Noteworthy Chemistry

January 20, 2014


Copper nanoclusters are excellent luminescence sensors. Metal nanoparticles, such as gold and silver nanoclusters, have been explored extensively as luminescent probes for biomedical imaging and sensing. Copper is an abundant, inexpensive nonprecious metal; but its nanoclusters (CuNCs) are difficult to synthesize and have been studied much less than gold and silver.

E. Wang and coauthors at the Chinese Academy of Sciences (Changchun and Beijing) developed a straightforward, effective method for synthesizing stable luminescent CuNCs, which paves the way for developing CuNC-based functional materials.

The authors synthesized CuNCs by using a “green” procedure: Stirring an aqueous mixture of Cu(NO3)2 and D-penicillamine at room temperature produces the nanoclusters. When stored in a refrigerator, the nanocluster powders are stable for >1 year without being protected by an inert gas. The molecules do not emit in solution; but as aggregates, they luminesce efficiently in solid state, exhibiting the aggregation-induced emission (AIE) phenomenon.

The long lifetimes (up to 150.6 ms) and large Stokes shift (295 nm) of red light emission from CuNC aggregates indicate that the emission is phosphorescent. The AIE-active CuNCs are effective catalysts, stimulus-responsive materials, and sensitive bioprobes. (Chem. Commun. 2014, 50, 237–239; Ben Zhong Tang)

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Fluorinate nitrogen heterocycles simply and safely. Fluorinated compounds are important in organic synthesis and medicinal chemistry because fluorine atoms modulate the electronic properties of a compound without large conformational changes. They also improve metabolic stability in vivo. Most fluorination methods such as direct fluorination and the Balz–Schiemann reaction require hazardous fluorine gas or expensive, toxic fluorinating agents.

The Chichibabin reaction is a classical method for aminating pyridines. The substrate is converted to a 2-aminopyridine when it reacts with NaNH2 through a sodium–pyridine complex (Figure 1).

Chichibabin amination reaction

Inspired by the mechanism of the Chichibabin reaction, P. S. Fier and J. F. Hartwig* at the University of California, Berkeley, developed a mild, regioselective fluorination method for pyridine- and diazine-based heterocycles that uses AgF2 as the fluorinating agent.

The authors believed that they could achieve a fluorination process similar to the Chichibabin amination by combining a suitable Lewis acid and a sufficiently nucleophilic fluoride with the required oxidation potential. They used 2-phenylpyridine as their model substrate and 2 equiv AgF2, which is commercially available and less costly than traditional fluorinating agents, to obtain 2-fluoro-6-phenylpyridine in 88% yield at room temperature in the presence of MeCN (Figure 2). 

AgF2 fluorination of pyridines

This protocol is highly regioselective toward the site adjacent to nitrogen, not only in pyridines but also in other nitrogen-containing heteroarenes such as quinolines and diazines. It is compatible with many functional groups, including ketones, esters, and amides. The authors scaled the reaction of a 2,5-substituted pyridine up to 5 mmol.

The reaction can be readily applied to the regioselective fluorination of several pyridine-based compounds with medicinal activity. For example, the authors used it to prepare a derivative of tropicamide, an anticholinergic drug.

The authors propose a reaction mechanism that is similar to the Chichibabin reaction. In it, AgF2 coordinates to pyridine; a Ag–F bond complexes with the π-system; and a second AgF2 molecule abstracts hydrogen to eliminate two molecules of AgF and one of HF (Figure 3). 

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Mechanism of fluorination with AgF2

This safe, efficient halogenation reaction is likely to be adopted by organic and medicinal chemists. (Science 2013, 342, 956–960; José C. Barros and Xin Su)

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Use a biosynthetic pathway as an antibiotic drug target. Mycobacterium tuberculosis (Mtb), the pathogen that causes tuberculosis (TB), evades many host antibacterial defenses. Although the human immune system has numerous ways to counter Mtb infection, the bacteria usually cannot be cleared completely from the body.

CD4 T cells are important in limiting Mtb growth and preventing the spread of the disease in infected individuals. Whereas CD4 T cells are essential for TB immunity, they cannot eliminate Mtb. Surviving bacteria can be a source of host disease in the future.

E. J. Rubin and coauthors at the Harvard School of Public Health (Boston), Texas A& M University (College Station), the University of Massachusetts Medical School (Worcester), and New Jersey Medical School (Newark) studied how CD4 T cells limit Mtb growth and yet do not kill all Mtb cells. They discovered that CD4 T cells induce amino acid starvation in intracellular Mtb bacteria. The immune cells secrete the cytokine IFN-γ, which likely stimulates tryptophan (Trp) depletion mediated by transcriptional transduction of indoleamine-2,3-dioxygenase.

Because Trp is required for Mtb growth during infection, when the Mtb bacteria are starved of exogenous Trp, they must produce their own Trp or die. Loss or inhibition of the Trp biosynthetic pathway makes Mtb sensitive to IFN-γ–mediated killing within macrophages.

To target Trp biosynthesis for TB drug development, the authors focused on anthranilate analogues and looked for Mtb growth inhibition in the presence and absence of Trp. They identified a fluorinated compound, 2-amino-6-fluorobenzoic acid, that is bactericidal because it inhibits Trp biosynthesis. They assessed the structural and biochemical basis of the inhibitor activity and demonstrated that the small molecule works in conjunction with host CD4 T cells to eliminate Mtb in in vitro and in vivo model infections. This study chemically validates that biosynthetic pathways can be targets for antibiotic drug development. (Cell 2013, 155, 1296–1308; Abigail Druck Shudofsky).

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Copper-based hydrogels switch from stiff to soft states. T. Y. Meyer and colleagues at the University of Pittsburgh developed a redox-sensitive hydrogel based on a metallopolymer. They synthesized the polymer via free-radical polymerization of a 16:4:1 w/w/w mixture of sodium 4-styrenesulfonate, 4-vinylpyridine, and poly(ethylene glycol) diacrylate (PEG-DA).

The electroplastic elastomer hydrogel (EPEH) was infused with Cu2+ by soaking it in an aqueous solution of 0.5 M CuCl2 and 0.25 M urea for ≈1–2 days to yield a bright blue EPEH that was stiffer than the starting hydrogel. The modulus and degree of pyridine coordination could be varied by adjusting the CuCl2 concentration.

The authors doped the EPEH with Cu+ with 0.1 M CuCl–0.5 M NH4OH in water or 0.1 M CuCl in MeCN under a nitrogen blanket to produce softer, light yellow hydrogels. They attribute the softness to weaker Cu+ coordination compared with Cu2+ (see figure).

Soft Cu+ hydrogel (left) and stiff Cu2+ hydrogel

The tensile moduli for the Cu2+-coordinated EPEHs varied from 10 to 18 MPa, whereas the Cu+ EPEHs had values between 0.15 and 0.16 MPa. The authors used electrochemical stimulation to switch from the soft Cu+ state to the stiff Cu2+ form, but this process is somewhat limited because of Cu2+ shell formation. The reverse process is also limited.

Chemical oxidation from exposure to air causes reversible switching between the Cu+ and Cu2+ EPEHs, accompanied by color and stiffness changes caused by Cu2+ cross-linking. The authors note that chemical reduction can be used to switch from stiff to soft in these EPEH systems, leading to a repeatable shape-memory response by coupling a copper-coordinated dynamic network with a covalently cross-linked PEG-DA network. (ACS Macro Lett. 2013, 2, 1095–1099; LaShanda Korley)

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An impure reagent improves a Vorbrüggen glycosylation. Bis(trimethylsilyl)-2-chloroadenine, an intermediate in the synthesis of clabridine (2-chloro-2′-deoxyadenosine), can be prepared by the reaction of 2-chloroadenine with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) or N,O-bis(trimethylsilyl)acetamide (BSA). The intermediate is subjected directly to a Vorbrüggen glycosylation with protected deoxyribofuranose. With trimethylsilyl triflate (TMSOTf) as the catalyst, the α/β selectivity of the product ranges from 0.8:1 to 1:2.

When J. P. Henschke and co-workers at ScinoPharm (Tainan, Taiwan, and Changshu, China) used BSA for the persilylation, the α/β ratios were always poor (0.8–0.9:1) compared with BSTFA, which gave ratios of 1:1.4–1.8 under identical conditions. When the BSTFA silylation mixture was stripped to dryness before the glycosylation reaction, the α/β ratio dropped to 1:1. The ratio was similar when a new batch of BSTFA was used (97% pure compared with 75% for the previous batch).

Studies on possible impurities showed that the change in stereoselectivity was probably caused by CF3SO3H that formed by the hydrolysis of TMSOTf. The authors revised the protocol to use BSTFA for silylation followed by CF3SO3H as the glycosylation catalyst.

The yield of the β-anomer also increases if the reaction mixture is allowed to age. This allows the β-anomer to precipitate and the dissolved α-anomer to re-equilibrate. (Org. Process Res. Dev. 2013, 17, 1419–1429; Will Watson)

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Reduce lubricating oil's carbon footprint by re-refining used oil. Re-refining used oil reduces the need to produce base oil from crude oil sources, and it eliminates emissions associated with disposing used oil. Base oil, also known as mineral oil, is a finished petroleum stock that can be blended with additives to produce lubricants for internal combustion engines.

Re-refined base oil has properties that are almost identical to those of base oil produced from crude oil in a refinery. L. N. Grice, C. E. Nobel, and coauthors at ENVIRON International (Denver) and Safety-Kleen Systems (Plano, TX) found that the life-cycle carbon footprint for re-refined base oil is 81% lower than that for an equivalent product derived from virgin stock (see figure). 

Comparison of carbon footprints of re-refined and non–re-refined oils

Previous studies evaluated the waste management aspects of re-refining used oil compared with burning it to produce heat or electricity; but these studies did not factor in the upstream greenhouse gas emissions during the production and processing phases. Grice et al. evaluated greenhouse gas emissions in all phases: extraction, transport, base oil production and refinement, and end-of-life management.

The authors did not address transport to the customer or customer use of the base oil because these factors are similar for re-refined and virgin-stock base oils. For the re-refinement scenario, they assumed that the oil would be reused and re-refined repeatedly until it was used up. This meant that 1 gal of re-refined oil would have the usage equivalent of 7.14 gal of one-use oil.

The study factored in operations information, including electricity used and miles traveled, based on primary data from Safety-Kleen operations records. Base case (first-use oil) process activity data and emission factors were obtained from academia and industry data.

The key differences in life cycle emissions between the base case and the re-refined oil are associated with production and waste management. Electricity, natural gas, and refinery fuel used during re-refinement account for 57% of the carbon footprint of re-refined base oil, whereas initial production of the base oil accounts for only 29%. For base oil that is not re-refined after the first use, the initial production accounts for 34% of the carbon footprint, and disposal (combustion or dumping) accounts for 56%.

The authors summarized the ranges of results that they obtained using various values for their model parameters. In all cases, the re-refined base oil produced less than half of the greenhouse gas emissions over the course of its life cycle than did non–re-refined base oil. (ACS Sustainable Chem. Eng. 2014, 2, Article ASAP; Nancy McGuire

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