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Noteworthy Chemistry

August 10, 2015


Make a chiral β–hydroxyaminoamide without protecting groups. M. A. Schmidt, L. T. Rossano, and co-workers at Bristol-Myers Squibb (New Brunswick, NJ) needed an efficient synthesis to make large quantities of the tartrate salt of β-hydroxyaminoamide 5 (see figure). They developed a two-step route in which the two chiral centers are set in a single D-threonine aldolase–catalyzed aldol reaction between pyridine-4-carboxaldehyde (1) and glycine (2).

Synthesis of β–hydroxyaminoamide 5

The amide was prepared by treating product 3 with pyrrolidine and dimethyldichlorosilane (Me2SiCl2), but the formation of byproduct pyrrolidine hydrochloride was a problem. The authors’ elegant solution was to treat pyrrolidine with Me2SiCl2 to make dimethyldipyrrolidinosilane (4) “offline” and then introduce it into the synthesis as a toluene solution.

After the amide coupling, the reaction mixture was cooled from 40 ºC, methanol was added, and excess pyrrolidine and toluene were distilled off. Diluting the resulting solution with ethanol, adding L-tartaric acid, seeding, and adding an antisolvent (ethanol) provided 5 in 83% yield, 99.8% purity, >99.9% diastereomeric excess, and >99.9% enantiomeric excess. (Org. Process Res. Dev. DOI: 10.1021/acs.oprd.5b00192; Will Watson)

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Extend simple molecular tweezers to chiral derivatives. Molecular tweezers are compounds that feature two large, flat pincer groups, usually aromatic, connected by a flexible bridge. Therefore they can adapt their conformation and/or configuration to recognize and bind guest molecules, which makes them useful as biomimetic receptors, among other applications.

The classic molecular tweezers compound, bisnaphthalene derivative 3, and structurally related 4 and 5 have naphthalene pincers and dioxocin bridges. Z. He, X. Yang, and W Jiang* at South University of Science and Technology of China (Shenzhen) and North University of China (Shanxi) synthesized more complex chiral tweezers-like compounds by extending the scaffold of 3 to introduce a new class of molecular tweezers.

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Chiral tweezers molecules

Whereas 3 can be readily obtained by the condensation reaction between 1,1,3,3-tetramethoxypropane (1) and 2-naphthol (2), the authors used a disubstituted naphthalene (2,6-dihydroxynaphthalene, 6) that could be linked to two 2-naphthol units via the dioxocin linker to prepare trisnaphthalene 7. (TFA is trifluoroacetic acid; THF is tetrahydrofuran.)

Compound 7 was obtained as two chiral configurational isomers 7a (the U-shaped syn isomer) and 7b (the Z-shaped anti isomer), in 3% and 4% yields, respectively. Similarly, the coupling between bisnaphthalene 5 and 1 gives the tetranaphthalene 8 in its less symmetric configuration 8a in 8% yield.

Unexpectedly, 7a is more soluble in chloroform than 7b. In the solid-state, U-shaped isomer 7a exists in intercalating enantiomeric pairs, whereas Z-shaped isomer 7b lines up as homochiral polymeric chains. Isomer7a also provides a molecular cavity that could host guest molecules, and it shows higher affinity toward the 1,4-diazabicyclo[2.2.2]octane (DABCO)–derived dication (9) than 3, 4, or 8a.

In this work, the authors upgraded a simple molecular tweezers backbone into a more complex one. This coupling-based extension strategy can be used to explore further the structural diversity of these molecular tweezers. The introduction of chirality will allow them to be used in asymmetric recognition and separation. (Org. Lett. DOI: 10.1021/acs.orglett.5b01871; Xin Su)

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Gold cations make atomic rocker switches. The potential uses for atomic switches in data storage and processing are well known, but these switches also might be used to control the formation of chemical bonds. G. Meyer and colleagues at IBM Research-Zurich (Switzerland) and the University of Liverpool (UK) made atomic “rocker switches” from individual gold(I) cations (Au+) adsorbed on a NaCl film. Each Au+ forms a tilted linear complex with the two nearest chloride ions, creating an anisotropic electrostatic field. The tilt can be toggled repeatedly and reversibly by using a probe tip (see figure). 

Gold cation toggling between two mirror-image electrostatic fields

The authors deposited neutral gold atoms onto a NaCl film that had been coated on a single-crystal copper substrate. Cations were made one at a time by using the probe tip to apply a voltage. Scanning tunneling microscope (STM) images show small round protrusions, which appear as bright spots, adjacent to larger oblong depressions, which appear as dark areas. The protrusions and depressions appear to switch places, accompanied by a sudden frequency shift, as the STM tip (with voltage set to zero) scans the surface.

Atomic force microscopy scans show that the field can be switched back and forth repeatedly when the fast scan direction is perpendicular to the switching axis. Only one switching event is observed when the fast scan direction is parallel to this axis.

The authors replicated this effect with density functional theory calculations. When the gold atom is centered in the linear Cl–Au–Cl complex, the complex is parallel to the surface. When it is shifted off-center, the complex tilts by ≈10º. The observed negative electrical charge and interatomic distances support the identification of the bright protrusions in the experimental images as chlorine atoms lifted from the surface in the tilted complexes.

The observed switch always occurs at the position of the lower-lying chloride ion in the tilted complex. The authors conclude that the probe tip exerts an attractive force that pulls this anion up, forcing the other Cl down. The local contact potential difference changes by several hundredths of an electron volt during switching, depending on the tip height.

This potential shift could be used to manipulate reactions of nearby molecules, for example, intramolecular hydrogen transfers in porphycene. Because the Au+ is embedded in the NaCl film, the switch remains stable while it influences its surroundings. (Nano Lett. DOI: 10.1021/acs.nanolett.5b02145; Nancy McGuire)

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Which amine donor is best for a transamination reaction? Biocatalytic transamination reactions typically use alanine or isopropylamine as the amine donor. These reactions must be operated so that the product amine, the coproduct ketone, or both are removed during the reaction to alter the unfavorable equilibrium position between amine donor–starting ketone and product amine–coproduct ketone.

In this example, T. Börner and coauthors at Lund University (Sweden) and the Technical University of Denmark (Lyngby) used a membrane system to separate the basic reaction mixture (pH  ³9) from the acidic extraction phase (pH <3). In this system, alanine is a superior amine donor because it exists as the carboxylate salt in the basic reaction medium and thus will not pass in to the liquid (undecane) membrane. In contrast, isopropylamine passes into the liquid membrane layer and then into the acidic extraction medium. This technique has the added advantage of simplifying product isolation and purification. (Org. Process Res. Dev. DOI: 10.1021/acs.oprd.5b00055; Will Watson)

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Manage nanoparticle self-assembly with a photoacid. Gaining control over the assembly and disassembly of nanoparticles is crucial to many aspects of their applications. Although these processes have been managed with the use of magnetic fields, light as an external stimulus is easier to control and can be applied to nonmagnetic particles. But to use light to assemble nanoparticles reversibly, the particles must be functionalized with photoresponsive groups, such as azobenzenes or sipropyrans, which degrade their properties and functions.

R. Klajn and colleagues at Weizmann Institute of Science (Rehovoth, Israel), the University of Southampton (UK), Tel Aviv University (Israel), and Leipzig University (Germany) developed a strategy for light-controlled self-assembly of nanoparticles that are not intrinsically photoresponsive. They achieved orthogonal control by introducing light-responsive materials to the reaction media instead of to the nanoparticles.

The researchers foresaw that the assembly behavior of nanoparticles modified with pH-sensitive ligands could be tuned with light through a photoacid, a compound that releases or captures protons in response to the presence or absence of light irradiation. The photoacid they chose was a protonated merocyanine (2 in the figure), which they obtained by protonating the spiropyran 1′,3′,3′-trimethylspiro[chromene-2,2′-indoline] (1). Irradiating 2 with blue light releases a proton to yield 1

Protonation of 1 to give 2 and the reverse reaction

The authors synthesized 5.5-nm gold nanoparticles (AuNPs) that were surface-functionalized with 11-mercaptoundecanoic acid. The particles were insoluble in methanol unless hydrochloric acid was added to break interparticle hydrogen bonding.

When the solution of acid-stabilized AuNPs was treated with 1, and a critical number of protons were removed from the NPs, the particles precipitated quantitatively, leaving a supernatant liquid with the yellow color of 2. Irradiating the mixture with visible light released protons from 2 and rapidly redissolved the precipitate to give a red solution, typical of a stable dispersion of AuNPs.

The assembly–disassembly process can be repeated for multiple cycles by turning the visible light off and on. This method also is applicable to AuNPs of different sizes or with shorter surface ligands. The light-sensitive system also can be embedded in a polymeric gel matrix; the authors demonstrated self-erasing images created by shining light through masks.

This strategy paves an entirely new, orthogonal way to control the assembly and disassembly of nanoparticles. It requires only minimal modification to the nanoparticles, largely preserving their surface functionality. The degree of assembly can be fine-tuned by modulating the basicity of 1 via chemical functionalization.

More importantly, the scope of the process is not limited to AuNPs: It can be extended to include other inorganic or hybrid particles. When combined with the magnetic method, it offers the possibility of dual control over nanoparticle self-assembly. (Nat. Chem. DOI: 10.1038/nchem.2303; Xin Su)

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