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An Azulene-Based Discovery Experiment: Challenging Students To Watch for the “False Assumption” Charles M. Garner Department of Chemistry, Baylor University, Waco, TX 76798;
[email protected] It is widely accepted (1) that experiments that incorporate a significant discovery component are more effective than the traditional “verification” experiments in which a student is told the outcome in advance and instructed to verify it. This being said, there are various approaches to discoverybased organic laboratory instruction. Most organic experiments of this type ask the student to determine a structure, either with no information beyond knowing the reactants (2) or else choosing between a short list of possible products (3) (e.g., endo vs exo Diels–Alder products). There is one report of using a discovery approach to teaching purification techniques (4) (e.g., distillation) and another that uses “data pooling” (5) to discover trends. We have developed a discovery-based experiment depending on a “false assumption”: the students mistakenly assume they know the structure of a reaction product and are forced to reconcile observations (colors, solubilities, spectral data) that are inconsistent with this assumption. This experiment involves the chemistry of azulenes, an interesting class of intensely colored aromatic compounds. The students are first told of the facile trifluoroacylation of azulene, 1 (Figure 1). The reaction of azulenes with trifluoroacetic anhydride (6) occurs very rapidly at the C1 or C3 positions, dictated by retention of partial aromaticity in the intermediate. The resulting 1-trifluoroacetylazulene, 2, is a dramatically different color (red) from the starting azulene (blue), a trend that is generally observed with a variety of azulenes (7) and is a consequence of conjugation with the carbonyl group. Subsequent reaction with aqueous base results in a haloform reaction to give the carboxylic acid salt, 3. The students are given an article (6) describing the chemistry in Figure 1, and the instructor discusses both reactions, including certain experimental procedural details. In particular, the instructor explains (a) the high reactivity of azulenes that allows this Friedel–Crafts acylation to proceed in the absence of a catalyst; (b) the mechanism of the cleavage step of the haloform reaction; and (c) the high water-solubility of carboxylic acid salts. It is also important to point out how conjugation of the azulene ring to a carbonyl group has a dramatic effect on the color and that any process that removes this conjugation (i.e., reduction to the alcohol; ref 6 ) causes the color to revert to that of the parent azulene. The instructor should also mention the effect of 19F on a 13C NMR spectrum (i.e., large JCF), perhaps in the context of discussing the trifluoroacetyl derivative. The students are then informed that azulene is too difficult to make and too expensive to purchase (∼$120gram, ref 8 ) so they will be using 4,6,8-trimethylazulene, 4 (TMA) instead. TMA is easier to make than azulene (9),1 and easier to handle because of its lower volatility. The students naturally assume that TMA undergoes the same reactions as azulene, though they are never explicitly told that. The trifluoroacylation of purple TMA proceeds normally to give 1686
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the red–orange trifluoroacyl derivative, 5. But interestingly, the 8-methyl group of TMA causes the second reaction to proceed very differently (Figure 2), leading to a cyclization product, 6, (first identified by Anderson, ref 10 ) rather than the “expected” carboxylic acid salt. The cyclization reaction is a result of the acidity of the methyl groups in TMA; the unusually high acidity of these groups is attributed to stabilization of the anionic intermediate by a cyclopentadienyllike resonance form. Interestingly, the commercially available guaiazulene (1,4-dimethyl-7-isopropylazulene, ∼$3g) has a methyl group in the correct position but does not work in this experiment. Although it does give an orangish–brown trifluoroacetyl derivative, under our conditions this does not cyclize to any appreciable extent, but rather seems to decompose to multiple products (11). Noticeable Inconsistencies There are several points at which the students should notice an inconsistency between the product of this reaction, 6, and the expected carboxylic acid: (a) The students work up the reaction without acidification, yet isolate the product from the organic phase. The carboxylic acid salt would be present almost entirely in the aqueous phase, but the water layer is nearly colorless. (b) The color of the product (purple, almost identical to TMA) is inconsistent with conjugation
5
4
3
6
2 7
1
8
(blue) 1 O
O O
1. CF3
CF3
2. H2O
NaOH, H2O
O F3C (red) 2
Na O
O
(red) 3
Figure 1. Reaction of azulene, 1, with trifluoroacetic anhydride followed by aqueous base.
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In the Laboratory
of the azulene to a carbonyl group; the acid would be expected to be some shade of orange or red (7).2 (c) The product moves much faster on silica TLC than a carboxylic acid (or especially a salt) should. Typically, carboxylic acids require ∼30% ethyl acetate in hexanes to give an Rf of ∼0.3, whereas the product moves this much in 5% ethyl acetate. (d) The 1 H NMR spectrum is drastically different from what is expected, particularly in that there is an AB pattern at 3.8 and 4.2 ppm, and there are only two methyl groups (3H each) present. (e) The 13C spectrum is also different from what is expected, particularly with respect to two quartets (125.6 ppm, JCF = 280 Hz, CF3; and 79.0 ppm, JCF = 31 Hz, C– CF3). Here it helps if the students are aware of the effect of 19 F on a 13C spectrum. Discussion The experiment requires 2 hours or less in each of two lab periods at least a day apart. All of the students obtain enough product (typically ∼60–80 mg) to easily get proton NMR, though the carbon NMR (which can be made optional) requires rather long acquisition times (we used ∼600 scans). While the other observations are important, the NMR data most clearly reveal that the product is not the “expected” one. Consequently, I consider this experiment to be appropriate for any undergraduates with enough NMR interpretation skills to recognize the structural significance of an AB pattern. We use this experiment in our advanced organic laboratory, a junior–senior level course in which students use the NMR and other instruments hands-on. However, the degree to which the instructor equips the students with the information and skills necessary to notice the discrepancies and solve the correct structure is critically important. Too much guidance makes the exercise too easy and too little makes the
experiment confusing and of limited educational value. When this experiment was carried out with no special insistence on a critical comparison of expected versus observed results, other than to explain their proton NMR spectrum, only about 25% of the students realized there was an inconsistency, and some of the others felt afterward that they had been tricked, though an equal number appreciated the challenge. Consequently, the procedure now insists on a good deal more comparisons and critical examination of the results. However, each instructor should carefully choose what level of prompting he or she feels is appropriate. In any event, the realization that they are not always given the “correct” structure in advance makes the students analyze their NMR spectra (and other data) more critically thereafter, a very useful result, especially when it occurs early in the semester. This experiment makes an excellent followup to the preparation of TMA (9), itself a very interesting and informative exercise. Experiment Our approach is essentially a microscale one, though larger scale should not be problematic. A hexane solution containing approximately 100 mg of TMA is treated with a small excess of trifluoroacetic anhydride, resulting in very rapid trifluoroacylation. A small-scale water workup is done, followed by TLC analysis to verify completion of the reaction. The trifluoroacetyltrimethylazulene is more polar than TMA and is easily distinguished by color as well. It is important to use enough trifluoroacetic anhydride, and of good quality, so that no TMA remains, as this will otherwise carry through to the final product. After evaporation of the solvent, the material is taken up in ethanol, treated with an excess of solid NaOH, and allowed to stir at least overnight. The red-orange solution becomes brownish over a few hours and a deep purple overnight. The product is extracted into diethyl ether during a water workup (without acidification) and, after drying and evaporation of the solvent, is quite pure as long as no TMA remained unreacted in the first step. Hazards Trifluoroacetic anhydride is corrosive and very water sensitive. Reaction with water rapidly forms trifluoroacetic acid, which is corrosive and toxic. The solvents used here (hexanes, diethyl ether) are highly flammable. There appear to be no reports of hazards associated with trimethylazulene, but azulene and guaiazulene are listed as irritants. Sodium hydroxide is corrosive.
(purple) 4 O 1. CF3
O O
CF3
2. H2O
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Instructions for the students, NMR data and spectra, and a procedure for the preparation of 4,6,8-trimethylazulene are available in this issue of JCE Online.
NaOH, H2O
O
CF3
H-a
OH CF 3 H-b
(purple) 6
(red-orange) 5
Figure 2. Reaction of 4,6,8-trimethylazulene, 4, with trifluoroacetic anhydride followed by aqueous base.
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Notes 1. There are several procedures for the preparation of TMA by reaction of sodium cyclopentadienide with 2,4,6-trimethylpyrilium tetrafluoroborate (9). The use of 2,4,6-trimethyl-pyrilium perchlorate should be avoided because it is explosive.
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In the Laboratory 2. Although 4,6,8-trimethylazulene-1-carboxylic acid has apparently never been reported (no references in Scifinder as of Apr 2004), the colors of azulene-1-carboxylic acids are almost always very similar to that of the corresponding 1-trifluoroacetyl derivatives (7).
Literature Cited 1. Domin, D. S. J. Chem. Educ. 1999, 76, 543–547. 2. See, for example: Stradling, S. S. J. Chem. Educ. 1991, 68, 378–379. 3. See, for example: Ginion, K. E.; Yoder, C. H. J. Chem. Educ. 2004, 81, 394. 4. Horowitz, G. J. Chem. Educ. 2003, 80, 1039–1041. 5. Adrian, J. C., Jr.; Hull, L. A. J. Chem. Educ. 2001, 78, 529– 530. 6. Anderson, A. G.; Anderson, R. G. J. Org. Chem. 1962, 27, 3578–3581.
7. (a) Liu, R. S. J. Chem. Educ. 2002, 79, 183–185. (b) McDonald, R. N.; Reitz, R. R.; Richmond, J. M. J. Org. Chem. 1976, 41, 1822–1828. 8. 2003–2004 Handbook of Fine Chemicals; Aldrich Chemical Company: Milwaukee, WI. 9. (a) Garst, M. E.; Hochlowski, J.; Douglass, J. G., III; Sasse, S. J. Chem. Educ. 1983, 60, 510–511. (b) Garner, C. M. Techniques and Experiments for Advanced Organic Laboratory; John Wiley & Sons: New York, 1997. (c) Robinson, R. E. Organic Chemistry Laboratory Manual; The Solomon Press: New York, 1998. 10. Anderson, A. G.; Anderson, R. G.; Hollander, G. T. J. Org. Chem. 1965, 30, 131–138. 11. There is one obscure reference to trifluoroacetylguaiazulene cyclizing under the influence of base: Sato, K.; Yamaguchi, M.; Ogura, I. Kinki Daigaku Genshiryoku Kenkyusho Nenpo 1981, 18, 51–57.
edited by
JCE Featured Molecules
William F. Coleman Wellesley College Wellesley, MA 02481
Azulene Chemistry November Featured Molecules The month’s featured molecules come from the paper by Charles Garner illustrating some of the chemistry of a substituted azulene (pages 1686–1688). Azulene is a structural isomer of naphthalene and differs from it in several important ways, the most obvious being azulene’s intense blue color, which arises from the S0 → S2 transition. Another unusual feature of this molecule is that its fluorescence arises from the reverse of this transition rather than from S1 → S0. Castanho has described some of the reasons behind these phenomena in this Journal (Castanho, Miguel A. R. B. J. Chem. Educ. 2002, 79, 1092–1093).
Included on the Web site this month are interactive molecular orbitals for azulene and naphthalene computed using the semi-empirical AM1 model. In order to visualize the orbitals the user must install the ActiveX version of the HyperChem Web Viewer (http://www.hyper.com/products/ Professional/WebViewer.htm). An introduction to using the viewer is available at: http://www.JCE.DivCHED.org/JCEDLib/WebWare/ collection/open/JCEWWOR004/index1.html
Fully manipulable (Chime and Jmol) versions of these and other molecules are available at the Only@JCE Online Web site: http://www.JCE.DivCHED.org/JCEWWW/Features/ MonthlyMolecules/2005/Nov
azulene 4,6,8-trimethylazulene
reaction product of 4,6,8-trimethylazulene with trifluoroacetic anhydride followed by aqueous base
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