Laboratory Experiment pubs.acs.org/jchemeduc
Exploring the Wittig Reaction: A Collaborative Guided-Inquiry Experiment for the Organic Chemistry Laboratory James A. MacKay* and Nicholas R. Wetzel Department of Chemistry and Biochemistry, Elizabethtown College, Elizabethtown, Pennsylvania 17022, United States S Supporting Information *
ABSTRACT: A two-week guided-inquiry Wittig reaction experiment was developed for the undergraduate organic laboratory. In week one, groups are assigned a research topic to investigate the Wittig reaction, such as the effect that substituents on the carbonyl compound may have on E/Z selectivity. A hypothesis, controlled by a provided chemical list, is developed along with a series of experiments to test predictions. For example, more Z isomer might be expected from a steric effect of methyl substituents on o-, m-, and ptolualdehydes. In the second week, students perform reactions by adapting a general procedure and obtain E/Z selectivities from 1H NMR. Compiled data are shared online as groups aim to support or refute their hypotheses. As a result of the experiment, students gain insights into the nature of science and the analysis of data as well as a better understanding of the research process. KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Collaborative/Cooperative Learning, Hands-On Learning/Manipulatives, Inquiry-Based/Discovery Learning, Alkenes, NMR Spectroscopy, Stereochemistry, Synthesis
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nquiry-based learning has gained increasing prominence in laboratory curricula. These methods are inductive, have an outcome that is not predetermined, and typically give students more control over procedural options than expository experiments.1 They allow students more involvement in their learning,1b,2 are linked to improved formal reasoning,3 improve attitudes toward science,4 and provide collaborative opportunities through sharing of data and ideas.5 In an effort to introduce inquiry experiments into the curriculum, reactions were sought where multiple variables could be investigated to test student hypotheses. The Wittig reaction is ideal due to the availability of many inexpensive carbonyl compounds, phosphonium salts, and phosphonium ylides and because it affords high yields in a reasonable period of time. The literature contains many experiments using the Wittig reaction6 owing to a unique mechanism,6b,i stereoselectivity,6c−g,i and the potential for green reactions.6d,f−h However, few inquiry experiments exist6j,k and none fully met desired learning objectives to (1) apply the process of the scientific method, (2) build teamwork skills, (3) interpret NMR data of complex mixtures, and (4) build knowledge of the Wittig reaction. Though not a major aim, water was chosen as a green alternative to organic solvents.7 This experiment was designed for second-semester organic chemistry and has been completed by 227 students over five years. The experiment is offered toward the end of a 14-week semester after students are exposed to carbonyl reactivity and many common laboratory techniques including NMR spectroscopy. It requires two 3-hour laboratory periods with an optional meeting following the second week between student groups and the instructor(s). © 2014 American Chemical Society and Division of Chemical Education, Inc.
EXPERIMENTAL OVERVIEW
In the first week of the experiment, students are divided into teams of 3−4. Each team is assigned a research problem and spends the period discussing their problem, devising a testable hypothesis and series of experiments, and making predictions. Keeping to the theme of guided inquiry, the research problems are intentionally left open but are carefully designed to direct students toward a logical set of experiments by requiring them to utilize reagents from a list of chemicals. A general procedure for conducting the reaction using any carbonyl, alkyltriphenylphosphonium salt (or ylide), and base is also provided. Alkene stereoselectivity can be investigated by individually controlling variables such as the structure of the carbonyl, ylide, or base employed. Each group has their plan approved by the instructor and submits a specific procedure to be performed in week two. Table 1 shows examples of research problems, representative student derived hypotheses, and the reagents used to test them. The second week involves individuals performing reactions and obtaining 1H NMR data on product mixtures. The general procedure follows: A vial is charged with aldehyde (1.0 mmol), water (4 mL), phosphonium salt or phosphonium ylide (1.1 mmol), and base (3 mmol), if necessary. The reactions are vigorously stirred for 45 min. Extraction using an organic solvent and solvent evaporation affords crude product for NMR analysis from which the E/Z ratio of products and percent conversion are calculated. Scheme 1 shows a typical studentperformed reaction. Published: April 7, 2014 722
dx.doi.org/10.1021/ed3003836 | J. Chem. Educ. 2014, 91, 722−725
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Table 1. Representative Problems, Student Hypotheses, and Key Variables Studied Research Problems Effect that substituents on aromatic aldehydes have on E/Z selectivity. Effect of the structure of the ylide on E/Z selectivity. Effect of the base on E/Z selectivity when using phosphonium salts.
Representative Hypothesis
More E-isomer will form as the substituent is positioned closer to the Vary the aldehyde: benzaldehyde, o-, carbonyl carbon. m-, and p-tolualdehyde. The more nucleophilic the ylide, the faster the reaction and, thus, the more Vary the ylide: benzyl, cyanomethyl, of the Z-isomer formed due to kinetic control. ethyl ester, methyl ketone. Because all bases form the same ylide, there is no effect on the E/Z Vary the base: KOH, KOtBu, K2CO3, selectivity. K3PO4.
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DISCUSSION Distinctive to this experiment is the opportunity to make and test hypotheses. From each of the research problems, multiple hypotheses were devised where the outcome was truly unknown by both student and instructor. Student hypotheses were both supported and refuted with the understanding that a “correct” prediction was not the main goal. Rather, the goal was to learn lessons in chemical reactivity. For example, students often proposed comparing monosubstituted benzaldehydes to test the first hypothesis in Table 1. Students predicted varying E/Z selectivities for o-, m-, and p-tolualdehydes due to the presence or absence of cis steric interactions in the transition state or oxaphosphetane intermediate. Increasing steric demand around the carbonyl might also slow the reaction leading to an increase in the E selectivity. The student generated E/Z ratios for the tolualdehydes, however, were identical within experimental error (see the Supporting Information for data), apparently refuting the hypothesis. Yet, using 2,6-dimethylbenzaldehyde led to an increased E-selectivity due to its conformational symmetry compared to the monosubstituted tolualdehydes. Other similar lessons learned are included in the Supporting Information along with years’ worth of student data to help instructors adopting this experiment anticipate unique phenomena and trends. Through this experiment, students gained not only the experience of encountering both expected and unexpected results10 but also the chance to apply their knowledge of chemistry toward explaining unexpected results. Thus, the laboratory does not fit the typical model of a discovery (or guided-inquiry) experiment where the instructor is privy to the outcome and all students obtain the same result but rather mimics the true nature of science where results rarely fit into a set of simple rules. Related is the fact that students do not have a fully mature appreciation for mechanistic organic chemistry at this point in their education, leading to many somewhat simplistic hypotheses. Though much is known
Scheme 1. Reaction Between 2-Nitrobenzaldehyde and Methyl(triphenylphosphoranylidene)acetate
Following week two, groups have the option of meeting with the instructor to discuss data analysis and are required to post their data to a wiki for sharing across laboratory sections. With student collaboration as a major aim of the experiment, a convenient and easily accessible means of data sharing is crucial. There are currently few examples using cloud computing as a tool in the undergraduate laboratory,8 and this experiment underscores the cloud as a powerful tool to aid in collaboration in the laboratory. Google Documents9 was chosen because of its ease of use and general familiarity by both faculty and students. Finally, in a group report, students use compiled class data to help support or refute their hypothesis or explain how and why the data were inconclusive.
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Key Variable and representative reagents
HAZARDS
Consult MSDS sheets for the handling of all chemicals and wear gloves to minimize contact. Aldehydes used are generally irritants, some flammable and toxic. Most bases used are caustic. Phosphonium salts/ylides are irritants. Diethyl ether and hexanes are flammable and should be handled in a fume hood. The n-hexane in hexanes is a neurotoxin. CDCl3 is toxic and a cancer-suspect agent. Descriptions of the hazards associated with all chemicals are available in the Supporting Information. Waste should be disposed of in the appropriate containers.
Figure 1. 1H NMR of the reaction product between 2-nitrobenzaldehyde and methyl(triphenylphosphoranylidene)acetate. 723
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regarding the mechanism of the Wittig reaction,11 this experiment was not intended to delve into advanced mechanistic phenomena. Rather, it demonstrated to students that simplistic explanations do not always suffice when multiple variables are involved. Analysis of large data sets is another distinctive aspect to this experiment. Though some confusion resulted from inconsistent data from student to student, lessons in finding trends, demonstrating reproducibility, and the importance of multiple trials to obtain reliable data were learned. Individuals did not have time to replicate experiments, but the wiki was used to compare results to those who did the same experiment. As a result of the challenges encountered in the first several years, this year, the experiment was followed with an in-class discussion in the lecture course where students observed and discussed five years of compiled data. Most noteworthy in this exercise was that students had enough exposure to the chemistry that they could intelligently contribute and gain additional insight into the reaction itself using data analysis skills. The exercise revealed that often it requires more data than one class generates to make concrete conclusions and that data inconsistencies are usually the exception and not the norm. Finally, most expository laboratories that involve organic transformations focus on obtaining pure products for analysis. This experiment differs in that the major aim was to report stereoisomeric ratios. Thus, the procedure was designed with minimal product purification. Students obtained difficult to interpret spectra where not all peaks were important. For example, product mixtures contained triphenylphosphine oxide and often solvent impurities. The spectral analysis gave the chance to (1) assign key peaks from different molecules to determine the ratio of the key components of the reaction mixture, (2) use coupling constants to assign E/Z ratios, (3) disregard unimportant impurities including triphenylphosphine oxide and solvent peaks, (4) obtain percent conversions and E/ Z ratios, and (5) work with spectra with overlapping peaks. Shown in Figure 1 is a student generated 1H NMR spectrum with the key peaks identified. Table 2 shows the results of a survey given over the past four years intended to gauge student perception of learning. The questions were scored on a scale of 1−5 and the % positive responses were those students scoring a 4 or a 5. Students overwhelmingly responded positively to this experiment. Each of the questions in Table 2 was answered with a high degree of
favorability. Not unexpectedly, the lowest rated question was the one involving the group formal report, which is attributed to a perception that peers could influence one another’s grade. However, value was placed on working together and the opportunity to build teamwork skills that are necessary to most professions. Students also provided written feedback and, similar to the survey questions, the comments were generally positive showing an understanding for the objectives. The experiment clearly demonstrated student learning. Written reports typically showed understanding of the reaction and clear articulation of the NMR spectra (objectives 3−4) as measured by a rubric for the formal report. In addition to a deepened understanding of the Wittig reaction and carbonyl reactivity, a marked increase in scientific maturity (objectives 1−2) was observed. An increased interest and a greater preparedness for undergraduate research was noted since the introduction of this experiment. Although many students will never perform another alkene synthesis, gains in formal reasoning, teamwork, creativity, and experimental design were apparent particularly as compared to cohorts who predate this experiment.
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CONCLUSION The Wittig reaction was ideal for a collaborative guided-inquiry experiment due to the ability to manipulate multiple reaction variables and analyze a variety of predicted trends, including alkene stereoselectivity, ylide reactivity, and base strength. The approach afforded students the opportunity to design a unique set of experiments to probe the stereoselectivity of the reaction. Students valued the opportunity to test their own ideas, resulting in more thoughtfulness and intellectual investment compared to expository experiments. There was additional value in the opportunity to challenge and develop interpretive NMR skills through the analysis of crude reaction mixtures. Finally, the collaborative experiment developed teamwork skills that will be crucial for their intended profession.
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* Supporting Information Student handout; chemical list with associated hazards; instructor notes; student data tables; student-generated NMR spectra. This material is available via the Internet at http:// pubs.acs.org.
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Table 2. Student Responses to Select Survey Questions Positive Responsesb (%)
Question
Average
Standard Deviation
This experiment promoted appreciation and understanding of design of organic experiments. This experiment helped me apply course material in a laboratory setting. My team worked collaboratively. As a team we were able to develop a testable hypothesis. The group report helped foster better understanding of the experiment.
4.20
0.66
90%
4.51
0.64
95%
4.23 4.67
0.80 0.54
85% 97%
3.91
1.06
71%
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ASSOCIATED CONTENT
S
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge the students of CH114 who helped this laboratory develop into its current form. J.A.M. thanks the National Science Foundation for support of this work under CHE-0958425.
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a
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A total of 177 students over four years; questions answered on a scale of 1−5 (1 = Strongly Disagree; 2 = Disagree; 3 = Neutral 4 = Agree; 5 = Strongly Agree). bPositive responses were those students scoring a 4 or a 5. 724
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