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Noteworthy Chemistry

August 26, 2013

A chiral polymer emits anisotropic circularly polarized light. When a chiral polymeric luminogen is excited, it can generate circularly polarized luminescence (CPL). The extent to which the light emission is polarized is quantified by its luminescence dissymmetry (or anisotropy) factor, glum. The glum value for a small molecule is normally small (<0.01).

Chiral conjugated polymer with highly anisotropic light emission

Y. Cheng, C. Zhu, and co-workers at Nanjing University (China) developed a chiral conjugated polymer (1) that has very large emission anisotropy—a glum value as high as 0.44.

The team synthesized the chiral polymer by coupling 1,2-bis(4-ethynylphenyl)-1,2-diphenylethylene with 3‛,5'-diiodo-N-α-tert-butoxycarbonyl-O-octyl-L-tyrosine methyl ester. When it is dissolved in an organic solvent, 1 is weakly fluorescent, but when it is suspended in an aqueous medium, it emits light strongly at a λmax of ≈500 nm. This is a new example of aggregation-induced emission. The polymer’s glum value can easily be tuned over a wide range (0.08–0.44) by varying the H2O/THF ratio in the solvent. (J. Mater. Chem. C 2013, 1, 4713–4719; Ben Zhong Tang)

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Should you use catalytic or stoichiometric trifluoromethylation? In the course of developing a scalable route to the key pharmaceutical intermediate methyl 6-chloro-5-(trifluoromethyl)nicotinate, J. A. Mulder and colleagues at Boehringer Ingelheim Pharmaceuticals (Ridgefield, CT) investigated the trifluoromethylation of the substrate methyl 2-chloro-3-iodopyridine-5-carboxylate. They chose copper-mediated trifluoromethylation with ClF2CCO2Me and KF because the reagents are inexpensive and readily available.

The authors developed a catalytic reaction that uses copper thiophene-2-carboxylate as the catalyst at 80°C. They chose 1,10-phenanthroline as the ligand and dipolar aprotic solvents such as N-methylpyrrolidinone or N,N-dimethylacetamide. Under these conditions, however, the reaction produced significant amounts—up to 20%—of impurities that contained perfluoroalkyl groups. This result was not unexpected with a poorly activated substrate because the relatively long lifetime of CuCF3 in the reaction medium favors chain extension.

The authors then developed a stoichiometric reaction that uses CuI and the slow addition of ClF2CCO2Me at 120 °C. In the workup, aqueous oxalic acid is added to give a product suitable for filtration. The assay yield is 68%, and the product is 92.3% pure. (Org. Process Res. Dev. 2013, 17, 940–945; Will Watson)

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The type of force applied to a luminogen affects its emission. Mechanochromic luminescence is an intriguing phenomenon that has not been thoroughly explored. In particular, it is still unclear how different types of mechanical force affect luminescent mechanochromism. To determine the effects of various forces, S. Saito, S. Yamaguchi, and coauthors at Nagoya University (Japan), the Japan Science and Technology Agency (Nagoya), the National Institute for Materials Science (Ibaraki, Japan), the National Institute of Advanced Industrial Science and Technology (Ibaraki), Rigaku Corp. (Tokyo), and JEOL Resonance Inc. (Tokyo) measured the changes in the solid-state luminescence of a thiophene-based luminophore caused by mechanical grinding or hydrostatic compression.

A Stille coupling reaction between tetrabromothiophene and 2-stannylthiazole gives 2,3,4,5-tetra(2-thiazolyl)thiophene (1) in 71% yield. In the crystal structure of 1, the thiazole rings in the 3- and 4-positions twist away from the thiophene core, whereas the rings in the 2- and 5-positions are coplanar with it. Compound 1 exhibits blue fluorescence (λmax 453 nm) in CH2Cl2 solution and in a poly(methyl methacrylate) (PMMA) film (10 wt%). In its crystalline state, however, it emits yellow light (λmax 556 nm).

Luminogen 1 and its solid-state emissions

The emission of crystalline 1 blue-shifts from yellow to green (λmax 490 nm) when it is subjected to anistropically applied mechanical grinding. On the other hand, the emission red-shifts to orange (λmax 609 nm) under isotropically applied hydrostatic compression. The original crystals can be recovered by recrystallization and decompression, respectively.

The authors attribute the yellow emission from crystalline 1 to excimer formation. Mechanical grinding disrupts the excimeric arrangement and consequently enhances the emission of monomeric 1, leading to blue-shifted emission. Strong hydrostatic compression, however, facilitates the formation of excimer pairs with strong intermolecular interactions, which red-shifts the emission. (J. Am. Chem. Soc. 2013, 135, 10322–10325; Xin Su)

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Use vibrational circular dichroism as an alternative to crystallography. Most drugs that reach the market are chiral, making it important to determine absolute stereochemistry during drug development. The gold standards for assigning absolute stereochemistry are single-crystal X-ray crystallography or a stereocontrolled synthetic route. S. Wesolowski* and D. Pivonka at AstraZeneca Pharmaceuticals (Wilmington, DE) report that vibrational circular dichroism (VCD) is a more rapid alternative for assigning absolute stereochemistry.

A VCD spectrum is the differential absorbance between left and right circularly polarized IR light from a chiral sample. This method has limited sensitivity, but it has advantages such as well-defined bands for assigning absolute configurations and no need for a crystal sample. The authors give examples of the application of VCD in the drug-development process. In most examples, the experimental VCD spectrum is compared with a quantum mechanical simulation.

In one example, the authors applied the technique to determine unambiguously the stereochemistry of neurokinin-3 antagonist AZD2624 by analyzing its amine intermediate. In another, VCD was used to reassign the configuration of cipralisant, a histamine-3 ligand, to (1S,2S); it was originally reported as (1R,2R). A third example is the recognition of an unanticipated effect of substituents in N-methyl-D-aspartic acid antagonists: Upon methylation, the biologically more active compound changes from one with an amino group on one side of the plane to another with the amine on the other side. [Interestingly, by nomenclature rules, both compounds have the (S)-configuration.].

The authors conclude that VCD is a valuable tool for drug development. They believe that partnerships between pharmaceutical companies, universities, and fee-for-service companies can expand the use of VCD by the drug industry. They also point out that this technique has been recognized by the US Food and Drug Administration as an acceptable method for assigning stereochemistry. (Bioorg. Med. Chem. Lett. 2013, 23, 4019–4025; José C. Barros)

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Make photohealable disulfide networks with shape-memory behavior. A research team at Case Western Reserve University (Cleveland) and Hathaway Brown School (Shaker Heights, OH) led by S. J. Rowan prepared healable shape-memory materials that contain dynamic disulfide bonds. Specifically, they synthesized a semicrystalline polydisulfide network by oxidatively coupling a bisthiol oligomer to a tetrathiol cross-linker. Their targeted cross-link densities were 4, 8, and 12 kDa.

The semicrystalline, covalent network systems were photohealable with complete restoration of mechanical properties at 5 min of irradiation. Healing was induced above the materials’ melting transitions by thermal treatment and low-dose irradiation or by high UV intensity. One-way shape memory was achieved for all targeted densities, with shape recoveries of >95%.

The authors showed that the dynamic nature of the covalent cross-links allowed the “permanent” shapes of these materials to be reprogrammed. Of particular interest is the ability to combine shape memory and photohealing to reduce the size of a large surface scratch before healing so that the material’s mechanical strength is recovered. (ACS Macro Lett. 2013, 2, 694–699; LaShanda Korley)

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Agitating the gelator forms the gel. The gelation of supramolecular systems can be stimulated by a variety of external driving forces, including pH, light, redox, and ultrasound. Most these stimuli rely on chemical modification to function. W. R. Browne, B. L. Feringa, and co-workers at the University of Groningen (The Netherlands) show that gel formation can be triggered by mechanically stimulating a bisurea gelator at room temperature. This finding introduces a new route to stimulus-induced gelation of low–molecular-weight gelators.

The authors synthesized organogelator 1,1′-(9-tetradecyl-9H-carbazole-3,6-diyl)bis(3-ethylurea) from 9H-carbazole in four steps. A solution of the gelator in DMSO (20–40 mg/mL) forms a stable gel upon mechanical agitation such as shaking or stirring. Longer, more vigorous agitation leads to turbid gels, whereas shorter, milder treatment gives a more translucent appearance.

Shaking gels the solution; heating reliquefies it

When a heated solution of the molecule is heated and then cooled to room temperature, it converts to a gel or remains a solution depending on the heating temperature. When the solution is heated to <75 °C, the gel fibers disperse into fibrils but do not fully dissolve and therefore return to the gel form upon cooling.

The authors propose a gel-formation mechanism in which small hydrogen-bonded aggregates are susceptible to mechanical disturbances that provide energy for further aggregation. Alternatively, it is possible that mechanical agitation breaks existing fibrils into fragments that act as nucleation points that trigger fiber growth via rapid formation of larger fibrils. (Langmuir 2013, 29, 8763–8767; Xin Su)

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