In the Laboratory
Incorporation of Microwave Synthesis into the Undergraduate Organic Laboratory
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Alan R. Katritzky,* Chunming Cai, Meghan D. Collins, Eric F. V. Scriven, and Sandeep K. Singh Department of Chemistry, University of Florida, Gainesville, FL 32611-7200; *
[email protected] E. Keller Barnhardt Life Sciences Division, CEM Corporation, Matthews, NC 28106-0200
As recent literature indicates (1), microwaves are quickly becoming an accepted tool for investigators in the organic laboratory. Microwave synthesis enables reactions to proceed more rapidly with greater yields than many conventional techniques. As more and more reactions are performed using a microwave, it becomes increasingly important for students to fully understand how to use this enabling technology. There have been several articles published describing the possible use of microwave synthesis in the undergraduate laboratory (2). Most of this literature, however, utilizes domestic microwave ovens. This type of microwave synthesis has received criticism owing to reports of low reproducibility (1e), uncontrolled heating (3), and an inability to stir reactions during irradiation resulting in splashing of the chemicals (2d). Also, the use of open beakers covered with a watch glass in domestic ovens has been considered hazardous (4). Single-mode microwave synthesis provides a safe, effective alternative and has been successfully incorporated into the undergraduate curriculum. Advantages of Microwave Chemistry The most important reason reactions proceed faster in a microwave than with conventional heating is that energy is transferred directly to the reactants. In conventional heating, there is considerable energy loss as the energy is transferred thermally through multiple layers. With microwaves, each transfer results in more efficient energy delivery directly to the desired destination, the reacting molecules. The second advantage of the direct transfer is the rapid rate at which the energy is passed. Energy is supplied to the molecules faster than they are able to relax,1 creating high instantaneous temperatures. These rapid transfers generate more than enough energy to overcome the activation energy barrier (Ea) to form the desired product(s).2 An additional advantage of microwave use is its safe and efficient means for rapidly reaching high overall temperatures in a closed system. In order to achieve the best rate increase possible, many microwave reactions are performed at high temperatures or pressures. A pressurized reaction is able to achieve temperatures substantially higher than the atmospheric boiling point of the solvent, thereby increasing the reaction rate beyond that of the same non-pressurized reaction. These properties of microwaves have enabled reactions to proceed more rapidly, given the same temperature point as the conventional reaction. As a result of these rate enhancements, many studies have shown reactions proceed with lower concentrations or no catalyst (5), under solvent-free conditions (6), and in a more environmentally friendly manner (green chemistry reactions) (7). 634
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The advantages inherent in microwave use make it ideal for the undergraduate laboratory. Although students are exposed to many different reactions in the classroom, many important organic reactions described in undergraduate textbooks are presently not included in the laboratory course owing to long reaction times, high temperatures, or sensitive reagents that present a potential danger to the students.3 Some researchers have found these advantages and have used domestic microwave ovens in the undergraduate classroom for experiments such as Wolff–Kishner reduction (2a), Diels– Alder reaction (2b), Fries rearrangement (2c), synthesis of analgesic drugs (2d), and functional-group transformations (2e). The experiments described herein require short reaction times of 4–5 minutes, hence only one microwave synthesizer is needed for a group of 12 students in a lab section. These experiments can easily be incorporated into the curriculum and still allow time to perform the workup, isolation, recrystallization, melting-point determination, and spectral analysis of the products. The use of microwaves also eliminates the need for heating mantles or oil baths, resulting in fewer hazards associated with exposure to hot surfaces (2b). Instrumentation The advent of industrial microwaves has significantly increased the safety of microwave use (8). Reaction temperatures and pressures now can be continuously monitored and the applied power can be adjusted automatically to prevent exceeding set limits. Stirring has also been added, as well as safety features to guard against runaway reactions. In order to better meet the specific needs of synthetic organic chemists, single-mode microwaves were designed. Unlike multiple-mode microwaves, which have multiple modes of energy throughout the cavity, both high and low, a single-mode system, by definition, has only one mode of energy. The sample will continuously be in the field of high energy, sometimes referred to as the “hot spot” in multiple-mode microwaves. A greater power density is generated, 900 W兾L with a 300 W output, as opposed to approximately 30 W兾L with a 1200 W output found with multiple-mode microwaves (9). Multiple-mode microwaves have a larger cavity, enabling the use of larger-sized vessels or a set of reactions run in parallel. Single-mode cavities are smaller and are equipped with a self-tuning feature, capable of maximizing the quantity of energy delivered to the sample, as opposed to being reflected back into the instrument (9). This self-tuning feature makes certain every reaction will receive the same quantity of energy, thus ensuring uniformity and repeatability. A single-mode microwave has been designed specifically for use in the undergraduate laboratory course.4 These mi-
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In the Laboratory
crowaves maintain the high safety standards of all single-mode microwaves; complete with applied power control, constant temperature monitoring and control, pressure management, and complete sample containment. Because microwave reactions can be brought up to high temperatures, the reaction vessel is completely contained, away from the student. Upon completion of the reaction, a cooling cycle commences that will bring the temperature of the vessel back to ambient before the student has an opportunity to come in contact with the vessel. The microwave instruments chosen for this course were utilized for several reasons. The industry standard has proven to be single-mode systems, as they are used almost exclusively in industrial organic applications. As a result, the use of a single-mode system, and therefore the training that is associated with learning about a new instrumental technique, will prove useful for those students who wish to pursue organic synthesis in the future. The mobility of the system is important. Although the systems are reasonably priced,5 the added feature of being able to utilize the microwave for both undergraduate and graduate work is important. The size and simple setup enables the system to be physically be moved throughout the building when necessary.6 An additional advantage of the system is the ability to work under both open and closed vessel format. One of the major advantages of microwave synthesis is the ability to heat reactions without the use of thermal aids, which can cause burns (2b). Yet, at the same time, an important tool taught in the undergraduate laboratory is refluxing reactions. The particular system chosen enables the use of standard reflux glassware, thus students can still learn this valuable technique. Because microwaves accelerate the rates of reactions in both an open and a pressurized system, the same rate increase will be gained through both open and closed vessel reactions.
Experimental We have developed optimized microwave reaction conditions designed for use in the undergraduate organic laboratory for several types of experiments using a single-mode cavity microwave synthesizer. Of the seven developed, four were used in the undergraduate course: (i) Diels–Alder reaction, (ii) Paal–Knorr condensation, (iii) Williamson ether synthesis, and (iv) ester hydrolysis. The undergraduate students study the theoretical background to these important organic reactions, but several of the reactions have not been included in the organic laboratory course owing to reaction conditions that are unsuitable for the undergraduate setting. We have now found that these reactions proceed under mild conditions using a microwave synthesizer and could, therefore, be included in the undergraduate organic laboratory. For comparison, the typical thermal conditions required have also been provided along with the microwave reaction conditions (Table 1).7 These reactions were performed,8 in conjunction with other experiments, as part of the undergraduate organic laboratory. A group of students was selected for the pilot program and their response to the course was determined at the end.9 Overall, the comments received were favorable. Students felt that microwaves had an important place in both the organic laboratory and the undergraduate curriculum. As they were able to perform the same workups, lab writeups, and other techniques learned during the typical laboratory course, the same skill-sets were developed. In addition, the level of student enthusiasm increased when learning about a new technique and being “on the cutting edge”. The course was determined to be a success and steps are now being taken to continue to work with microwaves in the undergraduate laboratory.
Table 1. Optimized Experiments Conventional Reaction
Microwave
Reaction Timea/min
Yield (%)
Total Timeb/min
Yield (%)
Diels–Alder Reactionc
240
80 (10a)
4
97
Paal–Knorr Condensation
600d
96d (10b)
5
75
Williamson Etherification
330d
87d (10c)
4
71
Ester Hydrolysis
045
88 (10d)
5
82
a Total reaction time at temperature. bTime to warm to temperature, react, and cool to 50 ⬚C. performed with the yields and times given.
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Open vessel conditions.
d
Similar reactions were
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Hazards
9. A full summary of the student comments is included in the Supplemental Material.W
Ethyl acetate, diethyl ether, and hexane are flammable solvents; there should be no open flame in the laboratory. Iodopropane, phenylhydrazine, and toluidine are all suspected of being cancer-causing agents. Hydrochloric acid is corrosive and may cause damage to the skin. To prevent the possibility of severe burns, ensure that insulated gloves and protective gear are worn. Acknowledgments We would like to thank Eric Scriven and the fall 2003 CHEM 2211L class for their help in executing the curriculum set forth and CEM Corporation for providing the Discover microwave synthesizers. W
Supplemental Material
An explanation of microwave theory, the experimental details including NMR data, and a summary of the student comments are available in this issue of JCE Online. Notes 1. Molecular relaxation rates are on the order of 10᎑5 seconds, while microwave energy is transferred 2.45 billion times a second. 2. A full explanation of microwave theory is included in the Supplemental Material.W 3. Examples include: SnAr, Friedel–Crafts, Wittig, Cope rearrangement, Knovenagel, Michael addition, Wolf–Kishner reduction (2a), and Fries rearrangement (2c). 4. The BenchMate, a single-mode microwave system based on the Discover System platform and designed specifically for use in the undergraduate laboratory, is now available from CEM Corporation. This system is based on the same cavity utilized by the more advanced microwave synthesizers. 5. The BenchMate System is the most affordable industrial microwave system, priced at $10,000 specifically for use in the undergraduate organic laboratory. In addition, special grant programs as well as academic discounts are available for the implementation of the system into the undergraduate curriculum. 6. The microwave synthesizer weighs 30 lbs and is 14. in. wide, 17.2 in. deep, and 8.7 in. tall. 7. Full experimental details are provided in the Supplemental Material.W 8. For the pilot course implemented, the Diels–Alder reaction and Paal–Knorr synthesis were run for 10 minutes each while the Ester hydrolysis and the Williamson ether synthesis reactions were run for 5 minutes. Each of the reactions has since been found to proceed in less time, some using atmospheric pressure (open vessel). The equivalents were the same and the yields were comparable for the unoptimized and optimized reactions. These optimized reactions are reported herein.
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Literature Cited 1. (a) Hayes, B. L. Microwave Synthesis: Chemistry at the Speed of Light; CEM Publishing: Matthews, NC, 2002. (b) Larhed, M.; Hallberg, A. Drug Discovery Today 2001, 6, 406. (c) Lidström, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225. (d) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199. (e) Bradley, D. Modern Drug Discovery 2001, August, 32. (f ) Fini, A.; Breccia, A. Pure Appl. Chem. 1999, 71, 573. (g) Sridar, V. Curr. Sci. 1998, 74, 446. (h) Caddick, S. Tetrahedron 1995, 51, 10403. (i) Majetich, G.; Hicks, R. Radiat. Phys. Chem. 1995, 45, 567. (j) Majetich, G.; Hicks, R. J. Microwave Power Electromagnetic Energy 1995, 30, 27. (k) Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, Germany, 2002. (l) Katritzky, A. R.; Singh, S. K. Arkivoc 2003, xiii, 68. (m) Varma, R. S. Green Chem. 1999, 1, 43. 2. (a) Parquet, E.; Lin, Q. J. Chem. Educ. 1997, 74, 1225. (b) Bari, S. S.; Bose, A. K.; Chaudhary, A. G.; Manhas, M. S.; Raju, V. S.; Robb, E. W. J. Chem. Educ. 1992, 69, 938. (c) Trehan, I. R.; Brar, J. S.; Arora, A. K.; Kad, G. L. J. Chem. Educ. 1997, 74, 324. (d) Mirafzal, G. A.; Summer, J. M. J. Chem. Educ. 2000, 77, 356. (e) Elder, J. W.; Holtz, K. M. J. Chem. Educ. 1996, 73, A104. (f ) Bose, A. K.; Manhas, M. S.; Kanik, B. K.; Robb, E. W. Res. Chem. Intermed. 1994, 20, 1. 3. Kuhnert, N. Angew. Chem., Int. Ed. Engl. 2002, 41, 1863. 4. Ardon, M.; Hayes, P. D.; Hogarth, G. J. Chem. Educ. 2002, 79, 1249. 5. (a) Xu, G.; Wang, Y. G. Org. Lett. 2004, 6, 985. (b) Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003, 68, 5660. (c) Jeselnik, M.; Varma, R. S.; Polanc, S.; Kocevar, M. Chem. Commun. 2001, 1716. 6. Solvent-free examples include: (a) Yadav, L. D. S.; Singh, S. Synthesis 2003, 1, 63. (b) Wang, C.; Hang, T.; Zhang, H. Synth. Commun. 2003, 33, 451. (c) Bailliez, V.; de Figueiredo, R. M.; Olesker, A.; Cleophax, J. Synthesis 2003, 7, 1015. (d) Loupy, A. Tetrahedron Lett. 2003, 44, 9091. (e) Wang, L.; Li, P. H. Chin. J. Chem. 2003, 21, 710. (f ) Karchgaudhuri, N.; De, A.; Mitra, A. K. J. Chem. Res. (S) 2002, 180. 7. Green chemistry examples include: (a) Banik, B. K.; Jayaraman, M.; Srirajan, V.; Manhas, M. S.; Bose, A. K. J. Indian Chem. Soc. 1997, 74, 943. (b) Loupy, A. Comptes Rendus Chim. 2004, 7, 103. (c) Frere, S.; Thiery, V.; Besson, T. Synth. Commun. 2003, 33, 3795. (d) Diaz-Ortiz, A.; de la Hoz, A.; Langa, F. Green Chem. 2000, 2, 165. 8. Cresswell, S. L.; Haswell, S. J. J. Chem. Educ. 2001, 78, 900. 9. Ferguson, J. D. Molecular Diversity 2003, 7, 281. 10. (a) Song, C. E.; Shim, W. H.; Roh, E. J.; Lee, S.-G.; Choi, J. H. Chem. Commun. 2001, 1122. (b) Samajdar, S.; Becker, F. F.; Banik, B. K. Heterocycles 2001, 55, 1019. (c) Jur√ic, B. Tetrahedron 1988, 44, 6677. (d) Khurana, J. M.; Sehgal, A. Org. Prep. Proced. Int. 1994, 26, 580.
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