In the Laboratory

edited by

Green Chemistry

Mary M. Kirchhoff
ACS Education Division Washington, DC 20036

Greening Up the Suzuki Reaction

Evangelos Aktoudianakis, Elton Chan, Amanda R. Edward, Isabel Jarosz, Vicki Lee, Leo Mui, Sonya S. Thatipamala, and Andrew P. Dicks* Department of Chemistry, University of Toronto, Toronto, Ontario, Canada, M5S 3H6; *adicks@chem.utoronto.ca

The Suzuki cross-coupling reaction dates from 1979 (1) and represents a mild and facile method of carboncarbon -bond formation. Typically, an aryl or vinyl halide is reacted with a boronic acid or boronic ester under basic conditions in the presence of catalytic Pd(0) (Scheme I). Pd(0) is often conveniently generated in situ from PdCl2 or Pd(OAc)2 (2). Callam and Lowary reported an undergraduate Suzuki reaction in this Journal utilizing palladium(II) acetate and triphenylphosphine in conjunction with sodium carbonate as base and aqueous isopropanol as solvent (3). Their approach facilitates the preparation of several biaryl compounds and requires an organic extraction as part of product isolation. We have designed a Suzuki cross-coupling reaction having a certain greenness to it, concerning preparation of a biaryl substance students recognize as a component of important pharmaceuticals. Our methodology employs water as the sole reaction solvent and inexpensive palladium on carbon as the active catalyst and features no purification other than recrystallization of the solid product (Scheme II). There is currently great interest in the implementation of aqueous organic reactivity into student laboratories (4, 5). Water is non-flammable, has no related toxicity issues and is the cheapest solvent for processes on an industrial scale (6, 7). The last decade has seen an explosion in literature documenting aqueous Suzuki reactions, leading to a dedicated review of the subject (8). Leadbeater exploited such chemistry in a commercial microwave reactor (9, 10) that has been introduced into the undergraduate curriculum (11). Similar results were obtained at

150 C by conventional oil bath heating in a sealed tube with a blast shield in place (10). Owing to the cost associated with purchasing a laboratorygrade microwave (12), our approach involves modification of reports using 10% Pd/C or Pd black as the catalyst and heating under reflux (13, 14). Crude 4-phenylphenol is recrystallized from aqueous methanol to afford pure product readily characterized by 1H and 13C NMR spectroscopy, IR spectroscopy, and mass spectrometry. This compound was additionally chosen to profile the industrial significance of biaryls as non-steroidal antiinflammatory drugs (NSAIDs, Figure 1). Diflunisal is marketed in the United States by Merck under the brand name Dolobid and is a structural derivative of 4-phenylphenol (15). Experimental Overview Phenylboronic acid (1.00 mmol), K2CO3 (3.00 mmol), and 4-iodophenol (1.00 mmol) are combined in a 50 mL roundbottomed flask, followed by addition of water (10 mL). Water (1 mL) is added to a vial containing pre-weighed 10% palladium on carbon (3 mg)1 to create a suspension. The suspension is added to the flask. The mixture is stirred and refluxed vigorously for 30 min. After this time the reaction mixture is allowed to cool to room temperature. The crude product (containing catalyst) is precipitated and collected after acidification with 2 M HCl. The solid is dissolved in methanol and Pd/C removed by filtration. Recrystallization from a 50:50 methanol:water mixture typically yields 5580% of 4-phenylphenol: mp 163164 C (lit 164165 C; ref 16).

Y R B Y R X

Pd(0), base organic solvent

Y = OH, OR

X = Cl, Br, I R , R = aryl, vinyl

COOH

Scheme I. A traditional Suzuki reaction.

felbinac

OH B OH I OH
10% Pd/C K2CO3, H2O

F F diflunisal

COOH OH

OH

Scheme II. Suzuki synthesis of 4-phenylphenol in water.

Figure 1. Representative biaryl non-steroidal anti-inflammatory drugs (15).

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In the Laboratory
I

O OH
PdCl2 Na2CO3, H2O

O OH

dational reaction (19). The microscale Suzuki cross-coupling of phenylboronic acid and 4-iodophenol is performed in purely aqueous media on heating under reflux for thirty minutes. This procedure exemplifies the contemporary approach of utilizing water as an alternative to common organic solvents. Students appreciate learning about an industrially significant process in the context of green chemistry principles. Acknowledgments We are grateful to the Department of Chemistry, University of Toronto for financial support via a Chemistry Lecturer Scholar Fund and to the Faculty of Arts and Science for development of the ROP 299Y Research Opportunity Program. We also thank Rose Balazs for technical assistance. Notes
1. 10% Palladium on carbon (3 mg) is pre-weighed by the laboratory technician and provided to each student separately in a vial. 2. Percentage atom economy for a reaction is designated by Trost (17a) as: [(M of desired product)/(M of reactants)] 100, where M is the molar mass. 3. This experiment has been incorporated into a third-year undergraduate laboratory and undertaken by over seventy students in two years. Smaller classes should permit individual preparation of both Suzuki and Heck products during a single four hour laboratory session.

O Scheme III. Heck synthesis of (E)-4-acetylcinnamic acid in water (18).

Hazards Potassium carbonate is irritating to the eyes, respiratory system, and skin. Phenylboronic acid and 4-iodophenol are also skin irritants and harmful if inhaled. 10% Palladium on carbon is harmful if swallowed. Methanol is highly flammable and toxic if swallowed. Hydrochloric acid causes burns and is irritating to the respiratory system. Appropriate gloves, safety goggles, and a laboratory coat should be worn at all times. Discussion Performing a Suzuki cross-coupling reaction in pure water, with no organic co-solvent present, facilitates consideration of green chemistry principles. Water is consequently used with methanol as the recrystallization solvent mixture. Reduction (or preferable elimination) of organic solvents from carboncarbon bond forming reactions is a current research focal point (7). Students additionally appreciate that CC -bond generation is possible under catalytic conditions. Recent literature describes the Pd/C in this reaction being recyclable up to five times with minimal loss of efficiency (13). A drawback of this process from a green perspective is usage of an aryl iodide reactant, rather than the corresponding bromide or chloride, as this leads to lowered atom economy2 (17). The class is therefore encouraged to think about advantages (short time, environmentally benign solvent, no phosphine ligand required, ease of work-up and purification) and primary disadvantage (reduced efficiency) of the reaction they have undertaken. We routinely run this experiment in tandem with an analogous aqueous Heck reaction involving catalysis by PdCl2 (18). Students work in pairs with one preparing 4-phenylphenol and the other synthesizing (E)-4-acetylcinnamic acid from 4-iodoacetophenone and acrylic acid3 (Scheme III). Accomplishment of both reactions per student pair within a single laboratory session permits a direct comparison between closely related synthetic approaches. Opportunities exist to consider operative reaction mechanisms, product purities, overall yields, and other aspects of two critically important reactions. Conclusion The experiment outlined herein underscores improvements that can be made in the environmental friendliness of a foun556

Literature Cited
1. Miyaura, N.; Suzuki, A. Chem. Commun. 1979, 866867. 2. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 24572483. 3. Callam, C. S.; Lowary, T. L. J. Chem. Educ. 2001, 78, 947 948. 4. (a) Gandhari, R.; Maddukuri, P. P.; Vinod, T. K. J. Chem. Educ. 2007, 84, 852854. (b) Crouch, R. D.; Richardson, A.; Howard, J. L.; Harker, R. L.; Barker, K. H. J. Chem. Educ. 2007, 84, 475476. (c) Sobral, A. J. F. N. J. Chem. Educ. 2006, 83, 16651666. (d) Wallace, J. R.; Lieberman, D. L.; Hancock, M. T.; Pinhas, A. R. J. Chem. Educ. 2005, 82, 12291230. (e) Cheung, L. L. W.; Lin, R. J.; McIntee, J. W.; Dicks, A. P. Chem. Educator 2005, 10, 300302. (f ) Fringuelli, F.; Piermatti, O.; Pizzo, F. J. Chem. Educ. 2004, 81, 874876. (g) Harper, B. A.; Rainwater, J. C.; Birdwhistell, K.; Knight, D. A. J. Chem. Educ. 2002, 79, 729731. 5. Greener Approaches To Undergraduate Chemistry Experiments; Kirchhoff, M., Ryan, M. A., Eds.; American Chemical Society: Washington, DC, 2002. 6. Li, C.-J.; Chan, T.-H. In Organic Reactions In Aqueous Media; Wiley: New York, 1997; p 23. 7. Li, C.-J. Chem. Rev. 2005, 105, 30953165. 8. Franzn, R.; Xu, Y. Can. J. Chem. 2005, 83, 266272. 9. Leadbeater, N. E. Chem. Commun. 2005, 28812902. 10. Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003, 68, 888 892. 11. Leadbeater, N. E.; McGowan, C. B. Clean, Fast Organic ChemistryMicrowave Assisted Laboratory Experiments. http://www. cem.com/support/labmanual.asp (accessed Jan 2008). 12. Crouch, R. D.; Howard, J. L.; Zile, J. L.; Barker, K, H. J. Chem. Educ. 2006, 83, 16581660.

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In the Laboratory 13. Sakurai, H.; Tsukuda, T.; Hirao, T. J. Org. Chem. 2002, 67, 27212722. 14. Kuznetsov, A. G.; Korolev, D. N.; Bumagin, N. A. Russ. Chem. Bull., Int. Ed. 2003, 52, 18821883. 15. (a) Hannah, J.; Ruyle, W. V.; Jones, H.; Matzuk, A. R.; Kelly, K. W.; Witzel, B. E.; Holtz, W. J.; Houser, R. A.; Shen, T. Y.; Sarett, L. H.; Lotti, V. J.; Risley, E. A.; Van Arman, C. G.; Winter, C. A. J. Med. Chem. 1978, 21, 10931100. (b) DeVasher, R. B.; Moore, L. R.; Shaughnessy, K. H. J. Org. Chem. 2004, 69, 79197927. 16. Lu, G.; Franzn, R.; Zhang, Q.; Xu, Y. Tet. Lett. 2005, 46, 42554259. 17. (a) Trost, B. M. Science 1991, 254, 14711477. (b) Cann, M. C.; Dickneider, T. A. J. Chem. Educ. 2004, 81, 977980. 18. Cheung, L. L. W.; Aktoudianakis, E.; Chan, E.; Edward, A. R.; Jarosz, I.; Lee, V.; Mui, L.; Thatipamala, S. S.; Dicks, A. P. Chem. Educator 2007, 12, 7779. 19. Novak, M.; Wang, Y.-T.; Ambrogio, M. W.; Chan, C. A.; Davis, H. E.; Goodwin, K. S.; Hadley, M. A.; Hall, C. M.; Herrick, A. M.; Ivanov, A. S.; Mueller, C. M.; Oh, J. J.; Soukup, R. J.; Sullivan, T. J.;Todd, A. M. Chem. Educator 2007, 12, 414418.

Supporting JCE Online Material

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http://www.jce.divched.org/Journal/Issues/2008/Apr/abs555.html Full text (PDF) with links to cited URLs and JCE articles Supplement Student handouts, instructor notes, including spectroscopic data JCE Featured Molecules for April 2008 (see p 592 for details) Structures of 9 molecules discussed in this article are available in fully manipulable Jmol format in the JCE Digital Library at http://www.JCE.DivCHED.org/JCEWWW/Features/ MonthlyMolecules/2008/Apr/. The molecules featured are: phenylboronic acid and 4-phenylphenol (from the Suzuki synthesis of 4-phenylphenol) diflunisal and felbinac (representative biaryl non-steroidal anti-inflammatory drugs) acrylic acid, 4-iodoacetophenone, and (E)-4-acetylcinnamic acid (from the Heck synthesis of (E)-4-acetylcinnamic acid) oximidine II (example of a Suzuki synthesis) boron trianion

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