Unraveling the Structure and Reactivity Patterns of the Indole Radical Cation in Regioselective Electrochemical Oxidative Annulations.

Oxidation-induced strategy for inert chemical bond activation through highly active radical cation intermediate has exhibited unique reactivity. Understanding the structure and reactivity patterns of radical cation intermediates is crucial in the mechanistic study and will be beneficial for developing new reactions. In this work, the structure and properties of indole radical cations have been revealed using time-resolved transient absorption spectroscopy, in situ electrochemical UV-vis, and in situ electrochemical electron paramagnetic resonance (EPR) technique. Density functional theory (DFT) calculations were used to explain and predict the regioselectivity of several electrochemical oxidative indole annulations. Based on the understanding of the inherent properties of several indole radical cations, two different regioselective annulations of indoles have been successfully developed under electrochemical oxidation conditions. Varieties of furo[2,3-b]indolines and furo[3,2-b]indolines were synthesized in good yields with high regioselectivities. Our mechanistic insights into indole radical cations will promote the further development of oxidation-induced indole functionalizations.

Hydroxyl-Binding Energy-Induced Kinetic Gap Narrowing between Acidic and Alkaline Hydrogen Oxidation Reaction on Intermetallic Ru3 Sn7 Catalyst.

Developing highly efficient catalysts toward alkaline hydrogen oxidation reaction (HOR) and narrowing the kinetic gap between acidic and alkaline electrolytes are of great importance for the practical application of alkaline exchange membrane fuel cell . Herein, ordered Ru3 Sn7 /C intermetallic compound has been developed for the HOR under alkaline and acidic conditions. The authors demonstrate that the ordered intermetallic Ru3 Sn7 /C shows much enhanced HOR activity, stability, and CO-tolerance compared with its disordered RuSn solid solution alloy counterpart. More importantly, the authors find that the kinetic gap of HOR between acidic and alkaline media is significantly narrowed in the as-synthesized intermetallic Ru3 Sn7 /C catalysts. Combined experiment results and theoretical calculations, the authors understand that promoted hydroxyl-binding energy on Ru3 Sn7 /C derived from the intermetallic-induced strong electron interaction is responsible for the accelerated alkaline HOR performance and narrowed kinetic gap.

Exfoliation of MoS2 Nanosheets Enabled by a Redox-Potential-Matched Chemical Lithiation Reaction.

Ion intercalation assisted exfoliation is the oldest and most popular method for the scalable synthesis of molybdenum disulfide (MoS2) nanosheets. The commonly used organolithium reagents for Li+ intercalation are n-butyllithium (n-BuLi) and naphthalenide lithium (Nap-Li); however, the highly pyrophoric nature of n-BuLi and the overly reducing power of Nap-Li hinder their extensive application. Here, a novel organolithium reagent, pyrene lithium (Py-Li), which has intrinsic safe properties and a well-matched redox potential, is reported for the intercalation and exfoliation of MoS2. The redox potential of Py-Li (0.86 V vs Li+/Li) is located just between the intercalation (1.13 V) and decomposition (0.55 V) potentials of bulk MoS2, thus allowing precise Li+ intercalation to form a lamellar LiMoS2 compound without undesirable structural damage. The lithiation reaction can be accomplished within 1 h at room temperature and the exfoliated nanosheets are almost single layer. This method also offers the advantages of low cost, high repeatability, and ease in realizing large-scale production.

Unveiling the Electrolyte Cations Dependent Kinetics on CoOOH-Catalyzed Oxygen Evolution Reaction.

The electrolyte cations-dependent kinetics have been widely observed in many fields of electrocatalysis, however, the exact mechanism of the influence on catalytic performance is still a controversial topic of considerable discussion. Herein, combined with operando X-ray diffraction (XRD) and high-resolution transmission electron microscopy (HRTEM), we verify that the electrolyte cations could intercalate into the layer of pristine CoOOH catalyst during the oxygen evolution reaction (OER) process, while the bigger cations lead to enlarged interlayer spacing and increased OER activity, following the order Cs+ >K+ >Na+ >Li+ . X-ray absorption spectroscopy (XAS), in situ Raman, in situ Ultraviolet-visible (UV/Vis) spectroscopy, in situ XAS spectroscopy, cyclic voltammetry (CV), and theoretical calculations reveal that the intercalation of electrolyte cations efficiently modify the oxidation states of Co by enlarging the Co-O bonds, which in turn enhance the d-band center of Co, optimize the adsorption strength of oxygen intermediates, facilitate the formation of OER active Co(IV) species, and reduce the energy barrier of the rate-determing step (RDS), thereby enhancing the OER activity. This work not only provides an informative picture to understand the complicated dependence of OER kinetics on electrolyte cations, but also sheds light on understanding the mechanism of other electrolyte cation-targeted electrocatalysis.

Enantioselective Nickel-Catalyzed Reductive Aryl/Alkenyl-Cyano Cyclization Coupling to All-Carbon Quaternary Stereocenters.

An enantioselective nickel-catalyzed intramolecular reductive cross-coupling of C(sp2) electrophiles and cyano groups is reported. Enantioenriched CN-containing all-carbon quaternary stereocenters are assembled by desymmetrizing cyclization of aryl/alkenyl halide-tethered malononitriles. The use of an organic reductant, (EtO)2MeSiH, is crucial to the enantioselectivity and reactivity. Applications of the method are demonstrated through the synthesis of bioactive molecules and their cyanated analogues and the total synthesis of the natural product diomuscinone. This study exhibits the potential of desymmetrizing reductive coupling strategies to access structurally rigid and synthetically versatile molecules from readily available starting materials.

Electronic Modulation of Ru Nanosheet by d-d Orbital Coupling for Enhanced Hydrogen Oxidation Reaction in Alkaline Electrolytes.

The alkaline polymer electrolyte fuel cells (APEFCs) hold great promise for using nonnoble metal-based electrocatalysts toward the cathodic oxygen reduction reaction (ORR), but are hindered by the sluggish anodic hydrogen oxidation reaction (HOR) in alkaline electrolytes. Here, a strategy is reported to promote the alkaline HOR performance of Ru by incorporating 3d-transition metals (V, Fe, Co, and Ni), where the conduction band minimum (CBM) level of Ru can be rationally tailored through strong d-d orbital coupling. As expected, the obtained RuFe nanosheet exhibits outstanding HOR performance with the mass activity of 233.46 A gPGM -1 and 23-fold higher than the Ru catalyst, even threefold higher than the commercial Pt/C. APEFC employing this RuFe as anodic catalyst gives a peak power density of 1.2 W cm-2 , outperforming the documented Pt-free anodic catalyst-based APEFCs. Experimental results and density functional theory calculations suggest the enhanced OH-binding energy and reduced formation energy of water derived from the downshifted CBM level of Ru contribute to the enhanced HOR activity.

Intermolecular Energy Gap-Induced Formation of High-Valent Cobalt Species in CoOOH Surface Layer on Cobalt Sulfides for Efficient Water Oxidation.

Transition metal-based electrocatalysts will undergo surface reconstruction to form active oxyhydroxide-based hybrids, which are regarded as the "true-catalysts" for the oxygen evolution reaction (OER). Much effort has been devoted to understanding the surface reconstruction, but little on identifying the origin of the enhanced performance derived from the substrate effect. Herein, we report the electrochemical synthesis of amorphous CoOOH layers on the surface of various cobalt sulfides (CoSα ), and identify that the reduced intermolecular energy gap (Δinter ) between the valence band maximum (VBM) of CoOOH and the conduction band minimum (CBM) of CoSα can accelerate the formation of OER-active high-valent Co4+ species. The combination of electrochemical and in situ spectroscopic approaches, including cyclic voltammetry (CV), operando electron paramagnetic resonance (EPR) and Raman, reveals that Co species in the CoOOH/Co9 S8 are more readily oxidized to CoO2 /Co9 S8 than in CoOOH and other CoOOH/CoSα . This work provides a new design principle for transition metal-based OER electrocatalysts.

A Modular Approach for Diversity-Oriented Synthesis of 1,3-trans-Disubstituted Tetrahydroisoquinolines: Seven-Step Asymmetric Synthesis of Michellamines†B and C.

1,3-trans-Disubstituted tetrahydroisoquinoline (THIQ) is a common heterocyclic structural unit of naphthylisoquinoline alkaloids. The assembly of this structural unit is not trivial, which constitutes a substantial challenge in the total synthesis of naphthylisoquinoline alkaloids and related pharmaceuticals. Herein, we report a modular and convergent method for the rapid assembly of 1,3-trans-disubstituted THIQ frameworks through a three-component Catellani reaction and a AuI -catalyzed cyclization/reduction cascade. With widely available simple aryl iodides, aziridines and (triisopropylsilyl)acetylene as the building blocks, this method paves a practical way for the diversity-oriented synthesis of 1,3-trans-disubstituted THIQs. Based on this new method, concise syntheses of an analogue of the new drug mevidalen and four naphthylisoquinoline alkaloids have been accomplished, demonstrating the broad synthetic utility of this approach.

ß-Substituted Alkenyl Heteroarenes as Dipolarophiles in the Cu(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides Empowered by a Dual Activation Strategy: Stereoselectivity and Mechanistic Insight.

The catalytic asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides with various electron-deficient alkenes provide the most straightforward protocol for the preparation of enantioenriched pyrrolidines in organic synthesis. However, the employment of conjugated alkenyl heteroarenes as dipolarophiles in such protocols to afford a class of particularly important molecules in medicinal chemistry is still a great challenge. Herein, we report that various ß-substituted alkenyl heteroarenes, challenging internal alkene substrates without a strong electron-withdrawing substituent, were successfully employed as dipolarophiles for the first time in the Cu(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides. This reaction furnishes a large array of multistereogenic heterocycles incorporating both the biologically important pyrrolidine and heteroarene skeletons in good yields with exclusive diastereoselectivity and excellent enantioselectivity. Our extensive density functional theory (DFT) calculations proposed a working model to explain the origin of the stereochemical outcome and elucidated uncommon dual activation/coordination of both the dipole and dipolarophile substrates by the metal, in which a sterically bulky, rigid, and monodentate phosphoramidite ligand with triple-homoaxial chirality plays a pivotal role in providing an effective chiral pocket around the metal center, resulting in high enantioselectivity. The additional coordination of the heteroatom in the dipolarophile substrate to Cu is also critical for the exclusive diastereoselectivity and enhanced reactivity. Our calculations also predicted the reverse and high enantioinduction for the corresponding substrates with monocyclic heteroarenes as well as regiospecific cycloaddition to the less reactive internal C═C bond of one related dipolarophile diene substrate. Such unique steric effect-directed enantioswitching and coordination-directed regioselectivity were verified experimentally.

Catalytic Synthesis of Atropisomeric o-Terphenyls with 1,2-Diaxes via Axial-to-Axial Diastereoinduction.

Herein, we report a modular and convergent strategy for the assembly of atropisomeric o-terphenyls with 1,2-diaxes via palladium/chiral norbornene cooperative catalysis and axial-to-axial diastereoinduction. Readily available aryl iodides, 2,6-substituted aryl bromides, and potassium aryl trifluoroborates are used as the building blocks, laying the foundation for diversity-oriented synthesis of these scaffolds (46 examples). Other features include the unique axial-to-axial diastereoinduction mode, construction of two axes in a single operation, and step economy. DFT calculations are performed to rationalize the axial-to-axial diastereoinduction process. Synthetic utilities of this method in preparation of atropisomeric oligophenyls, chiral catalysts, and ligands are demonstrated.

Hexagonal RuSe2 Nanosheets for Highly Efficient Hydrogen Evolution Electrocatalysis.

Layered transition metal dichalcogenide (TMD) nanomaterials are promising alternatives to platinum (Pt) for the hydrogen evolution reaction (HER). However, the family of layered TMDs is mainly limited to Group IV-VII transition metals, while the synthesis of layered TMDs based on metals from other groups still remains a challenge. Herein, we demonstrate by atomic-resolution transmission electron microscopy that hexagonal RuSe2 (h-RuSe2 ) nanosheets with a mixture of 2H and 1T phases can be obtained by a facile bottom-up colloidal synthetic approach. The obtained h-RuSe2 , which can be transformed into the thermodynamically favorable phase of cubic RuSe2 (c-RuSe2 ) only after annealing at 600 °C, exhibits Pt-like HER performance, with a fivefold turnover frequency enhancement compared to the c-RuSe2 in alkaline media. Experimental results and density functional theory (DFT) calculations reveal that the enhanced adsorption free energies of H2 O (ΔG H 2 O * ), optimized adsorption free energies of H (ΔGH* ), and increased conductivity of h-RuSe2 contribute to its superior HER activity.

Electrochemical Oxidative Carbon-Atom Difunctionalization: Towards Multisubstituted Imino Sulfide Ethers.

Ethers (C-O/S) are ubiquitously found in a wide array of functional molecules and natural products. Nonetheless, the synthesis of imino sulfide ethers, containing an N(sp2 )=C(sp2 )-O/S fragment, still remains a challenge because of its sensitivity to acid. Developed here in is an unprecedented electrochemical oxidative carbon-atom difunctionalization of isocyanides, providing a series of novel multisubstituted imino sulfide ethers. Under metal-free and external oxidant-free conditions, isocyanides react smoothly with simple and readily available mercaptans and alcohols. Importantly, the procedure exhibited high stereoselectivities, excellent functional-group tolerance, and good efficiency on large-scale synthesis, as well as further derivatization of the products.

Enantioselective Assembly of Cycloenones with a Nitrile-Containing All-Carbon Quaternary Center from Malononitriles Enabled by Ni Catalysis.

Chiral nitriles are valuable molecules in modern organic synthesis and drug discovery. Selectively differentiating the two nitrile groups of widely available malononitrile derivatives is a straightforward yet underdeveloped route to construct enantioenriched nitriles. Here we report an enantioselective nickel-catalyzed desymmetrization of malononitriles for the generation of nitrile-containing all-carbon quaternary stereocenters. This protocol involves a nickel-catalyzed addition of aryl boronic acids to alkynes, followed by a selective nitrile insertion, providing unprecedented access to enantioenriched 5-7-membered α-cyano-cycloenones with a fully substituted olefin from a broad range of substrates. The synthetic utility of these nitrile products is demonstrated by gram-scale synthesis and conversion to several useful functional groups.

Comparative Investigation into Formycin A and Pyrazofurin A Biosynthesis Reveals Branch Pathways for the Construction of C-Nucleoside Scaffolds.

Formycin A (FOR-A) and pyrazofurin A (PRF-A) are purine-related C-nucleoside antibiotics in which ribose and a pyrazole-derived base are linked by a C-glycosidic bond. However, the logic underlying the biosynthesis of these molecules has remained largely unexplored. Here, we report the discovery of the pathways for FOR-A and PRF-A biosynthesis from diverse actinobacteria and propose that their biosynthesis is likely initiated by a lysine N6-monooxygenase. Moreover, we show that forT and prfT (involved in FOR-A and PRF-A biosynthesis, respectively) mutants are correspondingly capable of accumulating the unexpected pyrazole-related intermediates 4-amino-3,5-dicarboxypyrazole and 3,5-dicarboxy-4-oxo-4,5-dihydropyrazole. We also decipher the enzymatic mechanism of ForT/PrfT for C-glycosidic bond formation in FOR-A/PRF-A biosynthesis. To our knowledge, ForT/PrfT represents an example of ß-RFA-P (ß-ribofuranosyl-aminobenzene 5'-phosphate) synthase-like enzymes governing C-nucleoside scaffold construction in natural product biosynthesis. These data establish a foundation for combinatorial biosynthesis of related purine nucleoside antibiotics and also open the way for target-directed genome mining of PRF-A/FOR-A-related antibiotics.IMPORTANCE FOR-A and PRF-A are C-nucleoside antibiotics known for their unusual chemical structures and remarkable biological activities. Deciphering the enzymatic mechanism for the construction of a C-nucleoside scaffold during FOR-A/PRF-A biosynthesis will not only expand the biochemical repertoire for novel enzymatic reactions but also permit target-oriented genome mining of FOR-A/PRF-A-related C-nucleoside antibiotics. Moreover, the availability of FOR-A/PRF-A biosynthetic gene clusters will pave the way for the rational generation of designer FOR-A/PRF-A derivatives with enhanced/selective bioactivity via synthetic biology strategies.

Mesoporous Cages in Chemically Robust MOFs Created by a Large Number of Vertices with Reduced Connectivity.

We report the design and synthesis of two metal-organic frameworks (MOFs) with permanent porosity, MOF-818 and MOF-919, using a small ditopic organic linker, 1H-pyrazole-4-carboxylic acid (H2PyC), 0.4 nm in length. Three mesoporous cages of unprecedented polyhedra are identified in these MOFs, a wuh cage in MOF-818 and yys and liu cages in MOF-919, with diameters of 3.8, 4.9, and 6.0 nm, respectively. The ditopic H2PyC linker functions as the edge in the structure, while two types of metal-containing second building units (SBUs) function as the vertices. 28 vertices are present in the wuh cage; 50 in the yys cage; and 70 in the liu cage. Systematic analysis of these cages along with other mesoporous cages in supramolecules and MOFs constructed by ditopic linkers reveals that the extension of cage size is dictated by both the number and connectivity of the vertices. The increase in cage size is proportional to the number of vertices, while the growth rate is determined by their connectivity. The reduction in connectivity is found to be an effective way to create large cages. All three cages in this report are constructed by three-connecting (3-c) vertices and two-connecting (2-c) vertices. This [2-c, 3-c] connectivity represents the least connectivity required for the construction of cages and the most effective one for cage size expansion. The largest cage, liu, exhibits a cage size to linker size ratio of 15, outstanding in supramolecules and MOFs. MOF-818 is stable in water with a wide pH range (pH = 2-12), and the wuh cage is big enough for the inclusion of biomolecules such as vitamin B12 and insulin.

Electrochemical Oxidative C-H Amination of Phenols: Access to Triarylamine Derivatives.

Dehydrogenative C-H/N-H cross-coupling serves as one of the most straightforward and atom-economical approaches for C-N bond formation. In this work, an electrochemical reaction protocol has been developed for the oxidative C-H amination of unprotected phenols under undivided electrolytic conditions. Neither metal catalysts nor chemical oxidants are needed to facilitate the dehydrogenation process. A series of triarylamine derivatives could be obtained with good functional-group tolerance. The electrolysis is scalable and can be performed at ambient conditions.

Structural and Biochemical Insight into the Mechanism of Rv2837c from Mycobacterium tuberculosis as a c-di-NMP Phosphodiesterase.

The intracellular infections of Mycobacterium tuberculosis, which is the causative agent of tuberculosis, are regulated by many cyclic dinucleotide signaling. Rv2837c from M. tuberculosis is a soluble, stand-alone DHH-DHHA1 domain phosphodiesterase that down-regulates c-di-AMP through catalytic degradation and plays an important role in M. tuberculosis infections. Here, we report the crystal structure of Rv2837c (2.0 Å), and its complex with hydrolysis intermediate 5'-pApA (2.35 Å). Our structures indicate that both DHH and DHHA1 domains are essential for c-di-AMP degradation. Further structural analysis shows that Rv2837c does not distinguish adenine from guanine, which explains why Rv2837c hydrolyzes all linear dinucleotides with almost the same efficiency. We observed that Rv2837c degraded other c-di-NMPs at a lower rate than it did on c-di-AMP. Nevertheless, our data also showed that Rv2837c significantly decreases concentrations of both c-di-AMP and c-di-GMP in vivo. Our results suggest that beside its major role in c-di-AMP degradation Rv2837c could also regulate c-di-GMP signaling pathways in bacterial cell.

Principles of Designing Extra-Large Pore Openings and Cages in Zeolitic Imidazolate Frameworks.

We report three design principles for obtaining extra-large pore openings and cages in the metal-organic analogues of inorganic zeolites, zeolitic imidazolate frameworks (ZIFs). Accordingly, we prepared a series of 15 ZIFs, members of which have the largest pore opening (22.5 Å) and the largest cage size (45.8 Å) known for all porous tetrahedral structures. The key parameter allowing us to access these exceptional ZIFs is what we define as the steric index (δ), which is related to the size and shape of the imidazolate linkers employed in the synthesis. The three principles are based on using multiple linkers with specific range and ratios of δ to control the size of rings and cages from small to large, and therefore are universally applicable to all existing ZIFs. The ZIF with the largest cage size (ZIF-412) shows the best selectivity of porous materials tested toward removal of octane and p-xylene from humid air.

Deciphering the Spatial Arrangement of Metals and Correlation to Reactivity in Multivariate Metal-Organic Frameworks.

Thirty-six porphyrin-based metal-organic frameworks (MOFs) with composition of (M3O)2(TCPP-M)3 and M3O trigonal SBUs of various metals, Mg3O, Mn3O, Co3O, Ni3O, and Fe3O including mixed-metal SBUs, MnxFe3-xO, NixFe3-xO, CoxNi3-xO, MnxCo3-xO, MnxMg3-xO, and MnxNi3-xO were synthesized and characterized. These multivariate MOFs (MTV-MOFs) were examined by X-ray photoelectron spectroscopy, UV-vis diffuse reflectance spectra, and for the first time, their metal spatial arrangement deciphered and were found to exist in the form of either domains or well-mixed. We find that MTV-MOFs with well-mixed metals in their SBUs, rather than the SBUs having one kind of metal but different from one SBU to another, perform better than the sum of their parts in the test reaction involving the photo-oxidation of 1,5-dihydroxynaphthalene.

Membrane association of SadC enhances its diguanylate cyclase activity to control exopolysaccharides synthesis and biofilm formation in Pseudomonas aeruginosa.

Cyclic diguanosine monophosphate (c-di-GMP) is one of the most important bacterial second messengers that controls many bacterial cellular functions including lifestyle switch between plankton and biofilm. Surface attachment defective (SadC) is a diguanylate cyclase (DGC) involved in the biosynthesis of c-di-GMP in Pseudomonas aeruginosa, an opportunistic pathogen that can cause diverse infections. Here we report the crystal structure of GGDEF domain from SadC and the critical role of the trans-membrane (TM) domain of SadC with regard to biofilm formation, exopolysaccharide production and motility. We showed that over-expression of SadC in P. aeruginosa PAO1 totally inhibited swimming motility and significantly enhanced the production of exopolysaccharide Psl. SadC lacking TM domains (SadC300-487 ) could not localize on cytoplasmic membrane and form cluster, lost the ability to inhibit the swimming and twitching motility, and showed the attenuated activity to promote Psl production despite that SadC300-487 was able to catalyze the synthesize of c-di-GMP in vitro and in vivo. The GGDEF domain of SadC has a typical GGDEF structure and the α-helix connected the TM domains with SadC GGDEF domain is essential for SadC to form DGC oligomers. Our data imply that membrane association of SadC promotes its DGC activity by affecting the formation of active DGC oligomers.