Mononuclear Bi^I and Bi^II compounds remained elusive for a long time, but recently, the isolation and characterization of such species were reported. They can be handled in solution at ambient temperature and show exceptional properties, which are expected to reveal new reactivity patterns, enabling the development of new catalytic processes. TEMPO=2,2,6,6-tetramethyl-1-piperidinyl N-oxide.

What’s a good fragment? Fragment-based drug discovery is well-established within many pharmaceutical, biotech, and academic institutions for generating new drugs. In this Essay, the opportunities and challenges for organic chemists to design and synthesize new fragments are described.

Fair trade: Transfer hydrosilylation is a technique that, unlike the conceptually related transfer hydrogenation, had not been considered for nearly a century. The recently developed radical and ionic transition-metal-free variants rely on aromatization of a cyclohexa-1,4-diene during release of a silicon radical and cation, respectively. Subsequent reaction with typical unsaturated substrates (e.g. alkenes) terminates the transfer process (see scheme).

Safety net: Polymer electrolytes are a safe alternative to conventional liquid electrolytes in lithium batteries. Their main drawback is low ionic conductivity at room temperature. The most promising solution for this issue is incorporation of ionic liquids, which enhance the performance without decline in safety. This Review elucidates the interactions in these ternary polymer electrolytes and their performance in lithium-metal polymer batteries.

Lead the way to the tube: The first example of a metal-halide-based crystalline nanotube array is constructed from an unprecedented giant [Pb^II₁₈I₅₄(I₂)₉] wheel cluster (see picture, Pb green, I pink). It has typical semiconductive properties and highly anisotropic conductivity.

Tricolor switch: A single crystal of M-4-B was obtained by attaching the boron of BH₃ to the amine linker between a tetraphenylethylene unit and rhodamine B. M-4-B showed a novel sequential tricolor switching from deep-blue to bluish-green and to a reddish color upon grinding. The boron atom played a key role in obtaining the single crystal (see picture: O red, N blue, B yellow).

Concise and practical: D-Desosamine is synthesized in 4 steps (27.5 % yield) from methyl vinyl ketone and sodium nitrite. The key step in this chromatography-free synthesis is the Cs₂CO₃-mediated coupling of (R)-4-nitro-2-butanol and glyoxal, which affords in crystalline form 3-nitro-3,4,6-trideoxy-α-D-glucose, a nitro sugar stereochemically homologous to D-desosamine.

Improve your image! Dual labeling of antibody fragments with a fluorophore or ¹⁸F isotope for multimodal imaging and with a PEG moiety or a second antibody fragment to improve circulatory half-life or avidity led to constructs that recognized Class II MHC products (see picture) and CD11b with high specificity. PET imaging with the constructs enabled the detection of tumors as small as a few millimeters in size.

With iron hand: The title reaction proceeds at room temperature and tolerates a broad range of both unfunctionalized and highly functionalized olefins. It also provides a convenient synthetic approach to a variety of nitrogen-containing building blocks. Preliminary mechanistic studies suggest both Lewis acid activation and iron-enabled redox catalysis are crucial for the selective azido-group transfer.

Electron transfer made easier: Electron transfer (ET) to electron-deficient quinones is facilitated through the use of dicationic hydrogen-bond donors (HBDs) as the large thermodynamic barrier is surmounted through strong association between the HBD and the reduced quinone. The use of an HBD also accelerates the rate of the electron-transfer event by up to twelve orders of magnitude.

A mononuclear manganese(II) complex of a new oxime-dipyridyl ligand activates O₂. Catalytic methylene CH oxidation of the ligand then yields an alkoxide and finally a ketone in a stepwise process. Bis(manganese) complexes of the ligand in its various stages of oxidation were structurally characterized.

Fragile cargo: By vortex mixing, polyion complex vesicles (PICsomes) were readily loaded with enzymes, which were then delivered to tumor tissue without loss of enzyme activity. Importantly for future therapeutic applications as well as tumor imaging, the enzyme-loaded PICsomes could be used to convert a model prodrug into a highly fluorescent product at the tumor site (see picture).

Membrane proteins: Gas-phase dissociation of membrane proteins in nanodisc lipoprotein complexes by collisional activation yielded membrane proteins with many lipids bound in distinct shells. High-resolution orbitrap mass spectrometry provided unprecedented resolution of the dissociation products.

Rescue me: Adjuvants that rescue the activity of fluoroquinolone antibiotics against multidrug-resistant and extremely drug-resistant Pseudomonas aeruginosa can be generated by linking tobramycin to ciprofloxacin. The adjuvant combines the antibacterial modes of ciprofloxacin with the membrane-destabilizing effects of aminoglycosides, thereby resulting in enhanced cell penetration of fluoroquinolones and other antibiotics into P. aeruginosa.

Bridging the gap: A 100-mer ssDNA was developed as a potent hepatocyte growth factor (HGF) mimetic. This ssDNA was designed to induce receptor dimerization at the cell surface and subsequent signal transduction in the same way as the natural growth factor. This new class of synthetic ligands reproduced growth factor induced cellular behaviors, including cell migration and proliferation.

An organic acid catalyzed direct arylation of aromatic C(sp²)H bonds in phenols and naphthols was developed. This transformation is operationally simple, does not require an external oxidant, is readily scaled up, and the structurally diverse biaryls are formed with complete regioselectivity. Density functional calculations suggest a mechanism involving a mixed-acetal formation/[3,3]-sigmatropic rearrangement sequence.

A protease-resistant cyclic peptidomimetic for brain delivery was developed by minimizing the neurotoxin apamin. Toxicity, immunogenicity, and synthetic complexity were decreased while preserving metabolic stability and enhancing transport across the blood–brain barrier (BBB). The new vector is capable of delivering cargoes into the brain parenchyma of mice and across a tight monolayer of human endothelial cells mimicking the BBB.

What's going on in Dronpa? Computational simulations reveal that structural heterogeneity divides the ground state ensemble of reversibly photo-switchable fluorescent proteins into two populations, of which the major one fluoresces upon photon absorption, whereas the minor population deactivates into a dark non-fluorescent state.

Nanoscale optical voltage sensors: The nanoscale integration of plasmonic and nonlinear optical materials can enable the creation of a new generation of sub-wavelength “electric-plasmonic-optical” modulators and nanoscale optical voltage sensors.

Rhodopsin was incorporated into artificial membranes. The activated MII state (3PXO; yellow) of the membrane-embedded rhodopsin (left) overlaid its dark state (1U19; blue). The cytoplasmic “ionic lock” (i.e. Glu134-Arg135 salt bridge) in the dark state (top right) is broken by attractive charge interactions between the cationic membrane surface moieties and deprotonated Glu134 (bottom right).

A visible-light-triggered drug delivery system is constructed based on a double-layered stack of TiO₂ nanotubes. The key for visible light drug release is a hydrophobic cap on the nanotubes containing Au nanoparticles, where SPR with the TiO₂ conduction band provides the active species for chain scission. The system was tested in antibacterial experiments against E. coli.

Delivering the goods: After functionalization of the cyclic peptide (Ka)₄ with a single guanidiniocarbonyl pyrrole (GCP) moiety, cationic nanofibers of micrometer length are formed. These aggregates are efficient gene transfection vectors. DNA binds to their cationic surface and is efficiently delivered into cells. GFP=green fluorescent protein.

Skp2 inhibitor: The discovery of a chemical inhibitor of the Skp2/p300 interaction is reported. The inhibitor is able to specifically inhibit non-proteolytic activity without affecting Skp2 proteolytic activity. Thus, the inhibitor can be developed as a chemical probe of Skp2 non-proteolytic function during tumorigenesis.

Easy gold–graphene nanohybrid catalysts: Graphene and 1.1.1 facet-oriented Au nanoparticles form simultaneously upon pyrolysis of chitosan-embedding AuCl₄⁻, and exhibit high catalytic activity.

Trap and transfer: The bicyclo[1.1.0]tetraphosphabutane anion (see scheme, center), generated from P₄ and Mes*Li (Mes*=2,4,6-tBu₃C₆H₂), can be trapped by BPh₃ in THF. The anion can be used as an [RP₄]⁻ transfer agent, reacting with neutral Lewis acids (B(C₆F₅)₃, BH₃, and W(CO)₅) to afford unique singly and doubly coordinated butterfly anions and with the trityl cation to form a neutral, nonsymmetrical P₄ derivative.

Record-breaking amyloid sheets: The self-assembly of microtubule-binding R3 fragment from Tau protein in the absence of heparin induces the formation of record-length, well-ordered, 2D laminated amyloid ribbon structures.

Let's face't: The methanol-to-dimethyl ether (DME) reaction was unambiguously identified to occur by the dehydration coupling of methoxy species at the fourfold-coordinated Ti⁴⁺ sites (Ti_4c) on a mineral anatase TiO₂(001)-(1×4) surface. The results show, for the first time, the predicted higher reactivity of this facet relative to other reported TiO₂ facets.

Optimization of donor–acceptor electronic coupling remarkably inhibits the undesirable rapid decay of the singlet charge-separated state to the ground state, yielding the final long-lived, triplet charge-separated state with circa 100 % efficiency. This finding is relevant to the rational design of artificial photosynthesis and organic photovoltaic cells.

Make the swap: Substitution of histidine, comprising part of the catalytic base group in the ent-copalyl diphosphate synthases, leads to rearrangements. Through a series of 1,2-hydride and methyl shifts of the initially formed bicycle, predominant formation of (−)-kolavenyl diphosphate is observed. Further mutational analysis and quantum chemical calculations provide mechanistic insight into the basis for this profound effect on product outcome.

Enhanced membrane permeability: The effects of the chlorosulfolipid danicalipin A on the membranes of mammalian cells and on the walls of Gram-negative bacteria are investigated. These studies were enabled through the development of a novel, scalable synthesis. The ability of danicalipin A to facilitate the diffusion of fluorescent dyes into cells is described.

Lithium carbide (Li₂C₂) is shown to function as a potential cathode material for lithium ion batteries. At least half of the lithium can be extracted and reinserted in Li₂C₂ during cycling. These results open the door to future applications of alkali and alkaline earth metal electrodes.

A copper(I)-catalyzed interrupted click reaction to access diverse 5-functionalized triazoles is reported. Various 5-amino-, 5-thio-, and 5-selenotriazoles were assembled in a single step in high yields. The reaction proceeds under mild conditions with complete regioselectivity and features a broad substrate scope and compatibility with various functional groups.

Glycan signature: Chloroviruses glycosylate their capsid protein in a host-independent process. These N-linked glycans have unprecedented structures, and each is virus-specific, but all share the same core motif. Conservation in the core region occurs at two different levels: the most conserved region comprises five residues and inclusion of the sixth extends this strictly conserved core. This core oligosaccharide represents a new type of N-glycosylation.

DNA base pairing is used to produce hydrogen-bonded macrocycles whose supramolecular structure can be transferred from solution to a solid substrate. A hierarchical assembly process ultimately leads to two-dimensional nanostructured porous networks that are able to host size-complementary guests.

The highly reducing and non-reducing polyketide synthase pair that is responsible for the production of cladosporin in Cladosporium cladosporioides has been identified and heterologously expressed, and its functional activity has been demonstrated. A putative lysyl-tRNA synthetase is also contained within the cladosporin gene cluster and proposed to be necessary for self-resistance in the organism.

Methyls by design: Systematic three-point optimization affords an amine catalyst which provides ready access to chiral α-methyl-substituted and other α-alkyl-substituted thioesters in high enantiomeric purity (see example). Natural product building blocks, such as the C4–C13 segment of bistramide A, can be quickly accessed with the catalyst.

A variation of the “shake-flask method” was developed for the straightforward determination of the lipophilicity (log P) of fluorinated compounds and is based on the relative integration of the ¹⁹F NMR peaks of a sample and an internal reference for each phase (oct=octanol). The influence of different fluorination motifs on the lipophilicity of various aliphatic alkanols and carbohydrates was determined.

Stacking blocks: Two nanosized Mn₂₅Na₄ and Mn₄₉ clusters consisting of four and eight decametallic supertetrahedral subunits, respectively, are reported. These clusters are unique examples of oligomeric species based on magnetic subunits and have large spin ground-state values S=51/2 (Mn₂₅Na₄) and 61/2 (Mn₄₉). The Mn₄₉ cluster displays single-molecule magnet (SMM) behavior and is the second largest reported homometallic SMM.

Combining single electron transfer between a donor substrate and a catalyst-activated acceptor substrate with a stereocontrolled radical–radical recombination enables the visible-light-driven synthesis of 1,2-amino alcohols from trifluoromethyl ketones and tertiary amines. With a chiral iridium complex acting as both a Lewis acid and a photoredox catalyst, enantioselectivities of up to 99 % ee were achieved.

The FRET of pain: Resonance energy transfer, detected by a combination of cold ion spectroscopy and mass spectrometry, is used to estimate the Tyr–Phe spacing for enkephalins in the gas phase. These distances appear to differ substantially in enkephalins (pain-relief drugs) with different pharmacological efficiencies.

Low-cost electrocatalysts: Ultrathin nickel nanosheets were synthesized by gently reducing a Ni(OH)₂ nanosheet array on a metal substrate (see picture). The electrocatalytic performance of the Ni nanosheets was tested on the oxidation of hydrazine and the hydrogen-evolution reaction.

The thinner, the better: 1.72 nm thick Co₃O₄ layers were synthesized through a fast-heating strategy. Benefiting from the ultralarge fraction of surface atoms and increased density of states, the 1.72 nm thick Co₃O₄ layers are active in the electrocatalytic reduction of CO₂ to formate and have a current density over 20 times higher than bulk samples.

Supramolecular polymers: The integrated actuation of switchable mechanical bonds in bundles of supramolecular polymers leads to dynamic mesostructures (see picture). A new kind of hydrogen-bonded supramolecular polymers is described which incorporate molecular machines in the form of acid–base switchable [c2]daisy chain rotaxanes.

Solitary confinement: The controlled assembly of polythiophene within the channels of a metal–organic framework was carried out. This system was used to demonstrate the assembly packing structure as a way of controlling the optical and electronic properties of the conjugated polymer.

How many steps? One great stride: The regio- and stereoselective carbometalation of cyclopropenyl amides and addition of an acyl silane gave polysubstituted cyclopropyl derivatives, which underwent a Brook rearrangement with inversion of configuration and selective ring cleavage when the reaction mixture was warmed to room temperature. Hydrolysis then completed the one-pot synthesis of δ-ketoamides with a quaternary stereocenter (see scheme).

Wild and mutant imaging: Dual-targeting nanovesicles based on consensus DNA-functionalized plasmonic gold nanoparticles (AuNPs) are designed and used for the simultaneous plasmonic imaging of wild-type p53 and fluorescence imaging of mutant p53.

Dioxygen-tolerant [NiFe] hydrogenases catalyze not only the conversion of H₂ into 2 H⁺ and 2 e⁻ but also the reduction of O₂ to H₂O. A new [NiFe]-based complex is a synthetic mimic of such hydrogenases and catalyzes O₂ reduction via an O₂ adduct, which was shown to be the first example of a side-on iron(IV) peroxo complex.

Chained together: Mitochondrial complex I is crucial for respiration, but its reactions with ubiquinone-10 (Q₁₀) are poorly understood because Q₁₀ is extremely hydrophobic. An artificial electron transport chain comprising complex I, Q₁₀, and a quinol oxidase was self-assembled in synthetic vesicles and used to study Q₁₀ reduction in a fully defined environment. This self-assembled system is suitable for studying any enzyme that uses a quinone/quinol substrate.

Glucose & Personal: A wide range of non-glucose targets can be detected by using the dose-dependent response of personal glucose meters to nicotinamide coenzymes, such as the reduced form of nicotinamide adenine dinucleotide (NADH). Cascade enzymatic reactions result in the target-induced consumption or production of NADH, which in turn is detected by the glucose meter. This point-of-care device can be used for highly sensitive blood analysis in a single step.

Water can enhance the synthesis of C₂–C₄ alcohols (C₂₊OH) from CO₂ hydrogenation over Pt/Co₃O₄ significantly. The alcohols can be produced at a lower temperature with satisfactory activity and selectivity. DMI=1,3-dimethyl-2-imidazolidinone.

Electrolysis: The environmentally friendly synthesis of a highly active iridium-based oxygen evolution reaction (OER) catalyst for proton exchange membrane (PEM) electrolysis is reported. The catalyst is capable of significantly decreasing the reaction overpotential, allowing for more sustainable hydrogen production.

Staying neutral: Pd(OAc)₂ promotes the addition of aryl and heteroaryl boronic acids to the sulfur dioxide surrogate 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) (DABSO) thus delivering the corresponding sulfinates. When combined with an electrophilic trap, this redox-neutral system provides a straightforward route for the one-pot preparation of a broad range of sulfones and sulfonamides.

A direct asymmetric dearomative amination of tryptamines with O-(2,4-dinitrophenyl)hydroxylamine (DPH) was achieved using CuBr-bisoxazoline complex as a catalyst, affording 3a-amino-pyrroloindolines in good enantioselectivity under mild reaction conditions. The synthetic value of this method was demonstrated in the total synthesis of (−)-psychotriasine in a highly concise manner.

Reliable transport and delivery: Bioreducible cationic nanomicelles exhibited remarkably high DNA-binding affinity to completely condense DNA at an N/P ratio of 1. The efficiency with which the resulting nanomicelle/DNA polyplexes delivered genes into cells was much higher than that of a cationic polymer (see picture). In some cases, even at a low N/P ratio of 2, the gene-transfection efficiency was similar to that observed with viral vectors.

Be divergent: Concise total syntheses of (−)-rhazinilam, (−)-leucomidine B, and (+)-leuconodine F were accomplished from the common intermediate A. A homogeneous palladium catalyst was exploited for the first time to accomplish a substrate-directed highly diastereoselective hydrogenation of a sterically unbiased double bond. A self-induced diastereomeric anisochronism (SIDA) phenomenon was observed for leucomidine B.

Light giveth and light taketh: A new catalyst promotes olefin metathesis when irradiated with UV-A and is decomposed by UV-C. Complex light-guided chemical processes based on olefin metathesis, including polymerization, can be carried out by this protocol.

The local Na⁺ concentration near an anionic tetramethylammonium dodecyl sulfate (TMADS) micelle surface was determined with new fluorescent photoinduced electron transfer (PET) sensors. Electrostatic interactions with the negatively charged sulfonate groups of the surfactant induce an increase in the Na⁺ concentration compared with bulk water.

Green primers: Potassium 4,5-bis(dinitromethyl)furoxanate (see structure) was prepared by the nitration of 4,5-dichloroximefuroxan, followed by treatment with potassium iodide. Its high sensitivity and detonation performance along with its positive oxygen balance endow it with high potential as a green primary explosive for the replacement of lead azide.

A regio- and enantioselective formal hydroamination of unsymmetrical, unactivated internal alkenes occurs with a silane and hydroxylamine derivative. The regioselectivity is controlled by the electronic effects of ether, ester, and sulfonamide groups in the homoallylic position. This method provides direct access to 1,3-aminoalcohols with high enantioselectivity.

Work of a Pro: A Zn/Prophenol-catalyzed direct Mannich reaction using α-fluoroketones allows efficient construction of β-fluoroamine motifs with high enantio- and diastereoselectivities. A stereocomplementary aldol reaction is also described. Boc=tert-butoxycarbonyl.

A quinoline-based ligand promotes the efficient palladium-catalyzed borylation of primary β-C(sp³)H bonds in carboxylic acid derivatives as well as secondary C(sp³)H bonds in a variety of carbocycles. This directed borylation method complements existing iridium(I)- and rhodium(I)-catalyzed CH borylation reactions in terms of scope and reaction conditions.

trans-Oxasilacycloheptenes are strained seven-membered-ring trans-alkenes that underwent [4+2] cycloaddition reactions faster than a bicyclic trans-cyclooctene. They also reacted with quinones and dimethyl acetylenedicarboxylate to form adducts with high diastereoselectivity. Kinetic studies showed that ring strain increases nucleophilicity by approximately 10⁹.

Good as gold: The gold-catalyzed CH annulation of anthranil derivatives with alkynes offers a facile, flexible, and atom-economical one-step route to unprotected 7-acylindoles. The reaction proceeds via an α-imino gold carbene intermediate, which promotes ortho-aryl CH functionalization to afford the product. The transformation proceeds with a broad range of substrates under mild conditions.

Fueled by methanol: Peroxygenases catalyze stereoselective oxyfunctionalizations by utilizing H₂O₂. To efficiently generate this oxidant in situ, a new enzymatic cascade process for the reductive activation of molecular oxygen with methanol as a stoichiometric reductant has been developed. This system was applied to the stereoselective hydroxylation of ethylbenzene to (R)-1-phenylethanol.

Aryne insertion of stannylated phosphanes (R₃SnPR₂) occurs with high yields under mild conditions. ortho-Stannylarylphosphanes obtained in this reaction are highly valuable compounds for follow-up transformations.

Induced protein degradation is an emerging field that has the potential to overcome many challenges faced by traditional inhibitor-based drug design. A modular approach to PROTAC design is presented that enables targeted degradation of the therapeutically relevant BCR-ABL oncogenic protein.

The force chokes: A polymer chain is substantially weakened by a knot and ruptures at its “entry” or “exit”, because the torsions in the curved part of the chain act as “work funnels” that localize the mechanical stress in this region. As a result, the knot chokes off the chain in its immediate vicinity. This shows that bonds do not have to be extensively stretched to be broken in mechanochemical pulling experiments.

Usually electron-transfer rates decrease with increasing separation between the donor and the acceptor. However, the interplay between reorganization energy and electronic coupling can lead to opposite, counter-intuitive behavior.