Noteworthy Chemistry

May 12, 2014


Reveal latent fingerprints with Nile blue A. Latent fingerprints (LFPs) are important direct forensic evidence for solving crimes and convicting criminals. Many methods exist for detecting LFPs, but chemists and forensic scientists want to develop more efficient techniques with improved sensitivity and contrast.

A method for developing latent fingerprints by aggregation-induced emission was previously described in Noteworthy Chemistry. Now S. W. Lewis and coauthors at Curtin University (Perth, Australia) and Australian Federal Police Forensics (Canberra) report a protocol for imaging LTPs that uses Nile blue A (1), an inexpensive dye.

Proposed mechanism of Nile blue A hydrolysis to Nile red

Nile blue A is an alkaline phenoxazine compound; it hydrolyzes spontaneously to produce the phenoxazone Nile red (2). The authors’ proposed mechanism for this transformation is shown in the figure. When these dyes are used as staining reagents, Nile blue A has an affinity toward acidic residues, whereas Nile red binds to neutral lipids.

The authors treated LFPs on white paper with Nile blue reagent, a standard aqueous solution of Nile blue A. After the FTPs were developed, a faint blue impression could be seen with the naked eye under ambient light. When the LFPs were irradiated at 505 nm and viewed through an orange filter, they photoluminesced strongly; and the visible area and resolution of the LTPs improved significantly. Because LFP residues consist mostly of sebaceous lipids, the authors attribute the enhancement to the lipophilicity of Nile red.

In addition to porous surfaces such as paper, the authors tested Nile blue A on nonporous surfaces, including plastics, ceramics, and glass. In all three cases, LFPs were satisfactorily revealed when the photoluminescence method was used.

LFPs on the adhesive side of electrical tape can be detected by a modified method. Fingerprints appear as blue, non-photoluminescent impressions against a highly photoluminescent background. The authors believe that this effect is the result of the red component partitioning into the adhesive and the blue dye interacting with the LFPs. (Chem. Commun. 2014, 50, 3341–3343; Xin Su)

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How best to test N-bromosuccinimide’s reactivity toward solvents? N-bromosuccinimide (NBS) is a widely used brominating agent in organic synthesis, but unanticipated exothermic reactions of NBS with solvents have been reported. S. Shimizu*, Y. Imamura, and T. Ueki at Shionogi & Co. (Hyogo, Japan) studied the reactivity of NBS with a range of common solvents (see box).

The authors initially tested NBS’s reactivity with differential scanning calorimetry (DSC). They found that pinholes can form in the gold-plated DSC test cells and allow the sample to come into contact with the underlying copper or nickel. This concern led to the selection of an advanced reactive system screening tool (ARSST) for the investigation. ARSST uses a glass cell and a poly(tetrafluoroethylene)-coated thermocouple. In addition to NBS, the authors tested another brominating agent, 1,3-dibromo-5,5-dimethylhydantoin (DBDMH).

The authors recommend acetonitrile, dichloromethane, and ethyl acetate as solvents to use with NBS because they showed no significant incompatibility with the reagent. DBDMH behaved similarly to NBS toward the solvents, but with increased activity because it contains two bromine atoms. (Org. Process Res. Dev. 2014, 18, 354–358; Will Watson)

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These small molecules block the entry of fatal disease viruses. Severe acute respiratory syndrome coronavirus (SARS-CoV), Ebola virus (EBOV), Hendra virus (HeV), and Nipah virus (NiV) are infectious zoonotic viruses that cause severe and often deadly diseases. These enveloped viruses deliver their genomes to cells after they fuse with the host cell membrane. For entry and infection, the viruses require cathepsin L (catL), a host intracellular lysosomal protease that processes and cleaves the viral envelope glycoproteins, activating them for membrane fusion.

The lack of effective vaccines or therapies for these highly virulent viruses led H. A. Elshabrawy and colleagues at the University of Illinois at Chicago, the Uniformed Services University (Bethesda, MD), and Cairo University (Egypt) to seek a broad-spectrum antiviral drug that would inhibit infections. They used a fluorescence resonance energy transfer (FRET)–based high-throughput screening assay (HTSA) to identify lead compounds that could prevent viral entry into cells by blocking CatL viral glycoprotein cleavage and maintain its critical host protease functions. They identified a noncytotoxic candidate molecule 1 and its derivative 2(see figure) that inhibit the cleavage of peptides derived from all four viruses in a dose-dependent manner with only minimal cleavage inhibition of the host peptide control. 

The compounds also prevent the viruses’ entry into mammalian cells. Compound 2 inhibits SARS-CoV and EBOV better than parent compound 1. Additional enzymatic studies based on Michaelis–Menten kinetics suggest that 1 is a mixed inhibitor of CatL activity.

These small molecules specifically inhibit the entry of viruses that require CatL cleavage for fusion with target cells by selectively blocking CatL-mediated cleavage of viral glycoproteins. The authors’ screening approach selects for compounds that do not directly block CatL and therefore do not prevent processing of host protein substrates. The molecules can be optimized and developed into broad-spectrum antivirals that prevent the entry of the pathogenic viruses with minimal side effects. (J. Virol. 2014, 88, 4353–4365; Abigail Druck Shudofsky)

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Make nanofiber mats by blow-spinning. Nanofiber mats and scaffolds have many biomedical applications, including drug delivery, wound dressings, tissue engineering, and enzyme immobilization. Nanofibers are usually made by electrospinning, but this process requires specialized equipment, high voltages, and electrically conductive targets.

P. Kofinas and coauthors at the University of Maryland (College Park), the US Food and Drug Administration (Silver Spring, MD), Children’s National Medical Center (Washington, DC), and the National Institute of Standards and Technology (Gaithersburg, MD) explored a blow-spinning technique for generating conformal fibrous mats from poly(lactic acid-co-glycolic acid) (PLGA) solutions. Their method rapidly produces PLGA mats with ≈475-nm diameter nanofibers when the PLGA solution concentration exceeds the overlap concentration. The method uses simple tools: a commercial airbrush and compressed CO2.

The mechanical properties of the solution-blown PLGA fibers are suitable for tissue engineering applications. Degradation studies in phosphate-buffered saline solution over 42 days showed a loss in mat integrity and porosity and PLGA molecular weight via a bulk erosion mechanism. The solution-blown PLGA fibers are biocompatible; the CO2 and acetone used in the process did not affect cell viability. The authors demonstrated their technique by using it to coat a liver injury site in a pig model in ≈1 min. (ACS Macro Lett. 2014, 3, 249–254; LaShanda Korley)

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Trifluoromethylate N-heteroaromatics under mild conditions. Trifluoromethylated compounds are widely used in organic and medicinal chemistry. Current syntheses of these compounds usually require toxic fluorinating agents and harsh conditions. M. Kanai and coauthors at the University of Tokyo and the Japan Science and Technology Agency (Tokyo) developed a mild method for trifluoromethylating nitrogen heteroaromatics by activating C–H bonds on the rings.

The authors’ key finding is that N-adjacent C–H bonds of heterocyclic N-oxide–trifluoromethyldifluoroborane derivatives (e.g., quinoline derivative 1) are activated toward trifluoromethylation more strongly than those of the corresponding underivatized heterocycles or their N-oxides. This finding is supported by lowest unoccupied molecular orbit (LUMO) calculations. The authors prepared compound 1 and treated it with Me3SiCF3 in the presence of CsF and 4-Å molecular sieves (MS4A) to obtain 2-trifluoromethylquinoline (2) in 91% yield.

Trifluoromethylation of activated quinoline N-oxide

The researchers telescoped the reaction sequence by making 2-trifluoromethyl-6-chloroquinoline without isolating the intermediates. Oxidizing 6-chloroquinoline with m-chloroperoxybenzoic acid, treating the oxide with BF2CF3·OEt, and trifluoromethylating with Me3SiCF3–CsF gave the product in 69% overall yield.

The authors assessed the synthetic utility of their method by scaling up the reaction to the gram scale and by trifluoromethylating quinine at the 7-position in 75% yield. The authors believe that the reaction mechanism is based on the dearomatizing nucleophilic attack of the CF3 anion (formed from Me3SiCF3 and CsF) on the activated heterocycle. This is followed by the elimination of the borate anion [HOBF2CF3] to recover the aromatic system.

This reaction is practical, scalable, and highly regioselective when six-membered heterocycles are used. It does not work, however, for electron-rich five-membered heterocycles. The process complements previously reported electrophilic radical trifluoromethylation reactions. (Nat. Commun. 2014, 5, No. 3387; José C. Barros)

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Use supported metal oxide catalysts to synthesize biodiesel. Biodiesel fuel has been around for many years, but the use of strong alkaline reagents to transesterify the plant oil feedstocks hinders its widespread adoption as an automotive fuel source. The best oil feedstocks for use with homogeneous alkaline catalysts contain low levels of free fatty acids. But these oils are also used as food sources; they include soybean, canola, sunflower, rapeseed, and palm oils.

Tree-borne oil seeds, including those from Jatropha curcas and Pongamia pinnata, are often inedible, even poisonous; but they can be grown on degraded land that is unfit for agricultural production. Oils from these seeds typically contain 5–15% free fatty acids. When the oils are transesterified with homogeneous alkaline catalysts, they tend to form soaps. This complicates the separation and recovery of glycerol from the resulting biodiesel fuel.

S. Mahajani and co-workers at the Indian Institute of Technology Bombay (Mumbai) developed a method that uses supported metal oxide catalysts for making biodiesel from jatropha oil. Their evaluation of ZnO and PbO catalysts on zeolite substrates showed that both catalysts have reasonably good activity and can be reused under the reaction conditions. Excess methanol was added to the reaction mixture to accelerate the reaction and increase the conversion of oil to biodiesel.

The authors used ZSM-5 zeolite, β-zeolite, α-alumina, or γ-alumina as the catalyst supports. Because of the high Si/Al ratios (low acidities), these supports showed no catalytic activity on their own. The zeolites minimized metal-ion leaching during the reaction, an important environmental consideration. Alumina did not bind the metal oxides as strongly as the zeolites, and it released more metal ions during the reaction.

The PbO/zeolite catalyst performed especially well for oils with <1 wt% free fatty acids. For PbO/ZSM-5, triglyceride conversion was almost 100% after 30 min. The ZnO/zeolite catalyst was better for feedstocks that contained >10 wt% free fatty acids; it also worked well with oleic acid.

The fatty acid methyl ester yields with ZnO/zeolite and PbO/zeolite were ≈94% and >90%, respectively. The reactions were run at 200 °C, an oil/MeOH mol ratio of 1:30, 1 h reaction time, and a catalyst loading of 1.0 wt% (ZnO) or 0.5 wt% (PbO). (Energy Fuels 2014, 28, 2743–2753; Nancy McGuire

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Potential broad-spectrum antivirals