Noteworthy Chemistry

January 3, 2011

  • Couple generation 4 dendrimers with DNA templates
  • Water can be a beneficial impurity
  • Betaines efficiently catalyze carbon dioxide–epoxide coupling
  • Enhance thermal conductivity without sacrificing electrical resistivity
  • Use a safer process for generating phosgene
  • This process improves fabric coatings for bacterial resistance
  • Convert diketones to enantiopure 1,3-diols enzymatically

Couple generation 4 dendrimers with DNA templates. K. V. Gothelf and colleagues at Aarhus University (Denmark) used a “click” coupling approach to generate hierarchical assemblies of dendrimers templated by DNA. They synthesized generation 4 (G4) polyamidoamine (PAMAM) dendrimers (~5 nm diam) with 64 carboxylic acid groups on the surfaces [(a) in the figure]. They then converted the carboxyls to alkyne or azide units to set up “click” chemistry (b); these reactions increased the dendrimers to ~6.5 nm diam.

DNA coupling was achieved by the reaction of azide- or alkyne-derivatized DNA with the complementary functionalized dendrimer. As expected, the DNA–dendrimer conjugates’ mobility was lower than that of the carboxylated dendrimers. Oligomers of the DNA conjugates were prepared by using a single-stranded DNA a’–b’ template, which mediated the assembly of DNAa–G4 alkyne and DNAb–G4 azide assemblies and resulted in fast (<30 min) Cu(II) ligand–catalyzed click coupling with no side reactions.

Similarly, linear polymers were obtained via supramolecular association by using two DNA–G4 conjugates with two DNA templates. With this assembly method, the authors demonstrated that complex superstructures also can be obtained by using a 2-D pattern and streptavidin–biotin binding strategies. (J. Am. Chem. Soc. 2010, 132, 18054–18056; LaShanda Korley)

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Water can be a beneficial impurity. Using sodium tert-pentoxide in 1,2-diethoxyethane, J. G. Ford and co-workers at AstraZeneca (Macclesfield and Charnwood, UK) carried out an SNAr reaction of 2-(N-methylpiperazinyl)ethanol with 7-fluoro-N-(5-chloro-1,3-benzodioxol-4-yl)-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine. The reaction produced a total of 8% of two impurities from displacement of the tetrahydropyranyloxy and chlorobenzodioxole groups.

One source of the piperazineethanol reagent contained ~4 wt% water (~0.3 equiv), but instead of rejecting it, the authors subjected it to a use test. In a nice example of serendipity, the reaction proceeded smoothly and resulted in a lower impurity level (2.5%). Further development showed that 1.9–3 equiv of water was optimal. (Org. Process Res. Dev. 2010, 14, 1088–1093; Will Watson)

Betaines efficiently catalyze carbon dioxide-epoxide coupling. The poor reactivity of CO2 has led to research to activate it catalytically for organic synthesis. T. Sakai and co-workers at Okayama University (Japan) note that betaines are effective catalysts for Mannich-type reactions (Uraguchi, D.; Koshimoto, K.; Ooi, T. J. Am. Chem. Soc. 2008, 130, 10878–10879 and subsequent reports). They used this organocatalyst for direct activation of CO2 to investigate subsequent coupling with epoxides, and found that betaine structure 1 most effectively promotes the reaction of CO2 with various substituted epoxides. In several cases, cyclic carbonate 4 is produced in near-quantitative yields (99%).

The researchers isolated and characterized a key intermediate that they describe as a betaine–CO2 adduct (2). To confirm its participation in the reaction they treated it with excess epoxide under standard reaction conditions to obtain the expected cyclic carbonate. They postulate that the carboxylate anion in 2 cleaves the epoxide to form transient acyclic carbonate 3, which cyclizes to product 4.

The authors note that catalyst 1 functions with high efficiency without metals, halogens, or solvents. Adduct 2 forms at temperatures as low as 15 °C, which suggests that this type of betaine might be useful in industrial applications for carbon capture and storage. (Org. Lett. 2010, 12, 5728–5731; W. Jerry Patterson)

Enhance thermal conductivity without sacrificing electrical resistivity. A good thermal conductor is often a good electrical conductor. In the field of electronic packaging, however, materials with high thermal conductivity but low electrical conductivity are desirable. Epoxy resins are widely used for electronic packaging applications because of their superb electrical resistivity, but their poor thermal conductivity has been a significant problem. X. Xie and coauthors at Huazhong University of Science and Technology (Wuhan, China), the University of Sydney, and Hubei University (Wuhan) developed an elegant solution that boosts the thermal conductivity of epoxy resins to a high level but has little effect on their electrical resistivity.

The researchers coated multiwalled carbon nanotubes (MWCNTs) with silica via a sol–gel process and embedded the resulting core–shell MWCNT@SiO2 in an epoxy matrix. The intermediate silica layer around the MWCNTs not only alleviated the modulus mismatch between stiff MWCNTs and soft epoxy but also improved the interactions between them. As a result, thermal conductivity of the epoxy–MWCNT@SiO2 composites increased by 67% at a low filler loading of 1 wt%. The silica shell helped retain the high electrical resistivity of the composites. (Carbon 2010, 49, 495–500; Ben Zhong Tang)

Use a safer process for generating phosgene. Phosgene (COCl2) is useful in organic synthesis for chlorination, chlorocarbonylation, carbonylation, and dehydration; but its high toxicity discourages its use. Until now, the best substitute for COCl2 has been triphosgene [(CCl3O)2CO], a stable solid that has low vapor pressure. Although (CCl3O)2CO can be used in phosgenation reactions, removing the unreacted reagent from reaction mixtures is difficult because of its high boiling point. In contrast, COCl2 is easily removed by evaporating it.

(CCl3O)2CO reacts with silica gel, metal salts, or Lewis acids to generate 1 equiv of phosgene by an electrocyclic reaction. H. Eckert* and J. Auerweck at the University of Technology, Munich (Germany) report that pyridine and phthalocyanine derivatives catalyze the decomposition of (CCl3O)2CO to generate 3 equiv of COCl2.

The catalysts, phenanthridine (1), poly(2-vinylpyridine) (2), and phthalocyanines (3), convert liquid (CCl3O)2CO to the desired COCl2. The size and structure of the catalysts allow (CCl3O)2CO to react by the mechanism shown. The reaction was run at the 100-g scale to generate 22 L of gaseous COCl2 with an oil bath or an IR heater as the heat source. Because the catalysts are not soluble in (CCl3O)2CO, the process is considered to be heterogeneous catalysis.

Catalyst 3b has been used for >10 years to produce hundreds of batches of COCl2 without loss of activity. Catalysts 1, 2, and 3ac achieve reaction times from minutes to 1 h; whereas 3d and 3e are the choices for longer reaction times. In all cases, the yields are excellent.

Because the reaction is controlled by temperature, turning off the heat source causes the liquid (CCl3O)2CO to crystallize and stops the reaction, making the process safe. The reaction can be used to generate COCl2 externally or to produce it in situ. According to the authors, this method fulfills the goal of “safety phosgenation on demand of consumer”. (Org. Process Res. Dev. 2010, 14, 1501–1505; José C. Barros)

This process improves fabric coatings for bacterial resistance. B .B. Hsu and A. M. Klibanov* at MIT (Cambridge, MA) developed a technique for UV light–triggered bactericidal coating of textiles with efficiencies comparable with more laborious fabric treatment processes. They modified poly(ethyleneimine) (PEI) with a photosensitive cross-linker, 6-(4’-azido-2’-nitrophenylamino)hexanoyl (ANPAH), in a five-step synthetic sequence to yield a UV-activated polycation.

Simple polycation dipping followed by UV exposure produced a densely covered bactericidal cotton fabric; the coverage was confirmed by elemental analysis. The authors report almost 100% efficacy against Escherichia coli and Staphylococcus aureus bacteria for the UV-immobilized modified PEI cotton films. (Biomacromolecules 2010, 11, Article ASAP DOI: 10.1021/bm100934c; LaShanda Korley)

Convert diketones to enantiopure 1,3-diols enzymatically. D. Kalaitzakis and I. Smonou* at the University of Crete (Heraklion, Greece) describe an effective cascade process in which achiral 2-alkyl-1,3-diketones (1) are reduced by a multienzyme system to form almost enantiopure 1,3-diols. A useful feature of this method is the formation of single diastereomers of the product diol by tailoring the enzyme system. The reductive enzymes are stereo- and regioselective, allowing them to distinguish between the “faces” of the prochiral ketones for highly stereoselective reduction.

The two-step, one-pot reductions are carried out with commercially available nicotinamide adenine dinucleotide phosphate oxidase (NADPH)–dependent ketoreductase (KRED) enzymes combined with a glucose–glucose dehydrogenase recycling system that regenerates NADPH. In all cases, the first enzymatic reduction leads to the intermediate β-hydroxy ketone 2. The corresponding diol 3 is then formed by adding a second ketoreductase enzyme to the reaction mixture without isolating 2.

In this biocatalytic cascade, the enzyme systems are added in two consecutive steps. The first step is highly stereoselective; it forms one of the four possible hydroxy ketone stereoisomers and leads to the optically pure 1,3-diol product, again as a single stereoisomer. The authors attribute the efficiency of their method to complete enzymatic reduction of starting material, along with absence of any detectable byproduct. In all studied reductions, the diols were isolated without the need for chromatographic purification.

This environmentally benign process carried out in aqueous media forms high-value enantiopure 1,3-diols in one pot, with minimal waste and correspondingly improved economics. (J. Org. Chem. 2010, 75, 8658–8661; W. Jerry Patterson)

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