Experimental and Guided Theoretical Investigation of Complex

Laboratory Experiment pubs.acs.org/jchemeduc

Experimental and Guided Theoretical Investigation of Complex Reaction Mechanisms in a Prins Reaction of Glyoxylic Acid and Isobutene Gaetano Angelici,*,†,‡ Stefan Nicolet,† Narasimha R. Uda,† and Marc Creus*,† †

Department of Chemistry, University of Basel, Spitalstrasse 51, CH-4056 Basel, Switzerland S Supporting Information *

ABSTRACT: A laboratory experiment was designed for undergraduate students, in which the outcome of an easy single-step organic synthesis with well-defined conditions was not elucidated until the end of the exercise. In class, students predict and discuss the possible products using their knowledge of reaction mechanisms. In the laboratory, they learn how to carry out a reaction safely with gaseous isobutene, and to isolate and identify the two main products. The class and the laboratory components are completed in 10 h, including laboratory time of 6 to 7 h, divided in two sessions. The class-component could also be implemented independently as a theoretical exercise in a “virtual experiment” simply by presenting the methods and results to students using a guided-inquiry approach, appropriate for a standard 3 h undergraduate class. The finding that the simple reaction leads to a largely unexpected product, together with open discussions with students covering several theoretical aspects applicable to this reaction, helps to promote critical thinking and to provide an effective educational tool to better understand the process of scientific research in chemistry. KEYWORDS: Inquiry-Based/Discovery Learning, Upper-Division Undergraduate, Laboratory Instruction, Organic Chemistry, Addition Reactions, Mechanisms of Reactions, NMR Spectroscopy, Reactive Intermediates

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INTRODUCTION AND TIMETABLE A research-based experiment was envisioned to promote critical thinking, initiative and curiosity through a Guided Inquiry approach1 in an upper-division (advanced) undergraduate organic chemistry course. A Prins reaction of glyoxylic acid and isobutene was developed and carried out on three independent occasions with 10 students typically working in pairs. The experimental results were reported by the students to their peers in the class, which allowed detailed discussion of theoretical aspects with a further 30 students. Students are presented with an easy-to-perform and robust reaction in a two day experiment, for a total laboratory time of 6 to 7 h. In most research situations in synthetic chemistry, it is unclear whether the reaction conditions will yield the desired products, for which it is important to develop the skill of identifying the products and to develop an understanding of what transformation actually took place, including elucidation of the likely reaction mechanism. However, only seldom is such an experience offered in the undergraduate teaching laboratory: instead, the expected products are usually clearly defined a priorialmost deterministicallyand any minor or unexpected products are typically either avoided or dismissed. The experiment and guided theoretical investigation presented here have the specific pedagogic goal of developing under© XXXX American Chemical Society and Division of Chemical Education, Inc.

standing of reaction mechanisms, focusing on the useful and important Prins reaction, and to develop an ability to determine reaction products experimentally through thin layer chromatography (TLC), nuclear magnetic resonance (NMR), and electrospray ionization mass spectrometry (ESI−MS). In addition, the exercise mimicked a typical research situation and provided the valuable experience of realizing that theory and experiment complement and mutually advance each other. The Prins reaction is particularly suitable for exploration of mechanisms, consisting of an electrophilic addition of an aldehyde or ketone to an alkene or alkyne, followed by capture of a nucleophile. After initial activation of an aldehyde with a Brønsted or Lewis acid, followed by addition of an olefin to form a cationic intermediate, multiple products can be formed. The versatility of the reaction is widely recognized and has been used, for example, to highlight the importance of Multicomponent reactions in green chemistry.2 The apparently straightforward synthesis presented here was chosen as a teaching tool because of the many different possible mechanistic pathways that may occur after electrophilic addition, which challenge the experimentalist to analyze complex and insightful theoretical aspects. Particularly since the reaction led to what many at first glance would describe as

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dx.doi.org/10.1021/ed400594r | J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

Laboratory Experiment

unexpected products, students were required to resort to their knowledge of thermodynamics and kinetics for a satisfactory explanation. The exercise is divided into four parts: (i) a class discussion to predict the products of the given reaction (1 h); (ii) an experimental part (6 to 7 h divided in 2 days, 2 h the first day and 5 h the second; however, the students that could not separate the products at the first attempt required an additional 1 to 2 h); (iii) structure determination by spectroscopy (1 h); and (iv) presentation of the results to the class and conclusions to determine agreement or disagreement between data and predictions (1 h). In the Supporting Information, each part is accompanied by some questions, answers, comments and points of discussion to guide a student’s understanding of the exercises.

at room temperature. The next day, the glass tube is cooled in a dry ice bath several minutes before the screw-cap is removed to allow excess isobutene to evaporate in a fume hood at room temperature. The reaction is quenched with water, extracted with dichloromethane, and dried, and the solvent is removed with a rotoevaporator to give crude products. A TLC analysis is done using a UV lamp and potassium permanganate stain for visualization. The products are purified by silica gel chromatography. The pure products are characterized by 1H NMR and 13C NMR, and by ESI−MS, if available. A detailed laboratory procedure for students, notes for instructors, student’s results and characterizations are in the Supporting Information.

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HAZARDS General laboratory safety procedures, such as wearing safety goggles, a laboratory coat and nitrile gloves must always be followed. All organic and inorganic chemicals in this experiment are considered hazardous, and direct physical contact must be avoided. Glyoxylic acid is corrosive for the skin and irritating for the eyes. All experiments must be performed in a fume hood. Particular care should be taken when using methylene chloride as solvent during the reaction and deuterated chloroform as solvent for NMR spectra, as both are suspected carcinogenic compounds. Care must also be taken when using sulfuric acid, a corrosive chemical. Isobutene gas is flammable, and the experiment has to be conducted under a well-ventilated fume hood, in the absence of free flames or heat sources. For a more detailed description of how to use a spray can of isobutene, carefully read the Supporting Information. Cyclohexane and ethyl acetate are both flammable solvents and, additionally, skin contact and inhalation must be avoided. Although dry ice (CO2) is not classified as toxic or harmful in accordance with the Globally Harmonized System of Classification and Labeling of Chemicals (GHS), prolonged exposure to dry ice can cause severe skin damage through frostbite. Dry ice sublimates into large volumes of carbon dioxide gas that could pose a danger of hypercapnia and should therefore only be exposed to open air in a well-ventilated environment. For precaution, the unknown products must be considered as potentially hazardous and handled with the same care as their precursors. The hazard and precautionary statements reported in the Supporting Information must be carefully read and understood by students before entering the lab.

CLASS DISCUSSION A class discussion is ideally suited for peer-discussion in pairs. Initially, students are asked to “list the possible products of a given reaction” (Scheme 1) individually, knowing the experimental conditions used, and then to reconsider the predictions after a brief discussion with their neighbors.3 Scheme 1. Reaction Scheme

The reaction between glyoxylic acid (1) and isobutene (2) in dichloromethane catalyzed by sulfuric acid provides an interesting source of discussion,4 because glyoxylic acid has two reactive groups, a carboxylic acid and an aldehyde5 and two transformations can occur: the alkylation of the acidic moiety through the tertiary carbocation formed after electrophilic addition of isobutene to sulfuric acid,6 and the electrophilic addition of the aldehyde to the alkene.2 Crucial questions used to guide students to consider alternative reactivities and to discuss with them mechanistic aspects are in the Notes for Instructors (Supporting Information). In the initial class discussion, a first pedagogic goal was to promote the creativity of students, letting them imagine possible outcomes. Moreover, such speculation was designed to make students realize that despite the strong theoretical grounding of chemistry as a science, the outcome of even an apparently simple reaction, although it may be robust and easily reproducible, is not always evident before it is investigated; in essence, chemistry remains an experimental science and, consequently, the reaction products of any new reaction condition need to be determined empirically.

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REASSESSMENT OF INITIAL HYPOTHESIS After encouragement to speculate upon multiple possible outcomes in the initial class discussion, students were asked to compare their predictions with experimental results. Students either collected data in the laboratory themselves, or were confronted with raw data given by instructors in the form of exercises for interpretation, i.e., TLC, yields, 1H NMR, 13C NMR, and ESI−MS data. In some cases, students who collected the data were asked to present results to their peers. This deceptively simple setup (Scheme 1) was a rich source of theoretical discussion due to several mechanistic possibilities: the experimental outcome was found by many to be counterintuitive, forcing a reassessment of initial hypotheses. As well as teaching valuable experimental methods and procedures, the overall exercise helped to illustrate clearly the scientific method in organic synthesis.

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EXPERIMENTAL SECTION A glass tube that can be sealed with a screw-cap (15 mL) is used. In a well-ventilated fume hood, a magnetic stir bar, glyoxylic acid (500 mg), dry dichloromethane, and a catalytic amount of conc. sulfuric acid are added to the glass tube and stirred in a dry ice bath (liquid nitrogen cannot be used) for 10 min. Isobutene (excess) is bubbled into the glass tube from a pressurized gas canister. The glass tube is sealed tightly with a screw-cap, removed from the dry ice bath, and stirred overnight B



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RESULTS AND DISCUSSION During initial class discussion, nearly 90% of the students involved in this project recognized immediately that isobutene can give electrophilic addition to sulfuric acid to form a tertiary carbocation (Scheme 2a), leading to further reaction with the

Although in the initial class-discussion, more than 90% of students had correctly expected the formation of the hydroxylactone (4) as the major product, upon being challenged which of the two possible minor products (6) or (7) would be expected, about 80% of students had argued for (6) as the more stable product. However, the experimental finding, to the surprise of most students, revealed the less substituted olefin (7) as the minor product. Specific points for discussion are reported in the Notes for Instructors (Supporting Information). The pedagogic goals were similar for students that did the experimental part versus those that did not partake in the laboratory component. However, the experimental part helped to underline the message that chemistry is an experimental science and, in addition, provided important hands-on experience on how to perform a reaction with gas-isobutene and handle common laboratory techniques safely. All students were asked to provide a report for assessment (marked pass/fail), which had to include written answers to questions posed during discussions. Students who carried out the experimental part were also asked to hand-in their labbooks, including spectra and their filled-in result table, as part of the assessment. Moreover, some students who carried out the experiment were asked to report, in small groups, their findings to their fellow students who did not do the laboratorycomponent. This student-reporting to peers also promoted the skill of presenting scientific data in public. Students received feedback but were not assessed on their presentation.

Scheme 2. Schematic Representation of the Prins Addition of Isobutene to the Aldehyde and of the Electrophilic Addition of Isobutene to Sulfuric Acid

acidic moiety of glyoxylic acid, which ends-up alkylated (Supporting Information Scheme S1). However, only about 60% realized that isobutene can also act as a nucleophile on the activated aldehyde in a formal Prins addition (Scheme 2b). The carbocation resulting from the Prins addition can react further in ways that students were asked to critically assess. After class discussion, they were able to propose additional reaction pathways and list the possible products (Scheme 3), speculating about the more reasonable mechanisms. In the experimental part, all of the students were able to set up the experiment correctly using the guidelines provided on all three occasions. However, in the workup, about 2 in 10 students could not separate efficiently the two main products in their first attempt: a colorless oil and a white powder, whose structures should be determined by NMR. The colorless oil was found to be the olefin (7) (yield = 20%), whereas the white powder corresponded to the protected hydroxylactone (4) (yield = 60%). The reported yields were obtained from the average yields of the students, which in the best case were 70% for (4) and 25% for (7).

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CONCLUSION In a typical laboratory situation by practising organic chemists, students were called to predict the possible products of a given reaction with the help of guiding questions. The initial class discussion helped students to define and to analyze a problem, and to improve their critical skills. In the laboratory, students learned how to handle a reaction with gaseous isobutene, to purify products and, finally, to identify these through spectroscopy. At the end of this experiment, students were faced with the general problem “why was this the outcome of the reaction?”. The educational achievement for the students

Scheme 3. Proposal of Reaction Pathways and Possible Products from Further Reaction of the Carbocation Intermediate That Is Formed by Formal Prins Addition of Isobutene to the Activated Aldehydea

a

The four arrows represent four different pathways leading to four products (4−7). C



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was to redefine their hypotheses in a reiterative process after the products had been characterized experimentally. Students involved in this experiment found it exciting to work in a typical research situation encountered by chemists that was not merely a predictable textbook exercise. Judging from student feedback, this exercise provided the valuable lesson that chemistry remains an empirical science and that even a simple reaction cannot be easily explained or predicted: conclusions and results need to be supported by solid data, which provide a test for hypothesis and provide a basis for theoretical models. Conversely, the discussion of ideas and of chemical theory is important in guiding experimental approaches. Our experience of students reporting their results to peers suggests that the experimental part can be provided “virtually” with the methods and results provided by the demonstrator. In this case, the theoretical aspects alone may be sufficient to provide a valuable lesson and shorten the time for the whole exercise to 3 h, which combines Part 1 (class discussion), Part 3 (structure determination by NMR spectroscopy), and Part 4 (reassessment of initial hypothesis). Finally, the materials described here offer additional possibilities to expand critical thinking in more advanced courses, such as design of additional experiments to elucidate reaction mechanisms (trapping, crossover, isotope effects, etc.) in graduate level organic chemistry courses.

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REFERENCES

(1) See for example: (a) Laredo, T. Changing the First-Year Chemistry Laboratory Manual To Implement a Problem-Based Approach That Improves Student Engagement. J. Chem. Educ. 2013, 90, 1151−1154. (b) Hein, S. M. Positive Impacts Using POGIL in Organic Chemistry. J. Chem. Educ. 2012, 89, 860−864. (c) Tomasik, J. H.; Cottone, K. E.; Heethuis, M. T.; Mueller, A. Development and Preliminary Impacts of the Implementation of an Authentic ResearchBased Experiment in General Chemistry. J. Chem. Educ. 2013, 90, 1155−1161. (d) Balija, A. M.; Reynolds, A. M. A Mixed-Aldol Condensation Reaction with Unknown Aldehydes and Ketones: Employing Modern Methods To Improve the Learning Process for Second-Year Undergraduate Organic Chemistry Students. J. Chem. Educ. 2013, 90, 1100−1102. (e) Gaddis, B. A.; Schoffstall, A. M. Incorporating Guided-Inquiry Learning into the Organic Chemistry Laboratory. J. Chem. Educ. 2007, 84, 848−851. (f) Mohrig, J. R.; Hammond, C. N.; Colby, D. A. On the Successful Use of InquiryDriven Experiments into the Organic Chemistry Laboratory. J. Chem. Educ. 2007, 84, 992−998. (g) Mason, D. S. Inquiry Methods in Chemistry. J. Chem. Educ. 2002, 79, 281. (2) (a) Crane, E. A.; Scheidt, K. A. Prins-Type Macrocyclizations as an Efficient Ring-Closing Strategy in Natural Product Synthesis (Review). Angew. Chem., Int. Ed. 2010, 49, 8316−8326. (b) Dintzner, M. R.; Maresh, J. J.; Kinzie, C. R.; Arena, A. F.; Speltz, T. A ResearchBased Undergraduate Organic Laboratory Project: Investigation of a One-Pot, Multicomponent, Environmentally Friendly Prins−Friedel− Crafts-Type Reaction. J. Chem. Educ. 2012, 89, 265−267. (c) Delmas, M.; Kalck, P.; Gorrichon, J.-P.; Gaset, A. An Easy Student Synthesis of a Substituted 1,3-Dioxane by use of an Ion-exchange Resin as Catalyst: Clean Illustration of the Prins Reaction. J. Chem. Educ. 1982, 59, 700− 701. (3) Smith, M. K.; Wood, W. B.; Adams, W. K.; Wieman, C.; Knight, J. K.; Guild, N.; Su, T. T. Why Peer Discussion Improves Student Performance on In-Class Concept Questions. Science 2009, 323, 122− 124. (4) (a) Plusquellec, D.; Le Floc’h, Y.; Paillon-Jegou, D. Réactions de dérivés de l’acide glyoxylique avec des oléfins: synthèses de γ-lactones α-substituée. Bull. Soc. Chim. Fr. 1979, II, 552−558. (b) Jarvis, B. B.; Wells, K. M.; Kaufmann, T. A New Synthetic Route to α-Hydroxy Butyrolactones. Synthesis 1990, 11, 1079−1082. (5) (a) Klinger, F. D.; Ebertz, W. Oxocarboxylic Acids. In Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2012; Vol. 25, pp 601−608. (b) Kerber, R. C.; Fernando, M. S. α-Oxocarboxylic Acids. J. Chem. Educ. 2010, 87, 1079−1084. (6) Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry; Oxford University Press: Oxford, 2001; pp 503−521.

ASSOCIATED CONTENT

S Supporting Information *

A full experiment section with detailed instructions for students and notes for instructors; list of required reagents with CAS numbers; full characterization of the purified compounds (4) and (7), with copies of NMR spectra and assignments. This material is available via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

* E-mail: [email protected]. * E-mail: [email protected]. Present Address ‡

Institute of Chemistry Clermont-Ferrand (ICCF) - UMR 6296, University “Blaise Pascal”, Campus des Cézeaux, 24 Avenue des Landais, BP 80026, 63171 Aubière, France.

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NOTE ADDED AFTER ASAP PUBLICATION This paper was published to the Web on 10/10/2014 with an error in Figure S3 in the Supporting Information. This was fixed in the version published on 10/14/2014.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank the financial support from the Swiss National Science Foundation (Grants 200021-116344 and CR22I3_143770), the State Secretariat for Education and Research (Grant C11.0054) and COST Actions TD0905 and CM0902. M.C. is particularly grateful for the support from the Holcim Foundation and G.A. from the Novartis Foundation. The authors would also like to acknowledge Thomas R. Ward for general encouragement and for allowing the use of laboratory facilities, as well as the students who participated in the exercises presented here. This work is dedicated to the memory of our research-colleague and friend Dr. Yvonne Wilson (1970−2014), who taught us bravely to remain kind and positive in the face of adversity. D


Experimental and Guided Theoretical Investigation of Complex

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