Noteworthy Chemistry

How many bubbles are in a glass of champagne? Since champagne was developed in the late 17th century, people have been amused by CO2 escaping from it in the form of bubbles. This process intrigues not only wine lovers, but scientists who want to describe it accurately. For example, people wonder about the number of bubbles in a glass.

As a result of secondary fermentation, champagne is heavily carbonated (≈11.8 g CO2/L) and bubbles spontaneously after it is poured. After using physical chemistry models to analyze the effervescence process, G. Liger-Belair at the University of Reims Champagne-Ardenne (Reims, France) derived a theoretical method for predicting the number of bubbles in a glass.

Liger-Belair first devised a theoretical model in which he simplified the situation to the release of 5 L gaseous CO2 (for a standard 750-mL bottle) from a supersaturated multicomponent aqueous alcohol system at standard temperature and pressure. Most estimates give ≈100 million bubbles in a bottle of champagne; but the author believes that this number is inaccurate because not all CO2 forms bubbles, and the bubble size is not constant during effervescence.

The author identified several parameters for determining the number of bubbles, including temperature, size of gas cavity, glass orientation while pouring, and depth of champagne in the glass (see figure). Taking into account ascending bubble dynamics and mass transfer, he calculated that ≈1 million bubbles form when 100 mL of champagne is poured straight down. Higher temperatures and pouring onto the walls of tilted glasses result in more bubbles because of the decrease in CO2 solubility and better CO2 preservation, respectively. (J. Phys. Chem. B 2014, 118, 3156–3163; Xin Su)

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What do sugarcane juice and azo dyes have in common? Photocatalysts are useful for degrading organic pollutants, but preparing nanoparticles of these materials typically involves energy- and capital-intensive methods that use harsh or toxic chemical reagents. These factors counterbalance the sustainability of the photocatalysts. A greener synthesis method would avoid the use of solvents and stoichiometric reagents, limit waste production, and use available, renewable resources.

A. A. Kulkarni and B. M. Bhanage* at the Institute of Chemical Technology (Mumbai, India) developed a method that uses sugarcane juice to produce AgCl nanoparticles with doped silver on their surfaces (Ag@AgCl). They used these particles to promote the visible-light photocatalytic degradation of two azo dyes, methyl orange and methylene blue, in aqueous solution. The catalyst can be reused as many as four times without significant loss of catalytic activity.

The authors call sugarcane juice “a bag full of reducing agents (glucose), well-known capping agents (organic acids), and halide ion sources (chloride ion) that can be utilized for preparation of nanomaterials”. They dissolved AgNO3 in sugarcane juice and heated the mixture at 80 °C for 20 min to produce Ag@AgCl particles with an average size of 37 nm. They determined that the sugarcane juice plays a key role in producing well-dispersed, uniform particles and reducing the AgCl to form elemental silver on the particle surfaces. This silver activates the catalyst by absorbing visible light and transferring electrons to the AgCl conduction band.

The authors added 100 mg of the nanoparticles to 25 mL of dye solution and allowed the mixture to stand in the dark for 1 h. They observed an adsorption−desorption equilibrium of the dye on the catalyst surface. They then irradiated the mixture with UV-free visible light from a quartz halogen lamp.

The catalyst was removed via centrifugation, and the degree of dye degradation was measured with UV−vis spectroscopy. Methyl orange is completely degraded after 21 min; 50 min is required for methylene blue. (ACS Sustainable Chem. Eng. 2014, 2, 1007–1013; Nancy McGuire)

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Oxadiazoles show promise for treating MRSA. Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for thousands of deaths annually in the United States, many in intensive-care units of hospitals. Historically, β-lactam antibiotics were used to treat S. aureus infections, but these agents became obsolete with the emergence of MRSA in the early 1960s. Current MRSA treatments are based on three drugs: vancomycin, daptomycin, and linezolid; only linezolid is available orally.

S. aureus’s resistance to β-lactams is based on a gene that encodes penicillin-binding protein 2a (PBP2a). S. Mobashery, M. Chang, and co-workers at the University of Notre Dame (IN) discovered a class of oxadiazoles that inhibit this protein.

When the authors screened in silico a database of 1.2 million compounds that complex with the PBP2a receptor, they identified 29 inhibitor candidates. They obtained the compounds and tested them against a collection of bacteria. Compound 1 in the figure was active against S. aureus and Enterococcus faecium. They then synthesized a library of 370 analogues of 1 and tested them against MRSA and vancomycin-resistant E. faecium (VRE). Compounds 24 had excellent activity.

Oxadiazoles that are potential MRSA drugs

The three compounds were evaluated for in vitro cytotoxicity. Compounds 2 and 3 exhibited little (3%) red blood cell hemolysis; 4 was not hemolytic. All were metabolically stable.

In vivo studies of the compounds’ pharmacokinetic properties showed that 3 and 4 are more bioavailable than 2 and can be administered orally. Evaluation of the mechanism of action of compound 3 indicated inhibition of peptidoglycan synthesis, a result expected for an inhibitor of PNB2a, the enzyme responsible for cell-wall biosynthesis. This class of non–β-lactam antibacterials that contain oxadiazole rings may lead to drugs for treating MRSA infections. (J. Am. Chem. Soc. 2014, 136, 3664–3672; José C. Barros)

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How proteins are unfolded makes a big difference. Knowledge of a protein’s tertiary structure—its geometry—is important for understanding its normal bioactivity. Proteins rely on interactions between polypeptide chains to fold into stable conformations with well-defined protein domains. The study of protein folding and unfolding is key to understanding proteins’ structure–property relationships.

Unfolding studies traditionally were conducted by chemically denaturing protein ensembles. Single-molecule mechanical force techniques have only recently been introduced. Do these two methods lead to the same unfolded protein? B. J. Berne and colleagues at Columbia University (New York City) and IBM T. J. Watson Research Center (Yorktown Heights, NY) used molecular dynamics (MD) to simulate the unfolded states from each method.

The authors chose ubiquitin, a well-characterized protein with 76 residues, as their model. They used all-atom, explicit-solvent MD simulations to generate force-unfolded and chemically unfolded ubiquitin structures. Ubiquitin is completely extended under force but only partially extended in the presence of the denaturant urea. They observed no contacts or retained secondary structure in force-unfolded ubiquitin. In contrast, many nonnative contacts and α-helices emerged during chemical unfolding.

The distributions of backbone dihedral angles were significantly different in the two cases. In the case of force unfolding, the distribution was force-dependent. The authors devised a model that uses the dialanine peptide to elucidate the role of force in terms of changing dihedral angles and to understand the differences between the two unfolding mechanisms. (Proc. Natl. Acad. Sci. USA 2014, 111, 3413–3418; Xin Su)

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Glycosides inhibit abnormal prion formation in prion-infected cells. Prion diseases are fatal neurodegenerative disorders that affect humans and animals. These transmissible spongiform encephalopathies are characterized by pathogenic deposits of an abnormal, protease-resistant isoform (PrPsc) of prion protein, which is converted from the normal, protease-sensitive cellular isoform (PrPc). To date there is no treatment—molecular compound or biological material—that stops disease progression in prion-infected animals and would be applicable to humans.

K. Doh-ura and colleagues at the Tohoku University Graduate School of Medicine (Sendai, Japan) screened compounds with chemical structures that are unrelated to previously reported structures that have antiprion activity. They identified glycosides as a new type of antiprion compound. These compounds are formed from monosaccharides by replacing the hydrogen atom of a hydroxyl group with a bond to another biologically active molecule. Glycosides are abundant in plants and are used in medicines, cleansing agents, and dyes.

Height of the champagne in a glass may play a role in the number of bubbles

The authors describe the efficacy and mechanism of a representative glycoside compound, Gly-9 (4-methoxyphenyl 2-amino-3,6-di-O-benzyl-2-deoxy-β-D-glucopyranoside, 1) in prion-infected cells and animals. Gly-9 inhibits PrPsc formation in prion-infected neuroblastoma cells independently of the prion strain.

The investigators determined that antiprion activity for Gly-9 and related compounds is related to the methoxyphenol glycoside that contains two benzyl groups via ether linkages. The in vivo efficacy is marginal, but the pharmokinetic parameters for the animals used at this stage in the study were unknown. The Gly-9 pharmacophore still must be determined, and its chemical structure must be optimized for safety and antiprion efficacy. (J. Virol. 2014, 88, 4083–4099; Abigail Druck Shudofsky)

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Reorder reaction steps to improve safety and lower costs. In the discovery synthesis of a potent, selective estrogen-related receptor 1 inhibitor, expensive indazole-5-carboxaldehyde was used in step 1, expensive thiazolidine-2,4-dione was used in step 3, and the final step was a reductive amination with formaldehyde (a human carcinogen) and NaBH4 to carry out the N-methylation of a piperidine nitrogen. During process development scale-up, X. Li and co-workers at Janssen Research & Development (Spring House, PA) revised the sequence to make the synthesis safer and less expensive.

Preparing the piperidine fragment with the N-methyl group already in position allows the reductive amination to be carried out early in the synthesis and reduces concerns about formaldehyde contamination of the final product. The piperidine is then attached to the thiazolidinedione, and the product is coupled with the indazole fragment in the final step. Reordering reduces costs by introducing the expensive raw materials as late as possible in the sequence. (Org. Process Res. Dev. 2014, 18, 321–330; Will Watson)

These nanoparticles play a dual role in drug delivery and MRI. J. N. Anker at Clemson University (SC) and Vanderbilt University (Nashville, TN) developed a synthetic technique for accessing iron-based magnetic nanocapsules. When these bifunctional nanoparticles are loaded with an appropriate cargo, they can be used for pH-triggered drug release and as dual magnetic resonance imaging (MRI) contrast agents.

The authors first prepared rice grain–shaped hematite (α-Fe2O3) nanoparticles from FeCl3 and KH2PO4 in aqueous solution. They then used Ti(OEt)4 to coat the particles with mesoporous silica and produce an α-Fe2O3@mSiO2 structure. After oxalic acid etching, air-calcining, and hydrogen reduction, monodispersed silica-coated magnetic “nanoeyes” (Fe@mSiO2) were obtained.

The authors further coated the Fe@mSiO2 nanoeyes with eight alternating layers of biocompatible electrolytes: four of positively charged poly-L-lysine (PLL) and four of negatively charged sodium alginate (AL). The Fe@mSiO2@AL/PLL nanoeyes measured ≈420 nm long and ≈110 nm wide. Their 85-nm-long, 60-nm-diam magnetic cylindrical iron cores strongly resisted oxidation.

Schematic of the synthesis of sodium alginate– and poly-L-lysine–coated nanoeyes

Neither Fe@mSiO2@AL/PLL nor any of its subcomponents is cytotoxic. But when the nanocapsules are loaded with doxorubicin, a broad-spectrum anticancer agent, and gadolinium diethylenetriaminepentacetate (Gd-DTPA; a common MRI contrast agent), the polyelectrolyte coating allows pH-triggered doxorubicin release. The combination of ferromagnetic α-Fe and Gd-DTPA provides a dual MRI contrast agent that can be used to track the drug release process. (Chem. Mater. 2014, 26, 2105–2112; Xin Su

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