In the Laboratory
JCE Concept Connections: Using Aspirin as a Teaching Tool Hartel and Hanna describe a laboratory experiment useful in the high school through organic chemistry setting. The experiment begins with one familiar substance (aspirin), and students use acyl substitution to generate another (wintergreen fragrance). One could generate a unit in an existing course focusing on aspirin to teach about drug discovery, organic synthesis and modification, and quantitative analysis. Below, Liana Lamont of the Editorial Staff suggests additional resources that are available through JCE Online (http://www.jce.divched.org) for exploring these topics. To provide students with background information, check out the following articles at JCE Online: Old Yet New–Pharmaceuticals from Plants. Houghton, Peter J. J. Chem Educ. 2001, 78, 175. JCE Featured Molecules: Acetaminophen, Aspirin, and Caffeine. Coleman, William F; Wildman, Randall J. J. Chem. Educ. 2003, 80, 176. Book & Media Reviews: Drug Discovery: A History (by Walter Sneader). Schedler, David J. A. 2006, 83, 215.
In addition to using aspirin tablets as described in the experiment by Hartel and Hanna and the articles cited therein, students could initially synthesize the aspirin using a Greener approach: A Greener Approach to Aspirin Synthesis Using Microwave Irradiation. Montes, Ingrid; Sanabria, David; García, Marilyn; Castro, Joaudimir; Fajardo, Johanna. J. Chem. Educ. 2006, 83, 628.
Finally, students could apply quantitative analysis techniques to the aspirin and wintergreen oil: Simultaneous Determination of Aspirin, Salicylamide, and Caffeine in Pain Relievers by Target Factor Analysis. Msimanga, Huggins Z.; Charles, Melissa J.; Martin, Nea W. J. Chem. Educ. 1997, 74, 1114. A General Chemistry Laboratory Theme: Spectroscopic Analysis of Aspirin. Byrd, Houston; O’Donnell, Stephen E. J. Chem. Educ. 2003, 80, 174. Quantitation of Phenol Levels in Oil of Wintergreen Using Gas Chromatography–Mass Spectrometry with Selected Ion Monitoring. A Quantitative Analysis Laboratory Experiment. Sobel, Robert M.; Ballantine, David S.; Ryzhov, Victor. J. Chem. Educ. 2005, 82, 601.
Explore the wealth of JCE resources.
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Journal of Chemical Education • Vol. 86 No. 4 April 2009 • www.JCE.DivCHED.org • © Division of Chemical Education
In the Laboratory edited by
The Microscale Laboratory
R. David Crouch
Preparation of Oil of Wintergreen from Commercial Aspirin Tablets
Dickinson College Carlisle, PA 17013-2896
A Microscale Experiment Highlighting Acyl Substitutions Aaron M. Hartel* and James M. Hanna, Jr. Department of Chemistry, Winthrop University, Rock Hill, SC 29733; *
[email protected] Many fruits and herbs owe much of their distinctive fragrances and flavors to naturally occurring esters. Preparations of such esters have been popular experiments used in the instructional chemistry laboratory (1–10), as familiarity with their fragrances gives these experiments an immediate relevance to students. The reactions and preparations of esters are major topics taught in the organic chemistry sequence, and these experiments also provide a valuable link between the lecture and laboratory. The most commonly employed reaction in these experiments is the Fischer esterification (1–9): the acid-catalyzed acyl substitution of a carboxylic acid with a nucleophilic alcohol to give an ester. While the Fischer esterification has been widely employed for the laboratory preparation of esters, the use of transesterification has been limited (11–14). Acid-catalyzed transesterification is mechanistically related to the Fischer esterification but involves the acyl substitution of one ester with a nucleophilic alcohol to give a new ester. Salicylic acid is unusual in that it can form an ester using either its carboxylic acid or phenol group. This bifunctional compound has two well-known esters: acetylsalicylic acid (aspirin) and methyl salicylate (oil of wintergreen). Both the preparation of aspirin via the esterification of salicylic acid (15–20) and the reverse process, hydrolysis of aspirin to give salicylic acid (19–22) have been incorporated into instructional laboratory experiments. The preparation of methyl salicylate using diazotization chemistry has also appeared in this Journal (10). Experiment A short, single-pot preparation of methyl salicylate from commercial aspirin tablets can be performed via a tandem transesterification–Fischer esterification. The crushed aspirin tablets are mixed with methanol to dissolve the aspirin and insoluble material is removed by filtering through a plug of cotton. Concentrated sulfuric acid is added to the aspirin solution, and it is either refluxed for 90 minutes or heated in a scientific microwave system at 120 °C for 5 minutes. It is then basified with aqueous sodium bicarbonate, and the methyl salicylate product is extracted using dichloromethane. The organic solution is dried and evaporated to give a fragrant, colorless to pale yellow oil. While student yields approaching 70% have been achieved O
OH
O O
O CH3
OCH3 OH
CH3OH, H2SO4 reflux or microwave
acetylsalicylic acid
Scheme I. Preparation of methyl salicylate.
methyl salicylate
using both heating methods, typical student yields are 25% for conventional heating and 48% for microwave heating. Hazards Concentrated sulfuric acid is corrosive. Contact can cause severe damage to skin and eyes. Methanol is extremely flammable and toxic by inhalation. Dichloromethane is a carcinogen, is toxic by inhalation, and causes irritation and burning pain on prolonged contact. Chloroform-d (used for NMR) is a carcinogen, is toxic by inhalation, and can cause respiratory irritation. Acetylsalicylic acid and methyl salicylate are irritants. Anhydrous sodium sulfate is a mild skin irritant. Removal of solvents by evaporation should be performed in a fume-hood or using a fume snorkel. All manipulations should be performed wearing safety glasses and protective gloves. The microwave heating procedure is carried out in a sealed vessel. Only reaction vessels designed to withstand pressure should be used and this method should not be attempted without temperature control. Discussion The synthesis proceeds via a tandem transesterification– Fischer esterification (Scheme I). The acetate ester group of aspirin is initially transesterified to form methyl acetate and salicylic acid (methanolysis). Under the same conditions, the carboxylic acid group of the resulting salicylic acid undergoes Fischer esterification to form methyl salicylate. Any salicylic acid intermediate that is not esterified is removed by extraction with aqueous base. The volatile methyl acetate is removed during the evaporation of solvent at the end of the procedure. The procedure gives methyl salicylate in moderate yield and high purity as determined by 1H NMR. Traces of dichloromethane sometimes remain if insufficient time is devoted to solvent evaporation. The methyl salicylate product can be analyzed by 13C 1 or H NMR spectroscopy as an excellent tool for instructing students on the use of the spectrometer and interpretation of spectra. The NMR spectra of methyl salicylate (23) demonstrate the concepts of deshielding, diamagnetic anisotropy, and molecular asymmetry. The 13C NMR spectrum demonstrates the lack of symmetry in the product, showing distinct resonances for each of the eight carbons in the molecule. Additionally, the 1H NMR spectrum shows both short range ( J ) and long range 3 ( J4) coupling in the aromatic region, which can be used in conjunction with the chemical shifts to unambiguously assign each peak in the spectrum. The transformation of common aspirin tablets into the familiar and distinctive wintergreen fragrance promotes student interest and adds relevance to the application of organic chemistry. This experiment uses common reagents and equipment, is relatively safe and procedurally straightforward, tak-
© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 86 No. 4 April 2009 • Journal of Chemical Education
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In the Laboratory
ing approximately three hours to complete. The procedure is simple enough for use in an advanced high school laboratory to introduce organic chemistry and help stimulate interest in the science. It can be used in a college organic chemistry laboratory for majors or non-majors to demonstrate acyl substitutions and synthesis, as well as provide further experience with laboratory techniques such as refluxing and extraction. The complete interpretation of the NMR spectra is also an excellent exercise in spectral interpretation and problem solving. Summary The preparation of oil of wintergreen from commercial aspirin tablets is an excellent instructional experiment appropriate for the high school, introductory, or organic chemistry laboratory. It demonstrates acyl substitution chemistry while generating student interest in organic chemistry. The experimental procedure can be performed in approximately three hours using either conventional or microwave heating giving moderate yields of an analytically pure, familiarly fragrant ester, which can be characterized by 1H and 13C NMR spectroscopy. Literature Cited 1. Doyle, M. P.; Plummer, B. F. J. Chem. Educ. 1993, 70, 493–495.
2. Branz, S. E. J. Chem. Educ. 1985, 62, 899–900. 3. Puterbaugh, W. H.; Vanselow, C. H.; Nelson, K.; Shrawder, E. J. J. Chem. Educ. 1963, 40, 349–350. 4. Birney, D. M.; Starnes, S. D. J. Chem. Educ. 1999, 76, 1560–1561. 5. Naff, M. B.; Naff, A. S. J. Chem. Educ. 1967, 44, 680–681. 6. Solomon, S.; Hur, C.; Lee, A.; Smith, K. J. Chem. Educ. 1996, 73, 173–175. 7. Williamson, K. L. Macroscale and Microscale Organic Experiments, 4th ed.; Houghton Mifflin: New York, 2003; pp 486–500.
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8. Schoffstall, A. M.; Gaddis, B. A.; Druelinger, M. L. Microscale and Miniscale Organic Chemistry Laboratory Experiments, 2nd ed.; McGraw-Hill: New York, 2004; pp 430–440. 9. Whitlock, C. R.; Bishop, P. A. Chem. Educator 2003, 8, 352. 10. Zanger, M.; McKee, J. R. J. Chem. Educ. 1988, 65, 1106. 11. Rebolledo, F.; Liz, R. J. Chem. Educ. 2005, 82, 930–933. 12. Breton, G. W.; Belk, M. K. Chem. Educator 2004, 9, 27–29. 13. Lam, R. B.; Palocsay, F. A.; Gallaher, T. N.; Leary, J. J. J. Chem. Educ. 1983, 60, 769–771. 14. Williamson, K. L. Macroscale and Microscale Organic Experiments, 4th ed.; Houghton Mifflin: New York, 2003; pp 755–761. 15. Pandita, S.; Goyal, S. J. Chem. Educ. 1998, 75, 770. 16. Vinson, J. A.; Hocker, E. K. J. Chem. Educ. 1969, 46, 245. 17. Olmsted, J. A. J. Chem. Educ. 1998, 75, 1261–1263. 18. Schoffstall, A. M.; Gaddis, B. A.; Druelinger, M. L. Microscale and Miniscale Organic Chemistry Laboratory Experiments, 2nd ed.; McGraw-Hill: New York, 2004; pp 480–488. 19. Borer, L. L.; Barry, E. J. Chem. Educ. 2000, 77, 354–355. 20. Brown, D. B.; Friedman, L. B. J. Chem. Educ. 1973, 50, 214–215. 21. Bugg, T. D. H.; Lewin, A. M.; Catlin, E. R. J. Chem. Educ. 1997, 74, 105–107. 22. Marrs, P. S. J. Chem. Educ. 2004, 81, 870–873. 23. Snider, B. B.; Patricia, J. J. J. Org. Chem. 1989, 54, 38–46
Supporting JCE Online Material
http://www.jce.divched.org/Journal/Issues/2009/Apr/abs475.html Abstract and keywords Full text (PDF) with links to cited URLs and JCE articles Supplement Student handouts Instructor notes including a list of chemicals and safety hazards NMR spectra
Journal of Chemical Education • Vol. 86 No. 4 April 2009 • www.JCE.DivCHED.org • © Division of Chemical Education
