Laboratory Experiment pubs.acs.org/jchemeduc
A Research-Based Undergraduate Organic Laboratory Project: Investigation of a One-Pot, Multicomponent, Environmentally Friendly Prins−Friedel−Crafts-Type Reaction Matthew R. Dintzner,* Justin J. Maresh, Charles R. Kinzie, Anthony F. Arena, and Thomas Speltz Department of Chemistry, DePaul University, Chicago, Illinois 60614, United States S Supporting Information *
ABSTRACT: Students in the undergraduate organic laboratory synthesize tetrahydro-2-(4nitrophenyl)-4-phenyl-2H-pyran via the Montmorillonite K10 clay-catalyzed reaction of pnitrobenzaldehye with methanol, 3-buten-1-ol, and benzene. The synthesis comprises an environmentally friendly tandem Prins−Friedel−Crafts-type multicomponent reaction (MCR) and sets the stage for investigation of reaction scope through student research projects with other carbonyl substrates. KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Inquiry-Based/Discovery Learning, Problem Solving/Decision Making, Aldehydes/Ketones, Aromatic Compounds, Green Chemistry, Spectroscopy, Undergraduate Research
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umerous studies, including many reported in this Journal, have demonstrated the importance of independent research experiences in undergraduate chemistry education.1−4 The development of projects that expose students to authentic research experiences, however, can be logistically challenging, especially when dealing with large student enrollments. For many years, a research experience has been incorporated into the third quarter of a three-quarter sequence of organic chemistry labs through a polymer synthesis project that was developed by Gregory Kharas in the late 1990s.3 This project remains robust to this day and results in the annual publication of peer-reviewed journal articles with significant numbers of undergraduate students as coauthors.5 Similar to Kharas’s polymer synthesis project, this project is simple in its design: students carry out a clay-catalyzed multicomponent reaction in an effort to synthesize different tetrahydropyran products (2, Scheme 1); variation of the starting carbonyl substrates (1) and
incorporation into the undergraduate laboratory due to long reaction times and expensive or sensitive reagents. For example, a one-pot multicomponent synthesis of 4-aryltetrahydropyrans (2) catalyzed by the Lewis acid complex boron trifluoride diethyl etherate, BF3·OEt2, was recently reported by Reddy et al.8 Reactions catalyzed by BF3·OEt2 are not well suited for the undergraduate organic laboratory because they must be conducted in rigorously dried glassware and under an inert environment. On the other hand, Montmorillonite K10 clay (Mont-K10), which has been shown to effectively catalyze an array of organic reactions,9 is much more amenable to use by undergraduates.10 In addition to being considerably less expensive than BF3·OEt2, Mont-K10 is also nontoxic, noncorrosive, and much simpler to handle. Mont-K10 catalyzed reactions can be conducted open to the air and workup typically involves only a filtration step, which minimizes waste. Montmorillonite clays are layered alumiosilicate smectite minerals mined from the earth, with intercalated cations between the layers that give them Bronsted and Lewis acidic properties.11 Preliminary work in the Dintzner laboratory12 demonstrated that Mont-K10 successfully catalyzed the MCR of p-nitrobenzaldehyde with 3-buten-1-ol and benzene to give racemic cis-2,4-diarylaryltetrahydropyran 2a, the product of a tandem Prins−Friedel−Crafts-type reaction (Scheme 2).13 For this MCR, a mechanism is proposed in which Mont-K10 initially catalyzes the reaction of p-nitrobenzaldehyde with methanol via activation of the carbonyl oxygen toward nucleophilic substitution to give the corresponding dimethyl acetal (3, Scheme 2). Subsequently, coordination of 3 with the Mont-K10 promotes its reaction with 3-buten-1-ol to give oxonium ion intermediate 4, which in turn undergoes a Prins cyclization to give carbocation 5. Benzene reacts with 5 in a Friedel−Crafts-type alkylation reaction14 to give the observed product as a racemic mixture of the cis-2,4-diarylaryltetrahy-
Scheme 1. Multicomponent Synthesis of Tetrahydropyrans
arenes allows for the potential generation of hundreds of possible products. The project not only gives students an opportunity to gain experience in doing research, but also introduces them to the concepts of green chemistry6 and multicomponent reactions.7 Multicomponent reactions (MCR) are reactions that result in the formation and breaking of multiple bonds in a single step or in one reaction flask.7 They constitute an important component of green chemistry6 as they typically proceed in the presence of a catalyst and with excellent atom economy. Although the recent chemical literature is replete with reports on multicomponent reactions, most are unsuitable for © 2011 American Chemical Society and Division of Chemical Education, Inc.
Published: December 5, 2011 265
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Journal of Chemical Education
Laboratory Experiment
Scheme 2. Mont-K10 Catalyzed MCR
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HAZARDS General laboratory safety procedures, including wearing safety goggles and gloves, must be followed at all times. All organic chemicals involved in these experiments are considered hazardous, and direct physical contact with them should be avoided. All wet-laboratory experiments must be performed in a fume hood, and wearing a laboratory coat or apron is advised. Hazards of the specific chemicals are listed in the Supporting Information.
dropyran (2a); relative stereochemistry was determined with an X-ray crystal structure. As the tetrahydropyran moiety is abundant in nature and has been implicated in the physiological activity of a host of natural and synthetic products,15 further investigation of the scope of this clay-catalyzed MCR was warranted and ideally suited for the undergraduate organic laboratory curriculum. This laboratory project also dovetails nicely with topics covered concurrently in lecture, including electrophilic aromatic substitution, substituent effects, and the chemistry of carbonyl compounds.
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DISCUSSION Building on the SIPCAn (separation, isolation, purification, characterization, and analysis) techniques16 introduced during the first quarter laboratory course at this university and the reaction and synthesis skills developed in the second quarter laboratory project (The Cyclohexanol Cycle and Synthesis of Nylon 6,6),17 the third quarter of lab presents students with a synthesis research project. Prior to conducting any laboratory work, students are instructed on searching the primary literature using online search engines and literature resources available in the library (SciFinder, Web of Science, Science Direct, etc.). In the first phase of the project (model reaction), students carry out the Mont-K10 clay-catalyzed synthesis of compound 2a (Scheme 2), for which the reaction conditions were previously optimized.12 In the second phase of the project (research), students repeat the reaction with different aldehydes or ketones (1) as starting materials to give new tetrahydropyran products (2, Scheme 1). Pairs of students are assigned an aldehyde or ketone (other than p-ntirobenzaldehyde) to investigate the reaction scope. Some of the reactions will work and others will notthis is the research component of the project. It is up to the student researchers to analyze their results and determine how they should proceed: (a) pursue the reaction further and optimize conditions or (b) try a different aldehyde or ketone starting material. If it is decided that the reaction is promising and conditions should be optimized (to optimize yield of the desired product), it is up to the student researchers to decide which reaction parameters to investigate: temperature, time, stoichiometry, type of clay, and so forth. Students may also choose to work with other carbonyl compounds or arenes. Students may consult with one another, their instructor, and TA for help with this troubleshooting process. A typical laboratory schedule is presented in Table 1.
EXPERIMENTAL OVERVIEW
Phase 1Model Reaction: Synthesis of Tetrahydro-2-(4-nitrophenyl)-4-phenyl-2H-pyran
All students carry out this reaction individually. Prior to setting up the reaction, p-nitrobenzaldehyde is purified by recrystallization from 95% ethanol and 3-buten-1-ol is purified by vacuum distillation. In a 25 mL round-bottomed flask, equipped with a magnetic stir bar, the Mont-K10 clay (200 mg) and pnitrobenzaldehyde (151 mg, 1.00 mmol) are combined with 10 mL of benzene. Methanol (202 μL, 5.00 mmol) is added, followed by the 3-buten-1-ol (94 μL, 1.10 mmol). The reaction mixture is refluxed with stirring until complete by thin-layer chromatography (TLC) analysis, using a solution of the starting aldehyde dissolved in CH2Cl2 as a reference and developing the plate in 1:1 hexanes/ethyl acetate. When the reaction is complete, the reaction mixture is allowed to cool to room temperature, then vacuum filtered through a bed of silica gel (approximately 1 g) using a Hirsch funnel. The filtrate is transferred to a tared round-bottomed flask or vial and rotavaped to remove the benzene and methanol. The product is analyzed by GC−MS, IR, 1H, and 13C NMR spectroscopy. Typical yields range from 70 to 90%. Phase 2Research: Investigation of Reaction Scope
Pairs of students are assigned an aldehyde or ketone as the starting compound (1, Scheme 1) and conduct a literature search to determine how it is purified. The purified carbonyl compound is treated in the same manner as described above, and students analyze and discuss their results. Depending on the results students may choose to optimize the reaction conditions or work with a different carbonyl compound. If their results indicate a successful reaction with benzene, students may also choose to rerun the reaction with a different arene.
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CONCLUSIONS As concern for the environment continues to shape the way chemists think about the construction of physiologically active compounds, the development of synthetic methodologies that 266
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(5) Kharas, G. B.; Flynn, K. T.; Hill, B. L.; Ishaq, M. R.; Kopp, D. A.; Korrol, B. G.; Kupczyk, K. M.; Schulte, D. M.; Vera, U.; Aparece, M. D.; Atlas, S.; Raihne, M. J. Macromol. Sci., Part A: Pure Appl. Chem. 2011, 48, 95 and references cited therein.. (6) Khan, A. T.; Choudhry, L. H.; Parvin, T.; Ali, M. A. Tetrahedron Lett. 2006, 47, 8137. (7) Kirchhoff, M. M. J. Chem. Educ. 2001, 78, 1577. (8) Reddy, U. C.; Bondalapati, S.; Saikian, A. K. J. Org. Chem. 2009, 74, 2605. (9) Nagendrappa, G. Applied Clay Science 2010, in press. (10) Dintzner, M. R.; Wucka, P. R.; Lyons, T. W. J. Chem. Educ. 2006, 83, 270. (11) Nagendrappa, G. Resonance 2002, 64. (12) Dintzner, M. R.; Aparece, M. D.; Unger, B.; Mondjinou, Y. A. From Abstracts of Papers, 239th ACS National Meeting, San Francisco, CA; American Chemical Society: Washington, DC, 2010; ORGN 938; cis relative stereochemistry determined by X-ray crystallography. (13) Surrey, A. R. Name Reactions in Organic Chemistry, 2nd ed,; Academic Press: New York & London, 1961; pp 184−197. (14) Gowan, J. E.; Wheeler, T. S. Named Organic Reactions; Butterworths: London, 1969; pp 143−147. (15) Tian, X. T.; Jaber, J. J.; Rychnovsky, S. D. J. Org. Chem. 2006, 71, 3176. (16) Dintzner, M. R.; Kinzie, C. R.; Pulkrabek, K. A.; Arena, A. F. J. Chem. Educ. 2011, 88, 1434−1436. (17) Dintzner, M. R.; Kinzie, C. R.; Pulkrabek, K. A.; Arena, A. F. J. Chem. Educ. DOI: 10.1021/ed2000878.
Table 1. Laboratory Schedule for the Third Quarter Organic Laboratory Laboratory
Topic or Activity
Check-in; Introduction; Library tour and workshop on Dry Lab searching the primary literature Phase OneModel Reaction Lab 1 Preparation of reagents Laboratories 2 Synthesis of tetrahydro-2-(4-nitrophenyl)-4-phenyl-2Hand 3 pyran; product analysis and purification Phase TwoResearch Lab 4 Preparation of reagents Lab 5 Research reaction Laboratories 6, Research continued: product analysis, purification, 7, and 8 optimization of reaction conditions (trouble-shooting), and reaction scale-up Poster Presentations
promote greener reactions is essential. Environmentally benign clays are not only ideally suited for the “greening” of modern synthetic chemistry, but they are also ideally suited for incorporation into a research-based project for the undergraduate organic laboratory curriculum. In addition, multicomponent reactions are an important component of green chemistry. The ability to vary multiple reactants also makes them ideally suited for incorporation into an open-ended research-based project for the undergraduate organic laboratory curriculum. Results of the research component of this project and discussion of reaction scope are forthcoming and will be reported in appropriate journals. Although this research project is one that is unique to the chemistry curriculum at this university, it may be emulated or adapted elsewhere as an environmentally friendly (green) multicomponent reaction laboratory experiment.
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ASSOCIATED CONTENT
* Supporting Information S
Detailed instructions for the students and notes for instructors This material is available via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected].
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ACKNOWLEDGMENTS We thank the National Science Foundation CCLI A&I program (Grant No. DUE-0310624) for support in purchasing our Bruker Avance 300 MHz NMR spectrometer and DePaul University’s College of Liberal Arts & Sciences for funding and support of this work. Greg Kharas is respectfully acknowledged for inspiring this project. Christopher Parker is gratefully acknowledged for guiding students through their navigation of the primary literature. Massimo Pacilli is gratefully acknowledged for his assistance in data acquisition. The following DePaul undergraduate students are acknowledged for their participation and contributions: all CHE 175 L-2011 students and TAs from spring quarter, 2011.
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(1) (2) (3) (4)
REFERENCES Kirchhoff, M. M. J. Chem. Educ. 2007, 84, 1090. Smales, C. M.; Harding, D. R. J. Chem. Educ. 1999, 76, 1558. Kharas, G. B. J. Chem. Educ. 1997, 74, 829. Amenta, D. S.; Mosobo, J. A. J. Chem. Educ. 1994, 71, 661. 267
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