Noteworthy Chemistry

January 26, 2015


Blue laser light makes black "nanoflowers" glow red. The distinctive optical and magnetic properties of cobalt oxide (Co3O4) micro- and nanostructures make this material a strong contender in the development of photoelectronic devices. Most recent research on Co3O4, however, has focused on its applications as a catalyst and gas sensor and in lithium-ion batteries.

W. Wang* and J. Xu of Minzu University of China (Beijing) investigated the influence of the shape and size of Co3O4 nanostructures on the properties of the bulk material. These nanostructures include cubes, rods, sheets, and belts; but the current study focuses on flowerlike structures composed of thin plates (see figure).

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Co3O4 nanostructures composed of porous hexagonal plates

The authors used a surfactant-free hydrothermal synthesis to produce hierarchically structured α-Co(OH)2 assemblies that consist of green hexagonal plates a few tens of nanometers thick. The overall assemblies range from 2 to 10 μm along the diagonal direction. Annealing these structures in air converts them to black Co3O4 without changing the flowerlike morphology. High-resolution scanning electron microscope images of single hexagonal plates reveal that they are porous.

When they are excited by a helium–cadmium laser at 325 nm (visible blue light), these flowerlike assemblies have a broad photoluminescence band between 650 and 800 nm (visible red to near-infrared light), with a peak at 710 nm (1.75 eV). This result agrees well with the indirect optical band gap of 1.60 eV observed in Co3O4 thin films. The authors attribute the broad photoluminescence band to the wide range of sizes of the hexagonal plates. (ACS Appl. Mater. Interfaces DOI: 10.1021/am506414n; Nancy McGuire)

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Chemistry is a critical part of emergency response. On January 9, 2014, >10,000 gal of an industrial coal-processing liquid spilled from a Freedom Industries facility into the Elk River, just upstream from the West Virginia American Water (WVAW) treatment plant near Charleston, WV. The Elk River is the sole source of drinking water for more than 300,000 people.

The earliest suggestions that something might be wrong with the water supply came from residents and workers at the treatment plant who reported a foul licorice-like odor coming from the water. That odor persisted for weeks.

At first, the only known chemical in the spill was 4-methylcyclohexanemethanol (4-MCHM), and very little information was available about it. The Material Safety Data Sheet from Eastman Chemical states that 4-MCHM is a skin irritant that can be harmful if ingested. On the day of the spill, WVAW president Jeff McIntyre conceded that the company knew little about the problem it was facing. “We don’t know that the water is not safe,” McIntyre told reporters, “but I can’t say that it is safe.” Water analysis later revealed other hazardous chemicals in the spill.

As Andrew J. Whelton at the University of South Alabama (Mobile) learned the details of the disaster, it was clear to him that the responders were not dealing with the overall chemistry of the spill or its impact on home water supplies. He and colleague Kevin White funded and assembled a team of four students. After a 900-mi trip from Mobile to Charleston, the team arrived on January 17 for 4 intensive days of sampling the water supply at 16 homes and gathering health and additional data. Their objectives were to determine resident behaviors and perceptions following the spill, characterize plumbing system characteristics and chemical levels in homes, and determine the ability of the flushing procedure to reduce chemical levels.

A year later, Whelton and coauthors at South Alabama, Purdue University (West Lafayette, IN), and the Kanawha Charleston Health Department have published this article on their findings and observations about the limitations and implications of their rapid-response efforts. This was the only residential study during the Freedom Industries chemical spill disaster. The article and its supporting information include statistical data and analysis of the material collected during the team’s 4 days in West Virginia; the authors also discuss lessons learned from their experiences.

Although the spill affected about 300,000 people, the first responders did not initiate in-home testing and missed critical information about the chemical concentration and the effects of the contaminated tap water on residents. The maximum concentration of 4-MCHM within the utility system was 3.8 mg/L; when tap water was tested 2 weeks after the spill, the maximum was 420 µg/L. Were the residents initially exposed to concentrations as high as 3.8 mg/L?

Volatilized chemicals released during the recommended flushing procedure caused headaches, nausea, dizziness, and eye inflammation. Whelton’s team modified the flushing process and produced a public service video that detailed the revised process. There are no inhalation data.

Many lessons were learned from the Freedom Industries disaster. Some of the mistakes will not be repeated, at least not in West Virginia. From the onset, according to Whelton, responders must factor the chemistry and science associated with these disasters into the overall plans and actions. (Environ. Sci. Tech. DOI: 10-1021/es5040969 and supporting information; Beth Ashby Mitchell)

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Synthesize asymmetric thiols with phosphoric acid catalysts. Pure asymmetric thiols are useful in industry and academia, but few methods exist for directly synthesizing them. M. R. Monaco, S. Prévost, and B. List* at Max Planck Institute for Coal Research (Mülheim an der Ruhr, Germany) developed a method for preparing enantiopure thiols that is based on opening epoxide rings.

Inspired by a heterodimeric association (1) that they observed between thiobenzoic acid and a chiral phosphoric acid derived from BINOL (see figure), the authors treated epoxides (2) with thiobenzoic acids (3) in the presence of the phosphoric acid chiral catalyst to produce thioesters (4). (BINOL is 1,1′-bi-2-naphthol.) Heating the thioesters isomerizes them to the free thiol (5). 

Heterodimeric association between thiobenzoic acid and chiral phosphoric acid; reaction that produces asymmetric thioesters

In one case, the researchers combined cyclohexene oxide, thiobenzoic acid, and the catalyst under cryogenic conditions (–78 ºC) to produce thioesters with enantiomeric ratios as high as 98:2. Heating the reaction mixture to 40 ºC caused a second reaction that released the free-thiol.

1,2-Hydroxythiols that are protected on the sulfur or oxygen groups can be obtained with this method. Free 1,2-hydroxythiols can be produced by the reaction of O-acyl free thiols with hydrazine. This direct asymmetric preparation of free thiols should be widely applicable in organic chemical synthesis. (J. Am. Chem. Soc. DOI: 10.1021/ja510069w; José C. Barros)

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Improve selectivity by understanding byproduct formation. The key step in the synthesis of a 6-bromo-2-naphthylamine sulfonamide pharmaceutical intermediate is a Semmler–Wolff aromatization. The initial goal of W. Li and co-workers at AbbVie (North Chicago, IL) was to avoid the formation of a naphthylacetamide; this would require the use of a reagent other than acetic anhydride (Ac2O).

After they screened several reaction conditions, the authors replaced Ac2O with 1 M hydrochloric acid in acetic acid, but this led to the formation of ≈14 mol% of a 2-aminotetralone impurity. The mechanism for forming the aminotetralone depends on water, so adding some Ac2O was necessary to remove water and reduce the amount of 2-aminotetralone produced. Acetamide formation was minimized at 3.2 mol% by adding 1.2 equiv Ac2O. The 2.4 mol% of the aminotetralone in the product can be removed by hot filtration. (Org. Process Res. Dev. DOI: 10.1021/op500247h; Will Watson)

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Make ibuprofen in 3 minutes. The continuous-flow technique in organic synthesis has many advantages over batch production, including high energy efficiency, flexible configurations, and high throughput. These merits are particularly desirable in pharmaceutical manufacturing where cost, time, and waste factors must be considered.

D. R. Snead and T. F. Jamison* at MIT (Cambridge, MA) optimized the production of ibuprofen [rac-2-(4-isobutylphenyl)propanoic acid, 1; see figure], a common anti-inflammatory drug, in a continuous-flow reaction sequence. Their scalable protocol consists of three synthesis steps and two workup steps. It assembles ibuprofen from its basic building blocks in 3 min.

Structure of ibuprofen and the reaction sequence used to synthesize it

The authors first modified the route to 1 to achieve high yields with high substrate concentrations under continuous-flow conditions. They also minimized the use of hazardous materials and reagents. They started with the solventless Friedel–Crafts acylation of isobutylbenzene (2) with propionyl chloride (3) in the presence of aluminum chloride to produce aryl ketone 4 in 95% yield. Ketone 4 is then converted to methyl ester 5 via oxidative 1,2-aryl migration mediated by iodine monochloride. Finally, 5 is saponified to yield 6, the sodium salt of 1.

This continuous-flow protocol gives an average yield of >90% for each step. The total residence time for all chemical transformations is only 3 min. The scaled-up procedure produces ibuprofen at a rate of 8.09 g/h, the equivalent of 70.8 kg/year. The apparatus’ footprint is half the size of a standard laboratory fume hood.

Using simple, low-cost, readily available chemicals and reagents, the authors improved the production efficiency for ibuprofen without increasing economic or environmental costs. As an example that takes full advantage of the continuous-flow technique, it should influence the development of practical continuous-flow synthetic protocols for other important active pharmaceutical ingredients. (Angew. Chem., Int. Ed. DOI: 10.1002/anie.201409093; Xin Su)

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High-throughput profiling identifies HIV-1 genomic point mutations. The HIV-1 pandemic is caused by an ever-changing, genetically diverse virus population. This rapid, constant evolution leads to drug resistance and makes virus treatment difficult. Knowing the mutational tolerance of each residue would help in designing antivirus strategies.

R. Sun and colleagues at the University of California, Los Angeles, use a high-throughput genetic approach to learn the impact of individual point mutations on the replication capacity (RC) of HIV-1 strains under experimental conditions. Their single-experimental platform, called quantitative high-resolution genetics (qHRG), combines high-density mutagenesis with next-generation sequencing (NGS). qHRG can identify amino acid residues that are critical for viral replication. It is sensitive enough to quantify the RC of individual virus variants, even within a large population of diverse mutants.

The authors generated mutagenic HIV-1 genomic libraries and monitored the frequency change of each variant with NGS following cell passage. They analyzed approximately 500,000 distinct mutant HIV-1 genomes and evaluated the effects of single point mutations in more than half of the HIV-1 genome on viral replicative capacity.

The RC map of HIV-1 generated by qHRG defined regions that are less supportive to mutations and identified nucleotide changes that are lethal to viral replication. Among other things, the generated data can be used for structural annotation to help in vaccine development and drug-binding site design.

This study represents the first application of qHRG to an entire virus genome. The authors believe that qHRG can be applied to other pathogens under immune or drug pressure to identify genetic elements that contribute to host or drug interactions. (Retrovirology DOI: 10.1186/s12977-014-0124-6; Abigail Druck Shudofsky)

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