Noteworthy Chemistry

May 30, 2011

Organometallic complexes detect β-amyloid peptides and inhibit fibrillogenesis. The neurodegenerative syndrome Alzheimer’s disease (AD) afflicted more than 5 million people in the United States in 2009. Genetic, pathological, and biochemical evidence indicates that neurodegeneration in AD patients is linked to β-amyloid (Aβ) peptide aggregation. One of the therapeutic strategies against AD is to prevent monomeric Aβ peptides from misfolding and aggregating into neurotoxic fibrils.

A team led by H.-W. Li and D.-L. Ma at Hong Kong Baptist University developed a series of group 9 transition-metal complexes as luminescent Aβ peptide probes and fibrillation inhibitors.

The complexes are cyclometalated Ir(III) and Rh(III) species with various C^N ligands. Two examples in which C^N is 2-phenylpyridine are shown in the figure. Complex 1 becomes luminescent when incubated with Aβ1–40 peptide. It can distinguish among different forms of the peptide: The complex is more luminescent in the presence of the fibrils than the monomers.

Complex 2 almost completely inhibits Aβ1–40 peptide aggregation at a concentration of 5 μM. This complex is covalently bound to the Aβ1–40 peptide, presumably by coordinating the N-donor functionality of the histidine residues. (Chem. Sci. 2011, 2, 917–921; Ben Zhong Tang)

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Make solar cells one nanowire layer at a time. D. Gao and co-workers at the University of Pittsburgh developed a multilayer strategy to create efficient, economical dye-sensitized solar cells (DSCs) from 1-D nanostructures. They prepared multistage ZnO nanowires with a four-step wet-chemical growth process that gives controlled results up to ≈5 layers:

  1. growing vertical nanowire in ≈10-µm increments;
  2. coating with self-assembled monolayers (SAMs) of n-C18H37SiCl3 to prevent wire fusion and widening;
  3. removing top-end SAM coatings with UV ozone before growth of the next layer of ZnO nanowires; and
  4. removing all of the SAM coating via calcination before device production.

This method controls aligned nanowire assembly length and internal surface area; and it tunes the hydrophobicity of the resulting nanowire array. Scanning electron microscopy images illustrate the templated growth process of the multilayer nanowire assembly and variations in nanowire width and density between layers of the assembly.

For a four-layer stack of nanowires, the roughness factor (a measure of the internal surface area) is >5 times larger than that of a single-layer assembly of the same thickness. The surface area depends on the diameter of the nanowire and area density.

To explore the utility of this process for DSCs, the authors coated the nanowire multilayer assembly with TiO2 before sensitization. The 40-µm thick four-layer assembly had a 7% power conversion efficiency, comparable with TiO2 nanoparticle–based DSCs. (J. Am. Chem. Soc. 2011, 133, 8122–8125; LaShanda Korley)

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Use a click reaction for intramolecular cyclization. One potential application of copper-catalyzed azide–alkyne cycloaddition (the “click” reaction) is to form macrocyclic structures that may lead to bioactive molecules. Finding no systematic study of the use of ligands for this type of reaction, G. Chouhan and K. James* at the Scripps Research Institute (La Jolla, CA) began a study for optimizing click chemistry to promote efficient intramolecular macrocyclization rather than the competing intermolecular reaction. A key finding was the value of tris(triazole) ligand 1 for maximizing the macrocycle/dimer product ratio in these reactions.

In a typical reaction, starting azide–alkyne 2 (prepared in two steps from ephedrine) is treated with Cu(MeCN)4PF6 catalyst and ligand 1 to form the desired macrocycle 3 in yields as high as 95% and a 3/dimer ratio of 12.3:1. The preferential formation of the macrocycle is achieved with only modest dilution in the reaction medium (concentrations as high as 0.02 M). The importance of the ligand is emphasized by conducting reactions without 1, in which oligomers are primarily formed.

To explain the mechanism of the macrocyclization, the authors suggest that the steric environment of the copper in a proposed 1–BF4–alkyne complex favors reaction with an intramolecular azide instead of an azide in a neighboring molecule.

Elaborating this method resulted in the synthesis of a small library of unusual druglike macrocycles that incorporate features typically found in bioactive compounds. The procedure for making these compounds is simple, and the product is isolated in good-to-excellent yields after solvent evaporation and column chromatography. (Org. Lett. 2011, 13, 2754–2757; W. Jerry Patterson)

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Minimize impurities by choosing the right catalyst and solvent. S. Broxer and co-workers at Bristol-Myers Squibb (New Brunswick, NJ) chlorinated a hydroxypyrazolotriazine under standard conditions with POCl3 in toluene to form an intermediate in the synthesis of a corticotropin-releasing factor receptor 1 antagonist. Adding BnBu3NCl and i-Pr2EtN provides additional chloride ion and accelerates the reaction, but it forms a troublesome dimeric impurity at a level of ≈1%.

When MeCN is used as the solvent, BnBu3NCl is not required; and at higher dilution, impurity formation is reduced by 50%. The reaction can be accelerated by adding diazabicyclo[2.2.2]octane (DABCO) as the catalyst; but this forms a new chloromethylpiperazine impurity, a potential alkylating agent, that arises from adding DABCO to the ring system. Screening alternative catalysts showed that N-methylmorpholine was best; and, whereas a similar addition impurity is formed, it appears at significantly lower levels and is not an alkylating agent. (Org. Process Res. Dev. 2011, 15, 343–352; Will Watson)

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Here’s a new fluorinating agent: aqueous HF–PhIO. Fluorinated compounds are useful structures in agrochemicals and pharmaceuticals. Current ways to introduce fluorine atoms, such as direct fluorination, require molecular fluorine or electrophilic fluorinating agents. These methods are usually accompanied by explosion risks, difficult manipulations, or the need for a specific apparatus.

Hypervalent iodine compounds such as stable difluoroiodoarenes (ArIF2) are fluorinating agents that have recently been used in organic synthesis. T. Kitamura and co-workers at Saga University (Japan) developed a fluorination method that uses ArIF2 compounds prepared by the reaction of aqueous HF with hypervalent iodine compounds.

The authors investigated the direct fluorination of ethyl 3-oxo-3-phenylpropionate (1) with 55% aq HF and one of three hypervalent iodine compounds: PhI(OAc)2, PhI(OCOCF3)2, and PhIO. The use of PhIO produced PhIF2 in situ and resulted in a 98% yield of fluorinated product.

Evaluation of several 1,3-dicarbonyl compounds showed that diketones and ketoesters are superior substrates to ketoamides. The authors propose a mechanism for the reaction in which the enol form of the 1,3-dicarbonyl compound (2) reacts with PhIF2 to form a 2-iodoanyl-1,3-dicarbonyl intermediate. Displacing PhI and fluoride by another fluoride ion generates the desired fluorinated compound. (Org. Lett. 2011, 13, 2392–2394; José C. Barros)

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Solvent evaporation time affects conductive polymer properties. E. Reichmanis, M. Srinivasarao, and colleagues at Georgia Tech (Atlanta) used polarized Raman spectroscopy to explore the structural development of poly(3-hexylthiophene) (P3HT) chains as a function of evaporation time for the high-boiling solvent 1,2,4-trichlorobenzene (TCB). A measurement of the angle between the P3HT chain backbone and the polarized incident light at 660 min after solution deposition showed anisotropic ordering. This structural evolution is only discernible in a short deposition window (630–720 min) because of competition between chain mobility and the development of polymorphic, statistically similar nanoscale domains.

The authors believe that an intermediate liquid crystalline phase is formed during film formation from TCB solutions. This proposed process is supported by the anisotropic ordering of the P3HT main chain, as indicated by C=C and C–C stretching vibrations in the thiophene ring and gradual changes in the full width at half-maximum of the C=C stretching Raman peak. Liquid crystalline textures are also seen in some regions of the P3HT film by using polarized optical microscopy.

This study may open new possibilities for developing film architecture to optimize polymers’ electrical properties. (J. Am. Chem. Soc. 2011, 133, 7244–7247; LaShanda Korley)

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Terphenyl films fluoresce efficiently with large Stokes shifts and tunable colors. Many luminophores are highly emissive in the solution state; in contrast, few fluorophores emit with quantum yields (ΦF) near 100% in the solid state. C.-H. Zhao and co-workers at Shandong University (China) synthesized a series of terphenyl derivatives laterally substituted with bulky diphenylamino units (15); Mes in 3 is mesityl. They found that solid films produced from these terphenyls fluoresced more efficiently (up to 99% ΦF) than their dilute solutions.

The researchers believe that the terphenyls’ nonplanar conformation and structural flexibility are responsible for their weak emission in solution. In contrast, the prevention of intermolecular interactions by the steric effect of the lateral substituents and the rigidification of molecular conformation caused by spatial congestion in the solid state accounts for the efficient film emissions.

The Stokes shifts of 15 are large, up to 122 nm, because of the planarity of their oligo(p-phenylene) skeletons in the excited state. The terphenyls contain electron-donating (D) and electron-accepting (A) units, so the color of their emission can be tuned internally or externally. Internally, changing the electron-withdrawing capability of the R groups affects the extent of the intramolecular D–A charge transfer: Terphenyls with stronger A units emit redder light (λem = 421 nm for 1; λem = 495 nm for 5). Externally, varying the solvent polarity causes solvatochromism: The emission color red-shifts with increasing the solvent polarity (for 2, λem = 432 nm in cyclohexane, and λem = 486 nm in MeCN). (Chem. Commun. 2011, 47, 5518–5520; Ben Zhong Tang)

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