Noteworthy Chemistry

November 17, 2008

• Biodegradable peptides “clicked” together by 1,3-dipolar cycloaddition
• Carbon nanotubes catalyze the oxidative dehydrogenation of n-butane
• Chemosensors fluoresce in the presence of silver and mercury ions
• Directly analyze aliphatic acids in breath
• Prepare specific deuterated anilines easily and inexpensively
• Use design of experiments to optimize a Suzuki–Miyaura coupling
• Tune nanoparticle size in photosensitive copolymers

Peptide units “clicked” together by 1,3-dipolar cycloaddition are readily cleaved by enzymatic biodegradation. Peptide-based polymers are promising biomedical materials because their primary structure allows specific cleavage by endogenous proteases. Polypeptide synthesis, however, is difficult; current processes require the elaborate use of protecting groups and unstable preactivated building blocks.

R. M. J. Liskamp and co-workers at Utrecht University (The Netherlands) found that microwave-assisted, Cu(I)-catalyzed 1,3-dipolar cycloadditions—“click” reactions—can be used to prepare polymers with peptide sequences (e.g., 2) from oligopeptide monomers that contain unprotected amino groups (e.g., 1). The polymers are sensitive to proteases such as chymotrypsin and trypsin. For example, when 2 is degraded by trypsin, a single defined degradation product (3) is formed. This sequence demonstrates that the click reaction is an effective tool for synthesizing biodegradable polymers. (Biomacromolecules 2008, 9, 2834–2843; Ben Zhong Tang)

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Carbon nanotubes catalyze the oxidative dehydrogenation of n-butane. This reaction—catalyzed by complex metal oxide catalysts—is an important industrial process for producing C₄ alkenes. However, selectivity to the alkenes is low because they can undergo further oxidation under the reaction conditions.

D. S. Su and co-workers at the Fritz Haber Institute of the Max Planck Society (Berlin) conducted this reaction over surface-functionalized carbon nanotubes as catalysts with a low oxygen/butane ratio. The products were mainly 1-butene, 2-butene, and butadiene. The reaction is mildly catalyzed by ketone carbonyl groups and occurs via a combination of parallel and sequential oxidation steps. Kinetic data show that carbon nanotubes modified with phosphorus display high selectivity because the combustion rate is strongly suppressed. (Science 2008, 322, 73–77; George Xiu Song Zhao)

[See also this week’s Patent Watch.—Ed.]

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These chemosensors fluoresce in the presence of silver and mercury ions. Research has established Hg(I) ions as dangerous environmental pollutants. Based on many reports of silver bioaccumulation and toxicity, it is also known that silver ions also exhibit adverse biological effects. Although methods are available to determine trace quantities of Ag⁺ and Hg²⁺, most are based on the concept of fluorescence quenching.

D. Zhang and co-workers at the Chinese Academy of Sciences (Beijing) report highly efficient fluorescence “turn-on” sensors based on the aggregation-induced emission feature of functionalized tetraphenylethylene scaffolds. They used the selective binding abilities of adenine functional groups (1) for Ag⁺ and thymine groups (2) to selectively bind Hg²⁺.

The authors synthesized 1 and 2 in three steps. The key to the efficiency of 1 and 2 appears to be aggregation in solution, mediated by the presence of Ag⁺ and Hg²⁺, respectively. The fluorescence intensities of 1 and 2 are greatly enhanced when the two ions are introduced, leading to the description of 1 and 2 as fluorescence “turn-on” chemosensors for Ag⁺ and Hg²⁺.

The selectivity of 1 for Ag⁺ ion is high in the presence of other metal ions (Ba²⁺, Ca²⁺, Cd²⁺, Co²⁺, Cu²⁺, Fe³⁺, Hg²⁺, Mg²⁺, Mn²⁺, Ni²⁺, Pb²⁺, Zn²⁺, Cs⁺, and K⁺); only Hg²⁺ shows any significant interference. Similarly, the fluorescence spectrum of 2 in the presence of a similar group of metal ions demonstrates the very high selectivity of 2 for Hg²⁺.

The sensitivity of these sensors is also impressive. Ag⁺ concentrations as low as 0.34 μM can be detected with 1, and Hg²⁺ concentrations as low as 0.37 μM can be detected with 2. The authors are developing variants of 1 and 2 with good water solubility to enhance the application of these types of sensors. (Org. Lett. 2008, 10, 4581–4584; W. Jerry Patterson)

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Directly analyze aliphatic acids in breath. Breath analysis is useful in medical diagnosis and helps to monitor disease development. The standard GC–MS characterization method requires time-consuming sample preparation before analysis and is limited to compounds with molecular weight (MW) <200. P. Martínez-Lozano and J. Fernández de la Mora* at SEADM (Valladolid, Spain) and Yale University (New Haven, CT) discovered that atmospheric pressure ionization mass spectrometry (API-MS) is a convenient method for examining breath components.

In their method, a sample of expelled gas is deprotonated with NH₄OH at ambient pressure. (Breath components are typically a series of fatty acids.) The subsequent identification process can be done in minutes. Compounds of MW 250 are easily detected, and saturated aliphatic acids that cannot be detected via GC–MS can be identified. The quantitative determination of parts-per-trillion levels of compounds is as accurate as in blood tests; however, nonpolar alkane compounds cannot be detected. The procedure must be adjusted for breath components that may be in ambient air. The authors are continuing to improve this technique. (Anal. Chem. 2008, 80, 8210–8215; Sally Peng Li)

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Prepare specific deuterated anilines easily and inexpensively. Isotopically labeled molecules are versatile tools for studying reaction mechanisms and metabolic pathways, and they are useful internal standards in analytical methods. The deuterium atom is the most commonly used isotope.

Unfortunately, the cost of deuterated molecules is extremely high, and synthetic methods to produce them usually use scarce and expensive transition metals complexes and ligands. A. Martins and M. Lautens* at the University of Toronto report a simple microwave-assisted method that uses the reagents HCl and D₂O to synthesize deuterated anilines.

Their protocol consists of heating an anilinium hydrochloride formed in situ in acidic deuterium oxide. They believe that the mechanistic path for the deuteration reaction proceeds via electrophilic aromatic substitution with deuteronium ion (D₃O⁺); thus a low concentration of H₃O⁺ compared with D₃O⁺ would permit almost complete deuteration.

The authors chose 2-methyl-3-nitroaniline as a model substrate and screened several Brønsted and Lewis acids in stoichiometric and catalytic concentrations. They obtained the best results by using 1 equiv of HCl in D₂O and heating the solution to 180 °C by microwave irradiation for 30 min. Using microwaves was superior to conventional heating.

The authors achieved high levels of aromatic-ring deuteration in the positions ortho and para to the aniline amino group in a range of electron-rich and electron-deficient anilines (see figure). p-Aminoacetophenone was also deuterated at the α-position. The presence of phenol or pyridyl groups suppressed deuteration.

The deuterated anilines can be conveniently transformed to aryl iodides by using the conventional diazotization–iodination reaction without reducing the deuterium content. (Org. Lett. 2008, 10, 4351–4353; José C. Barros)

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Use design of experiments to optimize a Suzuki–Miyaura coupling. K. M. Bullock, M. B. Mitchell, and J. F. Toczko* of GlaxoSmithKline (Research Triangle Park, NC) show that several variables must be considered when optimizing a Suzuki–Miyaura coupling reaction. In the case of coupling ethyl 3-bromoindole-2-carboxylate and p-tert-butylbenzeneboronic acid, they first optimized four discrete variables—the ligand, the solvent, the base, and the effect of water. The initial set of experiments identified three sets of conditions that were superior to the starting conditions:

In all cases, the presence of water is beneficial.

A second set of four experiments using various combinations of KHCO₃ or t-BuNH₂ as base and dppb or P(o-tol)₃ as ligand revealed that the base–ligand combination is critical. The best combination is KHCO₃ and P(o-tol)₃, which gives 94% yield with only minimal amounts of ethyl indole-2-carboxylate, an unwanted side product. All other base–ligand combinations form 6–7% of the side product. (Org. Process Res. Dev. 2008, 12, 896–899; Will Watson)

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Tune nanoparticle size in photosensitive copolymers. M. Akashi and co-workers at Osaka University (Japan) use the photosensitivity of cinnamic acid–derived copolymers to develop stimuli-responsive nanoparticles. Specifically, they prepared poly(3,4-dihydroxycinnamic acid)-co-poly(4-hydroxycinnamic acid) [P(3,4DHCA-co-4HCA), 1, n = m] via melt condensation of the corresponding monomers. They obtained P(3,4DHCA-co-4HCA) nanoparticles by centrifuging a suspension of equivalent volumes of solutions (10 mg/mL) in DMF and CF₃CO₂H followed by lyophilization. UV cross-linking of P(3,4DHCA-co-4HCA) was performed in THF (0.04 mg/mL) at wavelengths >280 nm; this resulted in nanoparticles with 860 nm average diam. Irradiation at 254 nm for 30 min reduced nanoparticle size to 420 nm.

Dynamic light scattering and scanning electron microscopy confirmed that this process is reversible (~3 cycles) and that the nanoparticles remain monodisperse; size recovery is almost complete. The authors propose that this reversible size effect is the result of a balance of photo-cross-linking and photocleavage in the chromophoric copolymer system. ¹H NMR studies and UV–vis spectroscopy support the premise that photo-cross-linking dominates the diameter decrease observed upon irradiation at >280 nm. Photocleavage, however, is the dominant mode during the diameter recovery at 254 nm, although the authors also observed photo-cross-linking in this process. The degree of size reduction at >280 nm and the extent of hydrolysis in alkaline buffer are influenced by the degree of cross-linking.

Whereas solvent polarity influences the nonirradiated nanoparticle diameter, the extents of size reduction (~50%) and size recovery (70%) are independent of solvent polarity. P(3,4DHCA-co-4HCA) nanoparticles are soluble in DMF before UV irradiation, but photo-cross-linking of the nanoparticles in the dry state (for 4 or 8 h) results in dispersions and precipitates upon dissolution in DMF. Subsequent irradiation of the nanoparticles (for 8 h) at 254 nm for 30 min confers solubility in DMF, highlighting the reversibility of the photochemical process. This area of research may have direct implications in controlled release applications. (Macromolecules 2008, 41, 8167–8172; LaShanda Korley)

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