Noteworthy Chemistry

January 24, 2011

Here’s a high-yield synthesis of a para-bridged cyclophane. T. Ogoshi and co-workers at Kanazawa University (Japan) previously reported a new class of para-bridged cyclophane derivatives called pillar[5]arenes with general structure 2. The name comes from X-ray crystal analyses that show highly symmetrical pillarlike architecture. The analyses also suggest a conformationally stable structure because the average C–C–C methylene bridge angle between units of 2 is very close to stable tetrahedral C–C–C bond angles of 109.5°. Structurally, 2 is a cyclic pentamer composed of phenolic units similar to typical calixarenes.

The earlier synthesis of pillar[5]arene gave low yields. The authors now report a simple, rapid, high-yield preparation from commercially available reagents.

The cyclization reaction is carried out rapidly by the BF3-mediated reaction of 1,4-dimethoxybenzene with paraformaldehyde to form dimethoxypillar[5]arene 1. Only a small amount of competing linear oligomer is formed; pure 1 is isolated in 71% yield. Subsequent removal of the methoxy groups with BBr3 quantitatively produces free hydroxy derivative 2.

The hydrogen bonding in 2 disturbs the pentagonal structure and induces conformational “flipping” of two of the five units at positions 1 and 3 in the macrocycle. The flipping phenomenon is not observed in 1.

The authors emphasize the unusually high yields of 1 and 2 compared with other macrocycles such as crown ethers and calixarenes. This is additional evidence that the pentagonal cyclic structure of 1 represents a conformationally stable architecture. (J. Org. Chem. 2011, 76, 328–331; W. Jerry Patterson)

Improve a diphenylzinc–bromination protocol. A protocol developed by T. Studemann and P. Knochel (Angew. Chem., Int. Ed. Engl. 1997, 36, 93–95) uses 4 equiv of expensive Ph2Zn to add only one phenyl group to 1-butynylbenzene. R. O. Cann and colleagues at Bristol-Myers Squibb (New Brunswick, NJ) reduced the amount of Ph2Zn to 1.5 equiv without affecting the yield.

They achieved a more significant reduction in Ph2Zn usage by first preparing a mixed zinc reagent, EtPhZn, from Et2Zn and Ph2Zn in situ. This protocol requires 0.7 equiv each of Et2Zn and Ph2Zn.

The subsequent bromination of the organozinc intermediate is best carried out with N,N’-dibromo-5,5-dimethylhydantoin. This change avoids the formation of a thick gelatinous precipitate when N-bromosuccinimide is used as the brominating agent. (Org. Process Res. Dev. 2010, 14, 1147–1152; Will Watson)

Modified rhodamines fluoresce strongly in the aggregated state. Rhodamine is highly emissive in dilute solution and is used as a fluorophore in a variety of applications, particularly in molecular biology. Aggregation-related quenching of light emission in the concentrated solution or in the solid state, however, affects the dye adversely.

S. Kamino and coauthors at RIKEN Kobe Institute, Okayama University, Osaka University of Pharmaceutical Sciences (Takatsuli), Suzuka University of Medical Science, Nihon University (Narashino), Hitachi High-Technologies Co. (Hitachinaka), and Nara Institute of Science and Technology (Ikoma, all in Japan) elegantly modified the molecular structure of rhodamine and generated a series of derivatives (1) that are highly emissive in the aggregated state.

In contrast to parent compound rhodamine, the cationic derivatives are almost nonfluorescent when they are dissolved in “good” solvents under acidic conditions. The active intramolecular rotations of the carboxyphenyl and dialkylamino groups may nonradiatively deactivate the excited states of the dye molecules. The dyes become emissive when they supramolecularly aggregate in “poor” solvents.

The authors’ studies of the effects of viscosity and temperature on the emission processes of the cationic dyes indicate that the restriction of intramolecular rotation plays a crucial role in enhancing the rhodamine emission by aggregate formation. (Chem. Commun. 2010, 46, 9013–9015; Ben Zhong Tang)

Synthesize sulfonated pyridines in one pot. The pyridyl sulfone scaffold is used widely in pharmaceuticals, including anti-inflammatory, antihyperglycemic, and immunosuppressive agents and HIV-1 reverse transcriptase inhibitors. A direct, simple preparation of these pyridine derivatives would be of value to synthetic chemists.

K. M. Maloney*, J. T. Kuethe*, and K. Linn at Merck (Rahway, NJ) developed a process that sulfonylates 2-chloropyridine substrates with a sulfinic acid salt in a phase transfer–catalyzed SNAr reaction.

A key to their process is the addition of n-Bu4NCl to the reaction mixture, which results in >90% conversion. Without this reagent, the conversion is <20%. The reaction proceeds in high yields in the presence of many substituents, including carboxamide, trifluoromethyl, nitro, ester, and nitrile. Tol is p-tolyl; DMAc is N,N-dimethylacetamide.

The authors developed two procedures for pyridine sulfonylation. Method A gives excellent yields for electron-deficient chloropyridines such as 1, but it does not work for electron-neutral or electron-rich substrates. For these, they used acid-promoted sulfonylation (method B), which gives excellent yields from substrates such as 2.

The authors expanded the scope of the reaction to include iodo- and bromopyridines and pyridine trifluoromethanesulfonates in place of chloropyridine substrates, and again they obtained good-to-excellent yields. This procedure is easy to carry out in one pot without the need for chromatographic separation in product workup. One product was isolated in analytically pure form by simply adding water at the end of the reaction and filtering the resulting slurry. This method is safe, scalable, and significantly “greener” than alternative methods. (Org. Lett. 2011, 13, 102–105; W. Jerry Patterson)

Aminated mesoporous nanoparticles have potential medical uses. Ulrich Wiesner and coauthors at Cornell University (Ithaca, NY) and Memorial Sloan-Kettering Cancer Center (New York) used a simple, robust synthesis to develop nanoscale, high–amine content, mesoporous silica particles for biological applications. They prepared these highly porous Pm3n cubic symmetry nanoparticles (~220 nm diam) with room-temperature, base-catalyzed sol–gel chemistry that uses significant quantities (~54 mol%) of amine-functionalized silanes without affecting pore size and structure. This strategy also accommodates the condensation of other compounds, which the authors demonstrated with a fluorescent dye.

Using a pore expander to increase pore diam from 2.7 to 5 nm (and decrease particle size to ~110 nm) allows high amine loadings—up to 23.5 mol%. Incorporating the dye into the expanded pore structure leads to even smaller particle size (~100 nm) and maintains the structural integrity and morphology of the mesoporous nanosilica. Particle aggregation is suppressed by using poly(ethylene glycol) succinimidyl succinate, which aids particle uptake by cells for imaging applications. This technology may also be useful in catalysis and drug delivery. (J. Am. Chem. Soc. 2011, 133, 172–175; LaShanda Korley)

A sustainable piperylene sulfone process may help replace DMSO. Polar aprotic solvents such as DMSO are useful in organic synthesis because they dissolve inorganic salts and organic substrates. This solvent, however, has a high boiling point, which means that isolating the product is tedious and generates much waste.

Piperylene sulfone (2) is a new polar aprotic solvent that has solvent strength similar to DMSO, and it can be fully recycled. It is prepared by the cheletropic reaction of trans-piperylene (1) and SO2 in 45–55% yield. Heating 2 to 100 °C induces the reverse reaction to recover gaseous piperylene and SO2; this allows product isolation and solvent recycling.

C. A. Eckert and co-workers at Georgia Tech and Specialty Separations Center (both in Atlanta) developed a sustainable and scalable synthesis of 2. They used in situ NMR spectroscopy of the reaction mixture to screen for optimum reaction conditions. The results showed that the ionic radical inhibitor magnesium 8-anilino-1-naphtalenesulfonate is necessary to avoid radical-induced piperylene polymerization. An excess of SO2 must be used, and only trans-piperylene results in 2; the cis isomer does not react.

The authors then scaled up the reaction with 20 mL of industrial-grade piperylene (a 1:1 mixture of the isomers) and 200 mL of liquid SO2 as the starting materials and 2.75 g of the inhibitor. The yield was comparable with the milligram-scale reaction. They also modified the workup procedure: Liquid CO2 was introduced into the reaction mixture as a nonpolar “antisolvent” to precipitate the inhibitor. Filtration and low-pressure distillation give 2 in 75% yield based on trans-piperylene.

This method is sustainable on the industrial scale and may lead to replacing DMSO as a widely used polar aprotic solvent. (Ind. Eng. Chem. Res. 2011, 50, 23–27; JosÉ C. Barros)

Make renewable nanopipet sensors for metal ions. There is an increasing demand for small-scale tools and techniques to probe living cells and organisms without causing irreparable damage. Nanopipets are useful for detection and imaging because of their sizes and structures.

The response of nanoscale frameworks to metal ions is studied widely because it resembles many biological processes. N. Sa, Y. Fu, and L. A. Baker* at Indiana University (Bloomington) made renewable imidazole-modified quartz nanopipets and studied their reversible interactions with cobalt ions in acidic environments.

To accomplish imidazole functionalization, the authors treated quartz capillaries with N-[3-(triethoxysilyl)propyl]-4,5-dihydroimidazole. The imidazole groups are grafted onto the tips of the nanopipets. In a neutral environment, the imidazole groups bind metal ions, in this case, Co(II). Protons gradually replace the metal ions when an acid is added to the medium. When the pH value reaches 2.6, the replacement process becomes rapid. Addition of base deprotonates the probes and metal ions re-coordinate on the tips. (Anal. Chem. 2010, 82, 9963–9966; Sally Peng Li)

What do you think of Noteworthy Chemistry? Let us know.