Noteworthy Chemistry

September 12, 2011

“Pool chlorine” converts aryl trifluoroborates to aryl chlorides. G. A. Molander* and L. N. Cavalcanti at the University of Pennsylvania (Philadelphia) studied the use of potassium organotrifluoroborates as substrates for late-stage aryl ring chlorination. Chlorinating electron-rich aryltrifluoroborates with common agents such as NaOCl proceeds readily in good yields. However, the authors found that aryltrifluoroborates with electron-withdrawing groups resisted all attempts at chlorination.

The authors subsequently evaluated other chlorinating agents for electron-poor aryltrifluoroborates (e.g., 1), with less than desirable results. When they treated these resistant substrates with trichloroisocyanuric acid (2) as an electrophilic chlorinating agent, however, the desired chlorinated product 3 formed in high yield under mild conditions. Reagent 2 is also an excellent choice for economic reasons—it is commercially available (notably as swimming pool “chlorine”) and inexpensive.

Encouraged by the positive results with aryl- and heteroaryltrifluoroborate reactants, the authors extended the study to the corresponding alkyl, alkenyl, and alkynyl substrates with equally efficient results (products 4, 5, and 6 in the figure). The variety of substrates demonstrates that the reaction is tolerant to functional and protecting groups. The researchers note that in these cases, product formation is somewhat unpredictable.

The authors also treated the aryltrifluoroborate substrate with NaBr under standard conditions to obtain the brominated product in 94% yield. This metal-free reaction method is the first reported example of chlorodeboronation of organotrifluoroborates. (J. Org. Chem. 2011, 76, 7195–7203; W. Jerry Patterson)

Use vinyl group polymerization to make functional polypeptides. J. Cheng and coauthors at the University of Illinois at Urbana-Champaign and the University of Connecticut (Storrs) developed a flexible synthetic route to functional polypeptides that is based on benzyl-L-glutamate. Specifically, they synthesized derivatives of γ-(4-vinylbenzyl)-L-glutamate (VB-Glu) by the ring-opening polymerization of its stable (>6 months), N-carboxy anhydride (VB-Glu-NCA) in multigram quantities.

The authors optimized the polymerization by initiating the reaction with hexamethyldisilazane (HDMS) and using a radical retarder (PhNO2) and a catalyst (1,5,7-triazabicyclo[4.4.0]dec-5-ene) to yield high–molecular weight (≈47 kDa), low-polydispersity (1.08) poly‍[γ-(4-vinylbenzyl)-L-glutamate] (PVBLG). The optimized polymerization ran at a faster rate with higher conversions than the original reaction.

The vinyl unit in PVBLG can be postfunctionalized to incorporate a variety of functional groups—such as carboxylic acid, aldehyde, alcohol, and allyl chloride—in yields between 60 and 90%. It can also be used to prepare organogels via cross-linking with UV light. In one example, functionalization to form a 1,2-diol makes the derivatized PVBLG water soluble.

The authors point out that this method can be used to prepare block copolypeptides with poly‍(ε-Cbz-L-lysine); Cbz is carbobenzoxy. This synthetic method may simplify the design of functional polypeptides for biotechnological applications. (Macromolecules 2011, 44, 6237–6240; LaShanda Korley)

Enhance chemistry education for children. Many parents complain that American education is deficient in science, technology, engineering, and mathematics (STEM) instruction. Some educators believe that students should begin STEM studies as early as possible and that appropriate STEM-related material should be covered in non-STEM courses.

T. S. Kuntzleman* and B. W. Baldwin at Spring Arbor University (MI) are among these educators. To fulfill their mission, they organize science-based activities in nearby elementary and middle schools throughout the school year. They frequently visit shopping centers, fairs, and places of worship to perform hands-on chemistry experiments. They also hold “Math and Science Night” at elementary schools. Around Halloween, the authors invite children to come to their campus in costume to perform lab experiments. Their major outreach program is “Cougar Science Camp”, which runs for one week each summer.

College students participate in events during the school year by giving lessons, setting up experiments, and supervising the younger students. During the summer, when college students are not available, parental assistance proves invaluable. The organizers involve faculty members from other departments, such as mathematics, physics, and computer science, to round out the students’ experiences. The authors recommend these types of activities to educators to spur children’s interest in STEM studies. (J. Chem. Educ. 2011, 88, 863−867; Sally Peng Li)

A fluorescent nanoprobe selectively images cancer cells. Preparing dendrimeric polymers involves tedious multistep reactions, and making nanoparticles with desired sizes and morphologies from linear polymers requires complex engineering control. Hyperbranched polymers, on the other hand, can be readily synthesized in one-pot reactions and are intrinsic molecule-based nano-objects whose sizes and structures are easily manipulated by changing the number of generations and center–periphery combinations.

Taking advantage of the unique features of hyperbranched polymers, B. Liu and coauthors at the National University of Singapore and the Beijing Institute of Technology developed the first example of a fluorescent nanoprobe system based on a hyperbranched conjugated polyelectrolyte (HCPE), and they applied it to targeted imaging of cancer cells.

The researchers synthesized the HCPE with a core–shell structure by using alkyne polycyclotrimerization, and they functionalized its shell with poly‍(ethylene glycol) with a click reaction. The HCPE is soluble in water and emits visible light at 565 nm with a large Stokes shift of 143 nm. The HCPE spontaneously forms spherical nanoparticles that minimize nonspecific interactions with biomolecules in aqueous media, paving the way for the efficient bioconjugation of the nanoparticle shell with the anti–human epidermal growth factor receptor 2 (anti-HER2) Affibody.

The bioconjugated HCPE nanoparticles are cytocompatible and photobleaching-resistant. They function as an excellent bioprobe for targeted imaging of HER2-overexpressed cancer cells. This study presents a new molecular design strategy for overcoming intrinsic limitations of conventional polymers for developing efficient fluorescent biosensors. (Biomacromolecules 2011, 12, 2966–2974; Ben Zhong Tang)

Form mature amyloid fibrils in seconds with protic ionic liquids. N. Debeljuh, C. J. Barrow, and N. Byrne* at Deakin University (Geelong, Australia) show that the rate of β-amyloid Aβ16-22 peptide fibrilization follows a reverse Hofmeister trend in protic ionic liquids (PILs). PILs that contain “kosmotropic” anions accelerate Aβ fibrilization by a “salting-out”–like process.

The authors found that in some kosmotropic PILs, fibrilization occurs in <1 min, compared with days or even weeks required for Aβ to fibrilize in traditional buffered aqueous solutions. The accelerated fibrilization holds promise for biomaterial applications because amyloid fibrils are exceptionally strong materials. The authors believe that the production of Aβ peptides on a time scale of seconds is a key step toward making the manufacture of amyloid-based materials practical.

The ability to form amyloid fibers rapidly should facilitate higher-throughput amyloid inhibitor bioassay development for Alzheimer’s, Parkinson’s, Huntington’s, and Creutzfeldt–Jakob diseases. The controlled formation of amyloid over short time scales should also encourage research on more fundamental mechanistic studies of amyloid formation, which could lead to an improved understanding of the role of amyloid formation in neurodegeneration. (Phys. Chem. Chem. Phys. 2011, 13, 16534–16536; Gary A. Baker)

Which is the stronger base: hydroxide or tert-amylate? The final step in the original synthesis of the sarcoma kinase inhibitor AZD0530 consists of an SNAr alkoxide displacement with a piperazinylethanol that uses sodium tert-amylate as the base in tert-amyl alcohol solvent with 1 equiv water. The isolated yield of AZD0530 is 63%. This system presumably generates NaOH in situ.

S. A. Raw*, B. A. Taylor, and S. Tomasi at AstraZeneca (Macclesfield, UK) first improved the process by changing the solvent to toluene. Computational studies showed that NaOH is a much stronger base than sodium tert-amylate in the gas phase and a much weaker base in water. In toluene, the two bases are almost equal in strength. Running the reaction with NaOH as the only base and 1 equiv water in toluene gave a cleaner reaction and a higher yield (80%) of product. (Org. Process Res. Dev. 2011, 15, 688–692; Will Watson)

Use copper nanoparticles to reduce azides to amines. S. Ahammed, A. Saha, and B. C. Ranu* at the Indian Association for the Cultivation of Science (Jadavpur) found that copper nanoparticles promote the highly chemoselective reduction of substrates such as aryl azides. This process proceeds by hydrogenation on the Cu‍(0) particle surfaces in aqueous media to form the corresponding amine. The presence of NH4HCO2 is essential for promoting this reaction.

The authors prepared 6–8-nm diam copper nanoparticles from CuSO4 and NH2NH2·H2O in ethylene glycol according to a literature procedure (Zhu, H.; Zhang, C.; Yim, Y. Nanotechnology 2005, 16, 3079–3089). The study encompassed a wide range of substituents on the phenyl azide to demonstrate the chemoselectivity and functional group tolerance of the reaction. Particularly interesting examples are o-, m-, and p-nitrophenyl azide, each of which gives clean reduction to the desired amine with no nitro group reduction.

The authors illustrated the specific value of copper nanoparticles for this reduction by comparing product yields from nanoparticles with those from freshly prepared metallic copper powder. The reduction of p-cyanophenyl azide using nanoparticles gives a 91% yield of the amine product, compared with a 14% yield when the powder is used.

The authors believe that the reaction mechanism involves adsorbed hydrogen on the nanoparticle surfaces and that this is the first reported use of copper nanoparticles as a catalytic surface for hydrogenation. The process has several advantages:

  • use of water as the reaction medium,
  • cost-effectiveness of the nanoparticles,
  • operational simplicity of the reaction,
  • excellent chemoselectivity,
  • functional group tolerance, and
  • easy accessibility to the azide substrates from the corresponding halides or sulfonates.

(J. Org. Chem. 2011, 76, 7235–7239; W. Jerry Patterson)

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