Issue Date: June 27, 2011
Academic Award: Bruce H. Lipshutz, University of California, Santa Barbara
Organic chemist Bruce H. Lipshutz of the University of California, Santa Barbara, received the Academic Award for creating a low-cost designer surfactant that allows most common transition-metal-catalyzed organic reactions to run in water at room temperature. The achievement is a key milestone toward Lipshutz’ goal of developing chemistry “that will allow the synthetic organic community to get organic solvents out of organic reactions,” he says.
Lipshutz began formulating his idea when quizzing process chemists in industry about the most common reactions they used. The response was invariably transition-metal catalysis, he says. Then he began looking at how this type of chemistry could be carried out in water at production scale at room temperature, which would be a coup for process chemistry.
The answer has come in the form of a new type of amphiphilic molecule, which he named TPGS-750-M, made from environmentally benign ingredients: racemic α-tocopherol (vitamin E), succinic acid, and a methyl-terminated polyethylene glycol (MPEG-750). In water, the amphiphile forms nanomicelles, which function as tiny reaction vessels. The lipophilic vitamin E orients to the center of the nanomicelles and serves as a solvent, and the hydrophilic polyethylene glycol orients toward the water. The two ends of the amphiphile are connected by a succinic acid linker.
Thousands of surfactants have been used for decades in many organic and aqueous micellar chemical processes, Lipshutz says. For example, vitamin E-polyethylene glycol surfactants, such as TPGS-1000, have been around for decades. One of TPGS-1000’s primary uses is as an excipient to dissolve active pharmaceutical ingredients for drug delivery.
“But no one thought to design a surfactant specifically for transition-metal-based catalysis,” Lipshutz says. “What organic chemists seem to have missed when it comes to micelles 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.”
The key is nanomicelle size and shape, which can be controlled by selecting the length of the polyethylene glycol segment and/or by adding salts to the water to control ionic strength and pH, Lipshutz says. Spherical nanomicelles in the 50- to 100-nm-diameter range best accommodate the constant flux of reactants, catalyst, and product into and out of the micelles, Lipshutz notes. Typical micelles formed from traditional surfactants have much smaller diameters, only about 10 to 15 nm, which appear to limit this exchange and explain why the enhanced reactivity hasn’t been observed in the past, he believes.
“By understanding these effects, we can really make these nanomicelles dance,” Lipshutz says. “We get better chemistry.”
In water, the organic components, including the reactants, catalyst-ligand system, and product, all crowd into the nanomicelles, Lipshutz explains. The high concentration of reactants and catalyst within the micelles leads to increased rates of reactions, which dispense with the need for heating or cooling.
Lipshutz’ group has demonstrated the capabilities of TPGS-750-M through more than 30 side-by-side comparisons with standard organic reactions, achieving high yields and high enantioselectivities (J. Org. Chem., DOI: 10.1021/jo101974u; 10.1021/jo200746y). These reactions include ruthenium-catalyzed olefin ring-closing and cross-metathesis reactions; palladium-catalyzed Suzuki-Miyaura, Heck, and Sonogashira cross-couplings; palladium-catalyzed Negishi reactions with in situ-formed, water-sensitive organozinc reagents; aromatic halide amination reactions; and reactions leading to allylic amines, allylic silanes, and arylboronates.
The route to prepare TPGS-750-M has already been scaled to more than 170 g by chemists at medicinal chemistry contract research firm Kalexsyn, based in Kalamazoo, Mich. The surfactant became available from Sigma-Aldrich in January and joins PTS-600, an earlier version used in Lipshutz’ lab, which has been sold for two years.
These micellar systems make product isolation simple, Lipshutz adds. The organic product can be extracted by adding a single, recoverable solvent such as diethyl ether, ethyl acetate, or petroleum ether, which leaves the intact micelles in the reaction vessel. Alternatively, the reaction mixture can be filtered through a water-absorbent material to remove the micellar particles and water.
Lipshutz believes his system could be a huge success for the pharmaceutical, specialty and fine chemicals, agricultural, and flavors and fragrances industries, which operate on modest scale but for which product purification, recovery of metal catalysts and solvents, and water use are safety and cost considerations. His lab has run reactions up to about the 1-g scale, he notes, but he assumes users who buy TPGS-750-M have used it on a larger scale.
On a yearly basis, a conservative estimate suggests that 3.2 million metric tons of organic solvents are used in chemical manufacturing, Lipshutz says. A shift of only 1% of that chemistry to water as the reaction medium would amount to a savings of 32,000 metric tons of organic solvents, he points out. In addition, many of those reactions require heating or cooling to control temperature—neither is required with nanomicelles, which provides a bonus both in energy savings and fewer impurities in each product.
“Future generations of designer surfactants are anticipated that may lead to even better performance,” Lipshutz says, “as we begin to accumulate a library of information on these nanomaterials.”
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