Laboratory Experiment pubs.acs.org/jchemeduc
Green Oxidative Homocoupling of 1‑Methylimidazole C. Eric Ballard* Department of Chemistry, Biochemistry, and Physics, The University of Tampa, Tampa, Florida 33606, United States S Supporting Information *
ABSTRACT: Relatively few experiments for the introductory organic chemistry laboratory demonstrate the utility of metal-catalyzed reactions in organic chemistry. A copper-catalyzed aerobic oxidative dimerization of 1-methylimidazole is described that introduces this topic. The reaction uses a low-cost substrate, a low-cost precatalyst that is stable to air and moisture, and a readily prepared base. The experiment can be performed using equipment found in a typical organic teaching lab. The crude product can be analyzed by 1H NMR spectroscopy. The experiment allows for a general discussion of redox processes of organic substrates and green chemistry.
KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives, Inquiry-Based/Discovery Learning, Catalysis, Green Chemistry, NMR Spectroscopy, Organometallics
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mixtures, understand how pH can affect the liquid−liquid extraction, and apply this experiment as a model for predicting the product of other oxidative dimerization reactions. It also illustrates how catalysts can be used in green chemical processes.
etal-catalyzed reactions have been central to synthetic organic chemistry for the last several decades.1 Although these processes include a broad variety of transformations, relatively little space is dedicated to this topic in most introductory organic textbooks besides that given to hydrogenation reactions.2 Even carbon−carbon bond-forming reactions receive little attention,3,4 although the 2010 Nobel Prize for Chemistry was awarded for groundbreaking research in “palladium-catalyzed cross couplings in organic synthesis”.5 Because transition-metal-catalyzed reactions pervade contemporary organic chemistry, they should be discussed in the introductory organic chemistry curriculum. The teaching laboratory offers an opportunity to cover this subject matter. Indeed, a few pedagogical experiments relate to this topic;6−8 however, most of these examples focus on palladium- or ruthenium-catalyzed reactions. Precious metals, such as palladium and ruthenium, catalyze many commonly applied reactions. The base metal copper can also catalyze several carbon−carbon bond formations.4 One example of these methods that can be adapted to the teaching lab is the aerobic oxidative homocoupling of relatively acidic arenes and heteroarenes.9 The product of the homocoupling presented here, 1,1'dimethyl-2,2'-biimidazole, is important for a number of reasons. Derivatives of this compound show antiprotozoal and cytotoxic activities.10 The structure is also a ligand of some catalysts11 and a component of some sensors.12 This distinguishes the biimidazole from compounds that are prepared during many pedagogical experiments.13 The experiment described here has several objectives. It emphasizes the redox process occurring in the reaction and introduces aryl−aryl bond formation as a reaction possible due to a metal catalyst. Postlab exercises require students to interpret the NMR spectrum of the crude product, understand how liquid−liquid extractions can aid in purifying reaction © XXXX American Chemical Society and Division of Chemical Education, Inc.
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EXPERIMENTAL OVERVIEW Daugulis’s procedure9 for oxidative homocoupling was adapted with modifications so that it could be conducted in one 4-h lab period (Scheme 1). In an oven-dried flask, 1-methylimidazole, Scheme 1. Copper-Catalyzed Oxidative Homocoupling of 1Methylimidazole (Cy = Cyclohexyl)
magnesium chloride dicyclohexylamide-lithium chloride and copper(II) chloride are stirred at room temperature under dry air for 15 min to form 1,1′-dimethyl-2,2′-biimidazole. The crude product is obtained after an aqueous quench, a series of extractions, and solvent evaporation. Students prepare samples of their crude products so that the instructor can collect 1H NMR spectra for them to analyze. The required Knochel−Hauser base,14 magnesium chloride dicyclohexylamide-lithium chloride complex, is easily prepared by the instructor in advance of the lab period.15 A magnesium amide is required instead of a lithium amide to avoid formation of phenolic side products.9 This magnesium amide is sufficiently reactive to quickly deprotonate the 1-methylimidazole substrate, but it forms a less polar carbon−metal bond than lithium does. Because the carbon−magnesium bond is less
A
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Figure 1. 1H NMR spectra of (A) 1-methylimidazole and (B) the crude biimidazole product.
The catalytic cycle of the reaction (Scheme 2) was also discussed in the Student Handout.9,15,17 The substrate (pKa in
polarized than a carbon−lithium bond, it reacts more slowly with oxygen to form a phenol. It should be noted that the base can be prepared in 125 mL batches, and it is stable when stored in the refrigerator (∼4 °C) for over two months. This experiment has been performed by about 230 students during four terms of the introductory organic lab required of all the university’s chemistry, biochemistry, forensic science, and B.S. biology students. Students worked in pairs with one student doing the experiment using copper(II) chloride and the other student performing the control experiment with no copper(II) chloride; the pairs of experiments confirmed that the copper catalyzed the homocoupling. Given the range of students present in these sections and the number of traditional topics presented in the lecture text, this area of metal-mediated chemistry was introduced in the lab, but not in the lecture.
Scheme 2. Proposed Mechanism of the Oxidative Homocoupling ([Cu] Is a Catalytically Active Copper Fragment, Including Any Ligands)
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HAZARDS 1-Methylimidazole, magnesium chloride dicyclohexylamidelithium chloride complex, and 1,1′-dimethyl-2,2′-biimidazole are corrosive. Drierite (calcium sulfate) is hygroscopic. Copper(II) chloride is harmful and hazardous to the environment. Tetrahydrofuran (THF) is highly flammable and an irritant. Ether is extremely flammable and harmful. Ammonium chloride and chloroform-d are harmful. Gloves are worn while manipulating the reagents for this experiment. The experiments should be performed in a fume hood. Wastes should be disposed appropriately.
THF = 33.7)18 is deprotonated by the magnesium amide to form a Grignard reagent. The metal catalyst, copper(II) chloride, reacts with the Grignard reagent to form an organocopper intermediate. In the presence of oxygen, this intermediate reacts to form a homocoupling product containing a new carbon−carbon bond and regenerate the metal catalyst. The catalytic cycle was covered during the prelab briefing for the experiment. Very few details are known about the mechanism.17 Examination of the reaction also allowed for a discussion of reductions and oxidations involving organic substrates. Students may recognize that a net loss of C−H bonds occurs during the reaction. Otherwise, they may apply the rules they learned in general chemistry for assigning oxidation states: the oxidation state of C-2 increases from +2 to +3. The stoichiometric oxidant in this reaction is molecular oxygen. Based on examination of literature precedent,19 the oxygen probably is reduced to water. This involves a change in oxidation state from 0 to −2. Most students recognized both redox processes. The breadth of topics relating to this experiment challenged students’ analytical thinking skills. The emphasis on critical thinking largely offset a limitation of the reaction.
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DISCUSSION Analysis of the crude product was easily performed by 1H NMR spectroscopy. In a 300 MHz spectrum, each aromatic resonance of the substrate, 1-methylimidazole, appeared as a pseudosinglet, as seen in a spectrum collected by the instructor (Figure 1A). Students were referred to the Spectral Database of Organic Compounds16 for the assignment of the spectrum to the structure. With some guidance, students recognized that the biimidazole did not contain a proton bonded to C-2 and that this was manifested by the absence of the corresponding resonance (δ 7.4 ppm) in the representative student spectrum of the product (Figure 1B). Some students also recognized the significant amount of dicyclohexylamine that was present in the crude product; it was present in about a 1:1 molar ratio with the desired biimidazole. B
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that both molecules would partition into the aqueous layer if hydrochloric acid were used for the workup. One interpretation of the lack of success in answering this question would be that students did not appreciate the physical significance of a compound’s pKa.
The mean yield of biimidazole that was obtained by students was 48%, with a range of 0−98% Nevertheless, most (>90%) students obtained enough product to analyze it by NMR. There are a few reasons why the students’ yields for this experiment were significantly lower than those reported in the original publications.9 Perhaps the most important reason lay in the nature of the substrate, 1-methylimidazole. This commercially available substrate was not reported in the original papers, but an analogous substrate, 1-butylimidazole, was described. 1Butylimidazole (and the resulting dimer) are expected to be less hydrophilic than 1-methylimidazole and the related dimer;20 this could affect the recovery during the liquid−liquid extraction of the workup procedure. In addition, the experiments in the research publication were conducted under different conditions than those reported here. The original reactions were run under an atmosphere of pure oxygen rather than air. The purifications conducted in the original publications were also more rigorous, so they led to higher yields. Finally, all of the experiments in the original articles utilized bases that gave higher yields than the one used in this experiment. The limitation of the other Knochel−Hauser bases is that they are significantly more expensive or more difficult to handle or store. All of these parameters were changed to make the experiment more feasible in the introductory organic chemistry lab. The typical instructional organic chemistry lab has fewer resources than a research lab in a graduate program, and, ideally, experiments should be completed in a 3- or 4-h time block. Because this reaction used a catalyst, this experiment also provides a venue for discussing green chemistry and sustainability.21 Some previous versions of this transformation used stoichoiometric quantities of copper- or nickel-containing compounds,22 so the use of a catalytic amount of copper is an improvement in the greenness and elegance of the reaction. A growing number of lab experiments incorporate green chemistry.6−8,23 An introduction to green chemistry was given in the student handout for the experiment.
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SUMMARY An experiment was developed from a literature procedure9 to introduce catalytic organometallic chemistry in the undergraduate curriculum. The reaction was straightforward to perform in most teaching labs. Analysis of the product by 1H NMR was straightforward. It illustrated that organic chemistry involves more than the chemistry of carbon. Topics of discussion included redox processes of organic substrates and green chemistry.
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ASSOCIATED CONTENT
S Supporting Information *
A student handout, consisting of a prelab worksheet, an introduction to the experiment, full experimental details, and postlab questions, and notes for instructors. This material is available via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The author thanks his colleagues, students, and lab mentors who piloted and have performed this experiment; the University of Tampa for support in the form of Dana Foundation, David Delo Research Professor, and Alumni Association Grants; Olafs Daugulis (University of Houston) for helpful discussions; and Ken Doxsee and Jim Hutchison (University of Oregon) for his participation in a Green Chemistry in Education Workshop. He also thanks the reviewers for their suggestions on the manuscript.
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ASSESSMENT OF LEARNING OUTCOMES The goals of the experiment were to increase skill in interpreting 1H NMR spectra (particularly in predicting changes to a substrate’s spectrum upon conversion to product), introducing a model for preparing biaryl compounds, emphasizing the redox aspect of the reaction, understanding how pH can affect the liquid−liquid extraction of some compounds, and illustrating some principles of green chemistry. Skill in interpreting NMR spectra was assessed in the notebook submissions for the experiment. The other goals were assessed by postlab questions and questions on a final exam. A majority of students achieved the goals except for appreciating the impact of pH on liquid−liquid extraction. About three-fourths of students interpreted the 1H NMR spectrum of the crude product sufficiently to determine if the expected product had been formed and analyzed the redox nature of the reaction. Over 90% of students predicted the products of reactions of analogous substrates. Less than 50% of the students understood the effect of pH on the partitioning of the product and byproduct during the liquid−liquid extraction. Students were asked to predict what would happen if they used saturated ammonium chloride (pH ≈ 8) and 1 M hydrochloric acid (pH ≈ 0) to separate the biimidazole product (pKa of the conjugate acid ≈7) and dicyclohexylamine (pKa of the conjugate acid ≈10).15 Less than 20% of students indicated
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REFERENCES
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Liquids. Org. Lett. 2003, 5, 3209−3212. (b) Park, S. B.; Alper, H. Recyclable Sonogashira Coupling Reactions in an Organic Liquid, Effected in the Absence of Both a Copper Salt and a Phosphine. Chem. Commun. 2004, 1306−1307. (12) (a) Forrow, N. J.; Karinka, S. A. PCT Int. Appl., WO 2009129108 A1 20091022, 2009. (b) Ouyang, T.; Liu, Z.; Latour, J.; Chen, T.; Tran, L. M.; Feldman, B.; Mao, F.; Heller, J. U. S. Pat. Appl. Publ. 2009, US 20090095642 A1 20090416. (13) Selected examples of experiments for the organic chemistry lab that involve the synthesis of compounds with practical biological or material properties: (a) Stabile, R. G.; Dicks, A. P. Semi-Microscale Williamson Ether Synthesis and Simultaneous Isolation of an Expectorant from Cough Tablets. J. Chem. Educ. 2003, 80, 313−315. (b) Stabile, R. G.; Dicks, A. P. Microscale Synthesis and Spectroscopic Analysis of Flutamide, an Antiandrogen Prostate Cancer Drug. J. Chem. Educ. 2003, 80, 1439−1443. (c) Stabile, R. G.; Dicks, A. P. Two-Step Semi-Microscale Preparation of a Cinnamate Ester Sunscreen Analog. J. Chem. Educ. 2004, 81, 1488−1491. (d) Aktoudianakis, E.; Dicks, A. P. Convenient Microscale Synthesis of a Coumarin Laser Dye Analog. J. Chem. Educ. 2006, 83, 287−289. (e) Aktoudianakis, E.; Lin, R. J.; Dicks, A. P. Keeping Your Students Awake: Facile Microscale Synthesis of Modafinil, a Modern AntiNarcoleptic Drug. J. Chem. Educ. 2006, 83, 1832−1834. (f) Cheung, L. L. W.; Styler, S. A.; Dicks, A. P. Rapid and Convenient Synthesis of the 1,4-Dihydropyridine Privileged Structure. J. Chem. Educ. 2010, 87, 628−630. (g) Koruluk, K. J.; Jackson, D. A.; Dicks, A. P. The Petasis Reaction: Microscale Synthesis of a Tertiary Amine Antifungal Analog. J. Chem. Educ. 2012, 89, 796−798. (14) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Mixed Mg/Li Amides of the Type R2NMgCl·LiCl as Highly Efficient Bases for the Regioselective Generation of Functionalized Aryl and Heteroaryl Magnesium Compounds. Angew. Chem., Int. Ed. 2006, 45, 2958−2961. (15) See Supporting Information for details. (16) Spectral Database of Organic Compounds. http://riodb01.ibase. aist.go.jp/sdbs/cgi-bin/cre_index.cgi?lang=eng (accessed May 2013). (17) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Copper-Catalyzed Aerobic Oxidative C-H Functionalizations: Trends and Mechanistic Insights. Angew. Chem., Int. Ed. 2011, 50, 11062−11087. (18) Fraser, R. R.; Mansour, T. S.; Savard, S. Acidity Measurements in THF. V. Heteroaromatic Compounds Containing 5-Membered Rings. Can. J. Chem. 1985, 63, 3505−3509. (19) Fujieda, N.; Ikeda, T.; Murata, M.; Yanagisawa, S.; Aono, S.; Ohkubo, K.; Nagao, S.; Ogura, T.; Hirota, S.; Fukuzumi, S.; Nakamura, Y.; Hata, Y.; Itoh, S. Post-Translational His-Cys Cross-Linkage Formation in Tyrosinase Induced by Copper(II)-Peroxo Species. J. Am. Chem. Soc. 2011, 133, 1180−1183. (20) Per calculations performed on Advanced Chemistry Development software (version 11.02), the solubility of 1-methylimidazole is about nine times as great as 1-butylimidazole at pH 7 and pH 8. Those pH values correspond to those present in the liquid−liquid extraction. (21) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 1998; p 30. (22) 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. (23) Selected examples of green inquiry-oriented pedagogical experiments: (a) Goodwin, T. E. An Asymptotic Approach to the Development of a Green Organic Chemistry Laboratory. J. Chem. Educ. 2004, 81, 1187−1190. (b) Ballard, C. E. pH-Controlled Oxidation of an Aromtic Ketone: Structural Elucidation of the Products of Two Green Chemical Reactions. J. Chem. Educ. 2010, 87, 190−193. (d) Cunningham, A. D.; Ham, E. Y.; Vosburg, D. A. Chemoselective Reactions of Citral: Green Syntheses of Natural Perfumes for the Undergraduate Organic Laboratory. J. Chem. Educ. 2011, 88, 322−324. (e) Ballard, C. E. Green Reductive Homocoupling of Bromobenzene. J. Chem. Educ. 2011, 88, 1148−1151.
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