Laboratory Experiment pubs.acs.org/jchemeduc
Green Oxidation of Menthol Enantiomers and Analysis by Circular Dichroism Spectroscopy: An Advanced Organic Chemistry Laboratory H. Cristina Geiger* and James S. Donohoe Department of Chemistry, State University of New York College at Geneseo, Geneseo, New York 14454, United States S Supporting Information *
ABSTRACT: Green chemistry addresses environmental concerns associated with chemical processes and increases awareness of possible harmful effects of chemical reagents. Efficient reactions that eliminate or reduce the use of organic solvents or toxic reagents are increasingly available. A two-week experiment is reported that entails the calcium hypochlorite oxidation of menthol to menthone. The experiment enhances student interest, knowledge, and techniques in organic chemistry, while promoting the development of socially responsible citizens. The experiment is suitable for an advanced organic chemistry laboratory. The first objective of this experiment is to perform an oxidation reaction that uses environmentally friendly, nonhazardous, and costeffective reactants. A second objective is to introduce circular dichroism spectroscopy, a powerful analytical technique typically overlooked in the undergraduate curriculum. The students also gain experience in IR and NMR spectroscopies. KEYWORDS: Second-Year Undergraduate, Upper-Division Undergraduate, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives, Chirality/Optical Activity, Green Chemistry, IR Spectroscopy, Oxidation/Reduction, NMR Spectroscopy
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friendly, inexpensive oxidizing reagent8−11 with sufficient strength to produce high yields of product (eq 1):
reen chemistry addresses environmental concerns associated with chemical processes and increases awareness of possible harmful effects of chemical reagents.1 Although interest has been growing since the early 1990s, green chemistry is still not found extensively in the chemistry curriculum.2 However, laboratory experiments that eliminate or reduce the use of organic solvents or toxic reagents and employ efficient reactions are becoming increasingly available.3,4 A twoweek experiment is reported that entails the calcium hypochlorite oxidation of menthol to menthone. This experiment is suitable for an advanced organic chemistry course. The experiment was designed to enhance student interest, knowledge, and techniques in organic chemistry while promoting the development of socially responsible citizens. The first objective of this laboratory is to perform an oxidation reaction that uses environmentally friendly, nonhazardous, and cost-effective reactants. A second objective is to introduce the concept of circular dichroism (CD) spectroscopy, a powerful analytical technique typically overlooked in the undergraduate curriculum.5 Students will also gain experience in IR and NMR spectroscopies. The oxidation reaction of (+) and (−)-menthol is well documented in the literature but usually employs expensive or toxic reagents such as Dess−Martin periodinane6 or chromic acid.7 A laboratory experiment was developed that employs calcium hypochlorite, Ca(ClO)2, a more environmentally © 2012 American Chemical Society and Division of Chemical Education, Inc.
Ca(ClO)2 is a common chemical typically found in swimming pool products. The easy-to-handle solid can be used to make solutions of much higher hypochlorite concentration than household bleach.
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EXPERIMENTAL OVERVIEW The experiment was carried out over two laboratory periods of 4 h each with students working in pairs. One student carried out a 0.5 g scale synthesis with the naturally occurring (−)-menthol enantiomer, while the other student performed a 0.25 g scale synthesis with the (+)-menthol enantiomer. During the first period students worked through the synthesis and isolation procedure. The second period focused on the IR, NMR, and CD spectroscopic analyses of their final products. Part of the laboratory was dedicated to a short lecture on Published: September 26, 2012 1572
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the presence of a carbonyl group and success of the reaction (Figure 1).
circular dichroism spectroscopy that covered basic concepts,12,13 practical applications in chemistry and biochemistry, and the use of the instrument. Oxidation of the naturally occurring (−)-menthol enantiomer was done by slowly adding freshly prepared concentrated calcium hypochlorite aqueous solution to a stirred solution of (−)-menthol (0.50 g) in glacial acetic acid at 15−20 °C. Reaction progress was monitored by the change in color of the reaction mixture. Calcium hypochlorite solution has a yellow color, which dissipated as it reacted with the alcohol. When the solution mixture maintained a yellow color for several minutes, addition of calcium hypochlorite was stopped. The reaction was worked up to give an average student yield of 0.37 g (75%) of a white powder. Experimental details are provided in the Supporting Information. Students were encouraged to waft carefully the product. (−)-Menthone has a characteristic minty smell that is quite different from the starting material, (−)-menthol. The same procedure for oxidation of the (+)-menthol enantiomer was run at halfscale to reduce costs. During the second laboratory period, students carried out the spectroscopic characterization of menthone and menthol. Infrared spectroscopy (Thermo Scientific Nicotlet iS10) was used to evaluate the success of the oxidation reaction by observing the disappearance of the hydroxyl absorption band of the reactant and the appearance of a strong carbonyl absorption band of the product. 1H and 13C NMR spectroscopies (Agilent 400-MR NMR spectrometer) were used to confirm the structures of the products. Circular dichroism (Jasco J-815 spectropolarimeter) spectra of dilute solutions of the products in hexane or ethanol clearly showed the success of the oxidation reaction and the chirality of the products. The students paired up with their original partners to discuss their findings after they obtained the spectra.
Figure 1. IR spectrum of student oxidation product (−)-menthone. No alcohol peak was detected indicating complete oxidation. The spectrum was taken on a Thermo Scientific Nicotlet iS10 solid−liquid FT-IR spectrometer.
The 1H NMR spectra of both menthols showed a peak at 3.4 ppm corresponding to the proton of the hydroxyl group. This peak was not present in the 1H NMR spectra of the products. Analysis of the 13C NMR (decoupled) spectra of the products confirmed the formation of menthone by the signal observed at 212.4 ppm. (The carbonyl chemical shift of pure menthone was reported at 212.9 ppm.14) The observation of other peaks in the proton and carbon NMR of the crude product suggested possible formation of isomenthone along with menthone. Examples of student NMR spectra are provided in the Supporting Information. Because the purpose of this laboratory was to show the success of this environmentally friendly oxidation reaction and the emphasis is on the CD analysis, no further purification was performed. Neither of the alcohol starting materials exhibited a CD band because of the lack of a chromophore, but the presence of a carbonyl group in the products resulted in a significant CD signal (Figure 2). The CD analysis not only confirmed the success of the oxidation reaction but also illustrated the enantiomeric relationship between the products.
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HAZARDS Care should be taken when working with the calcium hypochlorite. As with any hypochlorite source, it will bleach clothing. Any skin contact should also be washed immediately though it poses little risk. All hypochlorite reactions have the ability to expel chlorine gas. This is uncommon under the weakly acidic conditions used in this experiment. However, all reactions should be performed in a ventilation hood to ensure safety. Care should be taken when neutralizing the remaining hypochlorite solution. The reaction is exothermic and produces HCl and this could facilitate the expulsion of chlorine gas. To avoid any formation of chlorine gas, this step should be done in an ice−water bath. Any diethyl ether waste should be properly disposed in the appropriate waste container. Inhalation of diethyl ether should be avoided and the extraction should be done in a ventilation hood. Glacial acetic acid may cause irritation to skin, eyes, and respiratory tract and may be harmful if swallowed or inhaled. Sodium hydroxide is caustic and causes burns to any area of contact.
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RESULTS AND DISCUSSION The oxidation of menthol using calcium hypochlorite was not only environmental friendly, but also produced the oxidation product in higher yields than previously reported.6 The IR spectra of the products showed the disappearance of the hydroxyl peak at 3400 cm−1 present in the starting materials and the appearance of an intense peak at 1700 cm−1 indicated
Figure 2. CD spectra of student-prepared menthone enantiomers. All spectra were obtained with a Jasco-815 spectrophotometer, with 1 nm bandwidth, 0.1 nm step, and 1 accumulation at 25 °C. 1573
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(2) Braun, B.; Charney, C.; Clarens, A.; Farrugia, J.; Kitchens, C.; Lisowski, C.; Naistat, D.; O’Neil, A. J. Chem. Educ. 2006, 83, 1126− 1129. (3) Haack, J. A.; Hutchison, J. E.; Kirchoff, M. M.; Levy, I. J. J. Chem. Educ. 2005, 82, 974−976. (4) Anastas, P. T., Williamson, T. C., Eds.; Green Chemistry: Frontiers in Benign Chemical Synthesis and Processes; Oxford University Press: Oxford, 1998; pp 166−250. (5) Urbach, A. R. J. Chem. Educ. 2010, 87, 891−893. (6) Reed, N. A.; Rapp, R. D.; Hamann, C. S.; Artz, P. G. J. Chem. Educ. 2005, 82, 1053−1054. (7) Haut, S. A. J. Agric. Food Chem. 1985, 33, 278−280. L. T. Sandborn. Organic Syntheses; Wiley & Sons: New York, 1941; Collect. Vol. 1, p 340. (8) Nwaukwa, S. O.; Keehn, P. M. Tetrahedron Lett. 1982, 23, 35−38. (9) McDonald, C. E. J. Chem. Educ. 2000, 77, 750−751. (10) Schneider, M.; Weber, J. V.; Faller, P. J. Org. Chem. 1982, 47, 364−365. (11) Arterburn, J. B. Tetrahedron 2001, 57, 9765−9788. (12) Nakanishi, K., Berova, N., Woody, R. W.; Eds. Circular Dichroism: Principles and Applications, Wiley: New York, 2000, 1−28; pp 261−299. (13) Rodger, A.; Norden, B. Circular Dichroism and Linear Dichroism; Oxford University Press: Oxford, 1997; pp 66−106. (14) Skakovskii, E. D.; Kiselev, W. P.; Tychinskaya, L. Y.; Schutova, A. G.; Gonsharova, L. W.; Spiridowish, E. W.; Bovdey, N. A.; Kiselev, P. A.; Gaidukevich, O. A. J. Appl. Spectrosc. 2010, 77, 329−334. (15) Lancaster, M. Green Chemistry: An Introductory Text; Royal Society of Chemistry: Cambridge, 2002; pp 2−8. (16) András Szilágyi CD Animated Website, http://www.enzim.hu/ ∼szia/cddemo/edemo0.htm (accessed Sep 2012). (17) McNaught, I. J.; Pecham, G. D. J. Chem. Educ. 2012, 89, 557− 558. (18) Andraos, J.; Murtuzaali, S. J. Chem. Educ. 2007, 84, 1004−1010.
CONCLUSIONS This experiment was developed as a learning experience for students on multiple levels. The oxidation reaction gave students more experience in the techniques involved in synthetic organic chemistry. Furthermore, the experiment encouraged students to think about the choices that a researcher can make in the laboratory.15 The procedure using Ca(ClO)2 is safe, inexpensive, environmentally friendly,9 and effective as observed by the ∼75% yield obtained. This experiment was tested in three laboratory sections with a total of 34 undergraduate students taking advanced organic chemistry laboratory. The highest yield obtained was 91% and the lowest 6% (student spilled the solution). One goal of this laboratory was to give students more handson experience in structure elucidation of products and starting materials. At the end of this laboratory, students exhibited greater skill obtaining and interpreting FT-IR, 1H, 13C NMR spectra. Another important goal of this lab was to introduce circular dichroism spectroscopy and to provide experience using a spectropolarimeter. Because (−)-menthone and (+)-menthone absorb the circularly polarized light differently, the CD spectra of these enantiomers have the opposite sign. An excellent Web site that gives an animated introduction to CD is available.16 (−)-Menthone shows a positive Cotton effect, whereas (+)-menthone shows a negative Cotton effect12 of the same intensity at the same concentration in a dilute hexane solution. This laboratory was aimed at students that have completed introductory organic chemistry and can be used as a simple introduction to the theory of circular dichroism spectroscopy without a need to include an extensive and advanced analysis of the octant rules.17 However, depending on student curiosity and academic level, it provides an opportunity to explore this concept in more detail. Additionally, if time permits, a green metrics analysis18 of the reaction may be introduced. Details are provided in the Supporting Information.
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ASSOCIATED CONTENT
S Supporting Information *
Step-by-step procedures for students; general comments for instructors; stockroom preparation procedures; green metric analysis; a prelaboratory quiz with solutions; student-obtained 1 H and 13C spectra. This material is available via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This project was made possible by the SUNY Geneseo Chemistry Department and a grant from the Geneseo Foundation. The authors thank students taking CHEM 313 at SUNY-Geneseo during the 2011-2012 academic year for piloting this experiment.
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REFERENCES
(1) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press, Inc.: New York, 1998; pp 1−30. 1574
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