Noteworthy Chemistry

March 17, 2014

Print with water on rewritable paper. Global paper production reached 400 million tonnes in 2012. The adverse effects of producing and using paper, such as deforestation and paper waste, pose imminent threats to the environment. Used ink and toner cartridges from printing also cause pollution.

Because most printed paper is used temporarily and then discarded, it is desirable to use rewritable paper to minimize waste generation. Efforts to develop rewritable paper are limited by the stability of leuco dyes that can be switched between colorless and colored states. To address this issue, M. Li, S. X.-A. Zhang, and coauthors at Jilin University (Changchun, China) and Northwestern University (Evanston, IL) developed a rewritable paper that uses water to trigger molecular switches. Their system can be used for printing with a commercial ink-jet printer.

The authors first analyzed the structural features of spiropyrans, a well-known class of solvatochromic dyes, and hypothesized that disabling the conjugation between the charged ends of certain ring-opened zwitterions could improve their stability. They then synthesized and screened a variety of oxazolidine-, oxazine-, and spiropyran-based switchable compounds. They identified oxazolidines 14 as stable hydrochromic dyes that develop into colors for use in rewritable paper. The structures in the figure are shown in color, but they represent the closed, colorless forms of the molecules.

Closed, colorless oxazolidines and the reaction with water to produce the blue form

The authors prepared rewritable paper by using a layer-by-layer technique. They coated passivation, imaging, and protection layers onto a filter paper substrate with poly(ethylene glycol) (PEG), dye–PEG, and PEG solutions, respectively. In PEG, the dyes exist in the closed, colorless forms; when they are exposed to water, they open to the colored forms (e.g., 5; see figure). The authors chose hygroscopic NaNO3 as an additive to lengthen the duration of legible color.

The authors printed on the rewritable paper with good resolution by using commercial ink-jet printers with cartridges filled with water instead of ink. Legible monochromic print on rewritable papers based on 14 lasted for 22 h. The printed paper can be erased by heating it at 70 ºC. Color intensity decreases only slightly after >10 print–erase cycles. (Nat. Commun. 2014, 5, No. 3044; Xin Su)

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Determine single-crystal structures without growing crystals. Single-crystal X-ray diffraction (SCD) is an important method for determining crystal structures. The preparation of single crystals, however, is time-consuming and, in the case of liquid substrates, impossible at room temperature.

Y. Inokuma, M. Fujita, and co-workers at the University of Tokyo developed a method in which the molecule to be analyzed is trapped inside a “crystal sponge”. The sponge (2) is a porous coordination network that they prepared from 2,4,6-tri(4-pyridyl)-1,3,5-triazine (1) and ZnI2. The sponge absorbs “guest” molecules for structure determination by SCD.

Synthesis of the “crystal sponge” and one of the molecules tested

The reaction of 1 with ZnI2 is run in the presence of nitrobenzene to form crystalline PhNO2. Nitrobenzene is then replaced by cyclohexane, which is necessary for rapid inclusion of the guest compound.

After the solvent is evaporated over ≈2 days, the guest molecule in the crystal matrix is analyzed from conventional SCD images of the entire complex. The host complex has a maximum cross-sectional area of 8 Å x 5 Å, so molecules with larger dimensions cannot be analyzed. The process takes ≈16 days to complete.

Because conventional SCD can analyze crystals as small as ≈0.1 mm on a side, <1 μg of a sample can be analyzed by this method. The authors only needed 80 ng of guaiazulene (3) and standard laboratory X-ray equipment to determine its crystal structure. (Nat. Protoc. 2014, 9, 246–252; José C. Barros)

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Hydroxamic acid derivatives may help treat Chagas disease. An estimated 8 million people are infected with the parasite Trypanosoma cruzi, which causes Chagas disease. The pathogenesis of this disease is divided into three phases: A short acute phase, a long-lasting latent phase, and a chronic phase. Drug treatment is limited to nifurtimox and benznidazole, which are predominantly active during the acute phase but are highly toxic, have low efficacy, and cause adverse side effects.

An α-carbonic anhydrase that was recently characterized in T. cruzi is a putative anti–Chagas disease drug target. During the T. cruzi acute infection phase, mice express increased levels of endopeptidases, especially metallopeptidases in the matrix metalloproteinase (MMP) class, in their heart tissue. These MMPs may play a role in the acute myocardial disease associated with T. cruzi.

Hydroxamic acids have been studied as a pharmacophore group in the context of other diseases because they coordinate with metal ions in metalloenzymes and inhibit them. A. B. Vermelho and colleagues at the Military Institute of Engineering (Rio de Janeiro), the Federal University of Rio de Janeiro, the University of the Rio Grande (Rio de Janeiro), the University of Tampere and its hospital (Finland), the University of Florence (Italy), and the Institute of Protein Biochemistry (Naples, Italy) investigated 3-aryl-4,5-dihydroisoxazol-5-carboxyhydroxamic acid derivatives as scaffolds for potential Chagas disease drugs. They looked for the influence of the hydroxamic acid group in the molecular structure.

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The authors first assembled a small library of hydroxamic acid derivatives incorporated in heterocyclic structures and then carried out in vitro and in vivo assays on promising compounds. Only some of the derivatives inhibited parasite growth efficiently; all of these contained substituents on the aromatic rings. 

The most promising compound, 1 in the figure, is highly lipophilic and inhibits 100% of one form of parasite growth at a concentration of 32 μM. It is more potent than benznidazole and showed a reduced parasite burden in infected cells. Compound 1 is a potential prototype for drugs used to treat Chagas disease. (J. Med. Chem. 2014, 57, 298–308; Abigail Druck Shudofsky)

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Safely scale up a m-chloroperbenzoic acid reaction. A. Hu and co-workers at Suzhou Novartis Pharma Technology (Changshu, China) used a rapid detection of exothermic reaction (RADEX) instrument to compare the stability of m-chloroperbenzoic acid (m-CPBA) in various solvents (CHCl2, DMF, N,N-dimethylacetamide, acetone, and MeCN). At 1.1 g/mL m-CPBA concentration, CHCl2 is the safest solvent, but even with CHCl2, the mixture releases 417 J/g (919 J/g m-CPBA) with an onset temperature of 56 ºC.

DMF is often the preferred solvent for m-CPBA oxidations, but this reaction can cause explosions. When the m-CPBA concentration in DMF is decreased to 0.13 g/mL, the potential heat release is 168 J/g versus 798 J/g at 1.1g/mL concentration. The onset temperature is 36 ºC.

The authors recommend that a solution of m-CPBA in DMF be prepared by adding m-CPBA to DMF. This order of addition is important to avoid high concentrations of m-CPBA that would occur when DMF is added to m-CPBA. The solution should be added immediately to the substrate solution in DMF. The reaction temperature must be kept at <10 ºC. (Org. Process Res. Dev. 2013, 17, 1591–1596; Will Watson)

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Modulate light emission by photonic and electric excitation. A variety of stimulus-responsive chemical systems have been developed, but most of them respond only to a single stimulus. Systems with responses to multiple stimuli are rare.

Azobenzene has been studied extensively as a photoresponsive molecule. Its E-to-Z isomerization can be reversibly manipulated by photoirradiation, but its light emission is weak. α-Cyanostilbenes are highly emissive in the solid state, but little is known about their E-to-Z isomerization processes. H. Lu, L. Qiu, J. Yang, and coauthors at Hefei University of Technology (China) and Anhui University (Hefei) developed an α-cyanostilbene luminogen (1) and tuned its photoluminescence by using photonic and electric stimuli.

α-Cyanostilbene derivative with photo- and electric field–switchable photoluminescence

The as-prepared luminogen has the Z-conformation, which converts to the E-conformation under irradiation with UV light. The photoinduced Z-to-E transition weakens the fluorescence of the solid film, demonstrating that the molecule’s light emission can be photonically controlled. When 1 is irradiated inside liquid crystals, the photoisomerization decreases its compatibility with the crystals.

The authors used the change in internal scattering caused by isomerization-induced phase separation to switch off the fluorescence of a luminogen-dispersed liquid-crystal cell by applying an electric field. Thus electricity as well as irradiation can modulate the light emission of 1. (J. Mater. Chem. C 2014, 2, 1386–1389; Ben Zhong Tang)

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These optical waveguides can bend and stretch. Flexible, stretchable electronic materials have led to applications such as sensitive robotic skin, wearable sensing devices, and monitoring systems for moving machine parts. Similar flexible optical devices, however, are at a much earlier stage of development. Preparing stretchable optical interconnects is problematic because most conventional optical waveguide materials have limited or no flexibility.

J. Missinne and co-workers at the Center for Microsystems Technology (Ghent, Belgium) and Ghent University used commercially available polydimethylsiloxane (PDMS) materials to produce optical waveguides that bend and stretch. PDMS with a refractive index of 1.57 is introduced via capillary filling into channels in a cladding material that was made from another PDMS polymer with a 1.41 refractive index. As the refractive index difference between core and cladding increases, the achievable bending radius of the resulting waveguide decreases.

Because actively aligning light sources and detectors at the input and output ends of a bending optical fiber is difficult, the authors devised a process for producing waveguides with integrated optoelectronic components. They embedded thinned, bare-die vertical-cavity surface-emitting lasers (VCSELs, λ = 850 nm) and photodiodes in flexible polyimide foils and coupled the foils to 50 μm x 50 μm x 6 cm waveguide arrays. The figure shows the bending of the complete assembly.

Bending of optical waveguide assembly
Courtesy of the Optical Society.

The authors characterized the waveguide assemblies by measuring propagation, stretching, and bending losses and reliability. The total link loss, including coupling loss, is 2–4.5 dB. Waveguide losses are negligible (≤0.1 dB) for bending radii as small as 7 mm. Stretching the waveguide regions by as much as 30% and subsequently releasing them contributes <0.7 dB to the total optical link loss.

Stretching the waveguides by >30% causes stability problems in the coupling region, but the waveguide substrate can be stretched as much as 140% before the PDMS material breaks. After 80,000 stretching cycles at 10% elongation, the small long-term average insertion loss indicates that stretching does not introduce noticeable degradation. (Opt. Express 2014, 22, 4168–4179; Nancy McGuire)

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Reductively couple olefins simply and inexpensively. Olefins are versatile building blocks for C–C bond formation and are used frequently in natural product synthesis and drug discovery. Synthetically important classic olefin reactions include Diels–Alder cycloaddition, metathesis, epoxidation, and hydroxylation reactions. In addition, unactivated olefins are used as “hidden” radical donors; they can be coupled to carbon or heteroatom acceptors under reductive conditions.

The unique reactivity of olefins suggests the possibility of direct coupling between them. J. C. Lo, Y. Yabe, and P. S. Baran* at the Scripps Research Institute (La Jolla, CA) developed a Fe(III)-catalyzed reductive coupling reaction between unactivated and electron-deficient olefins with PhSiH3 as the hydrogen source.

The authors first screened several catalytic reducing systems for the intramolecular coupling of enone 1. They found that 1 is converted exclusively into cis-fused decalin coupling product 2 by PhSiH3 in the presence of 30 mol% Fe(acac)3 catalyst at 60 °C. (The ligand acac is acetylacetonato.) 

Hydroxamic acid derivative that shows promise against Chagas disease
Reductive olefin coupling reaction

The reaction has a broad scope for intramolecular and intermolecular couplings. For example, the authors used it to form hindered bicyclic systems with vicinal quaternary centers, including bicyclic cyclopropanes.

This transformation proceeds rapidly, is highly air- and moisture-resistant, and it uses an inexpensive catalytic reductive system. It is synthetically practical because it can be scaled up to produce several grams of product without significant yield reduction. Because the reaction provides easy access to structural features that are otherwise challenging or impossible to create, the authors believe that it can be used in improved synthetic routes to many natural products, especially terpenes. (J. Am. Chem. Soc. 2014, 136, 1304–1307; Xin Su)

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