Noteworthy Chemistry

May 2, 2011

Use stainless steel to catalyze hydrogenation reactions. The standard way to convert carbohydrate-derived biomass to petrochemicals and fuels is to use acid-catalyzed dehydration followed by metal-catalyzed hydrogenation. These processes are usually conducted under high pressure and temperature under homogeneous or heterogeneous metal or acid catalysis in a 316 stainless steel (316SS) reactor. The 316SS alloy is composed of iron, chromium, nickel, molybdenum, and manganese, and in some cases silicon, phosphorus, or sulfur. It is often considered to be inert because it passivates itself by forming a chromium oxide layer on the surface.

M. Schlaf and co-workers at the University of Guelph (ON) show that a 316SS vessel can be acid-activated to act as a catalyst for hydrogenating oxygenated bio-derived compounds. They exposed glycerol or levulinic acid in an aqueous CF3SO3H solution to 800 psi hydrogen pressure at 250 °C. When glycerol was the substrate, a low concentration of acid (20 mM) catalyzed the formation of mixtures of n-PrOH and i-PrOH. Using excess acid produced only i-PrOH. Continued hydrogenation deoxygenated the alcohols to propylene. Water was a superior solvent to sulfolane for hydrogen uptake.

The deoxygenation of levulinic acid under the same conditions gave a mixture of γ-valerolactone and pentanoic acid in the liquid phase and butane and 1-butene in the headspace. The authors suggest possible reaction cascades for both substrates.

The authors attribute the catalytic properties of 316SS to the presence of mixed chromium oxides leached from the reactor walls, as indicated by the precipitation of Cr(OH)3(H2O)3 when the reaction mixture is treated with base (see figure). No structural damage to the reactor was detected after several reaction cycles. (ACS Catalysis 2011, 1, 355–364; JosÉ C. Barros)

Polymer membranes respond at ambient temperature. Poly(N-isopropylacrylamide) (PNIPAM) is a well-known temperature-sensitive material that undergoes a phase transition at 33 °C. Below this temperature, the polymer absorbs water and becomes greatly enlarged. When heated, it discharges the liquid and shrinks. This unique property has many applications, and more will likely be developed, especially for pharmaceuticals. G. Stoychev, N. Puretskiy, and L. Ionov* at the Leibniz Institute of Polymer Research Dresden (Germany) prepared PNIPAM-based temperature-responsive polymer membranes and investigated their behavior at room temperature.

The two-layer, star-shaped polymer membranes have multiple arms. The first layer, PNIPAM with a small amount of 4-acryloylbenzophenone cross-linker, is coated on an inert substrate. The second layer, biocompatible polycaprolactone, is then applied. The films are stabilized by UV irradiation cross-linking, and yeast cells are applied to the surface.

Above 28 °C, the films are flat, and the cells are exposed. As the temperature decreases, the PNIPAM arms stretch and the PCL arms tend to keep their shape. This causes the arms to bend and encapsulate the cells. Eventually, the membrane resembles a closed bud. Folding can be reversed by raising the temperature. (Soft Matter 2011, 7, 3277–3279; Sally Peng Li)

Imidazo[1,2-a]pyridines may combat drug-resistant tuberculosis. The causative agent of tuberculosis (TB) is an airborne pathogen, Mycobacterium tuberculosis, which is spread by close contact among individuals. Proliferation of this disease has resulted in 14.4 million cases worldwide, based on 2006 estimates (WHO Report 2008. WHO/HTM/TB/2008). Almost 13,000 cases of TB were reported in the United States in 2008 (Pratt, R., et al. MMWR 2009, 58, 249–253). This dilemma is exacerbated by the emergence of several drug-resistant TB strains, including a strain that resists all first- and second-line TB drugs.

M. J. Miller and coauthors at the University of Notre Dame (IN), Eli Lilly (Indianapolis), the National Institutes of Health (Bethesda, MD), and the University of Illinois at Chicago describe a promising way to combat drug-resistant TB that uses the imidazo[1,2-a]pyridine-3-carboxamide scaffold. Their study was based on a series of compounds readily synthesized by the reaction of picoline derivative 1 with ethyl 2-chloroacetoacetate (2) to produce the desired heterocyclic ring system, followed by saponification to produce free acid 3.

EDC-mediated coupling of 3 with benzylamine derivatives produced a series of nine compounds (illustrated by 4 in the figure) for structure–activity relationship (SAR) evaluation. [EDC is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; DMAP is dimethylaminopyridine.] Most of the compounds in this series were produced by varying substituent groups on the phenyl ring of the benzyl substituent. The authors also included a core structure variation by changing the amine substrate to an imidazo[1,2-a]pyrimidine derivative.

In vitro screening of these compounds showed that 6 of the 10 analogues had encouraging submicromolar MIC values against the H37Rv Mtb strain of TB. (MIC is the minimum concentration of an antimicrobial agent that inhibits the growth of the microorganism.)

The potency of these agents against various drug-resistant strains indicates that they inhibit a previously undiscovered mycobacterium target. Also, in vivo evaluation of four of the compounds showed favorable pharmacokinetics, including clearance rates, aqueous solubilities, and oral bioavailabilities. (ACS Med. Chem. Lett. 2011, 2, Article ASAP DOI: 10.1021/ml200036r; W. Jerry Patterson)

Spirocyclize an amino nitrile with a ketone. A spirocyclic imidazolidinone is a key intermediate in the synthesis of a potent, selective glycine transporter type-1 inhibitor. To avoid a lengthy, low-yielding synthesis of this compound, J. P. Graham and co-workers at GlaxoSmithKline (Stevenage, UK) propose a synthetic route in which 4-bromobenzaldehyde is subjected to a Strecker reaction to generate an amino nitrile that then undergoes a spirocyclization reaction with cyclopentanone. Conditions cited in the literature suggest that the reaction could be carried out neat with a catalytic amount of NaOMe.

In practice, a better yield (40%) is obtained by running the reaction in n-butyl alcohol solvent at 80 °C. The product is easily to isolate because it crystallizes on cooling. (Org. Process Res. Dev. 2011, 15, 44–53; Will Watson)

A redox strategy induces solution-based self-assembly and molecular delivery of amphiphilic materials. H. Kim, S.-M. Jeong, and J.-W. Park* at Gwangju Institute of Science and Technology (Korea) examined the redox-switchable assembly of amphiphilic tetraaniline–poly(ethylene glycol) (TAPEG) rod–coil systems. The tetraaniline’s packing behavior (the less compact leucoemeraldine base [LEB, 1] vs the emeraldine base [EB, 2]) depends on the applied electrical potential.

The interconversion between the EB and LEB states in 0.05 wt% solutions containing 0.05 M NaCl occurs when the potential is cycled between 0.2 and –0.5 V. Dynamic light scattering shows larger aggregates (≈120 nm diam) in the LEB form of TAPEG in comparison with smaller ≈75 nm-diam assemblies in the EB state. The aggregation change is illustrated by the cartoons at the bottom of the figure.

The authors note that lateral reduction of the hydrophobic core upon oxidation, not chemical doping, is the origin of these rapid, reversible, electrically induced morphology changes. Dye-release studies show the utility of this strategy for small-molecule encapsulation and delivery. (J. Am. Chem. Soc. 2011, 133, 5206–5209; LaShanda Korley)

Three-component layer-by-layer self-assembly gives functional polymer–nanoparticle capsules. Two-component polyelectrolyte layer-by-layer (LbL) self-assemblies are an economical, versatile technique for making hollow organic capsules. Little work, however, has been done on three-component LbL systems that have inorganic nanoparticles as one of the components. The preparation of polyelectrolyte–nanoparticle hybrid capsules is of interest because they combine the best properties of their organic and inorganic components: The polymer provides flexibility and versatility; and the nanoparticles offer superior electrical, optical, and magnetic properties and maintain the functionalities of the hollow spheres.

W. Yuan, Z. Lu, and C. M. Li* of Nanyang Technological University (Singapore) developed an elaborate three-component LbL self-assembly process for making hollow polyelectrolyte–nanoparticle capsules. A weak polyelectrolyte–nanoparticle blend and another weak polyelectrolyte are the components of the alternating layers. The process parameters were optimized to control the assembly of blend multilayers on a CaCO3 colloidal template without aggregation.

The microcapsules obtained from removing the template cores contain well dispersed nanoparticles with the desired concentration, size, and interparticle spacing. The hybrids exhibit broadly tunable localized surface plasmon resonance and ultrahigh permeability, which are difficult to obtain with other LbL self-assembly processes. (J. Mater. Chem. 2011, 21, 5148–5155; Ben Zhong Tang)

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