Noteworthy Chemistry

February 25, 2013

These Schiff bases are selective turn-on sensors for metal ions. Cu(II) is an essential micronutrient for all life forms; but, because of copper’s widespread use, it is also a pollutant. Similarly, Fe(III) is essential for the functioning of living cells but is detrimental when present in excess.

Many sensors can detect the Cu2+ and Fe3+ ions. They are, however, often difficult to prepare; and only a few are “turn-on” systems. H.-C. Lin and co-workers at National Chiao Tung University (Hsinchu, Taiwan [Province of China]) used simple synthetic methods to develop Cu2+ and Fe3+ sensors. The sensors are specific for the ions and have fluorescence turn-on responses.

Pyrene- and anthracene-based Schiff base derivatives 1 and 2 respond to Cu2+ and Fe3+ ions, respectively. The 2:1 sensor–metal complexes form excimers that undergo chelation-enhanced fluorescence. The sensing systems operate in the full pH range (0–14). Their detection limits are as low as 9.7 × 10–7 M for Cu2+ and 2.95 × 10–6 M for Fe3+. Their association constants are as high as 1.96 × 106/M and 1.88 × 105/M, respectively. (J. Mater. Chem. A 2013, 1, 1310–1318; Ben Zhong Tang)

Cyclize an amino amide to form an imidazoline. During the development of a kilogram-scale synthesis of a triarylimidazoline MDM2 antagonist, L. Shu and co-workers at Hoffmann-La Roche (Nutley, NJ) coupled meso-2,3-diamino-2,3-bis(4-chlorophenyl)butane with the sodium salt of 2-tert-butyl-4-ethoxypyridine-5-carboxylic acid. The coupled product is then cyclized to form the imidazoline ring. (MDM2 is the mouse double minute 2 homologue, a protein that is a negative regulator of the p53 tumor suppressor in humans.)

The dehydrating agent used in the cyclization reaction has a large effect on the outcome of the reaction. POCl3 gives a de-ethylated pyridone as the major product and only 10% of the desired imidazoline. The pyridone is the only product obtained when P2O5 is the dehydrating agent.

The imidazoline is the major product (90%) when the cyclic anhydride of n-PrPO3H2 is used to dehydrate and cyclize the amino amide. The reaction, however, is not robust because the coupled product slowly degrades to the pyridone after it is formed.

Adding 2,6-lutidine significantly reduces the degradation rate without affecting the cyclization. But the best option is to use p-toluenesulfonic acid in pyridine and to remove the byproduct water with a Dean–Stark apparatus. Crystallization of the p-toluenesulfonate salt of the imidazoline from the reaction mixture prevents degradation problems. (Org. Process Res. Dev. 2012, 16, 1940–1946; Will Watson)

Adding a thiazole ring makes an antifungal agent more soluble. Opportunistic fungal infections are a major cause of morbidity and mortality in seriously ill patients. The growing number of fungal infections and evolving drug resistance make it constantly necessary to find new antifungal agents. Albaconazole (1), with its broad-spectrum antifungal properties, is a promising molecule; but its low water solubility may hinder treatment in acute cases.

F. Pagniez, C. LogÉ, and coauthors at the Universities of Nantes and Rouen (both in France) modified albaconazole to improve its solubility. A structure–activity relationship study suggested that adding a thiazole ring to the quinazolinone ring of 1 would increase the water solubility of its analogues.

The authors synthesized compounds 2 and 3 and tested their antifungal activity on various yeasts and molds. Compound 2 showed a broader activity spectrum than 3and was selected for testing on yeast-infected mice.

Compound 2 led to a high mouse survival rate almost 2 weeks after infection, similar to the results from 1. All of the mice in the control group died within a few days. Compound 2 is a promising antifungal agent, but additional optimization and in vivo studies are needed. (ACS Med. Chem. Lett. 2013, 4, 288–292; Chaya Pooput)

What are the ingredients in a 2000-year-old medicine? Information about ancient medicines can found in old texts, but the archeological discovery of medicines is rare. E. Ribechini and colleagues at the Superintendence for Archaeological Heritage of Tuscany (Florence) and the Universities of Pisa and Florence conducted a thorough chemical, mineralogical, and botanical investigation of tablets found in a tin pyxis (cylinder) aboard recovered ship Pozzino, which was wrecked in ≈140–130 BCE.

By using scanning electron microscopy combined with energy-dispersive X-ray spectroscopy, the authors found traces of hydrozincite, smithsonite, and hematite [Zn5(CO3)2(OH)6, ZnCO3, and Fe2O3, respectively]. Analysis by Fourier transform IR spectroscopy showed the presence of starch, beeswax fatty acids, and vegetable and animal lipids. The presence of dehydroabietic and 7-oxo-dehydroabietic acids indicated the use of pine resin, which may have been added because of its antioxidant and antiseptic properties. Scanning electron microscopy identified small amounts of phenanthrenes, which are present in vegetable charcoal.

Small pollen grains were also found, but presumably they were not added to the mixture intentionally. The authors believe that vegetable fibers were added to prevent the tablets from breaking or crumbling.

What were the tablets used for? Their shape is described as “small round loaves”, κoλλύρα in Greek. This name was adopted in Latin as collyrium, or eyewash. The authors conclude that the tablets were used ophthalmically. (Proc. Natl. Acad. Sci. U.S.A. 2013, 103, 1193–1196; José C. Barros)

Here’s a reversal of the keto−enol equilibrium. In the well-known keto−enol equilibrium, the enol form is normally the unstable tautomer and is present in low concentrations, if at all. For decades, chemists have tried to make stable enols, not only for their unique structural properties, but also because of their role in chemical and biochemical transformations.

N.-X. Wang and co-workers at the Chinese Academy of Sciences (Beijing) synthesized a series of acyclic aliphatic enols from azodicarboxylates and 1,3-dicarbonyl compounds, β-carbonyl esters, or ketones. The enols are stable in the solid state and in aprotic solvents

The authors first prepared a stable enol using the reaction between ethyl acetoacetate and diethyl azodicarboxylate in the presence of quinine. Optimization of the reaction conditions (2 mol% quinine and Cs2CO3 as catalysts and CH2Cl2 solvent) resulted in the synthesis of enol 1 in 99% yield. Additional reactions of β-carbonyl esters and ketones with azodicarboxylates gave the corresponding enols in almost quantitative yields (93−99%).

The crystal structure of 1 showed that an O−H···O intramolecular hydrogen bond between an enol OH group and the adjacent carbonyl oxygen is responsible for the stability of the enol form. Computational simulation showed that 1 is more stable than its keto form 2 in the gas phase and in CH2Cl2 solution. The authors believe that p−π and π−π conjugation between the C=C and the C=O bonds in 1 decrease the ground-state energy, whereas in 2 conjugation is prohibited because of the large rotational barrier of the tertiary carbon center. (Sci. Rep. 2013, 3, DOI: 10.1038/srep01058; Xin Su)

Control electrolyte morphology via ionic interactions. I. Manners, C. F. J. Faul, and coauthors at the Universities of Bristol and Reading (both in the UK) prepared block copolymers (BCPs) that ionically assemble into unconventional microstructures. They used living polymerization techniques to synthesize poly(ferrocenylethylmethylsilane)-b-poly[ferrocenylmethyl(dimethylaminopropynyl)silane]s with varying mol ratios. Quaternization of the BCPs with (MeO)2SO2 formed the corresponding block electrolytes.

Ionic complexation of the electrolytes with AOT-based surfactants resulted in cylinder-within-lamellar, lamellar-within-lamellar, tetragon-within-lamellar, and helical hierarchical morphologies, depending upon block size, BCP molecular weight, and surfactant substituents (e.g., octyl and aryl). These unanticipated supramolecular morphologies controlled by ionic association and the resulting asymmetry and volume constraints may lead to nanolithography applications. (J. Am. Chem. Soc. 2013, 135, 2455−2458; LaShanda Korley)

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