Tuning in to New Solvents

Tunable solvents, including supercritical fluids and ionic liquids, may not be in your stockroom — yet — but they offer significant environmental and manufacturing benefits.

By Charles A. Eckert, Charles L. Liotta, Christopher L. Kitchens and Jason P. Hallett, Georgia Institute of Technology

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What more could a pharmaceutical chemist ask for?

According to a 2004 Chemical Week article, Novartis (Basel, Switzerland) has replaced six chemical steps in an established process with a two-step Friedel-Crafts alkylation in an ionic liquid. Not only is the process run at pilot scale, but the use of ionic liquids was deemed patentable. Other major manufacturers are also investigating ionic liquids, according to chemical suppliers quoted in the article.

K.R. Seddon, Ph.D., chair of inorganic chemistry at Queen's University (Belfast, Northern Ireland), a leading authority on ionic liquids, sees “no great obstacles” to adopting liquids in drug-making.

He dismisses the notion that these solvents are toxic. “The knock on ionic liquids is more a result of image than of fact. Ionic liquids consist of mostly simple ions, many of which have already been designated as safe for ingestion.”

BASF (Florham Park, N.J.) is already using ionic liquids on large-scale chemical processes as part of its Strategy 2015 sustainable manufacturing initiative. The company’s BASIL (biphasic acid scavenging using ionic liquids) process is applicable to about one-third of all industrial chemical processes that require acid scavenging.

Normally, acidic by-products are scavenged with amines, which results in viscous, white slurries that are difficult to remove from the product. BASF’s work-around uses methyl imidazole, whose hydrochloride salt happens to be an easily-removable ionic liquid. According to Calvin J. Emanuel, Ph.D., manager of new business development, benefits include easier product isolation, higher yield, and an 80,000-fold improvement in operating efficiency (you read that right). “Without all those solvents around, the process requires less energy to overcome heat transfer issues,” he explains. After the reaction, the ionic liquid is converted back to imidazole and reused.

BASF sees ionic liquids as more than simple solvents. “Calling them solvents doesn’t do them justice,” Emanuel says. “It’s impossible to compare the utility of a simple solvent like THF with ionic liquids.” Prof. Seddon agrees. In his estimation, ionic liquids’ true benefit is their ability to provide greater selectivity and higher yield than traditional solvents.

Since BASIL was introduced in 2002, chemical companies have used it in production of alkoxyphenylphosphines on a multiton scale. An “important” pharmaceutical industry customer has also licensed the process, says William Pagano, a BASF spokesman. BASIL’s potential applications include chlorinations by nucleophilic HCL, azeotropic distillations, and extractions. In addition to using ionic liquids, BASF offers a broad portfolio of them in bulk quantities through its BASIONICS product line. Investigators can purchase development and laboratory quantities through Sigma-Aldrich.





About the Authors

Dr. Charles A. Eckert and Dr. Charles L. Liotta have been research partners for 16 years; they occupy a common laboratory space and codirect students in both Chemistry and Chemical Engineering. Their research focus is on the use of novel solution chemistry for sustainable technology, and for their contributions to industry they jointly received the 2004 Presidential Green Chemistry Challenge Award. Both have joint appointments at Georgia Tech in the Schools of Chemical and Biomolecular Engineering and in the School of Chemistry and Biochemistry. Their group’s website is http://www.che.gatech.edu/ssc/eckert/.

Dr. Christopher L. Kitchens is a Post Doctoral Researcher in the Eckert-Liotta Joint Research Group at Georgia Institute of Technology. He received a B.S. in Chemistry from Appalachian State University and a Ph.D. in Chemical Engineering from Auburn University, where he worked on nanoparticle synthesis and processing in tunable fluids.

Dr. Jason P. Hallett is a Research Engineer in the Eckert-Liotta Joint Research Group at Georgia Institute of Technology. He received a B.S. in Chemical Engineering from the University of Maine and a Ph.D. in Chemical Engineering from Georgia Institute of Technology, where he worked on novel methods for homogeneous catalyst recycle.



References
  1. McHugh, M; Krukonis, V., Supercritical Fluid Extraction: Principals and Practice, Butterworth Publishers, Stoneham, Mass., 1986.

  2. York, P.; Kompella, U.; Shekunov, B., Supercritical Fluid Technology for Drug Product Development. Drugs and the pharmaceutical sciences ; v. 138 M. Dekker, New York, 2004.

  3. Staks, C.; Liotta, C.; Halpern, M., Phase-Transfer Catalysis: Fundamentals, Applications, and Industrial Perspectives. Chapman & Hall, New York, 1994.

  4. Xie, X.; Brown, J.; Joseph, P.; Liotta, C.; Eckert, C.,“Phase-Transfer Catalyst Separation by CO2 Enhanced Aqueous Extraction”, Chemical Communications, 2002, 1156.

  5. Eckert, Charles A.; Liotta, Charles L.; Bush, David; Brown, James S.; Hallett, Jason P. “Sustainable Reactions in Tunable Solvents.” J. Phys. Chem. B 2004, 108, 18108.

  6. Brown, J.; Gläser, R.; Liotta, C.; Eckert, C.,“Acylation of Activated Aromatics without Added Acid Catalyst”, Chem. Commun., 2000, 1295-1296.

  7. Chandler, K.; Deng, F.; Dillow, A.; Liotta, C.; Eckert, C., “Alkylation Reactions in Near-Subcritical Water in the Absence of Acid Catalysts,” Ind. Eng. Chem. Res., 1997, 36, 5175.

  8. Nolen, S.; Liotta, C.; Eckert, C.,“The Catalytic Opportunities of Near-Critical Water: A Benign Medium for Conventionally Acid and Base Catalyzed Organic Synthesis,” Green Chem., 2003, 663.

  9. West, K.; Wheeler, C.; McCarney, J.; Griffith, K.; Bush, D.; Liotta, C.; Eckert, C.; “In Situ Formation of Alkylcarbonic Acid with CO2J. Phys. Chem. A, 2001. 105, 3947.


  10. Xie, X.; Liotta, C.; Eckert, C., CO2-Catalyzed Acetal Formation in CO2-Expanded Methanol and Ethylene Glycol. Ind. Eng. Chem. Res. 2004, 43, 2605.

  11. Chamblee, T.S., R.R. Weikel, S.A. Nolen, C.L. Liotta, and C.A. Eckert, “Reversible in situ acid formation from beta-pinene hydrolysis using CO2 expanded liquid and hot water” Green Chem., 2004, 6.

  12. Nolen, S.; Lu, J.; Brown, J.; Pollet, P.; Eason, B.; Griffith, K.; Glaser, R.; Bush, D.; Lamb, D.; Eckert, C.; Liotta, C.; Thiele, G.; Bartels, K.,“Olefin Epoxidations Using Supercritical Carbon Dioxide and Hydrogen Peroxide Without Added Metallic Catalysts or Peroxy Acids,” Ind. Eng. Chem. Res., 2002. 41, 316.

  13. West, K.; Hallett, J.; Jones, R.; Bush, D.; Liotta, C.; Eckert, C. "CO2-Induced Miscibility of Fluorous and Organic Solvents at Ambient Temperatures." Ind. Eng. Chem. Res., 2004. 43, 4827.

  14. Lu, J.; Lazzaroni, M.; Hallett, J.; Bommarius, A.; Liotta, C.; Eckert, C. “Tunable Solutions for Homogeneous Catalyst Recycle.” Ind. Eng. Chem. Res. 2004, 43, 1586.
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