LABORATORY EXPERIMENT pubs.acs.org/jchemeduc
Green Reductive Homocoupling of Bromobenzene C. Eric Ballard* Department of Chemistry, Biochemistry, and Physics, University of Tampa, Tampa, Florida 33606-1490, United States
bS Supporting Information ABSTRACT: Although transition-metal-catalyzed reactions are important in contemporary organic chemistry, relatively few resources for the second-year organic chemistry curriculum discuss the subject. The inquiry-based experiment described here, an ironcatalyzed preparation of biphenyl from bromobenzene, introduces this topic. The reaction uses an inexpensive and relatively benign iron precatalyst that is air- and moisture-stable, and the experiment can be performed using the equipment found in a typical organic teaching laboratory. The crude product can be analyzed by melting point determination or by gas chromatography. The experiment allows for a general discussion of redox cycles common in many metal-catalyzed reactions, redox processes of organic substrates, and green chemistry. The experiment can be used in organic or inorganic laboratories. KEYWORDS: Second-Year Undergraduate, Inorganic Chemistry, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives, Inquiry-Based/Discovery Learning, Catalysis, Green Chemistry, Mass Spectrometry, Organometallics
’ EXPERIMENT Xu, Cheng, and Pei’s procedure9 was adapted with only slight modification for the teaching laboratory (Scheme 1). Their procedure was on the microscale, but it was readily increased to miniscale. In an oven-dried flask, magnesium turnings, iron(III) acetylacetonate [Fe(acac)3], THF, and bromobenzene are stirred at room temperature under dry air for 30 min to form biphenyl. The color of the reaction mixture changes from red to brown or black after an induction period. The crude product is obtained after an acidic quench, a series of extractions and a wash, and solvent evaporation. The product is a pale yellow or reddish brown solid. The crude product is analyzed by melting point determination and gas chromatography mass spectrometry (GC MS). Students can assess whether bromobenzene, biphenyl, or other compounds (e.g., benzene) are present in their crude products. If impurities are present, they can describe how pure the product is based on these techniques. Typical yields of the crude biphenyl are 60 65%. Per GC analysis, most students’ products are quite pure. This experiment is ideal for introducing metal-catalyzed reactions because the iron precatalyst is relatively benign and inexpensive and is air and moisture stable. The less costly iron(III) chloride is also a competent catalyst for this reaction. Although it is less expensive than Fe(acac)3, it is also hygroscopic. Because the reaction is somewhat sensitive to moisture, Fe(acac)3 was chosen as the precatalyst because it is not hygroscopic. The experiment can also include a discovery component10 if a control experiment is conducted. This makes the experiment ideal for laboratory partners; each student in the pair can run
T
ransition-metal-mediated reactions have become a cornerstone of organic chemistry during recent decades.1 These processes include a wide variety of transformations, such as reductions, oxidations, C H activations, and carbon heteroatom bond formations. Although metal-catalyzed reactions are a growing and significant area of chemistry, little space is dedicated to this topic in most second-year organic textbooks besides that given to hydrogenation reactions.2 Particularly important are carbon carbon bond-forming reactions.3,4 Seminal research “for palladium-catalyzed cross couplings in organic synthesis” by Heck, Negishi, and Suzuki was recognized with the 2010 Nobel Prize for chemistry.5 Given the value of this chemistry, it merits coverage in the second-year organic chemistry curriculum. However, because the organic chemistry curriculum is already filled with many worthy topics, it is difficult to add this material to the classroom portion of the course without removing other material. The associated teaching laboratory offers an opportunity to discuss complementary subject matter. A few pedagogical experiments are available to introduce the topic;6 8 most of these focus on palladium- or ruthenium-catalyzed reactions. Although palladium-catalyzed cross coupling and rutheniumcatalyzed metathesis are powerful synthetic tools, they are not the entirety of metal-mediated reactions. In recent years, carbon carbon bond formations that are catalyzed by iron compounds have received much attention.4 These recently discovered reactions often exhibit yields and selectivities that are comparable to or complementary to those of palladium- and nickel-catalyzed coupling reactions. One example of a synthetic method that can be adapted to the teaching laboratory is the iron-catalyzed homocoupling of alkyl and aryl halides reported by Xu, Cheng, and Pei.9 Copyright r 2011 American Chemical Society and Division of Chemical Education, Inc.
Published: May 17, 2011 1148
dx.doi.org/10.1021/ed100945h | J. Chem. Educ. 2011, 88, 1148–1151
Journal of Chemical Education Scheme 1. Iron-Catalyzed Reductive Homocoupling of Bromobenzene
Scheme 2. Possible Catalytic Cycle for the Homocoupling (adapted from ref 9. Copyright 2006 American Chemical Society)
either the control experiment or the experiment containing iron. A comparison of the data from the two experiments serves as a textbook illustration of how the scientific method works. Typically, the crude product of the control experiment is a colorless oil whose mass is e10% of the theoretical yield of biphenyl. Because one of the main components in the worked-up reaction mixture is volatile (benzene), it is important that a GC sample be collected before the solvent is evaporated from the mixture to give the crude product.
’ HAZARDS Wear gloves while manipulating the reagents for this experiment. Bromobenzene is flammable, an irritant, and dangerous for the environment. Magnesium is a flammable solid. Fe(acac)3 is harmful. THF is highly flammable and an irritant. Hydrochloric acid is corrosive. Ether is harmful and extremely flammable. Biphenyl is an irritant and dangerous for the environment. Dispose of wastes in the appropriate waste containers. ’ DISCUSSION This reaction provides an opportunity to discuss a general redox cycle that is part of many metal-catalyzed reactions.1,3,4 Although the mechanisms of iron-catalyzed couplings have not been investigated as extensively as those of their nickel- and palladium-catalyzed counterparts,1,3 in recent years some reasonable hypotheses with experimental support have been put forward to describe these transformations.4,11 A possible catalytic cycle is shown in Scheme 2.4,9,11 Some of the bromobenzene is assumed to react with magnesium to form phenylmagnesium
LABORATORY EXPERIMENT
bromide. Either this Grignard reagent or the magnesium turnings reduce the Fe(acac)3 precatalyst to a low-valent form of iron, [Fe(MgBr)2]. Note that the oxidation state of iron is 2 in this proposed intermediate. This intermediate undergoes a formal σ-bond metathesis with bromobenzene to give an organoiron intermediate, in which iron has an oxidation state of 0. This σ-bond metathesis corresponds to the oxidative addition step observed in many nickel- and palladium-catalyzed reactions; this step is also analogous to the hydroboration of olefins.12 Upon addition of an equivalent of phenylmagnesium bromide, a diorganoiron intermediate forms; the iron still has an oxidation state of 0. It undergoes reductive elimination to generate the biphenyl product and reform the active catalyst. This mechanism is consistent with the observation that a catalyst for this homocoupling can also catalyze the cross coupling of bromobenzene and phenylmagnesium bromide to form biphenyl.9 Examination of the reaction equation also allows for a discussion of reductions and oxidations involving organic substrates. If students are told that magnesium bromide is an inorganic product of the reaction, most of them see that magnesium is oxidized during the reaction. However, students less quickly recognize that the carbon atom that is bonded to bromine in the substrate is reduced during the reaction. When asked to assign specific oxidation states to that carbon atom, some students initially balk at the question. If they are shown how the rules for assigning oxidation states apply to organic carbon, they soon understand that the reaction is a reduction of the starting material. This experiment has been performed during one term of the second-year organic laboratory required of chemistry, biochemistry, forensic science, and BS biology students. Given the range of students present in these sections and the number of traditional topics present in the lecture text, the area of metal-mediated chemistry was introduced in the laboratory but not in the lecture. The conceptual focus was placed on emphasizing the net redox process according to a balanced equation for the reaction and introducing aryl aryl bond formation as a reaction possible only with involvement of a metal. The metal redox cycle was covered during the prelaboratory briefing for the experiment. If the class had consisted only of chemistry majors more emphasis would have been given to the catalytic cycle. Assessment of student learning consisted of a prelaboratory quiz, postlaboratory questions, and a problem on the laboratory final exam related to this experiment, and the focus was placed on understanding redox changes during such reactions and predicting the products of analogous reactions. Almost all students understood the redox change occurring at magnesium (oxidation), and 58% understood the change occurring at the carbon at the reactive site (reduction) and at the bromine (no redox change). About 73% of students were able to predict correctly, including the regiochemistry, the products of the analogous homocouplings of 3-bromoanisole, 3-bromotoluene, and 2-bromonaphthalene.
’ GREEN CHEMISTRY Because this reaction uses a relatively benign iron catalyst, this experiment also provides a venue for discussing green chemistry and sustainability.13 Because previous versions of this transformation used catalytic or even stoichoiometric quantities of copper- or nickel-containing compounds,14,15 the reaction described here is significantly greener because iron compounds are more benign. A growing number of laboratory experiments 1149
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Journal of Chemical Education incorporate green chemistry.6 8,16 An introduction to green chemistry was given in the student handout for the experiment (see the Supporting Information). One aspect of the reaction that students can analyze is how it could be made greener.16a
’ SUMMARY An experiment has been developed from a literature procedure9 to introduce catalytic organometallic chemistry in the undergraduate curriculum. The reaction is straightforward to perform in most teaching laboratories. It illustrates that organic chemistry involves more than the chemistry of carbon, and it can be performed in undergraduate organic or inorganic laboratories. Topics of discussion include a proposed catalytic cycle for the transformation, redox processes of organic substrates, and green chemistry. ’ ASSOCIATED CONTENT
bS
Supporting Information A student handout, consisting of a prelaboratory worksheet, an introduction to the experiment, full experimental details, postlaboratory questions, and notes for instructors, including typical GC-FID chromatograms and GC MS chromatograms and spectra of the substrate and crude product. This material is available via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected].
’ ACKNOWLEDGMENT The author thanks the students and laboratory mentors who piloted this experiment, the University of Tampa for support in the form of Dana, Delo, and Alumni Grants, Professor Michelle Leslie for helpful discussions and suggestions, Professors Ken Doxsee and Jim Hutchison for his participation in a Green Chemistry in Education Workshop at the University of Oregon, and the three anonymous reviewers for their helpful comments and suggestions. ’ REFERENCES (1) Crabtree, R. H. The Organometallic Chemistry of the Transition Metals, 4th ed.; Wiley: Hoboken, NJ, 2005 and references therein. (2) Portions of some sophomore organic chemistry textbooks that discuss metal-catalyzed reactions: (a) Brown, W. H.; Foote, C. S.; Iverson, B. L.; Anslyn, E. V. Organic Chemistry, 5th ed.; Brooks/Cole: Belmont, CA, 2009; pp 433 435, 932 942, 957 963, 1111 1113. (b) Bruice, P. Y. Organic Chemistry, 6th ed.; Prentice Hall: Boston, MA, 2011; pp 456 464, 899, 1191 1192. (c) Carey, F. A.; Giuliano, R. M. Organic Chemistry, 8th ed.; McGraw Hill: New York, 2011; pp 625 636, 642 645, 657 658, 698 699. (d) Hornback, J. M. Organic Chemistry, 2nd ed.; Thomson Brooks/Cole: Belmont, CA, 2006; pp 449 450, 1062 1064. (e) Jones, M., Jr.; Fleming, S. A. Organic Chemistry, 4th ed.; Norton: New York, 2010; p 426. (f) Loudon, M. Organic Chemistry, 5th ed.; Roberts: Greenwood Village, CO, 2009; pp 831 858, 872 874. (g) McMurry, J. Organic Chemistry, 7th ed.; Thomson Brooks/Cole: Belmont, CA, 2008; pp 734 735, 1209 1210. (h) Smith, J. G. Organic Chemistry, 2nd ed.; McGraw Hill: Boston, MA, 2008; pp 451 454, 1003 1011, 1016 1025, 1085 1086, 1154 1155. (i) Solomons, T . W. G.; Fryhle, C. B. Organic Chemistry, 10th ed.; Wiley: Hoboken, NJ, 2011; pp 210, 365, 529 530, G1-G18. (j) Vollhardt, K. P. C.; Schore,
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N. E. Organic Chemistry: Structure and Function, 6th ed.; Freeman: New York, 2011; pp 197 198, 310 311, 536 537. (k) Wade, L. G., Jr. Organic Chemistry, 7th ed.; Prentice Hall: Upper Saddle River, NJ, 2010; pp 351 352, 369 372, 1230. (3) Recent review of homocoupling reactions: Stefani, H. A.; Guarezemini, A. R.; Cella, R. Tetrahedron 2010, 66, 7871–7918. (4) Review of iron-catalyzed cross-coupling reactions: Sherry, B. D.; F€urstner, A. Acc. Chem. Res. 2008, 41, 1500–1511. (5) The Nobel Prize in Chemistry 2010. http://nobelprize.org/ nobel_prizes/chemistry/laureates/2010/ (accessed May 2011). (6) Examples of pedagogical experiments that focus on palladiumcatalyzed cross coupling: (a) Lauron, H.; Mallet, J.-M.; Mestdagh, H.; Ville, G. J. Chem. Educ. 1988, 65, 632. (b) Brisbois, R. G.; Batterman, W. G.; Kragerud, S. R. J. Chem. Educ. 1997, 74, 832. (c) Goodwin, T. E.; Hurst, E. M.; Ross, A. S. J. Chem. Educ. 1999, 76, 74–75. (d) Herrmann, W. A.; Bohn, V. P. W.; Reisinger, C.-P. J. Chem. Educ. 2000, 77, 92–94. (e) Martin, W. B.; Kately, L. J. J. Chem. Educ. 2000, 77, 757–759. (f) Callam, C. S.; Lowary, T. L. J. Chem. Educ. 2001, 78, 947–948. (g) Harper, B. A.; Rainwater, J. C.; Birdwhistell, K.; Knight, D. A. J. Chem. Educ. 2002, 79, 729–731.(h) Gilbertson, R.; Doxsee, K. M.; Succaw, G.; Huffman, L. M.; Hutchison, J. E. In Greener Approaches to Undergraduate Chemistry Experiments; Kirchhoff, M., Ryan, M., Eds.; American Chemical Society: Washington D.C., 2002; pp 4 7. (i) Berry, D. E.; Fawkes, K. L.; Leighton, J. A. Chem. Educator 2003, 8, 192–194. (j) Doxsee, K. M.; Hutchison, J. E. Green Organic Chemistry: Strategies, Tools, and Laboratory Experiments; Thomson/Brooks-Cole: Belmont, CA, 2004; pp 189 196. (k) Hoogenboom, R.; Meier, M. A. R.; Schubert, U. S. J. Chem. Educ. 2005, 82, 1693–1696. (l) 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, 77–79. (m) 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, 414–418. (n) Aktoudianakis, E.; Chan, E.; Edward, A. R.; Jarosz, I.; Lee, V.; Mui, L.; Thatipamala, S. S.; Dicks, A. P. J. Chem. Educ. 2008, 85, 555–557. (o) Gozzi, C.; Bouzidi, N. J. Chem. Educ. 2008, 85, 1126–1128. (p) Pantess, D. A.; Rich, C. V. Chem. Educator 2009, 14, 258–260. (7) Examples of pedagogical experiments that focus on olefin metathesis: (a) Bennett, D. W. J. Chem. Educ. 1980, 57, 672–673. (b) Viswanathan, T.; Jethmalani, J. J. Chem. Educ. 1993, 70, 165–167. (c) France, M. B.; Uffelman, E. S. J. Chem. Educ. 1999, 76, 661–665. (d) Taber, D. F.; Frankowski, K. J. J. Chem. Educ. 2006, 83, 283–284. (e) Greco, G. E. J. Chem. Educ. 2007, 84, 1995–1997. (f) Pappenfus, T. M.; Hermanson, D. L.; Ekerholm, D. P.; Lilliquist, S. L.; Mekoli, M. L. J. Chem. Educ. 2007, 84, 1998–2000. (g) Moorhead, E. J.; Wenzel, A. G. J. Chem. Educ. 2009, 86, 973–975. (8) Examples of other pedagogical metal-catalyzed reactions: (a) Zilkha, A.; Calderon, N.; Rabani, J.; Frankel, M. J. Chem. Educ. 1958, 35, 344–345. (b) Wilen, S. H.; Kremer, C. B. J. Chem. Educ. 1962, 39, 209–210. (c) Kaye, I. A. J. Chem. Educ. 1972, 49, 131–132. (d) Kranbuehl, D. E.; Harris, T. V.; Howe, A. K.; Thompson, D. W. J. Chem. Educ. 1975, 52, 261–264. (e) Mangravite, J. A. J. Chem. Educ. 1983, 60, 439. (f) Byers, J. H.; Ashfaq, A.; Morse, W. R. J. Chem. Educ. 1990, 67, 340–341. (g) Birdwhistell, K. R.; Lanza, J. J. Chem. Educ. 1997, 74, 579–581. (h) Berry, D. E.; Fawkes, K. L.; Leighton, J. A. Chem. Educator 2003, 8, 192–194.(i) Doxsee, K. M.; Hutchison, J. E. Green Organic Chemistry: Strategies, Tools, and Laboratory Experiments; Thomson/ Brooks-Cole: Belmont, CA, 2004; pp 142 151. (j) Seery, M. K.; Clarke, L.; Pillai, S. C. Chem. Educator 2006, 11, 184–186. (k) Moura, F. C. C.; Pinto, F. G.; dos Santos, E. N.; do Amaral, L. O. F.; Lago, R. M. J. Chem. Educ. 2006, 83, 417–420. (l) Mattson, B.; Hulce, M.; Cheng, w.; Greimann, J.; Hoette, T.; Menzel, P. J. Chem. Educ. 2006, 83, 421–424. (m) Peeters, C. M.; Deliever, R.; De Vos, D. J. Chem. Educ. 2009, 86, 87–90. (n) Young, M. A. J. Chem. Educ. 2009, 86, 1082–1084. (o) Miecznikowski, J. R.; Caradonna, J. P.; Foley, K. M.; Kwiecien, D. J.; Lisi, G. P.; Martinez, A. M. J. Chem. Ed. 2011, 88, 657–661. (9) Xu, X.; Cheng, D.; Pei, W. J. Org. Chem. 2006, 71, 6637–6639. 1150
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(10) Examples of research- and discovery-oriented experiments: (a) Ruttledge, T. R. J. Chem. Educ. 1998, 75, 1575–1577. (b) Davis, D. S.; Hargrove, R. J.; Hugdahl, J. D. J. Chem. Educ. 1999, 76, 1127–1130. (c) Clarke, N. R.; Casey, J. P.; Brown, E. D.; Oneyma, E.; Donaghy, K. J. J. Chem. Educ. 2006, 83, 257–259. (d) Gaddis, B. A.; Schoffstall, A. M. J. Chem. Educ. 2007, 84, 848–851. (e) Mascarenhas, C. M. J. Chem. Educ. 2008, 85, 1271–1273. (f) Lazarski, K. E.; Rich, A. A.; Mascarenhas, C. M. J. Chem. Educ. 2008, 85, 1531–1534. (11) (a) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487–1489. (b) Smith, R. S.; Kochi, J. K. J. Org. Chem. 1976, 41, 502–509. (c) Aleandri, L. E.; Bogdanovic, B.; Bons, P.; D€urr, C.; Gaidies, A.; Hartwig, T.; Huckett, S. C.; Lagarden, M.; Wilczok, U.; Brand, R. A. Chem. Mater. 1995, 7, 1153–1170. (d) Bogdanovic, B.; Schwickardi, M. Angew. Chem., Int. Ed. 2000, 39, 4610–4612. (e) F€urstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856–13863. (f) F€urstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41, 609–612. (12) The author thanks an anonymous reviewer for this suggestion. (13) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 1998; p 30. (14) Lead reference for the Ullman reaction and closely related processes: Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanism and Structure, 6th ed.; Wiley: Hoboken, NJ, 2007; pp 897 899. (15) Example of a homocoupling of bromobenzene to form biphenyl that is mediated by stoichiometric lithium under ultrasonic conditions: Lash, T. D.; Berry, D. J. Chem. Educ. 1985, 62, 85. (16) Additional selected examples of green inquiry-oriented pedagogical experiments: (a) Goodwin, T. E. J. Chem. Educ. 2004, 81 1187–1190. (b) Ballard, C. E. J. Chem. Educ. 2010, 87, 190–193. (c) Wong, T. C.; Sultana, C. M.; Vosburg, D. A. J. Chem. Educ. 2010, 87, 194–195. (d) Nishimura, R. T.; Giammanco, C. H.; Vosburg, D. A. J. Chem. Educ. 2010, 87, 526–527.
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