Radical changes: The applicability of alkene hydroamination has recently been significantly expanded by the development of radical variants that are based on initial hydrogen atom transfer to the alkene. This Highlight assesses the current state of the art, focusing on an iron-catalyzed reaction that utilizes stable nitroarenes as the electrophilic N component and is based on the dual catalytic activation of both starting materials.

One hundred years after his Nobel Prize, Richard Willstätter’s achievements and the fascinating role he played in 20th century chemistry are discussed in this Essay. Several of his discoveries, such as the anthocyanidins, cyclooctatetraene, the ortho-quinones, and the structure of cocaine, will forever be associated with his name.

Squared away: Cyclobutanes and cyclobutenes are important structural motifs found in numerous biologically significant molecules, and they are useful intermediates for chemical synthesis. Consequently, catalytic enantioselective [2+2] cycloadditions to access cyclobutanes and cyclobutenes have emerged as an attractive target for method development. The advances made in catalytic enantioselective [2+2] cycloadditions are described herein.

Rule of three: Natural nucleic acids and the genetic information they encode are limited by the use of only four nucleotides that form two base pairs, (d)G-(d)C and d(A)-dT/U. In the past decade, three classes of unnatural base pairs have been developed to a high level of proof-of-concept. This Review summarizes their development and the potentially revolutionary applications that they are now enabling.

Ti-ed up: Cu⁺ active sites on a Cu₂O surface can be stabilized with TiO_x by forming a mixed oxide, TiCuO_x. The basicity of the surface-bound oxygen atoms thus decreases which inhibits combustion and promotes the formation of an oxametallacycle intermediate with propylene leading to higher selectivity for propylene epoxidation.

Understanding the outer membranes of Gram-negative bacteria is important for the development of new antibacterial compounds. However, their structure and dynamics are poorly understood because of their small in vivo size and inaccurate in vitro models. A stable asymmetric model of the outer membrane that can be analyzed by a range of biophysical techniques and accurately imitates the in vivo behavior of natural outer membranes is presented herein.

Get the axial: The title reaction involving diazo compounds was achieved with an axially chiral 2,2′-bipyridine ligand. Moreover, insertion into OH bonds of phenols was also realized with up to 99 % ee by using this catalytic system.

Green algae aggregates induced by biomineralization are a novel cell-material hybrid that can sustainably produce hydrogen even under natural aerobic conditions. Its evolution of photobiological hydrogen can be understood by the spatial–functional differentiation of the cells within the aggregate.

On “site”: A new retrosynthetic route to 4-O-acylated natural and unnatural glycosides is demonstrated. The title reaction of unprotected glycoside precursors, possessing multiple hydroxy groups, was performed successfully. The total syntheses of multifidosides A, B, and C were completed using this acylation strategy.

Square dance: A chiral shape-persistent macrocycle comprising four equivalent naphthalene diimide (NDI) subunits, which are almost perpendicular to each other (see figure), can be prepared in a stepwise fashion. EPR and ENDOR spectroscopy on the monoreduced state shows sharing of the unpaired electron over all four NDI subunits, despite the small overlap of the individual π systems.

Tiny but tip-top: Nanotip conical carbon-fiber microelectrodes were used for the intracellular quantification of vesicular transmitter content in single cells by a method introduced as intracellular vesicle electrochemical cytometry. It was shown that vesicular levels of catecholamines, such as dopamine (see scheme), can be altered by pharmacological manipulation, and that only partial release of neurotransmitters occurs during normal exocytosis.

It will knock you down: A functionalized nanoparticle, termed “NanoScript”, is the key component in a platform designed to knock down transcriptional gene expression in stem cells. The tunable and non-viral NanoScript platform, which is functionalized with specific small molecules, effectively knocks down GFP in GFP-labeled neural stem cells (NSCs), and represses Sox9 expression in NSCs to induce differentiation into functional neurons.

A triphase electrocatalyst composed of a Cr₂O₃-blended NiO coating on Ni nanocores (CrNN catalyst) synthesized on metal-foam substrates showed superior activity and stability for the hydrogen-evolution reaction in basic solutions. Using the CrNN catalyst, sustained electrolysis of water was achieved at a voltage lower than 1.5 V for at least 500 hours.

Under water: Nickel nanoparticles, formed in situ and used in combination with micellar catalysis, catalyze Suzuki–Miyaura cross-couplings in water under very mild reaction conditions. A wide range of substrates is tolerated and the reaction medium can be recycled.

Host–guest systems: Self-assembly of an organosilane precursor by hydrogen bonding is the key to construction of a new class of crystal-like periodic mesoporous organosilicas (see picture). The present mesoporous materials can stably accomodate silane-free H-bonding guest molecules within the pore walls, which is applicable to non-covalent modification of organosilica hybrids.

The shape of thins to come: Atomic layers bring better catalytic properties as shown by thermally exfoliating a lamellar CoSe₂–DETA hybrid to give single-unit-cell orthorhombic CoSe₂ sheets. The single-unit-cell thickness means that 66.7 % of the Co²⁺ ions are exposed on the surface and are low coordinate leading to a lower Tafel slope and higher turnover frequency in water splitting.

Expanding the nuclearity: Octairon clusters with a bicapped octahedral cluster core employing a polynucleating heptaamine ligand have been synthesized and isolated. This cluster core geometry is unprecedented for first-row transition metals. The design principles used to obtain these clusters may be extended to other transition metals or generalized to synthesize even larger clusters. Atom colors: Fe=orange; N=blue; P=purple; C=gray.

More than binding: Attachment of noroviruses to histo blood group antigens is a complex and cooperative process. This is in contrast to current perception conveying simple one-site binding. NMR spectroscopy and native mass spectrometry independently confirm this new paradigm of virus–carbohydrate interaction.

A chemoenzymatic conjugation method that is based on enzymatic prenylation and oxime ligation is a simple and efficient means for generating highly stable and homogeneous protein–drug conjugates in a site-specific manner. It can be generally applied to the conjugation of drugs to a wide range of protein binders, facilitating the development of targeted therapies with high efficacies and low off-target effects.

Better together: Engineered proteins were combined with nanofibrillated cellulose (NFC; gray/brown fibres) to show how a multimodular architecture leads to tuned properties. Two cellulose-binding modules (red and blue structures) were separated by 12-, 24-, or 48-mer linkers (red, green, and blue lines), with an optional multimerizing domain (green structure). The linkers significantly affect the interaction between protein and NFC in the wet colloidal and dry film states.

All rolled into one: A biologically inspired delivery vehicle for CRISPR–Cas9 is based on yarn-like DNA nanoparticles that are synthesized by rolling circle amplification. The DNA nanoclews were efficiently loaded with Cas9 protein/single guide RNA complexes and delivered them into human cells, enabling targeted gene disruption.

According to molecular orbital theory and relativistic Kohn–Sham density functional theory, six-coordinate clusters based on Group 13 elements bind through an electron-rich 7-center-12-electron pattern instead of using d orbitals. Strongly polar bonding and an affinity towards small anions are thus predicted, properties that are indeed associated with materials and molecules based on such clusters.

From micro to nano: Orthogonal topographic modification of planar DNA nanostructures combined with site-directed on-surface assembly provides a means to bridge top-down micropatterning with bottom-up nanotechnology.

The asymmetric synthesis of ent-ketorfanol from simple and commercially available precursors is reported. A Rh^I-catalyzed intramolecular CH alkenylation/torquoselective 6π electrocyclization cascade provides a fused bicyclic 1,2-dihydropyridine as a key intermediate. The ketone functionality and final ring are introduced in a single step through a redox-neutral acid-catalyzed rearrangement of a vicinal diol followed by intramolecular Friedel–Crafts alkylation.

You can count on it: Quantitative fluorescence microscopy requires calibration standards. A set of four protein standards was developed that enables the robust quantification of unknown protein complexes. This versatile method is compatible with various microscopy techniques and was demonstrated with confocal microscopy and super-resolution imaging to quantify the number of Nup133-containing subunits in the nuclear-pore complex.

A lamp to light the K: An intracellular mitochondria-specific K⁺ sensor, KS6, was developed. KS6 shows a K⁺ response range of 30–500 mM, sensitive fluorescence enhancement (F_max/F₀≈130), high brightness (ϕ_f=14.4 % at 150 mM of K⁺), and insensitivity to both pH (in the range 5.5–9.0) and other metal ions under physiological conditions. KS6 is thus the first sensor that can be used for monitoring K⁺ ion flux in the mitochondria of live cells

Standing up: The Langmuir–Blodgett method can be used to prepare two-dimensional supramolecular polymer (2DSP) sheets from nickel bis(dithiolene) complexes at the air–water interface (see figure). These free-standing single-layer sheets, which are 0.7–0.9 nm thick and square millimeters in area, showed excellent electrocatalytic activities in the hydrogen evolution reaction from water.

Optogenetic Apoptosis: An optogenetic design strategy is described that transforms the aberrant behavior of pro-apoptotic Bax mutants into light-responsive, genetically encoded constructs capable of triggering cell death in response to illumination.

The first transition-metal-only double perovskite, Mn²⁺₂Fe³⁺Re⁵⁺O₆, displays ferrimagnetic ordering up to 520 K and a giant positive magnetoresistance of up to 220 % at 5 K and 8 T. These properties result from the ferrimagnetically coupled Fe and Re sublattice and are affected by a two-to-one magnetic-structure transition of the Mn sublattice when a magnetic field is applied.

Double-perovskite magnetism: The double perovskite Mn₂FeReO₆ synthesized at high pressure has magnetic transition-metal cations at all sites. High-spin Mn²⁺ cations lead to record magnetizations for double-perovskite ferrimagnets and their frustrated magnetic order at 75 K switches magnetoresistance from negative to large positive values at low temperatures.

To gel or not to gel: A new class of organogelators having a cyclohexanediol motif uses molecular quorum sensing to make a definite choice between two competing modes of self-assembly: gelation or crystallization. When the concentration of gelator is less than that of adventitious water present in the system, the gelator molecules undergoes crystallization; when its concentration is more than water, it congeals the solvent to form a stable organogel.

Jamming PB into benzene: 1,2-Phosphaborines were synthesized by the ring expansion reaction of boroles with the cyclic phosphine [PPh]₅ under UV irradiation. The products were structurally characterized revealing a planar central ring. The nature of the bonding was analyzed computationally and indicated that the heterocycle had appreciable aromatic character.

On principle: Nucleophilic substitution reactions of acetals having benzyloxy groups four carbon atoms away can be highly diastereoselective. The selectivity in several cases increased as the reactivity of the nucleophile increased, in violation of the reactivity/selectivity principle. The increase in selectivity with reactivity suggests that multiple conformational isomers of reactive intermediates can give rise to the products.

Star-like amphiphilic triblock copolymers with narrow molecular weight distributions were synthesized by combining two sequential atom-transfer radical polymerizations with a click reaction. A family of uniform magnetic/plasmonic core/shell nanoparticles with precisely controllable core diameters and shell thicknesses were then obtained by capitalizing on these triblock copolymers as nanoreactors [PAA=poly(acrylic acid), PEO=poly(ethylene oxide)].

Regiocontrolled allene aziridination followed by diastereoselective epoxidation and rearrangement provides convenient access to densely functionalized azetidine scaffolds. The axial chirality of the allene can be transferred to the product to provide enantioenriched heterocycles.

A splash of EtOH: A highly facile, efficient, and enantioselective bromolactamization of olefinic amides was effected by a carbamate catalyst and ethanol additive. The amide substrates undergo N-cyclization predominantly to give a diverse range of enantioenriched bromolactam products which contain up to two chiral centers. Ts=4-toluenesulfonyl.

Active duty: 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) catalyzes the CN bond-forming reactions of active methylenes, as C nucleophiles, with α-diazocarbonyls, as N-terminal electrophiles, under ambient reaction conditions. DBU activates both the active methylene and α-diazocarbonyl.

A new addition: An efficient and straightforward access to vinylchlorides is reported. This selective ruthenium-catalyzed alkyne hydrochlorination proceeds in excellent yields under mild reaction conditions by the syn addition of HCl. cod=1,5-cyclooctadiene, Cp*=C₅Me₅, DCE=1,2-dichloroethane.

Formate formation: Hydrophosphination of CO₂ with 2-H-1,3,2-diazaphospholene afforded phosphorus formate, from which transfer of the formate to Ph₂SiH₂ produced Ph₂Si(OCHO)₂. These elementary reactions were applied to the metal-free catalytic N-formylation of various amine derivatives with CO₂ in a one-pot approach at room temperature.

Untapped reactivity: The title reaction affords 1H-benzo[g]indolines under mild reaction conditions and external oxidants are not required. The only by-products are dinitrogen and water. This reaction represents the first example of dual functionalization of unactivated primary C(sp³)H and C(sp²)H bonds with diazocarbonyl compounds. Moreover, a method to access various aminomandelic acid derivatives by an O-atom-transfer strategy is described.

Candidates for smart robotics: Self-healing conductive composites were prepared by connecting single-walled carbon nanotubes (SWCNTs) to a polymer network through host–guest interactions (see picture). The poly(2-hydroxyethyl methacrylate)–SWCNT composite combines bulk electrical conductivity, proximity sensitivity, humidity sensitivity, and autonomic self-healing properties.

Quite a gem: The first enantioselective copper-catalyzed 1,6-conjugate addition of bis(pinacolato)diboron to para-quinone methides is presented. It proceeds with excellent yields and good to excellent enantioselectivities, and provides an attractive approach for the construction of optically active gem-diarylmethine boronic esters, which can be converted into triarylmethanes with highly enantiospecificity.

Open and close! The title reaction provides a convenient and general route to relevant vinylcyclopropane derivatives. Mechanistic studies support the participation of a zinc vinylcarbene intermediate, which may be subsequently involved in a concerted cyclopropanation reaction. This method represents a step towards identifying suitable precursors for the catalytic generation of zinc carbenoids.

A triplet diradical that is formed in a thermally induced rotation around a main-group π bond, that is the SiSi double bond of 1, was directly observed by EPR spectroscopy. Both experiment and theory support a thermal equilibrium between singlet 1 and the perpendicular triplet diradical 2.

Be selective! A set of chiral Cp^xIr^III complexes (Cp^x=chiral cyclopentadienyl) based on atropchiral cyclopentadienyl ligands are presented. The complexes, in particular the tert-butoxy-substituted derivative (see picture), are shown to promote the asymmetric cycloisomerization of enynes to form fused cyclopropanes with high enantioselectivities.

Persistent cyclization: A unified radical approach to diverse bridged diketopiperazines was developed by taking advantage of the persistent radical effect. The method allows rapid access to three-dimensional heterocyclic architectures and was applied to a formal synthesis of the antibiotic bicyclomycin.

Well balanced: Wheland complexes that were generated by B(C₆F₅)₃-mediated hydride abstraction from cyclohexa-1,4-dienes engage in the transfer hydrogenation of alkenes. Problems arising from the involvement of carbenium ion intermediates, resulting in cationic hetero- or homodimerization, are overcome by sterically shielding the hydridic C3 position of the dihydrogen surrogate (see scheme). The mechanism was analyzed by quantum-chemical calculations.

Almost replaced: A direct transformation of carboxylic acid esters into benzenes, anthracenes, tetracenes, and pentacenes is described. Utilizing 1,5-bifunctional organomagnesium reagents, the reaction integrates the ester carbon atom into the newly formed aromatic ring. The method enables the transformation of different esters into arenes in yields of up to 99 %.

The sesquiterpenoid 7-epi-neopetasone was synthesized and shown to be identical to a previously tentatively identified headspace constituent of the fungus Penicillium roqueforti. Feeding with (11,12,13-¹³C₃)-7-epi-neopetasone revealed that the compound is a pathway intermediate for PR toxin, while feeding with ¹³C-labeled isotopomers of mevalonolactone gave additional insight into a double-bond isomerization/oxidation sequence along the pathway.

Keeping an ion guanidinate: Strontium guanidinate, SrC(NH)₃, the first compound with a doubly deprotonated guanidine unit, was synthesized, and its properties investigated using X-ray and neutron powder diffraction as well as IR spectroscopy. Combined with quantum-theoretical calculations, this allows a qualitative and quantitative discussion of some first insights into the structure of the anionic guanidine unit.