In the Laboratory
Solvent-Free Synthesis of 2,20 -Dinitrobiphenyl: An Ullmann Coupling in the Introductory Organic Laboratory Richard W. Gregor and Laurel A. Goj* Department of Chemistry, Rollins College, Winter Park, Florida 32789, United States *
[email protected] One of the challenges of chemistry today is to synthesize desired compounds in the most economical manner with minimal environmental impact. The manufacture of pharmaceuticals, polymers, and other synthetic materials often relies on catalysts to provide these products in an efficient manner with respect to cost and waste production. It is therefore difficult today to imagine a chemical landscape without transition metal-catalysis. The research on transition metal complexes to facilitate organic transformations continues to grow as academia and industry search for more energy efficient processes (1). Organometallic chemistry has traditionally been a topic for advanced undergraduate courses as well as graduate work. However, in the past decade, undergraduate organic chemistry textbooks have begun to incorporate transition metal-catalyzed coupling reactions in the main body of the work (2-6). The most common examples include the Heck, Stille, and Suzuki couplings that utilize palladium catalysts. Although students are most familiar with the use of acetylide anions, Grignard reagents, and Diels-Alder reactions to form carbon-carbon bonds in the laboratory, the transition metal-based approaches are accessible. The development of transition-metal-based carbon-carbon bond-forming reactions that are appropriate for the introductory organic laboratory is hampered in part by the expense, air and moisture sensitivity, and lack of commercial availability of the desired catalysts. Current undergraduate laboratory experiments for transition metal-catalyzed carbon-carbon bond-forming reactions typically use palladium and primarily fall into two categories: introductory and upper-level. The latter include experiments recently reported between 2000 and 2010 (7-13). The former category, experiments designed specifically for a first-year organic laboratory, includes good experiments but with caveats. Lowary's experiment is well designed; however, a small group of honor students were the participants rather than a large mainstream laboratory section (14). An automated synthesizer for highthroughput reactions, an instrument not readily available to most departments, is necessary for Schubert's experiment (15). Long reaction times and the cost of palladium affect others (16, 17). An inert atmosphere is a requirement in several; however, ways to perform Brisbois's procedure in air have been reported (18-21). One of the classic coupling reactions discussed in more advanced texts, but not yet in traditional introductory organic texts, is the Ullmann reaction, which utilizes a copper catalyst. Copper offers the advantages of low cost, air stability, and biological friendliness. In addition, students may be familiar with the use of organocuprates as a carbon-carbon bond-forming reagent as
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Scheme 1. Copper-Catalyzed Synthesis of 2,20 -Dinitrobiphenyl
illustrated with the Gilman reagent found in many common organic textbooks. Experimental Overview The copper-catalyzed synthesis of 2,20 -dinitrobiphenyl was designed with several objectives in mind (22). Students perform reactions identical to those found in textbooks (i.e., electrophilic aromatic substitution), as well as others that are analogous to reactions in the textbook (i.e., use of copper rather than palladium for carbon-carbon bond formation) (Scheme 1). The class is introduced to what organic chemists typically do by designing a 2-week laboratory sequence in which the product of the first week is the substrate in the second week. Confirmation of product synthesis can be performed by melting point and 1H NMR methods, depending on time and facilities. As many green chemistry principles as feasible are incorporated with the recognition that it is not always possible to create a fully green process (19, 21, 23). All chemicals, including the copper catalyst, are commercially available and reasonably priced at less than $3 total per student. Electrophilic aromatic substitution, including the methodology of an arenediazonium ion, is a cornerstone of the second semester of organic chemistry. However, available laboratory experiments for the diazotization of an aromatic amine often use solutions of hydrochloric acid and sodium carbonate (24, 25). Furthermore, these experiments involve discrete formation of the complexed dye rather than the reactive diazonium intermediate. Recently, an article on the iodination of aryl amines captured our attention, as we believed one of the procedures could be successfully modified for a traditional introductory organic laboratory (26). In fact, several undergraduate laboratory experiments with solvent-free procedures utilizing a mortar and pestle have been reported for the Cannizzarro reaction, synthesis of chalcones, a Grignard reaction, synthesis of quinones or quinhydrones, oxidation of alcohols, and a Wittig reaction (27-34). In week one, the synthesis of 1-iodo-2-nitrobenzene is achieved
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r 2010 American Chemical Society and Division of Chemical Education, Inc. pubs.acs.org/jchemeduc Vol. 88 No. 3 March 2011 10.1021/ed900024u Published on Web 12/21/2010
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In the Laboratory
by subsequent additions and grindings of 2-nitroaniline, minimal water, para-toluenesulfonic acid monohydrate, sodium nitrite, and potassium iodide in a mortar and pestle. The crude product is washed on a filter frit with a sodium sulfite solution and purified with a small column constructed of silica in a 10 mL graduated pipet. The bright yellow 1-iodo-2-nitrobenzene was synthesized with a range of yields (10-45%), typically in the low 40% range, a melting point of 44-47 °C, and easily assigned 1 H NMR. Students with low yields either repeated the experiment, time permitting, or used the 1-iodo-2-nitrobenzene purchased for such an occasion. The formation of carbon-carbon bonds is an essential theme throughout organic chemistry. The Ullmann coupling reaction of 1-iodo-2-nitrobenzene has been achieved with several different copper reagents (35, 36). Given the constraints of time, solvent choice, and air sensitive reagents, many of the procedures were unsuitable. We began to explore different reaction conditions using copper powder to couple the 1-iodo-2-nitrobenzene. The procedure that proved most interesting and effective was a solvent-free heating of the reagents. In week two, a test tube was charged with 1-iodo-2-nitrobenzene, sand, and copper, and then heated in a sand bath (∼350 °C) for 20-30 s. The reaction mixture was directly added to a small column constructed of silica in a 10 mL graduated pipet. The 2,20 -dinitrobiphenyl and residual 1-iodo-2-nitrobenzene can be seen on the column as two colored bands for easy fraction collection with minimal solvent for elution. The pale tan 2,20 -dinitrobiphenyl was synthesized with yields typically in the mid 50% range (50-90% conversion), melting point of 110-116 °C, and easily assigned 1H NMR. As an alternative ending to the experiment (no column purification), a 1H NMR of the crude reaction mixture can be analyzed to illustrate the conversion of 1-iodo-2-nitrobenzene to 2,20 -dinitrobiphenyl and a percent conversion calculated. The data presented are based on our work with secondsemester organic classes from 2008-2010 with lab sizes that ranged from 7 to 20 students. The average time for students to complete each experiment is 2 h, including taking their own 1 H NMR and melting point. Sections with greater student enrollments inherently took longer because of waiting time for the NMR. Hazards Students wore safety glasses and gloves while performing the experiments under a fume hood. All compounds were handled in a manner consistent with general chemical safety principles and recommendations from the material safety data sheets (MSDS) provided by the manufacturer. Hexane, dichloromethane, and ethyl acetate are flammable and irritants. Dichloromethane is a probable carcinogen. p-Toluenesulfonic acid monohydrate and sodium hydroxide are corrosive and may cause burns. 2-Nitroaniline and sodium nitrite are listed as toxic if inhaled or swallowed. 2-Nitroaniline, sodium nitrite, potassium iodide, sodium sulfite, β-naphthol, hexane, 1-iodo-2-nitrobenzene, copper, dichloromethane, ethyl acetate, and silica are all irritants (skin, eye, and respiratory). Conclusion The synthesis of 2,20 -dinitrobiphenyl introduces students to two new techniques, solvent-free reactions by crushing and 332
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heating, while reinforcing essential skills such as chromatography and spectroscopy. The experiment lends itself to a discussion of what is green about the reactions (microscale method leading to reduced waste, use of catalyst) and where improvements can still be made (finding substitutes for halogenated reagents or solvents). The supporting information includes a student handout with a procedure that focuses on the synthesis and analysis of the purified 2,20 -dinitrobiphenyl. Italicized segments offer a complete analysis of the reaction including additional 1H NMR spectrum for percent conversion and mass conservation calculations. Given the direct correlation to classroom material, difference of reaction methodology, solvent-free conditions, generation of minimal quantities of waste, and the low cost per student, we believe the synthesis of 2,2-dinitrobiphenyl to be an interesting experiment for both the students and the instructors. Acknowledgment We acknowledge Erich C. Blossey for helpful discussions as well as the students of second semester organic chemistry (CHM 221). Literature Cited 1. van Leeuwen, P. W. N. M. Homogeneous Catalysis: Understanding the Art; Kluwer Academic Publishers: Norwell, MA, 2004. 2. Bruice, P. Y. Organic Chemistry, 6th ed.; Pearson Prentice Hall: Upper Saddle River, NJ, 2010. 3. Carey, F. A.; Giuliano, R. M. Organic Chemistry, 8th ed.; McGrawHill: New York, 2010. 4. McMurry, J. Organic Chemistry., 7th ed.; Thomson Brooks/Cole: Belmont, CA, 2008. 5. Smith, J. G. Organic Chemistry, 3rd ed.; McGraw Hill: New York, 2010. 6. Vollhardt, K. P. C.; Schore, N. E. Organic Chemistry: Structure and Function, 6th ed.; Freeman: New York, 2010. 7. Ball, D. B.; Wilson, R. J. Chem. Educ. 2002, 79 (1), 112–114. 8. Berry, D. E.; Carrie, P.; Fawkes, K. L.; Rebner, B.; Xing, Y. S. J. Chem. Educ. 2010, 87 (5), 533–534. 9. Cheung, L. L. W.; Aktoudianakis, E.; Chan, E.; Edward, A. R.; Jarosz, I.; Lee, V.; Mui, L.; Thatipamala, S. S.; Dicks, A. T. Chem. Educator 2007, 12, 77–79. 10. Gozzi, C.; Bouzidi, N. J. Chem. Educ. 2008, 85 (8), 1126–1128. 11. Harper, B. A.; Rainwater, J. C.; Birdwhistell, K.; Knight, D. A. J. Chem. Educ. 2002, 79 (6), 729–731. 12. Hermann, W. A.; Bohm, V. P. W.; Reisinger, C.-P. J. Chem. Educ. 2000, 77 (1), 92–95. 13. Aktoudianakis, E.; Chan, E.; Edward, A. R.; Jarosz, I.; Lee, V.; Mui, L.; Thatipamala, S. S.; Dicks, A. T. J. Chem. Educ. 2008, 85 (4), 555–557. 14. Callam, C. S.; Lowary, T. L. J. Chem. Educ. 2001, 78 (7), 947–948. 15. Hoogenboom, R.; Meier, M. A. R.; Schubert, U. S. J. Chem. Educ. 2005, 82 (11), 1693–1696. 16. Lauron, H.; Mallet, J.-M.; Mestdagh, H.; Ville, G. J. Chem. Educ. 1988, 65 (7), 632. 17. Martin, W. B.; Kateley, L. J. J. Chem. Educ. 2000, 77 (6), 757–759. 18. Brisbois, R. G.; Batterman, W. G.; Kragerud, S. R. J. Chem. Educ. 1997, 74 (7), 832–833. 19. Doxsee, K. M.; Hutchison, J. E., Green Organic Chemistry, 1st ed.; Brooks/Cole: Pacific Grove, CA, 2004.
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In the Laboratory 20. Goodwin, T. E.; Hurst, E. M.; Ross, A. S. J. Chem. Educ. 1999, 76 (1), 74–75. 21. Kirchhoff, M.; Ryan, M. A. Greener Approaches to Undergraduate Chemistry Experiments. American Chemical Society: Washington, DC, 2002. 22. Noted is that Schambach reported a laboratory experiment to synthesize 2,20 -dinitrobiphenyl but the focus is a guided inquiry of reactivity trends in the organocopper intermediates rather than the synthetic formation of carbon-carbon bonds. Schambach, R. A. J. Chem. Educ. 1976, 53 (11), 735–736. 23. Goodwin, T. E. J. Chem. Educ. 2004, 81 (8), 1187–1190. 24. Lehman, J. W. Multiscale Operational Organic Chemistry, 2nd ed.; Pearson Prentice Hall: Upper Saddle River, NJ, 2009. 25. Schoffstall, A. M.; Gaddis, B. A.; Druelinger, M. L., Microscale and Miniscale Organic Chemistry Laboratory Experiments, 2nd ed.; McGraw Hill: New York, 2004. 26. Gorlushko, D. A.; Filimonov, V. D.; Krasnokutskaya, E. A.; Semenischeva, N. I.; Go, B. S.; Hwang, H. Y.; Cha, E. H.; Chi, K.-W. Tetrahedron Lett. 2008, 49, 1080–1082. 27. Eckert, T. S. J. Chem. Educ. 1987, 64 (2), 179.
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28. Esteb, J. J.; Gligorich, K. M.; O'Reilly, S. A.; Richter, J. M. J. Chem. Educ. 2004, 81 (12), 794–1795. 29. Esteb, J. J.; Schelle, M. W.; Wilson, A. M. J. Chem. Educ. 2003, 80 (8), 907–908. 30. Leung, S. H.; Angel, S. A. J. Chem. Educ. 2004, 81 (10), 1492– 1493. 31. Mohrig, J. R.; Hammond, C. N.; Schatz, P. F.; Davidson, T. A. J. Chem. Educ. 2009, 86 (2), 234–239. 32. Morey, J.; Fronteri, A. J. Chem. Educ. 1995, 72 (1), 63. 33. Palleros, D. R. J. Chem. Educ. 2004, 81 (9), 1345–1347. 34. Phonchaiya, S.; Panijpan, B.; Rajviroongit, S.; Wright, T.; Blanchfield, J. T. J. Chem. Educ. 2009, 86 (1), 85–86. 35. Nelson, T. D.; Crouch, R. D. Organic Reactions; John Wiley & Sons, Inc.: Hoboken, NJ, 2004; Vol. 63, pp 265-555. 36. Rausch, M. D. J. Org. Chem. 1961, 26, 1802.
Supporting Information Available Instructor notes including spectra; student handout for the experiment. This material is available via the Internet at http:// pubs.acs.org.
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