthesizing artificial biological entities not found in nature. This more knowledge-driven approach investigates the reconstruction of minimal biological systems that are capable of performing basic biological phenomena, such as self-organization, self-replication and self-sustainability. Moreover, the syntheses of artificial biological units, such as synthetic nucleotides or amino acids, and their implementation into polymers inside living cells currently set the boundaries between natural and artificial biological systems. In particular, the in vitro design, synthesis and transfer of complete genomes into host cells and the application of efficient genome-wide intervention techniques point to the future of synthetic biology: the creation of living designer cells with tailored desirable properties for biomedicine and biotechnology.
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50 (and more) Years of Propellane Chemistry - From a Chemical Curiosity to "Explosive" Applications in Material Sciences and Natural Product Chemistry ()
Propellanes are a unique class of compounds with well over 10000 members with an inverted tetrahedral configuration featuring a weak single bond between two carbon atoms linked by three additional bridge. Not only structurally interesting, these propella-type compounds exhibit unusual reactivities. In this review, we highlight their synthesis and applications in material sciences, natural product chemistry and medicinal chemistry. We feature the chemistry of [1.1.1]propellane like the synthesis of oligomeric and polymeric structures derived from it such as bicyclo[1.1.1]pentanes and staffanes. A selected number of natural products are discussed in detail. Heteropropellanes and inorganic propellanes are also addressed. The historical background is given in brief showing the pioneering work of David Ginsburg, Günther Snatzke, Günter Szeimies, Kenneth Wiberg and others.
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Label-free molecular imaging of biological cells and tissues by linear and non-linear Raman spectroscopic approaches ()
Raman spectroscopy is an emerging technique in bioanalysis and imaging of biomaterials due to its unique spectroscopic fingerprint capabilities. Imaging of cells and tissues by Raman microspectroscopy represents a non-destructive and label-free approach. All components of cells or tissues contribute to the Raman signals giving complex spectral signatures. Long acquisitions times are often required due to the relatively small Raman scattering cross sections. To overcome these limitations, Raman signal enhancing methods like resonance Raman scattering and surface enhanced Raman scattering can be applied that also reduce the spectral complexity because the enhancement is often restricted to selected bands. Raman-active labels can be introduced to increase specificity and multimodality. In addition, non-linear coherent Raman scattering such as coherent anti-Stokes Raman scattering and stimulated Raman scattering offer higher sensitivities which enable rapid imaging of larger sampling areas. Finally, fiber based imaging techniques open the way towards in vivo applications of Raman spectroscopy. This critical review summarizes theory, instrumentation, data processing and progress of medical Raman imaging since 2012.
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Metal Fluorides as Analogs for Studies on Phosphoryl Transfer Enzymes ()
The 1994 structure of a transition state analog with AlF4- and GDP complexed to G1, a small G protein, heralded a new field of research into structure and mechanism of enzymes that manipulate transfer of the phosphoryl (PO3-) group. The list of enzyme structures that embrace metal fluorides, MFx, as ligands that imitate either the phosphoryl group or a phosphate, is now growing at over 80 per triennium. They fall into three distinct geometrical classes: (i) Tetrahedral complexes, based on BeF3-, mimic ground state phosphates; (ii) Octahedral complexes, primarily based on AlF4-, mimic "in-line" anionic transition state for phosphoryl transfer; and (iii) Trigonal bipyramidal complexes, represented by MgF3- and putative AlF30 moieties, additionally mimic the tbp geometry of the transition state. The interpretation of these structures provides a deeper mechanistic understanding of the behavior and manipulation of phosphate monoesters in molecular biology. This review provides a comprehensive overview of these structures, their uses, and their computational development. It questions the identification of AlF30 and MgF4= as tbp species in protein complexes and discusses the relevance of physical organic chemistry and water-based model studies for understanding phosphoryl group transfer in enzymes. It describes two roles for amino acid side-chains that mediate proton transfers during phosphoryl transfer, based on the analysis of protein/MFx structures. First, they deploy hydrogen bonding to neutral oxygen nucleophiles so as to orientate them for correct orbital overlap with the electrophilic phosphorus center. Secondly, they behave as classical general acid/base catalysts.
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The Stability Challenges of Oxygen Evolving Electrocatalysts: Towards a Common Fundamental Understanding and Mitigation of Catalyst Degradation ()
The electrochemical oxygen evolution reaction (OER) is an important reaction in the industrial production of numerous inorganic chemicals. However, over the last decade it has also received growing attention as scalable proton- and electron-providing process for use in the production of solar fuels, such as hydrogen, hydrocarbons, or alcohols carried out in water- and CO2-electrolyzers. To operate these devices efficiently and economically , active and stable electrocatalysts are required. While advances have been made in understanding and tuning OER efficiency and activity, the stability of OER catalysts and the reduction of their degradation continue to be major challenges. While most stability studies limit themselves to short-term testing in idealized three-electrode set ups, a much stronger focus on advancing our understanding of degradation of OER catalysts in realistic Membrane Electrode Assemblies (MEAs) with industrial current densities, is critically needed. This review addresses the technical challenges, their scientific basis, as well as recent progress and the road ahead regarding stability and degradation of OER catalysts operating at electrolyzer anodes in acidic MEA environments. First, we start clarifying the complexity associated with the term "catalyst stability", cover today's performance targets and outline major catalyst degradation mechanisms and their mitigation strategies. Then we evaluate suitable in-situ experimental methods to get insight into catalyst degradation and describe achievements in tuning OER catalyst stability. Finally, we highlight the importance of identifying universal figures of merit for stability and develop a comprehensive accelerated life test (ALT) that would yield comparable performance data across labs and catalyst types. As a whole, this review will help to disseminate and highlight the important relations between structure, composition and stability of OER catalysis under different operating conditions.
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Power-to-Syngas - an enabling technology for the transition of the energy system? Production of tailored synfuels and chemicals using renewably generated electricity. ()
Power-to-X concepts promise a significant reduction of greenhouse gas emissions and simultaneously guaranteeing a safe energy supply even at high share of renewable power generation, thus becoming a cornerstone of a sustainable energy system. Power-to-Syngas, i.e. the electrochemical conversion of steam and carbon dioxide with the use of renewably generated electricity to syngas for the production of synfuels and high-value chemicals, offers an efficient technology to couple different energy-intense sectors, such as 'traffic and transportation' and 'chemical industry'. Consequently, co-electrolysis can be regarded as a key-enabling step for a transition of the energy system that offers additionally features of CO2-valorization and closed carbon cycles. In this Minireview, we outline and discuss advantages and current technical limitations of low- and high-temperature co-electrolysis. Advances in both, a fundamental understanding of the basic reaction schemes and in stable high-performance materials are essential to further promote co-electrolysis.
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Surface Modification of Water Purification Membranes: a Review ()
Polymer membranes are an energy-efficient means of purifying water, but they suffer from fouling during filtration. Membrane surface modification is one route to mitigate membrane fouling as it helps to maintain high levels of water productivity. Here, a series of common membrane surface modification techniques are reviewed, including surface coating, grafting, and various treatment techniques such as chemical treatment, UV irradiation, and plasma treatment, among others. Historical background on membrane development and surface modification is also provided. Finally, polydopamine, an emerging material that can be easily deposited onto a wide variety of substrates, is discussed in the context of membrane modification. The chemistry of polydopamine is also reviewed.
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One-Pot Assembly of Amino Acid Bridged Hybrid Macromulticyclic Cages through Multiple Multicomponent Macrocyclizations ()
An important development in the field of macrocyclization strategies towards molecular cages is described. The approach comprises the utilization of a double Ugi four-component macrocyclization for the assembly of macromulticycles with up to four different tethers, that is, hybrid cages. The innovation of this method rests on setting up the macromulticycle connectivities not through the tethers but through the bridgeheads, which in this case involve N-substituted amino acids. Both dilution and metal-template-driven macrocyclization conditions were implemented with success, enabling the one-pot formation of cryptands and cages including steroidal, polyether, heterocyclic, peptidic, and aryl tethers. This method demonstrates substantial complexity-generating character and is suitable for applications in molecular recognition and catalysis. Let's get together: A new multimacrocyclization strategy enables the one-pot multicomponent synthesis of hybrid molecular cages through reaction-based self-assembly. Dilution and metal-template-driven macrocyclization conditions proved efficient in the production of high cage complexity with low synthetic cost in a four-component reaction (4CR).
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A Stable Hexakis(guanidino)benzene: Realization of the Strongest Neutral Organic Four-Electron Donor ()
The growing demand for efficient batteries has stimulated the search for redox-active organic compounds with multistage redox behavior, as materials with large charge capacity. Herein we report the synthesis and properties of the first hexakis(guanidino)benzene derivative: a strong neutral organic electron donor with reversible multistage redox behavior and a record low redox potential for donation of four electrons. Detailed structural and spectroscopic characterization of three redox states (0, +2, and +4) reveal its unique electronic features. Despite its nitrogen richness, the compound is thermally robust and can be readily purified by sublimation. Multistage electron donor: The first hexakis(guanidino)benzene derivative donates four electrons at a record low potential.
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Palladium-Catalyzed Direct Stereoselective Synthesis of Deoxyglycosides from Glycals ()
Palladium(II) in combination with a monodentate phosphine ligand enables the unprecedented direct and α-stereoselective catalytic synthesis of deoxyglycosides from glycals. Initial mechanistic studies suggest that in the presence of N-phenyl-2-(di-tert-butylphosphino)pyrrole as the ligand, the reaction proceeds via an alkoxy palladium intermediate that increases the proton acidity and oxygen nucleophilicity of the alcohol. The method is demonstrated with a wide range of glycal donors and acceptors, including substrates bearing alkene functionalities. Sweet dreams (are made of this): Palladium(II) in combination with a monodentate phosphine ligand enables the unprecedented direct and α-stereoselective catalytic synthesis of deoxyglycosides from glycals. Mechanistic studies suggest that in the presence of N-phenyl-2-(di-tert-butylphosphino)pyrrole, the reaction proceeds via an alkoxy palladium intermediate that increases the proton acidity and oxygen nucleophilicity of the alcohol.
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Low-Temperature Anharmonicity in Cesium Chloride (CsCl) ()
Anharmonic lattice vibrations govern heat transfer in materials, and anharmonicity is commonly assumed to be dominant at high temperature. The textbook cubic ionic defect-free crystal CsCl is shown to have an unexplained low thermal conductivity at room temperature (ca. 1 W/(m K)), which increases to around 13  W/(m K) at 25 K. Through high-resolution X-ray diffraction it is unexpectedly shown that the Cs atomic displacement parameter becomes anharmonic at 20 K. Heating system: At room temperature CsCl has a very low thermal conductivity which increases at lower temperatures. High-resolution single-crystal X-ray diffraction unexpectedly reveals an increase of anharmonicity below 100 K.
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Hydronium-Ion Batteries with Perylenetetracarboxylic Dianhydride Crystals as an Electrode ()
An acidic aqueous solution acts as an electrolyte for a hydronium-ion battery where the charge carrier is H3O+. In their Communication (DOI: 10.1002/anie.201700148), X. L. Ji et al. provide the evidence that hydronium ions can be reversibly inserted into and extracted from 3,4,9,10-perylenetetracarboxylic dianhydride (PTCDA). The expansion and contraction of the PTCDA lattice correspond to H3O+ intercalation and deintercalation, respectively, as revealed by ex situ XRD studies and density functional calculations.
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Catalytic Asymmetric Intramolecular [4+2] Cycloaddition of In Situ Generated ortho-Quinone Methides ()
Herein, we describe the first catalytic asymmetric intramolecular [4+2] cycloaddition of in situ generated ortho-quinone methides. In the presence of a confined chiral imidodiphosphoric acid catalyst, various salicylaldehydes react with dienyl alcohols to give transient ortho-quinone methide intermediates, which undergo an intramolecular [4+2] cycloaddition to provide highly functionalized furanochromanes and pyranochromanes in excellent diastereoselectivity and enantioselectivity. Chromane synthesis: An organocatalytic asymmetric intramolecular [4+2] cycloaddition of in situ generated ortho-quinone methides is described. In the presence of a chiral imidophosphoric acid catalyst, various salicylaldehydes react with dienyl alcohols to afford highly functionalized furanochromanes or pyranochromanes in excellent diastereo- and enantoselectivity.
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Photoelectrochemical Reduction of Carbon Dioxide to Methanol through a Highly Efficient Enzyme Cascade ()
An artificial photosynthetic platform has been created by combining a photo-electrochemical cell and a multienzyme cascade to mimic natural photosynthesis in green plants. J. K. Lee, C. B. Park, and co-workers describe in their Communication (DOI: 10.1002/anie.201611379) how the use of water as an electron donor, a hematite photoanode and a bismuth ferrite photocathode for the regeneration of NADH with visible light, as well as a three-dehydrogenase cascade system allows the highly selective and fast conversion of carbon dioxide into methanol.
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Energy Transfer Dynamics of Formate Decomposition on Cu(110) ()
The butterfly effect: Decomposition of formate is a thermal non-equilibrium process from which a large amount of energy is released and transformed into the internal energies of CO2. In their Communication (DOI: 10.1002/anie.201611342), J. Nakamura et al. describe nascent CO2 molecules desorbing from a copper surface with vibrating “wings” analogous to translational and vibrational energies. A mountain depicted in the background represents the energetics of formate decomposition.
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Carbonyls as Latent Alkyl Carbanions for Conjugate Additions ()
Conjugate addition of carbon nucleophiles to electron-deficient olefins is one of the most powerful methods for forming carbon–carbon bonds. Despite great achievements in controlling the selectivity, variation of the carbon nucleophiles remains largely underexplored, with this approach relying mostly on organometallic reagents. Herein, we report that naturally abundant carbonyls can act as latent carbon nucleophiles for conjugate additions through a ruthenium-catalyzed process, with water and nitrogen as innocuous byproducts. The key to our success is homogeneous ruthenium(II) catalysis, combined with phosphines as spectator ligands and hydrazine as the reducing agent. This chemistry allows the incorporation of highly functionalized alkyl fragments into a vast array of electron-deficient olefins under mild reaction conditions in a reaction complementary to the classical organometallic-reagent-based conjugate additions mediated or catalyzed by “soft” transition metals. Hidden talents: Carbonyls can act as latent carbon nucleophiles for conjugate additions through a ruthenium-catalyzed process. The reaction relies on homogeneous ruthenium(II) catalysis combined with phosphines as spectator ligands and hydrazine as the reducing agent. This method enables the incorporation of highly functionalized alkyl fragments into a vast array of electron-deficient olefins under mild reaction conditions.
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Visible-Light-Promoted Asymmetric Cross-Dehydrogenative Coupling of Tertiary Amines to Ketones by Synergistic Multiple Catalysis ()
Reported herein is an unprecedented photocatalytic asymmetric cross-dehydrogenative coupling reaction between tertiary amines and simple ketones, and it proceeds by synergistic multiple catalysis with substoichiometric amounts of a hydrogen acceptor. This process is enabled by a simple chiral primary amine catalyst through the coupling of a catalytic enamine intermediate and an iminium cation intermediate in situ generated from tetrahydroisoquinoline derivatives by coupled Ru/Co catalysis. Working together: Synergistic multiple catalytic cycles enable an asymmetric cross-dehydrogenative coupling between tertiary amines and simple ketones with high diastereo- and enantioselectivity under visible-light irradiation. This process is enabled by a simple chiral primary amine catalyst through the coupling of a catalytic enamine intermediate and an iminium cation intermediate in situ generated from tetrahydroisoquinoline derivatives by Ru/Co catalysis.
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(Aminomethyl)pyridine Complexes for the Cobalt-Catalyzed Anti-Markovnikov Hydrosilylation of Alkoxy- or Siloxy(vinyl)silanes with Alkoxy- or Siloxyhydrosilanes ()
Cobalt-catalyzed anti-Markovnikov reactions that involve siloxy- or alkoxy(vinyl)silanes and siloxy- or alkoxyhydrosilanes are disclosed. More than 25 new cobalt–(aminomethyl)pyridine complexes were developed as catalysts for the hydrosilylation of industry-relevant and challenging siloxy- or alkoxy-terminated vinylsilanes. These transformations typically proceed in the presence of 0.25 mol % of the cobalt complex with 0.75 mol % of the alkylating agent to afford the desired products in up to >98 % yield with >98 % anti-Markovnikov selectivity in 30 min. The current protocol shows a broad substrate scope, delivering more than 25 siloxanes with siloxy or alkoxy functional groups at both termini, and can also be applied to polymeric vinyl- and hydrosiloxanes. More than 25 siloxanes with siloxy or alkoxy functional groups at both termini are obtained in high yields using a cobalt catalyst derived from (aminomethyl)pyridine ligands and CoBr2 (see Scheme). This protocol can also be applied for the hydrosilylation of polymeric vinylsilanes by hydrosilanes to prepare silicones.
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Enantioselective Aza-Ene-type Reactions of Enamides with Gold Carbenes Generated from α-Diazoesters ()
Carbophilic gold carbenes generated by the decomposition of α-diazoesters are highly reactive towards enamides, undergoing an unprecedented aza-ene-type reaction. In their Communication (DOI: 10.1002/anie.201612208), S.-W. Luo, L.-Z. Gong, and co-workers show that the presence of 0.1 mol % of a chiral Brønsted acid is sufficient to obtain synthetically significant γ-keto esters in high yields and with excellent enantioselectivities.
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Palladium-Catalyzed Oxidative Cascade Carbonylative Spirolactonization of Enallenols ()
A highly selective palladium-catalyzed oxidative carbonylation/carbocyclization/alkoxycarbonylation of enallenols to afford spirolactones bearing an all-carbon quaternary center was developed. This transformation involves the overall formation of three C−C bonds and one C−O bond through a cascade insertion of carbon monoxide (CO), an olefin, and CO. Preliminary experiments on chiral anion-induced enantioselective carbonylation/carbocyclization of enallenols afforded spirolactones with moderate enantioselectivity. All together now: A highly selective cascade reaction for C−C/C−O bond formation through palladium-catalyzed oxidative carbonylation/carbocyclization/alkoxycarbonylation of enallenols was developed, affording spirolactones bearing an all-carbon quaternary center. Preliminary attempts to obtain enantioselectivity in the carbonylative carbocyclization revealed that the VAPOL-type chiral phosphoric acid serves as a good anionic co-catalyst in this transformation.
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Synthesis of Active Hexafluoroisopropyl Benzoates through Hydrogen-Bond-Enabled Palladium(II)-Catalyzed C−H Alkoxycarbonylation Reaction ()
A PdII-catalyzed ortho C−H alkoxycarbonylation reaction of aryl silanes toward active hexafluoroisopropyl (HFIP) benzoate esters has been developed. This efficient reaction features high selectivity and good functional-group tolerance. Notably, given the general nature of the silyl-tethered directing group, this method delivers products bearing two independently modifiable sites. NMR studies reveal the presence of hydrogen bonding between HFIP and a pyrimidine nitrogen atom of the directing group, and it is thought to be crucial for the success of this alkoxycarbonylation reaction. Let's get active: The title reaction of aryl silanes to deliver active hexafluoroisopropyl (HFIP) benzoate esters features high selectivity and good functional-group tolerance. This method yields products bearing two independently modifiable sites. NMR studies reveal the presence of hydrogen bonding between HFIP and a pyrimidine nitrogen atom of the directing group (DG), and it is thought to be crucial for the success of this alkoxycarbonylation reaction.
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Supramolecularly Engineered Amphiphilic Macromolecules: Molecular Interaction Overrules Packing Parameters ()
We report molecular interaction-driven self-assembly of supramolecularly engineered amphiphilic macromolecules (SEAM) containing a single supramolecular structure-directing unit (SSDU) consisting of an H-bonding group connected to a naphthalene diimide chromophore. Two such SEAMs, P1-50 and P2-50, having the identical chemical structure and hydrophobic/hydrophilic balance, exhibit distinct self-assembled structures (polymersome and cylindrical micelle, respectively) due to a difference in the H-bonding group (hydrazide or amide, respectively) of the single SSDU. When mixed together, P1-50 and P2-50 adopted self-sorted assembly. For either series of polymers, variation in the hydrophobic/hydrophilic balance does not alter the morphology reconfirming that self-assembly is primarily driven by directional molecular interaction which is capable of overruling the existing norms in packing parameter-dependent morphology control in an immiscibility-driven block copolymer assembly. Amphiphilic block-copolymers: A directional molecular interaction overrules classical packing parameters and enacts new rules for the self-assembly of supramolecularly engineered amphiphilic polymer assemblies. The self-assembly is governed by a distinct H-bonding motif of a single H-bonding moiety present in the entire polymer chain.
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Selective Arene Cleavage by Direct Insertion of Iridium into the Aromatic Ring ()
We report an unprecedented selective cleavage of aromatic C−C bonds through the insertion of well-defined iridium complexes into the aromatic ring of simple alkylarenes. The insertion occurs at 50–100 °C without the activation of weaker C−H and C−C bonds and gives unique metallacycles in high yields. Key to the success of this approach is metal-induced deformation of the arene ring, which creates temporary ring strain and promotes direct and selective insertion of the metal into the otherwise inert arene ring C−C bonds. Running mild: A mild and selective insertion of a metal center into the arene ring is reported. The simple Cp*Ir fragment cleaves strong aromatic C−C bonds in alkylarenes without affecting weaker C−H and C−C bonds. This work reveals a conceptually new type of reactivity that could be important for a range of industrial processes involving the generation of chemicals and fuel from coal and plant biomass.
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Energy Transfer Dynamics of Formate Decomposition on Cu(110) ()
Energy transfer dynamics of formate (HCOOa) decomposition on a Cu(110) surface has been studied by measuring the angle-resolved intensity and translational energy distributions of CO2 emitted from the surface in a steady-state reaction of HCOOH and O2. The angular distribution of CO2 shows a sharp collimation with the direction perpendicular to the surface, as represented by cosnθ (n=6). The mean translational energy of CO2 is measured to be as low as 100 meV and is independent of the surface temperature (Ts). These results clearly indicate that the decomposition of formate is a thermal non-equilibrium process in which a large amount of energy released by the decomposition reaction of formate is transformed into the internal energies of CO2 molecules. The thermal non-equilibrium features observed in the dynamics of formate decomposition support the proposed Eley–Rideal (ER)-type mechanism for formate synthesis on copper catalysts. CO2 desorption during formate decomposition in the steady-state reaction of HCOOH with O2 on Cu(110) is a thermal non-equilibrium process. During formate decomposition a large amount of released energy is transformed into the internal energies of CO2 molecules, which supports an Eley–Rideal-type mechanism for formate synthesis on copper catalysts.
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Modern Synthetic Avenues for the Preparation of Functional Fluorophores ()
Biomedical research relies on the fast and accurate profiling of specific biomolecules and cells in a non-invasive manner. Functional fluorophores are powerful tools for such studies. As these sophisticated structures are often difficult to access through conventional synthetic strategies, new chemical processes have been developed in the past few years. In this Minireview, we describe the most recent advances in the design, preparation, and fine-tuning of fluorophores by means of multicomponent reactions, C−H activation processes, cycloadditions, and biomolecule-based chemical transformations. Functional fluorophores enable the fast and accurate profiling of specific biomolecules but these sophisticated structures are often difficult to access through conventional synthetic strategies. Recent advances in the design, preparation, and fine-tuning of fluorophores by means of multicomponent reactions, C−H activation processes, cycloadditions, and biomolecule-based chemical transformations are discussed.
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First Stereoselective Total Synthesis of a Dimeric Naphthoquinonopyrano-γ-lactone: (+)-γ-Actinorhodin ()
We have accomplished the first total synthesis of an isomerically pure naphthoquinonopyrano-γ-lactone dimer, γ-actinorhodin, in eleven steps. Two steps exploit pairs of peri-MeO groups as unusual selectivity controls. The respective MeO groups convey the steric bulk of a bromo or iodo substituent located ortho to one MeO group as steric hindrance into the vicinity of the second MeO group. This relay effect was indispensable for exerting regiocontrol in an aromatic bromination and diastereocontrol in an oxa-Pictet–Spengler cyclization. The absolute configuration of our target compound was established in an asymmetric Sharpless dihydroxylation of a β,γ-unsaturated ester, which was synthesized in a Heck coupling of a bromoiodonaphthalene with ethyl vinylacetate. The dihydroxylation provided the γ-hydroxylactone moiety of the bromonaphthalene that was used as the substrate in the oxa-Pictet–Spengler cyclization. Dimerization to the core of γ-actinorhodin occurred by two Suzuki couplings. Pairs of peri MeO groups as mediators allowed seemingly distant Br or I substituents to exert regio- and diastereocontrol during naphthalene functionalization by electrophilic aromatic substitution. A bromonaphthalene-fused pyrano-γ-lactone resulted, which was dimerized in a Suzuki coupling. Removal of the methoxy groups and oxidation gave isomerically pure (+)-γ-actinorhodin in eleven steps.
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Michael Polanyi: Patriarch of Chemical Dynamics and Tacit Knowing ()
Connecting Science and the Humanities was the title of the symposium on Michael Polanyi that took place at the Technische Universität Berlin (Technical University of Berlin) in October 2016. This essay, which appraises the scientific and philosophical contributions of Michael Polanyi, is based on the presentation given by Dr. Herschbach on this occasion. In the picture: Polanyi in 1931.
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Determining the Origin of Rate-Independent Chemoselectivity in CuAAC Reactions: An Alkyne-Specific Shift in Rate-Determining Step ()
We report a kinetic and spectroscopic analysis of alkyne-dependent chemoselectivity in the copper-catalyzed azide–alkyne click (CuAAC) reaction. Studies of six alkyne subtypes reveal that the rate-determining step (RDS) of an aromatic ynamine class is shifted from acetylide formation to the azide ligation/migratory insertion event allowing chemoselectivity independent of overall rate. The old switcheroo: A kinetic and spectroscopic analysis of alkyne-dependent chemoselectivity in the copper-catalyzed azide–alkyne click (CuAAC) reaction is reported. Studies of six alkyne subtypes reveal that the rate-determining step (RDS) of an aromatic ynamine class is shifted from acetylide formation to the azide ligation/migratory insertion event allowing chemoselectivity independent of overall rate.
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Patchy Nanofibers from the Thin Film Self-Assembly of a Conjugated Diblock Copolymer ()
An unexpected morphology comprising patchy nanofibers can be accessed from the self-assembly of an all-conjugated, polyselenophene-block-polythiophene copolymer. This morphology consists of very small (<10 nm), polythiophene- and polyselenophene-rich domains and is unprecedented for both conjugated polymers and diblock copolymers in general. We propose that the patchy morphology occurs from the enhanced miscibility of the blocks arising from the longer alkyl chains in comparison to similar block copolymers with shorter alkyl chains, which fully phase separate, as well as the difference in rigidity between the polythiophene and polyselenophene blocks. This work demonstrates a facile way to tune the self-assembly behavior of conjugated block copolymers by modification of the side chain substituents. Self-assembly required: Patchy nanofibers can be accessed from the self-assembly of an all-conjugated, polyselenophene-block-polythiophene copolymer. This unexpected morphology consists of sub-10 nm polythiophene- and polyselenophene-rich domains and is unprecedented for both conjugated polymers and diblock copolymers in general.
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Outer-Sphere 2 e−/2 H+ Transfer Reactions of Ruthenium(II)-Amine and Ruthenium(IV)-Amido Complexes ()
A diverse set of 2 e−/2 H+ reactions are described that interconvert [RuII(bpy)(en*)2]2+ and [RuIV(bpy)(en-H*)2]2+ (bpy=2,2′-bipyridine, en*=H2NCMe2CMe2NH2, en*-H=H2NCMe2CMe2NH−), forming or cleaving different O−H, N−H, S−H, and C−H bonds. The reactions involve quinones, hydrazines, thiols, and 1,3-cyclohexadiene. These proton-coupled electron transfer reactions occur without substrate binding to the ruthenium center, but instead with precursor complex formation by hydrogen bonding. The free energies of the reactions vary over more than 90 kcal mol−1, but the rates are more dependent on the type of X−H bond involved than the associated ΔG°. There is a kinetic preference for substrates that have the transferring hydrogen atoms in close proximity, such as ortho-tetrachlorobenzoquinone over its para-isomer and 1,3-cyclohexadiene over its 1,4-isomer, perhaps hinting at the potential for concerted 2 e−/2 H+ transfers. 2 e−/2 H+ transfer reactions: Multielectron redox chemistry is central to many catalytic and energy storage processes. A variety of 2 e−/2 H+ reactions are reported, with substrates that possess or form two O−H, N−H, S−H, or C−H bonds. The reactions interconvert RuII-bis(amine) and RuIV-bis(amido) complexes.
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Palladium-Mediated Arylation of Lysine in Unprotected Peptides ()
A mild method for the arylation of lysine in an unprotected peptide is presented. In the presence of a preformed biarylphosphine-supported palladium(II)–aryl complex and a weak base, lysine amino groups underwent C−N bond formation at room temperature. The process generally exhibited high selectivity for lysine over other amino acids containing nucleophilic side chains and was applicable to the conjugation of a variety of organic compounds, including complex drug molecules, with an array of peptides. Finally, this method was also successfully applied to the formation of cyclic peptides by macrocyclization. Defenses down: In the presence of a preformed biarylphosphine-supported palladium(II)–aryl complex and a weak base, lysine amino groups in unprotected peptides underwent C−N bond formation at room temperature (see scheme). The process was applicable to the conjugation of a variety of organic compounds, including complex drug molecules, to peptides and was also successfully applied to the formation of cyclic peptides through macrocyclization.
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Vesicles in Nature and the Laboratory: Elucidation of Their Biological Properties and Synthesis of Increasingly Complex Synthetic Vesicles ()
The important role of vesicles in many aspects of cell function is well-recognized, but only recently have sophisticated imaging techniques begun to reveal their ubiquity in nature. While we further our understanding of the biological properties of vesicles and their physiological functions, increasingly elegant artificial vesicles are being developed for a wide range of technological applications and basic research. Herein, we examine the state of the art of biological and synthetic vesicles and place their biological features in the context of recent synthetic developments, thus providing a unique overview of these complex and rapidly developing fields. The challenges and opportunities associated with future biological and synthetic studies of vesicles are also presented. Inspiration–imitation–innovation: Parallel to the elucidation of the biological properties and physiological function of vesicles, increasingly elegant artificial vesicles are being reported. This Review provides an overview of the complex and rapidly developing fields of natural and synthetic vesicles and shows how the two fields can profit from one another.
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Template-Assisted meta-C−H Alkylation and Alkenylation of Arenes ()
To expand the scope of meta-functionalization, a pyrimidine-based template effective for the formation of β-aryl aldehydes and ketones, using allyl alcohols, by meta-C−H activation of benzylsulfonyl esters is described. In addition, α,β-unsaturated aldehydes were generated by in situ olefination and deprotection of allyl benzyl ethers. These new functionalizations at the meta-position of an arene have also been successfully implemented in benzylphosphonate, phenethyl carbonyl, and phenethylsulfonyl ester scaffolds. Key to these successful new functionalizations is the creation of an electropositive palladium center by accepting the electron cloud from the metal to the energetically low-lying π-orbitals of pyrimidine ring, and it favors coordination of allyl alcohol to the metal center. On target: Pyrimidine-based, template-assisted meta-C−H alkylation and alkenylation with allyl alcohols and protected allyl alcohols has been developed. Sulfonyl, carbonyl, and phosphonyl esters were used as linkers between the directing group (DG) and target meta-C−H bond of arene.
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Protein-Templated Formation of an Inhibitor of the Blood Coagulation Factor Xa through a Background-Free Amidation Reaction ()
Protein-templated reactions enable the target-guided formation of protein ligands from reactive fragments, ideally with no background reaction. Herein, we investigate the templated formation of amides. A nucleophilic fragment that binds to the coagulation factor Xa was incubated with the protein and thirteen differentially activated dipeptides. The protein induced a non-catalytic templated reaction for the phenyl and trifluoroethyl esters; the latter was shown to be a completely background-free reaction. Starting from two fragments with millimolar affinity, a 29 nm superadditive inhibitor of factor Xa was obtained. The fragment ligation reaction was detected with high sensitivity by an enzyme activity assay and by mass spectrometry. The reaction progress and autoinhibition of the templated reaction by the formed ligation product were determined, and the structure of the protein–inhibitor complex was elucidated. A protein molds its own killer: The protein factor Xa induces the ligation of two weakly bound fragments into a potent, superadditive inhibitor through amide bond formation (see scheme, bottom). Suitable peptide esters react on the protein surface in a non-catalytic, autoinhibited mechanism without background reaction in the free solution.
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Photoresponsive Nanosheets of Polyoxometalates Formed by Controlled Self-Assembly Pathways ()
Anionic Keggin polyoxometalates (POMs) and ether linkage-enriched ammonium ions spontaneously self-assemble into rectangular ultrathin nanosheets in aqueous media. The structural flexibility of the cation is essential to form oriented nanosheets; as demonstrated by single-crystal X-ray diffraction measurements. The difference in initial conditions exerts significant influence on selecting for self-assembly pathways in the energy landscape. Photoillumination of the POM sheets in pure water causes dissolution of reduced POMs, which allowed site-specific etching of nanosheets using laser scanning microscopy. By contrast, photoetching was suppressed in aqueous AgNO3 and site-selective deposition of silver nanoparticles occurred as a consequence of electron transfer from the photoreduced POMs to Ag+ ions on the nanosheet surface. Controlling energy landscapes: Polyoxometalates and ether linkage-enriched ammonium ions spontaneously self-assemble into rectangular, ultrathin nanosheets under controlled conditions in water. These nanosheets are reduced by photoillumination. Site-specific photoetching and photodeposition of silver nanoparticles is demonstrated.
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Mechanical Trap Surface-Enhanced Raman Spectroscopy for Three-Dimensional Surface Molecular Imaging of Single Live Cells ()
Reported is a new shell-based spectroscopic platform, named mechanical trap surface-enhanced Raman spectroscopy (MTSERS), for simultaneous capture, profiling, and 3D microscopic mapping of the intrinsic molecular signatures on the membrane of single live cells. By leveraging the functionalization of the inner surfaces of the MTs with plasmonic gold nanostars, and conformal contact of the cell membrane, MTSERS permits excellent signal enhancement, reliably detects molecular signatures, and allows non-perturbative, multiplex 3D surface imaging of analytes, such as lipids and proteins on the surface of single cells. The demonstrated ability underscores the potential of MTSERS to perform 3D spectroscopic microimaging and to furnish biologically interpretable, quantitative, and dynamic molecular maps in live cell populations. Individual cells are captured by Au nanostar-coated micromechanical traps, which fold up and surround the cell surface and function as a surface-enhanced Raman spectroscopy sensor. Through this non-invasive label-free approach, proteins and lipids can be identified on the cell surface, and the spectra can be used to reconstruct a 3D microscopic image of the cellular surface chemical composition.
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Anaerobe-Inspired Anticancer Nanovesicles ()
An anaerobe-inspired drug delivery vehicle is described by Q. D. Shen, Z. Gu, and co-workers in their Communication (DOI: 10.1002/anie.201611783). The biomimetic nanovesicles are stable in cells with normal physiological redox and oxygen balance. Upon disruption by external light stimuli, they show dual synergistic anticancer actions with enhanced therapeutic efficacy.
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(Ge4Bi14)4−: A Case of “Element Segregation” on the Molecular Level ()
(Ge4Bi14)4− represents the largest Bi-containing main-group polyanion that is not stabilized by ligands or endohedral atoms. Its structure comprises motifs from smaller polybismuthide anions, like Bi73− or Bi113−, and clearly prefers the spatial separation of Bi atoms from a Ge4 waist in the center of the anion—unlike binary relatives with homologous element combinations that favor a maximum number of heteroatomic bonds, as confirmed by DFT calculations and described by S. Dehnen and R. J. Wilson in their Communication (DOI: 10.1002/anie.201611422).
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Cation-Selective Channel Regulated by Anions According to Their Hofmeister Ranking ()
Specificity of small ions, the Hofmeister ranking, is long-known and has many applications including medicine. Yet it evades consistent theoretical description. Here we study the effect of Hofmeister anions on gramicidin A channels in lipid membranes. Counterintuitively, we find that conductance of this perfectly cation-selective channel increases about two-fold in the H2PO4−
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Organoselenium-Catalyzed Regioselective C−H Pyridination of 1,3-Dienes and Alkenes ()
A gift from the moon goddesses Selene and Chang'e: Pyridinium salts are formed in an organoselenium-catalyzed regioselective C−H pyridination of alkenes as described by X. Zhao et al. in their Communication (DOI: 10.1002/anie.201610657). The new pyridinium salts were prepared from 1,3-dienes and fluoropyridinium salts using diselenide catalysts personified as lunar goddesses Selene (Greek) and Chang'e (Chinese).
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Remote Regulation of Membrane Channel Activity by Site-Specific Localization of Lanthanide-Doped Upconversion Nanocrystals ()
Spatiotemporal regulation of membrane channel activity in living systems has been achieved by irradiation with near-IR light (λ=808 nm), as reported by B. Xing and co-workers in their Communication (DOI: 10.1002/anie.201612142). Metabolic glycan biosynthesis is used to attach lanthanide-doped upconversion nanocrystals (UCNs) to the cell surface through copper-free click cyclization. Cation influx can be controlled by irradiation and membrane-associated activities manipulated in living cells and zebrafish.
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By-Product-Free Siloxane-Bond Formation and Programmed One-Pot Oligosiloxane Synthesis ()
Oligosiloxanes can be obtained in a single flask in a programmed fashion. In their Communication (DOI: 10.1002/anie.201611623), S. Shimada and co-workers report a novel oligosiloxane synthesis consisting of three successive reactions in one pot: iridium-catalyzed hydrosilylation, boron-catalyzed rearrangement, and boron-catalyzed cross coupling. The sequence of SiR2 units in the oligosiloxane product can be controlled by simply changing the order of hydrosilane addition.
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The First Biocatalytic Carbon–Silicon Bond Formation ()
Linking two worlds: As a further expansion of the biocatalytic repertoire, carbene insertion into Si−H bonds catalyzed by the heme protein cytochrome c was recently reported. This new biocatalyst holds great promise because it enables the highly selective incorporation of silicon into molecules without prior protection of existing functional groups.
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Surface-Enhanced Raman Spectra Promoted by a Finger Press in an All-Solid-State Flexible Energy Conversion and Storage Film ()
Raman signal enhancement by a finger press was realized by combining a flexible piezoelectric and dielectric energy conversion and storage film and silver nanowire layers. In their Communication (DOI: 10.1002/anie.201610737), Y. Zhang, Q. An et al. describe a self-energizing SERS (surface-enhanced Raman spectroscopy) substrate that converts film deformation into stored electrical energy, which then injects electrons into the silver nanowire layer and up-regulates the SERS signals measured therein.
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A Stable Saddle-Shaped Polycyclic Hydrocarbon with an Open-Shell Singlet Ground State ()
Diindeno-fused bischrysene, a new diindeno-based polycyclic hydrocarbon (PH), was synthesized and characterized. It was elucidated in detailed experimental and theoretical studies that this cyclopenta-fused PH possesses an open-shell singlet biradical structure in the ground state and exhibits high stability under ambient conditions (t1/2=39 days). The crystal structure unambiguously shows a novel saddle-shaped π-conjugated carbon skeleton due to the steric hindrance of the central cove-edged bischrysene unit. UV/Vis spectral measurements revealed that the title molecule has a very narrow optical energy gap of 0.92 eV, which is consistent with the electrochemical analysis and further supported by density functional theory (DFT) calculations. Stay in the saddle: A curved polycyclic hydrocarbon synthesized by extending the twisted bischrysene core by two indene units displayed a stable singlet biradical structure in the ground state. X-ray crystallographic analysis clearly revealed its saddle-shaped conformation.
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Cation Translocation around Single Polyoxometalate–Organic Hybrid Cluster Regulated by Electrostatic and Cation–π Interactions ()
We report herein an interesting dynamic translocation process of countercations around one polyoxometalate(POM)–organic hybrid anionic cluster at various concentrations and temperatures. It was found that both electrostatic interactions and cation–π interactions regulate the position of small countercations around single clusters. The dynamic geometry and the symmetry of the hybrid macroions are largely affected by the type of counterions, as shown by nuclear magnetic resonance (NMR) spectroscopy studies and all-atom molecular dynamics simulation. It is also shown that electrostatic interactions dominate over cation–π interactions in determining the locations of the counterions in the current system. Near and far: Spectroscopic and theoretical studies on the dynamic translocation process of countercations around a polyoxometalate–organic hybrid anionic molecular cluster show that electrostatic interactions and cation–π interactions regulate the position of small countercations around single clusters.
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Rapid and Complete Surface Modification with Strain-Promoted Oxidation-Controlled Cyclooctyne-1,2-Quinone Cycloaddition (SPOCQ) ()
Strain-promoted oxidation-controlled cyclooctyne-1,2-quinone cycloaddition (SPOCQ) between functionalized bicyclo[6.1.0]non-4-yne (BCN) and surface-bound quinones revealed an unprecedented 100 % conjugation efficiency. In addition, monitoring by direct analysis in real time mass spectrometry (DART-MS) revealed the underlying kinetics and activation parameters of this immobilization process in dependence on its microenvironment. Throwing DARTs at a surface: The strain-promoted oxidation-controlled cyclooctyne-1,2-quinone cycloaddition (SPOCQ) between bicyclo[6.1.0]nonyne (BCN) and a surface-bound quinone revealed an unprecedented 100 % conjugation efficiency.
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In Vivo Gold Complex Catalysis within Live Mice ()
Metal complex catalysis within biological systems is largely limited to cell and bacterial systems. In this work, a glycoalbumin–AuIII complex was designed and developed that enables organ-specific, localized propargyl ester amidation with nearby proteins within live mice. The targeted reactivity can be imaged through the use of Cy7.5- and TAMRA-linked propargyl ester based fluorescent probes. This targeting system could enable the exploitation of other metal catalysis strategies for biomedical and clinical applications. The first metal-catalyzed reaction that proceeds within live mice is based on a targeting approach with glycans. Glycoalbumin–AuIII complexes can be accumulated in specific organs where they catalyze amide bond formation between a propargyl ester probe and amine groups on nearby proteins. The selective targeting was confirmed by whole body fluorescence imaging and analysis of dissected tissues.
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Oxygen Activated, Palladium Nanoparticle Catalyzed, Ultrafast Cross-Coupling of Organolithium Reagents ()
The discovery of an ultrafast cross-coupling of alkyl- and aryllithium reagents with a range of aryl bromides is presented. The essential role of molecular oxygen to form the active palladium catalyst was established; palladium nanoparticles that are highly active in cross-coupling reactions with reaction times ranging from 5 s to 5 min are thus generated in situ. High selectivities were observed for a range of heterocycles and functional groups as well as for an expanded scope of organolithium reagents. The applicability of this method was showcased by the synthesis of the [11C]-labeled PET tracer celecoxib. No oxygen, no coupling: Molecular oxygen was shown to be crucial for the fast palladium-catalyzed cross-coupling of organolithium reagents developed herein. Reactions times down to 5 s provide a novel procedure for the preparation of radiolabeled compounds.
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A General and Highly Selective Cobalt-Catalyzed Hydrogenation of N-Heteroarenes under Mild Reaction Conditions ()
Herein, a general and efficient method for the homogeneous cobalt-catalyzed hydrogenation of N-heterocycles, under mild reaction conditions, is reported. Key to success is the use of the tetradentate ligand tris(2-(diphenylphosphino)phenyl)phosphine). This non-noble metal catalyst system allows the selective hydrogenation of heteroarenes in the presence of a broad range of other sensitive reducible groups. Reduction! Quinolines and related N-heteroarenes are hydrogenated using [Co]/L. The reactions proceed under mild conditions in a highly selective manner.
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Unexpected Ge–Ge Contacts in the Two-Dimensional Ge4Se3Te Phase and Analysis of Their Chemical Cause with the Density of Energy (DOE) Function ()
A hexagonal phase in the ternary Ge–Se–Te system with an approximate composition of GeSe0.75Te0.25 has been known since the 1960s but its structure has remained unknown. We have succeeded in growing single crystals by chemical transport as a prerequisite to solve and refine the Ge4Se3Te structure. It consists of layers that are held together by van der Waals type weak chalcogenide–chalcogenide interactions but also display unexpected Ge–Ge contacts, as confirmed by electron microscopy analysis. The nature of the electronic structure of Ge4Se3Te was characterized by chemical bonding analysis, in particular by the newly introduced density of energy (DOE) function. The Ge–Ge bonding interactions serve to hold electrons that would otherwise go into antibonding Ge–Te contacts. Ge–Ge contacts and the DOE: Ge4Se3Te, a layered structure with van der Waals interactions and unexpected Ge–Ge contacts, was crystallized, structurally characterized, and analyzed by electron microscopy. The nature of its electronic structure was characterized by chemical bonding analysis and the newly introduced density of energy (DOE) function.
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Inversion of the Side-Chain Stereochemistry of Indvidual Thr or Ile Residues in a Protein Molecule: Impact on the Folding, Stability, and Structure of the ShK Toxin ()
ShK toxin is a cysteine-rich 35-residue protein ion-channel ligand isolated from the sea anemone Stichodactyla helianthus. In this work, we studied the effect of inverting the side chain stereochemistry of individual Thr or Ile residues on the properties of the ShK protein. Molecular dynamics simulations were used to calculate the free energy cost of inverting the side-chain stereochemistry of individual Thr or Ile residues. Guided by the computational results, we used chemical protein synthesis to prepare three ShK polypeptide chain analogues, each containing either an allo-Thr or an allo-Ile residue. The three allo-Thr or allo-Ile-containing ShK polypeptides were able to fold into defined protein products, but with different folding propensities. Their relative thermal stabilities were measured and were consistent with the MD simulation data. Structures of the three ShK analogue proteins were determined by quasi-racemic X-ray crystallography and were similar to wild-type ShK. All three ShK analogues retained ion-channel blocking activity. Ch-ch-ch-changes: Guided by molecular dynamics calculations, chemical protein synthesis was used to explore the impact of allo-Thr and allo-Ile substitutions for individual Thr and Ile residues on the folding, crystal structure, and stability of the ShK protein. The experimental folding and thermal stability data matched well with the computational results.
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Hollow Iron–Vanadium Composite Spheres: A Highly Efficient Iron-Based Water Oxidation Electrocatalyst without the Need for Nickel or Cobalt ()
Noble-metal-free bimetal-based electrocatalysts have shown high efficiency for water oxidation. Ni and/or Co in these electrocatalysts are essential to provide a conductive, high-surface area and a chemically stable host. However, the necessity of Ni or Co limits the scope of low-cost electrocatalysts. Herein, we report a hierarchical hollow FeV composite, which is Ni- and Co-free and highly efficient for electrocatalytic water oxidation with low overpotential 390 mV (10 mA cm−2 catalytic current density), low Tafel slope of 36.7 mV dec−1, and a considerable durability. This work provides a novel and efficient catalyst, and greatly expands the scope of low-cost Fe-based electrocatalysts for water splitting without need of Ni or Co. Missing, but not missed: Vanadium-doped FeOOH is a low-cost, highly efficient iron-based electrocatalyst for water oxidation without Ni or Co participation. It exhibits a low overpotential 390 mV (10 mA cm−2 catalytic current density), low Tafel slope of 36.7 mV dec−1, and a considerable durability.
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Enhancement of C−H Oxidizing Ability in Co–O2 Complexes through an Isolated Heterobimetallic Oxo Intermediate ()
The characterization of intermediates formed through the reaction of transition-metal complexes with dioxygen (O2) is important for understanding oxidation in biological and synthetic processes. Here, the reaction of the diketiminate-supported cobalt(I) complex LtBuCo with O2 gives a rare example of a side-on dioxygen complex of cobalt. Structural, spectroscopic, and computational data are most consistent with its assignment as a cobalt(III)–peroxo complex. Treatment of LtBuCo(O2) with low-valent Fe and Co diketiminate complexes affords isolable oxo species with M2O2 “diamond” cores, including the first example of a crystallographically characterized heterobimetallic bis(μ-oxo) complex of two transition metals. The bimetallic species are capable of cleaving C−H bonds in the supporting ligands, and kinetic studies show that the Fe/Co heterobimetallic species activates C−H bonds much more rapidly than the Co/Co homobimetallic analogue. Thus heterobimetallic oxo intermediates provide a promising route for enhancing the rates of oxidation reactions. Odd couple: Treatment of a side-on dioxygen complex of cobalt with a low-valent iron or cobalt diketiminate complex affords a homobimetallic Co/Co or a heterobimetallic Fe/Co oxo complex, respectively. C−H activation in the Co/Fe complex is three orders of magnitude faster than in the homobimetallic analogue.
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An Electron Acceptor with Porphyrin and Perylene Bisimides for Efficient Non-Fullerene Solar Cells ()
A star-shaped porphyrin-based molecule with four perylene bisimide arms (PBI-Por) was designed as a non-fullerene electron acceptor for application in solar cells. In their Communication (DOI: 10.1002/anie.201612090), Z. Wang, W. Li, and co-workers show that the combination of a donor polymer with PBI-Por in a solar cell results in a photoresponse from λ=300 to 850 nm, with a maximum external quantum efficiency (EQE) of almost 0.70, and a promising power conversion efficiency of 7.4 %.
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Synthetic Channel Specifically Inserts into the Lipid Bilayer of Gram-Positive Bacteria but not that of Mammalian Erythrocytes ()
Synthetic transmembrane channels, a kind of rationally designed molecules that can transport ions by formation of nanopores that span the lipid bilayer, provide an alternative strategy for the development of membrane-active antimicrobials. However, few such channels show membrane selectivity. In their Communication (DOI: 10.1002/anie.201612093), J.-L Hou and co-workers report a channel that is able to specifically insert into the lipid bilayers of Gram-positive bacteria but not those of mammalian erythrocytes.
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Synthesis of Enantiopure C3-Symmetric Triangular Molecules ()
An asymmetric synthesis of C3-symmetric triangular macrocycles is reported. 1-Methylsulfonyl-4-(4-vinylphenyl)-1,2,3-triazole undergoes a rhodium(II)-catalyzed cyclotrimerization to establish an enantiopure C3-symmetric triangular macrocycle motif. This method can be applied to the synthesis of an enantiopure hydrocarbon, which owes its chirality to asymmetric distribution of H/D atoms on the benzene rings. My hat, it has three corners: Enantiopure C3-symmetric triangular macrocycles were synthesized by means of triple asymmetric cyclopropanation. This method is successfully extended to the synthesis of an enantiopure hydrocarbon, which owes its chirality to asymmetric distribution of H/D atoms on the benzene rings.
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On the Gold-Catalyzed Generation of Vinyl Cations from 1,5-Diynes ()
Conjugated 1,5-diynes bearing two aromatic units at the alkyne termini were converted in the presence of a gold catalyst. Under mild conditions, aryl-substituted dibenzopentalenes were generated. Calculations predict that aurated vinyl cations are key intermediates of the reaction. A bidirectional approach provided selective access to the angular annulated product in high yield, which was explained by calculations. Positive intermediates: The combination of non-terminal 1,5-diynes with cationic gold complexes enables the generation of highly reactive vinyl cations that can be used for the synthesis of unsymmetrically substituted dibenzopentalenes. Quantum-chemical calculations indicate a fast valence tautomer equilibrium between a gold alkyne complex and the vinyl cation.
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Enzyme-Initiated Free-Radical Polymerization of Molecularly Imprinted Polymer Nanogels on a Solid Phase with an Immobilized Radical Source ()
An enzyme-mediated synthetic approach is described for the preparation of molecularly imprinted polymer nanoparticles (MIP-NPs) in aqueous media. Horseradish peroxidase (HRP) was used to initiate the polymerization of methacrylate or vinyl monomers and cross-linkers by catalyzing the generation of free radicals. To prevent entrapment of the enzyme in the cross-linked polymer, and to enable it to be reused, HRP was immobilized on a solid support. MIPs based on 4-vinylpyridine and 1,4-bis(acryloyl)piperazine for the recognition of 2,4-dichlorophenoxyacetic acid (2,4-D) and salicylic acid were synthesized in an aqueous medium. MIPs for the protein trypsin were also synthesized. MIP nanoparticles with sizes between 50 and 300 nm were obtained with good binding properties, a good imprinting effect, and high selectivity for the target molecule. The reusability of immobilized HRP for MIP synthesis was shown for several batches. Mighty Immobilized Peroxidase: The radical polymerization of methacrylate or vinyl monomers and cross-linkers was initiated by immobilized horseradish peroxidase (HRP) to prepare molecularly imprinted polymer (MIP) nanogels in aqueous media (see scheme). MIP nanoparticles with sizes between 50 and 300 nm were obtained with good binding properties and high selectivity for the target molecule, the herbicide 2,4-dichlorophenoxyacetic acid.
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Steering Siglec–Sialic Acid Interactions on Living Cells using Bioorthogonal Chemistry ()
Sialic acid sugars that terminate cell-surface glycans form the ligands for the sialic acid binding immunoglobulin-like lectin (Siglec) family, which are immunomodulatory receptors expressed by immune cells. Interactions between sialic acid and Siglecs regulate the immune system, and aberrations contribute to pathologies like autoimmunity and cancer. Sialic acid/Siglec interactions between living cells are difficult to study owing to a lack of specific tools. Here, we report a glycoengineering approach to remodel the sialic acids of living cells and their binding to Siglecs. Using bioorthogonal chemistry, a library of cells with more than sixty different sialic acid modifications was generated that showed dramatically increased binding toward the different Siglec family members. Rational design reduced cross-reactivity and led to the discovery of three selective Siglec-5/14 ligands. Furthermore, glycoengineered cells carrying sialic acid ligands for Siglec-3 dampened the activation of Siglec-3+ monocytic cells through the NF-κB and IRF pathways. Clicking the immune system off: We report a method to rapidly reprogram the binding of sialic acid sugars on living cells to their cognate Siglec receptors through glycoengineering and click chemistry. Binding could be improved by more than 100-fold and in a selective manner. The modified cells showed potent immunosuppressive activity resulting from strong signaling through Siglecs on immune cells.
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Enantioselective Aza-Ene-type Reactions of Enamides with Gold Carbenes Generated from α-Diazoesters ()
Carbophilic gold carbenes generated from the decomposition of α-diazoesters show high reactivity towards enamides, leading to an unprecedented aza-ene-type reaction. The presence of 0.1 mol % of a chiral Brønsted acid co-catalyst is sufficient to give synthetically relevant γ-keto esters in excellent yields and selectivities (up to 99 % yield, 97 % ee). How low can you go? Carbophilic gold carbenes derived from α-diazoesters react with enamides in an unprecedented aza-ene-type reaction. The presence of 0.1 mol % of a chiral Brønsted acid is sufficient to achieve excellent yields and enantioselectivities.
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A Ruthenium Complex–Porphyrin–Fullerene-Linked Molecular Pentad as an Integrative Photosynthetic Model ()
A ruthenium complex, porphyrin sensitizer, fullerene acceptor molecular pentad has been synthesized and a long-lived hole–electron pair was achieved in aqueous solution by photoinduced multistep electron transfer: Upon irradiation by visible light, the excited-state of a zinc porphyrin (1ZnP*) was quenched by fullerene (C60) to afford a radical ion pair, 1,3(ZnP.+-C60.−). This was followed by the subsequent electron transfer from a water oxidation catalyst unit (RuII) to ZnP.+ to give the long-lived charge-separated state, RuIII-ZnP-C60.−, with a lifetime of 14 μs. The ZnP worked as a visible-light-harvesting antenna, while the C60 acted as an excellent electron acceptor. As a consequence, visible-light-driven water oxidation by this integrated photosynthetic model compound was achieved in the presence of sacrificial oxidant and redox mediator. Pent-up energy: A ruthenium-based water oxidation catalyst linked to porphyrin–fullerene units in a molecular pentad has been synthesized. Transient absorption indicated the photoinduced multistep electron transfer afforded a long-lived hole–electron pair, and photocatalytic water oxidation by the pentad was achieved in the presence of sacrificial oxidant.
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Enantioselective Dearomatization of Naphthol Derivatives with Allylic Alcohols by Cooperative Iridium and Brønsted Acid Catalysis ()
The combination of a transition-metal catalyst and organocatalyst was designed to achieve a highly enantioselective system for the allylic dearomatization reaction of naphthols with racemic secondary allylic alcohols. The desired β-naphthalenones, bearing an all-carbon quaternary center, were obtained in good yields with high chemo- and enantioselectivities. The cooperative catalytic system, involving a chiral iridium complex and phosphoric acid, provided measurable improvements in yields, and chemo- and enantioselectivities relative to single-catalyst systems. Control experiments indicated that the chiral iridium complex functions as a key species in the control of the absolute configuration, thus enabling the formation of both β-naphthalenone enantiomers by simply employing opposite enantiomeric ligands. Co-op: The cooperative dual-catalytic system of a chiral iridium complex and phosphoric acid achieves highly enantioselective allylic dearomatization reactions of naphthols with racemic secondary allylic alcohols. The desired β-naphthalenones, bearing an all-carbon quaternary center, were obtained in good yields. Both β-naphthalenone enantiomers can be obtained by simply employing opposite enantiomeric ligands.
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Reversible Stereoselective Folding/Unfolding Fueled by the Interplay of Photoisomerism and Hydrogen Bonding ()
A linear molecular architecture equipped with complementary three-fold hydrogen-bonding units embedded with a photoswitchable trans-tetrafluoroazobenzene moiety was synthesized. The transto cis photoisomerism of the azobenzene unit induced drastic changes in the molecular architecture as a result of intramolecular hydrogen bonding as evidenced by NMR spectroscopy and size exclusion chromatography. A minute stereogenic element in the linear trans state enabled stereoselective folding into the cis state, thus producing a globular architecture with enhanced chiroptical property. Know when to fold 'em: A linear molecular architecture equipped with complementary three-fold hydrogen bonding units embedded with a photoswitchable trans-tetrafluoroazobenzene moiety was synthesized. The trans to cis photoisomerism of the azobenzene unit induced changes in the molecular architecture as a result of intramolecular hydrogen bonding as evidenced by NMR spectroscopy and size exclusion chromatography.
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The Enzymology of Organic Transformations: A Survey of Name Reactions in Biological Systems ()
Chemical reactions that are named in honor of their true, or at least perceived, discoverers are known as “name reactions”. This Review is a collection of biological representatives of named chemical reactions. Emphasis is placed on reaction types and catalytic mechanisms that showcase both the chemical diversity in natural product biosynthesis as well as the parallels with synthetic organic chemistry. An attempt has been made, whenever possible, to describe the enzymatic mechanisms of catalysis within the context of their synthetic counterparts and to discuss the mechanistic hypotheses for those reactions that are currently active areas of investigation. This Review has been categorized by reaction type, for example condensation, nucleophilic addition, reduction and oxidation, substitution, carboxylation, radical-mediated, and rearrangements, which are subdivided by name reactions. Naming names: Chemical reactions that are named after their discoverers are known as “name reactions”. This Review is a collection of biological representatives of named chemical reactions. Emphasis is placed on reaction types and catalytic mechanisms that showcase both the chemical diversity in natural product biosynthesis as well as the parallels with synthetic organic chemistry.
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Binuclear, High-Valent Nickel Complexes: Ni−Ni Bonds in Aryl–Halogen Bond Formation ()
Metal–metal bonds play a vital role in stabilizing key intermediates in bond-formation reactions. We report that binuclear benzo[h]quinoline-ligated NiII complexes, upon oxidation, undergo reductive elimination to form carbon–halogen bonds. A mixed-valent Ni(2.5+)–Ni(2.5+) intermediate is isolated. Further oxidation to NiIII, however, is required to trigger reductive elimination. The binuclear NiIII–NiIII intermediate lacks a Ni−Ni bond. Each NiIII undergoes separate, but fast reductive elimination, giving rise to NiI species. The reactivity of these binuclear Ni complexes highlights the fundamental difference between Ni and Pd in mediating bond-formation processes. A couple of nickels: Well-defined, binuclear NiII–NiII, Ni(2.5+)–Ni(2.5+), and NiIII–NiIII complexes are isolated, which shed light on the mechanism of reductive elimination to form carbon–halogen bonds. Their reactivity is fundamentally different to that of the related palladium complexes.
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An Unconventional Mechanistic Insight into SCF3 Formation from Difluorocarbene: Preparation of 18F-Labeled α-SCF3 Carbonyl Compounds ()
Trifluoromethylthiolation by sulfuration of difluorocarbene with elemental sulfur is described for the first time, which overrides long-standing trifluoromethyl anion-based theory. Mechanistic elucidation reveals an unprecedented chemical process for the formation of thiocarbonyl fluoride and also enables transition-metal-mediated trifluoromethylthiolation and [18F]trifluoromethylthiolation of α-bromo carbonyl compounds with broad substrate scope and compatibility. A trifluoromethylthio anion generated from a S8/:CF2/F− system occurs by sulfuration of difluorocarbene rather than capture of difluorocarbene by fluoride. This process translates well to rapid trifluoromethylthiolation and [18F]trifluoromethylthiolation of α-bromo carbonyl compounds.
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Cover Picture: Modulation of the Thermodynamic Signatures of an RNA Thermometer by Osmolytes and Salts (Angew. Chem. Int. Ed. 9/2017) ()
The interplay between osmolyte, water, and salts in determining the free-energy landscape of a hairpin-structured RNA is discussed by R. Winter and co-workers in their Communication on page 2302 ff. They report the effect of common osmolytes on the folding equilibrium of the RNA and, by using pressure perturbation, provide novel thermodynamic and volumetric insights into the modulation mechanism. The study suggests that the working mechanism by which TMAO stabilizes and urea destabilizes folded proteins and the RNA is similar.
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Inside Cover: Conformational SERS Classification of K-Ras Point Mutations for Cancer Diagnostics (Angew. Chem. Int. Ed. 9/2017) ()
Discrimination of single-point mutations in large fragments of the K-Ras gene by an optical approach based on direct surface-enhanced Raman scattering coupled with chemometrics is presented by R. A. Alvarez-Puebla, L. Guerrini et al. in their Communication on page 2381 ff. The unambiguous classification of different mutations provides a potentially useful insight for diagnostics and treatment of cancer.
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Inside Back Cover: Breaking the Tetra-Coordinated Framework Rule: New Clathrate Ba8M24P28+δ (M=Cu/Zn) (Angew. Chem. Int. Ed. 9/2017) ()
Despite the common expectation of clathrates to embrace nearly tetrahedral coordination environments, a new clathrate structure type has been discovered in the Ba/Cu/Zn/P system with unique five- and six-coordinated framework atoms. In their Communication on page 2418 ff., K. Kovnir et al. show that high-resolution synchrotron X-ray and neutron diffraction in conjugation with advanced solid-state NMR spectroscopy and quantum-chemical calculations can be used for elucidation of the structure and chemical bonding.
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Back Cover: Methanol-Triggered Vapochromism Coupled with Solid-State Spin Switching in a Nickel(II)-Quinonoid Complex (Angew. Chem. Int. Ed. 9/2017) ()
A methanol-selective vapochromic response is realized in a nickel(II) quinonoid complex, which exhibits a reversible structural transformation including a coordination geometrical change between the square-planar and octahedral structure by the uptake and removal of methanol vapor. In their Communication on page 2345 ff. M. Kato and co-workers show that this process is accompanied by a remarkable color change as well as spin-state switching in the solid state under ambient conditions.
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Frontispiece: Ten-Minute Protein Purification and Surface Tethering for Continuous-Flow Biocatalysis ()
Biocatalysis C. L. Raston, G. A. Weiss et al. describe in their Communication on page 2296 ff. a highly efficient and scalable method for multistep biocatalysis by spatially segregating attached enzymes in a continuous-flow, vortex fluidic device.
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Graphical Abstract: Angew. Chem. Int. Ed. 9/2017 ()

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Corrigendum: Engineered Substrate-Specific Delta PKC Antagonists to Enhance Cardiac Therapeutics ()

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Corrigendum: Topological Polymer Chemistry Enters Surface Science: Linear versus Cyclic Polymer Brushes ()

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Spotlights on our sister journals: Angew. Chem. Int. Ed. 9/2017 ()

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Tamejiro Hiyama ()
“My motto is ‘do your best and leave the rest to Providence’. If I had one year of paid leave I would travel through Europe and Russia and learn western culture, art, and philosophy ...” This and more about Tamejiro Hiyama can be found on page 2242.
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John D. Roberts (1918–2016) ()
John D. (Jack) Roberts, Institute Professor of Chemistry Emeritus at the California Institute of Technology died on October 29, 2016, at the age of 98. Roberts was one of the of the iconic figures in physical organic chemistry of the 20th century. His achievements included proving the occurrence of benzynes and nonclassical carbocations as reaction intermediates, and he was instrumental in establishing NMR spectroscopy as a standard analytical technique in organic chemistry.
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Electron Paramagnetic Resonance. By Victor Chechik, Emma Carter, and Damien Murphy. ()
Oxford University Press 2016. 128 pp., softcover, £ 12.99.—ISBN 978-0198727606
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Quinoidal/Aromatic Transformations in π-Conjugated Oligomers: Vibrational Raman studies on the Limits of Rupture for π-Bonds ()
The vibrational Raman spectra of several series of aromatic and quinoidal compounds have been analyzed considering the downshifts and upshifts of the frequencies of the relevant Raman bands as a function of the number of repeating units. Oligothiophenes, oligophenylene-vinylenes, and oligoperylenes (oligophenyls) derivatives are studied in a common context. These shifts are taken as spectroscopic fingerprints of the changes in π-conjugation. For a given family, aromatic and quinoidal oligomers have been studied together, and according to their Raman frequency shifts located in the two-well BLA–energy curve of their ground electronic state as a function of the bond-length-alternation pattern (BLA). The connection among BLA values, π-conjugation, and Raman frequencies is taken here as the basis of the study. These Raman shifts/BLA changes have been related to important electronic properties of these one-dimensional linear π-electron delocalized systems such as quinoidal (polyene) and aromatic characters. Shifting patterns: Spectral Raman shifts of aromatic and quinoidal π-conjugated oligomers have been compared using the variations in the bond length alternation, and with changes in π-conjugation. Described is how Raman frequency shifts highlight the structural alteration within the limit of controlled formation and fission of π-bonds.
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Electrophilic Activation of Silicon–Hydrogen Bonds in Catalytic Hydrosilations ()
Hydrosilation reactions represent an important class of chemical transformations and there has been considerable recent interest in expanding the scope of these reactions by developing new catalysts. A major theme to emerge from these investigations is the development of catalysts with electrophilic character that transfer electrophilicity to silicon by Si-H activation. This type of mechanism has been proposed for catalysts ranging from Group 4 transition metals to Group 15 main group species. Additionally, other electrophilic silicon species, such as silylene complexes and η3-H2SiRR′ complexes, have been identified as intermediates in hydrosilation reactions. In this Review, different types of catalysts are compared to highlight the range of hydrosilation mechanisms that feature electrophilic silicon centers. The importance of these catalysts to the development of new hydrosilation reactions is also discussed. On active duty: Catalysts based on elements from Groups 4–15 and that operate through electrophilic silane activation pathways are currently intensively investigated for hydrosilylations. This Review surveys these catalysts and describes several related mechanisms for electrophilic Si-H activation (σ-H-Si coordination, M(H)2=SiRR′ formation, η3-H2SiRR′ binding).
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Ten-Minute Protein Purification and Surface Tethering for Continuous-Flow Biocatalysis ()
Nature applies enzymatic assembly lines to synthesize bioactive compounds. Inspired by such capabilities, we have developed a facile method for spatially segregating attached enzymes in a continuous-flow, vortex fluidic device (VFD). Fused Hisn-tags at the protein termini allow rapid bioconjugation and consequent purification through complexation with immobilized metal affinity chromatography (IMAC) resin. Six proteins were purified from complex cell lysates to average homogeneities of 76 %. The most challenging to purify, tobacco epi-aristolochene synthase, was purified in only ten minutes from cell lysate to near homogeneity (>90 %). Furthermore, this “reaction-ready” system demonstrated excellent stability during five days of continuous-flow processing. Towards multi-step transformations in continuous flow, proteins were arrayed as ordered zones on the reactor surface allowing segregation of catalysts. Ordering enzymes into zones opens up new opportunities for continuous-flow biosynthesis. Multi-step biocatalysis goes with the flow: Several enzymes were immobilized into distinct, ordered zones in a thin film continuous-flow reactor. Telescoping protein immobilization and purification creates a “reactor-ready” system in ten minutes from cell lysates. This advancement is poised to facilitate on-demand synthesis of compounds using enzymatic pathways.
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Modulation of the Thermodynamic Signatures of an RNA Thermometer by Osmolytes and Salts ()
Folding of ribonucleic acids (RNAs) is driven by several factors, such as base pairing and stacking, chain entropy, and ion-mediated electrostatics, which have been studied in great detail. However, the power of background molecules in the cellular milieu is often neglected. Herein, we study the effect of common osmolytes on the folding equilibrium of a hairpin-structured RNA and, using pressure perturbation, provide novel thermodynamic and volumetric insights into the modulation mechanism. The presence of TMAO causes an increased thermal stability and a more positive volume change for the helix-to-coil transition, whereas urea destabilizes the hairpin and leads to an increased expansibility of the unfolded state. Further, we find a strong interplay between water, salt, and osmolyte in driving the thermodynamics and defining the temperature and pressure stability limit of the RNA. Our results support a universal working mechanism of TMAO and urea to (de)stabilize proteins and the RNA. Interplay between osmolyte, water, and salts determines the free-energy landscape of a hairpin-structured RNA. Thermal and pressure perturbation experiments provide novel thermodynamic and volumetric insights into the modulation mechanism. Such results are important to understand the functional complexity of RNAs in vivo.
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Activation of Dioxygen at a Lewis Acidic Nickel(II) Complex: Characterization of a Metastable Organoperoxide Complex ()
In metal-mediated O2 activation, nickel(II) compounds hardly play a role, but recently it has been shown that enzymes can use nickel(II) for O2 activation. Now a low-coordinate Lewis acidic nickel(II) complex has been synthesized that reacts with O2 to give a nickel(II) organoperoxide, as proposed for the enzymatic system. Its formation was studied further by UV/Vis absorption spectroscopy, leading to the observation of a short-lived intermediate that proved to be reactive in both oxygen atom transfer and hydrogen abstraction reactions, while the peroxide efficiently transfers O atoms. Both for the enzyme and for the functional model, the key to O2 activation is proposed to represent a concomitant electron shift from the substrate/co-ligand. Nickel(II) can do it too: O2 activation can occur even at low temperature if nickel(II) cooperates with a redox-active ligand, as recently also suggested for the nickel-dependent quercitinase. First precedence is provided that a nickel(II)organoperoxo moiety can be generated when setting out from a nickel(II) complex and O2 (partial structure of crystallized metastable peroxide shown).
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A Hexasaccharide Containing Rare 2-O-Sulfate-Glucuronic Acid Residues Selectively Activates Heparin Cofactor II ()
Glycosaminoglycan (GAG) sequences that selectively target heparin cofactor II (HCII), a key serpin present in human plasma, remain unknown. Using a computational strategy on a library of 46 656 heparan sulfate hexasaccharides we identified a rare sequence consisting of consecutive glucuronic acid 2-O-sulfate residues as selectively targeting HCII. This and four other unique hexasaccharides were chemically synthesized. The designed sequence was found to activate HCII ca. 250-fold, while leaving aside antithrombin, a closely related serpin, essentially unactivated. This group of rare designed hexasaccharides will help understand HCII function. More importantly, our results show for the first time that rigorous use of computational techniques can lead to discovery of unique GAG sequences that can selectively target GAG-binding protein(s), which may lead to chemical biology or drug discovery tools. A computational strategy was used to identify a rare sequence of glucuronic acid 2-O-sulfate residues in a library of heparan sulfate hexasaccharides. The designed sequence was found to activate heparin cofactor II 250-fold, while leaving antithrombin, a closely related serpin, essentially unactivated.
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CO2-to-Methanol Hydrogenation on Zirconia-Supported Copper Nanoparticles: Reaction Intermediates and the Role of the Metal–Support Interface ()
Methanol synthesis by CO2 hydrogenation is a key process in a methanol-based economy. This reaction is catalyzed by supported copper nanoparticles and displays strong support or promoter effects. Zirconia is known to enhance both the methanol production rate and the selectivity. Nevertheless, the origin of this observation and the reaction mechanisms associated with the conversion of CO2 to methanol still remain unknown. A mechanistic study of the hydrogenation of CO2 on Cu/ZrO2 is presented. Using kinetics, in situ IR and NMR spectroscopies, and isotopic labeling strategies, surface intermediates evolved during CO2 hydrogenation were observed at different pressures. Combined with DFT calculations, it is shown that a formate species is the reaction intermediate and that the zirconia/copper interface is crucial for the conversion of this intermediate to methanol. Interface matters: A combination of solid-state NMR and IR spectroscopies with DFT calculations unravels the nature of reaction intermediates in the hydrogenation of CO2 to methanol on Cu/ZrO2 catalysts, pointing out the specific role of the metal–support interface in the formation and conversion of formate into methoxy species.
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Photoproduction of Hydrogen by Decamethylruthenocene Combined with Electrochemical Recycling ()
The photoinduced hydrogen evolution reaction (HER) by decamethylruthenocene, Cp2*RuII (Cp*=C5Me5), is reported. The use of a metallocene to photoproduce hydrogen is presented as an alternative strategy to reduce protons without involving an additional photosensitizer. The mechanism was investigated by (spectro)electrochemical and spectroscopic (UV/Vis and 1H NMR) measurements. The photoactivated hydride involved was characterized spectroscopically and the resulting [Cp2*RuIII]+ species was electrochemically regenerated in situ on a fluorinated tin oxide electrode surface. A promising internal quantum yield of 25 % was obtained. Optimal experimental conditions— especially the use of weakly coordinating solvent and counterions—are discussed. A Cp2*RuII single molecule photogenerated hydrogen with an internal quantum yield of 25 %. Cp2*RuII was electrochemically regenerated in situ and spectroscopic studies enabled deconvolution of the operating reaction mechanism. Combined with electrochemical recycling, metallocene electron donors such as Cp2*RuII could work in tandem with a water oxidation catalyst to photoproduce H2 from water.
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Sequence-Controlled Polymers with Furan-Protected Maleimide as a Latent Monomer ()
Herein, a novel methodology for preparing sequence-controlled polymers is illustrated by using a latent monomer, furan protected maleimide (FMI). At 110 °C, FMI is deprotected by retro Diels–Alder (rDA) reaction, and the released MI is immediately involved in the cross-polymerization with styrene (St) to deliver heterosegments. At 40 °C the rDA reaction does not proceed, therefore homo-poly(styrene) segments are produced. By implementing programmable temperature changes during polymerization of St and FMI, “living” polymers with tailored a sequence are created. A ternary copolymerization produces complex sequences as designed. Alkynyl-functionalized FMI, used as a latent monomer, leads to the desirable placement of functional groups along the polymer chain. This latent-monomer-based strategy opens a new avenue for fabricating sequence-controlled polymers. Temp control: A new method for preparing sequence-controlled polymers relies on a latent monomer, furan-protected maleimide, that releases maleimide at specific temperatures and permits temperature-controlled installation of maleimide units during polymerization reactions.
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Catalysis Meets Nonthermal Separation for the Production of (Alkyl)phenols and Hydrocarbons from Pyrolysis Oil ()
A simple and efficient hydrodeoxygenation strategy is described to selectively generate and separate high-value alkylphenols from pyrolysis bio-oil, produced directly from lignocellulosic biomass. The overall process is efficient and only requires low pressures of hydrogen gas (5 bar). Initially, an investigation using model compounds indicates that MoCx/C is a promising catalyst for targeted hydrodeoxygenation, enabling selective retention of the desired Ar−OH substituents. By applying this procedure to pyrolysis bio-oil, the primary products (phenol/4-alkylphenols and hydrocarbons) are easily separable from each other by short-path column chromatography, serving as potential valuable feedstocks for industry. The strategy requires no prior fractionation of the lignocellulosic biomass, no further synthetic steps, and no input of additional (e.g., petrochemical) platform molecules. Out of the woods: Selective hydrodeoxygenation of lignocellulose-derived pyrolysis bio-oil, catalyzed by MoCx/C, affords value-added alkylphenol (and phenol) products and hydrocarbons. The strategy requires no prior fractionation of the lignocellulosic biomass, no further synthetic steps, and no input of additional petrochemical platform molecules.
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Steep pH Gradients and Directed Colloid Transport in a Microfluidic Alkaline Hydrothermal Pore ()
All life on earth depends on the generation and exploitation of ionic and pH gradients across membranes. One theory for the origin of life proposes that geological pH gradients were the prebiotic ancestors of these cellular disequilibria. With an alkaline interior and acidic exterior, alkaline vents match the topology of modern cells, but it remains unknown whether the steep pH gradients persist at the microscopic scale. Herein, we demonstrate the existence of 6 pH-unit gradients across micrometer scales in a microfluidic vent replicate. Precipitation of metal sulfides at the interface strengthens the gradients, but even in the absence of precipitates laminar flow sustains the disequilibria. The gradients drive directed transport at the fluid interface, leading to colloid accumulation or depletion. Our results confirm that alkaline vents can provide an exploitable pH gradient, supporting their potential role at the emergence of chemiosmosis and the origin of life. At the interface: A 6 pH-unit gradient is shown to persist on the microscale in alkaline hydrothermal vents. Observation and modeling of directed transport by diffusiophoresis in the same setting further supports the potential role of electrochemical gradients in alkaline vents at the emergence of chemiosmosis and the origin of life.
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Methanol-Triggered Vapochromism Coupled with Solid-State Spin Switching in a Nickel(II)-Quinonoid Complex ()
A highly methanol-selective vapochromic response has been realized in a NiII-quinonoid complex, [Ni(HLMe)2] (H2LMe=4-methylamino-6-methyliminio-3-oxocyclohexa-1,4-dien-1-olate) which exhibits a reversible structural transformation including a coordination geometrical change between the square-planar and octahedral structure by the selective uptake of methanol vapor. This was accompanied by a remarkable color change between purple and orange, as well as temperature-robust spin-state switching in the solid state under ambient conditions. It is remarkable that the properties are derived by the fine structural modification of the quinonoid ligand such as methyl or ethyl analogues. Such a system has high potential for applications in memory devices as well as chemical sensors and smart responsive materials. Reversible transformation of a NiII-quinonoid complex between square-planar and octahedral geometry was selectively triggered by the uptake and removal of methanol vapor in solid state under ambient conditions. This transformation was coupled with the remarkable color change as well as the coordination induced spin-state switching.
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Retention of the Zn−Zn bond in [Ge9Zn−ZnGe9]6− and Formation of [(Ge9Zn)−(Ge9)−(ZnGe9)]8− and Polymeric 1∞ [−(Ge9Zn)2−−]1 ()
Reactions of ZnI2L2 (where L=[HC(PPh2NPh)]−) with solutions of the Zintl phase K4Ge9 in liquid ammonia lead to retention of the Zn−Zn bond and formation of the anion [(η4-Ge9)Zn−Zn(η4-Ge9)]6−, representing the first complex with a Zn−Zn unit carrying two cluster entities. The trimeric anion [(η4-Ge9)Zn{μ2(η1:η1Ge9)}Zn(η4-Ge9)]8− forms as a side product, indicating that oxidation reactions also take place. The reaction of Zn2Cp*2 (Cp*=1,2,3,4,5-pentamethylcyclopentadienyl) with K4Ge9 in ethylenediamine yielded the linear polymeric unit 1∞ {[Zn[μ2(η4:η1Ge9)]}2− with the first head-to-tail arrangement of ten-atom closo-clusters. All anions were obtained and structurally characterized as [A(2.2.2-crypt)]+ salts (A=K, Rb). Copious computational analyses at a DFT-PBE0/def2-TZVPP/PCM level of theory confirm the experimental structures and support the stability of the two hypothetical ten vertex cluster fragments closo-[Ge9Zn]2− and (paramagnetic) [Ge9Zn]3−. Zn atoms serve for both: Covalent coupling of two clusters through zinc vertex atoms or Lewis acid/base interactions lead to novel intermetalloid clusters with zinc.
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Dual Fluorescent- and Isotopic-Labelled Self-Assembling Vancomycin for in vivo Imaging of Bacterial Infections ()
The increase of bacterial resistance demands rapid and accurate diagnosis of bacterial infections. Biosurface-induced supramolecular assembly for diagnosis and therapy has received little attention in detecting bacterial infections. Herein we present a dual fluorescent-nuclear probe based on self-assembly of vancomycin (Van) on Gram-positive bacteria for imaging bacterial infection. A Van- and rhodamine-modified peptide derivative (Rho-FF-Van), as the imaging agent, binds to the terminal peptide of the methicillin-resistant staphylococcus aureus (MRSA) and self-assembles to form nanoaggregates on the surface of MRSA. In an in vivo myositis model, Rho-FF-Van results in a significant increased fluorescence signal at the MRSA infected site. Radiolabeled with iodine-125, Rho-FF-Van shows strong radioactive signal in the MRSA-infected lungs in a murine model. This novel dual fluorescent and nuclear probe promises a new way for in vivo imaging of bacterial infections. Image building: A dual fluorescent/nuclear probe based on the self-assembly of vancomycin on Gram-positive bacteria images bacterial infection. The probe aggregates on the surface of methicillin-resistant Staphylococcus aureus (MRSA) and can image MRSA-infected myositis and lungs in mice.
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Plasmonic Chirality Imprinting on Nucleobase-Displaying Supramolecular Nanohelices by Metal–Nucleobase Recognition ()
Supramolecular self-assembly is an important process that enables the conception of complex structures mimicking biological motifs. Herein, we constructed helical fibrils through chiral self-assembly of nucleobase–peptide conjugates (NPCs), where achiral nucleobases are helically displayed on the surface of fibrils, comparable to polymerized nucleic acids. Selective binding between DNA and the NPC fibrils was observed with fluorescence polarization. Taking advantage of metal–nucleobase recognition, we highlight the possibility of deposition/assembly of plasmonic nanoparticles onto the fibrillar constructs. In this approach, the supramolecular chirality of NPCs can be adaptively imparted to metallic nanoparticles, covering them to generate structures with plasmonic chirality that exhibit significantly improved colloidal stability. The self-assembly of rationally designed NPCs into nanohelices is a promising way to engineer complex, optically diverse nucleobase-derived nanomaterials. Amyloid fibrils were constructed through the self-assembly of nucleobase–peptide conjugates that were designed to repeatedly organize achiral nucleobases into helical patterns on the surface. The fibrils were utilized for the in situ nucleation and assembly of metallic nanoparticles through metal–nucleobase recognition.
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A Dual Functional Electroactive and Fluorescent Probe for Coupled Measurements of Vesicular Exocytosis with High Spatial and Temporal Resolution ()
In this work, Fluorescent False Neurotransmitter 102 (FFN102), a synthesized analogue of biogenic neurotransmitters, was demonstrated to show both pH-dependent fluorescence and electroactivity. To study secretory behaviors at the single-vesicle level, FFN102 was employed as a new fluorescent/electroactive dual probe in a coupled technique (amperometry and total internal reflection fluorescence microscopy (TIRFM)). We used N13 cells, a stable clone of BON cells, to specifically accumulate FFN102 into their secretory vesicles, and then optical and electrochemical measurements of vesicular exocytosis were experimentally achieved by using indium tin oxide (ITO) transparent electrodes. Upon stimulation, FFN102 started to diffuse out from the acidic intravesicular microenvironment to the neutral extracellular space, leading to fluorescent emissions and to the electrochemical oxidation signals that were simultaneously collected from the ITO electrode surface. The correlation of fluorescence and amperometric signals resulting from the FFN102 probe allows real-time monitoring of single exocytotic events with both high spatial and temporal resolution. This work opens new possibilities in the investigation of exocytotic mechanisms. The synthetic neurotransmitter FFN102 is employed to monitor coupled amperometric and fluorescence microscopy measurements of individual exocytotic events. This method capitalizes on the strengths of both individual techniques, and opens the way for new approaches to study the kinetics and mechanisms of vesicular secretion.
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Discrimination between Conglomerates and Pseudoracemates Using Surface Coverage Plots in 2D Self-Assemblies at the Liquid–Graphite Interface ()
The two-dimensional (2D) molecular ordering of two photochromic diarylethenes was investigated using scanning tunneling microscopy at the liquid–graphite interface. The racemic mixture of the closed-ring isomer of one of the diarylethenes showed spontaneous separation of its enantiomers upon 2D crystallization, whereas that of the other diarylethene formed a pseudoracemic crystal in which two enantiomers coexist in a 2D ordering domain. The mixing of enantiomers in 2D assemblies can be analyzed by the dependence of the surface coverage on the concentration of enantiomers at different enantiomeric ratios. Chiral 2D self-assemblies at the liquid–solid interface, that is, formation of conglomerates or mixed crystals, can be analyzed in detail by means of the dependence of the surface coverage on the concentration of enantiomers.
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Distal-Bond-Selective C−C Activation of Ring-Fused Cyclopentanones: An Efficient Access to Spiroindanones ()
A site-selective rhodium-catalyzed C−C activation of ring-fused cyclopentanones was achieved to afford efficient access to a range of spiroindanones. The use of bulky 2-amino-6-picoline as a cocatalyst is key to the excellent selectivity of this C−C bond cleavage in cyclopentanones. So far, so good: Rhodium-catalyzed C−C activation of ring-fused cyclopentanones was achieved site selectively for the distal over the proximal position. Key to this outcome is the combination of a bulky 2-amino-6-picoline (C1) with a bulky NHC ligand. This unusual intramolecular skeleton rearrangement offers rapid access to a diverse range of spiroindanones.
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Conformational SERS Classification of K-Ras Point Mutations for Cancer Diagnostics ()
Point mutations in Ras oncogenes are routinely screened for diagnostics and treatment of tumors (especially in colorectal cancer). Here, we develop an optical approach based on direct SERS coupled with chemometrics for the study of the specific conformations that single-point mutations impose on a relatively large fragment of the K-Ras gene (141 nucleobases). Results obtained offer the unambiguous classification of different mutations providing a potentially useful insight for diagnostics and treatment of cancer in a sensitive, fast, direct and inexpensive manner. Classification of mutations: An optical approach based on direct surface-enhanced Raman scattering (SERS) coupled with chemometrics was developed for discriminating single-point mutations in relatively large fragments of the K-Ras gene. This method exploits the specific conformations that base substitutions impose on the DNA strands.
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General Synthesis of Multishell Mixed-Metal Oxyphosphide Particles with Enhanced Electrocatalytic Activity in the Oxygen Evolution Reaction ()
We report a general approach for the synthesis of multishell mixed-metal oxyphosphide particles. Seven-layer Mn-Co oxide particles were first prepared by thermal treatment of Mn-Co coordination polymer precursors. Afterwards, these multishell Mn-Co oxide particles were further transformed into multishell Mn-Co oxyphosphide particles through a phosphidation reaction. This approach is very versatile and can be applied to synthesize other multishell mixed-metal oxyphosphide particles with different compositions. By applying a constant electrochemical potential, these multishell Mn-Co oxyphosphide particles can be activated to produce Mn-Co oxide/hydroxide species in their nanoshells and then show greatly enhanced electrocatalytic activity in the oxygen evolution reaction (OER). Multiple layers: Multishell mixed-metal oxyphosphide particles were synthesized by low-temperature phosphidation. After a simple activation process, these particles exhibited enhanced electrocatalytic activity in the oxygen evolution reaction.
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A Ternary Solvent Method for Large-Sized Two-Dimensional Perovskites ()
Recent reports demonstrate that a two-dimensional (2D) structural characteristic can endow perovskites with both remarkable photoelectric conversion efficiency and high stability, but the synthesis of ultrathin 2D perovskites with large sizes by facile solution methods is still a challenge. Reported herein is the controlled growth of 2D (C4H9NH3)2PbBr4 perovskites by a chlorobenzene-dimethylformide-acetonitrile ternary solvent method. The critical factors, including solvent volume ratio, crystallization temperature, and solvent polarity on the growth dynamics were systematically studied. Under optimum reaction condition, 2D (C4H9NH3)2PbBr4 perovskites, with the largest lateral dimension of up to 40 μm and smallest thickness down to a few nanometers, were fabricated. Furthermore, various iodine doped 2D (C4H9NH3)2PbBrxI4−x perovskites were accessed to tune the optical properties rationally. Star-crossed: Ultrathin and large two-dimensional (C4H9NH3)2PbX4 perovskites were synthesized by a ternary solvent method. The critical factors, including temperature, solvent volume ratio, and solvent types, that affect the growth dynamics were studied. ACN=acetonitrile, CB=chlorobenzene, DMF=N,N-dimethylformamide.
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Enrichment of Specifically Labeled Proteins by an Immobilized Host Molecule ()
Chemical proteomics relies primarily on click-chemistry-based protein labeling and biotin-streptavidin enrichment, but these techniques have inherent limitations. Enrichment of intracellular proteins using a totally synthetic host–guest complex is described, overcoming the problem associated with the classical approach. We achieve this by affinity-based protein labeling with a target-specific probe molecule conjugated to a high-affinity guest (suberanilohydroxamic acid–ammonium-adamantane; SAHA-Ad) and then enriching the labeled species using a cucurbit[7]uril bead. This method shows high specificity for labeled molecules in a MDA-MB-231 breast cancer cell lysate. Moreover, this method shows promise for labeling proteins in live cells. Supramolecular fishing with molecular bait: Intracellular proteins can be enriched using the synthetic host–guest pair cucurbit[7]uril and ammonium-adamantane. Specific proteins were labeled with an affinity-based probe that transfers an ammonium-adamantane group to the protein so that it can be selectively enriched by a cucurbit[7]uril bead.
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Observing Single-Molecule Dynamics at Millimolar Concentrations ()
Single-molecule fluorescence microscopy is a powerful tool for revealing chemical dynamics and molecular association mechanisms, but has been limited to low concentrations of fluorescent species and is only suitable for studying high affinity reactions. Here, we combine nanophotonic zero-mode waveguides (ZMWs) with fluorescence resonance energy transfer (FRET) to resolve single-molecule association dynamics at up to millimolar concentrations of fluorescent species. This approach extends the resolution of molecular dynamics to >100-fold higher concentrations, enabling observations at concentrations relevant to biological and chemical processes, and thus making single-molecule techniques applicable to a tremendous range of previously inaccessible molecular targets. We deploy this approach to show that the binding of cGMP to pacemaking ion channels is weakened by a slower internal conformational change. Dynamic duo: Nanophotonic zero-mode waveguides (ZMWs) have been combined with fluorescence resonance energy transfer (FRET) to resolve single-molecule association dynamics at concentrations of fluorescent species of up to millimolar. These concentrations are >100-fold higher than previously accessible with other methods, such as total internal reflection (TIRF).
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Synthesis of C70-Based Fluorophores through Sequential Functionalization to Form Isomerically Pure Multiadducts ()
Selective addition to the C70 cage divides its π-conjugated system into various smaller π-conjugated systems with enhanced fluorescent properties. Key reactions include chlorination, methoxylation, ozonation, and Bingel or Bingel–Hirsch reactions. The maximum emission wavelength of the C70 multiadducts ranges from 450 to 655 nm. Among the C70 multiadducts, C70(OMe)8(C(COOEt)2)3 showed the highest quantum yield (ΦF=0.18) and the largest Δ[λmax(emission)− λmax(absorption)] (402 nm), with maximum emission at 655 nm. Amazing Technicolor Dream-cage: Selective addition to the C70 cage divides its π-conjugated system into various smaller π-conjugated systems with enhanced fluorescence properties. Key reactions include chlorination, methoxylation, ozonation, and Bingel or Bingel–Hirsch reactions. C70(OMe)8(C(COOEt)2)3 (10) showed a quantum yield of ΦF=0.18 and a Δ[λmax(emission)−λmax(absorption)] of 402 nm, with maximum emission at 655 nm.
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[4+2] or [4+1] Annulation: Changing the Reaction Pathway of a Rhodium-Catalyzed Process by Tuning the Cp Ligand ()
A change in reaction pathway was achieved for the first time by tuning the cyclopentadienyl (Cp) ligand used for the rhodium-catalyzed cyclization of benzamides with conjugated enynones. Depending on the Cp ligand, the reaction pathway switched between [4+2] and [4+1] annulation. Electronic effects turned out to be crucial for the product distribution. The dichotomy was attributed to the alteration of the Lewis acidity of the resultant Cp-bound rhodium species. The choice is yours: A change in reaction pathway was achieved by tuning the cyclopentadienyl (Cp) ligand used for the rhodium-catalyzed cyclization of benzamides with conjugated enynones. Depending on the Cp ligand, the reaction pathway switched between [4+2] and [4+1] annulation. Electronic effects turned out to be crucial for the product distribution.
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Mechanical Alloying of Metal–Organic Frameworks ()
The solvent-free mechanical milling process for two distinct metal–organic framework (MOF) crystals induced the formation of a solid solution, which is not feasible by conventional solution-based syntheses. X-ray and STEM-EDX studies revealed that performing mechanical milling under an Ar atmosphere promotes the high diffusivity of each metal ion in an amorphous solid matrix; the amorphous state turns into the porous crystalline structure by vapor exposure treatment to form a new phase of a MOF solid solution. High and dry: Solvent-free mechanical milling promotes the high diffusivity of metal ions for two distinct metal–organic framework (MOF) crystals in the solid state. Furthermore, the process induced the formation of a new phase of a MOF solid solution.
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Breaking the Tetra-Coordinated Framework Rule: New Clathrate Ba8M24P28+δ (M=Cu/Zn) ()
A new clathrate type has been discovered in the Ba/Cu/Zn/P system. The crystal structure of the Ba8M24P28+δ (M=Cu/Zn) clathrate is composed of the pentagonal dodecahedra common to clathrates along with a unique 22-vertex polyhedron with two hexagonal faces capped by additional partially occupied phosphorus sites. This is the first example of a clathrate compound where the framework atoms are not in tetrahedral or trigonal-pyramidal coordination. In Ba8M24P28+δ a majority of the framework atoms are five- and six-coordinated, a feature more common to electron-rich intermetallics. The crystal structure of this new clathrate was determined by a combination of X-ray and neutron diffraction and was confirmed with solid-state 31P NMR spectroscopy. Based on chemical bonding analysis, the driving force for the formation of this new clathrate is the excess of electrons generated by a high concentration of Zn atoms in the framework. The rattling of guest atoms in the large cages results in a very low thermal conductivity, a unique feature of the clathrate family of compounds. A rule-breaking clathrate: A new clathrate type of the Ba/Cu/Zn/P system was synthesized and characterized by a combination of X-ray and neutron diffraction. The structure was confirmed by solid-state 31P NMR spectroscopy and shows that the framework atoms are not tetrahedrally coordinated.
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A PDE6δ-KRas Inhibitor Chemotype with up to Seven H-Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2 ()
Small-molecule inhibition of the interaction between the KRas oncoprotein and the chaperone PDE6δ impairs KRas spatial organization and signaling in cells. However, despite potent binding in vitro (KD<10 nm), interference with Ras signaling and growth inhibition require 5–20 μm compound concentrations. We demonstrate that these findings can be explained by fast release of high-affinity inhibitors from PDE6δ by the release factor Arl2. This limitation is overcome by novel highly selective inhibitors that bind to PDE6δ with up to 7 hydrogen bonds, resulting in picomolar affinity. Their release by Arl2 is greatly decreased, and representative compounds selectively inhibit growth of KRas mutated and -dependent cells with the highest activity recorded yet. Our findings indicate that very potent inhibitors of the KRas-PDE6δ interaction may impair the growth of tumors driven by oncogenic KRas. Small-molecule inhibition of the interaction between KRas oncoprotein and the chaperone PDE6δ impairs KRas spatial organization and signaling in cells. Deltasonamides are highly selective inhibitors that bind to PDE6δ with up to 7 hydrogen bonds, resulting in picomolar affinity.
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General Enantioselective C−H Activation with Efficiently Tunable Cyclopentadienyl Ligands ()
Cyclopentadienyl (Cp) ligands enable efficient steering of various transition-metal-catalyzed transformations, in particular enantioselective C−H activation. Currently only few chiral Cp ligands are available. Therefore, a conceptually general approach to chiral Cp ligand discovery would be invaluable as it would enable the discovery of applicable Cp ligands and to efficiently and rapidly vary and tune their structures. Herein, we describe the three-step gram-scale synthesis of a structurally diverse and widely applicable chiral Cp ligand collection (JasCp ligands) with highly variable and adjustable structures. Their modular nature and their amenability to rapid structure variation enabled the efficient discovery of ligands for three enantioselective RhIII-catalyzed C−H activation reactions, including one unprecedented transformation. This novel approach should enable the discovery of efficient chiral Cp ligands for various further enantioselective transformations. The discovery of chiral Cp ligands that unite the advantages of previously developed ligand classes is enabled by a novel approach. They can be readily synthesized on gram scale, and both their structures and configurations can be efficiently adjusted by means of flexible enantioselective [6+3] cycloaddition reactions. With these ligands, three rhodium(III)-catalyzed C−H activation reactions were rendered highly enantioselective.
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Nickel(0)-Mediated Transformation of Tetrafluoroethylene and Vinylarenes into Fluorinated Cyclobutyl Compounds ()
In the presence of Ni0/PCy3, styrene was found to participate in oxidative cyclization with tetrafluoroethylene, thus leading to the corresponding nickelacycle with a unique η3-π-benzyl structure. In addition, the flexibility of the coordination mode in the η3-benzyl moiety allowed the partially fluorinated nickelacycle to undergo unprecedented amine-induced α-fluorine elimination, thus leading to the construction of a fluorinated cyclobutyl skeleton. In the presence of Ni0/PCy3, styrene was found to participate in oxidative cyclization with tetrafluoroethylene, thus leading to the corresponding nickelacycle with a unique η3-π-benzyl structure. In addition, the flexibility of the coordination mode in the η3-benzyl moiety allowed the partially fluorinated nickelacycle to undergo unprecedented amine-induced α-fluorine elimination, thus leading to the construction of a fluorinated cyclobutyl skeleton.
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Efficient Access to Chiral Trisubstituted Aziridines via Catalytic Enantioselective Aza-Darzens Reactions ()
Herein, we report a Zn-ProPhenol catalyzed aza-Darzens reaction using chlorinated aromatic ketones as nucleophilic partners for the efficient and enantioselective construction of complex trisubstituted aziridines. The α-chloro-β-aminoketone intermediates featuring a chlorinated tetrasubstituted stereocenter can be isolated in high yields and selectivities for further derivatization. Alternatively, they can be directly transformed to the corresponding aziridines in a one-pot fashion. Of note, the reaction can be run on gram-scale with low catalyst loading without impacting its efficiency. Moreover, this methodology was extended to α-bromoketones which are scarcely used in enantioselective catalysis because of their sensitivity and lack of accessibility. A Zn-ProPhenol catalyzed aza-Darzens reaction using α-chloroketones allows the efficient construction of challenging trisubstituted aziridines with high enantio- and diastereoselectivities (up to 98 % ee, >20:1 d.r.). This method also provides an efficient access to complex chlorinated molecules featuring a tertiary stereogenic chloride.
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Preferential Carbon Monoxide Oxidation over Copper-Based Catalysts under In Situ Ball Milling ()
In situ ball milling of solid catalysts is a promising yet almost unexplored concept for boosting catalytic performance. The continuous preferential oxidation of CO (CO-PROX) under in situ ball milling of Cu-based catalysts such as Cu/Cr2O3 is presented. At temperatures as low as −40 °C, considerable activity and more than 95 % selectivity were achieved. A negative apparent activation energy was observed, which is attributed to the mechanically induced generation and subsequent thermal healing of short-lived surface defects. In situ ball milling at sub-zero temperatures resulted in an increase of the CO oxidation rate by roughly 4 orders of magnitude. This drastic and highly selective enhancement of CO oxidation showcases the potential of in situ ball milling in heterogeneous catalysis. The daily grind: In situ application of mechanical force by ball milling enhances the rate of CO oxidation over Cu-based catalysts in a H2-rich atmosphere while largely avoiding undesired oxidation of H2. At sub-zero temperatures, nearly 100 % selectivity is achieved at a reaction rate several orders of magnitude higher than in a conventional flow reactor. A kinetic model is proposed to explain the selective rate enhancement.
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Cobalt-Catalyzed Enantio- and Diastereoselective Intramolecular Hydroacylation of Trisubstituted Alkenes ()
Enantio- and diastereoselective synthesis of trans-2,3-disubstituted indanones is achieved by intramolecular hydroacylation of 2-alkenylbenzaldehydes bearing trisubstituted alkenyl groups under cobalt-chiral diphosphine catalysis. Notably, a high level of enantioselectivity is induced regardless of the stereochemistry (E/Z ratio) of the alkenyl group of the starting material. Deuterium-labeling experiments shed light on the productive reaction pathways of the E- and Z-isomers. EZ: Enantio- and diastereoselective synthesis of trans-2,3-disubstituted indanones is achieved by intramolecular hydroacylation of 2-alkenylbenzaldehydes containing trisubstituted alkenyl groups under cobalt-chiral diphosphine catalysis. High level of enantioselectivity is induced regardless of the stereochemistry (E/Z ratio) of the alkenyl group of the starting material.
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Enantioselective Synthesis of Chiral Oxime Ethers: Desymmetrization and Dynamic Kinetic Resolution of Substituted Cyclohexanones ()
Axially chiral cyclohexylidene oxime ethers exhibit unique chirality because of the restricted rotation of C=N. The first catalytic enantioselective synthesis of novel axially chiral cyclohexylidene oximes has been developed by catalytic desymmetrization of 4-substituted cyclohexanones with O-arylhydroxylamines and is catalyzed by a chiral BINOL-derived strontium phosphate with excellent yields and good enantioselectivities. In addition, chiral BINOL-derived phosphoric acid catalyzed dynamic kinetic resolution of α-substituted cyclohexanones has been performed and yields versatile intermediates in high yields and enantioselectivities. An ax to grind: A enantioselective synthesis of axially chiral cyclohexylidene oximes has been developed by catalytic desymmetrization of 4-substituted cyclohexanones with O-arylhydroxylamines in the presence of a chiral BINOL-derived strontium phosphate. In addition, the dynamic kinetic resolution of α-substituted cyclohexanones has been performed and yields versatile intermediates in high yields and enantioselectivities. M.S.=molecular sieves.
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Highly Stereoselective Gold-Catalyzed Coupling of Diazo Reagents and Fluorinated Enol Silyl Ethers to Tetrasubstituted Alkenes ()
We report a highly stereoselective synthesis of all-carbon or fluorinated tetrasubstituted alkenes from diazo reagents and fluorinated enol silyl ethers, using C−F bond as a synthetic handle. Cationic AuI catalysis plays a key role in this reaction. Remarkable fluorine effects on the reactivity and selectivity was also observed. A golden way to alkenes: A stereoselective synthesis of all-carbon or fluorinated tetrasubstituted alkenes from diazo reagents and fluorinated enol silyl ethers under cationic gold(I) catalysis was developed. Remarkable fluorine effects on the reactivity and selectivity were observed.
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Direct Syn Addition of Two Silicon Atoms to a C≡C Triple Bond by Si−Si Bond Activation: Access to Reactive Disilylated Olefins ()
A catalytic intramolecular silapalladation of alkynes affords, in good yields and stereoselectively, syn-disilylated heterocycles of different chemical structure and size. When applied to silylethers, this reaction leads to vinylic silanols that undergo a rhodium-catalyzed addition to activated olefins, providing the oxa-Heck or oxa-Michael products, depending on the reaction conditions. Disilylated olefins were obtained by a selective Si−Si bond palladium activation followed by intramolecular addition of two silicon atoms to the C≡C triple bond, thereby accessing a family of new silaheterocycles. The reaction affords vinylic silanols that engage in rhodium-catalyzed oxa-Heck or oxa-Michael additions. Tuning of the experimental conditions allows promotion of the preferred addition reaction.
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Gold-Catalyzed [3+2]/Retro-[3+2]/[3+2] Cycloaddition Cascade Reaction of N-Alkoxyazomethine Ylides ()
A novel cascade reaction has been developed for the synthesis of 2,6-methanopyrrolo[1,2-b]isoxazoles based on the gold-catalyzed generation of an N-allyloxyazomethine ylide. This reaction involves sequential [3+2]/retro-[3+2]/[3+2] cycloaddition reactions, thus providing facile access to fused and bridged heterocycles which would be otherwise difficult to prepare using existing synthetic methods. Notably, this reaction allows the efficient construction of three C−C bonds, one C−O bond, one C−N bond and one C−H bond, as well as the cleavage of one C−C bond, one C−O bond and one C−H bond in a single operation. The intermolecular cycloaddition of an N-allyloxyazomethine ylide and the subsequent application of the product to the synthesis of tropenol is also described. Going retro: A novel cascade reaction has been developed involving the gold-catalyzed generation of an N-allyloxyazomethine ylide and a subsequent [3+2]/retro-[3+2]/[3+2] cycloaddition cascade to give bridged isoxazolidines. This cascade reaction allows efficient construction of three C−C bonds, one C−O bond, one C−N bond, and one C−H bond, as well as the cleavage of one C−C bond, one C−O bond, and one C−H bond in a single operation.
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Palladium-Catalyzed Ring-Forming Aminoalkenylation of Alkenes with Aldehydes Initiated by Intramolecular Aminopalladation ()
A palladium-catalyzed aminopalladation reaction followed by nucleophilic addition with aldehydes and dehydration is described. This direct and operationally simple procedure provides a rapid and reliable approach to a wide range of functionalized tetrahydroisoquinolines with high selectivity. Mechanistic studies disclosed that the nucleophilic addition, performed via a highly ordered transition-state, is the turnover-limiting step in which the inherent β-hydride elimination of the key Csp3−Pd species was controlled by the confined conformation and the nucleophilicity of the Csp3−Pd bond was enhanced by the strong electron-donating effect of the nitrogen atom. Controlling β-hydride elimination: A palladium-catalyzed tandem reaction of aminoalkenes with aldehydes provides a simple and reliable approach for the synthesis of biologically active tetrahydroisoquinolines. The turnover-limiting step is shown to be nucleophilic addition via a highly ordered transition state.
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Selective Carbonyl−C(sp3) Bond Cleavage To Construct Ynamides, Ynoates, and Ynones by Photoredox Catalysis ()
Carbon–carbon bond cleavage/functionalization is synthetically valuable, and selective carbonyl−C(sp3) bond cleavage/alkynylation presents a new perspective in constructing ynamides, ynoates, and ynones. Reported here is the first alkoxyl-radical-enabled carbonyl−C(sp3) bond cleavage/alkynylation reaction by photoredox catalysis. The use of novel cyclic iodine(III) reagents are essential for β-carbonyl alkoxyl radical generation from β-carbonyl alcohols, including alcohols with high redox potential (Epox >2.2 V vs. SCE in MeCN). β-Amide, β-ester, and β-ketone alcohols yield ynamides, ynoates, and ynones, respectively, for the first time, with excellent regio- and chemoselectivity under mild reaction conditions. Aye, aye CIR: Novel cyclic iodine reagents (CIRs) are essential for β-carbonyl alkoxyl radical generation from β-carbonyl alcohols in carbonyl−C(sp3) bond cleavage/alkynylation reactions under photoredox catalysis. β-Amide, β-ester, and β-ketone alcohols yield ynamides, ynoates, and ynones, respectively, with excellent regio- and chemoselectivity.
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Rhodium-Catalyzed Decarbonylative Borylation of Aromatic Thioesters for Facile Diversification of Aromatic Carboxylic Acids ()
Transformation of aromatic thioesters into arylboronic esters was achieved efficiently using a rhodium catalyst. The broad functional-group tolerance and mild conditions of the method have allowed for the two-step decarboxylative borylation of a wide range of aromatic carboxylic acids, including commercially available drugs. Extreme Makeover: Transformation of aromatic thioesters into arylboronic esters was achieved efficiently using a rhodium catalyst. The broad functional-group tolerance and mild conditions of the method have allowed for the two-step decarboxylative borylation of a wide range of aromatic carboxylic acids, including commercially available drugs.
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Cs2CO3-Catalyzed Aerobic Oxidative Cross-Dehydrogenative Coupling of Thiols with Phosphonates and Arenes ()
An efficient Cs2CO3-catalyzed oxidative coupling of thiols with phosphonates and arenes that uses molecular oxygen as the oxidant is described. These reactions provide not only a novel alkali metal salt catalyzed aerobic oxidation, but also an efficient approach to thiophosphates and sulfenylarenes, which are ubiquitously found in pharmaceuticals and pesticides. The reaction proceeds under simple and mild reaction conditions, tolerates a wide range of functional groups, and is applicable to the late-stage synthesis and modification of bioactive molecules. Dehydrogenated: An efficient Cs2CO3-catalyzed aerobic cross-dehydrogenative coupling of thiols with phosphonates and arenes enables the synthesis of thiophosphates and sulfenylarenes, which are ubiquitously found in pharmaceuticals and pesticides. This method was also applied for the late-stage functionalization of bioactive molecules.
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Synthesis of Boron(III)-Coordinated Subchlorophins and Their Peripheral Modifications ()
A pyrrole-cleaving modification to transform boron(III) meso-triphenylsubporphyrin into boron(III) meso-triphenylsubchlorophin has been developed. Boron(III) subchlorophins thus synthesized show absorption and fluorescence spectra that are roughly similar to those of boron(III) subchlorins, but B-methoxy boron(III) subchlorophin showed considerably intensified fluorescence and a small Stokes shift. Peripheral modification reactions of B-phenyl boron(III) subchlorophin such as regioselective nitration with Cu(NO3)2⋅3 H2O, ipso-substitution reactions of boron(III) α-nitrosubchlorophin with CsF and CsCl, and Pd-catalyzed cross-coupling reactions of boron(III) α-chlorosubchlorophin with arylacetylenes, have been also explored to tune the optical properties of subchlorophins. Ring-contracted congeners of chlorophins, namely B-methoxy and B-phenyl boron(III) meso-triphenylsubchlorophins, where β-carbon atoms of one pyrrole unit are absent, were synthesized. These showed bright fluorescence (ΦF=0.35 and 0.18, respectively) and absorption spectra similar to that of boron(III) subchlorin rather than that of boron(III) subporphyrin. Modifications at the α-position were successfully explored.
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Functional Isoeugenol-Modified Nanogel Coatings for the Design of Biointerfaces ()
A new route for the synthesis of functional aqueous nanogels decorated with a controlled amount of surface-drafted isoeugenol molecules has been developed. Obtained nanogels exhibit two key functions: a) antibacterial activity against different oral pathogens and b) cell-adhesive and -growth-promoting properties. Functional nanogels can be potentially used as building blocks in the design of bioactive coatings on various implants preventing infections and accelerating tissue regeneration. Functional aqueous nanogels decorated with a controlled amount of surface-grafted isoeugenol molecules were synthesized. These nanogels have two key features: antibacterial activity against different pathogens and cell-growth-promoting properties. They can serve as building blocks in the design of bioactive coatings for use in implants.
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Isotope Probing of the UDP-Apiose/UDP-Xylose Synthase Reaction: Evidence of a Mechanism via a Coupled Oxidation and Aldol Cleavage ()
The C-branched sugar d-apiose (Api) is essential for plant cell-wall development. An enzyme-catalyzed decarboxylation/pyranoside ring-contraction reaction leads from UDP-α-d-glucuronic acid (UDP-GlcA) to the Api precursor UDP-α-d-apiose (UDP-Api). We examined the mechanism of UDP-Api/UDP-α-d-xylose synthase (UAXS) with site-selectively 2H-labeled and deoxygenated substrates. The analogue UDP-2-deoxy-GlcA, which prevents C-2/C-3 aldol cleavage as the plausible initiating step of pyranoside-to-furanoside conversion, did not give the corresponding Api product. Kinetic isotope effects (KIEs) support an UAXS mechanism in which substrate oxidation by enzyme-NAD+ and retro-aldol sugar ring-opening occur coupled in a single rate-limiting step leading to decarboxylation. Rearrangement and ring-contracting aldol addition in an open-chain intermediate then give the UDP-Api aldehyde, which is intercepted via reduction by enzyme-NADH. Coupled up: The reaction performed by UDP-apiose/UDP-xylose synthase proceeds by a mechanism in which substrate oxidation with NAD+ and sugar ring-opening by aldol cleavage are coupled with each other in the rate-determining step and occur before the irreversible decarboxylation. The C-branch of d-apiose is then installed by a ring-contracting aldol reaction and the exocyclic hydroxymethyl group is formed by NADH-dependent reduction.
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Proton-Detected Solid-State NMR Spectroscopy of a Zinc Diffusion Facilitator Protein in Native Nanodiscs ()
The structure, dynamics, and function of membrane proteins are intimately linked to the properties of the membrane environment in which the proteins are embedded. For structural and biophysical characterization, membrane proteins generally need to be extracted from the membrane and reconstituted in a suitable membrane-mimicking environment. Ensuring functional and structural integrity in these environments is often a major concern. The styrene/maleic acid co-polymer has recently been shown to be able to extract lipid/membrane protein patches directly from native membranes to form nanosize discoidal proteolipid particles, also referred to as native nanodiscs. In this work, we show that high-resolution solid-state NMR spectra can be obtained from an integral membrane protein in native nanodiscs, as exemplified by the 2×34 kDa bacterial cation diffusion facilitator CzcD. It's a kind of magic: High-resolution magic-angle spinning NMR spectra were obtained for the 2×34 kDa bacterial cation diffusion facilitator CzcD, following direct extraction of the membrane protein from the native membrane using a styrene/maleic acid co-polymer to form native nanodiscs.
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