In the Laboratory
W
Preparing Students for Research: Synthesis of Substituted Chalcones as a Comprehensive Guided-Inquiry Experience James R. Vyvyan,* Donald L. Pavia, Gary M. Lampman, and George S. Kriz Department of Chemistry, Western Washington University, Bellingham, WA 98225-9150; *
[email protected] Rationale and Background In the pedagogical migration from traditional expository laboratory experiments to more inquiry-based approaches (1), we have found that many “cookbook” organic synthesis experiments are readily modified to a project-based approach in which each student is assigned (chooses) a target compound different from the example illustrated in the laboratory textbook. The aldol condensation reaction is a cornerstone of organic synthesis and a common experiment in the undergraduate microscale organic laboratory (2). The crossed aldol reaction to prepare dibenzalacetone from benzaldehyde and acetone is a popular variation (3, 4 ), as is the preparation of chalcone from benzaldehyde and acetophenone (2, 5). An expanded approach utilizing substituted benzaldehydes and various symmetric ketones to prepare benzalacetone derivatives has been reported in this Journal (3, 4 ). Herein we describe the aldol condensation of substituted benzaldehydes (1) with substituted acetophenones (2) to produce substituted benzalacetophenones (chalcones) 3 (Scheme I) as an ideal comprehensive guided-inquiry experience that prepares chemistry students for the transition into a research laboratory (6 ). This approach includes online and traditional literature searching methods and each student prepares one of the substituted chalcones, comparing the characterization data to those found in the literature. O
O
C
C
H
+
H3C
base -H2O
X
Y 1
2 O H
C
H X
Y
3
Scheme I
The synthesis of substituted chalcones has many positive features. Chalcones have been the subject of extensive study over many decades (7 ). Many chalcones have significant biological activity (8–12) and numerous examples continue to be isolated from natural sources (13–18). Chalcones have also served as starting materials for the synthesis of more complex medicinal compounds and as substrates for new enantioselective synthetic methods (19–21). These facts convey the relevance of the investigation to the students and spark their interest in
the project. The chalcones obtained from this project can be used as starting materials for further experiments in the organic laboratory, such as a Michael aldol condensation with ethyl acetoacetate (4) to produce 6-ethoxycarbonyl-3,5-diaryl-2cyclohexenones 5 (Scheme II) (2). O H
C C
O
O
+
C H
EtO
Y
base -H2O
4 X
3
EtO
O
O
C
C
Y
X 5
Scheme II
Perhaps most importantly, the various substituted benzaldehydes and acetophenones needed for this experiment are abundantly available—literally hundreds of substituted benzaldehydes and substituted acetophenones are available from commercial suppliers—and the condensation to produce 3 tolerates a wide variety of functional groups. We usually use 13 different benzaldehydes and 9 different acetophenones in this experiment. Thus there are 117 possible products, but we have only assigned 65 of the possible combinations to date. The microscale reaction allows for the inclusion of more exotic aldehydes and ketones without unreasonable expense, however, even for classes with relatively large numbers of students. The preparation of the required benzaldehyde (via oxidation of the corresponding benzylic alcohol [22]) or acetophenone (via Friedel–Crafts acylation [2, 23, 24]) can be used to extend the project aspect of the experiment into a multistep synthesis experience. Finally, spectroscopic data for substituted chalcones is abundant in the literature, including UV–vis (25), IR (26 ), and 1H and 13C NMR (27–32). Assigning the Targets We conduct the chalcone synthesis project in the second quarter of a two-quarter organic chemistry laboratory sequence with annual enrollments averaging 75 students. The project begins two to three weeks before the date of the actual chalcone synthesis to allow time for searching the literature. Each
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In the Laboratory
student is assigned a target compound, in one of several ways: 1. The student selects the name of a substituted acetophenone and a substituted benzaldehyde at random from a hat. The student then determines the structure for each starting material and the structure of the condensation product expected to be formed during the condensation reaction. 2. The student selects the structures of the starting materials at random and determines their names and the structure of the condensation product. 3. The student randomly selects the name or structure of a substituted chalcone from the hat and then performs a simple retrosynthetic analysis to determine the starting materials necessary to prepare the target chalcone.
In all cases, the student must determine the molecular formula of the target compound and its systematic name before moving on with the project. The Literature Search The next step in the project is a literature search. The students are provided with a handout describing how to search Chemical Abstracts using STN Easy (33–36 ). The department computer laboratory is reserved for two or three evenings so that all of the students can accomplish the online search. The instructor controls the log-in codes and passwords and supervises the search. The aforementioned handout guides the students through the process for finding the registry number for their target compound and for finding pertinent references with particular attention to references describing the preparation of the compound. The instructor answers procedural questions related to the search, offers advice on search strategy, and provides insight into which references are most promising. Nearly all the chalcones that could be prepared from commercially available acetophenones and benzaldehydes are in the CAS registry file, and in many cases both E/Z isomers and even isotopically labeled derivatives are known. These circumstances force the students to think carefully before determining which entry matching the formula and chemical name is the compound likely to be produced in their reaction. Students are required to report the CAS registry number of their target compound, the number of references found for their compound, and the cost of their online search. References in hand, the students must then retrieve characterization data (mp, IR and/or NMR data) and, ideally, a method of preparation for their target compound. Most of the assigned chalcones were first prepared many decades ago, however, so recent references often provide only a reference to an earlier paper that describes the preparation and physical constants for the compound. It can be an eye-opening experience for the students when the information they need is not in the first journal they open! We encourage the students to use interlibrary loan to obtain promising articles from journals not carried in our library (even when they are not written in English—structures are universal!). Sometimes it becomes necessary for students to search for their compound in the print version of Chemical Abstracts or Beilstein (37 ).
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Conducting the Reaction After the literature search and calculations to determine the appropriate quantities of reagents, the actual synthesis of the chalcones is fairly straightforward. The standard protocol of dissolving the starting materials in ethanol and adding aqueous sodium hydroxide with stirring provides good yields of the chalcone product within 15 minutes in most cases (2). We have determined that vigorous stirring of the reaction mixture is important to induce precipitation of the chalcone product, especially for those with lower melting points. Some reagent combinations require heating the reaction mixture in a water bath to drive the condensation reaction to completion. The reaction can be monitored by TLC, but we have found this to be unnecessary in most cases. This is an excellent time, however, to discuss with the class how electron withdrawing versus electron donating substituents on the reaction partners may influence the rate of the condensation reaction. In some cases the initial aldol adduct is slow to dehydrate, as evidenced by a broad absorption at ~3400 cm᎑1 in the IR spectrum of the crude product. In these cases, it may be necessary to heat the crude material further or to treat the crude product with acid to complete the dehydration. Most reagent combinations yield a substituted chalcone that may be purified by recrystallization from methanol or 95% ethanol, although other solvents can be explored. Students are expected to characterize their final product by melting point, IR, and NMR spectroscopy with comparisons to literature data. The fluorinated chalcone derivatives are particularly interesting to the students because in most cases it is the first time they have encountered spin–spin splitting to nuclei other than 1H. Noncrystalline products can be purified by column chromatography at the instructor’s discretion (2, 38). Hazards Sodium hydroxide solutions are caustic. Substituted benzaldehydes and acetophenones used in the experiment should be handled in a manner consistent with information provided on the material data safety sheet (MSDS) for each compound. All students should wear appropriate personal protective equipment while conducting the experiment, and work in a well-ventilated area. W
Supplemental Material
Instructions to students, prelab assignment, sample lab report form, sample experimental procedure, and table of compounds prepared are available in this issue of JCE Online. Acknowledgments We thank Stephen Chrisman for conducting optimization experiments, the WWU Libraries for providing a STN Easy subscription and our Chemistry 355 students for testing this experiment. JRV is grateful to the National Science Foundation for supporting this and other educational initiatives through a CAREER grant (CHE-0094378).
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In the Laboratory
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