Noteworthy Chemistry

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This edition of Noteworthy Chemistry (NC) marks the first contribution of Beth Ashby Mitchell. Beth is a long-time copyeditor for NC and many other portions of the ACS Web site. She formerly wrote and edited for Chemical Innovation and CHEMTECH magazines and other ACS publications.

March 5, 2012

Make an insulated molecular wire with self-click polymerization. Insulated molecular wires (IMWs) are promising materials for building next-generation unimolecular electronic devices. The click reaction is a powerful synthetic tool that is used by polymer chemists to prepare dendritic, hyperbranched, and linear polymers. Few attempts, however, have been made to use the click reaction to synthesize π-conjugated polymers. J. Terao, S. Seki, and co-workers at Kyoto University and Osaka University demonstrate the utility of click polymerization for synthesizing IMWs.

The researchers attached a π-conjugated guest molecule to a permethylated α-cyclodextrin (PMCD) host. The lipophilic [2]rotaxane monomer (1) forms a guest–host self-inclusion complex (2) in a hydrophilic solvent. Click polymerization between the azido and alkynyl groups in 2 leads to a rigid IMW with high molecular weight (Mw = 100 kDa) and clad by PMCD rings (3). The IMW is highly soluble in common organic solvents and has high photoluminescence efficiency. (Chem. Commun. 2012, 48, 1577–1579; Ben Zhong Tang)

Detect DNA with a personal glucose meter. Detecting DNA typically requires sophisticated lab equipment and procedures that are too expensive and cumbersome to use in the field. Y. Xiang and Y. Lu at the University of Illinois at Urbana–Champaign used readily available, inexpensive personal glucose meters (PGMs) to develop a portable system for quantitatively detecting DNA, including hepatitis B virus DNA. In earlier work, the authors used PGMs linked to DNA sensors to quantify a variety of targets, including organic molecules, proteins, and metal ions (Xiang, Y.; Lu, Y. Nat. Chem. 2011, 3, 697–703).

PGMs are used to monitor blood glucose; thus the authors’ challenge was to transform the DNA strands in the samples into glucose. They had to establish a link between the target DNA, which was present at picomolar to nanomolar levels in the samples, and the millimolar levels of glucose needed for the signal readout of the PGM (0.6–33 mM).

The polymerase chain reaction method amplifies DNA strands to achieve sensitive detection, however, it is vulnerable to contaminants such as DNA polymerase inhibitors and reagents that lower polymerase specificity. To amplify the signal without amplifying the DNA strands, the authors introduced DNA–invertase conjugates that amplify the DNA signal based on enzymatic turnovers. The conjugates were immobilized and used to catalyze the hydrolysis of PGM-inert sucrose to PGM-detectable glucose.

The authors’ preparation steps make it possible to apply their method to complicated biological samples, such as body fluids. By taking DNA detection from large, expensive laboratory procedures to inexpensive, portable PGMs, they have opened up vast possibilities for analysis in the field, small laboratories, and even homes. (Anal. Chem. 2012, 84, 1975–1980; Beth Ashby Mitchell)

Synthesize artemisinin in a continuous-flow apparatus. Malaria is a global public health problem that causes one million deaths per year. Artemisinin, a natural product extracted from the sweet wormwood plant (Artemisia annua), is a sesquiterpene endoperoxide with antimalarial properties. Its total synthesis, however, is laborious and economically prohibitive.

One of the drawbacks to artemisinin’s total synthesis is a photochemical reaction step that involves singlet oxygen. It cannot be scaled up because of the instability of singlet oxygen in large vessels. F. LÉvesque and P. H. Seeberger* at the Max Planck Institute for Colloids and Interfaces (Potsdam, Germany) and the Free university of Berlin developed a semisynthesis of artemisinin using a flow-chemistry technique.

The authors’ starting material is artemisinic acid (1), a simpler compound that can be extracted or produced by a microbiological route. The first step is the reduction of 1 to produce dihydroartemisinic acid (2).[The reduction method is not mentioned in the article or supporting information.—Ed.] The key second step is a singlet-oxygen ene reaction of 2 under continuous flow conditions. To accomplish this, a reactor tube is wrapped helically around a lamp and surrounded by a cooled immersion well. When 2, CH2Cl2, tetraphenylporphyrin (TPP) photosensitizer, and oxygen are fed into the reactor, it continuously generates singlet oxygen, which reacts in situ to produce hydroperoxide 3.

The final steps are the acid-mediated cleavage of the O–O bond (Hock cleavage) and subsequent ring opening to make compound 4; oxidation by triplet oxygen to obtain hydroperoxide 5, and condensation–cyclization to produce artemisinin (6) in 39% overall yield after chromatographic purification. These three steps are performed consecutively in a continuous-flow reactor without isolating intermediates 4 and 5.

With a 20-mL photochemical reactor tube, 200 g of artemisinin can be synthesized per day. In principle, 1500 of these reactors could meet the global demand for artemisinin. Optimization of the procedure may lead to greater efficiencies. (Angew. Chem., Int. Ed. 2012, 51, 1706–1709; JosÉ C. Barros)

Make core–shell PEO-chitosan nanofibers by coaxial spinning. M. Pakravan, M.-C. Heuzey*, and A. Ajji* at Montreal Polytechnic made coaxially electrospun fibers that consist of a poly(ethylene oxide) (PEO) core and a functional chitosan shell. Smooth, uniform core–shell nanofibers were obtained with an inner PEO concentration of 3% and 4 wt% in 50% HOAc solutions to induce spinnability of the chitosan feed stream. Transmission electron microscopy showed that the PEO core has a ≈100-nm diam and that the chitosan shell is ≈200 nm thick. Simple extraction of the PEO core with water produces hollow chitosan nanofibers.

During the electrospinning process, controlling the rate of solvent evaporation resulted in almost completely amorphous chitosan and PEO with reduced crystallinity (e.g., a melt temperature decrease from ≈69 °C to ≈62 °C) in the coaxial fibers. Analysis of the nanofiber surfaces confirmed the presence of nitrogen in the chitosan shell. The authors calculated the surface area of the coaxial nanofibers to be ≈15 m2/g. They suggest that the hybrid nanofibers may have applications in tissue engineering and purification technologies. (Biomacromolecules 2012, 13, 412–421; LaShanda Korley)

Fluorescent molecular wires “conduct” neuronal signals. Fluorescence imaging by fluorescent voltage-sensitive dyes (VSDs) is widely used to monitor neuronal activity. Two major types of VSDs, electrochromic and Förster resonance energy transfer dyes, however, have intrinsic disadvantages such as low sensitivity, slow kinetics, and heavy capacitative loading. To improve the efficiency of this fluorescence imaging method, R. Y. Tsien and co-workers at the University of California, San Diego (La Jolla) introduced a type of VSD that detects neuronal voltage changes via a photoinduced electron transfer (PeT) mechanism.

The authors synthesized the fluorescent sensors (VoltageFluors, or VFs, 3) by coupling a phenylenevinylene-based conjugated molecular “wire” precursor (1) with a dichlorosulfo-fluorescein fluorophore (2). The wire contains N,N-dialkyl groups on one end that, as electron donors, effectively quench the excited state of the fluorophores. This design allows the molecular wires to adopt the optimum orientation in the membrane to take the full advantage of the directionality of the transmembrane electric field. The sulfofluorescein unit tends to absorb to the outer leaflet of the plasma membrane, whereas the lipophilic wire stays in the lipid bilayer.

During hyperpolarization, the orientation of the electric field is opposite to the direction of electron transfer, thus facilitating the PeT fluorescence quenching process. Depolarization reverses this orientation, hampering the PeT process and increasing fluorescence. Staining tests of VFs with human embryonic kidney 293 cells show a linear response range of –100 mV to +100 mV, with a highest voltage sensitivity of 27% ΔF/F per 100 mV.

Ultrafast electron transfer does not delay signal response to voltage change, resulting in the same time constants as measured by the electrophysiological method. In addition, VFs exert no influence on cells by capacitative loading.

As fluorescence imaging reagents, however, VFs are limited. VF dyes lack genetic targetability, which decreases the signal-to-noise ratio. There is also room for enhancing the sensitivity of VFs to match that of the electron transfer mechanism. (Proc. Natl. Acad. Sci. USA 2012, 109, 2114–2119; Xin Su)

Is tungstic acid–catalyzed hydrogen peroxide epoxidation safe? S. Shilcrat at GlaxoSmithKline (King of Prussia, PA) describes an investigation into a runaway reaction that occurred when a published procedure for epoxidizing 2,4-pentadien-1-ol with H2O2 and a H2WO4 catalyst was applied to trans,trans-2,4-hexadien-1-ol. The reaction was conducted on a 30-g scale. The flask contents erupted violently a few minutes after the H2O2 addition was completed, and the flask was too hot to touch.

Advanced Reactive System Screening Tool studies showed that, in the presence of the tungsten catalyst, H2O2 decomposition in the absence of a substrate initiates at 40–47 °C and generates gaseous byproducts. Higher catalyst loadings lead to lower onset temperatures and more rapid decomposition.

In the presence of the substrate, the onset temperature is similar (40–42 °C), but the amount of generated heat increases significantly. Gas generation, however, is reduced, presumably because the H2O2 reacts with the substrate. (Org. Process Res. Dev. 2011, 15, 1464–1469; Will Watson)

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