List of 2006 Award Winners

Science & Technology

July 10, 2006 • Volume 84, Number 28 • pp. 24-27

Going Green Keeps Getting Easier

Presidential honors reward advances in chemistry that promote pollution prevention and sustainability

Stephen K. Ritter

For more than a decade, proponents of green chemistry and green engineering have delivered the message that cleaning up chemical reactions and products is not only good for the environment but also good for a company's bottom line. Many chemists and chemical engineers were initially slow to embrace the principles of green chemistry, considering them sensible but not always practical to put into place.

Although it has never been easy to be green, it has gotten much easier as chemists and chemical engineers build a burgeoning portfolio of proven green accomplishments. The latest set of these accomplishments were recently honored with Presidential Green Chemistry Challenge Awards. The awards this year went to four companies and one academician selected from among some 90 nominations. They were presented during a ceremony held on June 26 at the National Academy of Sciences (NAS) in Washington, D.C.

5Courtesy of Codexis

GREEN BY DESIGN Ribbon structure of one of the four identical subunits of a halohydrin dehalogenase enzyme shows sections in gray modified by Codexis scientists to optimize the enzyme for a greener process to make the key chiral building block in atorvastatin (Lipitor).

"The need for green chemistry is growing, and fortunately the perception of the importance of green chemistry is also growing," commented NAS President Ralph J. Cicerone, who welcomed the award winners and guests to the ceremony.

Presidential science adviser John H. Marburger III, also speaking at the ceremony, noted that he, too, was impressed with the progress being made in green chemistry. "Few areas of science give us such scope for creativity as chemistry," he said. Marburger went on to read a congratulatory message from President George W. Bush, which noted that "through science and technology we can be better stewards of our natural resources and help confront and overcome environmental challenges."

Green chemistry is all about more efficient production of industrial chemicals, pharmaceuticals, and consumer products. That is to say, the goal of green chemistry is to find ways to develop chemical products and processes that require fewer reagents, less solvent, and less energy while being safer, generating less waste, and being profitable. The awards program, now in its 11th year, is administered by the Environmental Protection Agency's Office of Pollution Prevention & Toxics and sponsored in part by the American Chemical Society and its Green Chemistry Institute.

Recognition provided by the awards "not only focuses attention on the fundamental work being done" but also celebrates the scientists, technologists, and team leaders "responsible for bringing these concepts from ideation to commercial reality," commented ACS President-Elect Catherine T. Hunt, a chemist at two-time award-winner Rohm and Haas.

Hunt noted that green chemistry principles have allowed Rohm and Haas to review its R&D portfolio and identify specific opportunities where being greener would increase competitiveness. "Being environmentally friendly and economically savvy can, and does, go hand-in-hand, particularly when built on a foundation of first-class science and engineering," she added.

Biocatalytic process development firm Codexis was recognized with the award in the greener reaction conditions category for developing a "green-by-design" enzymatic process to replace a chemical process for making ethyl (R)-4-cyano-3-hydroxybutyrate. This chemical, also known as hydroxynitrile, is the key chiral building block used to make atorvastatin, the active ingredient in Pfizer's cholesterol-lowering drug Lipitor.

The new process is helping to lower atorvastatin's long-term production costs, according to John H. Grate, senior vice president of R&D and chief technology officer at Codexis. The savings could be financially significant for Pfizer and future generics manufacturers given that Lipitor is the world's top pharmaceutical, with annual sales of about $13 billion.


Hydroxynitrile is used in the early stages of atorvastatin synthesis to build the chiral dihydroxy acid side chain that's essential to the drug's activity, Grate told C&EN. Demand for the intermediate is about 200 metric tons per year, and it's currently being made by several fine chemicals producers. The competition to supply the intermediate to Pfizer has spurred several firms to chase after a better way to prepare hydroxynitrile (Angew. Chem. Int. Ed. 2005, 44, 362).

When Codexis was formed as a subsidiary of Maxygen in 2002, one of the first projects the company set its eyes on was an enzymatic process to make hydroxynitrile, Grate noted. "We were thinking: Why not go after the key building block of the best-selling drug in the world?"

Existing multistep commercial processes to make hydroxynitrile involve first preparing an enantiopure bromo- or chlorohydrin, followed by replacing the halogen with a cyano group, Grate explained. The cyanation step is tricky because it requires using potassium or sodium cyanide at an elevated temperature followed by high-vacuum fractional distillation to recover hydroxynitrile in acceptable purity, he said.

Codexis scientists used the company's MolecularBreeding accelerated directed-evolution technology to engineer three enzymes to accomplish all the chemistry. The new hydroxynitrile synthesis starts with reduction of the keto group of ethyl 4-chloroacetoacetate feedstock to form a chiral chlorohydrin. The reduction is facilitated by two of the engineered enzymes, a ketoreductase and a glucose dehydrogenase. The enzymes work in tandem with nicotinamide adenine dinucleotide to convert the chloroketone to the chlorohydrin using glucose as a reductant, which avoids the need to use hydrogen. More pivotal is the ensuing step in which the third enzyme, a halohydrin dehalogenase, catalyzes substitution of chlorine with a cyano group to form hydroxynitrile.

Both enzymatic reaction steps take place under aqueous conditions at neutral pH and at atmospheric pressure and just above room temperature, Grate pointed out. Overall, the Codexis process provides more than 90% yield for each step and provides hydroxynitrile in high enantiomeric purity, he said. In addition, the low enzyme loading avoids emulsion formation and allows product isolation by extraction rather than by more costly distillation.

Lonza is now using Codexis' process to manufacture hydroxynitrile for Pfizer. The hydroxynitrile synthesis "really validates the power of Codexis' technology for creating biocatalysts that enable new green chemical processes," Grate commented. "For us, this is really the tip of the iceberg for what we are accomplishing in biocatalytic chemical process development."

NuPro Technologies, Winston-Salem, N.C., and Arkon Consultants, Irving, Texas, teamed up to win the small-business award for developing novel flexographic printing washout solvents and alternative solvent-recycling systems. The lower emissions of volatile organic compounds (VOCs), lower worker exposure to hazardous solvents, lower fire and explosion potential, and reduced transport and maintenance requirements of NuPro's products "translate into decreased cost and improved safety in all aspects of the flexographic printing industry," according to the company's president, David C. Bradford.


GREENER PRINTING Bradford (left) and Hendrickson devised solvent replacement systems to benefit the flexographic printing industry.

Flexographic printing is the predominant method for printing food wrappers, shopping bags, cereal boxes, and shipping cartons, Bradford explained. Many of NuPro's customers are "trade shops" that produce printing plates for clients who do their own printing, such as large-scale producers of grocery and household goods.

The plates are made of a flexible polymer incorporating an unsaturated monomer that cross-links when exposed to laser or UV light, he noted. The image to be printed is fixed onto the plate by shining light through a mask. Exposed plates are immersed in solvent to remove, or wash out, unpolymerized material from the nonimage areas before being dried and loaded onto a printing press. The solvents are periodically vacuum-distilled to remove residual polymer and reused.

Washout solvents for flexographic printing traditionally have been chlorinated hydrocarbons or saturated cyclic hydrocarbons, Bradford said. Perchloroethylene was widely used until the mid-1990s, but advances in plate-making technology, as well as health and safety issues, led trade shops to drop perchloroethylene in favor of xylenes, he noted. Though xylenes are considered safer than perchloroethylene, these hydrocarbons are still rated as hazardous air pollutants and subject to regulatory reporting requirements. Xylenes also require additives, such as naphthalene, to help raise the flash point to avoid a fire hazard.

Thus the need for new types of washout solvents still exists, Bradford told C&EN. Working with chemist Connie M. Hendrickson, the principal of Arkon Consultants, NuPro has developed several new lines of washout solvents having negligible vapor pressures, higher flash points, and lower toxicity than xylenes.

One of these lines is Nutre Clean FPX solvents. These are proprietary mixtures of terpene ethers and esters derived from the limonene fraction of pine oil. Another line, Nutre Clean XP solvents, consists of substituted cyclic hydrocarbons, such as 1,4-di-tert-butylbenzene and 3,3,5-trimethylcyclohexanol. These compounds, while derived from petroleum, are widely used in the flavors and fragrance industry and already have "generally recognized as safe" designations, Hendrickson noted. Another line of solvents under late-stage development is based on fatty acid methyl esters derived from soybean oil.

The growing North American market for washout solvents stands at about 2 million gal per year at a cost of $15 or more per gal, Bradford said, with NuPro controlling just over a 10% share. NuPro is selling the terpene and cyclic hydrocarbon solvents in North America, while the methyl ester solvents are being marketed in China and Japan.

To recover NuPro's low-volatile solvents and to encourage their acceptance by trade shops, Bradford and Hendrickson realized that an alternative to vacuum distillation was needed for solvent recycling. Their answer was to come up with NuPro's Cold Reclaim Systems.

One model, occupying a footprint about the size of a bathtub, utilizes a series of vibrating 0.05-µm membrane filters that separate the solid polymer and other residues from the solvent at room temperature. The system recovers about 95% of solvent per recycle, and it's available in units with capacities up to 850 gal per day. A smaller benchtop centrifuge system uses a cartridge-type filter to clean the solvent, also at room temperature. The filter is designed so that it can be easily removed and safely discarded in the trash. Overall, the recycling systems reduce hazards associated with heating flammable solvents as well as reduce energy consumption and maintenance costs associated with vacuum distillation, Bradford added.

Chemical engineering professor Galen J. Suppes of the University of Missouri, Columbia, was honored with the academic award for his group's work to create a low-cost catalytic process to convert the glycerol by-product from biodiesel production into propylene glycol--turning 1,2,3-propanetriol into 1,2-propanediol. At first glance, this achievement may not sound that exciting. But the repercussions of Suppes's accomplishment are expected to have a major impact on the future use of biodiesel fuel, the world glycerol market, and the environmental health and safety of antifreeze and deicing chemicals.

4Photo by Rob Hill/MU Publications

GREEN SOLUTION Suppes and his group uncovered ideal reaction conditions for the catalytic conversion of by-product glycerol to useful propylene glycol.

Biodiesel is a mixture of fatty acid methyl esters made by esterifying soybean oil or other vegetable oil or animal fat. The triglycerides in the oil consist of three long fatty acid chains connected to a propyl headgroup. Sodium hydroxide is used to cleave the chains, which in turn are reacted with methanol to form methyl esters, leaving the residual glycerol headgroup as a by-product. About 1 kg of crude glycerol is formed for every 9 kg of biodiesel produced.

Millions of gallons of glycerol are flooding the world market as biodiesel production is ramping up in the U.S. and Europe, Suppes explained. The fallout from this glycerol glut is that chemical companies have shuttered some glycerol production plants and are considering glycerol as a starting material to make a host of feedstock chemicals (C&EN, Feb. 6, page 7).

Suppes entered the picture about four years ago when he realized that an inexpensive method to convert glycerol to propylene glycol could be valuable, he said. Utilizing the glycerol not only would help offset the cost of biodiesel production, but the inexpensive propylene glycol could be used as a low-toxicity replacement for ethylene glycol in automotive antifreeze.

Suppes's system involves low-pressure hydrogenolysis of glycerol using a copper chromite catalyst, CuO•Cr2O3 (Appl. Catal. A 2005, 281, 225). In the two-step process, glycerol is first dehydrated to form acetol (1-hydroxy-2-propanone), which is then hydrogenated to form propylene glycol.


GREEN LEFTOVERS Glycerol by-product from biodiesel production can be used as a feedstock in Suppes' process to produce acetol or propylene glycol from renewable resources.

Copper chromite hydrogenolysis catalysts aren't new, but the success of the Missouri process is in achieving high selectivity for propylene glycol by controlling the temperature and hydrogen pressure of the reaction, Suppes noted. In the past, researchers tended to use reaction temperatures that were too high, leading to a higher percentage of by-products. Thus, they "missed the window of opportunity to achieve high selectivity," Suppes said. Tinkering with temperature, pressure, and several different catalysts, Suppes and his colleagues optimized the system to operate at about 220 °C and less than 10 bar versus about 260 °C and more than 150 bar for other systems.

Another key part of the synthesis is the ability to isolate the acetol intermediate, Suppes added. Acetol is a synthetic starting material used to make polyols. But when made from petroleum, it costs about $5.00 per lb, discouraging its widespread use. Suppes envisions that producing acetol from biomass-based glycerol using his process could lower the cost to 50 cents per lb, "opening up even more potential applications and markets for products made from glycerol."

Suppes's propylene glycol process has been patented and is being licensed through the Missouri Soybean Merchandising Council, which provided partial funding for the research. The first commercial facility, with an annual capacity of 11.5 million gal, is being built in an undisclosed location in the U.S. by Senergy Chemical. It's expected to be in operation by the end of this year.

Merck was selected for the award in the greener synthetic pathways category for revising the synthesis for sitagliptin, a chiral β-amino acid derivative that is the active ingredient in Januvia, the company's pending new treatment for type 2 diabetes. The breakthrough leading to the new synthesis was the discovery that the amino group of the key enamine intermediate doesn't need to be protected prior to enantioselective catalytic hydrogenation of the double bond.

This development has solved a long-standing problem in the synthesis of β-amino acid derivatives, which are known for their pharmacological properties and are commonly used as chiral building blocks, noted Karl B. Hansen, a Merck process chemist involved with the synthetic effort. The outcome has been to slash the number of reaction steps in the sitagliptin synthesis from eight to three, leading to an equally dramatic reduction in the amount of chemicals and solvent needed and the amount of waste generated.

Merck's first-generation synthesis of sitagliptin involved preparing a β-hydroxy carboxylic acid, which was converted to a protected β-lactam and then coupled to a triazole building block. Deprotecting the resulting intermediate provided the β-amino acid moiety, and sitagliptin was isolated as a phosphoric acid salt.

This synthesis involved a roundabout route involving four steps to introduce the pivotal chiral amino group of sitagliptin. The synthesis worked well to prepare more than 100 kg of the compound for clinical trials, and with modifications it was deemed to be a viable though not very green manufacturing process, Hansen pointed out. For example, the original synthesis required a number of distillations and aqueous extractions to isolate intermediates, leading to a large volume of waste to treat.

"Being environmentally friendly and economically savvy can, and does, go hand-in-hand."

Merck process chemists recognized that a much more efficient process was possible by synthesizing the β-amino acid portion of the molecule directly from an enamine. But the protection-deprotection of the amine nitrogen with an acyl group during the hydrogenation is difficult on a large scale, and unprotected reactions generally result in lower yields and lower enantiomeric excesses, Hansen said.

Undaunted, the Merck scientists working on the revised synthesis discovered that the amino group could be efficiently introduced by an unprotected hydrogenation using a rhodium catalyst with a ferrocenyl phosphine ligand named Josiphos (C&EN, Sept. 5, 2005, page 40). Merck turned to Solvias, a Swiss company with experience in asymmetric hydrogenations that manufactures Josiphos, as a partner to help speed up the process development.

The new synthesis involves first coupling trifluorophenyl acetic acid and triazole building blocks to form a diketoamide, which in turn is converted to the enamine. This sequence is carried out without isolating intermediates. The enamine is then hydrogenated, sitagliptin is isolated and recrystallized as the phosphoric acid salt, and the rhodium Josiphos catalyst is recovered.

In sum, the revised synthesis increases the overall yield of sitagliptin by nearly 50% and reduces the amount of waste by more than 80%. A key difference is that the original synthesis produced more than 60 L of aqueous waste per kg of product, while the new synthesis completely eliminates aqueous waste. When tallied up, Merck expects these savings will prevent formation of 150,000 metric tons of solid and aqueous process waste over the lifetime of Januvia. Industry analysts speculate that regulatory approval of the drug will come by early next year and that it's destined to become a top-selling drug.

The novel enamine hydrogenation "is arguably the most efficient means to prepare β-amino acid derivatives," noted R. P. (Skip) Volante, Merck's vice president of process research. The company currently is using the procedure to make several other exploratory drug candidates, he added. Overall, the redesigned synthesis of sitagliptin "is a green chemistry solution to the preparation of a challenging synthetic target and is an excellent example of a scientific innovation resulting in benefits to the environment," Volante said.

Household consumer products company S.C. Johnson & Son garnered the award in the designing safer chemicals category for developing Greenlist, a patented "ecoeffectiveness" program that allows the company to formulate existing and new products based on environmental health and safety ratings of individual ingredients. Some familiar S.C. Johnson brands benefiting from the program include Saran Premium Wrap plastic film, Windex glass cleaner, Fantastik all-purpose cleaner, and Raid insecticide.

The firm has been building ecoefficiency into its product portfolio through strategic planning for many years, according to Scott E. Johnson, vice president of global environment and safety actions. By the late 1990s, S.C. Johnson began to add emphasis on providing company scientists and product developers with "the best information possible when formulating a product," he told C&EN. Environmental performance evaluations to that point didn't have rating levels and were evaluated on a pass-fail system, he said.

"But that approach didn't tell us how to make our products better or provide the product formulator with alternative raw material choices," Johnson added. "We wanted a mechanism to continuously improve our products and their environmental footprint--something transparent that would be widely accepted because it's based on sound science and it's compatible with our business needs."

Greenlist was the answer. Started in 2001, the system uses several criteria to evaluate the biological and environmental impact of 17 categories of ingredients and materials, Johnson explained. The criteria include biodegradability, aquatic and human toxicity, vapor pressure, and octanol-water partition coefficient. The various categories include surfactants, solvents, propellants, insecticides, dyes, preservatives, and packaging.

Evaluated ingredients each receive an environmental classification score: 0, for restricted-use material; 1, for acceptable use; 2, for better material; or 3, for best material. The idea is to get as many higher rated ingredients as possible into a product. But in some cases, restricted-use materials are used after careful consideration when there are no substitutes, Johnson said.

S.C. Johnson has used Greenlist to rate about 95% of the ingredients that go into its products, which adds up to some 3,500 individual items and some 1.4 billion lb of material. The simplicity of the rating system is that a "chemical chooser" doesn't need to know the intricate details of the chemistry or be an environmental toxicologist to decide between ingredients, he pointed out.

One Greenlist success story is Saran Premium Wrap, the clingy plastic film popularly used to store food leftovers. Saran products originated at Dow Chemical and were based on copolymers of polyvinylidene chloride (-CH2CCl2-)n. S.C. Johnson acquired the Saran Wrap brand and later used Greenlist to determine that low-density polyethylene would be a good substitute because the switch would eliminate chlorine. The move in 2004 raised the environmental classification score of the plastic one full point and eliminated nearly 4 million lb of polyvinylidene chloride production per year, Johnson noted.

In another example, the company used Greenlist to remove a solvent classified as a VOC from its Windex glass-cleaner products. Windex that is reformulated with a non-VOC solvent has eliminated 1.8 million lb of VOCs per year, and it cleans 30% better to boot, Johnson said.

"For S.C. Johnson, Greenlist is improving the environmental profile of our products," Johnson said. "It's about doing what's right for people, the planet, and future generations."


GREENING UP DRUGS Merck process chemists redesigned and significantly shortened the original synthesis of type 2 diabetes drug candidate sitagliptin (Januvia) to include an unprecedented efficient hydrogenation of an unprotected enamine.

Chemical & Engineering News • ISSN 0009-2347 • Copyright © 2006 American Chemical Society