Site-Selective Ortho/Ipso C-H Difunctionalizations of Arenes using Thianthrene as a Leaving Group.

Site-selective ortho/ipso C-H difunctionalizations of aromatic compounds were designed to afford polyfunctionalized arenes including challenging 1,2,3,4-tetrasubstituted ones (62 examples, up to 97 % yields). To ensure the excellent regioselectivity of the process while keeping high efficiency, an original strategy based on a "C-H thianthenation/Catellani-type reaction" sequence was developed starting from simple arenes. Non-prefunctionalized arenes were first regioselectively converted into the corresponding thianthrenium salts. Then, a palladium-catalyzed, norbornene (NBE)-mediated process allowed the synthesis of ipso-olefinated/ortho-alkylated polyfunctionalized arenes using a thianthrene as a leaving group (revisited Catellani reaction). Pleasingly, using a commercially available norbornene (NBE) and a unique catalytic system, synthetic challenges known for the Catellani reaction with aryl iodides were smoothly and successfully tackled with the "thianthrenium" approach. The protocol was robust (gram-scale reaction) and was widely applied to the two-fold functionalization of various arenes including bio-active compounds. Moreover, a panel of olefins and alkyl halides as coupling partners was suitable. Pleasingly, the "thianthrenium" strategy was successfully further applied to the incorporation of other groups at the ipso (CN/alkyl/H, aryl) and ortho (alkyl, aryl, amine, thiol) positions, showcasing the generality of the process.

Enhancing the Photo and Thermal Stability of Nicotine through Crystal Engineering with Gentisic Acid.

The use of crystal engineering to convert liquids into crystalline solids remains a powerful method for inhibiting undesired degradation pathways. When nicotine, a liquid sensitive to both light and air, is combined with the GRAS-listed compound, gentisic acid, the resulting crystalline solid, exhibits enhanced photo and thermal stability. Despite a modest ΔTm of 42.7 °C, the melting point of 155.9 °C for the nicotinium gentisate salt is the highest reported for nicotine-containing crystalline solids. An analysis of the crystal packing and thermodynamic properties provides context for the observed properties.

In Situ Hydrolysis of Block Copolymers at the Water-Oil Interface.

In situ manipulation of the chemical composition of block copolymers at the fluid interfaces affords a route by which the interfacial tension, the packing of the copolymers, and the penetration of the blocks into the two liquids can be controlled. Here, a series of linear block copolymers of poly(solketal methacrylate-b-styrene) (PSM-b-PS) are used, converting hydrophobic PSM block into a hydrophilic glycerol monomethacrylate (GM) block, that results in a marked decrease in the liquid-liquid interfacial tension. The kinetics of the first-order hydrolysis reaction was analyzed by monitoring the time-dependent interfacial tension as a function of pH, polymer concentration, molecular weight, and composition. Fluorescence recovery after photobleaching (FRAP) was used to measure the in-plane dynamics of the copolymers before and after hydrolysis. This work provides insights into a quantitative pathway by which in situ interfacial reactions may be performed and monitored in real time, completely changing the interfacial activity of the molecule.

Aqueous self-assembly of giant bottlebrush block copolymer surfactants as shape-tunable building blocks.

Programmed self-assembly of well-defined molecular building blocks enables the fabrication of precisely structured nanomaterials. In this work, we explore a new class of giant polymeric surfactants (Mn = (0.7-4.4) × 10(6) g/mol) with bottlebrush architecture and show that their persistent molecular shape leads to the formation of uniform aggregates in a predictable manner. Amphiphilic bottlebrush block copolymers containing polylactide (PLA) and poly(ethylene oxide) (PEO) side chains were synthesized by a grafting-from method, and their self-assembly in aqueous environment was studied by cryogenic transmission electron microscopy. The produced micelle structures with varying interfacial curvatures and core radii (19-55 nm) boasted rod-like hydrophilic PEO brushes protruding from the hydrophobic PLA cores normal to the interface. Highly uniform spherical micelles with low dispersities were obtained from bottlebrush amphiphiles with packing parameters of ∼0.3, estimated from the polymer structural data. Long cylindrical micelles and other nonspherical aggregates were observed for the first time for compositionally less asymmetric bottlebrush surfactants. Critical micelle concentration values of 1 nM, measured for PEO-rich bottlebrush amphiphiles, indicated an enhanced thermodynamic stability of the produced micelle aggregates. Shape-dependent assembly of bottlebrush surfactants allows for the rational fabrication of a range of micelle structures in narrow morphological windows.

Enhancing the Stability of Nicotine via Crystallization Using Enantiopure Tartaric Acid Salt Formers.

Crystallization of nicotine, an oil prone to degradation at room temperature, has been demonstrated to be an effective means of creating nicotine-based materials with tunable thermal properties and improved resistance to photo-induced degradation. Herein, we show that both isomers of enantiomerically pure tartaric acid are highly effective salt formers when combined with nicotine. Both salts exhibit enhanced photostability, and with a melting point of 143.1 °C, the salt prepared using d-(-)-tartaric acid possesses one of the highest melting points for a crystalline nicotine solid reported to date.

Large pore size nanoporous materials from the self-assembly of asymmetric bottlebrush block copolymers.

Asymmetric polystyrene-polylactide (PS-PLA) bottlebrush block copolymers have been shown to self-assemble into a cylindrical morphology with large domain spacings. PLA cylinders can be selectively etched out of the shear-aligned polymer monoliths to generate nanoporous materials with an average cylindrical pore diameter of 55 nm. The remaining bottlebrush backbone provides a functional, hydrophilic coating inside the nanopores. This methodology significantly expands the range of pore sizes attainable in block copolymer based nanoporous materials.

Upgrading Carbazolyl-Derived Phosphine Ligands Using RhI-Catalyzed PIII-Directed C-H Bond Alkylation for Catalytic CO2-Fixation Reactions.

We report an Rh(I)-catalyzed C-H bond alkylation of PhenCarPhos [N-(2-(diphenylphosphaneyl)phenyl)carbazole] and some congener phosphine ligands with alkenes. The C-H bond functionalization occurred exclusively at the C1 position of the carbazolyl unit because the trivalent phosphine acts as a directing group. This protocol provides straightforward access to a large library of C1-alkyl substituted PhenCarPhos, which outperformed common commercial or unfunctionalized phosphines and their precursors in the Pd-catalyzed carbon dioxide-fixation reactions with propargylic amines.

Charge and size selective molecular transport by amphiphilic organic nanotubes.

Amphiphilic constructs with accessible, nanometer-size cavities can enable selective encapsulation, separation, and purification of nanomaterials and biomacromolecules on a similar length scale. We have developed a new method for the fabrication of amphiphilic organic nanotubes from multicomponent bottlebrush copolymers with triblock terpolymer side chains. The obtained nanotubes were demonstrated to be very effective and highly selective carriers for positively charged molecules and nanometer-size macromolecules by means of liquid-liquid extractions. Unprecedented discrimination between dendrimers with about 2 nm size differential was achieved.

De novo synthesis and cellular uptake of organic nanocapsules with tunable surface chemistry.

Water-soluble organic nanocapsules were prepared from bottlebrush copolymers with triblock terpolymer side chains composed of a degradable inner block (polylactide), a cross-linkable middle block (poly(4-butenylstyrene)), and a functional outer block (poly(styrene-co-maleic anhydride)). Bottlebrush copolymers are macromolecules with a long linear backbone and shorter polymeric side chains densely grafted onto the backbone. Hollow cylindrical nanoparticles were prepared by peripheral cross-linking of the bottlebrush copolymers and subsequent selective removal of the core. Reactive anhydride groups of the outer functional layer allowed for the preparation of nanocapsules with tunable surface characteristics. Cellular uptake of negatively charged organic nanocapsules showed strong surface chemistry dependence. The presence of hydrophobic groups on the nanocapsule surface was necessary for their nonspecific association with the cell membrane and subsequent internalization by endocytosis. The length of surface grafted oligoethylene glycol chains also had a dramatic influence on the intracellular accumulation of nanocapsules. Macropinocytosis was shown to be the predominant pathway for the cellular uptake of organic nanocapsules.

Well-defined organic nanotubes from multicomponent bottlebrush copolymers.

Bottlebrush copolymers are comblike macromolecules with densely grafted polymeric branches that adopt a cylindrical shape in solutions. We demonstrate a new method for the preparation of organic nanotubes by single molecule templating of core-shell bottlebrush copolymers. Multicomponent bottlebrush copolymers with well-defined structural parameters are synthesized by a combination of different living polymerization methods. Tubular structures can be prepared by cross-linking the shell layer and selectively etching out the core. The shape and size of original bottlebrush macromolecules are preserved during these transformations, which leads to the formation of well-defined organic nanotubes. The length and diameter of nanotubes are dictated by the length of the backbones and branches of the polymeric precursors, respectively. Water-soluble nanotubes with a hydrophobic interior can be prepared from bottlebrush copolymers with triblock copolymer branches. Herein, we outline molecular design strategies to fabricate nanotubes with controlled lengths, open pores, and different solubility characteristics.

One-Shot Synthesis and Melt Self-Assembly of Bottlebrush Copolymers with a Gradient Compositional Profile.

Morphological control plays a central role in soft materials design. Herein, we report the synthesis of a gradient bottlebrush architecture and its role in directing molecular packing in the solid state. Bottlebrush copolymers with gradient interfaces were prepared via one-shot ring-opening metathesis polymerization of exo- and endo-norbornene-capped macromonomers. Kinetic studies revealed a gradient compositional profile separating the two blocks along the backbone. Side-chain symmetric gradient bottlebrush copolymers exhibited a strong tendency to assemble into cylindrical microstructures, in contrast to their block copolymer analogs with sharp interfaces. Such exquisite architectural control of the interfacial composition affords a delicate handle to direct macromolecular assembly.

Mesoporous Polymer Frameworks from End-Reactive Bottlebrush Copolymers.

Reticulated nanoporous materials generated by versatile molecular framework approaches are limited to pore dimensions on the scale of the utilized rigid molecular building blocks (<5 nm). The inherent flexibility of linear polymers precludes their utilization as long framework connectors for the extension of this strategy to larger length scales. We report a method for the fabrication of mesoporous frameworks by using bottlebrush copolymers with reactive end blocks serving as rigid macromolecular interconnectors with directional reactivity. End-reactive bottlebrush copolymers with pendant alkene functionalities were synthesized by a combination of controlled radical polymerization and polymer modification protocols. Ru-catalyzed cross-metathesis cross-linking of bottlebrush copolymers with two reactive end blocks resulted in the formation of polymer frameworks where isolated cross-linked domains were interconnected with bottlebrush copolymer bridges. The resulting materials were characterized by a continuous network pore structure with average pore sizes of 9-50 nm, conveniently tunable by the length of the utilized bottlebrush copolymer building blocks. The materials fabrication strategy described in this work expands the length scale of molecular framework materials and provides access to mesoporous polymers with a molecularly tunable reticulated pore structure without the need for templating, sacrificial component etching, or supercritical fluid drying.

Therapeutic surfactant-stripped frozen micelles.

Injectable hydrophobic drugs are typically dissolved in surfactants and non-aqueous solvents which can induce negative side-effects. Alternatives like 'top-down' fine milling of excipient-free injectable drug suspensions are not yet clinically viable and 'bottom-up' self-assembled delivery systems usually substitute one solubilizing excipient for another, bringing new issues to consider. Here, we show that Pluronic (Poloxamer) block copolymers are amenable to low-temperature processing to strip away all free and loosely bound surfactant, leaving behind concentrated, kinetically frozen drug micelles containing minimal solubilizing excipient. This approach was validated for phylloquinone, cyclosporine, testosterone undecanoate, cabazitaxel and seven other bioactive molecules, achieving sizes between 45 and 160 nm and drug to solubilizer molar ratios 2-3 orders of magnitude higher than current formulations. Hypertonic saline or co-loaded cargo was found to prevent aggregation in some cases. Use of surfactant-stripped micelles avoided potential risks associated with other injectable formulations. Mechanistic insights are elucidated and therapeutic dose responses are demonstrated.

Molecular Bottlebrushes: New Opportunities in Nanomaterials Fabrication.

This Viewpoint highlights the ability of molecular bottlebrushes to serve as highly tunable building blocks for creating nanostructured materials via molecular templating, solution aggregation, and melt self-assembly. Recent achievements in the synthesis of discrete nano-objects, micellar structures, and periodic nanomaterials from bottlebrush copolymers are emphasized, and future opportunities in this area of polymer science are briefly discussed.

Tandem RAFT-ATRP Synthesis of Polystyrene-Poly(Methyl Methacrylate) Bottlebrush Block Copolymers and Their Self-Assembly into Cylindrical Nanostructures.

A polystyrene-poly(methyl methacrylate) (PS-PMMA) bottlebrush block copolymer with asymmetric branches was synthesized by grafting from a symmetrical backbone containing a novel dual vinyl initiation system and characterized by atomic force microscopy (AFM) and small-angle X-ray scattering (SAXS). The block copolymer backbone was prepared by sequential reversible addition-fragmentation chain transfer (RAFT) copolymerization of solketal methacrylate (SM) and 2-(bromoisobutyryl)ethyl methacrylate (BIEM). From the poly(BIEM) segment, PMMA branches of 26 units were grafted by atom transfer radical polymerization (ATRP). Solketal groups were then subjected to hydrolysis and functionalized with a RAFT agent. Subsequently, from RAFT sites of the poly(SM) segment, polystyrene branches of 45 units were grafted to yield the final bottlebrush block copolymer. The resulting polymer was found to have a vertically oriented cylindrical morphology by AFM with an average cylinder diameter of 45 nm; morphology was also confirmed by SAXS analysis.

Synthesis of Degradable Organic Nanotubes by Bottlebrush Molecular Templating.

Degradable organic nanotubes were synthesized by a single-molecule templating of core-shell bottlebrush copolymers composed of an etchable inner block (polylactide) and a functional outer block (poly(styrene-co-maleic anhydride)). The pendant mercapto groups generated along the outer block chains by reacting the anhydride groups with cysteamine were oxidized to disulfide groups acting as degradable cross-linking units in the shell layer. Subsequent hydrolytic removal of the polyester inner core provided hollow organic nanotubes held together by disulfide groups as cross-linkers. The cleavage of disulfide linkers by reaction with dithiothreitol resulted in a complete disintegration of nanotube structures into small fragments.

A substrate-integrated and scalable templated approach based on rusted steel for the fabrication of polypyrrole nanotube arrays.

We report here a facile, generalizable, and entirely scalable approach for the fabrication of vertically aligned arrays of Fe(2)O(3)/polypyrrole core-shell nanostructures and polypyrrole nanotubes. Our "all electrochemical" approach is based on the fabrication of α-Fe(2)O(3) nanowire arrays by the simple heat treatment of commodity low carbon steel substrates, followed by electropolymerization of conformal polypyrrole sheaths around the nanowires. Subsequently, electrochemical etching of the nanowires yields large-area vertically aligned polypyrrole nanotube arrays on the steel substrate. The developed methodology is generalizable to functionalized pyrrole monomers and represents a significant practical advance of relevance to the technological implementation of conjugated polymer nanostructures in electrochromics, electrochemical energy storage, and sensing.

Organosoluble polypyrrole nanotubes from core-shell bottlebrush copolymers.

Well-defined, organosoluble polypyrrole nanotubes were synthesized by single-molecule templating of multicomponent bottlebrush copolymers with triblock terpolymer side chains.

Nanochannel array plastics with tailored surface chemistry.

The utilization of nanoporous substrates in applications such as selective ion transport, biomolecule separation, seeded templating, and catalysis necessitates the ability to efficiently control pore surface properties. We approached this task by preparing nanoporous polymer monoliths from ABC triblock copolymer precursors that assemble into a cylindrical morphology, where the A block constitutes matrix, C is the removable minor component, and B provides the functionality on the surface of the pores. Polystyrene-polydimethylacrylamide-polylactide (PS-PDMA-PLA) triblock copolymers were prepared by a combination of controlled ring-opening and free-radical polymerization techniques. After selective etching of the PLA cylinders from shear-aligned monoliths, a nanoporous polystyrene matrix containing a hexagonally packed array of hydrophilic, PDMA-coated channels was obtained. Extremely high degrees of alignment and order could be attained, and nanoporous substrates with second-order orientation factors of as high as 0.96 were prepared. PDMA brushes inside the pores were then hydrolyzed in a controlled fashion to introduce a desired number of carboxylic acid groups to the internal pore surface. Carbodiimide mediated couplings with amines were then used to confirm the accessibility of the interior acidic groups and to render materials with different functional content. This modular approach allows for the convenient preparation of functionalized nanoporous materials from a single block copolymer precursor.