Noteworthy Chemistry

March 26, 2012

Precisely control the structures of ionic polymers. Polyelectrolytes have unique structures and physical properties, but controlling the distribution of ionic monomers during their synthesis is difficult. J.-F. Lutz and co-workers at the Charles Sadron Institute (Strasbourg, France) developed a method for preparing polyelectrolytes with controlled ionic concentrations.

Three factors make the authors’ strategy successful:

  • They use a living radical vinyl polymerization technique controlled by nitroxide initiators. The commercial alkoxyamine initiator BlocBuilder-MA (1) provides particularly fine control of styrenic polymerization.
  • Sequential polymer addition controls the structure of the polymer chain. tert-Butyl p-vinylbenzoate (2) is homopolymerized to begin chain growth. After a predetermined time (in this case, 2 h), a substituted maleimide (3, 4, or 5) is added over a second 2 h. (TIPS is triisopropylsilyl.) After the maleimide is consumed, 2 is homopolymerized until high conversion is achieved. The relative lengths of these two components in the polyelectrolyte are controlled by the feed ratio.
  • Chemical modification of the resultant copolymer is essential for obtaining ionic polymers. Hydrolysis of the tert-butyl protecting group in monomer 2 releases the anionic groups. The degree of deprotection controls the ionic concentration.

All reactions were run at 100 °C in bulk or in anisole solvent. (Chem. Commun. 2012, 48, 1517−1519; Sally Peng Li)

Use light to control the viscosity of micelles. Controlling the formation and deformation of micelles with external stimuli is a promising tool for drug delivery and the release of fragrances and flavors. H. Sakai and co-workers at the Tokyo University of Science report that the viscosity of cetyltrimethylammonium bromide (CTAB) micelle solutions can be controlled by photoisomerizing sodium cinnamate.

Using rheological analysis and cryo–transmission electric microscopy observations, the authors characterized an equimolar aqueous CTAB–cinnamate solution (50 mM each) as a wormlike micelle solution. The solution’s zero-shear viscosity was 66.0 Pas. When the solution was irradiated with UV light from a 200-W Hg–Xe lamp, the gel-like solution slowly became liquid as the cis-cinnamate converted to its trans isomer. The viscosity decreased more than 30,000-fold to 2.1 × 10–3 Pas.

A 1H NMR study suggested that in the cis form, the carboxylic acid groups of cinnamate are exposed to a more hydrophilic environment, which turns the wormlike micelles into smaller spherical or rodlike micelles. At the same time, the polar CTA+ ions are forced apart as bulk cis-cinnamate forms within the micelles. (Chem. Lett. 2012, 41, 247–248; Xin Su)

Dimeric abacavir prodrugs may eradicate HIV in the brain. Although highly active antiretroviral therapy decreases HIV viral loads, some virus reservoirs, such as those in the central nervous system, prevent complete elimination of HIV. Drugs cannot attack HIV reservoirs in the brain because they cannot pass through the blood–brain barrier (BBB) and the presence of drug transporters such as P-glycoprotein (P-gp) at the barrier.

J. Chmielewski and coauthors at Purdue University (West Lafayette, IN) and the National Institutes of Health (Research Triangle Park, NC) propose that dimeric prodrugs formed from an antiretroviral agent and a traceless tether could be used to cross the BBB, inhibit P-gp, and regenerate the active molecule in the brain. They chose the reverse transcriptase inhibitor abacavir (1) as the antiretroviral, disulfide moieties as the tethers, and ester linkages to join the components.

Using standard esterification methods, the authors prepared three prodrugs (24) by the reaction of the tethers with 1. The compounds, which differ only by the number of methyl groups in the tethers, were first evaluated for P-gp inhibition. Prodrug 4 showed the best results.

The compounds were next tested against endogenous esterases to model stability under human plasma conditions. The two methyl groups on each end of 4 accounted for its high stability toward the esterases. An antiviral activity assay indicated that the effectiveness of all three prodrugs was the result of the decomposition of the dimers into 1. The authors believe that this strategy may lead to a platform technology that can allow other drugs cross the BBB. (J. Am. Chem. Soc. 2012, 134, 2976–2980; JosÉ C. Barros)

Use a vanadium catalyst to alkylate an imidazopyridazine. During the synthesis of a Janus kinase 2 inhibitor, D. Mitchell and co-workers at Eli Lilly (Indianapolis) initially installed a morpholinomethyl group on an imidazopyridazine substrate by using a Minisci free-radical alkylation with N-phthaloylglycine followed by hydrolysis of the phthalimide group and bisalkylation–cyclization with (ClCH2CH2)2O. This method, however, led to throughput problems and low yields because of the low selectivity of the Minisci reaction.

The authors developed an alternative procedure: an electrophilic aromatic substitution reaction with an iminium ion. They investigated the use of VO(acac)2-catalyzed alkylation with N-methylmorpholine N-oxide, based on reports of similar Mannich reactions on phenols and naphthols. EtOH was a good solvent for the reactions and provided a simple workup procedure: adding water and filtering the product. A yield of 68% of 99% pure product was obtained on a 1-kg scale. (Org. Process Res. Dev. 2012, 16, 70–81; Will Watson)

Make renewable gas-barrier and flame-retardant coatings. J. C. Grunlan and co-workers at Texas A&M University (College Station) prepared anionic montmorillonite clay–chitosan nanobricks via layer-by-layer (LbL) assembly and investigated their gas barrier properties and flame retardancy in coating applications. LbL clay–chitosan grows linearly to form thick layers when assembled at pH 6 when the chitosan amines are deprotonated (A in the figure) or thin layers at pH 3 when the chitosan is fully ionized (B). Clay loading is also pH-dependent; clay content is higher at pH 6 because of surface roughness.

The authors measured the oxygen barrier of poly(lactic acid) (PLA) films coated with clay–chitosan nanobricks. With a bilayer clay–chitosan coating containing ≈90% clay, the oxygen permeability of PLA, 14.6 x 10–16 cm3·cm/(cm2·s·Pa), was comparable to that of higher-barrier poly(ethylene terephthalate) film [17.3 x 10–16 cm3·cm/(cm2·s·Pa)].

Conformal clay–chitosan coatings were also applied to polyurethane foams. When the foams were ignited with a butane torch, the pH 6–assembled coating extinguished the flame in ≈30 s, preserved the original shape, and protected the foam structure and flexibility beneath the char. The peak heat-release rate was reduced by 52% compared with the control polyurethane foam. The authors’ method produces oxygen-barrier and flame-retardant coatings from renewable resources by controlling clay loading and deposition. (ACS Appl. Mater. Interfaces 2012, 4, Article ASAP DOI: 10.1021/am2017915; LaShanda Korley)

Here’s an improved synthesis of silicon nitride nanocrystals. Interest in 1-D silicon nitride (Si3N4) nanomaterials is growing because their chemical and thermal stability is greater than that of their elemental silicon counterparts. Si3N4 nanomaterials, however, are plagued by many synthetic challenges, including the use of hazardous reagents (e.g., NaN3), hard-to-separate intermediate products, polydispersity, and polymorph formation.

M. Dasog and J. Veinot at the University of Alberta (Edmonton) overcame these shortcomings and developed a method to produce highly luminescent Si3N4 nanoparticles. They began with a base-catalyzed sol–gel reaction to obtain 10–250-nm silica particles, which they then mixed with urea and magnesium and heated to 500 °C. Urea and magnesium form Mg3N2, which at temperatures >300 °C undergoes a solid-state metathesis reaction with SiO2 to form Si3N4 and MgO. The reaction proceeds to completion with smaller silica nanoparticles; larger ones do not react completely. After washing the products with HCl to remove soluble byproducts and etching them with a mixture of HF, EtOH, and water, the authors characterized the product as β-Si3N4, with no other polymorphs present.

High-resolution transmission electron microscopy measurements showed that the product’s particle size is 8.8 ± 0.8 nm. The nitrogen atoms are primarily on the particle surfaces, as shown by Fourier transform IR. Upon excitation at 325 nm, the β-Si3N4 nanocrystals emit blue light (λmax 417 nm), with a quantum yield in toluene of 10%. Although the exact origin of the luminescence is unknown, the nanoparticles may have potential applications such as light-emitting diodes and photovoltaics.

Although the researchers overcame many of the synthetic problems for β-Si3N4 nanoparticles (e.g., polymorph growth, polydispersity, and separating intermediates), their scheme still requires the use of hazardous reagents such as HCl and HF. (Chem. Commun. 2012, 48, 3760-3762; Gary A. Baker)

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