In the Laboratory
A Solvent-Free Claisen Condensation Reaction for the Organic Laboratory
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John J. Esteb* and Matthew B. Stockton Department of Chemistry, Butler University, Indianapolis, IN 46208; *
[email protected] Carbonyl condensation reactions are widely utilized in organic synthesis (1) and are routinely covered in organic chemistry textbooks. However, illustrating the reaction in an undergraduate teaching laboratory in a simple, yet effective manner is often difficult to achieve. As a result, only one exercise has been developed for the undergraduate laboratory involving the α-acylation of esters, commonly referred to as the Claisen condensation reaction (2). In the published procedure, no synthesis was performed but equilibrium model calculations were explored in great detail. This lack of good experiments is most likely the result of the long reaction times required for these systems to reach equilibrium. There have, however, been a handful of synthetic experiments involving other carbonyl condensation reactions published in this Journal (3), most prominently utilizing the aldol condensation. Unfortunately, a good number of these experiments suffer from difficult procedures or a lack of definite teaching goals. Recently, Yoshizawa, Toyota, and Toda (4) reported a solvent-free procedure for the α-acylation of esters. The relatively low toxicity and availability of the reagents (5) coupled with the simplicity and cleanliness of their procedure led us to investigate the possibility of converting this synthetic process into a form applicable to the teaching laboratory. The condensation of ester derivatives under solvent-free conditions has not yet been used in the undergraduate teaching laboratory. The laboratory we have developed offers several advantages over many of the existing exercises involving carbonyl condensations including the ease of reaction workup, the short reaction times needed, the ability to reduce the quantity of waste generated and hazardous materials used, and the overall cost effectiveness of the reactions. In addition, for a typical Claisen condensation reaction run in solution, the ester, metal alkoxide, and alcohol solvent should all be identical so as to eliminate exchange of the alkoxy group among the substrate, reagent, and solvent. Under solvent-free conditions, one is able to use an unmatched set of base and
ester without resulting in the exchange of alkoxy groups. All of these advantages were important considerations in the development and implementation of this new teaching laboratory. In this experiment, potassium tert-butoxide and ethyl phenylacetate, 1, are heated to 100 ⬚C for 30 min under solvent-free conditions to produce 2,4-diphenyl acetoacetate, 2, in 80% yield (Scheme I). Ethyl phenylacetate was selected as a suitable ester owing to its low cost, low toxicity, and for the fact that the reaction may be stopped after only 0.5 h with excellent conversion. Furthermore, the condensation product is a solid, which can be easily isolated from the reaction and purified by the students through recrystallization. Lastly, since the reaction yields are good, the students obtain enough material to characterize their product by NMR, GC– MS, or IR if desired. Experimental Procedure A mixture of 1.57 g (14 mmol) of KOt-Bu and 3.28 g (20 mmol) of ethyl phenylacetate were added to a 25-mL round bottom flask. The resulting mixture was stirred vigorously with a spatula until the contents appeared homogeneous. A reflux condenser was attached and the flask placed in a preheated hot water or steam bath at ca. 100 ⬚C. After 0.5 h, the flask was removed from the heat source. The mixture was cooled to room temperature and neutralized by the slow addition of ca. 15 mL of 1 M HCl. The residue was extracted with 2 × 15 mL portions of ether. The organic extracts were combined, dried with MgSO4, filtered, and the solvent removed by rotary evaporation. Trituration of the oily residue with 7 mL of cold pentane1 produced a white solid. Recrystallization of the product from hot hexanes afforded 2.25 g of 2,4-diphenyl acetoacetate (80%), mp 75–78 ⬚C. Purity of the product was assessed through melting point determinations. Typical student yields are in the 50–80% range. Hazards
OEt 2
Ph O
KOt-Bu
Ph
1
OEt Ph O
+
EtOH
O 2
Scheme I. Claisen reaction between potassium tert-butoxide and ethyl phenylacetate.
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Potassium tert-butoxide can react violently with water. Care should be taken when handling this chemical. Ether, pentane, and hexanes are flammable liquids; there should be no open flames in the laboratory. Hydrochloric acid is corrosive and may cause damage to the skin. Magnesium sulfate is hygroscopic. Further health and safety notes may be found in the Supplemental Material.W Acknowledgments The authors would like to thank Butler University’s 2002 summer organic chemistry classes for helping assist with the preparation and testing of this lab. The authors would also like to thank Anne Wilson for helpful discussion.
Journal of Chemical Education • Vol. 80 No. 12 December 2003 • JChemEd.chem.wisc.edu
In the Laboratory W
Supplemental Material
Instructions for the students and notes for the instructor are available in this issue of JCE Online. Note 1. It may be necessary for the students to cool the pentane mixture in an ice bath to force complete precipitation of their product, particularly if a large quantity of unreacted ethyl phenylacetate is still present.
Literature Cited 1. For representative references on Claisen condensation reactions, see (a) Claisen, L.; Claparede, A. Ber. 1881, 14, 2460. (b) Franzen, V. Reaktionsmechanismen 1; Huthig: Heidelberg, Germany, 1958, p 87. (c) Hauser, C. R.; Hudson, B. E. Organic Reactions Vol. I; Adams, R. A., Ed.; John Wiley and Sons: New York, 1942; p 266. (d) Fieser, L. F.; Fieser, M. Advanced Organic Chemistry; Reinhold Publishing Corp., Chapman Hall Ltd.: New York, 1961, p 470. 2. Garst, J. F. J. Chem. Educ. 1979, 56, 721.
3. (a) Wachter-Jurcsak, N.; Reddin, K. J. Chem. Educ. 2001, 78, 1264. (b) Harrison, E. A., Jr. J. Chem. Educ. 1998, 75, 636. (c) Clausen, T. P.; Johnson, B.; Wood, J. J. Chem. Educ. 1996, 73, 266. (d) Rowland, A. T. J. Chem. Educ. 1995, 72, 548. (e) Kolb, K. E.; Field, K. W.; Schatz, P. F. J. Chem. Educ. 1990, 67, A304. (f ) Kulp, S. S. J. Chem. Educ. 1988, 65, 742. (g) Hathaway, B. A. J. Chem. Educ. 1987, 64, 367. (h) GarciaRaso, A.; Garcia-Raso, J.; Sinisterra, J. V.; Mestres, R. J. Chem. Educ. 1986, 63, 443. (i) Rowland, A. T.; Brechbiel, M. W.; Gerelus, A. S. J. Chem. Educ. 1985, 62, 908. (j) Hawbecker, B. L.; Kurtz, D. W.; Putnam, T. D.; Ahlers, P. A.; Gerber, G. D. J. Chem. Educ. 1978, 55, 540. (k) Angres, I.; Zieger, H. E. J. Chem. Educ. 1974, 51, 64. (l) Stockel, R. F.; Oppelt, J. C.; Arendt, V. J. Chem. Educ. 1966, 43, 144. (m) Ketcham, R. J. Chem. Educ. 1964, 41, 565. (n) Maglio, M. M.; Burger, C. A. J. Chem. Educ. 1946, 23, 174. (o) Zuffanti, S.; Luder, W. F. J. Chem. Educ. 1944, 21, 485. (p) Howells, H. P. J. Chem. Educ. 1930, 7, 597. 4. Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983. 5. Gosselin, R. E.; Hodge, H. C.; Smith, R. P.; Gleason, M. N. Clinical Toxicology of Commercial Products, 4th ed.; Williams & Wilkins: Baltimore, MD, 1976.
JChemEd.chem.wisc.edu • Vol. 80 No. 12 December 2003 • Journal of Chemical Education
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