COURTESY OF BRUCE LIPSHUTZ
SCIENCE & TECHNOLOGY
Lipshutz and his colleagues evaluated the Lipshutz poses reactions on the basis with a schematic of their E factors, one drawing of one of the measures organic of his designer nanomicelles. chemists use to determine the greenness of a reaction. E factors are derived from the amount of solvents, reagents, and consumables used per kilogram of product made, Lipshutz explained. The higher the E factor of a chemical process, the more waste it generates, the greater its negative environmental impact, and the less sustainable it is. In most cases, using the nanomicelles reduces E factors by more than an order of magnitude, he said, while at the same time requiring less catalyst and improving yields. “This is a really nice piece of work,” organic chemistry professor Roger A. Sheldon of Delft University of Technology, in the Netherlands, told C&EN. “It is cutting-edge research that furthers the goals of green chemistry and sustainable technologies.” It was Sheldon who formally introduced the concept of E factors in 1992. From his experience at the Dutch company DSM in the 1980s, he knew firsthand how inefficient fine chemical synthesis could be. He wanted to share that knowledge with his students and inspire them to do something about it. FRIENDLY AMPHIPHILE
GREENER ORGANIC SYNTHESIS ACS MEETING NEWS: Running common reactions in aqueous
micelle solutions reduces their environmental impact STEPHEN K. RITTER, C&EN WASHINGTON
WHEN BRUCE H. LIPSHUTZ said he had
synthesis community how powerful his a goal to help the synthetic organic chemisapproach can be and challenging chemists try community get organic solvents out of to do better when it comes to making their organic reactions, he wasn’t kidding. The reactions greener. University of California, Santa Barbara, To do that, the Lipshutz group has sysSMALL-MOLECULE pharmaceuticals have chemistry professor had been quizzing tematically compared the surfactant-based among the highest E factors in the chemiprocess chemists in industry about the technology with traditional reactions for cal industry, in the range of 25 to 200. Fine most common reactions they use and what preparing key drug intermediates in orchemicals used as drug intermediates and they would like to do to improve the cost ganic media, as reported in the literature in flavors and fragrances aren’t far behind, and environmental profiles of the proby pharmaceutical companies. Lipshutz with E factors of 5 to 50. Bulk chemicals cesses—that is, how to make them greener presented the unpublished results of the such as propylene oxide and caprolactam and more sustainable. One of the biggest comparative studies for the first time durtypically have E factors less than 5; and obstacles, they said, was organic solvents. ing a symposium on advances in green petrochemicals such as polyethylene and That bit of information led Lipshutz chemistry sponsored by the Division of Orgasoline, less than 0.1. and his research group to develop a class of ganic Chemistry at the American Chemical In fairness to the pharmaceutical induslow-cost designer surfactants. These amSociety national meeting in New Orleans. try, its syntheses require phiphilic molecules form more reaction steps and nanomicelles, which act as Pd catalyst (5 mol%) Na2CO3, acetone 80% yield higher purity products reaction compartments. heat E factor: 83 than those of other inThey enable common dustries, which means transition-metal-cataB(OH)2 more waste and higher lyzed organic reactions I E factors. Most of that to run in water at produc+ Pd catalyst (1 mol%) waste is inorganic salt tion scale at room temTPGS-750-M 93% yield Br Br triethylamine, water E factor: 8 by-products and organic perature. For his efforts, solvents, and many of the Lipshutz received a Presisolvents are toxic. dential Green Chemistry In fact, organic solvent Challenge Award in 2011. E IMPROVEMENT Running this Suzuki-Miyaura coupling reaction in use accounts for approxiLipshutz has now a micellar solution using TPGS-750-M, a designer surfactant, improves mately 80% of the waste moved on to the next the yield and significantly reduces the environmental profile, or E factor, generated during typical phase of his goal: conof the reaction. pharmaceutical processvincing the organic CEN.ACS.ORG
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ing, according to John L. Tucker, a senior scientist at Amgen and the company’s representative to the ACS Green Chemistry Institute’s Pharmaceutical Roundtable. The roundtable is a group of pharmaceutical companies that have banded together to encourage innovation while catalyzing the integration of green chemistry and green engineering in the pharmaceutical industry. “The roundtable views developing alternatives to traditional organic solvents as a critical step toward safer and more sustainable pharmaceutical manufacturing,” Tucker said. “Lipshutz’ transition-metal crosscouplings performed with micellar catalysis in water demonstrate that a proliferate class of reactions can be performed in a benign environment and can provide a significant reduction in total process waste. His direct comparison between published pharmaceutical cross-coupling exemplifies a more efficient and environmentally superior methodology that is truly transformative.” IN NEW ORLEANS, Lipshutz described
how the designer surfactants are made from environmentally benign ingredients: racemic α-tocopherol (vitamin E), succinic acid, and polyethylene glycol. When the surfactants are added to water, they form the nanomicelles, which function as reaction compartments. The lipophilic vitamin E orients toward the center of the nanomicelles, and the hydrophilic polyethylene glycol orients toward the water. These two components of the surfactant are linked by the succinic acid. Similar surfactants have been used for decades in organic and aqueous chemical processes, Lipshutz said. But no one thought to design a surfactant specifically for transition-metal-based catalysis. “What organic chemists seem to have missed is that the lipophilic part on the inside functions as a solvent, and solvent effects in organic chemistry can make a huge difference in the success or failure of reactions.” Spherical nanomicelles in the 50- to 100-nm-diameter range best accommodate the flux of reactants, catalyst-ligand system, and product into and out of the micelles, Lipshutz noted. The high concentration of molecules within the micelles leads to increased reaction rates, which dispense with the need for heating and help reduce side products. Micelles formed from traditional surfactants have smaller diameters, only about 10 to 15 nm, he noted. The smaller size appears to lessen the binding of reactants and catalysts, which hints at
why the enhanced reactivity hasn’t been observed in the past, Lipshutz believes. Lipshutz’ group has tested the designer surfactants—which are now commercially available—in dozens of side-by-side comparisons of standard metathesis, crosscoupling, addition, and other reactions. For example, Heck coupling of 3-bromoquinoline with ethyl acrylate using a palladium catalyst in dimethylformamide solvent at 140 °C produces an unsaturated ester with an E factor of 137. The same reaction carried out in the micellar system at room temperature results in an E factor of only 7.5. But there’s more. Another advantage of the micellar catalysis is that the organic product can be extracted by adding a small amount of a recoverable, relatively benign solvent such as diethyl ether or ethyl acetate. The surfactant remains in the water in the reaction vessel and can be used over and over again. A single recycle of the micellar medium can result in significant reduction of wastewater and further lowering of the E factor compared with traditional reactions, Lipshutz said. The only contribution to the E factor in that case is the small amount
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of solvent needed to remove the product. “Micelle-enabled green chemistry is innovative,” commented Hong Hu, a research adviser in discovery chemistry research at Eli Lilly & Co. “It shifts the traditional paradigm of organic chemistry.” Hu envisions that the micelle technology could help push automated synthesis in drug discovery to achieve higher efficiency and throughput, a priority for Lilly scientists (C&EN, Nov. 26, 2012, page 12). “It could change the way of synthesizing organic molecules in the future,” Hu said. “This versatile and powerful methodological advance is garnering a great deal of attention from the pharma industry,” added Lawrence G. Hamann, executive director of global discovery chemistry at Novartis Institutes for BioMedical Research. “Pharmaceutical researchers are collectively striving for greener methods, catalyzed in part by consortia such as the Pharmaceutical Roundtable. The Lipshutz group’s chemistry is redefining what is possible in an aqueous reaction mixture and will be transformative to the pharma industry’s synthetic processes.” ◾
