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Noteworthy Chemistry

November 25, 2013

Make selenophenols from phenols. Selenophenols are an important class of organoselenium compounds that are used in a variety of chemistry subdisciplines. Existing methods for preparing selenophenols, however, usually involve highly reactive starting materials and harsh reaction conditions. M. Pittelkow and co-workers at the University of Copenhagen report an OAr→SeAr variation of the Newman–Kwart rearrangement that allows the preparation of selenophenols (4) from O-arylselenocarbamates (2).

Synthetic pathway from phenols to selenophenols

In the original Newman–Kwart rearrangement, O-arylthiocarbamates are converted to S-arylthiocarbamates via an OAr→SAr migration. The authors found that Se-arylselenocarbamates (3) can be obtained by a similar thermal OAr→SeAr rearrangement of compounds with structure2, which are prepared from phenols (1) in one step. Subsequent hydrolysis of 3 gives products 4 that are isolated as diselenides.

The selenium version of Newman–Kwart rearrangement takes place when compounds 2 are heated at >130 ºC neat or in anhydrous solvents. The reactions are faster and require lower temperatures when the aryl group substituents are electron-deficient. Whereas 2with electron-withdrawing groups gives corresponding compound 3 in almost quantitative yield, the conversion from 2 with electron-donating groups proceeds with low yields or not at all.

The kinetics of the OAr→SeAr rearrangement are first order, the same as the original OAr→SAr transformation. The authors propose a mechanism that involves a four-membered cyclic transition state, which is consistent with the original Newman–Kwart rearrangement. (Angew. Chem., Int. Ed. 2013, 52, 12346–12349; Xin Su)

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Prevent amine racemization during an SNAr displacement. M. Golden and co-workers at AstraZeneca (Macclesfield, UK) used ω-transaminase enzyme chemistry to synthesize a janus kinase 2 inhibitor. In one step, the reaction of enantiomerically pure (S)-1-(5-fluoropyrimidin-2-yl)ethylamine and 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine with Et3N as the base in n-BuOH solvent was susceptible to significant and unpredictable levels of epimerization (60–90% ee).

Because the product of the SNAr coupling appeared to be stable under the reaction conditions, it was apparent that the starting amine epimerized as the reaction progressed. The authors’ experiments ruled out mechanisms such as imine formation or a radical mechanism to account for this epimerization. A more likely mechanism, suggested by modeling studies, proceeds via an enamine or ylide produced by the action of Et3N and Et3N+ present in the reaction mixture.

The model predicted that epimerization would be greatly reduced in the absence of this buffer system. This was borne out when changing the base to KHCO3 significantly reduced the extent of epimerization. The product ee rose to 94%. (Org. Process Res. Dev. 2013, 17, 1123–1130; Will Watson)

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Use acids to tune the solid-state luminescence of luminogens. Molecules that luminesce efficiently in solution usually lose their light-emitting capability in the solid state. This photophysical phenomenon is often called aggregation-caused quenching (ACQ) of light emission. N. Tohnai, M. Miyata, and coauthors at Osaka University and PRESTO (Saitama, both in Japan) have overcome the ACQ problem.

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Conversion of a nonemitting solid to its fluorescent salt

Fluorophore 1 exhibits the typical ACQ phenomenon: Its strong emission in solution is completely quenched when it is a solid. Its fluorescence is revitalized, however, when a salt (2) is formed from 1and an inorganic acid. Varying the acid’s anion allows the fluorescence color of 2 to be tuned from blue to red. The fluorescence manipulation is accomplished by modulating the packing structure of the salt, particularly the π-interactions between the aromatic rings. (Dalton Trans2013, 42, 15922–15926; Ben Zhong Tang)

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Processing conditions affect graphene surface contamination and lattice defects. Graphene, a 2-D material that shows promise for a variety of electronics applications, is commonly prepared by exfoliating single carbon layers from bulk graphite. Mechanical exfoliation produces small amounts of highly pure graphene, whereas harsh chemical exfoliation produces larger amounts of graphene contaminated with oxides and amorphous carbon.

Milder chemical processes, coupled with ultrasonication, require stabilizing additives to prevent re-aggregation. Noncovalent stabilizers are preferable to covalent ones because they do not saturate the carbon–carbon bonds in the graphene layer.

N. Tagmatarchis and coauthors at the National Hellenic Research Foundation (Athens), the University of Antwerp (Belgium), and the University of Mons (Belgium) studied the effects of ultrasonication duration and power levels on the introduction of foreign species onto the graphene surface. They produced the highest concentrations of exfoliated graphene by tip ultrasonication at 60 min and 40 W. o-Dichlorobenzene (o-DCB) was a more efficient exfoliant than N-methyl-2-pyrrolidone (NMP).

A comparison of the Raman spectra of intact graphite and the exfoliated graphene showed that o-DCB and NMP promote exfoliation by physical processes rather than electronic interactions. The spectra also indicated that the graphene sheets were oligolayers rather than monolayers and that the graphene lattice contained sp3-hybridized carbon atoms that were bonded to oxygenated substituents. Thermal, attenuated total reflectance IR, and X-ray photoelectron spectroscopy (XPS) studies confirmed this and provided additional information about the concentration and identities of the foreign species.

Ultrasonication in NMP produced exfoliated graphene containing more oxygen than did o-DCB. The concentration of oxygen species was sensitive to ultrasonication power but not duration. With o-DCB, the oxygen content can be reduced by increasing the duration or the power. XPS showed the presence of carboxylic acids, ethers, and epoxides, but not carbonyl groups, which suggests that the oxygen-containing groups are produced by exposure to air, not to the solvent.

Increasing the power and/or duration of the ultrasonication appears to decompose some portion of the oxygenated species, but it also introduces defects into the graphene sheet. It is possible that sonication treatment further separates the oligolayered graphene flakes, but the authors could not verify this by using XPS analysis. (J. Phys. Chem. C 2013, 117, 23272–23278; Nancy McGuire)

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Base choice affects the pathway of pyridazine cyclization. Y. Chen and co-workers at Shanghai AoBo Bio-pharmaceutical Technology (Shanghai) developed an efficient manufacturing method for a key intermediate in the synthesis of the antihypertensive drug cilazapril. In one step, the cyclization of (S)-5-bromo-2-N,N′-di(benzyloxycarbonyl)hydrazino-1-pentanoic acid gave three products: a δ–lactone, a bis-Cbz–protected hexahydropyridazine, and a mono-Cbz–protected hexahydropyridazine. (Cbz is carbobenzoxy.)

In an initial screening of bases (Et3N, 4-dimethylaminopyridine, Na2CO3, and NaH), the lactone was the major product. But when NaH in DMF was used for initial deprotonation at 0 ºC, followed by warming to 25 ºC, a small amount of the desired mono-Cbz product was formed in 15% yield, along with the other two.

Extending the range of bases showed that NaOH in DMF results in 90% yield of the mono-Cbz–protected hexahydropyridazine. The authors describe a possible mechanism in which the key step is transfer of the Cbz group from nitrogen to the carboxylate ion in the α-position on the newly formed hexahydropyridazine ring. (Org. Process Res. Dev. 2013, 17, 1209–1213; Will Watson)

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