In the Laboratory
Chemoselective Reactions of Citral: Green Syntheses of Natural Perfumes for the Undergraduate Organic Laboratory Anna D. Cunningham, Eun Y. Ham, and David A. Vosburg* Department of Chemistry, Harvey Mudd College, Claremont, California 91711, United States *
[email protected] Citral, citronellal, geraniol, and nerol are fragrant natural products found in a variety of essential oils, including those of lemongrass, citronella, geranium, and rose (1). Their pleasant aromas make them attractive to students and counteract the common misconception that most chemicals are malodorous. Even more compelling from a pedagogical perspective is the potential for illustrating chemoselectivity (2, 3) in the conversions of citral into citronellal, geraniol, nerol, or epoxycitral (Scheme 1). The products have distinctive fragrances and are useful as insect repellants and perfumes. Epoxycitral may be less familiar than the others, but it is a mite pheromone (4) with significant anticancer activity (5). We describe an experiment that we have developed for and implemented in the second-semester organic laboratory course. Citral is an excellent example of a simple polyfunctional molecule, possessing two differentiable alkenes, one of which is conjugated to an aldehyde. Mild, chemoselective reduction of this electrophilic alkene can be performed using an organocatalyst and a Hantzsch ester, resulting in citronellal (6). This same alkene can be oxidized selectively to give epoxycitral upon treatment with alkaline hydrogen peroxide (7). Chemoselective reduction of the aldehyde with sodium borohydride in the presence of a guanidinium catalyst produces a mixture of the geometrical isomers geraniol and nerol (8) because citral is naturally a mixture of the E isomer geranial and the Z isomer neral. Not only are these reactions nicely chemoselective, they are also biomimetic and illustrate several principles of green chemistry. The Hantzsch ester (9) is a simpler and less expensive analogue of the biological reducing agent NADH (reduced nicotinamide adenine dinucleotide). Iminium and guanidinium organocatalysis are analogous to enzymatic reaction mechanisms, and conjugate additions are widely employed in biological systems (10, 11). Each of these reactions uses mild, inexpensive reagents, simple catalysts, and safe conditions (no pressurized hydrogen gas or extreme temperatures, for example). Experimental Overview Three reactions are described here, and instructors could in principle choose to include one, two, or all three in their laboratory curriculum. If chemoselectivity is to be emphasized, it is important for at least two of these reactions to be performed in the laboratory. This could mean that each student performs two reactions at the same time or that results are compiled after students perform different reactions. Any of these reactions may be performed in a single laboratory period, but we have found it most convenient to set up the conjugate reduction reaction to produce citronellal at the end of one laboratory period (requiring 322
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less than 30 min) and let it proceed until the following week to ensure completion and maximize effective use of laboratory time. This conjugate reduction reaction is readily contrasted with either of the other two reactions, which involve in one case reduction of the carbonyl and in the other case epoxidation at the same location as the conjugate reduction. For the conjugate reduction reaction, students simply mix citral, the Hantzsch ester (1.1 equiv), dibenzylammonium trifluoroacetate (13 mol %), and tetrahydrofuran in a vial and let the components react at room temperature, with or without stirring. For the carbonyl reduction, students gently heat citral and guanidinium chloride (13 mol %) in tetrahydrofuran/water (2:1) before adding sodium borohydride (50 mol % = 2 equiv of hydride).1 For the epoxidation, sodium hydroxide (0.6 equiv) is added to an ice-cold solution of citral and hydrogen peroxide (3 equiv) in methanol.2 In each case, the reaction mixture is easily compared with reference samples of citral, citronellal, geraniol, and nerol by thinlayer chromatography (epoxycitral coelutes with citral, but only citral absorbs light at 254 nm). A simple liquid-liquid extraction is performed, the solvent is removed, and the crude product is directly characterized by smell, GC-MS, and 1H NMR and IR spectroscopy. The difference in smell is most easily recognized when geraniol and nerol (rosy) are contrasted with citral, citronellal, and epoxycitral (lemony). Students report the identities of their products for each reaction and discuss the mechanistic highlights in the format of an Organic Letters manuscript. Hazards Citral, dibenzylamine, dichloromethane, guanidinium chloride, citronellal, geraniol, nerol, and 4-methoxybenzaldehyde are irritants. Trifluoroacetic acid, sodium hydroxide, and sulfuric acid are corrosive. Acetic acid is flammable and corrosive. Tetrahydrofuran and diethyl ether are flammable, irritants, and may form explosive peroxides. Sodium borohydride and methanol are flammable and toxic by inhalation, contact with skin, or ingestion. Ethanol is flammable. Deuterated chloroform is a cancer suspect agent and mutagen. Gloves and protective eyewear should be worn for this experiment. Caution should be exercised when smelling the concentrated perfumes (waft vapors with a hand toward the nose rather than placing nostrils directly above a flask or vial;in many cases, the fragrances are strong enough to be detected even when the vessels are capped). Discussion Although not completely benign, this experiment presents a good opportunity for students to discuss principles of green
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In the Laboratory
Scheme 1. Chemoselective Reactions of Citral To Provide Citronellal, Geraniol, Nerol, and Epoxycitral
Scheme 2. Mechanisms of Hydride Delivery for Two Organocatalytic, Chemoselective Reductions of Citrala
a
Scheme 3. Mechanism for the Nucleophilic Epoxidation of Citral Using Hydrogen Peroxide and Catalytic Sodium Hydroxidea
For simplicity, only the E isomer is shown in each.
chemistry (12). For example, the reactions are not performed at extreme temperatures or pressures and do not require inert atmospheres or complex apparatus. The reagents are inexpensive and the reactions do not require purification beyond a simple extraction. Each reaction uses a catalyst to promote the reaction of the stoichiometric reductant or oxidant. Only the conjugate reduction has poor atom economy; this is due to the Hantzsch ester and illustrates the need for the development of a NADH analogue that is inexpensive, practical, and recyclable (13). The reactions are generally rapid, with the citronellal reaction most conveniently run for a week between laboratory periods. Students may readily calculate the atom economy and experimental atom economy for each reaction. These and other considerations can lead to insightful analyses from students in their laboratory reports. In addition to illustrating concepts of green chemistry, chemoselectivity, and biomimicry, the reactions included in this experiment offer a rich array of mechanistic details. The guanidinium catalyst activates the aldehyde for nucleophilic hydride attack through hydrogen bonding (Scheme 2). Dibenzylamine condenses with citral to form an iminium ion that renders the conjugated alkene more electrophilic; the resulting enamine is then hydrolyzed to regenerate dibenzylamine for further catalysis. A major driving force for hydride delivery from the Hantzsch ester is the generation of an aromatic pyridine ring. These reduction reactions involve catalysts that activate citral to make it more electrophilic. In contrast, the oxidation reaction summarized in Scheme 3 does not involve activation of citral; rather, it features a catalyst (sodium hydroxide) that deprotonates hydrogen peroxide to increase its nucleophilicity. The intermediate enolate then
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a
For simplicity, only the E isomer is shown, though both the E and Z isomers react to produce a mixture of epoxide diastereomers.
forms an epoxide through breaking the weak O-O bond and regeneration of the sodium hydroxide catalyst. Once students have determined their products for each reaction, the instructor may either provide plausible mechanisms for the transformations or challenge students to devise mechanisms for the reactions they performed. Conclusion We found that this experiment effectively combines pleasant smells, chemoselective reactions, interesting biomimetic mechanisms, natural products, and green chemistry. The reactions are clean, easy-to-perform, and directly involve compounds of interest to students. The mechanisms are appropriate for students in second-semester organic chemistry courses and give them an introduction to some important concepts in biochemistry: hydrogen bonding, electrophilic carbonyls, iminium ions, NADH, aromaticity, conjugate addition, enolates, and redox reactions. Acknowledgment The authors thank the Harvey Mudd College (HMC) undergraduates who performed these reactions in Chemistry 111 and the HMC Chemistry Department for its support of this work. D.A.V. gratefully acknowledges a Camille and
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Henry Dreyfus Faculty Startup Award. This paper was presented at the Spring 2010 National ACS Meeting in San Francisco. Notes 1. Microwave heating at 100 °C shortens the carbonyl reduction to 5 min. 2. Lowering the molar equivalents of sodium hydroxide and hydrogen peroxide to 0.3 and 1.5, respectively, lengthens the epoxidation reaction to 15 min: see the supporting information.
Literature Cited 1. Bauer, K.; Garbe, D. Common Fragrance and Flavor Materials: Preparation, Properties, and Uses; VCH: Weinheim, 1985. 2. For other articles illustrating chemoselectivity from this Journal, see: (a) Organ, M. G.; Anderson, P. J. Chem. Educ. 1996, 73, 1193– 1196. (b) Baru, A. R.; Mohan, R. S. J. Chem. Educ. 2005, 82, 1674– 1675. (c) Sereda, G. A J. Chem. Educ. 2005, 82, 1839–1840. (d) Ballard, C. E. J. Chem. Educ. 2010, 87, 190–193. 3. For a recent review on the importance of chemoselectivity in synthesis, see: Shenvi, R. A.; O'Malley, D. P.; Baran, P. S. Acc. Chem. Res. 2009, 42, 530–541. 4. Mori, N.; Kuwahara, Y.; Kurosa, K. Bioorg. Med. Chem. 1996, 4, 289–295. 5. Rose, S. D.; Lefler, S. R.; Ottersberg, S. R.; Kim, A. Y.; Okolotowicz, K. J.; Hartman, R. F. PCT Int. Appl. WO 02/34247, 2002.
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6. Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. Angew. Chem., Int. Ed. 2004, 43, 6660–6662. 7. (a) Nair, G. V.; Pandit, G. D. Tetrahedron Lett. 1966, 7, 5097– 5100. (b) Wasson, R. L.; House, H. O. Org. Synth. Coll. 1963, 4, 552–553. 8. Heydari, A.; Arefi, A.; Esfandyari, M. J. Mol. Catal. A: Chem. 2007, 274, 169–172. 9. (a) Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1–82. (b) Ouellet, S. G.; Walji, A. M.; Macmillan, D. W. C. Acc. Chem. Res. 2007, 40, 1327–1339. 10. McMurry, J. E.; Begley, T. P. The Organic Chemistry of Biological Pathways; Roberts and Company: Englewood, CO, 2005. 11. For examples of arginine residues activating carbonyls for nucleophilic attack through hydrogen bonding, see discussions of lactate dehydrogenase and carboxypeptidase A: (a) Clarke, A. R.; Wigley, D. B.; Chia, W. N.; Barstow, D.; Atkinson, T.; Holbrook, J. J. Nature 1986, 324, 699–702. (b) Christianson, D. W.; Lipscomb, W. N. Acc. Chem. Res. 1989, 22, 62–69. 12. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 1998. 13. You, S.-L. Chem.-Asian J. 2007, 2, 820–827.
Supporting Information Available Instructions for students, notes for instructors, an equipment list, green chemistry handout, and representative student GC-MS, NMR, and IR data. This material is available via the Internet at http:// pubs.acs.org.
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