Noteworthy Chemistry

June 10, 2013

This metal-free, salt-mediated arene chlorination process proceeds under mild conditions. Chlorinated aromatics are important building blocks in organic and medicinal chemistry. These compounds are usually produced by treating arenes with molecular chlorine, reagents such as N-chlorosuccinimide, or chloride ion in the presence of an oxidant and a transition-metal catalyst.

Y. Zhang and co-workers at the Institute of Bioengineering and Nanotechnology (Singapore) developed a way to prepare chloroarenes by treating aromatics with chlorides in the absence of metal catalysts. The key to their method is using a peroxydisulfate salt (e.g., K2S2O8) as the oxidant—a better choice than CuCl2 or PhI(OAc)2—in a two-phase reaction medium composed of MeCN and a saturated aqueous chloride solution.

The researchers discovered that chloride counterion affects the selectivity of the reaction. Using NH4Cl gives monochlorinated products, whereas NaCl leads to dichlorinated products. The authors tested the process on several substituted arenes; the results indicate that their method works equally well for arenes that contain electron-withdrawing or weak electron-donating groups (R in the figure).

The authors have not fully worked out the reaction mechanism. Initial attempts to explain it suggest that the reaction proceeds via K2S2O8 (SO4.) oxidation of Cl to more reactive chlorinating species (“Cl+”, from Cl2O, or Cl2), which react with arenes in situ. The method is efficient and practical, uses inexpensive reagents, and proceeds under mild reaction conditions. (Adv. Synth. Catal. 2013, 355, 1077–1082; José C. Barros)

Scale up a Negishi coupling. In the course of improving the synthesis of a potent CRTH2 receptor antagonist for scale-up, L. Shu and co-workers at Hoffmann-La Roche (Nutley, NJ) modified the Negishi coupling reaction that leads to the desired product. They prepared the zinc reagent by inserting a zinc atom directly into 4-methanesulfonylbenzyl chloride.

The original zinc-activation procedure required a mixture of predried zinc dust and LiCl to be further dried at 170 °C, suspended in THF, and treated three times with 1,2-dibromoethane and once with Me3SiCl. However, a simpler procedure works equally well and is less exothermic: suspending zinc dust in DMF and adding Me3SiCl.

If the water content of the DMF is low upon scale-up, the authors add i-PrOH to help generate HCl—the actual reagent that cleans the zinc surfaces. The palladium catalyst was also simplified and made less expensive: They replaced Pd(OAc)2–S-Phos with (PPh3)2PdCl2. (Org. Process Res. Dev. 2013, 17, 651–657; Will Watson)

Make sugars from hazardous wood waste. Chromated copper arsenite (CCA) was used for decades as a wood preservative, but in the early 2000s, many countries began to limit its use. Large amounts of CCA-treated wood are decommissioned every year; most of it is taken to landfills. This disposal method is costly and creates potential environmental problems.

To overcome the drawbacks of disposing this wood waste and to convert it to useful materials, T. Repo and co-workers at the University of Helsinki and the VTT Technical Research Center of Finland (Otaniemi) developed a treatment protocol for CCA-treated wood that combines oxidation and extraction. The extracts can be hydrolyzed enzymatically to produce sugars.

In CCA-treated wood, copper exists mainly as Cu(II) carboxylates bound to cellulose. Chromium and arsenic exist as CrAsO4 and Cr(OH)3 bound to lignin. The authors found that ethylenediaminetetraacetic acid (EDTA), H2SO4, oxalic acid, and citric acid–H3PO4 remove these metals to various degrees. Steam explosion and pyrolysis reduce the extraction efficiency.

Based on these findings, the authors developed a three-step protocol to convert CCA-treated wood waste to sugars (see figure). In the first step, they subject the waste to catalytic (CatOx) or alkaline (AlkOx) oxidation, which solubilizes 56 and 58% of the material, respectively. Solubilized substances include lignins, hemicelluloses, and metals.

In step two, the cellulose fractions are extracted. EDTA-extracted CatOx cellulose and hydrogen oxalate–extracted AlkOx cellulose give high sugar yields (93–97%) in the subsequent hydrolysis step. Without extraction, the CatOx and AlkOx celluloses give sugar yields of 74 and 58%, respectively.

H2SO4 extraction appears to be the best method, giving ≈90% sugar yields from both types of oxidized celluloses. The sugars are potential feedstocks for biofuels. (ChemSusChem 2013, 6, 813–815; Xin Su)

Probe adhesive–adherent interfaces by using complementary DNA base-pair mimics. S. C. Zimmerman and colleagues in four departments at the University of Illinois at Urbana–Champaign explored the role of complementary, supramolecular interactions in bulk interfacial adhesion. They focused on the association of stable DNA base-pair analogues that have minimal self-associative characteristics: 2,7-diamidonaphthyridine (DAN) and ureido-7-deazaguanine (DeUG).

Polystyrene-containing DAN is prepared in reasonable yield via high-temperature borylation followed by Suzuki–Miyaura cross-coupling the DAN aryl bromide. Glass or silicon wafers treated with (3-aminopropyl)triethoxysilane are functionalized with DeUG via isocyanate chemistry to produce hydrophobic, smooth, stable, uniform surfaces.

The authors measured high shear strengths in lap-shear experiments for cured polystyrene-DAN and DeUG-functionalized surfaces; but they note that “urea [in the linkages], rather than the blocked DNA mimic, primarily contributes to the strength of the adhesion.” Cohesive failure is the dominant mechanical mode in the DAN- and DeUG-mediated surfaces under shear; but a mechanistic understanding of the interfacial strength as a function of diffusion, interfacial thickness, and tailored interactions is needed.

This complementary associative behavior can be extended to fiber surfaces. A complex relationship exists between interfacial strength, supramolecular interactions, and mechanical recovery in these systems. (J. Am. Chem. Soc. 2013, 135, 7288–7295; LaShanda Korley)

Monitor acetylcholinesterase activity with a pyrene probe. Acetylcholinesterase (AChE) is an important enzyme in the nervous system. Increases in its activity are associated with disorders such as Alzheimer's disease. Physicians and researchers need ways to monitor AChE activity in real time and to screen potential AChE inhibitors.

C. Yu and colleagues at the Chinese Academy of Sciences (Changchun and Beijing) developed a choline-labeled pyrene probe that uses the fluorescence change in pyrene’s monomer–excimer transition to detect AChE activity (top line in the figure). They synthesized fluorescent probe Py-Ch in two steps by coupling 1-pyrenebutyric acid with 2-bromoethanol, then using Me3N to form the product’s quaternary ammonium salt.

Py-Ch in solution exhibits characteristic pyrene monomer emission at 375 nm. When the authors added poly(vinylsulfonate) (PVS), a polymeric anion that aggregates Py-Ch by imparting electrostatic attraction, the fluorescence spectrum of Py-Ch contains a new broad band that peaks at 486 nm. The intensity of the 375-nm band decreases—indicative of a monomer-to-excimer transition. Adding AChE regenerates monomer fluorescence and decreases excimer emission because Py-Ch hydrolyzes to anionic 1-pyrenebutyrate and choline in the presence of AChE (bottom line in figure).

The authors demonstrated that the Py-Ch–PVS system can monitor AChE activity in real time and quantify AChE concentration by measuring the IM/IE value: the ratio of the emission intensities of monomer and excimer. The Py-Ch–PVS system is selective for AChE; it can detect AChE activity in concentrations as low as 0.1 unit/mL in physiological environments such as 2% fetal calf serum or 2% cell lysate. The Py-Ch–PVS system can be used for AChE inhibitor screening by estimating the IC50 values of potential inhibitors from fluorometric assays. (Org. Lett. 2013, 15, 2123–2135; Xin Su)

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