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Noteworthy Chemistry

April 29, 2013

Combine light and base to make biaryls. Biaryls, versatile building blocks in organic chemistry, are made mainly by heterocoupling aryl halides with organometallics or homocoupling either of these reagents. Homolytic aromatic substitution (HAS) is a more efficient, cost-effective way to make biaryls. M. E. BudÉn, J. F. Guastavino, and R. A. Rossi* at the National University of Córdoba (Argentina) report the direct C–H arylation of aryl halides with benzene via base-promoted HAS induced by photo-irradiation at room temperature.

The authors’ proposed mechanism is shown in the figure. Radical anion [ArX]•– can be generated by electron transfer (ET), which emits an anion to yield radical Ar. The radical couples with benzene (PhH), which, in the presence of a base (B),gives coupling product ArPh.


The authors studied the reaction between PhI and benzene and found that, with 150 equiv benzene, 3 equiv t-BuOK, and 13 equiv DMSO, PhI is converted to biphenyl under photo-irradiation in 90% yield within 1 h. They showed that DMSO and light are indispensable for the reaction to proceed and that t-BuOK cannot be replaced by Et4NOH or KOH.

A variety of aryl halide substrates are compatible with the reaction conditions. Aryl iodides with functional groups ranging from electron-donating to electron-withdrawing at the para, meta, and ortho positions give coupled biaryls in moderate-to-high yields (44–91%).

Similar results are obtained for heteroaryl halides such as iodopyridines, 6-chloroquinoline, 3-bromobenzo[b]thiophene, and naphthyl and phenanthryl halides. Haloiodobenzenes can undergo dual phenyl substitution. When thiophene is used instead of benzene, the major products are C2 regioisomers. (Org. Lett. 2013, 15, 1174–1177; Xin Su)

Reduce a 14-step synthesis to 5 steps. The route reported by Huber, J. D., et al. (J. Med. Chem. 2012, 55, 7114–7140) to 4-(1-acetylpiperidin-4-yl)-N-(diaminomethylene)-3-(trifluoromethyl)benzamide, a sodium–hydrogen exchange type I inhibitor, requires 14 steps. The overall yield was only ≈20%, and the synthesis uses the expensive reagent bis(pinacolato)diboron, none of whose atoms appear in the final molecule.

X. Wei and co-workers at Boehringer Ingelheim Pharmaceuticals (Ridgefield, CT) developed an optimized synthesis that requires five steps and the inexpensive, readily available building blocks pyridine, 2-bromobenzotrifluoride, MeCOCl, and guanidine hydrochloride. The Grignard reagent generated from 2-bromobenzotrifluoride is treated with in situ–generated 4-acetylpyridinium chloride and 0.1 mol% CuI catalyst to produce the N-acetyl-1,4-dihydropyridine adduct in 76% isolated yield.

Hydrogenation and subsequent bromination proceed in 78–80% yield to give the substrate for a palladium-catalyzed methoxycarbonylation (90–93% isolated yield). The reaction of the ester with guanidine forms the HCl salt of the desired product in 90% isolated yield. (Org. Process Res. Dev. 2013, 17, 382–389; Will Watson)

Crystallization induces bent luminogens to fluoresce. Nonplanar 3-D π-conjugated systems have unique properties (e.g., concave–convex interactions and strong emission), but they are difficult to synthesize. Cyclooctatetraene (COT) is the simplest and smallest nonplanar cyclic unsaturated hydrocarbon; its tub shape is a building block for 3-D π-systems.

D. Kim, M. Iyoda, and coauthors at Tokyo Metropolitan University and Yonsei University (Seoul) designed and prepared bent π-conjugated dibenzoCOT molecules 1 and 2 with two cyano groups on each COT unit. They then studied the luminescence properties of the two molecules.


Molecules 1 and 2 are almost nonluminescent in solution and in amorphous states because of their structural flexibility. Their emission is activated by crystallization because their structures become rigid in the crystalline state.

Compound 2 exhibits pseudopolymorphism, which can be tuned by changing the recrystallization solvent. It is vapochromic; its emission color can be switched by exposing it alternately to THF and CH2Cl2 vapors. Its crystal structure changes quickly and reversibly; the authors believe that this is the result of a rapid equilibrium between 2⋅THF and 2⋅CH2Cl2 crystals.

Crystals of 2⋅CH2Cl2 also show unique thermochromic behavior. Their emission changes from green at ambient temperature to blue at the temperature of liquid-nitrogen. (Chem.—Eur. J. 2013, 19, 4110–4116; Ben Zhong Tang)

Mimic the mechanical gradient of a natural material. Beaks of squids contain a nanocomposite that provides a stiffness gradient between the hard rostrum material and the soft buccal envelope. Inspired by the design of squid beaks, S. J. Rowan and colleagues at Case Western Reserve University (Cleveland) and the Louis Stokes Cleveland Department of Veteran Affairs Medical Center developed a nanocomposite with a mechanical gradient enhanced by hydration.

The researchers used allylamine surface–functionalized cellulose nanocrystals (CNCs) embedded in a poly(vinyl acetate) (PVAc) matrix that contained a tetrafunctional thiol cross-linker and photointiator. UV-initiated cross-linking of the water-responsive, stiff CNCs via thiol–ene chemistry created noncovalent and covalent interactions between the filler network and the PVAc matrix.

Under uniform UV irradiation, the tensile storage modulus (Eʹ) increases with exposure time because the cross-link density in the hydrated and dry states increases. The most dramatic differences occur in a wet environment in which the covalent thiol–ene cross-links provide reinforcement in the absence of hydrogen-bonding interactions of the CNCs network in the PVAc matrix.

Patterning this bioinspired gradient nanocomposite for increasing cross-linking times (0, 4, 8, 12, 16, and 20 min) leads to increasing mechanical gradients when hydrated compared with the dry state. In the hydrated material at 37 °C, Eʹ rises from 36.5 MPa with no cross-linking to 191 MPa after 20 min of cross-linking. In contrast, the dry composite modulus at room temperature increases from ≈2430 MPa to 2690 MPa over the same period. This method is a good first step toward mimicking the mechanics of the squid beak. (J. Am. Chem. Soc. 2013, 135, 5167–5174; LaShanda Korley)

Separate rare earths from transition metals with an ionic liquid. The miniaturization of electronic devices requires large amounts of rare earths (lanthanide metals), mainly for producing permanent magnets. Nd-Fe-B and Sm-Co magnets have higher energy densities than traditional ferrite magnets.

Electronic waste is an important source of rare earths, but separating them from transition metals is difficult. K. Binnemans and co-workers at the University of Leuven (Heverlee, Belgium) used an ionic liquid to separate the metals.

The authors chose the ionic liquid (IL) trihexyl(tetradecyl)phosphonium chloride (Cyphos) to separate the metals because iron and cobalt form stable, IL-soluble chloro complexes; and rare earths do not. The IL is used without cosolvents; HCl is the source of chloride ions.

The Nd/Fe and Sm/Co ratios are roughly those found in magnets. The Nd–Fe and Sm–Co separation factors are 5.0 × 106 and 8.0 × 105, respectively. The rare earths remain in the aqueous phase, whereas the transition metals are extracted into the IL phase.

After separation, cobalt can be extracted from the IL phase with water, but iron must be treated with Na2EDTA before stripping. (EDTA is ethylenediaminetetraacetic acid.) This method does not extract chromium, nickel, aluminum, calcium, or magnesium; but it demonstrates that nonfluorinated ILs can be used to separate rare earths from some transition metals. (Green Chem. 2013, 15, 919–927; José C. Barros)

Thiocyanate is a nontoxic cyanation agent for aryl halides. Nitriles are useful organic building blocks because the cyano group can be easily transformed into other functional groups. There is a gap, however, between the increasing demand for nitriles and the development of practical, safe cyanation methods. J. Cheng and colleagues at Changzhou University and Wenzhou University (both in China) report a palladium-catalyzed cyanation method for aryl halides that uses CuSCN as a nontoxic cyanide source.

The authors believed that CuSCN and palladium-coordinated arenes would form benzothioamides, which can decompose to aryl nitriles. In studying the model reaction between p-iodoanisole and CuSCN, they found that p-anisonitrile forms in 83% isolated yield at 100 °C in 36 h in the presence of 1 mol% PdCl2(dppe), 10 mol% HCO2H, and 3 equiv HCO2Na in DMSO–H2O. [The ligand dppe is 1,2-bis(diphenylphosphino)ethane.] The palladium catalyst, HCO2H, and HCO2Na are necessary for the reaction to proceed in high yield.


The same conditions can be applied to several substituted aryl iodides with moderate-to-high yields (33–84%). Electron-withdrawing and electron-donating substituents on the aryl substrates are compatible with the reaction conditions. Aryl bromides give lower yields of the corresponding nitriles than their iodo counterparts, and aryl chlorides do not react. Arylboronic acids and esters give low yields because of competitive homocoupling.

In the authors’ proposed mechanism, Pd(0) inserts into the aryl iodide to form ArPdI, which reacts with thiocyanate to form intermediate 1. HCO2H hydrolyzes 1 to release HCO2PdI and produce the aryl thioamide precursor to the nitrile. Basification of HCO2PdI releases CO2 and regenerates Pd(0). (J. Org. Chem. 2013, 78, 2710–2714; Xin Su)

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