The biology of healthy and disease-affected cells is often mediated by RNA structures, desirable targets for small molecule chemical probes and lead medicines. Although structured regions are found throughout the transcriptome, some even with demonstrated functionality, human RNAs are considered recalcitrant to small molecule targeting. However, targeting structured regions with small molecules provides an important alternative to oligonucleotides that target sequence. In this Perspective, we describe challenges and progress in developing small molecules interacting with RNA (SMIRNAs) to capture their significant opportunities at the intersection of chemistry, biology, and medicine. Key to establishing a new paradigm in chemical biology and medicine is the development of methods to obtain, preferably by design, bioactive compounds that modulate RNA targets and companion methods that validate their direct effects in cells and pre-clinical models. While difficult, demonstration of direct target engagement in the complex cellular milieu, along with methods to establish modes of action, is required to push this field forward. We also describe frameworks for accelerated advancements in this burgeoning area, their implications, key new technologies for development of SMIRNAs, and milestones that have led to broader acceptance of RNA as a small molecule druggable target.

Olefin metathesis is now one of the most efficient ways to create new carbon–carbon bonds. While most efforts focused on the development of ever-more efficient catalysts, a particular attention has recently been devoted to developing latent metathesis catalysts, inactive species that need an external stimulus to become active. This furnishes an increased control over the reaction which is crucial for applications in materials science. Here, we report our work on the development of a new system to achieve visible-light-controlled metathesis by merging olefin metathesis and photoredox catalysis. The combination of a ruthenium metathesis catalyst bearing two N-heterocyclic carbenes with an oxidizing pyrylium photocatalyst affords excellent temporal and spatial resolution using only visible light as stimulus. Applications of this system in synthesis, as well as in polymer patterning and photolithography with spatially resolved ring-opening metathesis polymerization, are described.

Could one manipulate nanoscale building blocks using chemical reactions like molecular synthesis to yield new supra-nanoscale objects? The precise control over the final architecture might be challenging due to the size mismatch of molecularly scaled reactive functional groups and nanoscale building blocks, which limits a control over the valence and specific locations of reaction spots. Taking advantage of programmable octahedral DNA frame, we report a facile approach of engineering chemical reactions between nanoscale building blocks toward formation of controlled nanoarchitectures. Azide and alkyne moieties were specifically anchored onto desired vertices of DNA frames, providing chemically reactive nanoconstructs with directionally defined valence. Akin to the conventional molecular reactions, the formation of a variety of nanoscale architectures was readily achieved upon mixing of the frames with the different reactive valence and at different stoichiometric ratios. This strategy may open a door for a programmable synthesis of supra-nanoscale structures with complex architectures and diversified functions.

The first porous molecular conductor (PMC), which exhibits porosity, a through-space conduction pathway and rich charge carriers (electrons), was prepared through electrocrystallization from Cd²⁺ and N,N′-di(4-pyridyl)-1,4,5,8-naphthalenetetracarboxdiimide (NDI-py). [Cd(NDI-py)(OH₂)₄](NO₃)_1.3±0.1·nDMA (PMC-1) was assembled by π–π stacking among one-dimensional (1D) linear coordination polymers. The NDI cores were partially reduced into radical anions to form conductive π-stacked columns, yielding (1.0–3.3) × 10^–3 S cm^–1 at room temperature. Moreover, the electrical conductivity was significantly enhanced by removing the solvent molecules from PMC-1, indicating that PMCs are promising as molecule-responsive conductive materials.

We have developed a Rh(III)-catalyzed diastereoselective [2+1] annulation onto allylic alcohols initiated by alkenyl C–H activation of N-enoxyphthalimides to furnish substituted cyclopropyl-ketones. Notably, the traceless oxyphthalimide handle serves three functions: directing C–H activation, oxidation of Rh(III), and, collectively with the allylic alcohol, in directing cyclopropanation to control diastereoselectivity. Allylic alcohols are shown to be highly reactive olefin coupling partners leading to a directed diastereoselective cyclopropanation reaction, providing products not accessible by other routes.

A 17-membered macrocyclolipopeptide, named dysoxylactam A (1) comprising an unprecedented branched C19 fatty acid and an l-valine, was isolated from the plants of Dysoxylum hongkongense. The challenging relative configuration of 1 was established by means of residual dipolar coupling-based NMR analysis. The absolute configuration of 1 was determined by single-crystal X-ray diffraction on its p-bromobenzoate derivative (2). Compound 1 dramatically reversed multidrug resistance in cancer cells with the fold-reversals ranging from 28.4 to 1039.7 at the noncytotoxic concentration of 10 μM. The mode-of-action study of 1 revealed that it inhibited the function of P-glycoprotein (P-gp), a key mediator in multidrug resistance.

Herein, we show the highly enantioselective borylation of unactivated methylene C(sp³)–H bonds in 2-alkylpyridines and 2-alkyl-1,3-azole derivatives using an iridium-BINOL-based chiral monophosphite catalyst system. Quantum chemical calculations using the artificial force induced reaction (AFIR) method suggested that a monophosphite-Ir-tris(boryl) complex generates a narrow chiral reaction pocket where the differentiation of the enantiotopic methylene C–H bonds is accomplished through an assembly of multiple noncovalent interactions.

Due to the structural advantages displayed by Metal–Organic Frameworks (MOFs), integrating Valence Tautomerism (VT) systems within MOFs could be an effective strategy in order to break through the constraints of the traditional ones. Herein, we report the first successful integration of a VT system into a MOF termed VT-MOF-1. The structural characteristics of VT-MOF-1, such as dinuclear cobalt-catechol clusters and solvent-accessible pores, are both innovative and novel, potentially yielding new vitality within VT field. In addition, VT-MOF-1 exhibits specific behaviors responsive to temperature and different solvent molecules as n-butanol, tert-butanol, and isopropyl alcohol. The entropy values and configurations of the solvent molecules might be responsible for the tunable sensing behaviors.

The self-assembly and reactivity of a robust multinuclear Pd catalyst based on the sterically expanded phosphine-bis-arenesulfonate ligand PPh(2-SO₃^–-4,5-(OMe)₂-Ph)₂ (OPO^2–, 2) are described. The reaction of Li₂[2] with (COD)PdMeCl and 4-(5-nonyl)-pyridine (py′) generates the tetranuclear complex {(OPO-Li)PdMe(py′)}₄Li₂Cl₂ (3) in which four (phosphine-sulfonate)PdMe(py′) units are arranged around the periphery of a Li₄S₄O₁₂·Li₂Cl₂ cage. The Pd atoms in 3 are arranged in pairs with a Pd–Pd distance of 6.6 Å within each pair. 3 is more resistant to disassembly to Pd₁ species than previously studied {(OPO-Li)PdMe(py)}₄ compounds based on Li₄S₄O₁₂ cages. 3 is a single-site catalyst for the polymerization of ethylene to high-molecular weight polyethylene hexanes suspension at 80 °C.

Flaviviruses, including dengue, West Nile and recently emerged Zika virus, are important human pathogens, but there are no drugs to prevent or treat these viral infections. The highly conserved Flavivirus NS2B-NS3 protease is essential for viral replication and therefore a drug target. Compound screening followed by medicinal chemistry yielded a series of drug-like, broadly active inhibitors of Flavivirus proteases with IC₅₀ as low as 120 nM. The inhibitor exhibited significant antiviral activities in cells (EC₆₈: 300–600 nM) and in a mouse model of Zika virus infection. X-ray studies reveal that the inhibitors bind to an allosteric, mostly hydrophobic pocket of dengue NS3 and hold the protease in an open, catalytically inactive conformation. The inhibitors and their binding structures would be useful for rational drug development targeting Zika, dengue and other Flaviviruses.

We report the design, synthesis, and post-assembly modification of a new phosphine-paneled supramolecular cage framework, the anion binding ability of which can be modified rationally through selective post-assembly functionalization. The parent phosphine-paneled cage can be modified in situ through oxidation, methylation, or auration. These covalent and coordinative modifications to the exterior of the cage strongly influence the guest-binding properties of the host.

Converting elemental white phosphorus directly into organophosphorus or polyphosphorus is meaningful, challenging and attractive. The ate-complexes of aluminacyclopentadienes 1a,b react with P₄ to afford selectively the cyclotetraphosphanes 2a,b featuring four newly formed P–C bonds and a planar square cyclo-P₄ ring. Density functional theory calculations show that the conversion of tetrahedral P₄ to planar cyclo-P₄ moiety undergoes through an unexpected 1,1-P-insertion/Diels–Alder reaction/isomerization cascade process. The reaction of 2a with iodomethane or p-benzoquinone afforded the P-methylation product 3 and the metal-free cyclotetraphosphane 4, respectively. Interestingly, reduction of 4 generated the phospholyl anions 5 and 6 while treatment of 4 with iodomethane afforded the phospholyl cation 7.

The first unsubstituted olefin-linked covalent organic framework, termed COF-701, was made by linking 2,4,6-trimethyl-1,3,5-triazine (TMT) and 4,4′-biphenyldicarbaldehyde (BPDA) through Aldol condensation. Formation of the unsubstituted olefin (-CH═CH-) linkage upon reticulation is confirmed by Fourier transform infrared (FT-IR) spectroscopy and solid-state ¹³C cross-polarization magic angle spinning (CP-MAS) NMR spectroscopy of the framework and of its ¹³C-isotope-labeled analogue. COF-701 is found to be porous (1715 m² g^–1) and to retain its composition and crystallinity under both strongly acidic and basic conditions. The high chemical robustness is attributed to the unsubstituted olefin linkages. Immobilization of the strong Lewis acid BF₃·OEt₂ in the pores of the structure yields BF₃⊂COF-701. In the material, the catalytic activity of the guest is retained, as evidenced in a benchmark Diels–Alder reaction.

Copper oxidative addition into organohalides is a challenging two-electron process. In contrast, formal oxidative addition of copper to C_sp² carbon–bromine bonds can be accomplished by employing latent silyl radicals under photoredox conditions. This novel paradigm for copper oxidative addition has now been applied to a Cu-catalyzed cross-coupling of C_sp³-bromides. Specifically, a copper/photoredox dual catalytic system for the coupling of alkyl bromides with trifluoromethyl groups is presented. This operationally simple and robust protocol successfully converts a variety of alkyl, allyl, benzyl, and heterobenzyl bromides into the corresponding alkyl trifluoromethanes.

With tunability and porosity, nanoscale metal–organic frameworks (nMOFs) can incorporate multiple components to realize complex functions for biomedical applications. Here we report the synthesis of W₁₈@Hf₁₂-DBB-Ir, a new nMOF assembly hierarchically incorporating three high-Z components—Hf-based metal-oxo clusters, Ir-based bridging ligands, and W-based polyoxometalates (POMs)—as a multifarious radioenhancer. Cationic Hf₁₂-DBB-Ir was built from Hf₁₂ secondary building units (SBUs) and [Ir(bpy)₂(ppy)]⁺ (bpy = 2,2′-bipyridine, ppy = 2-phenylpyridine) derived dicarboxylate ligands (DBB-Ir) and then loaded with Wells–Dawson-type [P₂W₁₈O₆₂]^6– (W₁₈) POMs to afford W₁₈@Hf₁₂-DBB-Ir. Upon X-ray irradiation, W₁₈@Hf₁₂-DBB-Ir significantly enhances hydroxyl radical generation from Hf₁₂ SBUs, singlet oxygen generation from DBB-Ir ligands, and superoxide generation from W₁₈ POMs, respectively. Through synergistic cell killing by these distinct reactive oxygen species, W₁₈@Hf₁₂-DBB-Ir elicited superb anticancer efficacy with >98% tumor regression at a low X-ray dose of 5 × 1 Gy.

A regiodivergent catalytic method for direct conversion of aldehydes to branched or linear alkyl ketones is described. Rhodium complexes modified by P^tBu₂Me catalyze formate-mediated aldehyde–vinyl bromide reductive coupling–redox isomerization to form branched ketones. Use of the less strongly coordinating ligand, PPh₃, promotes vinyl- to allylrhodium isomerization en route to linear ketones. This method bypasses the 3-step sequence often used to convert aldehydes to ketones involving the addition of pre-metalated reagents to Weinreb or morpholine amides.

An intermolecular coupling of primary alcohols and organotriflates has been developed to provide ketones by the action of a Ni(0) catalyst. This oxidative transformation is proposed to occur by the union of three distinct catalytic cycles. Two competitive oxidation processes generate aldehyde in situ via hydrogen transfer oxidation or (pseudo)dehalogenation pathways. As aldehyde forms, a Ni-catalyzed carbonyl-Heck process enables formation of the key carbon–carbon bond. The utility of this rare alcohol to ketone transformation is demonstrated through the synthesis of diverse complex and bioactive molecules.

The fluorescent 9′-anthracenyl-functionalized dithiadiazolyl radical (3) exhibits four structurally determined crystalline phases, all of which are monomeric in the solid state. Polymorph 3α (monoclinic P2₁/c, Z′ = 2) is isolated when the radical is condensed onto a cold substrate (enthalpically favored polymorph), whereas 3β (orthorhombic P2₁2₁2₁, Z′ = 3) is collected on a warm substrate (entropically favored polymorph). The α and β polymorphs exhibit chemically distinct structures with 3α exhibiting face-to-face π–π interactions between anthracenyl groups, while 3β exhibits edge-to-face π–π interactions. 3α undergoes an irreversible conversion to 3β on warming to 120 °C (393 K). The β-phase undergoes a series of reversible solid-state transformations on cooling; below 300 K a phase transition occurs to form 3γ (monoclinic P2₁/c, Z′ = 1), and on further cooling below 165 K, a further transition is observed to 3δ (monoclinic P2₁/n, Z′ = 2). Both 3β → 3γ and 3γ → 3δ transitions are reversible (single-crystal X-ray diffraction), and the 3γ → 3δ process exhibits thermal hysteresis with a clear feature observed by heat capacity measurements. Heating 3β above 160 °C generates a fifth polymorph (3ε) which is distinct from 3α–3δ based on powder X-ray diffraction data. The magnetic behavior of both 3α and the 3β/3γ/3δ system reflect an S = 1/2 paramagnet with weak antiferromagnetic coupling. The reversible 3δ ↔ 3γ phase transition exhibits thermal hysteresis of 20 K. Below 50 K, the value of χ_mT for 3δ approaches 0 emu·K·mol^–1 consistent with formation of a gapped state with an S = 0 ground-state configuration. In solution, both paramagnetic 3 and diamagnetic [3][GaCl₄] exhibit similar absorption and emission profiles reflecting similar absorption and emission mechanisms for paramagnetic and diamagnetic forms. Both emit in the deep-blue region of the visible spectrum (λ_em ∼ 440 nm) upon excitation at 255 nm with quantum yields of 4% (3) and 30% ([3][GaCl₄]) affording a switching ratio [Φ_F(3⁺)/Φ_F(3)] of 7.5 in quantum efficiency with oxidation state. Solid-state films of both 3 and [3][GaCl₄] exhibit emission bands at a longer wavelength (490 nm) attributed to excimer emission.

We show here for the first time that short chain poly(N-isopropylacrylamide) (PNIPAM), one of the most famous thermoresponsive polymers, self-assembles in water to form (i) discrete nanometer-globules and (ii) micrometric sheets with nm-thickness upon addition of the well-known Keggin-type polyoxometalate (POM) H₃PW₁₂O₄₀ (PW). The type of self-assembly is controlled by PW concentration: at low PW concentrations, PW adsorbs on PNIPAM chains to form globules consisting of homogeneously distributed PWs in PNIPAM droplets of several nm in size. Upon further addition of PW, a phase transition from globules to micrometric sheets is observed for PNIPAMs above a polymer critical chain length, between 18 and 44 repeating units. The thickness of the sheets is controlled by the PNIPAM chain length, here from 44 to 88 repeating units. The PNIPAM sheets are electrostatically stabilized PWs accumulated on each side of the sheets. The shortest PNIPAM chain with 18 repeating units produces PNIPAM/PW globules with 5–20 nm size but no sheets. The PW/PNIPAM self-assembly arises from a solvent mediated mechanism associated with the partial dehydration of PW and of the PNIPAM, which is related to the general propensity of POMs to adsorb on neutral hydrated surfaces. This effect, known as superchaotropy, is further highlighted by the significant increase in the lower critical solubilization temperature (LCST) of PNIPAM observed upon the addition of PW in the mM range. The influence of the POM nature on the self-assembly of PNIPAM was also investigated by using H₄SiW₁₂O₄₀ (SiW) and H₃PMo₁₂O₄₀ (PMo), i.e. changing the POM’s charge density or polarizability in order to get deeper understanding on the role of electrostatics and polarizability in the PNIPAM self-assembly process. We show here that the superchaotropic behavior of POMs with PNIPAM polymers enables the formation and the shape control of supramolecular organic–inorganic hybrids.

Understanding catalytic mechanisms at the nanoscale is essential for the advancement of lithium–oxygen (Li–O₂) batteries. Using in situ electrochemical atomic force microscopy, we explored the interfacial evolution during the Li–O₂ electrochemical reactions in dimethyl sulfoxide-based electrolyte, further revealing the surface catalytic mechanism of the soluble catalyst 2,5-di-tert-butyl-1,4-benzoquinone (DBBQ). The real-time views showed that during discharge flower-like Li₂O₂ formed in the electrolyte with DBBQ but small toroid without DBBQ. Upon charge, Li₂O₂ decomposes at a slow rate from bottom to top in the absence of DBBQ, yet with an outside-in approach in the presence of DBBQ. Bigger discharge products and more efficient decomposition pathways in the DBBQ-containing system reveal the catalytic activity of DBBQ straightforwardly. Our work provides a direct insight into the surface effect of soluble catalyst DBBQ on Li–O₂ reactions at the nanoscale, which is critical for the performance optimization of Li–O₂ batteries.

Ergothioneine is an emergent factor in cellular redox biochemistry in humans and pathogenic bacteria. Broad consensus has formed around the idea that ergothioneine protects cells against reactive oxygen species. The recent discovery that anaerobic microorganisms make the same metabolite using oxygen-independent chemistry indicates that ergothioneine also plays physiological roles under anoxic conditions. In this report, we describe the crystal structure of the anaerobic ergothioneine biosynthetic enzyme EanB from green sulfur bacterium Chlorobium limicola. This enzyme catalyzes the oxidative sulfurization of N-α-trimethyl histidine. On the basis of structural and kinetic evidence, we describe the catalytic mechanism of this unusual C–S bond-forming reaction. Significant active-site conservation among distant EanB homologues suggests that the oxidative sulfurization of heterocyclic substrates may occur in a broad range of bacteria.

Due to the composed α-helical/β-strand structures, β-amyloid peptide (Aβ) is sensitive to chiral environments. The orientation and chirality of the Aβ strand strongly influence its aggregation. Aβ-formed fibrils have a cascade of chirality. Therefore, for selectively targeting amyloid aggregates, chirality preference can be one key issue. Inspired by the natural stereoselectivity and the β-sheet structure, herein, we synthesized a series of d- and l-amino acid-modified polyoxometalate (POM) derivatives, including positively charged amino acids (d-His and l-His) and negatively charged (d-Glu and l-Glu) and hydrophobic amino acids (d-Leu, l-Leu, d-Phe, and l-Phe), to modulate Aβ aggregation. Intriguingly, Phe-modified POMs showed a stronger inhibition effect than other amino acid-modified POMs, as evidenced by multiple biophysical and spectral assays, including fluorescence, circular dichroism, NMR, molecular dynamic simulations, and isothermal titration calorimetry. More importantly, d-Phe-modified POM had an 8-fold stronger inhibition effect than l-Phe-modified POM, indicating high enantioselectivity. Furthermore, in vivo studies demonstrated that the chiral POM derivatives crossed the blood–brain barrier, extended the life span of AD transgenic Caenorhabditis elegans CL2006 strain, and had low cytotoxicity, even at a high dosage.

Modest exciton diffusion lengths dictate the need for nanostructured bulk heterojunctions in organic photovoltaic (OPV) cells; however, this morphology compromises charge collection. Here, we reveal rapid exciton diffusion in films of a fused-ring electron acceptor that, when blended with a donor, already outperforms fullerene-based OPV cells. Temperature-dependent ultrafast exciton annihilation measurements are used to resolve a quasi-activationless exciton diffusion coefficient of at least 2 × 10^–2 cm²/s, substantially exceeding typical organic semiconductors and consistent with the 20–50 nm domain sizes in optimized blends. Enhanced three-dimensional diffusion is shown to arise from molecular and packing factors; the rigid planar molecular structure is associated with low reorganization energy, good transition dipole moment alignment, high chromophore density, and low disorder, all enhancing long-range resonant energy transfer. Relieving exciton diffusion constraints has important implications for OPVs; large, ordered, and pure domains enhance charge separation and transport, and suppress recombination, thereby boosting fill factors. Further enhancements to diffusion lengths may even obviate the need for the bulk heterojunction morphology.

The anomalously high mobility of hydroxide and hydronium ions in aqueous solutions is related to proton transfer and structural diffusion. The role of counterions in these solutions, however, is often considered to be negligible. Herein, we explore the impact of alkali metal counter cations on hydroxide solvation and mobility. Impedance measurements demonstrate that hydroxide mobility is attenuated by lithium relative to sodium and potassium. These results are explained by ab initio molecular dynamics simulations and experimental vibrational hydration shell spectroscopy, which reveal substantially stronger ion pairing between OH^– and Li⁺ than with other cations. Hydration shell spectra and theoretical vibrational frequency calculations together imply that lithium and sodium cations have different effects on the delocalization of water protons donating a hydrogen bond to hydroxide. Specifically, lithium leads to enhanced proton delocalization compared with sodium. However, proton delocalization and the overall diffusion process are not necessarily correlated.

Carbon nanothreads are a new one-dimensional sp³-bonded nanomaterial of CH stoichiometry synthesized from benzene at high pressure and room temperature by slow solid-state polymerization. The resulting threads assume crystalline packing hundreds of micrometers across. We show high-resolution electron microscopy (HREM) images of hexagonal arrays of well-aligned thread columns that traverse the 80–100 nm thickness of the prepared sample. Diffuse scattering in electron diffraction reveals that nanothreads are packed with axial and/or azimuthal disregistry between them. Layer lines in diffraction from annealed nanothreads provide the first evidence of translational order along their length, indicating that this solid-state reaction proceeds with some regularity. HREM also reveals bends and defects in nanothread crystals that can contribute to the broadening of their diffraction spots, and electron energy-loss spectroscopy confirms them to be primarily sp³-hybridized, with less than 27% sp² carbon, most likely associated with partially saturated “degree-4” threads.

The interaction of water with metal surfaces is at the heart of electrocatalysis. But there remain enormous uncertainties about the atomistic interactions at the electrode–electrolyte interface (EEI). As the first step toward an understanding of the EEI, we report here the details of the initial steps of H₂O adsorption and complex formation on a Ag(111) surface, based on coupling quantum mechanics (QM) and ambient-pressure X-ray photoelectron spectroscopy (APXPS) experiments. We find a close and direct comparison between simulation and experiment, validated under various isotherm and isobar conditions. We identify five observable oxygen-containing species whose concentrations depend sensitively on temperature and pressure: chemisorbed O* and OH*, H₂O* stabilized by hydrogen bond interactions with OH* or O*, and multilayer H₂O*. We identify the species experimentally by their O 1s core-level shift that we calculate with QM along with the structures and free energies as a function of temperature and pressure. This leads to a chemical reaction network (CRN) that we use to predict the time evolution of their concentrations over a wide range of temperature (298–798 K) and pressure conditions (10^–6–1 Torr), which agree well with the populations determined from APXPS. This multistep simulation CRN protocol should be useful for other heterogeneous catalytic systems.

Combinatorial chemo and gene therapy provides a promising way to cure drug-resistant cancer, since the codelivered functional nucleic acids can regulate drug resistance genes, thus restoring sensitivity of the cells to chemotherapeutics. However, the dramatic chemical and physical differences between chemotherapeutics and nucleic acids greatly hinder the design and construction of an ideal drug delivery system (DDS) to achieve synergistic antitumor effects. Herein, we report a novel approach to synthesize a nanosized DDS using drug-integrated DNA with antisense sequences (termed “chemogene”) to treat drug-resistant cancer. As a proof of concept, floxuridine (F), a typical nucleoside analog antitumor drug, was incorporated in the antisense sequence in the place of thymine (T) based on their structural similarity. After conjugation with polycaprolactone, a spherical nucleic acid (SNA)-like two-in-one chemogene can be self-assembled, which possesses the capabilities of rapid cell entry without the need for a transfection agent, efficient downregulation of drug resistance genes, and chronic release of chemotherapeutics for treating the drug-resistant tumors in both subcutaneous and orthotopic liver transplantation mouse models.

The structural diversity of highly connected metal–organic frameworks (MOFs) has long been limited due to the scarcity of highly connected metal clusters and the corresponding available topology. Herein, we deliberately chose a series of tritopic linkers with multiple substituents to construct a series of highly connected rare-earth (RE) MOFs. The steric hindrance of these substituents can be systematically tuned to generate various linker rotamers with tunable configurations and symmetries. For example, the methyl-functionalized linker (L-CH₃) with C_2v symmetry exhibits larger steric hindrance, forcing two peripheral phenyl rings perpendicular to the central one. The combination of C_2v linkers and 9-connected RE₆ clusters leads to the formation of a new fascinating (3,9)-c sep topology. Unlike Zr-MOFs exhibiting Zr₆ clusters in various linker configurations and corresponding different structures, the adaptable RE₆ clusters can undergo metal insertion and rearrange into new RE₉ clusters when connected to an unfunctionalized linker (L–H) with C₁ symmetry, giving rise to a new (3,3,18)-c ytw topology. More interestingly, by judiciously combining the linkers with both small and bulky substituents through mixed-linker strategies, an RE₉-based MOF with an engaging (3,3,12)-c flg topology could be obtained as a result of continuous steric hindrance control. In this case, the two mixed linkers adopt configurations with moderate steric hindrances. Molecular simulation demonstrates that the combination of substituents with various steric hindrances dictates the resulting MOF structures. This work provides insights into the discovery of unprecedented topologies through systematic and continuous steric tuning, which can further serve as a blueprint for the design and construction of highly complicated porous structures for sophisticated applications.

The stoichiometry of protein complexes is precisely regulated in cells and is fundamental to protein function. Singe-molecule fluorescence imaging based photobleaching event counting is a new approach for protein stoichiometry determination under physiological conditions. Due to the interference of the high noise level and photoblinking events, accurately extracting real bleaching steps from single-molecule fluorescence traces is still a challenging task. Here, we develop a novel method of using convolutional and long-short-term memory deep learning neural network (CLDNN) for photobleaching event counting. We design the  convolutional layers to accurately extract features of steplike photobleaching drops and long-short-term memory (LSTM) recurrent layers to distinguish between photobleaching and photoblinking events. Compared with traditional algorithms, CLDNN shows higher accuracy with at least 2 orders of magnitude improvement of efficiency, and it does not require user-specified parameters. We have verified our CLDNN method using experimental data from imaging of single dye-labeled molecules in vitro and epidermal growth factor receptors (EGFR) on cells. Our CLDNN method is expected to provide a new strategy to stoichiometry study and time series analysis in chemistry.

For long-term storage of renewable energy, the electrochemical carbon dioxide reduction reaction (CO₂RR) offers a promising option for converting electricity to permanent forms of chemical energy. In this work, we present highly selective ethylene production dependent upon the catalyst morphology using copper oxide nanoparticles. The branched CuO nanoparticles were synthesized and then deposited on conductive carbon materials. After activation, the major copper species changed to Cu⁺, and the resulting electrocatalyst exhibited a high Faradaic efficiency (FE) of ethylene reaching over 70% and a hydrogen FE of 30% without any byproducts in a neutral aqueous solution. The catalyst also showed high durability (up to 12 h) with the ethylene FE over 65%. Compared to cubic morphology, the initial branched copper oxide structure formed highly active domains with interfaces and junctions in-between during activation, which caused large surface area with high local pH leading to high selectivity and activity for ethylene production.

In the course of a total synthesis effort directed toward the natural product curcusone C, the Stoltz group discovered an unexpected thermal rearrangement of a divinylcyclopropane to the product of a formal Cope/1,3-sigmatropic shift sequence. Since the involvement of a thermally forbidden 1,3-shift seemed unlikely, theoretical studies involving two approaches, the “trial-and-error” testing of various conceivable mechanisms (Houk group) and an “automatic” approach using the Maeda–Morokuma AFIR method (Morokuma group) were applied to explore the mechanism. Eventually, both approaches converged on a cascade mechanism shown to have some partial literature precedent: Cope rearrangement/1,5-sigmatropic silyl shift/Claisen rearrangement/retro-Claisen rearrangement/1,5-sigmatropic silyl shift, comprising a quintet of five sequential thermally allowed pericyclic rearrangements.

Ni or Co is commonly required in efficient electrocatalysts for oxygen evolution reaction (OER). Although Fe is much more abundant and cheaper, full-Fe or Fe-rich catalysts suffer from insufficient activity. Herein, we discover that Se-doping can drastically promote OER on FeOOH and develop a facile on-site electrochemical activation strategy for achieving such a Se-doped FeOOH electrode via an FeSe precatalyst. Theoretical analysis and systematic experiments prove that Se-doping enables FeOOH as an efficient and low-cost OER electrocatalyst. By optimizing the electrode structure, an industrial-level OER current output of 500 mA cm^–2 is secured at a low overpotential of 348 mV. The application of such an Fe-rich OER electrode in a practical solar-driven water splitting system demonstrates a high and stable solar-to-hydrogen efficiency of 18.55%, making the strategy promising for exploring new cost-effective and highly active electrocatalysts for clean hydrogen production.

Silicon monoxide is a promising alternative anode material due to its much higher capacity than graphite, and improved cyclability over other Si anodes. An in-depth analysis of the lithium silicide (Li_xSi) phases that form during lithiation/delithiation of SiO is presented here and the results are compared with pure-Si anodes. A series of anode materials is first prepared by heating amorphous silicon monoxide (a-SiO) at different temperatures, X-ray diffraction and ²⁹Si NMR analysis revealing that they comprise small Si domains that are surrounded by amorphous SiO₂, the domain size and crystallinity growing with heat treatment. In and ex situ ⁷Li and ²⁹Si solid-state NMR combined with detailed electrochemical analysis reveals that a characteristic metallic Li_xSi phase is formed on lithiating a-SiO with a relatively high Li concentration of x = 3.4–3.5, which is formed/decomposed through a continuous structural evolution involving amorphous phases differing in their degree of Si–Si connectivity. This structural evolution differs from that of pure-Si electrodes where the end member, crystalline Li₁₅Si₄, is formed/decomposed through a two-phase reaction. The reaction pathway of SiO depends, however, on the size of the ordered Si domains within the pristine material. When crystalline domains of >3 nm within a SiO₂ matrix are present, a phase resembling Li₁₅Si₄ forms, albeit at a higher overpotential. The continuous formation/decomposition of amorphous Li_xSi phases without the hysteresis and phase change associated with the formation of c-Li₁₅Si₄, along with a partially electrochemically active SiO₂/lithium silicate buffer layer, are paramount for the good cyclability of a-SiO.

Ruthenium nanocrystals with both a face-centered cubic (fcc) structure and well-controlled facets are attractive catalytic materials for various reactions. Here we report a simple method for the synthesis of Ru octahedral nanocrystals with an fcc structure and an edge length of 9 nm. The success of this synthesis relies on the use of 4.5 nm Rh cubes as seeds to facilitate the heterogeneous nucleation and overgrowth of Ru atoms. We choose Rh because it can resist oxidative etching under the harsh conditions for Ru overgrowth, it can be readily prepared as nanocubes with edge lengths less than 5 nm, and its atoms have a size close to that of Ru atoms. During the seed-mediated growth, the atomic packing of Ru overlayers follows an fcc lattice, in contrast to the conventional hexagonal close-packed (hcp) lattice associated with bulk Ru. The final product takes an octahedral shape, with the surface enclosed by {111} facets. Our in situ measurements suggest that both the octahedral shape and the fcc crystal structure can be well preserved up to 400 °C, which is more than 100 °C higher than what was reported for Ru octahedral nanocages. When utilized as catalysts, the Ru octahedral nanocrystals exhibited 4.4-fold enhancement in terms of specific activity toward oxygen evolution relative to hcp-Ru nanoparticles. We also demonstrate that Ru{111} facets are more active than Ru{100} facets in catalyzing the oxygen evolution reaction. Altogether, this work offers an effective method for the synthesis of Ru nanocrystals with an fcc structure and well-defined {111} facets, as well as enhanced thermal stability and catalytic activity. We believe these nanocrystals will find use in various catalytic applications.

The formation of inorganic nanoparticles has been understood based on the classical crystallization theory described by a burst of nucleation, where surface energy is known to play a critical role, and a diffusion-controlled growth process. However, this nucleation and growth model may not be universally applicable to the entire nanoparticle systems because different precursors and surface ligands are used during their synthesis. Their intrinsic chemical reactivity can lead to a formation pathway that deviates from a classical nucleation and growth model. The formation of metal oxide nanoparticles is one such case because of several distinct chemical aspects during their synthesis. Typical carboxylate surface ligands, which are often employed in the synthesis of oxide nanoparticles, tend to continuously remain on the surface of the nanoparticles throughout the growth process. They can also act as an oxygen source during the growth of metal oxide nanoparticles. Carboxylates are prone to chemical reactions with different chemical species in the synthesis such as alcohol or amine. Such reactions can frequently leave reactive hydroxyl groups on the surface. Herein, we track the entire growth process of iron oxide nanoparticles synthesized from conventional iron precursors, iron-oleate complexes, with strongly chelating carboxylate moieties. Mass spectrometry studies reveal that the iron-oleate precursor is a cluster comprising a tri-iron-oxo core and carboxylate ligands rather than a mononuclear complex. A combinatorial analysis shows that the entire growth, regulated by organic reactions of chelating ligands, is continuous without a discrete nucleation step.

Reaction of the mononuclear nonheme complex [Fe^II(CH₃CN)(N3PyS)]BF₄ (1) with an HNO donor, Piloty’s acid (PhSO₂NHOH, P.A.), at low temperature affords a high-spin (S = 2) Fe^II–P.A. intermediate (2), characterized by ⁵⁷Fe Mössbauer and Fe K-edge X-ray absorption (XAS) spectroscopies, with interpretation of both supported by DFT calculations. The combined methods indicate that P.A. anion binds as the N-deprotonated tautomer (PhSO₂NOH^–) to [Fe^II(N3PyS)]⁺, leading to 2. Complex 2 is the first spectroscopically characterized example, to our knowledge, of P.A. anion bound to a redox-active metal center. Warming of 2 above −60 °C yields the stable {FeNO}⁷ complex [Fe(NO)(N3PyS)]BF₄ (4), as evidenced by ¹H NMR, ATR-IR, and Mössbauer spectroscopies. Isotope labeling experiments with ¹⁵N-labeled P.A. confirm that the nitrosyl ligand in 4 derives from P.A. In contrast, addition of a second equivalent of a strong base leads to S–N cleavage and production of an {FeNO}⁸ species, the deprotonated analog of an Fe–HNO complex. This work has implications for the targeted delivery of HNO/NO^–/NO· to nonheme Fe centers in biological and synthetic applications, and suggests a new role for nonheme Fe^II complexes in the assisted degradation of HNO donor molecules.

Nanodevices have potential as intelligent sensing systems for detection of microRNAs (miRNAs) in living cells. However, the resolution offered by “always active” nanodevices is often insufficient to manipulate miRNA sensing with high spatiotemporal control. In this work, using DNA nanotechnology we constructed an activatable DNA nanodevice programmed to detect miRNAs in vitro and in vivo with the high spatial and temporal precision of NIR light. Our nanodevice is functionalized on the surface of upconversion nanoparticles (UCNPs) with a rationally designed DNA beacon that displays UV light-activatable miRNA sensing activity. The UCNPs absorb deep-tissue-penetrable NIR light and emit high-energy UV light locally, which serve as transducers to operate the nanodevice in the NIR window. The nanodevice can naturally enter cells and enable remote regulation of its fluorescent imaging activity for miRNAs in living cells by NIR light illumination in a chosen place and time. Furthermore, we demonstrate that the nanodevice can be expanded to activatable imaging of intratumoral miRNAs in living mice. This work illustrates the potential of DNA nanodevices for miRNA detection with high spatiotemporal resolution, which could expand the toolbox of technologies for precise biological and medical analysis.

We report a new system for the silylation of aryl C–H bonds. The combination of [Ir(cod)(OMe)]₂ and 2,9-Me₂-phenanthroline (2,9-Me₂-phen) catalyzes the silylation of arenes at lower temperatures and with faster rates than those reported previously, when the hydrogen byproduct is removed, and with high functional group tolerance and regioselectivity. Inhibition of reactions by the H₂ byproduct is shown to limit the silylation of aryl C–H bonds in the presence of the most active catalysts, thereby masking their high activity. Analysis of initial rates uncovered the high reactivity of the catalyst containing the sterically hindered 2,9-Me₂-phen ligand but accompanying rapid inhibition by hydrogen. With this catalyst, under a flow of nitrogen to remove hydrogen, electron-rich arenes, including those containing sensitive functional groups, undergo silylation in high yield for the first time, and arenes that underwent silylation with prior catalysts react over much shorter times with lower catalyst loadings. The synthetic value of this methodology is demonstrated by the preparation of key intermediates in the synthesis of medicinally important compounds in concise sequences comprising silylation and functionalization. Mechanistic studies demonstrate that the cleavage of the aryl C–H bond is reversible and that the higher rates observed with the 2,9-Me₂-phen ligand are due to a more thermodynamically favorable oxidative addition of aryl C–H bonds.

Functional mesoporous carbons have attracted significant scientific and technological interest owning to their fascinating and excellent properties. However, controlled synthesis of functional mesoporous carbons with large tunable pore sizes, small particle size, well-designed functionalities, and uniform morphology is still a great challenge. Herein, we report a versatile nanoemulsion assembly approach to prepare N-doped mesoporous carbon nanospheres with high uniformity and large tunable pore sizes (5–37 nm). We show that the organic molecules (e.g., 1,3,5-trimethylbenzene, TMB) not only play an important role in the evolution of pore sizes but also significantly affect the interfacial interaction between soft templates and carbon precursors. As a result, a well-defined Pluronic F127/TMB/dopamine nanoemulsion can be facilely obtained in the ethanol/water system, which directs the polymerization of dopamine into highly uniform polymer nanospheres and their derived N-doped carbon nanospheres with diversely novel structures such as smooth, golf ball, multichambered, and dendritic nanospheres. The resultant uniform dendritic mesoporous carbon nanospheres show an ultralarge pore size (∼37 nm), small particle size (∼128 nm), high surface area (∼635 m² g^–1), and abundant N content (∼6.8 wt %), which deliver high current density and excellent durability toward oxygen reduction reaction in alkaline solution.

Covalent organic frameworks (COFs) have emerged as a novel platform for material design and functional explorations, but it remains a challenge to synthetically functionalize targeted structures for task-specific applications. Optically pure 1,1′-bi-2-naphthol (BINOL) is one of the most important sources of chirality for organic synthesis and materials science, but it has not yet been used in construction of COFs for enantioselective processes. Here, by elaborately designing and choosing an enantiopure BINOL-based linear dialdehyde and a tris(4-aminophenyl)benzene derivative or tetrakis(4-aminophenyl)ethene as building blocks, two imine-linked chiral fluorescent COFs with a 2D layered hexagonal or tetragonal structure are prepared. The COF containing flexible tetraphenylethylene units can be readily exfoliated into ultrathin 2D nanosheets and electrospun to make free-standing nanofiber membrane. In both the solution and membrane systems, the fluorescence of COF nanosheets can be effectively quenched by chiral odor vapors via supramolecular interactions with the immobilized BINOL moieties, leading to remarkable chiral vapor sensors. Compared to the BINOL-based homogeneous and membrane systems, the COF nanosheets exhibited greatly enhanced sensitivity and enantioselectivity owing to the confinement effect and the conformational rigidity of the sensing BINOL groups in the framework. The ability to place such a useful BINOL chiral auxiliary inside open channels of COFs capable of amplifying chiral discrimination of the analytes represents a major step toward the rational synthesis of porous molecular materials for more chirality applications.

The effect of dynamic reorganization and confinement of isolated Ti^IV catalytic centers supported on silicates is investigated for olefin epoxidation. Active sites consist of grafted single-site calix[4]arene–Ti^IV centers or their calcined counterparts. Their location is synthetically controlled to be either unconfined at terminal T-atom positions (denoted as type-(i)) or within confining 12-MR pockets (denoted as type-(ii); diameter ∼7 Å, volume ∼185 ų) composed of hemispherical cavities on the external surface of zeotypes with *-SVY topology. Electronic structure calculations (density functional theory) indicate that active sites consist of cooperative assemblies of Ti^IV centers and silanols. When active sites are located at unconfined type-(i) environments, the rate constants for cyclohexene epoxidation (323 K, 0.05 mM Ti^IV, 160 mM cyclohexene, 24 mM tert-butyl hydroperoxide) are 9 ± 2 M^–2 s^–1; whereas within confining type-(ii) 12-MR pockets, there is a ∼5-fold enhancement to 48 ± 8 M^–2 s^–1. When a mixture of both environments is initially present in the catalyst resting state, the rate constants reflect confining environments exclusively (40 ± 11 M^–2 s^–1), indicating that dynamic reorganization processes lead to the preferential location of active sites within 12-MR pockets. While activation enthalpies are ΔH^‡_app = 43 ± 1 kJ mol^–1 irrespective of active site location, confining environments exhibit diminished entropic barriers (ΔS^‡_app = −68 J mol^–1 K^–1 for unconfined type-(i) vs −56 J mol^–1 K^–1 for confining type-(ii)), indicating that confinement leads to more facile association of reactants at active sites to form transition state structures (volume ∼ 225 ų). These results open new opportunities for controlling reactivity on surfaces through partial confinement on shallow external-surface pockets, which are accessible to molecules that are too bulky to benefit from traditional confinement within micropores.

We report a Pd-mediated synthesis and crystal structure of a new chiral Ag₃₃(SCH₂CH₂Ph)₂₄(PPh₃)₄ nanocluster with an open shell electronic structure. The single-crystal X-ray structure reveals that the kernel of the cluster comprises a keplerate Ag₁₃ icosahedron core with one Ag atom in the center and a shell framework of Ag₂₀S₂₄P₄ block. The Ag₂₀S₂₄P₄ shell framework is fully arranged by helical −S–Ag–S– staples along four Ag–P bonds involved C3 axis, which endows the kernel structure of the nanocluster chirality and symmetry in the T point group. The geometry and chirality of the Ag₃₃ nanocluster are further confirmed by nuclear magnetic resonance (NMR), electronic circular dichroism (ECD) spectra, and time-dependent density functional theory calculations. Our results show that the formation of the new chiral Ag₃₃ nanocluster is strongly dependent on the presence of Pd regent with the form of Pd(PPh₃)₄ functioning in the synthesis. This work not only presents a novel chiral structure of the silver nanocluster but also provides a new strategy for the development of a novel nanocluster.

In this study, we report the successful incorporation of the photoactive bis(4′-(4-carboxyphenyl)-terpyridine)ruthenium(II) (Ru(cptpy)₂) strut into a robust metal–organic framework (MOF), AUBM-4. The single crystal X-ray analysis revealed the formation of a new one-dimensional structure of Ru(cptpy)₂ complexes linked together by Zr atoms that are eight coordinated with O atoms. The chemically stable MOF structure was employed as an efficient photocatalyst for carbon dioxide conversion to formate under visible light irradiation. To the best of our knowledge, the obtained conversion rate is among the highest reported in the literature for similar systems. Our strategy of using the Ru(cptpy)₂ complex as a linker to construct the MOF catalyst appears to be very promising in artificial photosynthesis.

This theoretical study establishes ways of controlling and enabling an uncommon chemical reaction, the displacement reaction, B:---(X—Y) → (B—X)⁺ + :Y^–, which is nascent from a B:---(X—Y) halogen bond (XB) by nucleophilic attack of the base, B:, on the halogen, X. In most of the 14 cases examined, these reactions possess high barriers either in the gas phase (where the X—Y bond dissociates to radicals) or in solvents such as CH₂Cl₂ and CH₃CN (which lead to endothermic processes). Thus, generally, the XB species are trapped in deep minima, and their reactions are not allowed without catalysis. However, when an oriented-external electric field (OEEF) is directed along the B---X---Y reaction axis, the field acts as electric tweezers that orient the XB along the field’s axis, and intensely catalyze the process, by tens of kcal/mol, thus rendering the reaction allowed. Flipping the OEEF along the reaction axis inhibits the reaction and weakens the interaction of the XB. Furthermore, at a critical OEEF, each XB undergoes spontaneous and barrier-free reaction. As such, OEEF achieves quite tight control of the structure and reactivity of XB species. Valence bond modeling is used to elucidate the means whereby OEEFs exert their control.

Despite notable progress, olefin metathesis methods for preparation of (Z)-α,β-unsaturated carbonyl compounds, applicable to the synthesis of a large variety of bioactive molecules, remain scarce. Especially desirable are transformations that can be promoted by ruthenium-based catalysts, as such entities would allow direct access to carboxylic esters and amides, or acids (in contrast to molybdenum- or tungsten-based alkylidenes). Here, we detail how, based on the mechanistic insight obtained through computational and experimental studies, a readily accessible ruthenium catechothiolate complex was found that may be used to generate many α,β-unsaturated carbonyl compounds in up to 81% yield and ≥98:2 Z/E ratio. We show that through the use of a complex bearing an unsaturated N-heterocyclic carbene (NHC) ligand, for the first time, products derived from the more electron-deficient esters, acids, and Weinreb amides (vs primary or secondary amides) can be synthesized efficiently and with high stereochemical control. The importance of the new advance to synthesis of bioactive compounds is illustrated through two representative applications: an eight-step, 15% overall yield, and completely Z-selective route leading to an intermediate that may be used in synthesis of stagonolide E (vs 11 steps, 4% overall yield and 91% Z, previously), and a five-step, 25% overall yield sequence to access a precursor to dihydrocompactin (vs 13 steps and 5% overall yield, formerly).

The enantioselective total synthesis of cage-shaped alkaloid (+)-arboridinine is reported. The synthesis takes advantage of the stereoselective double-Mannich reaction to rapidly construct the aza[3.3.1]bicyclic core along with two quaternary stereocenters of the alkaloid. Key steps for the present synthesis include an enantioselective Michael addition establishing the original chiral center at C10 and intramolecular dearomative alkylation forging the cage-shaped ring system found in arboridinine, as well as creating the requisite quaternary carbon center at C3. The bridgehead hydroxyl moiety at C11 was installed through a late-stage cobalt-catalyzed decarboxylative acetoxylation reaction. This strategy enables a 14-step asymmetric total synthesis of (+)-arboridinine from the readily available starting materials with most of the transformations performed on the decagram scale.

Cyanine dyes play an indispensable and central role in modern fluorescence-based biological techniques. Despite their importance and widespread use, the current synthesis methods of heptamethine chain modification are restricted to coupling reactions and nucleophilic substitution at the meso position in the chain. Herein, we report the direct transformation of Zincke salts to cyanine dyes under mild conditions, accompanied by the incorporation of a substituted pyridine residue into the heptamethine scaffold. This work represents the first general approach that allows the introduction of diverse substituents and different substitution patterns at the C3′–C5′ positions of the chain. High yields, functional tolerance, versatility toward the condensation partners, and scalability make this method a powerful tool for accessing a new generation of cyanine derivatives.

We report a cobalt-based paramagnetic chemical exchange saturation transfer (PARACEST) magnetic resonance (MR) probe that is able to selectively bind and quantitate the concentration of Ca²⁺ ions under physiological conditions. The parent LCo complex features CEST-active carboxamide groups and an uncoordinated crown ether moiety in close proximity to a high-spin pseudo-octahedral Co^II center. Addition of Na⁺, Mg²⁺, K⁺, and Ca²⁺ leads to binding of these metal ions within the crown ether. Single-crystal X-ray diffraction and solid-state magnetic measurements reveal the presence of a cation-specific coordination environment and magnetic anisotropy of Co^II, with axial zero-field splitting parameters for the Na⁺- and Ca²⁺-bound complexes differing by over 90%. Owing to these differences, solution-based measurements under physiological conditions indicate reversible binding of Na⁺ and Ca²⁺ to give well-separated CEST peaks at 69 and 80 ppm for [LCoNa]⁺ and [LCoCa]²⁺, respectively. Dissociation constants for different cation-bound complexes of LCo, as determined by ¹H NMR spectroscopy, demonstrate high selectivity toward Ca²⁺. This finding, in conjunction with the large excess of Na⁺ in physiological environments, minimizes interference from related cations, such as Mg²⁺ and K⁺. Finally, variable-[Ca²⁺] CEST spectra establish the ratio between the CEST peak intensities for the Ca²⁺- and Na⁺-bound probes (CEST_80 ppm/CEST_69 ppm) as a measure of [Ca²⁺], providing the first example of a ratiometric quantitation of Ca²⁺ concentration using PARACEST. Taken together, these results demonstrate the ability of transition metal PARACEST probes to afford a concentration-independent measure of [Ca²⁺] and provide a new approach for designing MR probes for cation sensing.

Herein we report the synthesis of an elusive metal–organic framework, the iron(II) analogue of ZIF-8 with the formula Fe(2-methylimidazolate)₂, here denoted as MUV-3. The preparation of this highly interesting porous material, inaccessible by common synthetic procedures, occurs in a solvent-free reaction upon addition of an easily detachable template molecule, yielding single crystals of MUV-3. This methodology can be extended to other metals and imidazolate derivatives, allowing the preparation of ZIF-8, ZIF-67, and the unprecedented iron(II) ZIFs Fe(2-ethylimidazolate)₂ and Fe(2-methylbenzimidazolate)₂. The different performance of MUV-3 toward NO sorption, in comparison to ZIF-8, results from the chemisorption of NO molecules, which also causes a gate-opening behavior. Finally, the controlled pyrolysis of MUV-3 results in a N-doped graphitic nanocomposite that exhibits extraordinary performance for the oxygen evolution reaction (OER), with low overpotential at different current densities (316 mV at 10 mA cm^–2), low Tafel slope (37 mV per decade), high maximum current density (710 mA cm^–2 at 2.0 V vs RHE), and great durability (15 h).

Controlling the regioselectivity of ambident nucleophiles toward alkylating agents is a fundamental problem in heterocyclic chemistry. Unsubstituted triazoles are particularly challenging, often requiring inefficient stepwise protection–deprotection strategies and prefunctionalization protocols. Herein we report on the alkylation of archetypal ambident 1,2,4-triazole, 1,2,3-triazole, and their anions, analyzed by in situ ¹H/¹⁹F NMR, kinetic modeling, diffusion-ordered NMR spectroscopy, X-ray crystallography, highly correlated coupled-cluster computations [CCSD(T)-F12, DF-LCCSD(T)-F12, DLPNO-CCSD(T)], and Marcus theory. The resulting mechanistic insights allow design of an organocatalytic methodology for ambident control in the direct N-alkylation of unsubstituted triazole anions. Amidinium and guanidinium receptors are shown to act as strongly coordinating phase-transfer organocatalysts, shuttling triazolate anions into solution. The intimate ion pairs formed in solution retain the reactivity of liberated triazole anions but, by virtue of highly regioselective ion pairing, exhibit alkylation selectivities that are completely inverted (1,2,4-triazole) or substantially enhanced (1,2,3-triazole) compared to the parent anions. The methodology allows direct access to 4-alkyl-1,2,4-triazoles (rr up to 94:6) and 1-alkyl-1,2,3-triazoles (rr up to 99:1) in one step. Regioselective ion pairing acts in effect as a noncovalent in situ protection mechanism, a concept that may have broader application in the control of ambident systems.

While remarkable progress has been made over the past decade, new design strategies for chiral catalysts in enantioselective C(sp³)–H functionalization reactions are still highly desirable. In particular, the ability to use attractive noncovalent interactions for rate acceleration and enantiocontrol would significantly expand the current arsenal for asymmetric metal catalysis. Herein, we report the development of a highly enantioselective Ir(III)-catalyzed intramolecular C(sp³)–H amidation reaction of dioxazolone substrates for synthesis of optically enriched γ-lactams using a newly designed α-amino-acid-based chiral ligand. This Ir-catalyzed reaction proceeds with excellent efficiency and with outstanding enantioselectivity for both activated and unactivated alkyl C(sp³)–H bonds under very mild conditions. It offers the first general route for asymmetric synthesis of γ-alkyl γ-lactams. Water was found to be a unique cosolvent to achieve excellent enantioselectivity for γ-aryl lactam production. Mechanistic studies revealed that the ligands form a well-defined groove-type chiral pocket around the Ir center. The hydrophobic effect of this pocket allows facile stereocontrolled binding of substrates in polar or aqueous media. Instead of capitalizing on steric repulsions as in the conventional approaches, this new Ir catalyst operates through an unprecedented enantiocontrol mechanism for intramolecular nitrenoid C–H insertion featuring multiple attractive noncovalent interactions.

Liquid–liquid phase separation (LLPS) of proteins into concentrated microdroplets (also called coacervation) is a phenomenon that is increasingly recognized to occur in many biological processes, both inside and outside the cell. While it has been established that LLPS can be described as a spinodal decomposition leading to demixing of an initially homogeneous protein solution, little is known about the assembly pathways by which soluble proteins aggregate into dense microdroplets. Using recent developments in techniques enabling the observation of matter suspended in liquid by transmission electron microscopy, we observed how a model intrinsically disordered protein phase-separates in liquid environment. Our observations reveal the dynamic mechanisms by which soluble proteins self-organize into condensed microdroplets with nanoscale and millisecond space and time resolution, respectively. With this method, the nucleation and initial growth steps of LLPS could be captured, opening the door for a deeper understanding of biomacromolecular complexes exhibiting LLPS ability.