In the Laboratory edited by
Green Chemistry
Mary M. Kirchhoff ACS Green Chemistry Institute Washington, DC 20036
The Aldol Addition and Condensation: The Effect of Conditions on Reaction Pathway
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R. David Crouch,* Amie Richardson, Jessica L. Howard, Rebecca L. Harker, and Kathryn H. Barker Department of Chemistry, Dickinson College, Carlisle, PA 17013-2896; *
[email protected] Condensation reactions at the α carbon of carbonyl compounds present a challenge to many students. Discerning when a reaction undergoes simple addition of an α carbon to a carbonyl (aldol addition) or continues reacting via a dehydration (aldol condensation) is often of particular difficulty. Although many examples of aldol condensation reactions for the second-year organic lab are available (1–6), we sought a lab exercise that would produce aldol addition or condensation products depending only on the reaction conditions. Such an experiment requires students to “discover” the conditions that favor addition and those that favor a second step—an elimination—leading to an aldol condensation. A recent publication describes an easy-to-perform synthesis of β-hydroxy ketones that involves an aldol addition at room temperature in aqueous Na2CO3 (7). We have adapted this experiment to the teaching lab and extended it to include conditions that favor an aldol condensation. Experiment The reaction involves combining equimolar quantities of 2-acetylpyridine, 1, and 4-nitrobenzaldehyde, 2, in 10 mL of water using a small quantity of hot methanol to dissolve the aldehyde (Scheme I). We found that, at the small scales on which our labs are conducted, the use of hot methanol to dissolve the aldehyde was important in obtaining good yields. Addition of a catalytic quantity of Na2CO3 begins the reaction. When allowed to stir at room temperature for 1 hour, an aldol addition product, 3, is obtained, precipitating out of the aqueous reaction mixture. But, when the reaction mixture is heated to 50 ⬚C for 1 hour, aldol condensation predominates with the product, 4, again precipitating out of
solution upon cooling. As an option, students could perform TLC of the reaction at intervals to determine exactly when the reaction is complete. At room temperature, the aldol addition product is easily isolated and can be identified by its 1H NMR spectrum, which shows signals characteristic of a benzylic alcohol and diastereotopic hydrogens at the α carbon. At elevated temperatures, the base-mediated aldol condensation product forms and, again, the product can be identified by its 1H NMR spectrum, which shows no signals upfield of 7.3 ppm. The E geometry of the alkene can be assigned based on the doublet at ∼8.43 ppm that has a coupling constant of 16 Hz. Melting points are also sufficiently different to allow the products to be distinguished (7, 8). Although infrared spectroscopy seemed to be a good means to distinguish between the two products, students found it very difficult to obtain useful IR spectra owing to their limited solubility in the solvents typically used for solution cell IR. Hazards Although, with the exception of water, all of the reagents are listed as irritants, this experiment poses no special hazards. However, 2-acetylpyridine has an unpleasant odor. So, it is recommended that this experiment be conducted in fume hoods. Discussion This reaction can be considered as an example of green chemistry with little organic solvent being used. Although this is not part of our lab activity, it has been reported that
Scheme I: Reaction between 2-acetylpyridine, 1, and 4-nitrobenzaldehyde, 2.
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In the Laboratory
the aqueous filtrate from the reaction mixture has been used up to four more times without a decrease in yield (7). We had hoped to use the more readily-available acetophenone for this reaction but the extended reaction times required (at least 3 hours) make this a less attractive choice for the teaching lab (7). Some students expressed surprise that water could be used as a solvent in an organic reaction. But a quick search of the literature reveals numerous examples of organic reactions in water (9). Indeed, the potential advantages of using water as a solvent in organic reactions are many and include lower cost for solvents, lack of flammability, little to no concern about human exposure, and the elimination of solvents that are a growing environmental threat (9a). It is also important to note that, in reactions like these where smaller molecules are joined to form larger molecules, the products are often insoluble and product isolation is much easier. And, reactions in water sometimes exhibit unusual rate enhancements (9a) and stereoselectivities (9b, 9c). The presence of water, though, presents an interesting question with regard to the elimination step in the aldol condensation. One of the products of this step is water and, with a large excess of that product already present, Le Châtelier’s principle would seem to disfavor formation of the condensation product. But, the aldol condensation product, 4, is insoluble in water and, as it forms, a yellow precipitate falls out of solution, removing the organic product from the equilibrium. In our teaching laboratory, we use this experiment to illustrate the role that heating plays in driving the elimination step in the aldol condensation. Several students noted that, according to their textbook (10), the aromatic ketone and aromatic aldehyde “should” produce an aldol condensation even at low temperature owing to the resultant extended conjugation. This allowed us the opportunity to discuss the role of base strength. When the more basic NaOH is used, the aldol condensation product is isolated even at room temperature. Indeed, one can envision a lab exercise in which some students use NaOH and others use Na2CO3 at room temperature and at 50 ⬚C and then compare products. Another option allows students to observe that aldol addition product 3 is an intermediate in the formation of aldol condensation product 4. While one might reserve some of the isolated product 3 and expose it to Na2CO3 in water at an elevated temperature in a second step, our best results were obtained by stirring the reaction mixture at room temperature for about 45 minutes, pouring approximately half of the mixture into a 25-mL beaker, and placing the remainder of the reaction mixture in a sand bath that had been preheated to 70–80 ⬚C. The portion of the reaction mixture in the bea-
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ker was isolated to produce aldol addition product 3 as the elimination step proceeded in the original reaction flask. After about 45 minutes, the contents of the reaction flask changed color from white to yellow, signifying that product 4 had formed. After cooling, aldol condensation product 4 was isolated. This experiment is easily performed in a standard 3- or 4-hour laboratory session and generates reliable results. All students were able to identify their product based on knowledge of the reactivities of the reactants and the NMR spectra of the products and they were able to explain why the aldol addition was favored at room temperature while the aldol condensation was favored at elevated temperatures. Acknowledgments This project was partially supported by NSF-NUE grant #0406837 and by an award from Research Corporation. W
Supplemental Material
Instructions for the students and notes for the instructor including 1H NMR spectra are available in this issue of JCE Online. Literature Cited 1. 2. 3. 4.
5. 6. 7. 8.
9.
10.
Harrison, E. A., Jr. J. Chem. Educ. 1998, 75, 636–637. Smith, L. R. Chemical Educator 1996, 1 (3), 1–15. Hathaway, B. A. J. Chem. Educ. 1987, 63, 443. Mayo, D. W.; Pike, R. M.; Trumper, P. K. Microscale Organic Laboratory, 3rd ed.; John Wiley & Sons: New York, 1994; pp 313–321. Williamson, K. L. Macroscale and Microscale Organic Experiments, 4th ed.; Houghton Mifflin: Boston, 2003; pp 454–460. Gilbert, J. C.; Martin, S. F. Experimental Organic Chemistry, 3rd ed.; Harcourt College Publishers: Fort Worth, TX, 2002; pp 572–576. Wang, G.-W.; Zhang, Z.; Dong, Y.-W. Org. Process Res. Dev. 2004, 8, 18–21. Tsukerman, S. V.; Nikitchenko, V. M.; Bugai, A. I.; Lavrushin, V. F. Khim. Str., Svoistva Reaktivnost Org. Soedin. 1969, 53– 59; Chem. Abstr. 1970, 73, 45276. (a) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem., Intl. Ed. Eng. 2005, 44, 3275–3279. (b) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751–2772. (c) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209–217. (d) Engberts, J. B. F. N.; Blandamar, M. J. Chem. Commun. 2001, 1701–1708. McMurry, J. Organic Chemistry, 6th ed.; Brooks/Cole: Belmont, CA, 2004; Chapter 23.
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