Noteworthy Chemistry

October 29, 2012

Atomic force microscopy discriminates between bond lengths. The accurate determination of bond lengths relies mostly on diffraction methods if crystal structures are available; bond orders are determined from bond-length data. Traditional diffraction techniques provide averaged values from large collections of molecules. L. Gross and coauthors at IBM Research—Zurich, the University of Santiago de Compostela (Spain), and CEMES-CNRS (Toulouse, France) have developed a noncontact atomic force microscopy (NC-AFM) method that allows direct comparisons among bonds in individual molecules with high precision.

The authors studied the bond orders in buckminsterfullerene (C60, 1), hexabenzocoronene (2), and dibenzonaphthoperylene (3) at 5 K by combining scanning tunneling microscopy (STM) with AFM equipped with a CO-functionalized sensor tip. After using STM to identify the orientation of C60 on a Cu(111) surface, they switched to NC-AFM and optimized the tip height to obtain the best atomic contrast. The origin of the atomic contrasts is Pauli repulsion between overlapping electron clouds.

The authors differentiated between the p bond in 1 that fuses pentagons and hexagons and the shorter h bond that fuses two hexagons in two ways:

  • The frequency shift increases when the tip moves from the p bond to the h bond, that is, from lower to higher electron density.
  • In the AFM image of the studied fragment, the p bond is 30% longer than the h bond.

The actual difference between the bond lengths is only ≈5%. The authors attribute the discrepancy to an amplification caused by CO tilting at the tip’s apex.

Using the same method, the authors also show that the i and j bonds in 2 and the q, r, s, t, and u bonds in 3 can be differentiated. This sensitive method it distinguishes between the i and j bonds in 2, which differ by only 0.03 Å. (Science 2012, 337, 1326−1329; Xin Su)

Target cells with spherical nucleic acid–antibody hybrids. C. A. Mirkin* and co-workers at Northwestern University (Evanston, IL) designed spherical nucleic acids (SNAs) for targeting specific cells. They used Cu(I)-catalyzed Huisgen cycloaddition reactions or click chemistry to synthesize a DNA–monoclonal antibody (mAb) HER2 conjugate, which they hybridized to SNAs with gold nanoparticle cores.

Approximately two mAb–DNA conjugates were hybridized with each SNA unit. Hybridization increases the SNA’s hydrodynamic diameter from 19 to 23 nm. The antigen-binding ability of the mAb is retained after hybridization. These cell-targeting SNAs lead to a greater degree of cell association in HER2-overexpressing cell lines.

When the incubation temperature of 4 °C is increased to biologically relevant 37 °C, target specificity decreases somewhat. The authors attribute this result to temperature-dependent, nonspecific endocytosis. They also detected a relationship between cellular uptake and cell selectivity with time. Significant gene knockdown occurred at relatively low concentrations of the targeting nanoparticles. (J. Am. Chem. Soc. 2012, 134, 16488–16491; LaShanda Korley)

Make inexpensive microfluidic devices for instructional use. Preparing conventional microfluidic devices requires trained personnel, expensive equipment, clean-room techniques, and hazardous chemicals such as HF for patterning the glass surfaces. P. K. Yuen* and V. N. Goral at Corning Inc. (NY) report a rapid, low-cost method for making whole-glass microfluidic devices that can be used in undergraduate and graduate-level chemistry laboratories.

The authors used microscope glass slides (A–D in the figure) or Borofloat glass wafers (E–H) to make the microfluidic devices. Vinyl self-adhesive sheets prepared with a digital craft cutter are used as masks (A and E). The glass is covered by the vinyl mask, and glass-etching creams (mixtures of NH4F·HF and NaF·HF) are applied for 15 min to etch the surface (B and F). Removing the mask uncovers the etched slide (C and G), in which inlet and outlet holes are drilled. The etched slide is washed with aq Ca(OAc)2, clamped between two unetched glass slides, and heated to 115 °C for 2 h in a standard laboratory oven to effect glass-to-glass bonding and complete the microfluidic device (D and H).

Microscopy of the etched glass surfaces showed that microscope slides produce rough surfaces whereas the Borofloat wafers remain smooth and transparent. The etching rates of the creams are in the range 0.13–0.15 μm/min. The rates decrease with time, so the depth in the glass after 60 min of etching is ≈5 μm. Adding HCl to the etching creams increases the etching rate. (J. Chem. Ed. 2012, 89, 1288–1292; JosÉ C. Barros)

Cyclopropane [3 + 2] cycloadditions make useful heterocycles. Five-membered rings can be synthesized directly by [3 + 2] cycloaddition reactions of donor–acceptor cyclopropanes. To develop methods for the [3 + 2] cycloaddition of cyclopropanes to various substrates, B. M. Stoltz and co-workers at Caltech (Pasadena) investigated reactions of aryl-substituted cyclopropanes with allyl isothiocyanates. They found that using a stoichiometric amount of Sn(OTf)2 produces thioimidates in high yields.

When cyclopropanes with electron-rich aryl substituents are used, the reaction time is significantly shorter than with electron-withdrawing groups. The reaction also works well with carbodiimides to form amidines.

Isocyanates react poorly under the conditions that work well with isothiocyanates and carbodiimides. By replacing Sn(OTf)2 with FeCl3, the authors obtained moderate yields of lactams from isocyanates. Whereas reactions mediated by Sn(OTf)2 are highly stereospecific, inverting the cyclopropane chiral center in the products, FeCl3-mediated reactions result in completely racemized products.

This method may be useful for forming building blocks for optically active natural products or pharmaceutically relevant heterocyclic compounds. (Org. Lett. 2012, 14, 5314–5317; Chaya Pooput)

Optimize a lipase-catalyzed enantioselective hydrolysis. S. Yoshida and co-workers at Astellas Pharma and Astellas Research Technologies (Ibaraki, Japan, and Tokyo), developed a scalable synthesis of (R)- and (S)-3-amino-2-[(benzyloxy)methyl]propanol hydrochloride, a C4 chiral amine pharmaceutical building block. Except for one synthetic route that uses a chiral auxiliary, all of the routes they investigated use lipase-catalyzed enantioselective transformations.

The most successful method included an enantioselective hydrolysis of a diester. Optimization centered first on the source of the lipase and then on the ester grouping. Subsequent work evaluated the amount of lipase needed, the effect of cosolvents, and the pH of the buffer.

In the optimized process, 2-[(benzyloxy)methyl]-1,3-propanediol diacetate reacts with an Amano lipase in 1,2-dimethoxyethane and a phosphate buffer at pH 5.8 for 26 h at room temperature to produce the (S)-hydroxy acetate in 91% ee. The selectivity can be upgraded during the subsequent conversion to the R enantiomer. The overall synthesis gives the R product in 37.7% yield and >99.0% ee in eight steps from 2-hydroxymethylpropane-1,3-diol. (Org. Process Res. Dev. 2012, 9, 1527–1537; Will Watson)

Complete arylation flattens the corannulene “bowl”. Corannulene (1) is a polycyclic aromatic hydrocarbon that is also called a “buckybowl” because of its shape and structural connection with the C60 buckminsterfullerene. Although peripheral substitutions usually reduce the curvature of its bowl-shaped backbone to relieve steric congestion, the only examples of a planar corannulene are the result of coordination with a ruthenium complex (P. A. Vecchi et al. Organometallics 2005, 24, 4543–4552).

K. Itami at Nagoya University (Japan), L. T. Scott at Boston College (Chestnut Hill, MA), and coauthors report a series of almost planar perarylated corannulenes that they synthesized by palladium-catalyzed direct C−H arylation.

The authors first observed higher polyphenylcorannulenes while optimizing the synthesis of pentaphenylcorannulene. When they repeated the arylation for two more cycles with large excesses of triphenylboroxine (2a) in the presence of 2.5 mol% Pd(OAc)2 and 1 equiv o-chloranil, they isolated decaphenylcorannulene (3a) in 6% yield (Figure 1). Other products containing as many as 17 phenyl groups were isolated.

The authors obtained better yields with tris(p-tert-butyl)boroxine (2b; 23% yield of 3b) and tris(p-chlorophenyl)boroxine (2c; 54% yield of 3c). They believe that steric hindrance from the para substituents prevents undesired arylation as in 3a.

The crystal structure of 3c (Figure 2) features a near-planar corannulene bowl with a depth of only 0.25 Å, much smaller than that of 1 (0.87 Å). The bowl-to-bowl inversion barrier for 3c is estimated to be 2.5 kcal/mol at 100 K, also significantly lower than 11.5 kcal/mol for 1. The authors attribute this difference to the relief of steric congestion of the 10 substituted phenyl groups.

1H NMR data suggest a time-averaged D5h geometry for 3c in solution. The aryl groups in 3c are arranged in a twisted pattern toward the same direction, which creates helical chirality. The enantiomers do not racemize upon inversion. (J. Am. Chem. Soc. 2012, 134, 15664–15667; Xin Su)

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