Noteworthy Chemistry

August 8, 2011

Make nanoparticles at the flick of a switch. Chemists are always looking to improve reaction efficiencies and minimize byproducts. They now can create useful nanoparticles by using only light, without additional reactants or catalysts, as normally required. The trick is to use a photoreactive surfactant (PRS) that plays dual roles. The organic portion organizes into nanometer-sized domains (micelles) that serve as “nano–test tubes”. The inorganic part is a metal ion source for generating nanoparticles.

If the organic group is an efficient light-activated electron donor, it can be photochemically triggered to reduce the associated metal ions by switching on an external light. The result is a clean, highly controllable method for making valuable nanoparticles.

J. Eastoe at the University of Bristol (UK) and collaborators in Brazil and France show that with the help of a PRS it is possible to synthesize metal and metal oxide nanoparticles at the flick of a light switch. This photochemical technique requires a strong surfactant ligand-to-metal charge transfer (LMCT) band. Incident light triggers electron transfer that reduces metal ions inside the compartmentalized micellar nanoreactors and arrests the precipitation reaction. Additional inert surfactants stabilize and disperse the nanoparticles as they are formed, preventing separation and maintaining their dimensions.

For example, with cobalt 2-ethylhexanoate as the PRS and Aerosol-OT as added inert surfactant in heptane solution, monodisperse 5-nm cobalt oxide nanoparticles are obtained after illumination. A similar formulation, but with bismuth 2-ethylhexanoate, gives nominally 7-nm bismuth nanoparticles. The byproducts are only CO2, which bubbles off, and heptane or heptene, which partition into the organic solvent.

The advantages of this procedure are that it uses fewer chemicals and produces monodisperse metal or metal oxide nanoparticles that can be separated easily from the byproducts. It is an important advance in the continuing search for “greener” methods for making functional nanomaterials. (Langmuir 2011, 27, 9277–9284; Gary A. Baker)

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This polymeric conjugate is an efficient antiangiogenic agent. Angiogenesis is a normal physiological process that forms new blood vessels. It can activate or deactivate undesirably, however, during the onset of diseases such as cancer and macular degeneration. Current antiangiogenic agents have poor specificity and severe side effects.

Recent research suggests that dopamine (2), a catecholamine neurotransmitter, has a key role in regulating angiogenesis at nontoxic concentrations. In particular, dopamine prevents vascular endothelial growth factor (VEGF)–mediated angiogenesis, but its extremely short half-life (~2 min) makes it impractical for therapeutic benefits.

F. Greco and coauthors at the University of Reading (UK) and Tel Aviv University cite previous studies on paclitaxel–poly(glutamic acid) (PGA) conjugates that increase the half-life of dopamine by ≈10-fold. They postulate that this result should lead to prolonged circulation time for dopamine, improving its therapeutic response.

The authors report the formation of a polymer–dopamine conjugate that prolongs the antiangiogenic response of dopamine. They modified PGA (1) with controlled amounts of dopamine along the PGA polymer chain (3).

The selection of PGA with a molecular weight of ≈30 kDa as the polymeric matrix for the conjugate was based on its clinical safety, biodegradability, and structural features that allow high drug loading. The initial sodium salt of 1 was converted to the free carboxylic acid form via a proton-exchange resin. Only 50% of the glutamate units were activated this way to ensure water solubility of the subsequently formed conjugate.

Dopamine was conjugated to form 3 by coupling it with available carboxylic acid residues. (DIC is N,N’-diisopropylcarbodiimide; NHS is N-hydroxysuccinimide; DMAP is dimethylaminopyridine; DIEA is diisopropylethylamine.) NMR spectral data verified that dopamine was attached to ≈14% of the glutamate monomers. PGA–dopamine conjugate 3 was recovered as its sodium salt by dialyzing its aqueous solution against water. Purification of 3 by size-exclusion chromatography provided the desired form for physiological studies.

Migration studies of in vitro endothelial cells showed that conjugate 3 completely inhibits angiogenesis for ≥24 h—a dramatic increase over dopamine alone. The authors evaluated in vivo effects by a single injection of dopamine in female mice and comparing the results with an equivalent treatment with conjugate 3. The ability of dopamine to inhibit vascular permeability completely disappeared after 24 h, whereas 3 was still active at 24 h.

The authors plan to explore the ability of 3 to act as an anticancer agent and to investigate its specificity for localizing in tumor tissue. (J. Med. Chem. 2011, 54, 5255–5259; W. Jerry Patterson)

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Replicate mussels’ “glue”. The common blue mussel produces polymeric adhesives that allow it to stick to ocean rocks. One compound found in the adhesive is L-3,4-dihydroxyphenylalanine (DOPA, 1), an amino acid that is involved in cross-linking reactions in cohesive curing and in adhesive bonding to surfaces.

Although researchers have learned much about bioadhesives, the adhesive mechanism is still unknown, and synthetic replacements have not been extensively developed. J. D. White and J. J. Wilker* at Purdue University (West Lafayette, IN) report a synthetic copolymer that simulates the structure of DOPA and its balance between ionization and adhesive strength.

The copolymer contains three components evenly distributed throughout the polymer chain. The 3,4-dihydroxystyrene (2) and p-vinyltolyltriethylammonium ion (3) units mimic DOPA. Styrene is added make the polymer hydrophobic in aqueous media. The authors believe that the copolymer’s adhesive strength depends on the concentration of ammonium groups in the molecule.

Commercial adhesives, such as poly(vinyl acetate) emulsions (e.g., Elmer’s Glue) and ethyl cyanoacrylate (e.g., Krazy Glue), do not interact with metal substrates in water. The authors’ copolymer exhibits excellent adhesion to aluminum surfaces. A copolymer with ≈10% cationic groups has the strongest underwater bonding; additional cationic content greatly decreases the strength. (Macromolecules 2011, 44, 5085−5088; Sally Peng Li)

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What’s the best way to produce a chiral fluoromethyl γ-lactone? U. Zutter and co-workers at Hoffman-La Roche report several synthetic routes to (S)-3-fluoromethyl-γ-butyroactone. The routes include five ways to form the chiral center: classical resolution with a chiral auxiliary, a chiral pool starting material, chemical kinetic resolution, asymmetric oxidation, and biocatalytic desymmetrization.

The route used to produce up to 5 kg of the compound begins with racemic tert-butyl glycidyl ether, which is subjected to fluorinative ring opening followed by oxidation and reaction with the lithium enolate of tert-butyl acetate. The chiral center is introduced via asymmetric hydrogenation using a ruthenium (R)-3,5-t-Bu-MeOBIPHEMP catalyst system.

Another route selected for scale-up uses chirally pure tert-butyl glycidyl ether. This compound was initially produced by Jacobsen hydrolytic kinetic resolution, but it is now commercially available. The epoxide ring is opened with malonate anion. (Org. Process Res. Dev. 2011, 15, 515–526; Will Watson)

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Find the location of a double bond with cross-metathesis. Determining the double-bond position in unsaturated long-chain compounds is a challenge for organic and analytical chemists. NMR analysis usually fails to produce sufficiently useful information because of overlapping signals in the olefin region; MS analysis using electron impact can result in isomerization; and MS with chemical ionization may not produce useful fragments. Traditional derivatization agents may not work because of functional group incompatibility.

D.-C. Oh, S. Kim, and co-workers at Seoul National University report a method for derivatizing unsaturated compounds with a cross-metathesis reaction. Using this technique, the authors developed two methods to derivatize elaidic acid (1). The first, on the left in the figure, uses methyl acrylate (MA) as the second olefin and 5–10 mol% of second-generation Hoveyda–Grubbs catalyst 2; Mes is mesityl. This technique is more suitable for LC-MS analysis than the second method because its products (3 and 4) are hydrophilic.

The second method uses 2-methyl-2-butene and 5–10 mol% of Grubbs II catalyst 5 and generates volatile gem-dimethyl olefins (6 and 7) that are more suitable for GC-MS analysis. The position of the double bond is deduced by the molecular mass changes of the fragments.

The authors expanded the MA protocol to several fatty acids. The results showed that the cross-metathesis reaction cleaves only the double bond nearer to the carboxylic terminus in compounds, such as linoleic acid, with more than one double bond. Different diolefins can produce the same cross-metathesis fragment, as with trans-octadecenoic and cis-13-docosenoic acids, because in both cases the double bond lies at the same distance from the carboxyl group.

This method is mild and tolerates many functional groups. It is limited, however, to pure compounds and cannot be applied to olefin mixtures such as biological extracts. (Angew. Chem., Int. Ed. 2011, 50, Advance Article DOI: 10.1002/anie.201102634, José C. Barros)

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Make asymmetric ketones by using electron-deficient ligands. T. Ayad, V. Ratovelomanana-Vidal, and co-workers at Chimie Paris Tech describe a modification of the conjugate addition of boronic acids to α,β-unsaturated ketones. In this rhodium-catalyzed asymmetric process, the authors used ligands such as 1 that have multiple strongly electron-withdrawing trifluoromethyl groups. This reaction forms aryl-substituted maleimides (2) and cyclohexenones (3) with very high enantioselectivities.

Several cyclohexanone products had 99% ee. Five-, six-, and seven-membered cyclic enones and acyclic enones give the corresponding 1,4-addition products in good yields and high enantioselectivities.

Succinimide products are formed with enantioselectivities as high as 93%. A single recrystallization routinely enriches the succinimides to almost optically pure (>99% ee) form.

The authors studied a series of ligands with increasing levels of fluorination, primarily on the phosphine aryl groups. Reaction efficiency appears to increase as a function of increasing ligand fluorination, reaching optimum performance with 1.

The reaction is carried out under very mild conditions, and in particular, provides access to succinimide derivatives of biological interest. In addition, the authors believe that their results are the best reported so far with phosphine-based catalyst ligands for this substrate class. (J. Org. Chem. 2011, 76, 6320–6326; W. Jerry Patterson)

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Inter- and intramolecular bonding form liquid crystalline columns. K. Sato, Y. Itoh*, and T. Aida* at the University of Tokyo synthesized peptide-based macrocycles inspired by biomolecules found in species of the marine ascidian genus Lissoclinum. The macrocycles assemble into columnar liquid crystals (LCs) and are responsive to electric fields.

The cyclic core of these L-glutamate–based compounds adopts a bowl-shaped conformation that is stabilized by internal hydrogen bonds and is surrounded by three or four wedge-shaped hydrophobic moieties connected by amide linkages (see figure). These amide groups are designed to hydrogen-bond intermolecularly, whereas the ring amides bond intramolecularly. The two sets of amides function independently of each other.

The intercolumnar distance is 41–42 Å, and the peptidic macrocycles exhibit liquid crystalline mesophases with clearing temperatures >77 °C. Applying an electric field causes the columns to undergo large-area, unidirectional orientation. After the field is switched off, the columns are stable for at least 6 months. (J. Am. Chem. Soc. 2011, 133, Article ASAP DOI: 10.1021/ja203894r; LaShanda Korley)

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