Noteworthy Chemistry

March 7, 2011

Polysulfone–nanotube mats have antibacterial properties. Antibacterial mats have several applications, from biomedical implant coatings to prevent infections to reducing fouling on ship hulls. J. D. Schiffman* and M. Elimelech at Yale University (Hartford, CT) probed the antibacterial efficacy of electrospun polysulfone mats impregnated with purified single-walled carbon nanotubes (SWNTs) at 0.1, 0.5, and 1 wt%. They produced free-standing, flexible electrospun mats that contained dispersed bundles of SWNTs and displayed a slightly roughened surface morphology. The fiber diameter varied with SWNT loading, increasing from 159.5 ± 71.5 nm with no SWNTs to 293.14 ± 115.0 nm at 1 wt% loading.

Incorporating the SWNTs within the polysulfone nanofibers increased their degradation temperatures. When they were placed in contact with Escherichia coli bacteria, SWNT-containing polysulfone electrospun mats enhanced the bacterial inactivation rate compared with mats that did not contain SWNTs. Mats with 1% SWNT loading inactivated ~76% of the bacteria after 1 h and flattened the inactivated cells. The 1 wt% SWNT mats exhibited antibacterial activity comparable with that of a commercial filter fully coated with SWNTs. (ACS Appl. Mater. Interfaces 2011, 3, 462–468; LaShanda Korley)

Here’s a new route to an ancient dye. Indigo (1) is one of the oldest dyes used in textile dyeing and printing. Egyptians used natural indigo at least 4000 years ago.

The main manufacturing process for indigo was developed in 1901 and is still in use worldwide. In it, sodium N-phenylglycinate is cyclized with strong base, followed by oxidative dimerization to produce indigo. An alternative process, developed in the 1940s, uses PhNH2, HCHO, and HCN as starting materials.

These methods require multiple reaction steps and harsh conditions. Y. Yamamoto and coauthors at Mitsui Chemicals (Chiba, Japan) and the Tokyo Institute of Technology developed a one-step synthesis of indigo from readily available indole (2).

The authors first optimized the metal-complex catalyst used to oxidize indole to indigo with cumene hydroperoxide (CHP). Of the many metals tried, only molybdenum, titanium, ruthenium, and boron complexes produce the target molecule. Mo(CO)6 and molybdenum naphthenate give the best results; the molybdenum oxidation state does not influence the yields appreciably. The authors believe that molybdenum is oxidized in situ to a high oxidation state and that the resulting complex is the active species.

Solvent screening showed that cumene, heptane, or alcohols give the best results. CHP is a better oxidant than other hydroperoxides, and ≥ 2 equiv of CHP is needed. The first equivalent converts indole to indoxyl (3), in equilibrium with 3-oxyindole (4), and the second oxidizes 4 to indigo. Carboxylic acid additives improve the yields. The authors’ proposed reaction mechanism is shown in the figure.

Under the optimized conditions (t-BuOH and cumene solvents, 0.1 mol% molybdenum naphthenate catalyst, and AcOH), the preparation of indigo from 100 g indole gives an 80% yield after the product gradually precipitates and is filtered. All of the materials used are inexpensive, and the authors imply that the process can be used on an industrial scale. (Bull. Chem. Soc. Jpn. 2011, 84, 82–89; JosÉ C. Barros)

Use enzyme-catalyzed reaction products in microprinting. Microcontact printing is a lithographical technique in which images are formed by applying polymer templates in the micrometer range. In a recent advance in this field, patterns are printed with the assistance of an enzyme instead of ink. In this procedure, an enzyme is “written” on the surface and leaves an image that is copied onto the final substrate.

J. Tian and W. Shen* at Monash University (Melbourne, Australia) extended this concept by causing the developed image to be the product of an enzyme-initiated reaction instead of the enzyme itself. The image is specific to the enzyme used.

The chromogenic reagent 3,3′,5,5′-tetramethylbenzidine (TMB) is oxidized by peroxidase enzymes such as horseradish peroxidase to display a characteristic blue color. The enzyme is first dispersed on a nitrocellulose template. When TMB solution is added, the characteristic blue color appears on the surface and can be transferred onto a TMB-pretreated substrate. The recovered template can be used for several cycles, but the color decays gradually. More investigation is needed to preserve enzyme activity and maintain the unique color in image processing. (Chem. Commun. 2011, 47, 1583–1585; Sally Peng Li)

Bis(tetrahydrofuran) derivatives effectively inhibit HIV-1 protease. The bis(tetrahydrofuran) (BTF) scaffold is a useful structural element for designing HIV-1 protease inhibitor drugs such as darunavir (1). Structural studies of this type of drug molecule suggest that the BTF ligand participates in a network of hydrogen-bonding interactions with the protein backbone of HIV-1 protease.

Earlier work by A. K. Ghosh and coauthors at Purdue University (West Lafayette, IN), Georgia State University (Atlanta), Kumamoto University Graduate School of Medical and Pharmaceutical Sciences (Japan), and the National Institutes of Health (Bethesda, MD) indicated that incorporating alkoxy substituents at the C4-position of the BTF moiety can lead to useful interactions with the protease backbone. Based on this strategy, they designed a stereoselective synthesis that leads to the desired structural element via a [2,3]-sigmatropic rearrangement as a key step. The figure shows how the methoxy-substituent is incorporated at C4.

The authors formed the BTF ligand in several steps, starting with olefinic ester 2 that was prepared in multigram quantities. Compound 2 is converted in two steps to 3 to provide a platform for the key [2,3]-sigmatropic rearrangement to diastereomer 4 as the only product. The hydroxyl group in 4 establishes an important functional site for introducing C4 derivatives (5). Additional steps provide desired BTF scaffold 6 with methoxy substitution at C4.

The final sequence of this synthesis produces a series of protease inhibitor candidates. In the route that leads to the most active structure, 6 is activated with p-nitrophenyl chloroformate to form carbonate 7, which is treated with amine 8 to provide target inhibitor 9.

All of the inhibitors prepared in this study are potent enzyme inhibitors. However, 9 is the most active with an enzyme inhibitory activity (Ki) of 0.0029 nM and an antiviral activity (IC50) of 2.4 nM. This is a substantial improvement over the activity of darunavir, which has a Ki of 0.016 nM.

The results suggest that specific C4-alkoxy substitution in these inhibitors enhances ligand-binding site interactions in the HIV-1 protease active site. A protein-ligand X-ray analysis of compound 9–bound HIV-1 protease shows extensive interactions of the inhibitor in the active site of HIV-1 protease. (ACS Med. Chem. Lett. 2011, 2, Article ASAP DOI: 10.1021/ml100289m; W. Jerry Patterson)

What data should you use to optimize a hydrogenation reaction? B. J. Littler*, A. R. Looker, and T. A. Blythe at Vertex Pharmaceuticals (San Diego and Cambridge, MA) conducted an optimization study to overcome problems encountered during the scale-up of a nitro group hydrogenation. They used heat flow, gas uptake, stirring rate, and real-time mid-spectrum IR (mid-IR) data to study the reaction.

Mid-IR allowed the authors to track the levels of various reaction components, such as the starting nitro compound, the hydroxylamine intermediate, and the aniline product. The most exothermic step in the process is the reduction of the nitro group to form the hydroxylamine intermediate. The data made it possible to optimize the catalyst loading and investigate the stirring rate. At 200 rpm, the reaction was sluggish, but it speeded up when the stirring rate was increased to 500 rpm. This means that an exotherm in the pilot plant could be controlled by slowing or turning off the stirrer. (Org. Process Res. Dev. 2010, 14, 1512–1517; Will Watson)

Triptycene polyimides show unusually low refractive indices. Incorporating the triptycene moiety into the backbone of polyimide polymers produces several useful properties. Despite their rigid aromatic character, triptycene units enhance polymers’ solubility—an important feature for polyimide processing and film formation.

Triptycene groups help lower polymer refractive indices, which correlate with reduced dielectric constants. The highly aromatic character of such polyimides results in very high thermal stabilities. Polyimides that display this combination of features should be useful in optical and electronic applications.

S. A. Sydlik, Z. Chen, and T. M. Swager* at MIT (Cambridge, MA) devised a route to triptycene-based polyimides that is based on condensation polymerization of commercial dianhydrides with 2,6-diaminotriptycene or extended iptycenediamines. These triptycene-based comonomers had not been incorporated into polyimides previously.

The preparation of 2,6-diaminotriptycene 1 was based on an earlier synthesis (Klanderman, B. H.; Perkins, W. C. J. Org. Chem. 1969, 34, 630–633; Chen, Z.; Swager, T. M. Macromolecules 2008, 41, 6880–6885). The authors optimized it to give significantly higher yields. Their method includes modifying triptycene nitration to allow recovery of pure 2,6-dinitrotriptycene, which is reduced almost quantitatively to monomer 1.

The extended iptycene-based diamine monomer was prepared by the reaction of 2,6-diaminoanthracene with 1,4-dihydro-1,4-epoxynaphthalene (2) to produce Diels–Alder adduct 3. Simple HClO4-promoted dehydration of 3 gives iptycenediamine 4.

The authors devised two polymerization routes that lead to a series of fully imidized polymers. Method 1 is a conventional two-step polycondensation that uses pyridine and Ac2O as dehydrating agents in the second step to facilitate ring closure. Polymer 5 illustrates this method. Polymer 6 is prepared by alternative method 2, in which an acid catalyst is added during initial polymerization, and base is added during the imidization step.

Method 2 gives the highest molecular weight polymers (Mn 15–21 kDa), although polymer yields from both methods are about the same. All polyimides formed by both methods are soluble in DMF and DMSO; most structures were also quite soluble in toluene and xylenes, which are good solvents for spin-coating applications.

Refractive indices of the polymers are in the range 1.19–1.69. The refractive index value of 1.19 corresponds to a calculated dielectric constant as low as 1.42. The authors attribute this result to the presence of fluorine groups and an increase in nanoporosity resulting from the extended triptycene structure (polymer 5). Polymeric insulating materials with dielectric constants <2.0 are sought for a variety of electronic applications.

The authors emphasize the qualities of the triptycene structures, including their free volume, which enhances solubility and retains the rigidity of a fully aromatic polymer backbone. The increased free volume creates molecular-scale pores in the material that translate to much lower dielectric constants that are attributed to the air in the pores. (Macromolecules 2011, 44, 976–980; W. Jerry Patterson)

Visually evaluate ionic liquid–cytochrome c biocompatibility. Ionic liquids are promising “designer” solvents for many biotech applications that range from use in enzyme catalysis and lignocellulose pretreatment to reaction solvents, electrolytes, and components of biosensors and other biomedical devices. Nevertheless, because of the almost unlimited molecular diversity available for these solvents, it may be difficult to get comprehensive, reliable information about their compatibility with biomolecules. This deficiency hampers the hunt for superior ionic liquids for biotech applications.

A team led by G. A. Baker and coauthors at Oak Ridge National Laboratory (TN), Savannah State University (GA), the Indian Institute of Technology Delhi (New Delhi), and the State University of New York (Buffalo) developed an easy, effective method for ranking aqueous-phase ions for biocompatibility. They used fluorescence energy transfer (FET) “dequenching” as a rudimentary “ruler” to determine the relative distance between the heme group of yeast cytochrome c and a rhodamine fluorescent reporter conjugated to a known site in the protein. During protein unfolding, the probe’s fluorescence intensity increases exponentially as it moves farther away from the heme quencher to display a visual account of the degree of protein unfolding.

The researchers studied this effect in various ionic liquid mixtures with water and showed that the ionic liquid’s tendency to promote protein unfolding is strongly linked to the choice of anion. Moreover, changes in fluorescence intensity for the labeled cytochrome c can be viewed by the unaided eye by using only an inexpensive handheld UV lamp for excitation. This technique offers a simple tool for naked-eye screening of biocompatible ion formulations in hydrated ionic liquids. (Phys. Chem. Chem. Phys. 2011, 13, 3642–3644; Ben Zhong Tang)

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