COMMUNICATION pubs.acs.org/jchemeduc
Simple Microwave-Assisted Claisen and Dieckmann Condensation Experiments for the Undergraduate Organic Chemistry Laboratory Javier E. Horta*,† Department of Chemistry, Merrimack College, North Andover, Massachusetts 01845, United States
bS Supporting Information ABSTRACT: The Claisen condensation and its intramolecular variant the Dieckmann condensation are classic reactions studied in undergraduate organic chemistry courses because of their importance in organic synthesis and biochemical transformations. The growth in the use of microwave technology in both the synthetic and teaching laboratories warrants the modification of existing methodologies to incorporate this technology. This article presents simple microwave-assisted procedures for carrying out Claisen and Dieckmann condensation reactions that are suitable for organic chemistry teaching laboratories that utilize microwave technology. Although solvents can be used, the procedure is amenable to solvent-free conditions that promote green chemistry. KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives, Esters, Green Chemistry, Laboratory Equipment/Apparatus, Reactions, Synthesis Claisen Condensation5
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he Claisen condensation and its intramolecular variant named the Dieckmann condensation are important reactions in organic chemistry for historical reasons,1 for their wide applicability in synthesis, and because of their prevalence in many biochemical pathways.2 The Claisen and Dieckmann condensations typically require high temperatures,3 which makes the use of microwave energy ideal for carrying out these transformations. The experiments described here are simple procedures designed for organic chemistry curricula that utilize microwave technology and add to the important pool of existing microwave-assisted protocols for the teaching laboratory.4
To a 15 mL cylindrical microwave reaction vessel are added 2.63 g of potassium tert-butoxide (t-BuOK, 23.4 mmol) and 2.00 mL of diethyl succinate (2.04 g, 11.7 mmol) using an Eppendorf pipet (Scheme 1). Using a small spatula or glass rod, the reaction mixture is stirred until a paste results; a few (1 2) milliliters of a high-boiling point ether (e.g., 1,4-dioxane, 1,2dimethoxyethane, 1,2-diethoxyethane) or DMSO can be added if desired to better homogenize the mixture. The reaction vessel is capped as per the microwave instructions and is placed in the microwave. Using a variable power setting of up to 600 W, the reaction vessel is heated to 150 °C over 2 min, and then is maintained at 150 °C for 20 min. After cooling to less than 50 °C, the reaction vessel is removed from the microwave and 10 mL of 10% HCl is added to the reaction mixture. Using a spatula, the solid material in the reaction tube is carefully mixed with the aqueous solution, scraping the sides to remove any adhered material. A beige precipitate soon begins to form, and at this time, the tube is placed into a beaker with ice-water. The beige solid product is filtered under suction using ice-cold water to wash. Student yields ranged between 50 and 80%, and melting point (127 129 °C) as well as NMR and IR spectra obtained by the students were consistent with published data.
’ EXPERIMENT Overview
The Claisen and Dieckmann condensations requires a full equivalent of an alkoxide, typically the one derived from the alcohol used to prepare the ester substrate, but the use of a bulky non-nucleophilic alkoxide such as tert-butoxide (t-BuO ) can be used with excellent results, even in the absence of a solvent.3 Because the initial product of a Claisen or Dieckmann condensation is the enolate of a β-dicarbonyl compound, acidification is required upon completion of the reaction to produce the desired condensation product. The experiments use a CEM MARS 5 microwave unit with a variable power setting of up to 600 W. A carousel that can hold up to 40 reaction vessels is used to carry out the reactions of all the students simultaneously. The experiments should be easily adaptable to other commercially available microwave units. Experiments are designed for students working in pairs in a typical 3-h laboratory period, but they can easily be carried out by a single student. Copyright r 2011 American Chemical Society and Division of Chemical Education, Inc.
Dieckmann Condensation6
To a 15 mL cylindrical microwave reaction vessel are added 1.12 g of t-BuOK (9.94 mmol) and 2.00 mL of the ester (2.01 g, 9.94 mmol) using an Eppendorf pipet (Scheme 2). Using a small Published: April 25, 2011 1014
dx.doi.org/10.1021/ed1000944 | J. Chem. Educ. 2011, 88, 1014–1015
Journal of Chemical Education Scheme 1. Claisen Condensation of Diethyl Succinate
Scheme 2. Dieckmann Condensation of Diethyl Adipate
COMMUNICATION
with carrying out Claisen or Dieckmann condensations, which are typically discussed in the lecture course (e.g., a full equivalent of strong base is needed, as well as acidification of the crude material to isolate the desired β-ketoester product). Another important concept that students come to visualize with this experiment is that the short-chain length of diethyl succinate precludes any intramolecular reaction within that compound, but once an intermolecular reaction has taken place, the entropic advantage promotes a subsequent intramolecular reaction, as happens in the first place with diethyl adipate.
’ ASSOCIATED CONTENT
bS spatula or glass rod, the reaction mixture is stirred until a paste results; a few (1 2) milliliters of a high-boiling point ether (e.g., 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane) or DMSO can be added if desired to better homogenize the mixture. The reaction mixture is placed in the microwave. Using a variable power setting of up to 600 W, the reaction is heated to 150 °C over 2 min and then maintained at 150 °C for 20 min. After cooling to less than 50 °C, the reaction vessel is removed from the microwave and 10 mL of 10% HCl is added to the reaction mixture. Using a spatula, the solid material in the reaction tube is carefully mixed with the aqueous solution, scraping the sides to remove any adhered material. A light yellow oil soon begins to form over the aqueous solution, and at this time, the contents of the reaction vessel are transferred to a separatory funnel with the aid of 15 mL of diethyl ether. The aqueous layer is extracted three times with 15 mL of diethyl ether and the combined organic layers are then washed with 25 mL of saturated aqueous sodium chloride solution. The combined organic phases are dried over anhydrous sodium or magnesium sulfate, filtered by gravity, and concentrated under reduced pressure in a rotary evaporator. The result is a clear light-yellow oil (student yields ranged between 70 and 90%). NMR and IR spectra obtained by students was consistent with published data.
’ HAZARDS Potassium tert-butoxide is a flammable solid that can react violently with water. Handle all solvents and liquid reagents with care, as they may be flammable, toxic, and corrosive. If using DMSO as a solvent, warn students of its strong “garlicky” smell and that this solvent, as well as solutes contained in it, can readily pass through the skin, so it should be handled with extreme care. If using a solvent, ALL students should use the same solvent. When multiple reactions are being run, visually monitor the reaction vessels for any fumes or smoke, as in some cases overheating can occur due to poor mixing of the reactants and the vessel could explode if not removed from the microwave. If any fuming is noted, stop the reaction immediately and carefully inspect the fuming vessel. If the contents are black, remove from the microwave and place inside a hood to cool. ’ SUMMARY This article describes two simple microwave-assisted experiments designed for the undergraduate organic chemistry laboratory. Students find this experiment easy to execute and helpful in their understanding of the important technicalities associated
Supporting Information Student handout; notes for the instructor; CAS numbers. This material is available via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected]. Present Addresses †
Department of Clinical Laboratory and Nutritional Sciences, School of Health and Environment, University of Massachusetts Lowell, Lowell, Massachusetts 01854, United States.
’ ACKNOWLEDGMENT All the work leading to this publication was conceived and performed in its entirety while the author was an assistant professor at Merrimack College, in North Andover, Massachusetts. The author wishes to thank both his colleagues and students at Merrimack College, in particular those in the Chemistry Department, for providing the necessary resources and assistance that led to this publication. ’ REFERENCES (1) (a) Claisen, L. Ber. Dtsch. Chem. Ges. 1887, 20, 655. (b) Claisen, L.; Claparede, A. Ber. Dtsch. Chem. Ges. 1881, 14, 2460. (2) For a review of biological Claisen condensation reactions see Heath, R. J.; Rock, C. O. Nat. Prod. Rep. 2002, 19, 581. (3) For a Claisen condensation procedure utilizing conventional heating see Esteb, J. J.; Stockton, M. B. J. Chem. Educ. 2003, 80, 1446. Every attempt to adapt the procedure reported in this reference to a microwave method yielded primarily the decarboxylated product 1,3diphenylacetone. (4) For some interesting experiments for the undergraduate organic chemistry laboratory that incorporate microwave technology see (a) Baar, M. R.; Falcone, D.; Gordon, C. J. Chem. Educ. 2010, 87, 84. (b) Kappe, C. O.; Murphree, S. S. J. Chem. Educ. 2009, 86, 227. (c) Cook, A. G. J. Chem. Educ. 2007, 84, 1477. (d) Katritzky, A. R.; Cai, C.; Collins, M. D.; Scriven, E. F. V.; Singh, S. K.; Barnhardt, E. K. J. Chem. Educ. 2006, 83, 634. (e) Montes, I.; Sanabria, D.; García, M.; Castro, J.; Fajardo., J. J. Chem. Educ. 2006, 83, 628. (f) Coleman, W. F. J. Chem. Educ. 2006, 83, 621. (g) White, L. L.; Kittredge, K. W. J. Chem. Educ. 2005, 82, 1055. (5) For previously reported syntheses see (a) Nielsen, A. T.; Carpenter, W. R. Org. Synth. 1965, 45, 25. (b) Deorha, D. S.; Mukerji, S. K. J. Indian Chem. Soc. 1964, 41, 604. (6) For previously reported syntheses see (a) Zheng, S.; Gao, F.; Lu, C. Huaxue Shijie 2003, 44, 485; (b) Toda, F.; Suzuki, T.; Higa, S. J. Chem. Soc., Perkin Trans. 1 1998, 21, 3521; (c) Luche, J. L.; Petrier, C.; Dupuy, C. Tetrahedron Lett. 1984, 25, 753; (d) Org. React. 1967, 15, 1. (e) Zupancic, B. G.; Trpin, J. Monatsh. Chem. 1967, 98, 369. (f) Mayer, R.; Kubaschi, U. J. Prakt. Chem. 1959, 9, 4. (g) Pinkney, P. S. Org. Synth. 1937, 17, 30. 1015
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