Noteworthy Chemistry

August 29, 2011

Add phosphonic acid groups to a highly fluorinated polymer. V. Atanasov* and J. Kerres at Stuttgart University (Germany) incorporated a high concentration of phosphonate groups into polypentafluorostyrene scaffold 1. A key to their technique was treating commercially available 1 with tris‍(trimethylsilyl) phosphite (2) to make intermediate polymer 3 with phosphonate ester groups on as many as 90% of the aryl rings along the polymer chain.

The ester groups were hydrolyzed to the corresponding phosphonic acid groups in structure 4. Target product 4 had high molecular weight (Mw = 67 kDA), which is a prerequisite for the enhanced mechanical properties needed for durable polyelectrolyte membranes.

The phosphonation reaction proceeds via nucleophilic aromatic substitution facilitated by the strongly electron-withdrawing effect of the fluorine atoms. This property also increases the acidity of the phosphonic acid groups on 4. The importance of acidity is seen in the significant increase in its proton conductivity, giving 4 the highest conductivity value for a phosphonated polymer (σ = 0.1 S/cm at 108 °C) reported to date. This value is higher than that of Nafion 117, the current “gold standard” for polymer electrolytes for fuel cell applications.

Polymer 4 shows remarkable resistance to oxidative and thermal stress—its decomposition temperature is 340 °C in a 70% oxygen environment. This combination of properties makes the polymer a potentially useful material for fuel cell technology. (Macromolecules 2011, 44, 6416–6423; W. Jerry Patterson)


Peptides alter charged-lipid distribution in mixed-lipid vesicles. Cells naturally maintain a specific asymmetric distribution of lipids between the inner and outer leaflets of their membranes. This is accomplished by membrane proteins that transport lipids across the bilayer; the lipids would otherwise diffuse very slowly between the two leaflets. S. Qian and W. T. Heller* of Oak Ridge National Laboratory (TN) used small-angle neutron scattering (SANS) to study how peptides such as alamethicin and melittin alter the distribution of lipids in model membranes that consist of a mixture of charged and uncharged lipids.

Using SANS made it possible to investigate the distribution of charged and uncharged lipids with mixtures of charged hydrogenated dimyristoyl phosphatidylglycerol (DMPG) and uncharged deuterium-labeled dimyristoyl phosphatidylcholine (DMPC). Neutrons’ sensitivity to 1H and 2H makes the scattering signal from DMPG in the mixed-lipid vesicles in a H2O–D2O mixture much stronger than that of DMPC.

Unilamellar vesicles were prepared from a series of combinations of lipid mixture (3:1 DMPC/DMPG) and peptide (alamethicin or melittin). The peptides interact with lipid bilayers to form transmembrane pores in a concentration-dependent manner. The authors studied concentrations above and below the concentration required to form transmembrane pores.

By analyzing SANS data for the lipid vesicles in the presence and absence of peptide, the authors noted changes in the distribution of DMPG within the vesicle bilayers. Whereas both peptides enhance the amount of charged DMPG in the outer leaflet of the bilayer, melittin produces a stronger effect than alamethicin. Melittin is highly charged, which suggests that some charge neutralization is involved in the redistribution. However, alamethicin, which carries a single positive charge, also causes an enrichment of DMPG in the outer leaflet of the vesicles.

The amount of DMPG in the outer leaflet of the bilayer is further enhanced by peptide concentrations that allow transmembrane pores to form. These results suggest that membrane-active peptides may disrupt the lipid distribution between the inner and outer leaflets of the bilayer and cause secondary stress on target cells at concentrations that are insufficient for transmembrane pore formation. (J. Phys. Chem. B 2011, 115, 9831–9837; Gary A. Baker)


Do expectant mothers’ diets affect their children’s allergies? Allergies are among the most common childhood medical disorders. Some studies show that children’s risks of allergies may be increased by expectant mothers’ antioxidant consumption, whereas others report that consumption of the antioxidant vitamin E by pregnant women reduces the risk of asthma and wheezing in infants and toddlers.

B. I. Nwaru at the University of Tampere (Finland) and coauthors at eight other Finnish institutions conducted a detailed survey to clarify the relationship between antioxidant consumption during pregnancy and allergy occurrence in the offspring. They sent a questionnaire to pregnant women throughout Finland that asked the respondents to report whether they consumed any of 181 foods and supplements during the eighth month of pregnancy.

The data were sorted, and antioxidant intake was summarized. The authors reduced the results to the consumption of 12 antioxidants, predominantly vitamins and metals. After 5 years, the respondents were sent a follow-up questionnaire about the occurrence of eczema, asthma, and rhinitis among the children.

The results do not provide significant correlations between pregnant women’s antioxidant intake and allergy occurrence in their children. The only exception was that intake of dietary magnesium may decrease the occurrence of atopic eczema in offspring. The authors could not confirm the results of previous studies, and they believe that there may be a critical time during pregnancy when antioxidant intake might reduce children’s allergies. (Eur. J. Clin. Nutr. 2011, 65, 937−943; Sally Peng Li)


Use imidazole in dimethylformamide for N-formylation. Amine formylation is used in peptide synthesis and in the preparation of isocyanides for multicomponent reactions. Current formylation methods require harsh conditions, such as high temperatures, and toxic or unstable reagents. M. Suchý, A. A. H. Elmehriki, and R. R. Hudson* at the University of Western Ontario (London) developed a simple protocol to effect this transformation.

Their method uses imidazole in warm (60 °C) DMF solvent for the N-formylation of amino acid esters (see figure for examples). After purification by flash chromatography, the yields are in the 30–76% range. Amino acids do not react in absence of ester protecting groups. The stereochemistry is preserved under these conditions, except that glutamic acid dimethyl ester leads to racemic lactam 1 as the major product.

The authors expanded their method to other amines, but higher temperatures (≈120 °C) are required, and only primary amines give the desired formylated products. Secondary and aryl amines fail to react because of their poor nucleophilicity

Reactions in DMF-d7 showed that the formyl group originates from the solvent. The authors propose a mechanism for the transformation that proceeds through an N-formylimidazole.

This protocol uses inexpensive reagents and does not require dry reagents or an inert atmosphere. The authors warn that reactions performed in warm DMF in the presence of nucleophilic acyl transfer catalysts may give unintended formylated byproducts. (Org. Lett. 2011, 13, 3952–3955; JosÉ C. Barros)


Revise a nitric acid oxidation to make it safe and scalable. When H. Osato*, M. Kabaki, and S. Shimizu of Shionogi & Co. (Hyogo, Japan) added an AcOH solution of 3-bromo-2,2-bis(bromomethyl)propanol over 2 h to HNO3 containing 1 mol% NaNO2 at 65 °C, an induction period was followed by a significant exotherm with an adiabatic temperature rise of 113.8 K. NaNO2 is converted to HNO2, which then generates 2 mol of NO2 to oxidize the alcohol to the aldehyde and subsequently to the acid, regenerating HNO2 in the process.

Adding some of the tribromo alcohol substrate to the reaction vessel at the beginning allows the reaction to start immediately and avoids the induction period. When 10% of the substrate is added, the adiabatic temperature rise is a controllable ≈11 K. Adding the remainder of the alcohol in HOAc allows the reaction to be carried out safely on a 3000-L scale. (Org. Process Res. Dev. 2011, 15, 581–584; Will Watson)


Design microengines with bilayer templating. J. Wang and co-workers at the University of California, San Diego, used a templating technique to prepare conical microtubular nanostructures with high catalytic efficiency. They developed the microengines by using a polycarbonate membrane template (conical with 2 µm o.d. and 1 µm i.d.) into which polyaniline (PANI) and platinum were deposited sequentially. The conical shape is retained after the template is dissolved. The resulting microtubes are 8 µm long and consist of PANI–Pt bilayers 180 and 80 nm thick, respectively, with 1.5 and 0.5 µm i.d.

In 1% aq H2O2, the tubes act as microengines that move in spiral and circular trajectories at an average speed of 120 µm/s. Introducing a ferromagnetic nickel layer between the platinum and PANI layers makes it possible to guide the microtubules magnetically, but it decreases the average speed of the engine to 80 µm/s because the pore i.d. is reduced.

Increasing the H2O2 concentration enhances the speed of the microengines, which the authors attribute to higher pressure on the oxygen bubbles generated by H2O2. Inner surface roughness and its corresponding catalytic activity also improve performance over current microengine technology.

An increased surfactant concentration lowers surface tension, which increases the speed of the microengines. The authors show that the microengines function (e.g., for cell transport) in simulated biological fluids with reduced speeds that correlate with increased viscosity. (J. Am. Chem. Soc. 2011, 133, 11862–11864; LaShanda Korley)


Chiral pyridinones lead to chiral piperidines. The piperidine scaffold occurs in biological compounds with a wide range of biological activities. In 2009, N. Gouault and co-workers at the University of Rennes (France) reported their work on converting of amino ynones to pyrrolidones with moderate stereocontrol (Gouault, N., et al. J. Org. Chem. 2009, 74, 5614–5617). They now describe the gold-mediated cyclization of chiral amino ynones to pyridinones, with the goal of converting them to piperidines. They visualize their method as using a gold catalyst as a “soft” Lewis acid to initiate the process via a triple-bond electrophilic activation pathway, with subsequent nucleophilic attack of the N-protected amine to form the heterocycle.

The substrates exemplified by 1 are prepared from commercially available chiral amino acids via

  1. Arndt–Eistert homologation,
  2. Weinreb amide formation, and
  3. addition of lithium acetylides.

Pyridinones represented by 2 can be prepared in enantiopure form (>99% ee by chiral HPLC). It is easy to functionalize 2 at the 3-position to make products such as 3 and 4 as single diastereomers (cis/trans < 2:98 in both cases). Boc is tert-butoxycarbonyl; LiHMDS is lithium hexamethyldisilazide.

Product 2 also can be reduced to piperidone 5 as the single cis isomer. Converting 5 first to the enol trifluoromethanesulfonate, hydrogenating, and removing the amine protecting group lead to desired piperidine 6 as a single enantiomer with an overall yield of 61%.

This straightforward synthetic method leads to functionalized pyridinones and piperidines with remarkable stereocontrol. (Org. Lett. 2011, 13, 4371–4374; W. Jerry Patterson)


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