Noteworthy Chemistry

October 22, 2012

Use a copper catalyst to trifluoromethylate allylic halides. The high demand for compounds that contain trifluoromethyl groups has sparked research into new methods for introducing CF3 groups into molecules. Numerous trifluoromethylation methods are available for aromatic rings, but displacement reactions on nonaromatic carbon atoms are scarce.

Y. Miyake, S.-i. Ota, and Y. Nishibayashi* at the University of Tokyo report the copper-catalyzed nucleophilic trifluoromethylation of allylic halides. CF3SiMe3, the Ruppert–Prakash reagent, is the CF3 source.

Using (E)-cinnamyl bromide as the substrate, the authors tested various Cu(I) catalysts and solvents. They found that the reaction is completely regioselective toward trifluoromethylation on the α-position; no γ-trifluoromethylation product was obtained. Solvent is an important factor: Higher yields are obtained with less polar solvents (e.g., THF) than more polar solvents (e.g., DMF). No products were obtained, however, with nonpolar solvents.

Cu(I) thiophene-2-carboxylate (CuTC) was the best Cu(I) catalyst that the authors evaluated. Diverse functionalized aromatic and nonaromatic allylic halides give good-to-moderate yields with this method. The reaction is limited to allylic halides; no trifluoromethylation occurred with alkyl halides.

The reaction yields only E-configured products, even when the starting substrates have the Z-configuration because the catalyst promotes isomerization of the alkene moiety in the substrate. (Chem. Eur. J. 2012, 18, 13255–13258, Chaya Pooput)

Go through a fluoride intermediate to displace a sulfone. C. H. V. Kumar and co-workers at AstraZeneca (Bangalore, India, and Macclesfield, UK) chose 4,6-dichloro-2-methylthiopyrimidine as the starting material for synthesizing a 2,4,6-trisubstituted pyrimidine because it gives good regioselectivity for substituting the chlorine atoms. (The pyrimidine is an insulin-like growth factor-1 receptor modulator.) The chlorides are sequentially substituted with an aminopyrazole and methoxide to produce a late-stage intermediate whose sulfide linkage is oxidized to the sulfone.

The reaction to displace the sulfone with a substituted pyrrolidine is extremely sluggish. Attempts to speed up the reaction by increasing the temperature led to complex product mixtures. The authors used an alternative two-step procedure through an intermediate fluoride to circumvent this problem.

Displacing the sulfone with fluoride from n-Bu4NF produces an intermediate that reacts smoothly with the substituted pyrrolidine at 75–80 °C. The two reactions can be run in one pot with >90% conversion. (Org. Process Res. Dev. 2012, 16, 1416–1421; Will Watson)

Tartaric acid helps to isolate organotrifluoroborate salts. Organotrifluoroborate salts (e.g., RBF3K) were first prepared in the 1960s. In the mid-1990s, the salts became popular reagents in many reactions, including the Suzuki–Miyaura coupling.

Organotrifluoroborates are prepared by the reaction of compounds with the general formula RSnMe3 with BF3–KF or by treating boronate esters with HF–KOH or KHF2. The disadvantages of these methods are the corrosivity of BF3–KF, glassware etching by HF–KOH and KHF2, and the need to separate products from byproduct salts via Soxhlet extraction.

A. J. J. Lennox and G. C. Lloyd-Jones* at the University of Bristol (UK) report an efficient route to organotrifluoroborates. By using 19F NMR, they observed that the reaction of boronic acids with KF liberates hydroxide, and that adding a mild acid drives the equilibrium toward trifluoroborate formation. They chose tartaric acid because it is inexpensive and readily available, and it can be used in stoichiometric amounts. Another advantage is that its monopotassium salt (potassium hydrogen tartrate or “cream of tartar”) is insoluble in most organic solvents.

The authors’ optimized conditions include using

  • a slight excess (2.05 equiv) of L-(+)-tartaric acid to accommodate variations in commercial samples of boronic acids that are contaminated by boroxines or boric acid;
  • 4 equiv KF as the fluorination agent and as a flocculant for potassium hydrogen tartrate; and
  • solvent mixtures of MeCN, THF, and water to maintain the product organotrifluoroborate in solution while the tartrate and other salts precipitate.

The reaction is performed at room temperature in 1–10 min, after which the reaction mixture is filtered, and the solvent is evaporated to leave analytical-grade products.

The authors expanded the method to several boronic acids and, using MeOH as a cosolvent, to boronate esters. Other metals can be used as counterions, as illustrated by the preparation of RBF3Cs species.

The method is scalable to 5 g of product. No glassware etching was observed after 30 consecutive runs. This study also shows that tartaric acid can be used as an alkali “sponge” in other reactions such as fluoride-mediated desilylation. (Angew. Chem., Int. Ed. 2012, 51, 9385–9388; JosÉ C. Barros)

An injectable microgel forms synthetic vertebral disc material. B. R. Sanders and colleagues at the University of Manchester (UK) investigated injectable, doubly cross-linked microgels composed of poly(methyl methacrylate–methacrylic acid–ethylene glycol dimethacrylate) and glycidyl methacrylate for treating degenerated intervertebral discs (IVDs). This material system is designed for pH responsiveness and mechanical restoration at body temperature.

The system forms a physical gel at a pH higher than the microgel’s pKa value. The authors obtained the dual network structure via radical cross-linking. This stable, shear-thinning formulation exhibits high elasticity even in the hydrated state.

Injecting the doubly cross-linked microgels reinforces IVDs, restores toughness, and improves resiliency without inducing cell death. The authors foresee opportunities to tune the mechanics via compositional variations and to apply their technology to other cartilaginous sites. (Biomacromolecules 2012, 13, 2793–2801; LaShanda Korley)

Obtain relative kinetic data from multiple reactions in one pot. Well-established free-energy relationships (e.g., the Hammett equation) are useful for mechanistic studies of organic reactions, but parallel comparisons can be time-consuming and difficult to control precisely. This is also the case with commonly used binary competition experiments. Existing protocols for simultaneous multiple-species analyses are time-consuming or limited to particular reactions. To circumvent these problems, H. M. Yau, A K. Croft, and J. B. Harper* at the University of New South Wales (Sydney) and the University of Wales Bangor (UK) developed a general method for the direct kinetic analysis of multiple-species competition experiments in a simple, timely manner.

The authors’ method has its theoretical origin in the equation shown, which was derived by C. K. Ingold and F. R. J. Shaw in 1927 (J. Chem. Soc. 1927, 2918–2926). The equation relates the ratio of the rate constants for reactants x and y to the remaining amounts of the compounds (sx and sy) at the time of analysis. This equation makes it possible to calculate kx/ky without determining the absolute concentrations or the reaction progress for x and y if the starting (t = 0) amounts of the two are known.

The authors demonstrated the validity of this method by comparing competing Menschutkin reactions between pyridine and seven substituted benzyl bromides in one pot. Using 1H NMR spectroscopy, they determined the relative amounts of reactants and products from normalized integrals. Peak overlapping was not a problem because the relative quantities of all reactants were known. The obtained Hammett plot was consistent with previously reported data, underscoring the advantage of carrying out all reactions under identical conditions.

The efficacy of the method also was illustrated by the reduction of substituted acetophenones by NaBH4. The authors accurately measured rates within a 20-fold range. This technique allows the use of an analytical method with a longer time scale than the reactions studied.

Quantitative HPLC analysis gave similar results to those from 1H NMR. Because HPLC requires extra sample treatment and is time-consuming, 1H NMR is the more practical analytical method. (Chem. Commun. 2012, 48, 8937–8939; Xin Su)

Here’s an “easy-on, easy-off” carbon dioxide capture system. Developing a “low-carbon” economy requires efficiently removing CO2 from industrial emissions. Solutions of organic amines are widely used to capture CO2 discharged from power plants, but regenerating the amine solutions is costly. S. Yang, M. Schröder, and co-workers at the University of Nottingham (UK), Peking University (Beijing), Rutherford Appleton Laboratory (Chilton UK), the University of Oxford (UK), and Diamond Light Source (Didcot, UK) developed a porous material that efficiently captures CO2 and releases it economically.

The porous material is a non–amine-containing metal-organic framework (MOF). The hydroxyl groups in the pores of the framework bind CO2 through hydrogen bonds that are strengthened by supramolecular interactions with adjacent C–H groups on aromatic rings. The “soft” binding interactions are distinct from the direct bond formation between the nitrogen centers of amine groups and the carbon center of CO2 in conventional absorbers.

The combined hydrogen-bonding and supramolecular interactions in the MOF are strong enough to bind CO2 but weak enough to permit full desorption of the captured gas at ambient temperature. (Nat. Chem. 2012, 4, Advance Online Publication DOI: 10.1038/nchem.1457; Ben Zhong Tang)

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