In the Laboratory
Probing the Rate-Determining Step of the Claisen–Schmidt Condensation by Competition Reactions
W
Kendrew K. W. Mak,* Wing-Fat Chan, Ka-Ying Lung, Wai-Yee Lam, Weng-Cheong Ng, and Siu-Fung Lee Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong SAR; *
[email protected] The Claisen–Schmidt alkaline condensation of benzaldehyde and acetophenone yielding chalcone (benzalacetophenone) is a popular experiment in the undergraduate organic laboratory for illustrating the manipulation and mechanism of the aldol condensation (1–7). It enhances students’ understanding of the chemistry and reactivity of enolates and carbonyl compounds. The mechanism of the Claisen–Schmidt condensation has been extensively investigated for decades by kinetic measurements as well as computational studies (8–13). The generally accepted mechanism depicted in Scheme I involves two key elementary steps. It begins with a nucleophilic addition of the enolate derived from acetophenone to the carbonyl carbon of benzaldehyde yielding the intermediate β-hydroxy ketone, followed by dehydration to give chalcone as the product. We have incorporated the synthesis of chalcone in our undergraduate organic laboratory classes as a synthetic experiment for several years. Recently, we have extended this purely synthetic experiment into a mechanistic study that investigates the linear free energy relationship (LFER) of the reaction (14). Students were asked to identify the rate-determining step of the accepted mechanism by comparing the reaction rates obtained with different para-substituted acetophenones and benzaldehydes and then fitting the data into Hammett plots to evaluate how the reaction was affected by the electronic effects of the substrates. There are several articles published in this Journal describing the studies of linear free energy relationship (LFER) by using the Hammett equation to probe the mechanism of organic reactions (3, 15–17). Generally, LFER studies are carried out by measuring the rate constants with different para- or meta-substituted aromatic reactants using spectroscopic methods under precisely controlled reaction conditions and then plotting the logarithms of the relative rates versus the substituent constants to obtain the Hammett plot (14). The adoption of this kind of experiment into the undergraduate lab is often obstructed by the difficulties in finding the appropriate reactions and conditions that match the availability of equipment and time of the teaching laboratory, as
well as the level of precision required for controlling the reaction conditions. As a compromise, the Hammett plot can be constructed from the ratios of products obtained in competition experiments as the relative rates of different substrates are equal to the ratios of product concentrations in the reaction mixture. This is also a commonly used method in the primary literature for studying LFER (18–20). A recently published article in this Journal describes the use of 1 H NMR in competition experiments to study the substituent effects of several nucleophilic addition reactions of aromatic ketones (16). Herein, we describe our attempts of using competition experiments to identify the rate-determining step of the Claisen–Schmidt condensation. The students carry out the competing Claisen–Schmidt condensations under two different conditions: (i) the reactions of different para-substituted benzaldehydes with a limiting amount of acetophenone and (ii) the reactions of para-substituted acetophenones with a limiting amount of benzaldehyde. The reaction products are determined by gas chromatography. The product concentrations are plotted against the substituent constants to obtain a Hammett plot, from which mechanistic details are deduced. The experiment is completed in two half-day laboratory sessions. The first session focuses on the synthesis and purifications of chalcones as standard compounds and obtaining the 1H NMR and GC data for characterization. The competition reactions are carried out in the second laboratory session and the relative rates of reactions are determined. Each student in the class is assigned to work on a particular substituted substrate. The data from the class are pooled together to obtain the Hammett plots. Hazards The benzaldehydes and acetophenones used in this experiment are harmful and irritating. Students are advised to perform the experiment in fume hoods and put on proper protective gloves.
Scheme I. The accepted mechanism of the Claisen–Schmidt condensation.
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In the Laboratory Table 1. Reaction Yields for the Synthesis of Substituted Chalcones
Table 2. Relative Concentrations of Chalcones from Competition Reactions of para-Substituted Benzaldehydes with Acetophenone cX/cH
log(cX/cH)
–OCH3
0.197
᎑0.705
᎑0.27
0.469
᎑0.329
᎑0.14
–CH3 –H
1.00
0.000
–Cl
7.63
0.883
0.24
1.306
0.78
–NO2
X –OCH3 –CH3 –H –Cl –NO2 –H –H –H –H
Y –H –H –H –H –H –OCH3 –CH3 –Cl –NO2
Yield (%) 22 32 31 75 52 33 29 76 36
Results and Discussion The syntheses of substituted chalcones from appropriate acetophenones and benzaldehydes by alkaline Claisen– Schmidt condensations were straightforward and reasonably pure products were obtained after recrystallization from hot ethanol (21). Reaction yields obtained from the class are shown in Table 1. The purity of the products was checked by 1H NMR and GC. Competition reactions of acetophenone with two different para-substituted benzaldehydes were carried out by reacting mixtures of 4 mmol each of two appropriate benzaldehydes and 4 mmol of acetophenone in ethanol and aqueous NaOH at room temperature. Vigorous stirring was crucial to facilitate the reactions as some of the substrates have limited solubilities in the reaction media. The reaction mixtures were worked up by extraction with dichloromethane. Isolation of the products by precipitation should be avoided as different chalcones have different solubilities and thus complete recovery of products may not be achieved. The concentrations of chalcones were determined by GC. It is noteworthy that signal sensitivities of GC vary with different compounds. Therefore a calibration curve must be established for each chalcone. Although 1H NMR spectroscopy offers the advantage of directly obtaining the ratios of products from the integration values of resonance signals, GC was selected owing to extensive overlapping of resonance signals as a result of several compounds in the product mixtures. In most cases, the NMR spectra could not provide distinct resonance signals for an unambiguous determination of product ratios. Furthermore, high-field NMR spectrometers are not often available for undergraduate laboratories. GC measurements can be easily automated by using an autosampler. The chalcones separated nicely from each other as well as from the starting materials on the gas chromatograms. 1820
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σX
X
20.2
0
Figure 1. The Hammett plot for the Claisen–Schmidt condensation of para-substituted benzaldehydes with acetophenone.
Calibration was performed with 20 ppm and 100 ppm standard solutions of chalcones, with trans-stilbene added as the internal standard. The peaks on the chromatograms obtained from competition reactions were identified by comparing their retention times with those obtained from standard compounds. The relative concentrations of substituted chalcones obtained from the competition reactions and the respective substituent constants (σ) are shown in Table 2. A plot of log (cXcH) against the substituent constants (σX) is shown in Figure 1 (cX and cH are the concentrations of the substituted and unsubstituted chalcones, respectively). The plot showed an excellent linearity (R 2 = 0.99) with the reaction constant (ρ) found to be 3.09 (The data point for NO2-substituted benzaldehyde was neglected from the line fitting, vide infra). The relative large positive value of ρ suggests the transition state in the rate-determining step of the reaction is substantially stabilized by the electronic effects of the substituents at the para position of the benzaldehydes. The accepted mechanism of the Claisen–Schmidt condensation involves a nucleophilic addition of an enolate to the carbonyl carbon of benzaldehyde forming an intermediate β-hydroxyl ketone, followed by dehydration. Results of our studies indicated that the nucleophilic addition is the rate-determining step of the reaction. Electron-withdrawing groups on benzaldehyde render the carbonyl carbon more electron deficient and therefore, more susceptible to nucleophilic attack by the negatively charged enolates, leading to a faster reaction rate (15, 16). The dehydration step, on the other hand, is expected to be favored by electron-rich benzaldehydes that can better stabilize the partial positive charge formed at the benzylic carbon during the leaving of the OH− group (22–24). Another group of students carried out the competition reactions of benzaldehyde with para-substituted acetophenones. The results are summarized in Table 3. Before the experiment the students predicted that substituted aceto-
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In the Laboratory Table 3. Relative Concentrations of Chalcones from Competition Reactions of para-Substituted Acetopheones with Benzaldehyde σX
X
cX/cH
–OCH3
0.452
᎑0.345
᎑0.27
–CH3
0.666
᎑0.177
᎑0.14
–H
1.000
0.000
–Cl
2.91
0.464
0.24
᎑0.024
0.78
–NO2
0.946
log(cX/cH)
0
physical tool for studying the mechanism of organic reactions. The experiment can be easily adapted to most undergraduate laboratories without the need of acquiring specific and expensive equipment. Acknowledgments This project is partially supported by the Teaching Development Grants of the Chinese University of Hong Kong. The authors would like to thank Hung Kay Lee for providing valuable advice during the preparation of this manuscript and Chi-Chung Lee for obtaining the mass spectra. Supplemental Materials Instructions for students, notes for instructors, and spectroscopic and chromatographic data of the chalcone products are available in this issue of JCE online. W
Literature Cited
Figure 2. The Hammett plot for the Claisen–Schmidt condensation of para-substituted acetophenones with benzaldehyde.
phenones, taking the role of nucleophiles in the reaction, would give a negative ρ. Surprisingly, the Hammett plot obtained with substituted acetophenones (Figure 2) also gave a positive but a smaller absolute value for ρ (1.59) (The data point for NO2substituted acetophenone was neglected from the line fitting, vide infra). This indicates that the condensation reaction is also favored by electron-deficient aceto-phenones. The results prompted us to propose the rates of the condensation reactions correlate with the acidity of acetophenones (25). Theoretical studies have suggested that the reaction is initiated by the removal of an α-H atom of acetophenone by hydroxide anion, forming the acetophenonate ion (12). Electron-withdrawing groups on the acetophenones stabilized the negatively charged acetophenonate ion and increased its concentration in the reaction medium, and thus the reaction was accelerated. It is noteworthy that both p-nitrobenzaldehyde and pnitroacetophenone, despite being the most electron-deficient substrates among the list, reacted much slower than expected. Two explanations were proposed by the students to account for these observations. The poor solubility of the para-NO2 substrates might have significantly hindered the reactions. Alternatively, the concave-downwards Hammett plot might indicate a change of the rate-determining step for strongly electron-deficient substrates. In the cases of para-NO2 substrates, the dehydration step might become rate-determining since this step is expected to be impeded by electron-withdrawing groups. Summary We were successful in converting a purely synthetic experiment into a physical organic one with minor modifications. The experiment expands the students’ knowledge of carbonyl chemistry and also introduces them to a useful www.JCE.DivCHED.org
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