Noteworthy Chemistry

June 29, 2009

Water-soluble pyridinium salts as fluorescent “turn-on” bioprobes
Control noble-metal nanoparticle loading on titania
Run a copper-catalyzed reaction in a “tea bag”
Make visible moisture sensors with polymer–cobalt blends
Speed up an O-alkylation reaction by adding a solvent
How do you selectively alkylate pyrroles in the β-position?

Water-soluble pyridinium salts function as fluorescent “turn-on” bioprobes. In a fluorescent “turn-off” sensing system, the probe’s light emission is quenched when it binds to an analyte. A “turn-on” probe is more

sensitive and portable because its emission is readily distinguished from the nonemissive, dark background with the naked eye. X.-T. Tao and coauthors at Shandong University (Jihan, China) and Anhui University (Hefei, China) developed a series of turn-on bioprobes that light up when they bind to proteins.

The bioprobes are a family of Λ-shaped pyridinium salts with the anions shown. The luminogens are nonemissive when they are dissolved in “good” solvents such as water. They become highly emissive when they aggregate in “poor” solvents such as benzene, an example of aggregation-induced emission (AIE). Light emission from the luminogens is turned on when they bind to proteins such as bovine serum albumin (BSA) in an aqueous buffer that contains a small amount of a surfactant, as seen in the photographs for luminogen 1. OTs^– is p-toluenesulfonate.

The bioprobes show large Stokes’s shifts (>140 nm) and a wide linear working range (0–70 μg/mL), allowing quantitative protein assays without interference from background emission. The detection and quantification of BSA by the AIE luminogens may have applications for protein analysis in gel electrophoresis. AIE allows the use of high fluorophore/protein ratios, which makes the luminogens promising for trace assays of low-abundance proteins. (J. Phys. Chem. C 2009, 113, 6809–6814; Ben Zhong Tang)

Control noble-metal nanoparticle loading on titania. Metal–TiO₂ composites are used in applications from photochemistry to heterogeneous catalysis. Previous studies showed that the properties of these composites depend strongly on metal particle size, dispersion, and composition. As particle size falls below 2.0 nm, the composites display highly efficient catalytic activity.

Z. Liu and co-workers at the Chinese Academy of Sciences (Beijing) report a novel, simple, clean way to grow noble-metal (e.g., platinum) nanoparticles directly by using an in situ redox reaction between the reductive titanium support and aqueous solutions of metal-salt precursors. In a typical example, TiCl₃ and a platinum precursor are the starting materials. The Ti(III) oxide nanostructure is formed from TiCl₃ in an acidic aqueous medium that contains excess chloride ion, a strong reducing agent. The metal ions are then put in contact with the Ti(III) oxide nanostructure, where they are immediately reduced by the support and begin to grow as clusters and then nanoparticles on the oxide surfaces.

During this process, the support is converted to TiO₂ and forms the metal–TiO₂ nanocomposites. This process can be controlled to adjust metal particle size, loading, and distribution. TiO₂ nanorods of 10–50 nm diam and ~200 nm length are produced. The platinum particle size can be adjusted from ~0.5 to ~2.3 nm.

Scanning transmission electron microscopy of the composites shows a homogeneous deposit of the platinum nanoparticles throughout the TiO₂ support. The authors extended the process to form Au–TiO₂, Ru–TiO₂, and PtRu–TiO₂ composites and verified that in each case the TiO₂ nanorods are decorated with metal nanoparticles with ultrafine size and narrow size distribution. (J. Am. Chem. Soc. 2009, 131, 6648–6649; W. Jerry Patterson)

Run a copper-catalyzed reaction in a “tea bag”. L. H. Gade and co-workers at the University of Heidelberg (Germany) and the University of Strasbourg (France) prepared “tea bag” membranes with immobilized ligands (L) for Cu(II) Lewis acid catalysts from bisoxazolines (BOX, 1; R = i-Pr or Ph) and trisoxazolines (trisox, 2) with acetylenic backbone linkers attached to carbosilane dendrimers. LDA is lithium diisopropylamide. Zero- (G0), first- (G1), and second-generation (G2) dendrimers are shown. A membrane tea bag can be dipped in a solution of reactants and recycled several times.

The authors tested the activity of new ligands in copper-catalyzed α-hydrazination reactions and in the Henry reaction. The enantioselective α-hydrazination of ethyl 2-methylacetoacetate gave as much as 99% ee with 1 mol% of the BOX catalyst (R = Ph); Tf is CF₃SO₂. In the Henry reaction between 2-nitrobenzaldehyde and nitromethane, the trisox derivatives gave lower enantioselectivities than the BOX ligands.

Because the membrane bag is made from a dialysis material, it allows the migration of molecules with molecular weights as high as 2000. Consequently, the substrates pass through the membrane into the interior of the bag, reach the catalyst, and are converted to the products, which return through the membrane to the bulk solution. In the hydrazination reaction, the solution color changes from yellow (diazodicarboxylate substrate) to colorless (product), facilitating reaction monitoring. In recycling experiments, the enantioselectivities varied only slightly; and the yields increased, leveled off, and dropped gradually. (Chem. Eur. J. 2009, 15, 5450–5462; José C. Barros)

Make visible moisture sensors with polymer–cobalt blends. S. R. Halper* and R. M. Villahermosa at the Aerospace Corporation (Los Angeles) prepared moisture-responsive polyimide films by thermally curing blends of poly(amic acid)s and CoCl₂∙6H₂O in an inert environment. The imidization was complete and yielded stable (>300 °C), green polyimide–CoCl₂ films. The films’ CoCl₂ spectral bands broadened with increasing humidity. Submerging the polyimide–CoCl₂ films in water or exposing them to a humid environment resulted in a reversible color change to yellow as a result of H₂O–CoCl₂ coordination (see figure).

The time scale (minutes to hours) of moisture-induced color change depends on the films’ thickness. Minimal leaching of the CoCl₂ occurs. The authors determined that total water uptake is greater in the polyimide–CoCl₂ films than in the unmodified polyimide films and that, at 95% relative humidity, the sorption and desorption time to 90% capacity of the cobalt-modified polyimide is greater than that for polyimide films alone. They also observed a >3-fold increase over pure polyimide films in total water absorption with the addition of 15 wt% cobalt salt. (ACS Applied Materials & Interfaces 2009, 1, 1041–1044; LaShanda Korley)

Speed up trimethyloxonium tetrafluoroborate O-alkylation by adding a solvent. The reaction of an amide with trimethyloxonium tetrafluoroborate (MeO₃⁺BF₄^–) gives the corresponding imino ether, a useful intermediate. But the reaction of (R)-(–)-2-(2,6-dichlorophenoxy)propionamide with MeO₃⁺BF₄^– in CH₂Cl₂ during the scalable synthesis of the α₂-adrenergic agonist lofexidine is very sluggish, requiring >50 h.

However, when A. P. Vartak and P. A. Crooks* at the University of Kentucky (Lexington) ran the reaction in CH₂Cl₂–Et₂O (9:1), it was complete in 6 h. GC-MS analysis indicated that the intermediate was a mixture of methyl and ethyl imino ethers. MeO₃⁺BF₄^– is preferred to EtO₃⁺BF₄^– because it is more stable, less hygroscopic, and more readily available. (Org. Process Res. Dev. 2009, 13, 415–419; Will Watson)

How do you selectively alkylate pyrroles in the β-position? Because of the high degree of aromaticity in the pyrrole ring, direct introduction of alkyl groups by electrophilic aromatic substitution should lead easily to

β-alkylpyrroles. However, β-alkylation is actually made considerably more difficult by the preferential α-nucleophilicity of pyrroles. T. Tsuchimoto and co-workers at Meiji University (Kawasaki, Japan) found a novel way to fix this problem in a single-step synthesis. N-Methylpyrroles are treated with alkynes and Et₃SiH, mediated by an indium catalyst, to form the desired alkylated product. The alkyl groups are introduced at the β-position of the pyrrole ring in a completely regiospecific manner (β/α > 99:1). Tf is CF₃SO₂; Nf is C₄F₉SO₂; Cy is cyclohexyl.

The authors developed two methods, A and B, for carrying out this reaction, depending on the structure of the alkyl group to be added. Method A appears to work best for primary alkyl groups; it uses the catalyst In(NTf₂)₃ for optimum product formation (1); B works best, however, for branched structures such as cyclohexyl adjacent to the acetylene bond. In this case, In(ONf)₃ catalyst is used, and the alkyne reactant is pretreated with the catalyst before triethylsilane reduction. The product (2) was also formed with stereospecific β-alkylation.

The one-step strategy does not work well with pyrrole substrates without a substituent on the pyrrole nitrogen. In this situation, a reliable two-step method is used in which pyrrole is protected with a benzyl group and then subjected to
β-alkylation by method A or B. With the desired alkyl group in place, the benzyl group is removed by a titanium reagent to regenerate the basic pyrrole structure (3). (Org. Lett. 2009, 11, 2129–2132; W. Jerry Patterson)