Noteworthy Chemistry

September 9, 2013


The structure of the 2-norbornyl cation is finally resolved. For more than 50 years, there has been a vigorous debate over the structure of the 2-norbornyl cation. S. Winstein and P. D. Bartlett, among others, argued for the nonclassical structure (1), whereas H. C. Brown proposed rapidly equilibrating enantiomers (2). I. Krossing and colleagues at the University of Freiburg (Germany), the University of Erlangen-Nuremberg (Erlangen, Germany), and the University of Georgia (Athens) have finally pinned down the cation’s structure by X-ray diffraction (XRD) analysis.

Proposed structures for the 2-norbornyl cation and the complex used to study its crystal structure

A key step was the use of “soft” bromoaluminate anions (Al2Br7) to stabilize the carbocation. The authors treated 2-exo-norbornyl bromide (3) with Al2Br6 in the presence of CH2Br2 to obtain solvated [C7H11]+[Al2Br7]·CH2Br2 crystals (4). They observed phases in XRD structures at >86 K that contained ordered anions but disordered cations. They attribute this result to the near-spherical shape of the cations and 6,1,2-hydride shifts within them. When they cooled the material to ≈50 K with careful annealing, they obtained crystals suitable for analysis.

The experimental crystal structure agreed with computed structures of the cation and confirmed the nonclassical geometry. The authors believe that their new tool, the bromoaluminate anion, should be used to stabilize other carbocations so that their crystals can be studied. (Science 2013, 341, 62–64; José C. Barros)

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Modify a synthesis to improve stereoselectivity and avoid using azide. K. E. Henegar and co-workers at Pfizer Global Research and Development (Groton, CT) describe the synthesis of a spiropiperidine from (S)-benzyl 2-methyl-4-oxopiperidine-1-carboxylate. The first step is adding a trichloromethyl group to a piperidone derivative, which in the original version using CHCl3 and LiN(SiMe3)2 gave a 4:1 dr. The ratio can be improved to >20:1 by using in situ–generated Me3SiCCl3 and n-Bu4NOAc catalyst.

The second step in the original route was an azide displacement in which one nitrogen atom ends up as an amide that is then arylated. Treating the trichloromethyl alcohol directly with the aniline avoids the need for azide and for the later arylation step.

Acylation of the N-aryl compound requires more forcing conditions than the amine. The authors met this requirement by using ethyl malonyl chloride and 1,8-diazabicycloundec-7-ene (DBU) rather than ethyl hydrogen malonate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), and NEt3. (Org. Process Res. Dev. 2013, 17, 985–990; Will Watson)

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Watch the delivery of an anticancer drug to its target. Controlled drug-delivery systems (CDDSs) are preferable to conventional anticancer medications because they release the drug only when it reaches the targeted location. The CDDS process, however, is rarely observed because most antitumor drugs are intrinsically nonemissive or weakly fluorescent. K. S. Hong, C. Kang, J. S. Kim, and colleagues at Korea University (Seoul), Kyung Hee University (Yongin, Korea), and Korea Basic Science Institute (Cheongwon) synthesized a fluorogen with a CDDS that allows visible monitoring and accurate evaluation of the drug-release process.

The researchers synthesized a series of cyanine derivatives that contain carbamate and disulfide units and the anticancer drug gemcitabine, an example of which (1) is shown in the figure. The disulfide bond is reductively cleaved by thiols such as L-glutathione (GSH) to create additional thiol groups. The thiols initiate decomposition of the amide linkages to release gemcitabine (2).

Drug release from the cyanine carrier causes the cyanine to fluoresce

In the biological system, prodrug 1 is taken up by folate-positive cancer cells preferentially to folate-negative cells via receptor-mediated endocytosis. This process releases the drug in the endoplasmic reticulum to kill cancer cells and to allow the cyanine residue (3) to fluoresce. The therapeutic effect and drug-uptake process are easily followed at the subcellular level by a fluorescence imaging technique. (J. Am. Chem. Soc. 2013, 135, 11657–11662; Ben Zhong Tang)

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Thermosalient crystals relieve stress by jumping, spinning, or blowing themselves to bits. Thermosalient (TS) crystals (see examples) convert heat to mechanical energy, propelling themselves over distances thousands of times their own size in less than 1 ms. P. Naumov and co-workers at New York University Abu Dhabi (UAE) studied the thermodynamic, kinematic, structural, and macroscopic factors that drive these self-actuating crystals.

The researchers discovered a significant crystal-size effect on the differential scanning calorimetry profile and the temperature at which the TS phase transition occurs. Thermal cycling gradually reduces the force of the jumps, and the crystals eventually fragment and disintegrate. Grinding the crystals suppresses the TS transition, possibly because defects cannot form and propagate in crystals with less than a certain critical size.

In almost all cases, crystal symmetry is preserved across the phase transition. The unit-cell volumes show only modest expansion, ranging from 0.7% to 4.3%. Most of the crystals, however, show a marked expansion along one or two crystal axes, which is balanced by a reduction along the other axes.

The authors propose a two-stage process in which a small structural transformation causes a sufficient accumulation of internal strain to trigger a rapid second structural transformation that relieves the strain. Crystals that release strain gradually do not exhibit TS-type behavior.

The authors identified two main mechanisms for strain accumulation and release. The first applies to layered crystal structures composed of flat rigid molecules packed in layers that lack extended hydrogen bond networks or of layered molecular packings that saturate their hydrogen-bonding potential by dimerizing or polymerizing. These structures have limited degrees of freedom, and the molecules cannot rotate significantly. Heating or cooling produces anisotropic distortion, which introduces strain that eventually outweighs the weak cohesive interactions between the layers. This triggers a rapid sliding of the layers, manifested as crystal twinning and a change in unit-cell dimensions.

A second mechanism applies to crystals that have flexible bulky molecules composed of a central core bonded to multiple substituents that hinder hydrogen bonding between molecules. These molecules are more flexible and have more conformational freedom. Heating induces molecular torsion and

terminal-group rotation that produce strain. As the strain is released, the flexible molecules relax to their most stable conformation. After the phase transition, the molecular packing has the same relative orientation, but with increased intermolecular distances and increased conformational disorder of the terminal groups. (J. Am. Chem. Soc. 2013, 135, 12241–12251; Nancy McGuire)

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Determine enantiopurity by NMR without making diastereomers. The enantiopurity of chiral compounds is currently measured by various optical, chiral chromatographic, and other spectroscopic methods. When NMR is used for measuring enantiopurity, a chiral auxiliary reagent or the preformation of diastereomers is often required.

J. P. Hill and coauthors at National Institute for Materials Science (Ibaraki, Japan), Masaryk University (Brno, Czech Republic), Charles University in Prague, and the Japan Science and Technology Agency (Ibaraki) developed a prochiral solvating agent that can be used to determine enantiomeric excess (ee) values in a wide range of substrates without forming diastereomers.

Prochiral compounds are achiral molecules that, when induced by chiral inputs, become chiral in one step. Prochiral NMR reporter 1 is a porphyrinogen-based molecule with a C2-symmetry rigid saddle-shaped skeleton. It can bind chiral substrates via hydrogen bonding with the pyrrole NH groups.

Reporter compound for enantiopurity determination

When it forms complexes with analytes, the 1H NMR peaks of the enantiomeric CH groups split because of the differences in their spatial positions relative to the NH binding sites. The nonequivalence in chemical shifts is the basis for this method.

When the concentration of a chiral substrate remains constant, a linear correlation can be established between the magnitude of signal splitting and its ee. The correlation can be used as a quantitative indicator for the ee values of analytes.

The authors screened reporter 1 against a variety of chiral carboxylic acids, including ibuprofen, 2-phenylpropionic acid, and leucic acid. The binding constants were of the magnitude of 10 M–1. Compound 1 is also compatible with chiral esters, alcohols, and ketones. (Nat. Commun. 2013, 4, No. 2188; Xin Su)

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Optimize an amide coupling reaction. The impurity profile of the trimethobenzamide free base produced by coupling a benzylamine with 3,4,5-trimethoxybenzoic acid depends on the amide coupling agent used. When K. Neelakandan and coauthors at Emcure Pharmaceutical (Pune) and Annamalai University (Chidhambaram, both in India) used reported reaction conditions, two impurities formed: a desmethyl compound and the product from the desmethyl compound coupling reaction.

These impurities can be eliminated by using carbonyl diimidazole (CDI) as the coupling reagent, but the amount of CDI must be controlled to avoid forming a urea derivative that arises from the reaction of 2 mol of benzylamine with CDI. The authors found that the optimal quantity of CDI is 1.25 equiv. Using these conditions, they produced multikilogram quantities of trimethobenzamide hydrochloride that meets the regulatory specification. (Org. Process Res. Dev. 2013, 17, 981–984; Will Watson)

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