Noteworthy Chemistry

January 7, 2013

A fluorogenic bioprobe detects histone deacetylase activity. Many researchers target histone deacetylase (HDAC) enzymes to develop drugs for treating cancer and neurological and metabolic diseases. Detecting HDAC activity helps to solve many physiological and medicinal problems.

Although much research has been done to develop analytical methods for studying deacetylation processes, all of these methods require laborious steps to detect enzymatic activity. K. Kikuchi and co-workers at Osaka University report a one-step procedure for detecting HDAC activity.

The researchers prepared an acetylated fluorogenic molecule (1) and used it to detect the activity of the HDAC Sirt1. The deacetylation reaction leads to structure 2. Electrostatic interactions between the anionic sulfonate and cationic lysine units cause 2 to form aggregates that fluoresce efficiently (aggregation-induced emission, or AIE).

Enzymatic activity is definitively detected in one step by mixing the bioprobe with the enzyme. Because the AIE process is turned off in the presence of an HDAC inhibitor, this bioprobe can also be used as an inhibitor assay. (Chem. Commun. 2012, 48, 11534–11536; Ben Zhong Tang)

Upload green chemistry apps to your mobile device. It is important to incorporate green chemistry into a design process as early as possible when the cost is lower and the quantities of chemicals are much smaller than in the scaled-up process. To make green chemistry reference tools readily available to chemists at the bench or in the field, S. Ekins* at Collaborations in Chemistry (Fuquay-Varina, NC), A. M. Clark at Molecular Materials Informatics (Montreal), and A. J. Williams at the Royal Society of Chemistry (Wake Forest, NC) developed a series of apps that can upload the ACS Green Chemistry Institute (ACS GCI) Pharmaceutical Roundtable solvent-selection guide and other references to iPhones, iPods, and iPads.

The entry point to the Green Solvents app uses solvent structures grouped by chemical class. When the user scrolls through the list of solvents and clicks on a specific molecule, a box opens with the molecule name, CAS registry number, and scores for each category of consideration: safety, health, and environment (air, water, and waste). Links to the ChemSpider Web site, the Mobile Reagents app, and the Mobile Molecular data sheet are also provided.

The authors created this free green chemistry app as a way reach a larger audience for the ACS GCI Pharmaceutical Roundtable solvent-selection guide. In the article, they discuss the evolution of the app and describe others that are available on Android devices in addition to Apple products. (ACS Sustainable Chem. Eng. 2013, 1, 8-13, Article ASAP DOI: 10.1021/sc3000509; Beth Ashby Mitchell)

Turn waste fluoroform into a versatile trifluoromethylation reagent. Fluoroform (trifluoromethane, CHF3) is a large-volume byproduct from manufacturing poly(tetrafluoroethylene), refrigerants, foams, and fire-extinguishing agents. CHF3 is a gas that has a greater greenhouse effect than CO2. Most CHF3 is destroyed commercially via an expensive, complicated process.

The low boiling point (–83 °C), high pKa (25–28 in H2O), and low reactivity of CHF3 make it difficult to convert to a trifluoromethylation agent. G. K. Surya Prakash and co-workers at the University of Southern California (Los Angeles) developed a method that uses CHF3 to attach the CF3 group to silicon, boron, sulfur, and carbon centers in common organic solvents.

The authors investigated the reaction of equimolar amounts of Me3SiCl, CHF3, and potassium hexamethyldisilazide (KHMDS) in THF at –40 °C to produce Me3SiCF3 and Me3SiF. Changing the solvent to toluene improves the Me3SiCF3 yield to >90%. Diethyl ether is the preferred solvent for reactions with higher trialkylchlorosilanes.

The potassium counterion is crucial to the success of the reaction: LiHMDS and NaHMDS yield very little or no Me3SiCF3. The researchers believe that CF3 produced by the KHMDS deprotonation of CHF3 is rapidly trapped by Me3SiCl to form a pentacoordinated silicon complex, which loses KCl to give Me3SiCF3.

They expanded the method to the trifluoromethylation of borates followed by reaction with HF to obtain CF3BF3K. The reaction of CHF3 with elemental sulfur followed by H2O2 oxidation produces CF3CO2H. The nucleophilic trifluoromethyl group can react with aldehydes, benzophenones, chalcones, formates, benzyl bromide, or methyl benzoate to produce additional trifluoromethylated species.

This study identifies CHF3 as a source of the nucleophilic trifluoromethyl group that is inexpensive, readily available, and broadly applicable in organic synthesis. (Science 2012, 338, 1324–1327; José C. Barros, Xin Su)

Make nanotubes “universally” dispersible in solvents. A. Prevoteau, C. SouliÉ-Ziakovic*, and L. Leibler* at ESPCI Paris Tech created a dispersion strategy for carbon nanotubes (CNTs) that allows them to be widely used in polymer composites. They developed a host–guest supramolecular process in which CNTs are grafted with a thymine (Thy) derivative, and amine-terminated, low–molecular weight polystyrene (PS) and poly(propylene oxide–ethylene oxide) (PPO-PEO) are functionalized with 2,6-diamino-1,3,5-triazine (DAT).

The complementary Thy–DAT interaction is strong and highly specific; it creates CNT dispersions that are stable for ≈2 months in a range of solvents (see figure). Introducing competing or dissociating units into the dispersion promotes aggregation and recyclability of the CNTs; this process may be influenced by the degree of Thy or DAT solubility. For example, DMSO efficiently disrupts Thy–DAT association in PS-DAT–Thy-CNT dispersions in toluene. After recovery of Thy-CNTs via centrifugation, the CNTs can be redispersed in water by adding PPO-PEO-DAT.

Temperature changes can mediate reversible dispersion in θ-solvents because of the difference between the critical solution temperatures of PS and PPO–PEO. The authors describe their method as “universal, reversible, and controllable”. (J. Am. Chem. Soc. 2012, 143, 19961–19964; LaShanda Korley)

Minimize sulfonate ester formation when preparing pharmaceutical salts. A. Teasdale at AstraZeneca (Macclesfield, UK) and coauthors at GlaxoSmithKline (Ware, UK, and Research Triangle Park, NC), Eli Lilly (Indianapolis), Bristol-Myers Squibb (New Brunswick, NJ), and Hoffman-La Roche (Nutley, NJ) describe process control strategies that reduce or eliminate sulfonate ester formation in pharmaceutical manufacturing. Sulfonate esters are formed from alcohols and sulfonic acids via acid catalysis. The esters can form during the formation of pharmaceutical salts in alcohol solvents.

The authors’ recommendation is to add a minimal excess of the sulfonic acid slowly to the base with good mixing and, if possible, in the presence of water. Reducing the temperature also lessens sulfonate ester formation: Under favorable conditions, a 10 °C temperature drop lowers ester production by a factor of ≈4. (Org. Process Res. Dev. 2012, 16, 1707–1710; Will Watson)

A reversible divalent mercury sensor acts at the femtomolar level. Mercury is notorious for its neurological toxicity. Although fluorescence has been used to reversibly detect Hg2+, the major form of mercury pollution, very few systems can be used in physiological environments.

M. Taki and co-workers at Kyoto University report a rosamine-based fluorescent probe that binds Hg2+ efficiently and reversibly. It is suitable for monitoring Hg2+ levels in living cells in real time.

The authors synthesized sensor 2 from tribromide 1 in five steps with an overall yield of 1.7%. The sensor has a hexathioether group for recognizing Hg2+ that is attached directly to a rosamine fluorophore. In a buffer solution of 50 mM HEPES (pH 7.20, 0.1 M KNO3) and DMSO (4:1 v/v), 2 exhibits weak fluorescent emission with a quantum yield (Φ) of 0.005. When Hg2+ is added, the fluorescence of 2 is enhanced by 20-fold (Φ = 0.11).

The 2–Hg2+ complex has 1:1 stoichiometry with a dissociation constant of 1.04 × 10–16 M (0.1 fM). Adding glutathione (GSH) to the complex forms a GSH–Hg2+ complex with a log stability constant as high as 40.95. GSH reverses the binding of the sensor by displacing Hg2+ from 2–Hg2+.

The authors showed that 2 has high selectivity for Hg2+ over alkali, alkaline-earth, and most of the first-row transition metals. A drawback is interference by Cu+ and Ag+, which effectively bind with the hexathioether scaffold.

Hg2+-containing cells inoculated with 2 produce strong fluorescence when GSH complexation is blocked by N-ethylmaleimide, indicating the formation of the 2–Hg2+ complex. The fluorescence diminishes when N-acetylcysteine, a GSH precursor, is added, illustrating the complex’s reversibility in living cells. (Inorg. Chem. 2012, 51, 13075–13077; Xin Su)


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