Noteworthy Chemistry

September 10, 2012

Click polymers sort out nanotubes with specific chiral angles. The bulk production of single-walled carbon nanotubes (SWCNTs) is not selective: It produces mixtures of nanotubes with a range of diameters, lengths, degrees of metallicity, and chiral angles. Because the physical properties of SWCNTs are dictated by their chiral angles (Θ), postproduction sorting techniques are needed to obtain nanotubes with specific chiralities for studying fundamental properties and facilitating practical applications.

Conjugated polymers such as polyfluorenes can selectively disperse SWCNTs with certain chiral angles into liquid media. These polymers, however, often must be prepared under harsh conditions with demanding synthetic procedures that use expensive catalysts and starting materials. It is desirable to develop new polymers with comparable properties that can be easily and economically synthesized.

C. Barner-Kowollik, M. M. Kappes, and coauthors at the Karlsruhe Institute of Technology (Karlsruhe and Eggenstein-Leopoldshafen, Germany) and the University of Basel (Switzerland) achieved this goal by using click polymerization under mild conditions (see figure). The click polymers selectively distinguish specific SWCNTs from mixtures that contain more than 40 nanotube species. The click polymers are selective toward SWCNTs with large chiral angles (Θ > 20°). Their selectivity is almost identical to that of conventional polyfluorenes. (Polym. Chem. 2012, 3, 1966–1970; Ben Zhong Tang)

Use nanofiltration to recover organic solvents. Large amounts of solvents are necessary for developing and manufacturing active pharmaceutical ingredients (APIs). For each kilogram of API produced, ≈22 kg of organic solvents is used.

Distillation, the main process used for recovering solvents, consumes large amounts of energy. E. M. Rundquist, C. J. Pink*, and A. G. Livingston at GlaxoSmithKline (Stevenage, UK) and Imperial College London report that organic-solvent nanofiltration (OSN) would be useful for solvent recovery in the pharmaceutical industry.

The authors chose several commercial membranes and subjected them to 30 and 60 bar to investigate pressure effects. The results indicated that Starmem 122 (W. R. Grace) was the best membrane based on degree of API rejection (retention of the compound in the membrane).

Isopropyl acetate was chosen as the solvent for the recovery experiments. Recovered solvent was analyzed by GC, HPLC, and Karl Fischer titration. The results indicated that solvent recovered by OSN was as pure as that obtained by distillation.

The authors conducted a pilot-scale study in a prepacked membrane module. HPLC analysis indicated that the recovered solvent was <99% pure, making it reusable only for batch crystallizations. No differences in the type or amount of impurities were observed after four cycles.

Energy calculations showed that OSN consumes 1/25 of the energy per liter of solvent than distillation. Although the amount of solvent recovered by OSN is lower than by distillation (80% vs 90%), this process shows promise for recovering solvents used in API manufacturing. (Green Chem. 2012, 14, 2197–2205; JosÉ C. Barros)

Small changes in a Kv7.2 inhibitor make it an activator. Alzheimer’s disease (AD) affects >20 million people worldwide. Although there is no known cure, current drugs help lessen the symptoms by inhibiting the cholinesterase enzyme, which breaks down acetylcholine, a neurotransmitter in the central nervous system. Potassium channel Kv7.2 has become a new AD drug target because inhibiting it enhances acetylcholine release.

C. R. Hopkins at Vanderbilt University (Nashville, TN), M. Li at Johns Hopkins University (Baltimore), and coauthors set out to identify potent, selective Kv7.2 inhibitors. After screening >300,000 compounds from the NIH Molecular Library Small Molecule Repository, they narrowed the list to several inhibitors, among which compound 1 was the most potent. They found that the (S)-enantiomer of 1 was more potent than the (R)-enantiomer or the racemic mixture. In vivo studies showed that compound (S)-1 easily penetrates the brain.

The authors then synthesized several analogues of 1 and tested them for Kv7.2 inhibition. They unexpectedly discovered that replacing the ethyl group with hydrogen or fluorine changed the analogues to potent Kv7.2 activators.

The authors now plan to study the influence of (S)-1 on acetylcholine release. (J. Med. Chem. 2012, 55, 6975–6979; Chaya Pooput)

The right additives optimize an asymmetric hydrogenation. Asymmetric hydrogenation of the hydrochloride salt of 1-phenyl-3,4-dihydroisoquinoline is a key step in the synthesis of solifenacin, a urinary antispasmodic. M. Ružič, A. Zanotti-Gerosa, and coauthors at Krka d.d. (Novo Mesta, Slovenia) and Johnson Matthey (Cambridge, UK) explored ways to improve this reaction.

The initial screening of a variety of ruthenium- and iridium-based catalysts showed that Ir–BINAP and Ir–P-Phos systems gave the best results (up to 76% ee and 75% conversion). [BINAP is 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; P-Phos is 2,2′,6,6′-tetramethoxy-4,4′-bis(diphenylphosphino)-3,3′-bipyridine.]

The authors then studied the effect of additives on the hydrogenation in various solvents. Iodide salts, bromide salts, and amines reduced enantioselectivity; but acidic additives, especially H3PO4 or a chiral BINAP phosphoric acid, improved selectivities (up to 96% ee). The enantioselectivity of the reaction depended on the combination of additive and solvent used.

The authors ultimately scaled up the reaction with Ir–P-Phos in THF and anhydrous H3PO4 to 200 g. The product was recovered with an isolated yield of 95% with 98% ee and 99.2% purity by HPLC after recrystallization. (Org. Process Res. Dev. 2012, 16, 1293–1300; Will Watson)

Tune a luminogen’s aggregation-induced emission by changing its molecular and packing structures. Aggregation-induced emission (AIE) is a solid-state photophysical effect. Many research groups have tried to manipulate the AIE process in efforts to explore its potential for high-tech applications. A team led by A. K.-Y. Jen at the University of Washington (Seattle) succeeded in fine-tuning the AIE efficiency (quantum yield, Φ) of a luminogen by changing its molecular structure.

Luminogen 1 is AIE active, with a Φ value of ≈11%. When four methoxy groups are introduced into 1 to yield 2, the seemingly subtle change in molecular structure causes a major change in the packing structure. The molecular interactions of 2 are greatly enhanced, as evidenced by its much higher melting point and fusion enthalpy compared with those of parent compound 1. The better crystal packing of 2 blocks the nonradiative decay pathways of its excited states and dramatically increases its Φ value to >56%. (Chem. Commun. 2012, 48, 7880–7882; Ben Zhong Tang)

Magnetic whiskers strengthen all-cellulose nanocomposites. T. Pullawan, A. N. Wilkinson, and S. J. Eichhorn* at the University of Manchester (UK) report that the anisotropic magnetic susceptibility of cellulose nanowhiskers (CNWs) makes them useful as reinforcing fillers in a cellulose matrix. These all-cellulose nanocomposites were prepared under a 1.2-T magnetic field at 5 and 15 vol% in N,N-dimethylacetamide.

The polydisperse, rodlike CNWs had an average aspect ratio of (72.8 ± 40.8):1. Aligning the CNWs increased the overall mechanical properties of the nanocomposites when deformed along the long axis of the whiskers compared with an unaligned control and samples deformed in the transverse direction (i.e., perpendicular to the CNW axis).

The predicted mechanical enhancement was not achieved at 15 vol% CNWs, which suggests that the whiskers were not fully aligned in the cellulose matrix. Reducing the filler content to 5 vol% improved the mechanical behavior of magnetically aligned nanocomposites evaluated parallel to the CNW axis. These improvements demonstrate the relationship between filler content and excluded volume for maximum alignment.

The authors used polarized optical microscopy to probe the local anisotropy of the cellulose nanocomposites, which was greater for the more aligned 5 vol% materials. They emphasize that isotropic regions of CNWs still exist at the lower content. Raman spectroscopy confirmed the efficient stress transfer from the cellulose matrix to the aligned CNWs. (Biomacromolecules 2012, 13, 2528–2536; LaShanda Korley)

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