Noteworthy Chemistry

November 26, 2012

Use 13C NMR to assign 1H-1,2,3-triazole structures. 1H-1,2,3-Triazoles are important structures in organic chemistry. They are typically obtained by cycloaddition reactions between azides and alkynes. Copper-mediated cycloadditions give 1,4-disubstituted triazoles (the “click” reaction), whereas ruthenium catalysts produce 1,5 disubstituted triazoles.

In many studies, triazole structures are not “proven”, but are assigned according to the catalyst used. Until now, only crystallography and complex NMR methods (e.g., nuclear Overhauser effect and heteronuclear multiple quantum coherence) have characterized triazoles fully.

X. Creary and co-workers at the University of Notre Dame (IN) used an “old-school” gated decoupling sequence in 13C NMR spectroscopy (decoupler off during acquisition) to develop a method for assigning the correct structures of 1,4- and 1,5-disubstituted 1H-1,2,3-triazoles (1 and 2, respectively). In the decoupled spectrum, C5 in 1 appears as a doublet of triplets with a C–H coupling constant of 191 Hz and a secondary constant of 2.7 Hz from three-bond coupling with the benzylic hydrogen atoms. C4 in 2 has a coupling constant of 195 Hz and a much smaller triplet coupling constant than 1 because the benzylic hydrogens are one bond farther away.

The undecoupled C5 signals in triazoles such as 1 are upfield (≈120 ppm) of C4 signals in 2 (≈133 ppm). The authors explain this result in terms of valence bond considerations: Isomer 1 has a resonance form in which a formal negative charge can be placed on C5, whereas C4 in 2 does not. Computational studies confirmed the experimental findings. (J. Org. Chem. 2012, 77, 8756–8761; JosÉ C. Barros)

Take a bilayer route to tendon repair. W. Cui, C. Fan, and colleagues at Shanghai Jiao Tong University and Soochow University (Jiangsu, China) were inspired by natural tendon sheaths to develop an electrospun bilayer membrane consisting of a poly(ε-caprolactone)–hyaluronic acid (PCL-HA) inner sheet capped by a PCL barrier layer. They prepared the PCL layer by electrospinning and formed the tendon-inspired bilayer by sequentially microgel electrospinning PCL-HA.

The electrospun bilayer membranes with HA-embedded PCL as the synovial-like layer and PCL as the antiadhesion layer are composed of smooth, uniform fibers. The degree of hydrophilicity is tuned by adjusting the HA content.

After an initial burst release, HA undergoes sustained slow release. The release profile varies with HA fraction. The authors observed adhesion, cell proliferation, and cell viability on the PCL-HA inner layer. Treating tendon damage with this bioinspired construct prevents fibrous, peritendinous adhesions. (Biomacromolecules 2012, 13, 3611–3619; LaShanda Korley)

Here’s an air- and moisture-stable fluorinating agent. Organofluorine compounds, which are useful for drugs and agricultural chemicals, rarely occur in nature. Consequently, fluorination is an important organic reaction for producing these compounds. Most fluorinating agents, however, decompose and/or hydrolyze when they are exposed to air. S. Hara and co-workers at Hokkaido University (Sapporo, Japan) developed a solid-state fluorinating reagent that is air- and moisture-stable, which makes fluorination easier and safer.

The authors mixed equimolar amounts of IF5, an unstable fluorinating agent, and pyridine–HF to form an adduct of the two as a white solid. The product, IF5–pyridine–HF, consists of the three components in 1:1:1 stoichiometry. It dissolves well in DMF and is slightly soluble in MeCN. In addition to its excellent air and moisture stability, IF5–pyridine–HF has good thermal stability: It decomposes only gradually when heated to >100 °C.

IF5−pyridine−HF is less reactive than IF5, but it reacts with a variety of benzylic sulfides to undergo desulfurizing difluorination under mild conditions (≈20–40 °C) in high yields (79–99%). Treating aldehyde and ketone dithioacetals with IF5−pyridine−HF at ≈20 °C also gives the corresponding gem-difluorides in 62–92% yield.

The authors show that IF5−pyridine−HF converts the benzaldehyde dithioacetal group in compounds 1 to a trifluoromethyl group via 2-methylthio-1,3-dithiane intermediates 2. The reaction between 2 and IF5−pyridine−HF gives the corresponding trifluoromethyl derivatives 3 in 54–83% yield. (Tetrahedron 2012, 68, 10145–10150; Xin Su)

How is flow chemistry being implemented in drug development and production? P. Poechlauer and coauthors at DSM Innovative Synthesis B.V. (Geleen, The Netherlands), the ACS Green Chemistry Institute (Washington, DC), and AstraZeneca R&D Södertälje (Sweden) report the results of a survey of the eight largest pharmaceutical companies and one supplier of pharmaceutical intermediates and active ingredients. The survey covered the trend of converting from batch to continuous flow processes and its green chemistry implications.

The main hurdles to introducing continuous processes in pharmaceutical manufacturing are

  • the investment required when there is large existing capacity in standard batch and semibatch manufacturing plants,
  • uncertainty as to whether a continuous process will deliver sufficient benefits in light of a shortness of workers with the right skills,
  • difficulties with currently available systems, and
  • the shortness of equipment at all scale levels.

The second impediment led to the formation of multidisciplinary teams. These initiatives, however, have been sidetracked by financial problems, mergers, and acquisitions. (Org. Process Res. Dev. 2012, 16, 1586–1590; Will Watson)

Polymers without conventional fluorophores fluoresce strongly. “Traditional” fluorescent polymers usually contain fluorophore units with extended π-conjugation. Only a few polymers that do not contain these fluorophores are fluorescent, for example, colloidal nanoparticles of poly[(maleic anhydride)-alt-(vinyl acetate)], which has no aromatic rings (Hong, Y.; Lam, J. W. Y.; Tang, B. Z. Chem. Soc. Rev. 2011, 40, 5361–5388). Several new members have been added to this family by C.-Y. Hong, Y.-Z. You, and co-workers at the University of Science and Technology of China (Hefei).

The researchers used radical polymerization reactions of a variety of vinyl monomers that contain no fluorophore units in the traditional sense to synthesize a series of fluorescent polymers (see figure). Although none of the reagents (e.g., monomers, initiators, and chain-transfer agents) used in the polymerization process are fluorescent, the resulting polymers emit strongly. Their fluorescence intensities increase with increasing molecular weight. The authors identified the π–π interactions of the phenyl units with the neighboring carbonyl units as the main cause of the unusual fluorescence. (Adv. Mater. 2012, 24, 5617–5624; Ben Zhong Tang)

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