Noteworthy Chemistry

June 25, 2012

Supergelators have amplified properties in the gel state. Chemists are interested in developing intrinsic luminescent organogelators because these systems can transfer their molecular properties to the gel state. The properties may even be amplified to yield luminescent soft materials that can be used in high-tech applications such as optical sensors.

Although the pyrazole ring has a rich supramolecular chemistry, the gelation behavior of pyrazole derivatives was not investigated until now. A. Elduque, R. GimÉnez, and co-workers at the University of Zaragoza (Spain) studied self-assembly processes of pyrazole derivatives such as 1 and developed a group of pyrazole-based light-emitting supergelators.

The researchers designed and synthesized molecules that consist of a pyrazole ring, an amide bridge, and a trialkoxyphenyl “wedge”. Studies of gelation processes and structure–property relationships showed that the pyrazole and amide groups are both essential for the hydrogen-bonding–driven gelation processes. The molecules luminesce in solution and become more emissive in the gel state, exhibiting an excellent example of aggregation-induced emission enhancement.

Chiral isomers of 1 (e.g., 2S and 2R) produce aggregates and fibers with supramolecular chirality via a cooperative self-assembly mechanism that consists of an achiral nucleation step followed by a helical elongation step. These molecules’ properties such as luminescence and chirality can be amplified by transitioning from the molecular to the macroscopic level. (Soft Matter 2012, 8, 6799–6806; Ben Zhong Tang)

Quenching conditions affect the aldehyde yield from an aminal. In one step of the synthesis of a potential HIV drug, lithiating 4-bromo-2-chloro-1-fluorobenzene with LiN-i-Pr2 at –50 °C, followed by adding DMF, leads to an aminal intermediate that upon aqueous workup forms 6-bromo-3-chloro-2-fluorobenzaldehyde. A. Goodyear and co-workers at Merck Sharp and Dohme Research Laboratories (Hoddesdon, UK, and Rahway, NJ) observed that the aminal precursor was fully consumed, but the aldehyde yield was only 76%.

An investigation of the workup procedure showed that quenching with water or weak acid re-forms starting material 4-bromo-2-chloro-1-fluorobenzene and in addition to generating the desired aldehyde. This finding suggested that the aminal intermediate breaks down by two possible pathways. The authors adjusted the quench medium to 4 M HCl in MeO-t-Bu to effect complete conversion to the desired aldehyde. (Org. Process Res. Dev. 2012, 16, 605–611; Will Watson)

Silver impurities are crucial for gold(I) catalysis. In homogeneous Au(I) catalysis, the ligand–metal species [LAu]+ is believed to be the π-acid that activates alkene and alkyne substrates. AgCl formed by treating [LAu]Cl with AgA (A= OTf, BF4, or SbF6) during the preparation of gold catalysts is believed to be an inactive species. Therefore it should not make any difference whether Au(I) catalysts contain AgCl. (OTf is trifluoromethanesulfonate.)

X. Shi and co-workers at West Virginia University (Morgantown), however, report that gold catalysts prepared with and without AgCl differ drastically in their activity in certain reactions, and they have distinct NMR spectra. This finding identifies an overlooked “silver effect” in Au(I) catalysis.

The authors found that their triazole gold complexes 1 and 2 could catalyze the hydration of propargyl esters (3) to ketones (4) with high efficiency, a broad substrate scope, and good chirality retention. Traditional Au(I) catalysts such as [PPh3Au]+ and [i-PrAu]+ did not catalyze this reaction. This finding conflicts with an earlier report (Ghosh, N.; Nayak, S.; Sahoo, A. K. J. Org. Chem. 2011, 76, 500–511) that PPh3AuCl–AgSbF6 mixtures catalyze the same reaction.

To resolve this dilemma, Shi and colleagues performed parallel experiments with different catalysts. The results showed that neither AgA nor [PPh3Au]+A (prepared from PPh3AuCl–AgA mixtures followed by Celite filtration to remove AgCl) catalyzes the transformation from 5 to 6. Combinations of PPh3AuCl and AgOTf or AgSbF6 that were not filtered to remove AgCl catalyze the reaction effectively. The inactive [PPh3Au]+SbF6 (prepared by Celite filtration) mixed with AgSbF6 also shows excellent catalytic activity, indicating synergy between gold and silver.

When the authors examined another reported i-PrAu-catalyzed alkyne hydration (Marion, N.; Ramón, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009, 131, 448–449), they found similar results: Only the mixtures [i-PrAu]Cl–AgSbF6 and [i-PrAu]+SbF6–AgSbF6 could catalyze the reaction.

Additional spectroscopic studies confirmed these results. The authors prepared two LAuCl–AgSbF6 systems, using filter paper or Celite to remove AgCl. X-ray photoelectron spectroscopy results showed that all of the samples exhibited gold signals, but only the ones filtered through paper gave silver signals.

Examination of 31P NMR results from [PPh3Au]+TfO samples prepared with and without Celite filtration showed that the Celite-filtered [PPh3Au]+TfO had a more upfield-shifted 31P signal than its unfiltered counterpart, indicating that silver influences the structure of the gold complex in solution. These results indicate that silver may act as more than an “optimizer” for gold catalysis. The authors call for a re-evaluation of the existing mechanisms for related Au(I)-catalyzed reactions. (J. Am. Chem. Soc. 2012, 134, 9012–9019; Xin Su)

Adding a touch of water helps to optimize a classical resolution. S. Yoshida and colleagues at Astellas Pharma and Research Technologies (Ibaraka, Japan, and Leiderdorp, The Netherlands) describe two systems for the classical resolution of 4’,5’-dihydroxy-3’H-spiro[fluorene-9,2’-furan]-2-carboxylic acid. The (S)-enantiomer can be obtained by resolution with cinchonidine, but the eight recrystallizations required to obtain the required optical purity (>98% ee) significantly reduce the yield.

Alternatively, resolution with brucine generates the (R)-enantiomer, which can be purified in two recrystallizations. The authors found that the most efficient method for producing the desired (S)-enantiomer is to take the mother liquors from the brucine resolution, treat them with HCl to remove brucine, and then add cinchonidine. Using this technique they obtained 46.7 kg of the (S)-enantiomer in 99.3% ee and 42.6% yield.

Methyl propionate was the best solvent for crystallizing the cinchonidine salt. Adding 0.5 vol% water is crucial for maximizing the enantiopurity of the (S)-enantiomer; in the absence of water, only 97% ee was achieved. (Org. Process Res. Dev. 2012, 16, 654–663; Will Watson)

Make biocompatible dendrimers with a metal-free click reaction. Ethylene oxide (EO) is used extensively in biologically related materials because of its solubility in aqueous media, stability in physiological environments, compatibility with living cells, and prolonged circulation periods in the human body. The “conventional” syntheses of EO-based dendrimers, however, can involve toxic metals, harsh conditions, long reaction times, and excessive amounts of reagents that generate chemical waste.

The search for a “perfect” process to grow dendrimers is demanding because the synthesis strategy must be efficient, exclude toxic metals, and be free of side reactions and byproducts to ensure dendrimer monodispersity. It is important to avoid metals because polar dendrimers efficiently trap toxic metal ions.

M. Arseneault, I. Levesque, and J.-F. Morin* at Laval University (QuÉbec) report a divergent synthesis of the third- and fourth-generation EO-containing dendrimers that uses sequential azidation and metal-free click reactions. (The first few steps of one synthesis are shown in the figure; TsOH is p-toluenesulfonic acid.) The iodine atoms are displaced by azide groups to continue the sequence.

The authors synthesized the dendrimers in high yields with minimal purification requirements and without excessive amounts of reagents. In vitro tests showed that the dendrimers are cytocompatible and therefore promising for biomaterials applications. (Macromolecules 2012, 45, 3687−3694; Ben Zhong Tang)

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