Noteworthy Chemistry

April 25, 2011

A crystalline core drives micellar microstructures. L. Yin and M. A. Hillmyer* at the University of Minnesota (Minneapolis) explored the self-assembly behavior of amphiphilic poly(N,N-dimethylacrylamide)-b-polyethylene (PDMA-PE) in water and compared it with that of noncrystalline poly(N,N -dimethylacrylamide)-b-poly(ethylene-alt-propylene) (PDMA-PEP).

In water, PDMA-PE and PDMA-PEP form micellar assemblies at elevated temperatures and extended times, during which the PDMA block hydrolyzes minimally. Although they consist primarily of smaller aggregates, the micelles are polydisperse; the crystalline and amorphous block copolymers have two size regimes (≈25 and ≈95 nm).

Using cryogenic transmission electron microscopy, the authors observed a disklike morphology for the ≈30% crystalline PDMA-PE micelles, whereas PDMA-PEP structures are spherical. The core of the PDMA-PE micelles resembles pure PE, and no intermicelle chain exchange was detected. They believe that the driving force for the disklike nanostructure is crystallization upon cooling with “nanoconfinement” within the micelle cores. (Macromolecules 2011, 44, 3021–3028; LaShanda Korley)

A one-pot synthesis produces highly fluorescent pyrazoles. The ubiquitous pyrazole scaffold in bioactive compounds and pharmaceuticals offers a wide range of biological activity that includes anti-hyperglycemic, analgesic, anti-inflammatory, antipyretic, and antibacterial properties. Pyrazoles are also photoactive and can be incorporated into photoinduced electron transfer systems.

Interest in the photoactive properties of substituted pyrazoles led B. Willy and T. J. J. Muller* at Heinrich Heine University (DÜsseldorf, Germany) to develop a one-pot, four-step synthesis of 1,3,4,5-tetrasubstituted pyrazoles such as 1.

The sequence can be visualized as

  • the initial reaction of acid chloride 2 with terminal alkyne 3 under Sonogashira conditions;
  • cyclocondensation with MeNHNH2;
  • bromination with N-bromosuccinimide (NBS); and
  • PPh3-catalyzed Suzuki coupling with p-tolylboronic acid

to form densely functionalized pyrazole 1. This method tolerates numerous combinations of substituents on the pyrazole ring with yields of up to 63% and excellent regioselectivity (>95:<5 in some cases).

The peculiar electronic properties of the tetrasubstituted pyrazoles allow them to function as intense blue-light emitters. All pyrazole derivatives in this study show strong blue luminescence in solution, with emission maxima in the 373–395 nm range. Their solid-state emissions are red-shifted with bluish-green luminescence. Fluorescence efficiencies are high, with quantum yields up to 0.72.

The authors note that the electronic properties of the highly substituted pyrazoles can lead to tailor-made emitters for various organic light-emitting diode applications and fluorescent label markers for a range of materials. (Org. Lett. 2011, 13, 2028–2085; W. Jerry Patterson)

Make functional graphene oxide–hydrogel networks easily. Graphene is a carbon allotrope with a one-atom-thick sheet structure that shows extraordinary electronic, thermal, and mechanical properties. Graphene oxide (GO) is a graphene derivative with many reactive groups that allow it to be functionalized by simple chemical reactions. Although several graphene–polymer nanocomposites have been prepared, little research has been devoted to synthesizing graphene–hydrogel nanocomposites. S. Sun and P. Wu* of Fudan University (Shanghai) developed a one-step process for the making GO-functionalized interpenetrating network (IPN) hydrogels.

In the process, cross-linking reactions of GO sheets with poly[(N-isopropylacrylamide)-co-(acrylic acid)] microgels proceed directly in water. The GO sheets are uniformly and randomly dispersed in the IPN hydrogels, which are thermally responsive. Because of the restorative forces of the networks’ elasticity, the thermally shrunk hydrogels rapidly recover their originals structure upon cooling.

The IPN hydrogels are also pH-sensitive because of their residual carboxyl groups. The researchers believe that this simple procedure can be easily used to prepare other stimuli-responsive nanocomposites. (J. Mater. Chem. 2011, 21, 4095–4097; Ben Zhong Tang)

Here’s an autocatalytic route to efavirenz. The antiretroviral efavirenz (1) is one of the most effective drugs for treating HIV. A key step in manufacturing this compound is an asymmetric alkynylide addition to a carbonyl group that requires stoichiometric quantities of Et2Zn, a metalated acetylene, a chiral amino alcohol ligand, and CF3CH2OH as an additive.

Using asymmetric autocatalysis, N. Chinkov, A. Warm, and E. M. Carreira at ETH ZÜrich developed a synthesis of an intermediate (2) for this active pharmaceutical ingredient. They subjected trifluoromethylated ketone 3 and cyclopropylacetylene (4) to catalytic quantities of an amino alcohol derived from ephedrine (5), Et2Zn, and the previously synthesized intermediate. Using 2 as an autocatalyst in this reaction produced efavirenz in 67% yield and >99% ee. A larger scale (250 mmol) preparation also gave excellent yields and stereoselectivity.

The authors believe that the reaction passes through a chiral zincate intermediate and that ligand 5 is the controlling group that promotes the reaction and dictates the configuration of the product. The results of this study can help lower the production costs of efavirenz and improve worldwide access to this anti-HIV drug. (Angew. Chem., Int. Ed. 2011, 50, 2957–2961; JosÉ C. Barros)

Differing isomer stabilities require different reaction paths. During the early stages of developing a p38 MAP kinase inhibitor, R. R. Milburn and co-workers at Amgen (Thousand Oaks, CA) treated 2,4-difluorophenylhydrazine hydrochloride with ethoxymethylenemalononitrile to produce a 5-amino-1-(2,4-difluorophenyl)-1H-pyrazole-4-carbonitrile. During the course of development, however, the target compound was changed to the 2,6-difluorophenyl isomer. Although 2,4-difluorophenylhydrazine hydrochloride is a bench-stable solid, its 2,6-difluorophenyl isomer deliquesces and turns color in a few days and is therefore not a suitable starting material for long-term development.

The authors changed the route to the pyrazole by using 2,6-difluoroaniline instead of the hydrazine. The aniline can be diazotized and then reduced with ascorbic acid to give an adduct that can be solvolyzed with MeOH to produce the oxalate adduct of the hydrazine. Hydrolysis with NaOH followed by a reaction with ethoxymethylenemalononitrile gives the pyrazole. (Org. Process Res. Dev. 2011, 15, 31–43; Will Watson)

In situ formation of an allenylzinc reagent promotes homopropargyl alcohol synthesis. Chiral homopropargyl alcohols are high-value compounds for synthesizing bioactive natural products and pharmaceuticals that offer multiple reactive modes: The alkyne group can be oxidatively cleaved to form aldehydes or ketones, or it can be reduced to provide olefins. The chiral alcohol function can serve as a directing group for various synthetic transformations. The molecule is easily converted to synthetically useful heterocycles.

B. M. Trost and co-workers at Stanford University (CA) converted aldehydes to these chiral alcohols using a direct catalytic (as opposed to stoichiometric) asymmetric carbonyl propargylation. Their strategy uses a transitory allenylzinc species that is formed in situ from propargyl or allenyl iodide via Zn–I exchange. The allenylzinc intermediate and its propargyl isomer are interconvertible, but the allenyl form is thermodynamically more stable. The process is accelerated by adding naphthyl-substituted chiral amino alcohol ligand 1.

The resulting homopropargyl alcohols, illustrated by 2, form almost quantitatively in several cases and have enantiomeric ratios as high as 96:4. It is important to introduce the propargyl or allenyl iodide as a solution in toluene because using neat reagents reduces yields and selectivities.

The reaction works well for aldehyde substrates that contain aryl, alkyl, olefinic, or heterocyclic groups and is an attractive alternative to current methods. The authors emphasize such features as low cost and low toxicity of the active zinc reagents, ready availability of chiral ligand 1, mild conditions, and simplicity of the overall reaction. (Org. Lett. 2011, 13, 1900–1903; W. Jerry Patterson)

Carbon dioxide dissolves hydrophobic tertiary amines in water. Most tertiary amines are inherently hydrophobic and immiscible with water. Is there a way to make a homogeneous system from these two incompatible components? P. G. Jessop and co-workers at Queen’s University and Green Centre Canada (both in Kingston, ON) discovered that CO2 can be used to make this happen.

Carbonic acid formed when CO2 dissolves in water reacts with basic tertiary amines to give water-soluble ammonium salts. When a heterogeneous mixture of an amine and water is purged with CO2, the interface gradually disappears and a homogeneous solution results. When the solution is purged with an inert gas, such as argon, nitrogen, or air, CO2 is forced out and the mixture reseparates. Heating the solution also discharges the dissolved gas and separates the amine.

As an example, hydrophobic cyclohexyldimethylamine is a good solvent for polystyrene. When the polymer solution is added to carbonated water, the amine becomes miscible in the medium. The polymer precipitates from the aqueous system. (Green Chem. 2011, 13, 619–623; Sally Peng Li)

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