In the Laboratory
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Acid-Catalyzed Isomerization of Carvone to Carvacrol Richard A. Kjonaas* and Shawn P. Mattingly Department of Chemistry, Indiana State University, Terre Haute, IN 47809; *
[email protected] Routine hands-on use of 13C NMR in sophomore organic chemistry laboratories has been substantially limited by the impracticality of making these expensive and fragile high-field instruments available to a large and inexperienced group of students. Fortunately, permanent-magnet Fourier transform NMR instruments are now commercially available. For many institutions, the ease of maintenance and the low cost ownership of these instruments far exceed the disadvantages. One of these disadvantages is that the magnets are generally limited to 90 MHz or less. Another disadvantage is it is necessary to have reasonably concentrated samples (50– 100%) in order to complete both the chemical reaction and the spectral analysis in one lab period (i.e., about one minute of data acquisition per student). The acid-catalyzed isomerization of carvone to carvacrol (Scheme I) is especially well suited for use with a permanent-magnet FT instrument. The experiment safely and economically provides a sufficient quantity of a reasonably pure liquid product for “high throughput” 13C NMR analysis. Furthermore, the low-field 1 H and 13C NMR spectra are both appropriate for interpretation by these students. The acid-catalyzed isomerization of carvone to carvacrol was first reported by Ritter and Ginsburg (1). These workers obtained a 61% yield after a three-hour reflux with 30% aqueous sulfuric acid. In an article in this Journal, Stradling (2) described reaction sequences whereby students in a junior–senior advanced organic laboratory produced their own “unknowns”; one of these sequences was the formation of carvone oxime followed by heating with aqueous HCl for one hour to give carvacrol. This reaction sequence almost certainly involves hydrolysis of the oxime back to carvone followed by the same acid-catalyzed conversion to carvacrol that is reported herein. Although Stradling’s reaction sequence is a nice way of providing a real-world structure determination experience for advanced students, there is no indication in the article that the acid-catalyzed carvone to carvacrol isomerization is a desirable or even feasible experiment for a sophomore organic chemistry class.
Familiar Components (R )-(−)-Carvone is the major component in oil of spearmint, and (S )-(+)-carvone is the major component in oil of caraway. Both are commercially available, and either of them can be used in this experiment since the final product is not chiral. However, the isomer with an odor that is more familiar to the students—spearmint—also happens to be the less expensive of the two. Each student uses a quantity of starting material worth about $0.15. Carvone has been the subject of other experiments reported in this Journal (3–5), but are unrelated to this one. Carvacrol is the major component of oil of origanum. Its well-known isomer, thymol, is the active ingredient in Listerine. These two isomeric phenols differ only in the location of the hydroxyl group on the ring and they are the principle components of oil of thyme. Both compounds have long histories of medicinal use. Experiment In our experiment 1 mL of carvone and 10 mL of 6.0 M H2SO4 are heated under reflux for 35 minutes. Gas chromatographic analysis has shown us that carvone is quantitatively converted to carvacrol in that quantity of time. However, students typically report a 60–80% yield following a simple workup consisting of extraction with two 5-mL portions of petroleum ether, washing with aqueous NaHCO3, drying with Na2SO4, and solvent removal by rotary evaporation. The quantity and purity of this product is such that a high quality 13C NMR spectrum is obtained after about one minute of data acquisition even with a permanent-magnet instrument. When more than one rotary evaporator is used, the entire experiment, including either the 1H or 13C NMR, can be completed in less than three hours by a class of 24 students each working individually. Hazards To a greater extent than what we have observed with most other experiments, bumping tends to occur during the reflux portion of this reaction. This potential hazard can be eliminated by stirring with a magnet stir bar or, alternatively, by observing all of the following:
OH
O acid
1. Use about a dozen boiling chips rather than just three or four. 2. Use a flask that is larger than necessary (we recommend a 50-mL flask).
carvone
3. Place the heat source close to the flask rather than actually touching the flask.
carvacrol
Scheme I. Acid-catalyzed isomerization of carvone to carvacrol.
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4. Use a rubber band to secure a paper towel over the end of the condenser so that if bumping does occur, it will be contained.
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In the Laboratory
The fourth item listed above is a precaution that we often incorporate in our lab anyway. After doing this the first time, students tend to do it with every reflux even when it is not called for. Because a paper towel on top of a reflux condenser is highly visible, it is a precaution whose compliance is easy for the instructor to monitor and, in fact, it is one that hardly needs to be monitored because any student who forgets to do this will surely notice that the other students are doing it. Petroleum ether is flammable and 6 M sulfuric acid is corrosive.
CH2 C
C
H
H
C
H
C +
H
+ O
H
C
H
C
C
H
H
O C
CH3
CH3
+
C
H
H
+
C
H
H
O C
H
C +
H
H
Discussion This experiment illustrates some important chemical concepts including the following: 1. Formation of a carbocation by protonation of an alkene
C
O
H
C
H
2. Rearrangement of a carbocation 3. Deprotonation of a carbocation to give an alkene 4. Acid-catalyzed enolization `
Scheme II. (Top) Protonation of an alkene with the formation of a new double bond. (Bottom) Protonation of a carbonyl moiety with the formation of a new double bond.
5. Aromaticity
Although it is necessary to have discussed carbocations, aromaticity, and NMR in the lecture portion of the course prior to doing the experiment, it is not necessary for the students to have been exposed to enolization. This can be introduced rather quickly in a prelab lecture by treating it as a special case of number 3 above. That is, just as an alkene can be protonated to give a carbocation that can then lose a proton to give a new carbon–carbon π bond (Scheme II, top), so too can a carbonyl be protonated to give what might reasonably be considered to be an oxygen-stabilized carbocation that, like any carbocation, can then lose a proton to give a new carbon–carbon π bond (Scheme II, bottom). Aromaticity is perhaps the most logical central theme of the experiment. Students see for themselves that when one “puts” three π bonds into a six-membered ring, the ring becomes aromatic. In fact, this aromaticity is what drives the equilibrium to the right. Although our students know the identity of the product before carrying out the experiment, the spectral data are simple enough that they could certainly be expected to identify the product on their own. In other words, the experiment is well suited for use as a discovery-based experiment, especially if the IR spectrum is also obtained. The IR shows that a hydroxyl group has replaced the carbonyl; the 13C NMR shows that nine resonances have replaced ten; and the 1 H NMR has features that are recognizable to students at this level. The experiment’s main drawback is the fact that the medicine-like odor of carvacrol is somewhat unpleasant.
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However, this is largely remedied by doing the workup in a fume hood. Since the workup is both short and routine, and since the students are not all ready for the workup at the same time, we had no trouble in having 24 students using only six two-person fume hoods even when one of those 12 work places was dedicated to transferring the products to the NMR tubes. To further minimize the odor, each student transfers their entire portion of carvacrol to the NMR tube and these tubes are not emptied or cleaned by the students, but are retained by the instructor after the 1H or 13C NMR spectra have been run by the students. W
Supplemental Material
The students’ procedure, instructor’s notes, and spectra of the product are available in this issue of JCE Online. Literature Cited 1. Ritter, J. J.; Ginsburg, D. J. Am. Chem. Soc. 1950, 72, 2381. See also Sattar, A.; Ahmad, R.; Khan, S. A. Pak. J. Sci. Res. 1980, 23, 177. An, J.; Bagnell, L.; Cablewski, T.; Strauss, C. R.; Trainor, R. W. J. Org. Chem. 1997, 62, 2505. 2. Stradling, S. S. J. Chem. Educ. 1991, 68, 378. 3. Miles, W. H.; Nutaitis, C. F.; Berreth, C. L. J. Chem. Educ. 1994, 71, 1097. 4. Kelly, L. F.; Deeble, G. J. J. Chem. Educ. 1986, 63, 1107. 5. Rothenberger, O. S.; Krasnoff, S. B.; Rollins, R. B. J. Chem. Educ. 1980, 57, 741.
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