In the Laboratory
The Dibenzalacetone Reaction Revisited†
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Leslie A. Hull Department of Chemistry, Union College, Schenectady, NY 12308;
[email protected] Ideally we would like laboratory experiences to be like doing research. Students should use the literature, design and carry out experiments, and evaluate the results. In the area of synthesis this usually means analyzing the molecule, designing a synthetic route, modifying a published procedure, performing several variations of the modified reaction until a successful one is found, and then characterizing the product. In large classes it is difficult to design individualized synthetic exercises. The advent of microscale experiments and sensitive, powerful techniques for structural characterization have permitted the use of a greater diversity of reactions. Expensive reagents can be used by large numbers of students because the quantities used per student are small. In addition, the savings in time resulting from microtechniques permits more trial and error in the context of a 3–4-hour laboratory. The following describes the adaptation of the dibenzalacetone reaction (crossed aldol) to a synthetic laboratory exercise designed to resemble a small research project. As part of our effort to intellectually involve the students in the exercises they are performing, we modified the classic experiment in organic chemistry from a style that illustrates the reaction, to one that simulates a synthetic research project. The aldol condensation becomes a critical tool in building a target molecule. The Experiment One of the standard reactions used to illustrate the aldol condensation reaction in the organic laboratory is the reaction of benzaldehyde and acetone catalyzed by NaOH (Scheme I). H C
O O NaOH
+ CH3
CH3
EtOH/H2O
O C C H
C H
C H
C H
Dibenzalacetone
Scheme I
This experiment is easy to perform and gives satisfying yields of a recrystallizable product, and in recent years it has been adapted to microscale work. (1, 2) Unfortunately, when they do the experiment the students fail to see the significance of the reaction and, for the most part, treat the experiment as a cookbook type with little thought to experimental design. † Presented in part at the 12th Biennial Conference on Chemical Education, Davis, CA, August 1992.
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To introduce the notion of discovery and experimental design, we introduced a simple modification of the reaction that can be accomplished in one 4-hour laboratory period (3). The students, working in groups of four, are given a synthetic target of the dibenzalketone type: O H C
H C
Y
n = 0, 1
Y
n
Y = CH3, OCH3
The group is told to modify the dibenzalacetone procedure found in the laboratory text to synthesize their assigned target and to demonstrate by 1H NMR that they have indeed succeeded in the synthesis (4 ). The sample procedure does not have any of the quantities in moles. The experiment is scheduled for just after we cover the aldol reaction and some of its variations in lecture. No introductory lecture is given in the laboratory other than to summarize the structure of what they are doing as outlined in the laboratory text. No reagents are set out in the laboratory other than aqueous NaOH and ethanol. The student groups are instructed to propose a reaction and specify the reagents needed to prepare their target molecule, using their laboratory text as a reference. They are then asked to modify the sample procedure to include appropriate quantities of the proposed reagents. It is strongly suggested that dissecting the original procedure by back-calculating molar quantities would be of great help in this task. Each group is given an Aldrich catalog for reference. To add an additional real-world flavor, students are required to go to the stockroom and “order” the organic compounds they need by “name”. Our stockroom manager keeps the reagents in alphabetical order by the reagent’s name on the bottle as received from Aldrich. Students confront the issue of IUPAC and common names (e.g., p-tolualdehyde on the bottle instead of the logical 4-methylbenzaldehyde). After all the groups have made correct reaction proposals, done the calculations to come up with the correct amounts of their starting materials, and received all their “orders”, we get together in the laboratory to talk about other issues that need to be considered before a modified synthesis will be effective. To get things started the class is asked why ethanol is used in the sample procedure. Quickly the class realizes that the ethanol is used to make the reaction mixture homogeneous by solubilizing the benzaldehyde in the aqueous sodium hydroxide solution. With some prompting they realize that their carbonyl reagents (cyclopentanone or cyclohexanone and the substituted benzaldehydes) may be considerably less soluble in water than the reagents in the sample procedure and they may need to add additional ethanol to achieve homogeneity. Likewise it is pointed out that in the sample
Journal of Chemical Education • Vol. 78 No. 2 February 2001 • JChemEd.chem.wisc.edu
In the Laboratory
procedure the reaction appears to go at room temperature, as indicated by spontaneous formation of a precipitate after only a few minutes. If a precipitate does not appear it may be because the assigned dibenzalketone is formed slower than dibenzalacetone. The reaction may be slower for several reasons (more sterically hindered reagents, more dilute because of added ethanol). What should they do to speed things up? Possibly warm gently. It is also pointed out that the recrystallization solvent may not be appropriate for their products and, if not, they will need to find an appropriate solvent. In this way the groups are introduced to several experimental variables under their control that may need to be changed to make the reaction proceed as they have designed. Since the students are working in groups and each individual in the group performs the reaction, it is pointed out that each group member can try several modifications to determine the successful reaction conditions. They are given the task of designing the experimental variations depending on how their individual reactions appear to proceed. To complement the synthetic work, we incorporate a molecular modeling component to illustrate the electron distribution in an enolate anion. We incorporate molecular modeling as a component of most of our experiments much as spectroscopy is routinely incorporated in laboratory exercises, to provide students with practical experience in its use (5). The 1H NMR spectra of the cyclopentanone and cyclohexanone products are nice illustrations of the power of NMR for product identification. The coupling and integrations complement one another, the only surprise for the students being the overlap of the vinyl methine singlet with the aromatic AB quartet. The reaction gives crystallizable products from all nine variations shown in Table 1. It is largely successful even when experimental conditions are not optimal (too little ethanol is added or the reaction isn’t heated). Yields are lower, but products are still isolated. Other possible variations include producing the chalcones by crossed aldol condensations between acetophenone (and its substituted derivatives) and benzaldehyde (and its substituted derivatives) (6 ). In summary, the approach to the dibenzalacetone reaction proposed here provides a nice venue for illustrating how to
Table 1. Combinations of Ketones and Aldehydes That Give Cr ystallizable Products Ketone
Aldehyde
Acetone
Benzaldehyde
Cyclopentanone
Tolualdehyde
Cyclohexanone
Anisaldehyde
adapt a reaction described in the chemical literature to a particular target molecule and forces the students to carefully examine exactly what is involved in designing a synthetic experiment. Hazards The reactions should be carried out in a hood or very well ventilated area. The vapors from the ketones and aldehydes used in the experiment are generally considered irritants at low concentrations and can be toxic at high concentrations. W
Supplemental Material
Instructions for students, notes for the instructor, sample NMR spectra, and equipment and reagent lists are available in this issue of JCE Online. Literature Cited 1. Eaton, D. C. Laboratory Investigations in Organic Chemistry; McGraw-Hill: New York, 1989; p 466. Fieser, L. F.; Williamson, K. L. Organic Experiments, 7th ed.; Heath: Lexington, MA, 1992; p 339. 2. Williamson, K. L. Macroscale and Microscale Organic Experiments, 2nd ed.; Heath: Lexington, MA, 1994; p 417. 3. Domin, D. S. J. Chem. Educ. 1999, 76, 543. 4. Browne, L. M.; Blackburn, E. V. J. Chem. Educ. 1999, 76, 1104. 5. Shusterman, G. P.; Shusterman, A. J. J. Chem. Educ. 1997, 74, 771. 6. Wachter-Jurcsak, N.; Zamani, H. J. Chem. Educ. 1999, 76, 653.
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