Synthesis and Characterization of Aldol Condensation Products from

An experiment for the undergraduate chemistry laboratory in which students perform the aldol condensation on an unknown aldehyde and an unknown ketone...
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In the Laboratory

Synthesis and Characterization of Aldol Condensation Products from Unknown Aldehydes and Ketones

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An Inquiry-Based Experiment in the Undergraduate Laboratory Nicholas G. Angelo, Laura K. Henchey, Adam J. Waxman, James W. Canary, and Paramjit S. Arora* Department of Chemistry, New York University, New York, NY 10003; *[email protected] Donald Wink Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607

The aldol condensation is among the most important and most utilized transformations in synthetic chemistry (Scheme I) (1). This transformation has correspondingly been well-studied both in research and teaching laboratories. Previous reports in this Journal describe condensation of ketones and aldehydes and characterization of the aldol products by formation of suitable derivatives (2, 3) or spectroscopy (4). The aldol experiment has been included in standard organic chemistry laboratory textbooks because of its importance in synthetic organic chemistry as one of the most important methods for carbon–carbon bond construction (5). In our program, students engage in a multi-week module where they perform the aldol condensation between an unknown aldehyde and an unknown ketone (2), including decisions about how to plan and execute a reaction within a given time period. These decisions, in turn, affect the outcome of their experiment in ways that provide additional opportunities to learn. This experiment has been used in the latter half of the second-semester organic course, after earlier experiments in the course have introduced all of the required methodology and modern spectroscopic instruments. We find that, after completing this course, the students are ready to step into a research lab. The aldol experiment has been offered multiple times to classes of twenty to thirty students. The small class size allows sufficient one-on-one interaction with the instructor and enough time per student for equipment use. The stu-

dent–instructor interaction is especially important because the procedure allows room for alteration and students must make choices throughout the experiment. Experimental Procedure Summary Three lab periods were given to complete the experiment. Students were each given an unknown aldehyde and an unknown ketone from an array of different compounds (Figure 1). Over a five-year period, several of these combinations (Table 1) have been examined. The students were referred to a general procedure for performing the aldol condensation (Supplemental MaterialW) (5). As the reactivities of the compounds differ, students often had to modify the reaction conditions to optimize their reactions. TLC was used to monitor the reactions and students had to determine a suitable solvent system for their reaction mixtures. Additionally, they needed to decide the best way to visualize the spots on the TLC plate based on their knowledge of the probable structures of the compounds. They also had access to 1H NMR, GC–MS, FTIR, and wet chemistry techniques such as the Tollens test for aldehydes. Once the reaction was determined to be complete, students purified their products using either recrystallization or column chromatography. After the products were isolated, they were analyzed using the same techniques listed above for analyzing the starting materials (6). After completion of the experiment, students were expected to submit a concise report describing the experiment and the identity of their unknown starting materials and products. Students also met individually with the instructor to present their results and discuss how conclusions were reached. The emphasis was placed on obtaining clean products and spectra and correctly identifying the unknowns rather than on the yield obtained. Students who failed to complete the reaction properly were given the opportunity to repeat the experiment. In cases where spectra were messy or inconclusive, students were required to figure out what went wrong. Discussion

Scheme I. Reaction equation for the aldol condensation.

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This module allows students to experience what synthetic chemistry researchers do day-by-day in the lab. The outcome of the reaction ultimately depended on the ability of the students to carefully plan and perform the reaction and on his or her ability to make educated decisions based on observations. With such a wide variety of starting materials, this also meant that no two students in a given section had the same reaction, placing each of them in the position of carrying out

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In the Laboratory

Figure 1. Unknown aldehydes and ketones used in this experiment. Students were given one aldehyde and one ketone.

a reaction that differed from the others in multiple ways (2). Thus, the only way to optimize the reaction was to characterize it well and then to reflect on the results. Throughout the experiment, students were advised on the use of monitoring techniques (such as TLC) and reaction conditions (such as heating). Students had to calculate the quantities of starting materials, reagents, and solvents needed. In addition, they had to make well thought-out decisions on which reaction conditions to implement. The key skill, however, was the need to plan their experiment methodically (7), addressing key issues such as whether to identify the starting materials prior to performing the reaction. In most cases, though, ambiguity in their characterization of the starting material meant they still performed the reaction with only limited knowledge of the starting materials. In these cases, analysis of the product was used to elucidate the structures of the starting materials. Uncertainty about the structure of the starting material, of course, made it difficult to calculate precisely the amount of material needed for the reaction, resulting in an excess of one of the reactants and additional purification steps. In other cases, TLC evidence showed that there was more than one reaction product and students needed to separate and characterize each of these products to obtain the desired aldol product. Finally, some students learned enough in their initial attempts to lead them to choose to repeat the process so they could obtain their desired product in higher yields. We found these cases to be particularly rewarding. An example of the breadth of the decisions needed to complete this module is given by the results obtained by a student carrying out the reaction between 4-nitrobenzaldehyde (10) and 2-heptanone (19) (Scheme II). Table 2 shows how several unique steps provided the information needed to both plan the reaction and, ultimately, to complete the assignment of the structure of the product and the reactant. www.JCE.DivCHED.org

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Table 1. Combinations of Unknown Aldehydes and Ketones Used by the Students Ketone

Aldehyde 1

2

3

4

5

6

7

8

9 10 11 12 13

14

–

–

–

–

–

–

x

x

x

–

x

–

15

–

–

–

–

x

–

x

x

x

–

–

–

x

16

–

–

–

–

x

x

x

–

–

–

–

–

–

17

–

x

–

–

–

–

–

–

–

–

–

–

–

18

–

–

–

–

–

x

–

–

–

–

–

–

–

19

–

–

x

–

–

–

–

–

–

x

x

–

–

20

–

–

–

–

–

x

–

–

–

–

–

–

–

21

–

–

–

–

–

x

x

–

–

–

x

x

–

22

–

x

–

–

–

–

–

x

–

–

x

–

–

23

–

–

–

–

–

–

–

–

–

–

–

x

–

24

–

–

–

–

x

–

–

–

–

–

x

–

–

25

–

–

x

x

–

–

x

x

–

x

x

–

–

26

–

–

x

–

–

–

–

–

–

x

–

–

–

27

x

–

x

–

x

–

x

–

–

–

x

–

–

28

–

x

–

–

–

–

–

x

–

–

x

–

–

29

–

x

–

–

–

x

x

–

–

–

x

–

–

–

NOTE: The x indicates the ketone–aldehyde combination used in the lab.

What must be emphasized is that similar steps for other combinations of reactants would yield different results—sometimes very different results—placing the responsibility of the project itself in the hands of the student and his or her decision making. Unknowns may be selected so that the students obtain only solid products or only oils. The solids often may be purified by recrystallization, avoiding the chromatography step. Disparity arises in the length of time required for the stu-

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In the Laboratory

Scheme II. Reaction between 4-nitrobenzaldehyde, 10, and 2-heptanone, 19.

Table 2. Typical Results for a Student Carrying Out the Aldol Module Student Initiated Step

Result

Usefulness for the project

Analysis of reactants by 1H NMR

Presence of characteristic singlet at ca. 9 ppm indicated which compound was the aldehyde.

Identification of starting materials for later separation from reaction mixture.

Analysis of reactants by GC–MS

Molar masses of both compounds.

Used to determine masses of the compounds required for stoichiometric reaction.

Analysis of reactants by IR

Suggests absence of some functional groups (e.g., alkynes) and presence of others (e.g., nitro group).

Helps to identify possible alternative sites of reactivity that could interfere with the reaction.

Analysis of product by 1H NMR

Determination of which peaks are carried over from reactants and which are new to the product.

Elucidation of the site of the reaction in the ketone.

Observation of the coupling pattern within the olefin.

Confirmation of a single isomer as the product and the stereochemistry of the C=C bond.

Absence of an alcohol and presence of an olefin.

Confirmed formation of α,β-unsaturated ketone.

Analysis of product by IR

dent to complete the experiment if some students obtain nice solids and some must purify oils. Although possibly frustrating to the students, this phenomenon is reflective of real-life practicalities. Hazards All work should be done under a fume hood. Sodium hydroxide causes burns and should be handled with care. Ethanol is flammable and should be carefully handled around heating mantles. Silica is a respiratory irritant and should be stored and handled in a fume hood. It should be transferred from the storage area to the student work area in a sealed container and used silica should be disposed of properly. Conclusions This laboratory experiment is designed to provide students with exposure to independent research in organic chemistry near the end of their second-semester second-year organic chemistry course. The students begin this aldol experiment after having been introduced to common methods and instrumentation available to a contemporary organic chemist. The purpose of this experiment is to have the student work as independently as possible within the constraints of a teaching laboratory. They are allowed access to needed instrumentation and chemicals and are asked to chart their own course. This exercise has been a taxing experience for the students who are often not used to doing experiments that may not lead to the single desired outcome. Peer–peer interactions facilitated learning in this experiment. The natural tendency to compare color, smell, chromatographic properties and spectra of reagents and products led to useful discussions among students. This again resembles 1818

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the kinds of interactions among workers in a productive research group environment. Acknowledgments We thank Ibrahim Ghali, Ronald Callahan, and the students of the Honors Organic Chemistry Laboratory at NYU for their assistance. PSA thanks the Research Corporation for support of this project in the form of a Cottrell Scholar Award. This work was supported by a grant from the National Science Foundation (DUE-0126958) for augmenting traditional undergraduate laboratory curricula. W

Supplemental Material

List of chemicals, instruments, instructions for students, notes on common difficulties and possible solutions, syllabus for the entire course, and sample spectral data for the products are available in this issue of JCE Online. Literature Cited 1. Mahrwald, R. Modern Aldol Reactions; Wiley-VCH: Weinheim, Germany, 2004. 2. Hathaway, B. A. J. Chem. Educ. 1987, 64, 367–368. 3. Hawbecker, B. L.; Kurtz, D. W.; Putnam, T. D.; Ahlers, P. A.; Gerber, G. D. J. Chem. Educ. 1978, 55, 540–541. 4. Vyvyan, J. R.; Pavia, D. L.; Lampman, G. M.; Kriz, G. S. J. Chem. Educ. 2002, 79, 1119–1121. 5. Gilbert, J. C.; Martin, S. F. Experimental Organic Chemistry: A Miniscale and Microscale Approach, 3rd ed.; Harcourt College Publishers: Fort Worth, TX, 2002; pp 570–573. 6. Glagovich, N. M.; Shine, T. D. J. Chem. Educ. 2005, 82, 1382–1384. 7. Pickering, M. J. Chem. Educ. 1991, 68, 232–234.

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