Features GREEN CHEMISTRY
Five green chemistry success stories The 2017 Green Chemistry Challenge Awards recognize chemical innovations that prevent pollution and promote sustainability STEPHEN K. RITTER, C&EN WASHINGTON
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he 12 Principles of Green Chemistry are a how-to guide written 20 years ago for chemists and chemical engineers. They provide insight on developing new chemicals and chemical processes and revitalizing existing ones so that they achieve their desired function while being environmentally and economically friendly. It’s a creative challenge to put the 12 principles into action. Five technologies that have succeeded in meeting that creative challenge have received 2017 Green Chemistry Challenge Awards. Merck, Dow Chemical, Koehler, Amgen, Bachem, UniEnergy Technologies, and University of Pennsylvania chemistry professor Eric J. Schelter were honored for their achievements at a ceremony held on June 12 at the National Academy of Sciences in Washington, D.C. The award winners presented details of their technologies the next day at the annual Green Chemistry & Engineering Conference. The Environmental Protection Agency established the awards program in 1995 to help achieve federal goals set by the provisions of the Pollution Prevention Act of 1990. These include reducing toxicity of chemical products, saving water or energy, and reducing waste even if it’s not hazardous. The program is administered by EPA’s Green Chemistry Program and is supported by partners including the American Chemical Society and its Green Chemistry Institute. “The Green Chemistry Challenge Awards highlight the importance of sustainable chemistry and its impact across a range of disciplines,” says Princeton University’s Paul J. Chirik, a 2016 award recipient. “Striking features common among many of the winners is that green chemistry often results in an improved product or a cost savings, demonstrating that environmentally responsible science does not have to come with reduced performance or added cost.” The following vignettes tell the stories of this year’s award-winning technologies.
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Heat-and-serve thermal paper bypasses bisphenol A Chemists regularly come up with great products that are later discovered to have a shortcoming. With green chemistry principles as a guide, that’s an opportunity to go back to the drawing board and find a game-changing solution. Thermal paper used for printing cash register receipts, tickets, and labels is one such success story. In traditional thermal paper, a colorless dye and a chemical developer such as bisphenol A are coated on the paper. When heated, BPA interacts with and protonates the dye to alter the structure, switching its color from white to black. However, concerns over the estrogen-mimicking properties of bisphenols have led chemists to replace them where possible to reduce retail worker and consumer exposures. Dow Chemical and papermaker Koehler jointly landed the Designing Greener Chemicals Award for a technology that uses a polymer coating on paper to create fade-resistant thermal-printed images stemming from the altered refractive index of the coating. This physical process replaces the chemicals in the thermal paper. The coating is made from an opaque layer containing Dow’s Ropaque styrene acrylic resin hollow spheres and a colored layer containing a permanent pigment, such as carbon black. Dow originally developed Ropaque as a pigment to replace more expensive titanium dioxide in paint formulations, and it also has come to be used in personal care products such as sunscreens. The spheres function as air
technology really demonstrates the passion of our people to deliver inventive solutions to customer problems.” “It’s a classic approach to simply replace molecules that are discovered to have adverse environmental or health effects, such as BPA,” says In Dow and Koehler’s invention, paper is coated with an opaque polymer layer that is filled with chemistry professor Audrey air voids and has a colored layer below. When exposed to heat in a thermal printer, the air voids Moores of McGill University, collapse and become transparent, revealing the color layer. Absorbed light creates a permanent an expert in green chemistry and fade-resistant image for a thermal paper free of chemical developers. who focuses on recyclable nanoparticle catalysts. “Howvoids that scatter light. This is the same printers. The paper has been tested in a few ever, the replacement can be just as bad. effect that makes polystyrene foam and stores so far and will be in commercial use To escape this unproductive cycle, a more clouds appear white. this year. innovative approach is to reinvent the maWhen a thermal printhead heats the Ropaque-based thermal paper “is an terial from scratch so that it achieves the paper, the air voids collapse and become amazing innovation,” says A. N. Sreeram, same function with less chemistry. This is transparent, revealing the color below Dow’s chief technology officer. “It takes exactly what Dow and Koehler have done. without the need for a chemical developer. an entirely new approach by eliminating This is a true example of a material made The added benefit of the new technology chemical developers for improved safety, to be ‘benign by design’ by thinking outside is that it works using existing thermal yet it still works in existing equipment. This the box.”
Ligand seperates rare earths for recycling
CREDIT: DOW CHEMICAL (GRAPHIC); BREN COLE (SCHELTER)
The rare-earth metals are a group of 17 elements, lanthanum to lutetium along with scandium and yttrium, whose properties make them useful and often irreplaceable in electronics and lighting applications. Manufacturers often blend rare earths to tune the properties of the needed materials, such as permanent magnets for electronics and phosphors for lighting. But the chemical properties of rare-earth cations are similar, making separating them for recycling difficult. Eric J. Schelter’s group at the University of Pennsylvania got the nod for this year’s Academic Award for developing a simplified process that uses tailored nitroxide ligands to separate mixtures of rare-earth metals for recycling. The approach is expected
to reduce energy use and waste generated during recycling of rare-earth metals from cell phones, magnets used in motors, and other products to help minimize new rare-earth mining—a costly, energy-intensive, and waste-generating process. The ligand that the researchers designed, tris(2-tert-butylhydroxylaminato) benzylamine, or TriNOx, forms a size-sensitive, tripod-shaped aperture when it binds the metals. For larger diameter metals, a dimeric complex forms. For smaller diameter metals, a monomeric complex forms. For example, neodymium-based permanent magnets (Nd2Fe14B) contain some dysprosium to improve thermal perforN O O NO mance. When N N TriNOx is added M M N N to solutions O N O O N containing salts OH N N of the two metSolution als, neodymiOH N M = lanthanum to europium um—the larger metal—forms a soluSolid HO ble dimeric complex, N whereas dysprosium O O forms a monomeric O M N complex that precipiTriNOx ligand N O tates. Schelter’s group N UPenn’s Schelter developed a developed a complete N tripodal nitroxide ligand to selectively recycling process to bind different rare earths to facilitate recover the two metisolating and recycling them based on als by filtration and their size and solubility properties. reuse the ligand. M = gadolinium to lutetium, yttrium
Schelter poses in his lab with a wind turbine neodymium-based permanent magnet rotor that contains a small amount of dysprosium. His group’s chemistry is designed to separate the two rare-earth metals during magnet recycling. JUNE 26, 2017 | CEN.ACS.ORG | C&EN
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The team has also shown the ligand’s separation prowess for phosphor materials that include mixtures of yttrium and europium. Overall, the UPenn researchers have demonstrated the ability to separate more than 50 pairwise combinations of rare earths. The new approach offers an easier, less expensive alternative to redox chemistry, acid-leaching processes, and ionic liquid extraction currently being
used and explored for recycling rare earths. “Our method demonstrates that rare-earth mixtures can be purified by applying the principles of coordination chemistry,” Schelter says. “The work is still in the early stages, but the results are important because they demonstrate a new type of targeted metal separation specifically for recycling.”
“Rare-earth recycling has enormous potential benefits,” says chemistry professor Audrey Moores of McGill University, an expert in green chemistry who focuses on recyclable nanoparticle catalysts. “This discovery has a major impact on greener processes at multiple levels: It means less mining pollution, less e-waste, and better access to key elements for cleantech innovation.”
Chipping away at the cost of peptide manufacturing Peptides have gained increased interest as therapeutic drugs over the past three decades because of their high specificity and safety compared with small-molecule drugs. They are becoming the treatment of choice for some cancers, enzyme and protein disorders, and degenerative and infectious diseases. Their pharmaceutical rise has prompted companies to look at more efficient manufacturing processes for peptide-based therapeutics to reduce the environmental impact and production costs.
to a green and more efficient process,” says Margaret Faul, Amgen’s executive director of process development. “This new process for solid-phase synthesis leveraged the different areas of expertise across Amgen and Bachem.” Peptides are synthesized stepwise by coupling the carboxyl group, or C-terminus, of one amino acid to the amino group, or N-terminus, of another using liquid-phase or solid-phase synthesis. In solid-phase synthesis, which is now most common, the peptide backbone is assembled
The process development team, led by Amgen’s Sheng Cui, eliminated an ion-exchange column process requiring more than 3 L of water for every gram of drug and reduced the number of energy-intensive freeze-drying (lyophilization) purifications from 13 per batch of peptides to one. The results are a fivefold increase in manufacturing capacity while cutting manufacturing time by more than half and reducing solvent use by 71%. Overall, the new process cut manufacturing costs by 76%.
Standard peptide manufacturing platform Solid-phase peptide synthesis Cleavage and deprotection
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Conjugation Conjugation, preparative HPLC Preparative HPLC
Ion-exchange lyophilizations
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NH2
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O Etelcalcetide
Precipitation lyophilization
Biotechnology firm Amgen and peptide manufacturer Bachem teamed up to receive the Greener Reaction Conditions Award for improving the manufacturing process for etelcalcetide, the active ingredient in Parsabiv, a calcium inhibitor to help control overactivity of the thyroid gland in patients with kidney disease. The new process produces more peptide in less time while drastically cutting solvent and water use and reducing production costs. “We’re proud of this award that recognizes how scientific innovation can improve our manufacturing technologies and lead
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Amgen and Bachem teamed up to develop a streamlined peptide manufacturing technology for the thyroid medication etelcalcetide.
one amino acid at a time while attached to resin beads, which requires washing away residual reagents at each step. Producing 1 kg of peptide typically requires several metric tons of solvent and thousands of liters of water, according to the companies’ environmental analysis. As Amgen anticipated etelcalcetide approval, Faul and her colleagues realized the original production process would be problematic for commercial-scale manufacturing, given the amount of materials needed and the waste generated. Amgen and Bachem redesigned the process to bypass one of the five production stages and optimize the remaining four.
“This work constitutes a textbook example of how green chemistry and engineering improvements for a process can result in both clear and tangible environment benefits while making the costs of the process more favorable,” says chemistry professor Audrey Moores of McGill University, an expert in green chemistry who focuses on recyclable nanoparticle catalysts. “The green improvements to all stages of the manufacture of the active species essentially made it possible for the companies to launch this molecule. This is quite remarkable and shows that green chemistry and economics often operate hand in hand.”
Better batteries for the electrical grid As electrical grids become larger and more complex, supplemental energy storage using batteries and other technologies is needed to smooth out supply and demand peaks and troughs. Lithium-ion batteries have the energy density needed for this task, but they are capable of operating for only a couple of hours at a time and have a limited lifetime. In addition, lithium-ion batteries have notable challenges with thermal runaway of their layered materials and with flammability of their organic-based electrolyte. Redox flow batteries are a promising technology for long-duration applications for electrical grids and to manage power for commercial and industrial facilities. But scientists and engineers must improve flow battery efficiency and reduce their size and cost. UniEnergy Technologies, in collaboration with Pacific Northwest National Laboratory (PNNL), garnered the Small Business Award for its design of a next-generation vanadium redox flow battery system that takes a giant step in that direction. The company’s megawatt-scale Uni.System has double the energy density of previous vanadium redox flow batteries even though it’s one-fifth the size and requires smaller amounts of chemicals. Instead of storing electrical energy in solid electrodes, as most batteries do, a redox flow battery stores chemical energy in a pair of electrolyte solutions. The conversion from electrical energy to chemical energy (charging) and vice versa (discharging) occurs within the flow battery’s electrodes as the electrolytes circulate through the cell. UniEnergy’s vanadium redox flow battery chemistry originated at PNNL. Liyu
UniEnergy’s research team, led by Li (front and center) and Yang (to Li’s left), developed an advanced vanadium redox flow battery, which is inside the shipping containers in the background. Li and Gary Yang, two members of PNNL’s energy storage team, founded UniEnergy, licensed the technology, and recruited a technical and business team. The key innovation for the new battery was replacing a sulfate-based electrolyte with a chloride-based electrolyte. This seemingly simple switch improves the stability of the battery to increase its lifetime and enables it to function with a broader operating temperature range compared with the prior generation, so it can be deployed just about anywhere, even in extreme hot or cold climate zones. Furthermore, the electrolyte storage tanks act as a heat-exchange system, so the battery stays cool—no thermal runaway. And the aqueous electrolyte is nonflammable and recyclable. The previous generation of vanadium redox flow batteries took up the space of a tennis court. UniEnergy designed the new battery to fit in standard 20-foot shipping
containers, which reduces the amount of vanadium and construction materials needed. The Uni.System is now being used at multiple sites in the U.S. and Europe. “Advances in chemistry have made this flow battery competitive with lithium-ion batteries for long-duration applications,” says Imre Gyuk, director of energy storage research at the Department of Energy, which funded the original battery development. “This change in electrolyte chemistry has allowed these inventors to greatly improve the stability of flow batteries to reach unlimited cycles without flammability,” says chemistry professor Audrey Moores of McGill University, an expert in green chemistry who focuses on recyclable nanoparticle catalysts. “The discovery is an example of fundamental electrochemistry research leading to the design of better materials that are necessary to support the transition to renewable energy.”
CREDIT: UNIENERGY TECHNOLOGIES
Process chemists find a greener path to antiviral drug When pharmaceutical companies have a promising drug candidate that is ready to move forward for clinical testing, process chemists are called upon to develop a synthetic pathway to scale up production of the compound. Often the new synthesis is done in a hurry because time is of the essence to get the drug into the clinic. When the company is ready to move the drug forward for approval, process chemists revisit the synthesis, looking for ways to improve it for manufacturing. When Merck process chemists investigated ways to streamline the synthesis of the antiviral drug letermovir, they discov-
ered a number of new asymmetric reactions to reduce its environmental footprint and published their initial success story (Org. Process Res. Dev. 2016, DOI: 10.1021/acs. oprd.6b00076). The team’s revised synthesis could have been used as the manufacturing route. However, the new alkaloid-based quaternary ammonium phase-transfer catalyst for the key asymmetric cyclization step was ultimately not recyclable. The team went back to the screening phase and discovered a more stable and effective, fully recyclable catalyst. Merck’s overall achievement has been recognized with this year’s
Greener Synthetic Pathways Award.
Letermovir is currently awaiting approval for fighting human cytomegalovirus infections in organ transplant recipients, a condition that currently doesn’t have an effective drug. The award-winning synthesis reduces the process mass intensity for making letermovir, a sustainability measure of raw materials, solvents, and water used per amount of product made, by 73% compared with the original synthesis. “We’ve had a long-standing commitment to green and sustainable processes,” says Kevin R. Campos, who leads Merck’s process chemistry group. “We are proud of the fact that nearly every atom of every JUNE 26, 2017 | CEN.ACS.ORG | C&EN
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reagent in the commercial process for potential catalysts and reaction condimetric tons of waste over the lifetime of letermovir is either incorporated into tions. The researchers tested thousands of letermovir. the molecule or recycled—it’s highly combinations on a submilligram scale to “Merck really showcases production atom-economical.” find the optimal replacement for the prooptimization of letermovir in the context “Our ultimate goal is ‘zero waste’ pharcedure to isolate the needed stereoisomer. of its ‘zero waste’ goal,” says chemistry maceutical manufacturing,” adds Merck The outcome was the discovery of a new professor Audrey Moores of McGill process chemist Guy R. Humphrey, who asymmetric aza-Michael cyclization using University, an expert in green chemistry helped lead the discovery team and developDesign for atom CH3O economy ment of the manufacO O turing route. H2 N CF3 CF3 CH3O The original synInvent new HO thesis centered on a transformations O N OCH3 procedure involving O a guanidine intermeCl N N Prioritize and diate to obtain the Br N F OCH3 select route desired letermovir HN stereoisomer, which NH2 N OCH3 had limited the overall Optimize for F Letermovir product yield. Other sustainability inefficiencies were the use of a large Merck’s green chemistry strategy led to a highly efficient, waste-reducing, cost-cutting synthesis for amount of palladium converting inexpensive raw materials into the antiviral drug letermovir. catalyst to prepare an earlier intermediate in the synthesis a hydrogen-bonding chiral bistriflamide who focuses on recyclable nanoparticle pathway, as well as the use of nine different organocatalyst. catalysts. “Their strategy combining insolvents, including hazardous dioxane and The combined improvements increased novative organic synthesis methodology chlorobenzene. letermovir’s overall yield by more than 60% with life-cycle analysis results in an imUsing high-throughput screening tools, and reduced raw material costs by 93%. The pressive reduction of the carbon footprint the Merck team explored four alternative researchers estimate that the optimized and water usage with a direct economic asymmetric reactions with hundreds of process will eliminate more than 15,000 impact.” ◾
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