In the Laboratory
Microwave-Assisted Carbonyl Chemistry for the Undergraduate Laboratory S. Shaun Murphree* Department of Chemistry, Allegheny College, Meadville, PA 16335; *
[email protected] C. Oliver Kappe Christian Doppler Laboratory for Microwave Chemistry, Institute of Chemistry, Karl-Franzens University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
Microwave-assisted synthesis continues to make significant headway into mainstream of organic chemistry, as demonstrated by several recent reviews on the topic (1). Advantages of this technology have been realized throughout the length and breadth of the field, from total synthesis (2) to synthetic methodology (3) and from industrial research and development (4) to drug discovery (5). A literature search using the concepts of “microwave” and “organic synthesis” returns more than 500 journal articles over the past five years, more than twice the number in the previous five-year period (1998–2002). Similarly, the rate of patent publication in this area has more than tripled over the same time periods. Development of microwave-assisted synthesis in the college chemistry curriculum parallels the pioneering efforts in the literature—adaptations for the undergraduate instructional laboratory were reported as much as twenty years ago (6). Further developments have continued into the present, representing a diverse array of protocols, including macrocyclizations (7), rearrangements (8), catalytic transfer hydrogenation (9), and heterocyclic synthesis (10). Necessarily, the earlier reports involved irradiation in open vessels using domestic kitchen microwave ovens. While operationally straightforward and relatively inexpensive, this methodology suffers from the inherent vicissitudes of multimode equipment (uneven load distribution, hot spots, etc.), as well as technical limitations (lack of temperature control, uncontrolled loss of volatile components, etc.) that can make these protocols extremely sensitive to idiosyncratic experimental differences (type of equipment, size and shape of vessel, user technique, etc.). However, with the advent of dedicated monomode microwave reactors capable of closed-vessel reactions, the development of new methods is assisted by reliable temperature control and more predictable and consistent power density, consequently providing for more robust protocols. Recently, Katritzky and coworkers have showcased the utility of dedicated equipment with four microwave-assisted reactions adapted for the undergraduate laboratory, and the authors demonstrate persuasively the efficacy of monomode reactors in the undergraduate setting (11). The appearance of laboratory manuals featuring monomode microwave reactors also bears witness to the increasing importance of microwave-assisted synthesis as a pedagogical tool (12). Within this context, we report our results in developing a thematic microwave chemistry module for a second- to third-year organic chemistry instructional laboratory.1 Curricular Rationale Our impetus for developing an instructional laboratory around microwave chemistry was threefold. First, microwave reactors are rapidly becoming standard equipment in both in-
dustrial and academic laboratories. Therefore, it is necessary to provide opportunities for students to gain hands-on experience with these important tools. Moreover, incorporating state-ofthe-art technology into the standard curriculum can have a positive impact on student engagement and subsequent decisions to pursue research opportunities later on (i.e., technology as a recruitment tool). A third, but equally important, motivation for pursuing microwave-assisted experimental protocols was to achieve a greater curricular flexibility. For example, a reaction requiring a three-hour reflux would be difficult to incorporate into an instructional laboratory. However, the same reaction can often be completed in a matter of minutes with the assistance of a microwave reactor. The lab module consists of six experiments that share a common mechanistic theme of carbonyl chemistry (Table 1). Each experiment can be used for various pedagogical purposes. Thus, the catalytic oxidation not only exemplifies the important functional-group transformation of alcohol to ketone, but it also allows for discussion of catalytic cycles, terminal oxidants, and reactive intermediates. The Grignard reaction includes halogen– metal exchange, as well as nucleophilic addition onto a carbonyl group. The somewhat related Knoevenagel condensation also includes a nucleophilic addition step, but expands the mechanistic landscape into the territory of elimination. Moreover, this reaction features an active methylene compound, which allows for productive discussion about pKa values and the additive nature of electron-withdrawing substituents. Base-catalyzed esterification represents not only the functional-group transformation of acid to ester, but also the central mechanistic step of the SN2 reaction. In this particular example, mesitylenecarboxylic acid was chosen as a substrate because of its notoriously sluggish reactivity. This provides an entrée into the impact of sterics on reactivity and also showcases the utility of microwave methodology in surmounting issues of reduced kinetic activity. The equally important transformation of carboxylic acid (in this case formic acid) to carboxamide is explored in the N-formylation of o-nitroaniline, and the formal reversal of this process is seen in an acid-catalyzed amide hydrolysis, in which benzamide is converted to benzoic acid in the presence of mineral acid. These latter two examples serve as convenient illustrations of the impact of reaction conditions on position of equilibrium processes. With the exception of the Grignard example, all reactions in the module can be carried out in less than a half-hour (most in less than 15 min), and analytically acceptable products can be obtained without the need for chromatographic purification. All products except ethyl mesitylenecarboxylate are solids that can be purified by recrystallization if necessary. Detailed experimental procedures can be found in the online material.
© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 86 No. 2 February 2009 • Journal of Chemical Education
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In the Laboratory Table 1. Reaction Overview Reaction Type
Reaction O
OH
H
O
CO2H H
OEt
OH
NH2
HN NO2
O NO2
O
O NH2
Instrumentation Two types of microwave reactor were available for student use—the Discover Labmate from CEM Corporation (13) and the Initiator Exp 2.2 Eight manufactured by Biotage AB (14). Both are monomode devices, but with subtle differences in configurations and capabilities. Aside from proprietary (and non-trivial) differences in waveguide and cavity construction, the two instruments have variations in monitoring and control technology. For example, the Initiator measures vessel temperature from the side using an IR sensor, whereas the Discover uses a bottom IR sensor placement, allowing for low filling volumes. In addition, the microwave process vials designed for the Initiator are completely sealed, but the Discover process vials are equipped with an IntelliVent cap designed to relieve temporary overpressure by venting to the atmosphere. Finally, the Initiator has the advantage of being equipped with an eight-position vial rack and robot arm, which facilitates throughput in a multi-user instructional laboratory setting. Experimental The course began with a half-day seminar that provided a theoretical basis for microwave-assisted synthesis, covering such practical considerations as strongly and weakly absorbing solvents (and the use of chemically inert additives to increase absorption), the differences between monomode and multimode cavities, and an overview of techniques. In addition, a general introduction to the available equipment was presented, along with safety guidelines and course expectations. Students were given a 15-minute hands-on training session with the microwave reactors during the first lab day. While some of the more complex experiments in the course were carried out in pairs, all of the examples in the present laboratory were conducted individually. 228
110
20
78
100: step 1 100: step 2
40 20
80
140
10
89
150
10
99
160
3
82
160
7
91
O
O
Base-catalyzed esterification
Amide hydrolysis
Yield (%)
OH
O
Grignard reaction
N-Formylation
Reaction Time/min
Me
Me
Catalytic oxidation
Knoevenagel condensation
Temperature/ °C
OH
Students taking the course had already completed an initial laboratory in organic synthesis covering the basic techniques in organic synthesis and analysis. Students were given a laboratory manual at the beginning of the course that outlined basic experimental conditions, the day-to-day logistics, and provided primary literature references for all reactions (the instructions are available in the online material). On the day of each laboratory, students were asked to prepare a detailed experimental procedure for the examples planned for that period. Before practical work was begun, a brief one-on-one discussion between instructor and student was conducted to gauge the level of preparation, check calculational (stoichiometric) accuracy, and clarify any issues of synthesis, handling, or isolation. After the experiments were carried out, students initially checked sample purity using HPLC,2 and proton NMR (360 MHz) was employed for the characterization of the final product samples. All syntheses use readily available starting materials and are relatively economical to carry out. Total material costs (including extraction solvents) range from about $0.15 per experiment (Knoevenagel condensation) to about $4.00 per experiment (Grignard reaction). Treatment of the analytical data is adaptable to a range of curricular levels. For example, all of the products exhibit significantly different IR spectra compared to the starting materials, and these changes are easily interpreted in terms of functional-group transformation (i.e., alcohol → ketone; aldehyde → alcohol; aldehyde → conjugated alkene; acid → ester; primary amine → amide; primary amide → acid). Furthermore, IR spectra for all reactants and products (except ethyl 2,4,6-trimethylbenzoate) are available through a free Web database (15). Thus, from an analytical standpoint, all of the experiments are suitable for a typical first-semester organic laboratory.
Journal of Chemical Education • Vol. 86 No. 2 February 2009 • www.JCE.DivCHED.org • © Division of Chemical Education
In the Laboratory
For more advanced laboratories, NMR data can also be employed for evaluating the extent of reaction or purity of a sample. Five of the six syntheses have components with fairly straightforward 1H NMR spectra. The remaining example (borneol → camphor) presents some interesting opportunities. For example, at the most basic level, the proton spectrum can be used in a similar manner as an IR spectrum, observing the disappearance of the characteristic signal at δ 4.1 (α to the hydroxyl group). However, in a more advanced setting, camphor could serve as an interesting proton assignment problem, for which molecular modeling could be meaningfully applied (see the online material). At the end of the laboratory experience, students were given an opportunity to provide feedback and commentary. All participants found the laboratory to be intellectually stimulating and challenging, and all would recommend the course to other students. The overwhelming majority also reported an improvement in problem-solving skills as well as an increased interest in microwave chemistry and research. Furthermore, students commented positively on being engaged in “real” chemistry and using “up-to-date” procedures. Hazards Acetone, acetonitrile, bromoethane, ethanol, piperidine, and tetrahydrofuran are flammable liquids and must be handled in the absence of any sources of ignition. Magnesium is a flammable metal; Class D extinguishing material should be readily available when handling. Bromoethane and dichloromethane are classified as carcinogens; tetrahydrofuran is a possible carcinogen. Formic acid, 95%, and hydrochloric acid, conc (which may be used in the laboratory to prepare dilute solutions), and sulfuric acid, conc, are corrosive liquids that can cause severe burns. Oxone is an oxidizing agent and should be segregated from organic compounds. All vial preparation and reaction workup is carried out in a fume hood. The reaction vessels are transported from the hood to the microwave reactors in a sealed state, in which the risk of exposure is minimal. Acknowledgments The authors gratefully acknowledge Karl-Franzens University Graz for administrative support, facilities, and infrastructure; Allegheny College, the Fulbright Commission, and the Austrian–American Educational Commission for support of the international collaboration; Jamshed Hashim and Florian Reder for their contributions to the development of examples; and the students of the Mikrowellen Praktikum for their engagement and valuable input. Notes 1. The project was launched as a collaborative effort between Allegheny College, a small private American liberal arts college, and Karl-Franzens University Graz, a large public Austrian university. 2. If the HPLC results indicated that the purity or yield of the product was questionable, a student had the opportunity to carry out another recrystallization or reaction in the same lab period. The HPLC analyses were carried out by students using a Shimadzu LC-10 HPLC equipped with an E. Merck LiChrospher 100 RP-18 column and eluting with a solvent system of 5% → 34% acetonitrile in water. Retention times were usually less than 7 min.
Literature Cited 1. For recent books and monographs, see (a) Kappe, C. O.; Stadler, A. Microwaves in Organic and Medicinal Chemistry; Wiley: Weinheim, Germany, 2005. (b) Microwave-Assisted Synthesis of Heterocycles; van der Eycken, E., Kappe, C. O., Eds.; Springer: New York, 2006. (c) Microwaves in Organic Synthesis, 2nd ed.; Loupy, A., Ed.; Wiley-VCH: Weinheim, Germany, 2006. (d) Microwave Assisted Organic Synthesis; Lidström, P., Tierny, J. P., Eds.; Blackwell: Oxford, 2005. (e) Microwave Methods in Organic Chemistry; Larhed, M., Olofsson, K., Eds.; Springer: Berlin, 2006. For recent review articles, see Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284. (f ) Romanova, N. N; Gravis, A. G.; Zyk, N. V. Russ. Chem. Rev. 2005, 74, 969–1013. 2. (a) Artman, G. D., III; Grubbs, A. W.; Williams, R. M. J. Am. Chem. Soc. 2007, 129, 6336–6342. (b) Zhang, H.; Boonsombat, J.; Padwa, A. Org. Lett. 2007, 9, 279–282. 3. (a) Desai, H.; D’Souza, B. R.; Foether, D.; Johnson, B. F.; Lindsay, H. A. Synthesis 2007, 902–910. (b) Zhu, M.; Song, Y.; Cao, Y. Synthesis 2007, 853–856. 4. Kremsner, J. M.; Stadler, A.; Kappe, C. O. Top. Curr. Chem. 2006, 266, 233–278. 5. (a) Kappe, C. O.; Dallinger, D. Nature Rev. Drug Disc. 2006, 5, 51–63. (b) Chighine, A.; Sechi, G.; Bradley, M. Drug Disc. Today 2007, 12, 459–464. 6. (a) Smith, F. E.; Cousins, B. G.; Maillet, J. Y. Educ. in Chem. 1987, 24 (1), 13. (b) Gedye, R.; Smith, F.; Westaway, K. Educ. in Chem. 1988, 25 (2), 55–56. 7. Hayes, J. W., II; Taylor, C. J.; Hotz, R. P. J. Chem. Educ. 1996, 73, 991–992. 8. Trehan, I. R.; Brar, J. S.; Arora, A. K.; Kad, G. L. J. Chem. Educ. 1997, 74, 324. 9. Banik, B. K.; Barakat, K. J.; Wagle, D. R.; Manhas, M. S.; Bose, A. K. J. Org. Chem. 1999, 64 (16), 5746–5753. 10. Musiol, R.; Tyman-Szram, B.; Polanski, J. J. Chem. Educ. 2006, 83, 632–633. 11. Katritzky, A. R.; Cai, C.; Collins, M. D.; Scriven, E. F. V.; Singh, S. K.; Barnhardt, E. K. J. Chem. Educ. 2006, 83, 634–636. 12. McGowan, C.; Leadbeater, N. Clean, Fast Organic Chemistry: Microwave-Assisted Laboratory Experiments; CEM Publishing: Matthews, NC, 2006. 13. CEM Corp. Synthesis Web Site. http://www.cem.com/synthesis/ index.asp (accessed Sep 2008). 14. Biotage Home Page. http://www.biotage.com/ (accessed Sep 2008). 15. The Spectral Database for Organic Compounds (SDBS) maintained by the National Institute of Advanced Industrial Science and Technology of Japan. http://riodb01.ibase.aist.go.jp/sdbs/ cgi-bin/direct_frame_top.cgi (accessed Sep 2008).
Supporting JCE Online Material
http://www.jce.divched.org/Journal/Issues/2009/Feb/abs227.html Abstract and keywords Full text (PDF) with links to cited URLs and JCE articles Supplement Detailed experimental procedures Heating curves NMR data Sample laboratory instructions Student feedback
© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 86 No. 2 February 2009 • Journal of Chemical Education
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