In the Laboratory
Microwave-Enhanced Organic Syntheses for the Undergraduate Laboratory: Diels-Alder Cycloaddition, Wittig Reaction, and Williamson Ether Synthesis Marsha R. Baar,* Danielle Falcone, and Christopher Gordon Department of Chemistry, Muhlenberg College, Allentown, Pennsylvania 18104 *
[email protected] Although microwave enhancement of chemical reactions and applications such as sample digestion have been known for more than half a century, the first extensions of microwave enhancement to organic reactions were reported by Gedye et al. (1) and Giguere et al. (2) in 1986. Diels-Alder cycloadditions, Claisen rearrangements (2), amide hydrolyses, esterifications, and ether formations (1) were among the reactions studied. To take advantage of the greater quantity of energy delivered by microwave heating, the reactions were performed in sealed vessels and at temperatures exceeding the boiling points of the solvents.1 These higher temperatures led to increased pressures that could have resulted in vessel rupture. Since Gedye and Giguere's seminal work, there have been many additional articles describing microwave acceleration to a wide variety of organic reactions. Researchers have attempted to adapt the chemistry to the safety limitations of domestic microwave ovens by avoiding volatile solvents. Reactions were performed with pulverized solid reagents, reagents absorbed on solid supports, or high-boiling polar solvents in open vessels. Several microwave experiments suitable for the organic chemistry laboratory have been published (3a-3f), but they were performed in domestic microwave ovens, usually one sample at a time, with one of the above-mentioned accommodations. Ingenuous as their adaptations were, the explosion hazard and the lack of reproducibility owing to the inability to monitor reaction conditions were restrictive. Industry has responded to these concerns with laboratorygrade microwave ovens built with temperature and pressure feedback controls, other safety features, and multiple-sample carousels. In these laboratory-grade ovens, conditions can be monitored for reproducibility, safety, and translation to other ovens. The ability to run 14-24 reaction vessels simultaneously makes these ovens appropriate heat sources for the organic chemistry laboratory. Safety concerns as well as the need to modify standard experiments are minimized. Volatile and flammable materials can be used without fear of explosion or need to change purification methods. Although these laboratory-grade microwave ovens (∼$20,000) are more expensive than their domestic counterparts, the benefits outweigh the instrument's initial cost. We purchased a CEM Corp. MARS 5 microwave oven that has reinforced steel construction, a special door-locking mechanism in the event of vessel rupture, fiber-optic thermocouple temperature monitoring, and an automatic maximum temperature shutoff and can be operated at three different power settings. One must select the size, type (glass or Teflon), and number of 84
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reaction vessels, which determines the type of rotating carousel. We performed our three reactions on the same scale with two different-size glass reaction vessels and carousel assemblies. One carousel holds fourteen 100 mL glass reaction vessels, while another holds sixteen 20 mL vessels. The reaction conditions and results were transferable between the different-size reaction vessels and carousels by the following power-setting guide: 400 W for 0-25% occupied carousel; 800 W for 25-50% occupied carousel; and 1600 W for 50-100% occupied carousel. The cost of the laboratory-grade microwave oven includes the glass reaction vessels, caps, Kevlar sleeves, carousel, stir bars, fiberoptic temperature probe, glass thermowell, and wrenches. The glass vessels are thick-walled test tubes that are easily cleaned for reuse. There are minimum and maximum volumes for each size reaction vessel. For the 20 mL vessel, 5-15 mL of solvent is appropriate. The 100 ml reaction vessel's range is 10-60 mL. Also there is a minimal quantity of solvent required within the microwave oven during a run; 10 mL for a high-absorbing solvent and 50 mL for a poor-absorbing solvent. The thermowell and fiber-optic temperature probe are interchangeable between sets. We budget ∼$1,000/ year for replacement of glass reaction vessels (∼$61), fiber-optic temperature probe (∼$260), and thermowell (∼$205). CEM Corp. has recently published a laboratory textbook that describes their systems and 11 microwave-accelerated experiments for both multimode and single-mode microwave ovens (4). Traditional Experiments A Diels-Alder cycloaddition, a Williamson ether synthesis, and Wittig reaction (Scheme 1) are routinely performed in our organic chemistry laboratory curriculum.2 The latter two reactions have steps that proceed through SN2 mechanisms requiring long reflux times and giving low yields. Microwave heating was explored to shorten the “cook time” in these reactions and perhaps improve yields permitting a scale down of reagents. The time saved would allow for additional chemistry or more in-depth analyses of results. We recently reported a Diels-Alder cycloaddition of 1,3-cyclohexadiene and N-phenylmaleimide in ethyl acetate (5). Yields greater than 90% were obtained with 2.5 h of reflux or one week at ambient temperature. As our organic laboratory periods last 3 h, we shortened the reflux to 1.5 h, which afforded decent yields of 77-83% or approximately 1.00 g of product. The formation of the cycloadduct and its isolation were accomplished in one period, but the analyses were performed the next week (mass, mp, 1H NMR, and 13C NMR).
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Vol. 87 No. 1 January 2010 pubs.acs.org/jchemeduc r 2009 American Chemical Society and Division of Chemical Education, Inc. 10.1021/ed800001x Published on Web 12/18/2009
In the Laboratory
Scheme 1. Summary of the Three Microwave-Enhanced Reactions
agents. During all operations gloves should be worn and volatile reagents measured in the hood. All purifications should be performed in the hood as well. Results and Discussion
The Wittig reaction and Williamson ether synthesis employed were adapted from laboratory textbooks (6, 7). The Wittig reaction is a three-step synthesis, the first of which forms the Wittig salt, benzyltriphenylphosphonium chloride, from triphenylphosphine and benzyl chloride. Refluxing for 1.5 h in high-boiling xylenes (bp 140 °C) gave low yields (∼30%). This poor yield of the Wittig salt translated through to a small recovery of the final alkene. The basic conversion of the salt into the ylide and its subsequent reaction with (E)-cinnamaldehyde followed by purification and analysis of the resultant alkene were performed in a second period. The perfume-fixative nerolin, or 2-ethoxynaphthalene, was the synthetic goal in the Williamson ether reaction. Deprotonation of 2-naphthol by methanolic KOH occurred rapidly at ambient temperature. The resultant naphthoxide's attack on ethyl iodide required a minimum of 1.5 h of reflux and, following recrystallization, gave low yields (∼20%) for the ether. As nerolin is a lowmelting solid, large quantities of unreacted starting materials complicated the recrystallization. The length of the reflux again forced the purification and analyses to be performed in a second week. Hazards Acetonitrile, 1,3-cyclohexadiene, ethanol, ligroin, methanol, and xylenes are flammable. (E)-Cinnamaldehyde, iodoethane, N-phenylmaleimide, triphenylphosphine, and 2-naphthol are irritants. Benzyl chloride is a lachrymator, highly toxic, and a cancer-suspect agent. Ethanolic sodium ethoxide and methanolic potassium hydroxide solutions are corrosive. The spectral solvents CHCl3 and CDCl3 are toxic and cancer-suspect
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The three reactions (Scheme 1) have been tested by multiple sections of students and showed significant microwave enhancement when performed in a microwave oven set at 1600 W with a fully loaded sample carousel (Table 1). The Diels-Alder reaction was originally performed in ethyl acetate, but on scale-up to 14-16 samples, 9 min was required to obtain the hold temperature of 130 °C. A switch in solvent to absolute ethanol, an excellent absorber of microwave energy, shortened the ramp time to 1 min.3 Ten minutes of microwave heating produced student yields that ranged from 1.03 to 1.33 g (70.0-93.0%), most falling above 1.20 g (82%) out of a theoretical quantity of 1.46 g. The range in the yields reflected the number of rinses needed to remove color from the precipitated white crystals.4 Student melting points matched literature values of 204-206 °C (5). With the time savings in the “cook time”, the entire Diels-Alder experiment, including isolation, drying, melting point determination, and NMR analyses, was completed within one laboratory period instead of one and a half.5 The Wittig salt formation was originally performed in xylenes, but this poor microwave-absorbing solvent required 15 min to heat to 200 °C with a fully loaded carousel at maximum power. Despite the low absorption of microwave energy, the yields improved from 30-40% to 50-60%.6 Switching the solvent to acetonitrile, a moderate-absorber of microwave energy, shortened the heating time to 6.5 min and improved yields to over 90%. Student recoveries ranged from 2.45 to 3.07 g (75-94%) out of a possible 3.26 g with most students obtaining over 3.00 g (91%). However, the change in solvent required a modification of the purification; xylenes were added during the cooling phase to precipitate a higher yield of product. The benzyltriphenylphosphonium chloride was determined to be pure by 1H NMR and 13C NMR spectral analyses. With the time saved in preparing the salt, the experiment was completed in one and a half periods instead of two. The remaining time was used for a discussion of 31P effect on the 1H NMR and 13C NMR spectra of the Wittig salt and a calculation of the alkenyl and aromatic proton chemical shifts in 1,4-diphenyl-1,3-butadiene. The Williamson ether synthesis was performed in methanol, an excellent microwave absorber, which afforded a quick 40 s ramp to 130 °C. Following recrystallization, the yields ranged from 0.52-1.42 g (20-55%) out of a possible 2.56 g with most recoveries over 1.22 g (47%) of purified nerolin. This was an improvement over reflux yields ranging from 6-29%. The range in yields for both heating methods is due to varying student recrystallization abilities. Crude yields from the microwave heating ranged from 0.68-2.58 g with most over 1.41 g (55%). The higher yield allowed for scale down of reagents and an easier recrystallization. Student melting point ranges were narrow, 33.7-34.4 °C, and within error of literature values, 37-38 °C (8). The entire ether experiment, including recrystallization and analysis, was completed in one period instead of one and a half.7 The additional time was used to teach literature searching on SciFinder Scholar and more advanced PC Spartan molecular modeling. NMR and IR spectra for all starting materials and the products from the Williamson ether
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In the Laboratory Table 1. Comparison of Yields and Reaction Times for Microwave Heating versus Traditional Reflux Reaction Diels-Alder cycloaddition
Reflux for 1.5 h
Microwave for 10 min
77-83% EtOAc (bp 77 °C)
Microwave ramp Timea/Temperature
72-88% EtOAc
9 min to 130 °C
84-92% abs EtOH
40 s to 130 °C 15 min to 200 °C
Wittig salt formation
30-40% xylenes (bp 140 °C)
18-56% xylenes 75-94% AcCN (most >91%)
6.5 min to 200 °C
Williamson ether synthesis
6-29% (most >15%) MeOH (bp 64 °C)
20-55% MeOH (most >47%)
40 s to 130 °C
a
The ramp time is the period of time required to heat to desired cook temperature.
and Wittig reactions, including the Wittig salt, are available at the National Institute of Advanced Industrial Science and Technology Web page (9). Summary The incorporation of a laboratory-grade microwave oven into the organic chemistry laboratory permitted the safe rate enhancement of three reactions with higher yields and no major redesign of reaction conditions. In the case of the Wittig and Diels-Alder reactions, we switched solvents to shorten ramp times with no significant effect on the subsequent purification. The time savings permitted more discussion and in-depth spectral analyses, training in online literature searching and computer-generated molecular modeling. There are additional benefits associated with microwave heating. It is green technology, utilizing less electricity and no condenser water. Reactions involving microwave enhancement also expose students to a technique with rapidly growing industrial significance. Perhaps the most important contributions from microwave heating for the organic chemistry sequence have yet to be realized. Applications to asymmetric synthesis have barely been investigated. Accessing reactions that have prohibitively long reflux times is a definite possibility. Our research group is currently investigating a number of experiments along these lines. Acknowledgment Christopher Gordon's summer research was supported by donations from Muhlenberg College alumni. Thanks are given to two departmental colleagues, Christine Ingersoll and Joseph Keane, for their careful reading of this manuscript. Notes 1. An explanation of microwave versus thermal heating can be found in Chapter 1 of references 4 and 10. 2. All chemicals were purchased from Aldrich Chemical Co. and were used without further purification. 3. A useful guide to selecting excellent microwave absorbing solvents can be found in reference 10. 4. The faint yellow color from unreacted N-phenylmaleimide rinses off easily with chilled solvent. However, occasionally a pink color was obtained, the origin of which is still under investigation. Additional rinses were required to remove the pink. 5. Additional microwave-accelerated Diels-Alder reactions are reported in reference 11, Chapters 8 and 9, and reference 12. 6. James Kiddle reported a similar microwave-enhanced Wittig salt formation using benzyl bromide (13). A single sample in a 1100 W domestic microwave at high power in a pressure tube with xylene as the solvent gave an 83% yield after 3 min of heating.
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7. Majetich et al. report a Williamson ether synthesis of n-propyl p-tolyl ether in 65% yield in reference 11, p 518, and others in Chapter 8. Leadbeater and McGowan (4) prepare n-butyl p-tolyl ether in 68% in a Mars 5 oven using 14-100 mL vessels. Both of these ethers are high-boiling liquids.
Literature Cited 1. Gedye, R. N.; Smith, F. E.; Westaway, K. C.; Ali, H.; Baldisera, L.; Laberge, L.; Rousell, J. Tetrahedron Lett. 1986, 27, 279–282. 2. Giguere, R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G. Tetrahedron Lett. 1986, 27, 4945–4948. 3. (a) Bari, S.; Bose, A.; Chaudhary, A.; Manhas, M.; Raju, V.; Robb, E. J. Chem. Educ. 1992, 69, 938–939. (b) Elder, J.; Holtz, K. M. J. Chem. Educ. 1996, 73, A104–A105. (c) Elder, J. J. Chem. Educ. 1994, 71, A142–A144. (d) Parquet, E.; Lin, Q. J. Chem. Educ. 1997, 74, 1225. (e) Mirafzal, G.; Summer, J. J. Chem. Educ. 2000, 77, 356–357. (f) Trehan, I.; Brar, J.; Arora, A.; Kad, G. J. Chem. Educ. 1997, 74, 324. 4. Leadbeater, N.; McGowan, C. Clean, Fast Organic Chemistry: Microwave-Assisted Laboratory Experiments; CEM Publishing: Matthews, NC, 2006. 5. Baar, M. R.; Wustholz, K. L. J. Chem. Educ. 2005, 82, 1393– 1394. 6. Pavia, D.; Lampman, G.; Kriz, G.; Engel, R. Introduction to Organic Laboratory Techniques: A Microscale Approach, 1st ed.; Saunders College: Philadelphia, PA, 1990; pp 297-301. 7. Miller, J.; Neuzil, E. Modern Experimental Organic Chemistry; D.C. Heath and Co.: Lexington, MA 1982; pp 228-231. 8. The Merck Index, 13th ed.; O'Neil, M. J., Smith, A., Heckelman, P. E., Budavari, S. Eds.; John Wiley and Sons: New York, 2001. 9. National Institute of Advanced Industrial Science and Technology Home Page, http://www.aist.go.jp. 10. Hayes, B. Microwave Synthesis - Chemistry at the Speed of Light; CEM Publishing: Matthews, NC, 2002; p 35. 11. Microwave-Enhanced Chemistry - Fundamentals, Sample Preparation, and Applications; Kingston, H. M., Haswell, S. J. Eds.; American Chemical Society: Washington, DC, 1997. 12. Shaw, R.; Severin, A.; Balfour, M.; Nettles, C. J. Chem. Educ. 2005, 82, 625–629. 13. Kiddle, J. Tetrahedron. Lett. 2000, 41, 1339–1341.
Supporting Information Available The three student experimental handouts are available. This includes the one-step Diels-Alder synthesis, the two-step ether synthesis, and three-step alkene synthesis via a Wittig reagent. The Diels-Alder cycloadduct IR and NMR spectra are available. This material is available via the Internet at http://pubs.acs.org.
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