Size Selective Corona Interactions from Self-Assembled Rosette and Single-Walled Carbon Nanotubes.

Nanoparticle corona phases, especially those surrounding anisotropic particles, are central to determining their catalytic, molecular recognition, and interfacial properties. It remains a longstanding challenge to chemically synthesize and control such phases at the nanoparticle surface. In this work, the supramolecular chemistry of rosette nanotubes (RNTs), well-defined hierarchically self-assembled nanostructures formed from heteroaromatic bicyclic bases, is used to create molecularly precise and continuous corona phases on single-walled carbon nanotubes (SWCNTs). These RNT-SWCNT (RS) complexes exhibit the lowest solvent-exposed surface area (147.8 ± 60 m-1 ) measured to date due to its regular structure. Through Raman spectroscopy, molecular-scale control of the free volume is also observed between the two annular structures and the effects of confined water. SWCNT photoluminescence (PL) within the RNT is also modulated considerably as a function of their diameter and chirality, especially for the (11, 1) species, where a PL increase compared to other species can be attributed to their chiral angle and the RNT's inward facing electron densities. In summary, RNT chemistry is extended to the problem of chemically defining both the exterior and interior corona interfaces of an encapsulated particle, thereby opening the door to precision control of core-shell nanoparticle interfaces.

Advanced Continuous Flow Platform for On-Demand Pharmaceutical Manufacturing.

As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufacturing including the large production footprint and lengthy time-scale, we previously reported a refrigerator-sized continuous flow system for the on-demand production of essential medicines. Building on this technology, herein we report a second-generation, reconfigurable and 25 % smaller (by volume) continuous flow pharmaceutical manufacturing platform featuring advances in reaction and purification equipment. Consisting of two compact [0.7 (L)×0.5 (D)×1.3 m (H)] stand-alone units for synthesis and purification/formulation processes, the capabilities of this automated system are demonstrated with the synthesis of nicardipine hydrochloride and the production of concentrated liquid doses of ciprofloxacin hydrochloride, neostigmine methylsulfate and rufinamide that meet US Pharmacopeia standards.

Towards More Efficient, Greener Syntheses through Flow Chemistry.

Technological advances have an important role in the design of greener synthetic processes. In this Personal Account, we describe a wide range of thermal, photochemical, catalytic, and biphasic chemical transformations examined by our group. Each of these demonstrate how the merits of a continuous flow synthesis platform can align with some of the goals put forth by the Twelve Principles of Green Chemistry. In particular, we illustrate the potential for improved reaction efficiency in terms of atom economy, product yield and reaction rates, the ability to design synthetic process with chemical and solvent waste reduction in mind as well as highlight the benefits of the real-time monitoring capabilities in flow for highly controlled synthetic output.

On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system.

Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.

Rosette Nanotubes Alter IgE-Mediated Degranulation in the Rat Basophilic Leukemia (RBL)-2H3 Cell Line.

In this study, the effects of rosette nanotube (RNT) exposure on immune cell viability and function were investigated in vitro using the rat basophilic leukemia (RBL)-2H3 cell line. RBL-2H3 viability was decreased in a dose- and time-dependent manner after lysine-functionalized RNT (K-RNT) exposure. In addition, K-RNTs had a significant effect on RBL-2H3 degranulation. When K-RNT exposure was concurrent with IgE sensitization, 50 and 100 mg l(-1) K-RNTs elicited a heightened degranulatory response compared with IgE alone. Exposure to 50 and 100 mg l(-1) K-RNTs also caused degranulation in RBL-2H3 cells not sensitized with IgE (0 ng ml(-1) IgE). Furthermore, in cells preexposed to K-RNTs for 2 h and subsequently washed, sensitized, and stimulated with IgE, a potentiated degranulatory response was observed. Using confocal laser scanning microscopy and a fluorescein isothiocyanate (FITC)-functionalized RNT construct (termed FITC(1)/TBL(19)-RNT), we demonstrated a strong and direct affiliation between RNTs and RBL-2H3 cell membranes. We also demonstrated cellular internalization of RNTs after 2 h of exposure. Together, these data demonstrate that RNTs may affiliate with the cellular membrane of RBL-2H3 cells and can be internalized. These interactions can affect viability and alter the ability of these cells to elicit IgE-FcεR mediated degranulation.

Chiromers: conformation-driven mirror-image supramolecular chirality isomerism identified in a new class of helical rosette nanotubes.

Rosette nanotubes are biologically inspired nanostructures, formed through the hierarchical organization of a hybrid DNA base analogue (G∧C), which features hydrogen-bonding arrays of guanine and cytosine. Several twin-G∧C motifs functionalized with chiral moieties, which undergo a self-assembly process under methanolic and aqueous conditions to produce helical rosette nanotubes (RNTs), were synthesized and characterized. The built-in molecular chirality in the twin-G∧C building blocks led to the supramolecular chirality exhibited by the RNTs, as evidenced by the CD activity. Depending on the motifs and environmental conditions, mirror-image supramolecular chirality due to absolute molecular chirality, solvent-induced and structure-dependent supramolecular chirality inversion, and pH-controlled chiroptical switching were observed.

Synthesis of N-substituted pyrido[4,3-d]pyrimidines for the large-scale production of self-assembled rosettes and nanotubes.

N-substituted pyrido[4,3-d]pyrimidines are heterocycles which exhibit the asymmetric hydrogen bonding codes of both guanine and cytosine at 60° angles to each other, such that the molecules self-organize unambiguously into a cyclic hexamer, assembled via 18 intermolecular hydrogen bonds. The synthesis is straightforward and can be concluded in six steps from the commercially available malononitrile dimer. X-ray crystallographic analysis of the supermacrocyclic structure shows an undulating disk with a ca. 10.5 Å cavity, the centers of which do not overlap sufficiently to describe a channel in the solid state. However, AFM, SEM, and TEM imaging in solution reveals the formation of 1D nanostructures in agreement with their self-assembly into rosette supermacrocycles, which then stack linearly to form rosette nanotubes.

Novel injectable biomimetic hydrogels with carbon nanofibers and self assembled rosette nanotubes for myocardial applications.

The objective of the present in vitro study was to investigate cardiomyocyte functions, specifically their adhesion and proliferation, on injectable scaffolds containing RNT (rosette nanotubes) and CNF (carbon nanofibers) in a pHEMA (poly(2-hydroxyethyl methacrylate)) hydrogel to determine their potential for myocardial tissue engineering applications. RNTs are novel biocompatible nanomaterials assembled from synthetic analogs of DNA bases guanine and cytosine that self-assemble within minutes when placed in aqueous solutions at body temperatures. These materials could potentially improve cardiomyocyte functions and solidification time of pHEMA and CNF composites. Because heart tissue is conductive, CNFs were added to pHEMA to increase the composite's conductivity. Our results showed that cardiomyocyte density increased after 4 h, 1 day, and 3 days with greater amounts of CNFs and greater amounts of RNTs in pHEMA (up to 10 mg mL(-1) CNFs and 0.05 mg mL(-1) RNTs). Factors that may have increased cardiomyocyte functions include greater wettability, conductivity, and an increase in surface nanoroughness with greater amounts of CNFs and RNTs. In effect, contact angles measured on the surface of the composites decreased while the conductivity and surface roughness increased as CNFs and RNTs content increased. Lastly, the ultimate tensile modulus decreased for composites with greater amounts of CNFs. In summary, the properties of these injectable composites make them promising candidates for myocardial tissue engineering applications and should be further studied.

Water-soluble J-type rosette nanotubes with giant molar ellipticity.

A new self-assembling tricyclic module (×K1) featuring the Watson-Crick H-bonding arrays of guanine and cytosine fused to an internal pyridine ring was synthesized. When dissolved in water at room temperature, this module rapidly self-assembles into hexameric rosettes, which then stack to form J-type rosette nanotubes (RNTs) with increased inner/outer diameters and the largest molar ellipticity ever reported (4 × 10(6) deg·M(-1)·m(-1)). Using a combination of imaging and spectroscopic techniques we established the structure of ×K1-RNT and have shown that the extended π system of the self-assembling module resulted in a new family of J-type RNTs with enhanced intermodular electronic communication.

Synthesis of a tetracyclic G∧C scaffold for the assembly of rosette nanotubes with 1.7 nm inner diameter.

The synthesis of a tetracyclic self-complementary molecule 4 for self-assembly into rosette nanotubes is presented. This new heterocycle has a core structure containing two pyrido[2,3-d]pyrimidine molecules fused together and features the Watson-Crick hydrogen bond donor-acceptor arrays of both guanine (G) and cytosine (C). Current methods to synthesize pyrido[2,3-d]pyrimidines require harsh conditions and long reaction times and result usually in low product yields. This is particularly problematic for the direct incorporation of functional groups that cannot withstand these conditions. Here, we present an efficient approach to access the multifunctional pyrido[2,3-d]pyrimidine intermediate 2 under relatively mild conditions using three regioselective S(N)Ar reactions at C2, C4, and C7 on the trichloro compound 1. The electron-withdrawing group and amino functionalities on 2 are then used as a handle to install the third and fourth rings of 4 using a Friedländer-type condensation followed by mixed urea synthesis and cyclization.

Progress toward the total synthesis of (±)-havellockate.

Havellockate (1) was isolated from the soft coral Sinularia granosa located on the Havellock island in the Indian Ocean. This highly compact and polyoxygenated marine diterpene bears a cis-fused hydrindane core that contains eight stereogenic centers as well as a spiro-lactone. To the best of our knowledge, no syntheses of 1 have been reported yet. Herein, we describe the synthesis of the all-carbon framework of havellockate (1) in 18 chemical operations. Our approach highlights the efficiency and utility of the hydroxy-directed Diels-Alder (HDDA) reaction to quickly access the cis-fused hydrindane core and securing the correct stereochemistry at C6 and C7. Moreover, six of the eight stereogenic centers have been installed in the correct stereochemistry.

Rosette nanotubes with 1.4 nm inner diameter from a tricyclic variant of the Lehn-Mascal G--C base.

A new strategy to access rosette nanotubes with increased inner diameter is presented and demonstrated through the synthesis and self-assembly studies of a tricyclic variant of the Lehn-Mascal G--C base.

Synthesis, properties, and mechanistic insight into the self-assembly of a lamellar fibrous superstructure from a synthetically simple discotic molecule.

The discotic molecule 4-chloro-2,6-bis(octadecylamino)-pyrimidine-5-carbaldehyde, displays gelation behavior in dodecane, heptane, chloroform, and dichloromethane. The aggregation behavior of this material was studied by dynamic light scattering, differential scanning calorimetry, scanning electron microscopy, polarized optical microscopy, small-angle X-ray diffraction, and wide-angle X-ray diffraction techniques. Combined with molecular modeling calculations, Fourier transform infrared, and 1H NMR studies, we propose a mechanism for the self-assembly of this fibrous lamellar architecture. Notably, we have shown that the fibers grow via stacking interactions along their main axis, via hydrogen bonding along their short axis, and via van der Waals interactions (lamellae) along the third axis. This type of morphology is desirable since it provides an opportunity to synthetically control and optimize mechanical, electrical, optical, and transport properties along the length of the fiber.

A regioselective approach to trisubstituted 2 (or 6)-arylaminopyrimidine-5-carbaldehydes and their application in the synthesis of structurally and electronically unique GlambdaC base precursors.

An efficient regioselective synthesis of trisubstituted 2(or 6)-arylaminopyrimidine-5-carbaldehydes has been developed via an S(N)Ar reaction of 2,4,6-trichloropyrimidine-5-carbaldehyde with aniline, methylamine, and alkoxide nucleophiles using a combination of phase-transfer catalysis and more traditional SNAr reaction conditions. We demonstrate that in a few synthetic steps, highly functionalized fused-bicyclic pyrimidine substrates can be accessed from the trisubstituted 2-arylaminopyrimidine-5-carbaldehydes. Furthermore, these fused-bicyclic compounds are readily derivatized using the Suzuki cross-coupling reaction to generate electronically and structurally unique GlambdaC base precursors.

Enantioselective synthesis of bicyclo[6.1.0]nonane-9-carboxylic acids via Me2AlOTf-promoted intramolecular Friedel-Crafts alkylation of arenes with the gamma-lactone moiety of 3-oxabicyclo[3.1.0]hexan-2-ones.

A strategy to rapidly assemble enantiomerically pure bicyclo[6.1.0]nonane-9-carboxylic acids via Me2AlOTf-promoted intramolecular Friedel-Crafts alkylation of tethered pi-nucleophiles with the gamma-lactone moiety of 3-oxabicyclo[3.1.0]hexan-2-ones is described. The approach begins with the enantioselective synthesis of 3-oxabicyclo[3.1.0]hexan-2-ones bearing a tethered pi-nucleophile at the 6-position by intramolecular Rh(II)-catalyzed cyclopropanation of allylic diazoacetates, prepared from the corresponding (Z)-allylic alcohols. Me2AlOTf-induced intramolecular Friedel-Crafts cyclization provides medium-sized carbocycles and heterocycles in high yields without requiring high-dilution or slow substrate addition techniques. The scope and limitations of this synthetic methodology are presented.