In the Laboratory
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The Mechanism of the Ritter Reaction in Combination with Wagner–Meerwein Rearrangements A Cooperative Learning Experience María I. Colombo, María L. Bohn, and Edmundo A. Rúveda* Facultad de Ciencias Bioquímicas y Farmacéuticas, Instituto de Química Orgánica de Síntesis (CONICET-UNR), Casilla de Correo 991, 2000 Rosario, Argentina; *
[email protected] In 1948, Ritter and Minieri reported that the reaction of alkenes with nitriles in the presence of concentrated sulfuric acid yields an amide by simple dilution with water (1). Since alcohols can also be used as substrates instead of the alkenes, the Ritter reaction provides a particularly versatile synthetic method for the preparation of a variety of amides (2–5). The essential details of the mechanism of this reaction, that is, the generation of a carbocation that undergoes nucleophilic attack by the nitrile to produce a nitrilium ion whose hydrolysis in the aqueous workup affords the amide, were suggested by Ritter and Minieri (1) and have been supported by other workers by using substrates in which an intramolecular rearrangement of the Wagner–Meerwein type was observed. Good illustrations of such rearrangements were described by Jacquier and Christol (6 ) and by Edwards and Marquardt (7 ). The Ritter Reaction as an Instructional Laboratory Three publications in this Journal have highlighted the use of the Ritter reaction as an instructional laboratory (8– 10). Hathaway (8) described an open-ended investigation for students to examine a possible mechanism for the reaction of an acetic acid solution of benzonitrile and tert-butyl alcohol in the presence of concentrated sulfuric acid (Scheme I). By using benzamide as substrate and monitoring the reaction by TLC, students could observe that benzamide is not a reactive intermediate in this Ritter reaction. However, this additional experimental information does not address the accepted mechanism of this reaction as shown in Scheme II. Crouch described a discovery-based exercise using the same Ritter reaction under slightly different reaction conditions to demonstrate the trapping of a carbocation intermediate by a nitrile, which produces an amide by aqueous hydrolysis (9). Crouch notes that while the formation of a 3° carbocation is easily recognized by students, the benzamide product is not usually predicted, and this is precisely why this type of experiment helps students to develop analytical and problem-solving skills. Hessley reported an extension of Hathaway’s experiment involving molecular modeling computations to predict the mechanism of the Ritter reaction shown in Scheme I (10). In this computational exercise three mechanisms are analyzed as a prelab assignment. These mechanisms involve (i) the prior formation of benzamide in aqueous acid and reaction with the alcohol to yield the amide product (ii) the direct reaction of benzonitrile with tert-butyl alcohol in acidic medium, and (iii) the reaction involving the tert-butyl carbocation. On the basis of the computed ∆Hf values for the reactants, reaction intermediates, and products, the ∆Hrxn values are determined. The ∆Hf values for the transition states for pathways i and ii are also determined. With this information, the students 484
formulate a hypothesis about which pathway they expect to govern the course of the reaction. This, together with the results of Hathaway’s experiment, allows them to decide which is the most plausible mechanism for this reaction. Our Experiment As part of our effort to improve the laboratory experience of our students, we have extended this work by using the Ritter reaction with tert-butyl alcohol and substrates in which Wagner–Meerwein rearrangements can take place. In these experiments sec-butyl, isobutyl and n-butyl alcohols are treated with concentrated sulfuric acid in the presence of benzonitrile to yield, after the aqueous work-up, reaction products that are analyzed by TLC. Analysis of the recrystallized product from the reaction of tert-butyl and sec-butyl alcohols reveals the presence of pure compounds that are characterized, on the basis of their melting points and 1H NMR spectra, as N-tert-butylbenzamide and N-sec-butylbenzamide, respectively. These amides are used as reference compounds for the TLC identification of N-sec-
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Journal of Chemical Education • Vol. 79 No. 4 April 2002 • JChemEd.chem.wisc.edu
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In the Laboratory
butylbenzamide in the crude product from the reaction of n-butyl alcohol and of N-tert-butylbenzamide and N-secbutylbenzamide from the reaction of isobutyl alcohol. A small amount of benzamide is also detected in these crude reaction products. The reactions can be run simultaneously at room temperature and can be monitored by TLC. All reaction products are solid, and N-tert-butylbenzamide and N-secbutylbenzamide should be recrystallized for their identification. The 1H NMR spectra of the amides are so simple that even students with little experience in spectroscopy can analyze them. Furthermore, the product ratio in the mixture of N-tert-butylbenzamide and N-sec-butylbenzamide can be determined by analyzing the aliphatic region of the 1H NMR spectrum of the crude product of the reaction that produces these compounds. We use these experiments as an optional activity at the end of our one-year course in organic chemistry, which includes a laboratory that is required. The course is intended for majors in chemistry, cellular and molecular biology, and pharmacy. In this introductory course we encouraged students to expend a major portion of their efforts on the conceptual understanding of reaction mechanisms instead of just memorizing the growing set of reactions, reagents, reactive intermediates, etc. Therefore, they are ideally primed for an exposure to the chemistry of carbocations and to all the reactions where carbocations are intermediates, and also to the reactions of carboxylic acids and their derivatives. We start this laboratory exercise with the preparation and identification of N-tert-butylbenzamide, following essentially the experimental conditions described by Ritter and Minieri (1) using tert-butyl alcohol instead of isobutene, and benzonitrile. Each student carries out the reaction, determines the purity of the product by TLC, and identifies it by melting point. A sample is submitted for IR and 1H NMR spectroscopy and copies of these spectra are distributed to all students. The analysis of the three hypothetical mechanistic pathways suggested by Hessley (10) is assigned as homework before an in-class discussion. In this in-class discussion the students are encouraged to suggest experiments to test the postulated mechanistic pathways, using as many analogies as possible of mechanisms that were analyzed during the course. This experiment is useful to emphasize that testing possible intermediates is a well-known method for determining reaction mechanisms. The mechanism in which benzamide is suspected of being an intermediate is readily ruled out by its reluctance to give N-tert-butylbenzamide when subjected to conditions under which benzonitrile reacts smoothly. We found it more convenient to have two students work together to conduct this reaction, mainly because several TLC runs are used to check the reaction. We emphasize, however, that a group task is solvable only by the contribution of both participants. For the analysis of pathways ii and iii suggested by Hessley (10), we ask students to recall the chemistry of carbocations, including carbocation rearrangements. Because they already know about the relative stability of carbocations, it is easy to assert that hydride or methyl shift governs the reaction by forming the more stable intermediate. Since we have seen numerous times during the course that the occurrence of rearrangements in a reaction provides strong mechanistic evidence for the presence of carbocation intermediates, the students realize that experiments with substrates that can undergo such rearrangements could provide strong support for pathway iii.
Furthermore, since there are many textbook examples in which isobutyl halides and even n-butyl alcohol undergo rearrangements in reactions such as nucleophilic substitutions, electrophilic additions, eliminations, and Friedel–Crafts alkylations, the reactions using the remaining three isomeric butyl alcohols are readily suggested by the students. These reactions are run simultaneously by groups of three students. Since each student uses an alcohol as starting material, those who obtain pure amides have to share their samples with the others in order to identify all the reaction products. This encourages students to communicate with each other, adding a cooperative learning element to the experiments. These experiments also give the students an opportunity to observe by themselves how carbocations or their rearranged products are trapped, a fundamental topic in any introductory organic chemistry course. While we have not conducted a formal assessment, students indicated that they enjoyed the experience of analyzing the mechanism of a reaction by themselves instead of doing the typical experiments in which the whole class performs the same reaction on the same substrate. We believe that the experiments suggested in this report complement those in previous reports and also capture the essence of a research project that surely will challenge students. Hazards Standard laboratory safety practices should be observed at all times while performing these experiments. Concentrated sulfuric acid is corrosive and should be handled with the care normally taken with concentrated acids. Dispense this acid in a fume hood and avoid contact with skin, eyes, and clothing. Ether is extremely flammable. Acknowledgments We thank Brian Coppola for his critical review and suggestions to improve the final manuscript, and our students (J. A. Panichelli, N. Mamana, and V. Justribó) for many helpful suggestions. Financial support from UNR, CONICET, and Agencia Nacional de Promoción Científica y Tecnológica is also acknowledged. Supplemental Material Instructions for students and notes for the instructor are available in this issue of JCE Online. W
Literature Cited 1. Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045– 4548. 2. Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213–325. 3. Bishop, R. In Comprehensive Organic Synthesis, Vol. 6; Trost, B. M., Ed.; Pergamon: Oxford, 1991; pp 261–300. 4. Djaidi, D.; Leung, I. S. H.; Bishop, R.; Craig, D. C.; Scudder, M. L. J. Chem. Soc., Perkin Trans. 1 2000, 2037–2042. 5. Van Emelen, K.; De Wit, T.; Hoornaert, G. J.; Compernolle, F. Org. Lett. 2000, 2, 3083–3086. 6. Jacquier, R.; Christol, H. Bull. Soc. Chim. Fr. 1957, 600. 7. Edwards, S.; Marquardt, F.-H. J. Org. Chem. 1974, 39, 1963. 8. Hathaway, B. A. J. Chem. Educ. 1989, 66, 776. 9. Crouch, R. D. J. Chem. Educ. 1994, 71, A200–A202. 10. Hessley, R. K. J. Chem. Educ. 2000, 77, 202–203.
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