Noteworthy Chemistry

August 15, 2011

DNA plays dual roles in drug delivery. Our understanding of DNA has surpassed its role as the “stockroom” of genetic information for all living beings. One important application is its use as structural media for drug delivery. The long-chain molecule is frequently used as a transportation vesicle for therapeutic components. C. J. Yang, W. Tan, and coauthors at the University of Florida (Gainesville), Hunan University (Changsha, China), and Xiamen University (China) designed a modified DNA complex that has dual roles: carrier and drug.

The authors selected a G-quadruplex (1) to use as the DNA matrix. It forms a framework of guanine molecules (2) that has multiple hydrogen-bonding sites. The light-sensitive molecule 5,10,15,20-tetrakis(1-methyl-4-pyridyl)-21H,23H-porphine (TMPyP4, 3), which selectively reacts with leukemia cells, binds to the delivery matrix via intermolecular forces to produce complex 4. A specific type of DNA aptamer, shown in the figure as helical strands, is used for molecular recognition of the target cells.

After the complex enters the cell, exposure to light liberates the TMPyP4. The porphine molecules release gradually, embed in the cell environment, and damage the entire cell. Drug efficacy is maximized, and side effects are minimized. This technique is limited by the number of categories of aptamers. The mechanism of the process also needs further investigation. (Angew. Chem., Int. Ed. 2011, 50, 6098−6101; Sally Peng Li)

Block copolymer nanocomposites assemble in 3-D templates. H. Yabu and colleagues at Tohoku University (Sendai, Japan) and the Japan Science and Technology Agency (Saitama) demonstrate the confined assembly of polystyrene-b-polyisoprene (PS-b-PI)–PS-thiol–stabilized gold nanoparticle (AuNP) nanocomposites within colloidal templates. The volume fraction of PI in the 47-kDa block copolymer was 0.74; the AuNPs were ≈9 nm diam.

The interconnected, multilayered assemblage of PS colloids (248 and 498 nm diam) was embedded with poly(vinyl alcohol) (PVA). Removing the PS structure revealed an inverse opal PVA template film. The PS-b-PI–AuNP solution in CHCl3 was combined with the PVA array by drying at room temperature. The PVA template was removed by immersing it in water at 50 °C. This process formed concentric ring nanostructures with the functionalized AuNPs in the PS phase. The excess AuNPs were located at the PVA–block copolymer interface even though the bulk PS-b-PI had cylindrical morphology.

The authors believe that the observed nanostructure is caused by free PS-SH chains, which increase the PS content, and the low level of incommensurability between the PS-b-PI domain spacing and the void space. Extending this research may result in applications in metamaterials and plasmonics. (Macromolecules 2011, 44, 5868–5873; LaShanda Korley)

Fluorinated DDT derivatives may be useful alternative insecticides. The highly effective pesticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT, 1) was used worldwide to control insect-borne diseases such as malaria until it was banned in most developed countries. The bans are based in part on its chemical stability, which leads to persistence in the environment and bioaccumulation in the food chain.

G. K. S. Prakasy, G. A. Olah, and co-workers at the University of Southern California (Los Angeles) devised a synthetic strategy for fluorinated DDT analogues in which substituted arenes (e.g., 2) are treated with fluorinated acetaldehyde synthons (3) under superacid conditions. Boron trifluoride monohydrate (BF3·H2O) is used as the superacid catalyst; it is also the reaction medium. This high-yield, one-pot synthesis produces 1,1,1-trifluoro-2,2-diarylethanes (4) without the need for organic solvents.

This procedure uses fluoral as a reagent in the form of hemiacetal 3. This converts fluoral gas (with its preparation and handling difficulties) to a convenient, stable trifluoroacetaldehyde equivalent that is commercially available at reasonable cost. The scope of the process includes the use of difluoroacetaldhyde ethyl hemiacetal (5) to form corresponding 1,1-difluoro-2,2-diarylethane 6.

The authors note that this method is an example of a hydroxyalkylation Friedel–Crafts reaction. They prepared a variety of fluorinated structures, each of which can be considered a DDT analogue. This route to DDT analogues provides the potential for biodegradability and improved pesticidal activity. (Org. Lett. 2011, 13, 4128–4131; W. Jerry Patterson)

Use n-butyllithium as a metallurgical reagent. n-Butyllithium (n-BuLi) is commonly used in organic synthesis as a lithiating and reducing agent. A report by J. F. Bondi and R. E. Schaak* at Pennsylvania State University (University Park) shows that n-BuLi also can be used to lithiate gold nanoparticles to form the polar intermetallic compound Au3Li.

Polar intermetallic compounds form by combining electronegative and electropositive elements to yield interesting structures that contain polyionic clusters or networks. To synthesize polar intermetallic compounds, the constituent elements are usually directly combined at high temperatures. By using colloidal nanoparticles and n-BuLi as reagents, Au3Li is accessible at much lower temperatures and is amenable to nanostructuring, which is important for its applications.

To synthesize Au3Li nanoparticles, the authors first synthesized colloidal gold nanoparticles, then used them as reactive seeds. When the seeds reacted with n-BuLi under rigorous air-free conditions, lithium was inserted into the gold nanoparticles to form Au3Li. The Au3Li phase is believed to adopt the common Cu3Au intermetallic crystal structure type. The authors confirmed the formation of Au3Li nanoparticles by using X-ray diffraction, transmission electron microscopy, electron diffraction, and elemental analysis.

When dried, the Au3Li nanoparticles are stable in air. They decompose, however, when exposed to water to regenerate gold nanoparticles. This observation suggests that lithium can be readily inserted into and extracted from gold nanoparticles. The authors believe that it may be possible to extend this strategy to discover and synthesize novel polar intermetallic compounds. (Eur. J. Inorg. Chem. 2011, Early View DOI: 10.1002/ejic.201100276; Gary A. Baker)

Synthesize (E)-styryl ketones stereoselectively. P. Pawluc and co-workers at Adam Mickiewicz University (Poznan, Poland) report an efficient one-pot procedure for converting styrene derivatives (e.g., 1) to the corresponding (E)-styryl ketones (2). The reaction sequence is an initial highly E-selective ruthenium-mediated coupling of the styrene substrate with vinyltrimethylsilane to give a styryl intermediate (not isolated). This step is followed by rhodium-catalyzed desilylative acylation in the same pot to yield product 2.

Various substituents on the styrene phenyl ring and on the acid anhydride acylating agent lead to a range of styryl ketone products; each strongly favors the E-isomer (E/Z ≈ 99:1). This protocol for regioselective α,β-unsaturated ketones uses readily available, inexpensive reactants. (J. Org. Chem. 2011, 76, 6438–6441; W. Jerry Patterson)

Purify a developmental drug through its acetonitrile solvate. The free acid form of AMG 837, a GPR40 receptor agonist for treating type 2 diabetes, is unstable and forms a methyl ketone impurity. S. D. Walker and co-workers at Amgen (Thousand Oaks, CA) found that the sodium salt is significantly more stable, but it is poorly crystalline. The sodium salt, however, can be effectively purified by crystallization from acetonitrile (MeCN), which generates an MeCN solvate of the salt.

Unfortunately, vacuum drying to remove MeCN is unsuccessful—diene impurities form at elevated temperatures. After noting that analytical samples left on the open bench lost MeCN, the authors “wet dried” the solvate on the filter by passing humidified nitrogen through the cake to produce the sodium salt with 1–2% water and <400 ppm residual MeCN. (Org. Process Res. Dev. 2011, 15, 570–580; Will Watson)

Use cobalt(II) thiocyanate with TLC to identify cocaine. Cocaine is an illicit drug consumed by an estimated 13 million people around the world. It can be obtained as a free base (1) or its hydrochloride salt (crack). Less expensive cutting substances (e.g., procaine, lidocaine, or benzocaine) are added to provide complementary effects; inert materials such as NaCl or lactose may be added to increase profits.

Current methods for identifying cocaine in the field are based on its complexation with Co(SCN)2 in aqueous solution, but the methods are subject to false positives because cutting substances also form complexes. So the forensic laboratory must confirm the presence of cocaine, usually by chromatography and MS analysis.

O. Siri and co-workers at the University of the Mediterranean Aix-Marseille II (France) report a new method for identifying cocaine by using thin-layer chromatography (TLC) and complexation. They found that a 95:5 cyclohexane–ethanol solution and an alumina support make a suitable system for separating cocaine from its adulterants by TLC. The free base and crack cocaine have the same retention factor

Impregnating part of the TLC plate with Co(SCN)2 allows visual identification of cocaine by color change. To stabilize the TLC plate impregnated with the stain, the researchers use ethylene glycol as an adjuvant to maintain the humidity of the system. The limit of detection by the naked eye is 3 mg/mL.

The method was used to analyze 49 “street” samples. The lowest amount of cocaine that could be detected in a “cut” mixture was 15%. This method is simple, efficient, and practical for field identification. (New J. Chem. 2011, 35, 1351–1354; JosÉ C. Barros)

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