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 carbon–carbon σ-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 55–80% of 4-phenylphenol: mp 163–164 °C (lit 164–165 °C; ref 16).

Y R B Y R X

Pd(0), base organic solvent

Y = OH, OR

R

R

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).

© Division of Chemical Education  •  www.JCE.DivCHED.org  •  Vol. 85 No. 4 April 2008  •  Journal of Chemical Education

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W. Commun. as this leads to lowered atom economy2 (17).. Pinhas. (b) Crouch. Acknowledgments We are grateful to the Department of Chemistry. Vinod. A drawback of this process from a green perspective is usage of an aryl iodide reactant. A. Crouch. J. 10. Pizzo. M. P. N. A. F. L. W. C. 2007. 2003. H.. R. O Scheme III. D. We routinely run this experiment in tandem with an analogous aqueous Heck reaction involving catalysis by PdCl2 (18). A. respiratory system. 79. A. D. McGowan. Howard. rather than the corresponding bromide or chloride. (f ) Fringuelli.. http://www. N. J. Li. with no organic co-solvent present. Chem. N. K. O. L. Birdwhistell. Callam. Lowary. K. T. Rev. 3. R. p 2–3. 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. D. A. J. J. 1229–1230. 2005. safety goggles. Chem. Discussion Performing a Suzuki cross-coupling reaction in pure water. Appropriate gloves. 2. T. Chem. L.. Knight. Richardson. Chem.-H. Chem.. Educ. Educ. Educ. D.. cem. Zile. 95. Eds. overall yields. E. 10% Palladium on carbon (3 mg) is pre-weighed by the laboratory technician and provided to each student separately in a vial.. 300–302. This experiment has been incorporated into a third-year undergraduate laboratory and undertaken by over seventy students in two years.. 105. Phenylboronic acid and 4-iodophenol are also skin irritants and harmful if inhaled. 2881–2902. Recent literature describes the Pd/C in this reaction being recyclable up to five times with minimal loss of efficiency (13). and other aspects of two critically important reactions. 81. J. Suzuki. Educ. J. 1979. M. 6. 866–867.In the Laboratory I O OH PdCl2 Na2CO3.. Chan. Org. Dicks. Students appreciate learning about an industrially significant process in the context of green chemistry principles.. 2001. 68. where M is the molar mass. M. facilitates consideration of green chemistry principles. K. Methanol is highly flammable and toxic if swallowed. R. Hancock.. We also thank Rose Balazs for technical assistance. Suzuki. T. Miyaura. J. Barker.. C. Commun. and skin. Miyaura. no phosphine ligand required... 2006. 475–476. 2. Xu. L. T. Chem. 2006. 852–854. 1997. 7. P. 8.-J. A. R. (d) Wallace. F. 2002. J. N. 874–876. B.. Maddukuri. A. 2004. Chem. 84.asp (accessed Jan 2008). Water is consequently used with methanol as the recrystallization solvent mixture. Chem. (g) Harper. Heck synthesis of (E)-4-acetylcinnamic acid in water (18). J. The microscale Suzuki cross-coupling of phenylboronic acid and 4-iodophenol is performed in purely aqueous media on heating under reflux for thirty minutes. M. 2002. Journal of Chemical Education  •  Vol. product purities. Students additionally appreciate that C−C σ-bond generation is possible under catalytic conditions.. J. Chem. Kirchhoff. Leadbeater. J. L. 78. F. 10% Palladium on carbon is harmful if swallowed. 1658–1660. E. 84. J. Li.. Percentage atom economy for a reaction is designated by Trost (17a) as: [(M of desired product)/∑(M of reactants)] × 100. Rev. A. Smaller classes should permit individual preparation of both Suzuki and Heck products during a single four hour laboratory session. R. L. Wiley: New York. Educ. (a) Gandhari. C. J. ease of work-up and purification) and primary disadvantage (reduced efficiency) of the reaction they have undertaken. Ryan. J. Chem. E. Greener Approaches To Undergraduate Chemistry Experiments. Chem. Hazards Potassium carbonate is irritating to the eyes. Educ. 947– 948. Leadbeater..-J.. 83. 266–272. L.. 12. 4 April 2008  •  www. Harker. N. Educ. C. 3095–3165. 2005. In Organic Reactions In Aqueous Media. R. S. The class is therefore encouraged to think about advantages (short time. Conclusion The experiment outlined herein underscores improvements that can be made in the environmental friendliness of a foun556 Literature Cited 1. 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). American Chemical Society: Washington.. Clean. DC. B. Howard. Reduction (or preferable elimination) of organic solvents from carbon–carbon bond forming reactions is a current research focal point (7). environmentally benign solvent. Fast Organic Chemistry–Microwave Assisted Laboratory Experiments. 1995. L. 2005.. P. Accomplishment of both reactions per student pair within a single laboratory session permits a direct comparison between closely related synthetic approaches.. J.. R. (e) Cheung. 2457–2483. Chem. Rainwater. McIntee. Barker. R. 83. 5. Piermatti. Leadbeater. Hydrochloric acid causes burns and is irritating to the respiratory system. Notes 1. 11.. Chem. 85 No. Educ.. 729–731. 2007.. Y. (c) Sobral. This procedure exemplifies the contemporary approach of utilizing water as an alternative to common organic solvents.. N. Lin. Franzén.DivCHED... J. 1665–1666. 4. 9.com/support/labmanual. H2O O O OH dational reaction (19).JCE. J. and a laboratory coat should be worn at all times. 888– 892. A.org  •  © Division of Chemical Education . 3. 2005. 10. Marco. C. Opportunities exist to consider operative reaction mechanisms. Lieberman. 83. J. Can. K. H. Educator 2005. 82. Chem. Chem.

C. (b) DeVasher. E. A.. L. E. Soukup. Mueller.. K.. W. 46. Jones.html You will find that some molecules are simple. 1093–1100.JCE. 12. Aktoudianakis.. A. Dicks.DivCHED. 4255–4259.. M. T. S.. A. 414–418. 77–79. 1882–1883.JCE. Tsukuda. and (E)-4-acetylcinnamic acid (from the Heck synthesis of (E)-4-acetylcinnamic acid) oximidine II (example of a Suzuki synthesis) boron trianion Would you like to have a collection of molecules to use in teaching? Wouldn’t it be great if they were like dynamic clip art? Check out our collection of JCE Featured Molecules—they are fully manipulable. Xu. L. J.. Org. The collection grows each month as molecules that are related to an article or articles are added... Chem.. H. 67. H. A. R. Cheung. R. Holtz. A. 85 No. Chem. 17. Ed. J. P. 4 April 2008  •  Journal of Chemical Education 557 . Lett. Chem. M. Y. R... R.Todd. 1471–1477. Shaughnessy. Hirao. Davis. L. S.org/Journal/Issues/2008/Apr/abs555.. G. Educ. Sarett. B. Houser. 81.. A. Zhang.divched. 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. J. C. E... Witzel. Q. 14. Chem. using Jmol. Bull.org/JCEWWW/Features/ MonthlyMolecules/2008/Apr/. 69.. J. T. K. C. G. S. M. M.. Risley. H. Ambrogio.org/JCEWWW/Features/MonthlyMolecules/index. Van Arman. Franzén. Kelly. 1978. Med. T. (a) Hannah.. 12. 2004. E. Herrick. T. J.. A. Y. M. J. 2002. J... Jarosz.. 977–980. Edward.. Hadley. C.. Chem. S. 2005. E. M.org  •  Vol. Matzuk.. Korolev.In the Laboratory 13. A.-T. I... Science 1991.. Lu. Tet. M. V. Winter. B. (a) Trost. A... Hall.. Educator 2007. 15. J. K. Educator 2007.. Mui. Sakurai. Ruyle. N..jce. 254. N.. Russ. yet each is hyperlinked to one or more JCE articles that provide interesting information about the molecule. L. Dickneider. J. Ivanov. H.. 2721–2722. 52. Bumagin. Kuznetsov.. Goodwin. Supporting JCE Online Material Abstract and keywords http://www. L.. Oh. 16. instructor notes. J. Moore. M. V. G. Int. V. Lotti...html Full text (PDF) with links to cited URLs and JCE articles Supplement Student handouts. 2003. W.. A.. A.DivCHED. R. © Division of Chemical Education  •  www. Chem. R. Y. 4-iodoacetophenone. 21. Lee.. some are complex. H. Chan.divched.. J. 2004. 18. R. Wang. W. M. C. 19. B. (b) Cann. Sullivan. W. Thatipamala.. 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. W. Just go to http://www. C. A. 7919–7927. Shen. A. Chan. D. T.. Novak. A. Chem.jce. Org.

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