Noteworthy Chemistry

February 6, 2012


This edition of Noteworthy Chemistry (NC) marks the final submission from long-time contributor W. Jerry Patterson. Jerry has been writing informed summaries of journal articles since he began to write for CHEMTECH’s Heart Cut department in 1996, and the NC staff will miss his thorough, incisive write-ups. Jerry will continue to create chemical structures, reactions, and other images for NC, Patent Watch, and Molecule of the Week.

This issue also contains the first contribution from Xin Su of Dartmouth University. We welcome Xin to the NC “family”!

Prepare enantiopure β-trifluoromethyl-β-amino alcohols from oxazolidines. The β-trifluoromethyl-β-amino alcohol scaffold is useful for synthesizing biologically active compounds. Little has been reported, however, on analogues of this scaffold that are quaternarized at the β-position.

J. Simon, E. Chelain*, and T. Brigaud* at the University of Cergy-Pontoise (France) discovered an efficient route to this goal based on chiral trifluoromethyl oxazolidines. They previously reported the LiAlH4-based reduction of appropriately substituted oxazolidines to provide straightforward access to enantiopure (S)- and (R)-trifluoroalaninols (Pytkowicz, J., et al. Org. Biomol. Chem.2010, 8, 4540–4542). They extended this method to attain the desired goal by stereoselectively ring-opening fluorinated 2-hydroxymethyl oxazolidines (e.g., 1) with various organolithium reagents to form compounds such as 2.

The oxazolidine starting materials are obtained as a diastereomeric mixture by chemoselectively reducing a trifluoropyruvate-based oxazolidine withNaBH4. Each diastereomer is isolated by silica gel chromatography, allowing the subsequent products to have the (R)- or (S)-configuration. The (R)-configuration is shown in the figure.

The intermediate ring-opened structure 2 forms with complete diastereoselectivity (>98% de), as verified by NMR spectroscopy. Several organolithium reagents, including PhLi and trimethylsilylacetylide, are as diastereoselective as MeLi.

The authors cleanly removed the phenylethanol side chains on 2 by hydrogenolysis to yield the enantiopure targeted amino alcohols as their hydrochlorides (3). This reaction proceeds with product yields as high as 99% when the PhLi reagent is used. The authors confirmed the (R)-configuration of 3 by correlating its structure with known compounds. (Org. Lett. 2011, 13, 604–607; W. Jerry Patterson)

Should you use acid or base to hydrolyze a hydantoin? During process development of a key intermediate of a schizophrenia drug candidate, M. Waser and coauthors at DSM Fine Chemicals Austria (Linz) and Eli Lilly (Indianapolis) found that the basic hydrolytic cleavage of a spiro-tetrahydrothiophene hydantoin with 50% aq NaOH is slow and relatively inefficient: 80–85% yield after 40–50 h at reflux. Acid catalyzed hydrolysis is more efficient; 48% (9 M) aq HBr gives the best result: 94–96% yield after 18 h.

Surprisingly, the hydrolysis is less efficient with 9 M aq HCl, and the product from 9 M aq H2SO4 is contaminated with NaHSO4. The authors attribute the difference between HBr and HCl to the lower reflux temperature of aq HCl and the lower acid concentration at reflux. (Org. Process Res. Dev. 2011, 15, 1266–1274; Will Watson)

The kinetics of a key atmospheric species have been measured. Criegee intermediates (carbonyl oxides)—named after German chemist Rudolf Criegee, who proposed their existence in 1949—play a key role in the ozonolysis of alkenes in the troposphere (see figure). Despite laborious qualitative studies and indirect estimates over decades, accurate quantitation of Criegee radicals’ reactivity remains elusive because of their instability in the gas phase.

C. A. Taatjes and coauthors at Sandia National Laboratories (Livermore, CA), the University of Manchester (UK), and the University of Bristol (UK) overcame this problem in the laboratory. They generated the CH2I· radical by photolyzing CH2I2 with 248-nm UV light. CH2I· reacts with the large excess of oxygen present to give CH2O2 isomers (1 and 2 in the figure) as the predominant products.

Time-resolved mass spectra obtained from tunable synchrotron photoionization mass spectrometry as the reaction proceeds clearly show the formation of CH2OO· radicals (1; R3 = R4 = H), the simplest Criegee intermediate. This result confirms theoretical predictions made decades ago. CH2OO· radicals are generated in sufficient quantities and with long enough lifetimes (up to 2 ms) to allow direct pseudo–first-order measurements of their fast reactions with SO2, NO2, NO, and H2O.

Only water seems to behave consistently with reports in the literature, and the authors detected no reaction with NO. The reactions of CH2OO· with SO2 and NO2 are surprisingly fast—orders of magnitude faster than previous estimates—indicating that these species are more significant in the nitrate and sulfate chemistry of the atmosphere than previously believed. These measurements are pivotal for explaining the mechanism of ozonolysis, and they give quantitative insight into some key atmospheric chemistry processes. (Science 2012, 335, 204–207; Xin Su)

Use choline-derived solvents for rapid cellulose dissolution. The highly crystalline 3-D-biopolymer cellulose is insoluble in water and organic solvents. Its insolubility makes it difficult to hydrolyze before it can be transformed into biofuels. Decrystallizing cellulose to an amorphous solid makes it easier to hydrolyze. Imidazole-derived ionic liquids (ILs) dissolve and decrystallize cellulose; but the decrystallization rate is slow, and ILs are expensive and toxic.

F. JÉrÔme and co-workers at the University of Poitiers (France) used inexpensive, nontoxic, biodegradable choline-derived ILs to promote cellulose decrystallizaton. They first tested choline chloride, a solid at room temperature, as a solvent for the microcrystalline cellulose (MCC) AVICEL PH 105, one of the most recalcitrant MCCs on the market. The results were disappointing even when the choline chloride was combined with additives such as urea or ZnCl2.

They next tested choline acetate, a liquid at 80 °C, which dissolved the MCC to some extent. They screened several additives and obtained the best results with a 9:1 ratio of choline acetate to Bu3MeNCl, which dissolved 4 wt% MCC. Adding EtOH to the solution released amorphous cellulose, as verified by X-ray diffraction analysis. The choline acetate–Bu3MeNCl IL can be recycled as many as three times with no significant loss of activity by distilling it under reduced pressure. No IL contamination of the cellulose was observed.

This IL is an economical, “green” system for decrystallizing cellulose and has potential for large-scale use. The solvent is enzyme-compatible and biodegradable—advantages for subsequent cellulose fermentation. (Chem. Eur. J. 2012, 18, 1043–1046; JosÉ C. Barros)

Nanotubes crystallize polyethylene to form “shish-kebabs”. M. L. Minus*, H. G. Chae, and S. Kumar* at Georgia Tech (Atlanta) investigated the crystallization of polyethylene (PE) in PE–carbon nanotube (CNT) dispersions that were subjected to shear flow. Their apparatus is depicted in the figure.

The authors used single-wall (SW), multiwall, and few-walled CNTs in the study. After they washed a crystallized SWNT–PE fiber with xylenes for 10 min, they discovered a “shish-kebab” structure with a lamellar thickness of ≈40 nm beneath the outer amorphous PE layer. This morphology is preserved after the fiber is boiled in xylenes for 1 h. Control studies showed that the smaller-diameter SWNTs stabilized the PE microstructure. Smaller CNT diameters also give smaller PE d-spacings, which suggest stronger PE–CNT interactions.

Wide-angle X-ray diffraction studies showed that SWNT packing is frustrated because the PE crystallizes at the same time as the packing. Shear flow induces extended-chain PE crystals in a hybrid “shish” structure with SWNTs. An amorphous, but oriented, PE “kebab” forms after the xylene treatment. (ACS Appl. Mater. Interfaces 2012, 4, 326–330; LaShanda Korley)

This device unravels the optical behavior of thin polymeric films. The usefulness of a polymer system for any application is determined by its relevant fundamental properties: For example, a polymer’s optical response affects its performance in hybrid optical components such as polymer lenses or optical fibers. For many optoelectronic applications, polymers must be deposited as thin films.

The optical behavior of polymer thin films, however, is often more difficult to characterize than that of bulk polymer materials because of the wide range of polymeric chemistries, conformations, and physicochemical properties. All of these factors may vary when the polymer is confined to small microscale or nanoscale dimensions. A. M. Armani and coauthors at the University of Southern California (Los Angeles) and the University of Missouri (Columbia) used a microscale, integrated optical device, the silica microtoroid (a “whispering gallery”–mode optical resonator), to explore the optical properties of ultrathin (sub–100-nm) polymer films.

The authors’ test material was polyisobutylene (PIB), a unique polymer system that has broad industrial applications because it is impermeable to gases. PIB has not been used in optical systems because it is difficult to probe its optical properties, whether in bulk or thin films. To study PIB, the authors coated the surface of the silica microtoroid with ultrathin films of the polymer. The device confines light of well-defined, resonant wavelengths that change with slight variations in the refractive index of the platform. By monitoring the shift in resonant wavelength, the device can determine the refractive index of PIB accurately with 1 x 10–7 resolution.

By using this technique, the authors demonstrated that the transmission loss and thermo-optic coefficient of ultrathin PIB films can be determined. They also showed that changing the thin film–formation method (e.g. spin-coating or polymer brush deposition) significantly affects the optical properties of the ultrathin films. They conclude that small-scale integrated devices such as the silica microtoroid can improve our ability to study complex optical behaviors of confined polymers and may allow the integration of diverse new polymeric materials into optical applications. (Langmuir 2012, 28, 849–854; Gary A. Baker)

Selectively image and inactivate antibiotic-resistant bacteria with an enzyme-triggered ruthenium complex. Widespread bacterial strains that are resistant to β-lactam antibiotics (e.g., penicillins and cephalosporins) are becoming a health concern. The development of simple luminescent bioprobes for assaying β-lactamase and effective photodynamic chemotherapy reagents for inactivating drug-resistant pathogens is desirable but remains a challenge. Q. Shao and B. Xing* at Nanyang Technological University (Singapore) report a β-lactamase-responsive organometallic complex (1) that allows localized intracellular imaging and inactivation of penicillin-resistant bacteria with high specificity and susceptibility.

In the absence of β-lactamase, 1 is nonemissive because of efficient Förster resonance energy transfer (FRET) between the Ru(II) core and the “black hole quencher” 3 (BHQ3) cephalosporin group. When 1 is treated with β-lactamase, emission increases dramatically, indicating that 1 has been cleaved. Enzymatic hydrolysis releases luminescent Ru(II) complex 2 from cephalosporin unit 3, shutting down the FRET quenching process and triggering strong luminescence.

Whereas the proximity of BHQ3 to the Ru(II) core impedes 1 from generating singlet oxygen (1O2) via energy transfer or product scavenging, treating 1 with β-lactamase revives 1O2 productivity and makes complex 2 remarkably efficacious for killing antibiotic-resistant pathogens. (Chem. Commun. 2012, 48, 1739–1741; Ben Zhong Tang)

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