Noteworthy Chemistry

May 22, 2013

What is the key copper intermediate in azide–alkyne click reactions? The Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC), in which a triazole is formed from a terminal alkyne and an azide, is one of the most common click-chemistry reactions. Despite its versatility and popularity for creating covalent links between building blocks, the mechanism of the CuAAC reaction is unknown because of its complex reactants and equilibria.

B. T. Worrell, J. A. Malik, and V. V. Fokin* at the Scripps Research Institute (La Jolla, CA) tackled this challenge by conducting heat-flow reaction calorimetry and isotope-crossover experiments. Their studies show that a dinuclear copper complex is the key intermediate in CuAAC.

The authors used real-time heat-flow reaction calorimetry to study the reaction between azide 1 and the known intermediate Cu(I) acetylide 2. (NHC is an N-heterocyclic carbene.) Cycloaddition between 1 and 2 quickly forms Cu(I) triazolide 3 in the presence of 4.1 mM Cu(PPh3)2NO3 catalyst; the reaction rate has a positive-order dependence on catalyst concentration. Almost no detectable 3 is formed without a copper catalyst.

After confirming that a second copper atom is needed to form the active intermediate, the authors identified the role of each copper atom via isotope-crossover experiments. A stoichiometric amount of 63Cu(MeCN)4PF6 catalyst was used in the reaction between 1 and 2 to give triazolide 3 with 50% isotopic enrichment, indicating that the NHC migrates between the two copper atoms. Because neither 2 nor unlabeled 3 forms isotope-enriched Cu(I) species in the presence of 1 equiv of the labeled catalyst, it is clear that the enrichment of Cu(I) in 3 is not possible via intermediate 2 or unlabeled 3.

The authors therefore posited the formation of a labile dinuclear copper complex in which the second copper π-bonded to the acetylide reversibly coordinates with the azide. The rapid NHC–ligand exchange in this complex is responsible for the observed isotopic enrichment as a result of weakened Cu–carbene backbonding. The mechanism is shown in the lower portion of the figure. (Science 2013, 340, 457–460; Xin Su)

A robust isolation method produces bosutinib monohydrate. Bosutinib, a potential leukemia drug, easily forms solvates, including a monohydrate and a hexahydrate. The final step of the bosutinib production process is a POCl3-mediated cyclization carried out in sulfolane solvent.

An aqueous workup that includes basification produces the hexahydrate, which is recrystallized from i-PrOH–H2O to give a dihydrate–mono-i-PrOH solvate. The solvate is slurried in hot water to give the desired monohydrate.

Based on solvent screening and solubility studies, R. Vaidyanathan and co-workers at Pfizer (Groton, CT) chose methyl isobutyl ketone (MIBK) as an ideal solvent for extraction and crystallization. The cyclization reaction mixture is adjusted to pH 3–5 at 75–80 °C, and MIBK is added to extract the sulfolane. The aqueous layer is then adjusted to pH 10, and the product is extracted into MIBK at 75–80 °C.

Controlling the water content of the product-containing MIBK layer is critical to avoid forming the hexahydrate. Therefore, the MIBK solution is concentrated to 4 volumes, and 1–2% water is added. This allows a controlled seeded crystallization of the monohydrate with improved particle-size distribution. (Org. Process Res. Dev. 2013, 17, 500–504; Will Watson)

Ruthenium catalysis helps synthesize valsartan and losartan. Current strategies for combating hypertension are based on angiotensin II–receptor blockers (ARBs) such valsartan (1) and losartan (2). More than 100 t of these drugs is produced annually worldwide.

Both drugs contain biphenyl moieties. They are prepared from halides and organometallic nucleophiles by palladium-mediated cross-coupling techniques, but these reactions generate undesirable waste products. L. Ackermann and colleagues at Georg-August University (Göttingen, Germany) and Technion-Israel Institute of Technology (Haifa) developed an alternative ARB synthesis that uses catalytic Ru(II) C–H arylation.

The authors optimized the reaction between a phenyltetrazole and a p-bromoacetophenone in the presence of ruthenium catalysts. The best conditions were obtained using 5.0 mol% [RuCl2(p-cymene)]2 as catalyst, K2CO3 as base, toluene as solvent, and MesCO2H as a catalyst additive at 120 °C for 18 h. (Mes is mesityl.) They then expanded the method to aromatic bromides substituted with electron-withdrawing and electron-releasing groups and to heteroaromatic bromides.

Using these conditions, the authors coupled phenyltetrazole 3 to bromo ester 4 to make 5—a key intermediate in the synthesis of valsartan and losartan—in moderate yields (see figure). They propose a mechanism that includes the formation of a ruthenacycle, a reversible C–H arylation, and a reductive elimination as the rate-limiting step. (Tetrahedron 2013, 69, 4445–4453; José C. Barros)

Create nanostructured hybrid polymer–gold nanoparticles. T. Nakano, D. Kawaguchi, and Y. Matsushita* at Nagoya University (Japan) explored the assembly of gold nanoparticles (AuNPs) grafted with polyisoprene (55 kDa) and polystyrene (60 kDa) in symmetric proportions for use in plasmonic devices. They grafted dodecylamine-functionalized AuNPs (≈3-nm diam) in multiple steps via successive ligand exchange with an azide-thiol ligand and thiol-terminated polyisoprene at appropriate ratios. A subsequent alkyne–azide click reaction with ethynyl-capped polystyrene completed the grafting process.

The AuNP hybridization strategy yields a constant grafting density of 1.4 ± 0.1 chains/nm. The relative amounts of polystyrene and polyisoprene are controlled by adjusting the feed ratios. The amount of grafted polystyrene is limited by the excluded volume effect of preexisting polyisoprene chains.

With a symmetric polystyrene–polyisoprene composition, the functionalized AuNPs self-assemble into a lamellar microstructure (≈55-nm domain spacing). The AuNPs are located at the polystyrene–polyisoprene interface and are organized anisotropically. (J. Am. Chem. Soc. 2013, 135, 6798–6801; LaShanda Korley)

Chromatographically purify semiconducting carbon nanotubes. As the microelectronics industry approaches the upper limits of Moore's Law, the need for scaled-down devices to meet the requirements of future high-performance computing increases. Semiconducting carbon nanotubes (sc-CNTs) show promise, but they cannot be synthesized directly. To address this problem, G. S. Tulevski*, A. D. Franklin, and A. Afzali at IBM Thomas J. Watson Research Center (Yorktown Heights, NY) developed an efficient protocol for separating sc-CNTs from mixtures with metallic carbon nanotubes (m-CNTs) via column chromatography.

The authors sonicated 1 mg/mL concentrations of the CNT samples in 1% aqueous sodium dodecyl sulfate (SDS) solution. The resulting solution undergoes a step-gradient centrifugation step in which a high-density solution (0.25% SDS in 45% aqueous iodixinol) is layered under the CNT solution. Highly purified CNTs migrate to the middle of the tube, away from larger CNT bundles and other impurities.

The CNT solution is loaded onto a column packed with Sephacryl-200, a copolymer-based chromatography medium. Elution with 1% SDS solution gradually separates the initial black band (a mixture of sc-CNTs and m-CNTs) into blue and red bands that correspond to m-CNTs and sc-CNTs, respectively (see figure). Sephacryl-200 with a usable molar-mass range of 5 × 103–2.5 × 105 Da gave higher separation efficiencies than analogues with different pore sizes.

The initial separation yields sc-CNTs with >98% purity, which is beyond the upper detection limit of the traditional optical method. The authors developed a high-throughput testing method that uses an electrical test bed to quantify the ultrahigh purity of sc-CNTs. After three iterations of column separation, the sc-CNTs’ purity reached 99.9%. This purification protocol is more efficient and practical than earlier ones because the use of a single surfactant (SDS) allows easy multiple iterations. (ACS Nano 2013, 7, 2971–2976; Xin Su)

What do you think of Noteworthy Chemistry? Let us know.