In the Laboratory
Microwave-Mediated Synthesis of Lophine: Developing a Mechanism To Explain a Product
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R. David Crouch,* Jessica L. Howard, Jennifer L. Zile, and Kathryn H. Barker Department of Chemistry, Dickinson College, Carlisle, PA 17013; *
[email protected] Organic reactions leading to the synthesis of nitrogen heterocycles afford students the opportunity to apply reactions learned in the classroom to new examples in the laboratory. Several experiments have been described in which a mechanism can be developed from the reaction of aldehydes and ketones with nitrogen nucleophiles, such as the synthesis of 2,5-dimethyl-1-phenylpyrrole (1). Experiments of this sort mimic the research experience in that students are not simply performing an illustration of a reaction from the textbook. Instead, they perform a reaction, use spectral data to confirm the product’s structure, and develop possible mechanisms based on reactions learned in the classroom. We wish to describe an experiment in which students perform the microscale synthesis of lophine or 2,4,5-triphenylimidazole via a microwave-mediated reaction and use molecular modeling results to arrive at a mechanism for the synthesis of lophine. A synthesis of lophine has been described by Pickering as a prelude to its use in a kinetics experiment (2). Pickering’s protocol, based on Davidson’s modification (3) of the original synthesis by Radziszewski (4), requires gram quantities of reagent, large quantities of solvent, and reaction times of greater than 1 hour. Recently, however, a microwave-mediated synthesis of imidazoles was described (5). We have adapted this method to our second-year organic laboratories using a Milestone START Microwave Lab Station, allowing 16 students in the lab to simultaneously perform the reaction in less than 20 minutes. The advantages of microwave-assisted organic synthesis have been reviewed elsewhere (6, 7). In short, they include shorter reaction times, the possibility of performing reactions at temperatures above the boiling point of the reaction solvent, and, on some occasions, elevated reaction yields. A number of recent publications indicate that rate acceleration by microwave irradiation is simply due to more efficient heating of the reaction mixture (8). But, some evidence suggests that an unknown microwave effect may occur when solutions of high ionic concentration are irradiated (9). Although commercially available microwave ovens that were designed for kitchen use were initially used (10–14), single-mode microwave reactors that allow temperature control through pulsed irradiation are much safer to use. The Milestone system further reduces the likelihood of the failure of a reaction vessel through the use of pressure tubes fitted with caps that release pressure above 1.5 bars (1.5 × 105 Pa).
likelihood of the vessel rupturing. This allows the reaction to be performed at slightly above the temperature of refluxing glacial acetic acid without the danger of the reaction boiling to dryness. The crude crystalline product forms upon addition of concentrated ammonia upon workup and recrystallization (Scheme I). The reaction is operationally simple to conduct. Equal molar quantities of benzaldehyde and benzil (0.50 mmol of each, 51 µL and 105 mg, respectively) were dissolved in 5 mL of glacial acetic acid and 385 mg (5.0 mmol) of ammonia was added. When the mixture was homogenous, the pressure tube was capped and irradiated to raise the temperature from room temperature to 120 ⬚C over 10 minutes and then to 125 ⬚C over 5 more minutes. After cooling in an ice bath, 6 mL of concentrated ammonia was added to precipitate the product, which was collected and recrystallized from ethanol兾water. Student yields ranged from 2% to 90% with an average recovery of 38%. The crude product was moist and tended to form clumps. The slow rate of dissolution in hot ethanol caused some students to use more than the minimum quantity of solvent, reducing the yield of recrystallized product. Although we employed a single-mode microwave oven designed for chemical synthesis, the expense of these instruments may limit their availability. So, we also developed a version of this experiment for use in a conventional microwave intended for kitchen use. Since sealed glassware in kitchen microwave ovens creates a significant explosion hazard, we performed the reaction in a 50 or 100 mL-beaker that was topped with a watch glass that held a piece of dry ice. The gap near the beaker’s pouring spout allowed for release of gases that might create pressure and the dry ice cooled vapors to limit their escape. By reducing the power of the microwave oven to 30% and heating for 10 minutes, we were able to achieve comparable yields of the identical product. It is important to note that different models of microwave ovens have different heating characteristics and the conditions we developed may require some adjustment in other models. Hazards The experiment presents no significant hazards as described. Routine laboratory procedures such as the use of goggles and gloves should be followed. Specific reagent haz-
Experiment The reaction involves the heating of benzaldehyde, benzil, and ammonium acetate in glacial acetic acid under microwave irradiation in a 1.5 bar pressure tube (Scheme I). A pressure-release cap vents vapors from the tube in the event that the internal pressure rises above 1.5 bar, reducing the 1658
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Scheme I. Reaction under microwave irradiation in a 1.5 bar pressure tube to produce lophine.
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In the Laboratory
ards include the use of concentrated ammonia and glacial acetic acid, which are corrosive, and benzil, benzaldehyde, and ammonium acetate, which are irritants. However, owing to the lack of temperature and pressure regulation in kitchen microwave ovens, it is critical that sealed glassware not be used. The possibility of superheating of aqueous solvents in a kitchen microwave oven also requires that care be taken to ensure that the beaker has cooled to near room temperature before removing it from the oven. (The START system uses an automated cool-down period to ensure that the reaction mixture has cooled to room temperature.) And, since kitchen microwave ovens are not designed to handle volatile compounds, flammable solvents should not be placed near or in the oven. Results The 13C NMR spectrum of the recrystallized product shows signals in the aromatic region (between 125–150 ppm) with no evidence of carbonyl carbons. This leads students to conclude that the carbonyl carbons of benzil and benzaldehyde have been transformed into carbons of an aromatic ring. The 1H NMR spectrum provides confirmation that the product contains only aromatic hydrogens. After students drew this conclusion, the structure of the product was provided. Although some were able to arrive at a structure, most students required this help. With a structure in hand, a mechanism for this reaction can be developed using the chemistry of imines. Although most students were able to arrive at a basic mechanism on their own, a series of questions can be posed that will help lead students to a mechanism (Scheme II). Ammonium acetate兾acetic acid act as a source of NH3 and students recognize that a reaction with benzaldehyde to form an imine is likely. The imine can then react with a ketone of benzil. Another equivalent of NH3 must then react. But which of the two electrophilic carbons will be attacked? Molecular modeling using Spartan leads students to the completion of the mechanism. Computational analysis of the
neutral intermediate 1 indicates that the carbonyl carbon is more susceptible to nucleophilic attack than the imine’s carbon. But under the reaction conditions, it is likely that either the imine’s nitrogen or the carbonyl’s oxygen will be protonated. Computational results indicate that the carbonyl’s oxygen bears a slightly more negative charge. Thus, it is likely that the actual intermediate encountered by the nucleophilic NH3 is structure 2, which forms a second imine followed by cyclization. Deprotonation leads to the formation of the final product, lophine. This experiment is relatively brief. Reaction setup to isolation of pure product is about one hour. We have students simultaneously perform the synthesis of 2,5-dimethyl-1phenylpyrrole (1) using conventional heating in a sand bath. After setting up the conventional reaction, the microwavemediated synthesis of lophine can be completed before the first reaction is complete. Another option is to have students perform the conventional synthesis of lophine (2) along with microwave-assisted organic synthesis to gain a full appreciation of the advantages of this new technique. Both experiments can be easily completed in a normal lab period. Summary The experiment provides students with the opportunity to experience microwave-assisted organic synthesis, an emerging technology in synthetic chemistry, while developing a new mechanism using previously-learned reactions. By examining the nature of the reactants and with the aid of information provided by molecular modeling, they can arrive at a reasonable mechanism to explain its formation. Acknowledgments The support of the Arnold and Mabel Beckman Foundation through the Beckman Scholars Program is gratefully acknowledged. We also thank Dickinson College for funds toward the purchase of the Milestone START Microwave Lab Station.
Scheme II. Mechanism to form lophine.
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Supplemental Material
Instructions for the students, notes for the instructor, and 1H and 13C NMR spectra are available in this issue of JCE Online. Literature Cited 1. Al–awar, R.; Wahl, G. H., Jr. J. Chem. Educ. 1990, 67, 285. 2. Pickering, M. J. Chem. Educ. 1980, 57, 833. 3. Davidson, D.; Weiss, M.; Jelling, M. J. Org. Chem. 1937, 2, 319. 4. Radziszewski, B. Chem. Berichte 1882, 15, 1493. 5. Wolkenburg, S. E.; Wisnoski, D. D.; Leister, W. H.; Wang, Y.; Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6, 1453. 6. Caddick, S. Tetrahedron 1995, 51, 10403.
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7. Loupy, A.; Petit, A.; Hamelin, J.; Texier–Boullet, F.; Jacquault, P.; Mathe, D. Synthesis 2002, 1213. 8. Kuhnert, N. Angew. Chem., Int. Ed. Eng. 2002, 41, 1863. 9. Empfield, J. R.; Throner, S. R.; Pivonka, D. E. In Division of Organic Chemistry Abstracts, 228th National Meeting of the American Chemical Society, Philadelphia, PA, August 22–26, 2004; ORGN–043. 10. Bari, S. S.; Bose, A. K.; Chaudhary, M. S.; Manhas, M. S.; Raju, V. S.; Robb, E. W. J. Chem. Educ. 1992, 69, 938–939. 11. Elder, J. W. J. Chem. Educ. 1994, 71, A142–A144. 12. Elder, J. W.; Holtz, K. M. J. Chem. Educ. 1996, 73, A104– A105. 13. Mirafzal, G. A.; Summer, J. M. J. Chem. Educ. 2000, 77, 356– 357. 14. Shaw, R.; Severin, A.; Balfour, M.; Nettles, C. J. Chem. Educ. 2005, 82, 625–629.
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