Noteworthy Chemistry

August 20, 2012

Use amides as Friedel–Crafts acylating agents. In Friedel–Crafts acylation, aromatic rings react with acyl chlorides or anhydrides in the presence of the strong Lewis acid catalyst AlCl3 to form aryl ketones. This reaction has been known for more than a century, but almost nothing has been reported about the use of amides as the acylating agent. Amides have not been used in Friedel–Crafts reactions because their strong C–N bonds are difficult to cleave to form acyl cations.

In previous studies, D. A. Klumpp at Northern Illinois University (DeKalb) and colleagues showed that by reducing the amide-stabilizing resonance, amides could be used in Friedel–Craft acylation with moderate product yields (Org. Lett. 2004, 6, 1789–1792). To optimize the reaction, Klumpp and coauthors at Northern Illinois and the University of Gothenburg (Sweden) sought more highly activated amides. They first focused on intramolecular acylation: By using nitrogen substituents with various electron-withdrawing groups (R), they synthesized a series of 3-phenylpropanamides (1) and treated them with the Brønsted superacid triflic acid (CF3SO3H).

The authors found that 4-nitrophenyl was the most effective activating group because it gave high yields and >90% of byproduct 4-nitroaniline could be recovered. This method was also effective for intermolecular reactions, which gave yields comparable with those of equivalent reactions with acyl chorides or anhydrides. The triflic acid could easily be recycled and reused; this is almost impossible with AlCl3. Unlike traditional Friedel–Crafts reactions, this method produces minimal amounts of chemical waste. (J. Org. Chem. 2012, 77, 5788–5793; Chaya Pooput)

Flow lithiation helps with a tricky aldehyde synthesis. In the first step of the synthesis of 3-(N-Boc-amino)-6-chloropyridine-2-carboxaldehyde, P. Grongsaard and colleagues at Merck (Rahway, NJ) and WuXi AppTec (Shanghai) formed a dianion from 3-(N-Boc-amino)-2-bromo-6-chloropyridine with 1 equiv MeLi followed by 1 equiv n-HexLi at less than –45 °C. (Boc is tert-butoxycarbonyl.) Quenching the dianion with DMF and the subsequent aqueous workup produced the aldehyde in good yield.

In the second of two 5-kg batches of this reaction, however, a thick gel formed during the dianion stage. To avoid this problem, the researchers ran the reaction in a flow system in which a solution of preformed monoanion was mixed with 2.5 M n-BuLi, followed by adding DMF. The mixture was quenched in aq HOAc–t-BuOMe.

The streams were mixed via a T-connector and then a static line mixer. The 0.25-in. ID stainless steel tubing was immersed in a dry ice–acetone bath to maintain low temperature. The assay yield was higher than in the batch reaction (85% vs 76%), and less debrominated side product (4% vs 7–8%) was formed. (Org. Process Res. Dev. 2012, 16, 1069–1081; Will Watson)

Add π-conjugated ligands to stabilize gold nanoparticles. Gold nanoparticles (AuNPs) are usually modified with long-chain alkyl ligands that have thiol anchors to prevent aggregation. Whereas these modified AuNPs are soluble in nonpolar organic solvents and do not aggregate even in the solid state, their thermal stability is poor because alkyl ligands rely on weak van der Waals interactions to protect the gold cores. S. Machida and coauthors at Tokyo National College of Technology and Toshiba (Kanagawa, Japan) report that attaching large π-conjugated polynuclear aromatic groups to alkyl ligands dramatically enhances the thermal stability of AuNPs.

The authors previously reported that introducing a tolyl group to long-chain ligands increases the aggregation temperature of AuNPs (Tsuchido, Y., et al. Trans. Mater. Res. Soc. Jpn. 2010, 35, 271–274). Encouraged by these results, they synthesized three ligands with large pyrene (1), perylene (2), or coronene (3) π systems. The synthesis strategy was to form amides from 3-(tritylthio)propanoic acid and 11-amino-1-undecanol and then esterify them with butyric acid derivatives of the fused aromatic compounds.

The authors synthesized three types of AuNPs with ligands 13. The modified particles’ average size was ≈2 nm; they exhibited visible light absorption at 450–600 nm, characteristic of AuNPs. Thermogravimetric measurements showed a one-step weight loss process for the AuNPs caused by ligand desorption.

When they measured the modified AuNPs’ thermal stability, the authors found that introducing π-conjugated groups significantly increases the decomposition temperature, and that the increase is proportional to the size of the π system. For example, the decomposition temperature of AuNPs with ligand 3 is 417 °C, a 168 °C enhancement over AuNPs made with 1-undecanethiol. An amide group alone only slightly increases the decomposition temperature. (Chem. Lett. 2012, 41, 708–710; Xin Su)

Several factors affect the morphology of block copolymer films. S. Roland, R. E. Prud’homme*, and C. G. Bazuin at the University of Montreal detail the assembly of supramolecular block copolymers (BCPs) in thin films generated by dip-coating. They were motivated by the recent finding of a V-shaped relationship between dip-coating rate (1–80 mm/min) and film thickness that can be used to probe the connection to BCP morphology development.

The authors used a copolymer of polystyrene (41.5 kDa) and poly(4-vinylpyridine) (17.5 kDa) (PS-b-P4VP) with 1-naphthol or 1-naphthoic acid as a small molecule that is capable of hydrogen bonding with the P4VP block. The concentration of the small molecule in combination with the dip-coating rate influenced the evolution of the BCP film morphology. With 5 mg/mL naphthol, for example, a featureless film surface indicative of a brush layer is observed at intermediate rates (5–10 mm/min); but a transitional mixture of spherical P4VP–naphthol micellar dots and horizontal P4VP–naphthol cylinders is seen at 10 mg/mL under a similar dip-coating regime.

The hydrogen bonding strength of small molecules (naphthol vs naphthoic acid) influences the thin-film morphology in these systems. The correlation between the small molecule content in the film and that in the solution is influenced by the rate of dip-coating and the hydrogen bonding character of the solvent. These parameters are crucial to understanding the observed differences in thin-film nanostructures. (ACS Macro Letters 2012, 1, 973–976; LaShanda Korley)

Altered Mitsunobu reaction makes morpholines and oxathianes. Morpholines and oxathianes are saturated heterocycles present in some natural products and pharmacologically active compounds. Several methods for preparing these compounds are available; many of them involve the Mitsunobu reaction. S. Muthusubramanian and coauthors at Madurai Kamaraj University (Madurai, India) and Texas A&M University (College Station) report a method for making these heterocycles that is superior to the Mitsunobu protocol in terms of yield and waste generation.

Brominating acetophenones (1) gives α-bromo ketones (2), which react with Na2S or amines to generate 1,5-diones (3 or 7, respectively). Reducing the diones produces 1,5-diols (4 or 8). The key cyclization step is best performed with racemic camphorsulfonic acid [(±)-CSA] in DMF or with polyphosphoric acid (PPA) in toluene to obtain oxathianes (5 and 6) or morpholines (9 and 10), respectively. There are no configuration changes or equilibration; the yields of 9 and 10 reflect the original yields of diol 8.

The yields are in the 85% range, whereas the traditional Mitsunobu protocol with PPh3 and diethyl azodicarboxylate results in 20–50% yields. The method can also be used in intramolecular reactions, for example, in the synthesis of fused oxathianes such as 11 and 12. (Tetrahedron 2012, 68, 6892–6901; JosÉ C. Barros)

Isolated polymer chains phosphoresce at room temperature. Phosphorescence in pure organic molecules normally occurs only at low temperatures. Room-temperature phosphorescence (RTP) has never been observed in a π-conjugated polymer system because it is difficult to isolate long macromolecular chains with complicated, variable conformations. The strong phase segregation in blends of luminescent polymers with inert host polymers restricts phosphorescence to low temperatures. RTP from a polymer is thus the ultimate test for true individual chain isolation at the nanometer scale.

H. A. Al-Attar* and A. P. Monkman at the University of Durham (UK) developed a method for obtaining dense isolated polymer chains in the solid state. Using water-soluble conjugated polymers (WSCPs) and polymeric surfactants such as poly(vinyl alcohol) (PVA) and poly(vinylpyrrolidone) (PVP), they prepared films with WSCP/surfactant weight ratios of 1:1–1:32.

The films exhibited RTP, which indicates that a high degree of chain isolation was accomplished in these hosts. The formation of hydrogen bonds between the PVA or PVP chains upon drying locks in the isolation of the WSCP chains, avoids segregation, and increases the polymer nanomixtures’ stability. The method is applicable to a variety of WSCPs. (Adv. Funct. Mater. 2012, 22, Early View DOI: 10.1002/adfm.201200814; Ben Zhong Tang)

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