In the Classroom
A More Realistic Teaching Style in Spectroscopic Instruction Mar Gómez Gallego,* Santiago Romano, Miguel A. Sierra, and Enrique Nieto Departamento de Química Orgánica I, Facultad de Química, Ciudad Universitaria s/n, 28040 Madrid, Spain; *
[email protected] Spectroscopic techniques provide the essential information that allows us to determine the structure of an unknown compound. They are particularly useful for organic chemists. Spectroscopic analysis has become a central part of the introductory organic curriculum in most universities, and there is increasing awareness of the shortcomings of the way in which this discipline is being taught in lectures and the laboratory (1). Our chemistry students learn the precise methodology they must follow to gain information of value from 1-D and 2-D NMR spectra, how to recognize a functional group by IR, and which are the most important types of fragments in mass spectra. After that, in theory, they should be prepared to face the sometimes very difficult problem of determining the correct structure of a reaction product. The question that we are asking is, “Are we really training our students to solve real problems?” After many years teaching advanced organic chemistry, we were amazed to note that our undergraduates have serious difficulties when they are required to use simultaneously their organic chemistry knowledge (reactivity and mechanisms) and standard spectroscopic techniques to explain the outcome of a reaction. Although they have studied both subjects to some depth, they tend to consider each independent of the other. We are sure that the students become familiar with the relationship between reactivity and mechanism during the basic courses. Unfortunately, organic spectroscopy is taught, in many cases, as an isolated topic divorced from the rest of organic chemistry. In fact, although we are keen to introduce new ways of teaching the applications of spectroscopy in the laboratory (2) in the classroom, we still prefer lectures organized by technique (an approach supported by most texts). These are followed by exercises aimed at the identification of unknowns. Most structure determination workbooks (3) offer excellent collections of problems that present detailed spectroscopic information for a molecule and, as in a quiz, the students have to arrive at the structure that fits all the data. There is no additional information explaining how that compound was obtained or what reagents were employed in its synthesis. In consequence, we are missing the opportunity to combine reactivity, mechanism, and spectroscopic data in the discussion of the possible structure of the product. In real life, an organic chemist has all the spectra and all the information available (including his or her own knowledge and experience) to explain the outcome of a reaction. That is why we believe that during instruction in spectroscopic methods, students should get practice in combining their knowledge of basic organic chemistry with the interpretation of the data provided by the various spectroscopic techniques. A similar approach has been described for an introductory organic chemistry laboratory in an attempt to change the traditional experiments based on identification by qualitative analysis (2c). In this article we propose three examples for classroom discussion in a course on spectroscopic analysis. These are real cases. The examples are arranged in order of increasing
complexity and are suitable for undergraduates who have passed the basic organic chemistry courses. In each example, the reagents and reaction conditions are given, together with the most significant spectroscopic data for the compound obtained and also for the starting material, when needed. Our aim is to provoke a wide-ranging discussion of each example. This approach should encourage students to employ both their spectroscopic knowledge and their knowledge in organic chemistry to establish the structure of a reaction product. As in real-life chemistry, sometimes the reactions that occur are easily recognizable and all the data will agree with the predicted product. In other examples, the result will be completely unexpected and the solution will require an extra effort from the students. Even in these cases, with all the data in hand, a reasonable explanation can be found. Example 1 Allyl phenyl ether (1) (bp 192 °C) was boiled as a neat liquid for 6 h. The resulting reaction mixture was heated with a saturated potassium hydroxide solution at 110 °C. Careful neutralization, extraction, and distillation of the product under reduced pressure afforded a crystalline solid (75% yield, mp 37 °C, bp 80 °C). Identify the reactions that take place during the foregoing transformations and confirm, using the NMR spectroscopic data, the structure and stereochemistry of the predicted final product (Fig. 1) (4 ).1 Reaction Product. MS: m/z M+ 134 (100), 119 (45), 105 (26), 91 (52), 77 (28).
Solution The first step should be easily recognizable. It is the thermal rearrangement of allyl phenyl ether (1) to 2-allylphenol (2) by means of a [3,3]-sigmatropic reaction (the Claisen ether rearrangement). Treatment of 2 in a strongly basic medium yields the final product. This shows a singlet in the 1H NMR at 5.36 ppm (indicating the presence of the phenolic group) and maintains the ortho-substitution pattern in the aromatic region (6.8–7.4 ppm). Consequently, any structure derived from a possible doubly rearranged product 3 (5) has to be discarded. The reaction product is clearly isomeric with the starting material (M+ 134 [100]). Thus a rearrangement has occurred. The signals in the 1H NMR at 1.93 ppm (dd, J1 = 6.5 Hz, J2 = 1.5 Hz) and in the 13C NMR at 18.76 ppm confirm the presence of a methyl group. On the other hand, the signals in the 1H NMR at 6.2 ppm (dq, J1 = 16.0 Hz, J2 = 6.5 Hz) and at 6.6 ppm (d, J = 16.0 Hz) show that a CH=CH bond is still present in the structure. The coupling shows it to be adjacent to the methyl group. All these data corroborate that, under basic treatment, compound 2 rearranges to 2(trans-prop-1-enyl)phenol (4), and the stereochemistry of the double bond is unequivocally established as trans by the size of the coupling constant ( J = 16.0 Hz) in the vinylic system. The coupling between the methyl group and the allylic CH ( J = 1.5 Hz) is also clearly observed. Hence we would conclude
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In the Classroom
that the two steps of the synthetic sequence have proceeded as expected, and the structure of the final product is confirmed by the spectroscopic data (Scheme I). O
1
OH
OH heat
OH
2
CH3
-
4
this compound and propose a reasonable explanation for the outcome of the reaction (Fig. 2). Reaction Product. IR (KBr): 3382 cm᎑1 (sharp). Solution The reaction between an aldehyde and an amine should yield an imine. The stoichiometry of the reaction suggests that a diimine should be obtained in this case. However, a careful look at the spectra in Figure 2 shows that neither the possible monoimine 5 nor the possible diimine 6 was formed. OH
O
NH2
H
OH
H
Scheme I
O glyoxal
o-aminophenol
3
Example 2 The reaction between o-aminophenol (2 equiv) and glyoxal (1 equiv), in water at 80 °C affords a crystalline solid in almost quantitative yield (6 ). Determine the structure of
Figure 1. Product obtained in Example 1. (a) 1H NMR (300 MHz, CDCl3); (b) 13C NMR (75 MHz, CDCl3).
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OH
OH N
CH CHO
OH N
5
CH
CH
N
6
Figure 2. Product obtained in Example 2. (a) 1H NMR (200 MHz, CDCl3); (b) 13C NMR (50 MHz, CDCl3); (c) 135-DEPT (50 MHz, CDCl3).
Journal of Chemical Education • Vol. 78 No. 6 June 2001 • JChemEd.chem.wisc.edu
In the Classroom
The absence of a formyl group (the usual signals in the H NMR are at 9–10 ppm and in the 13C NMR at 190–200 ppm) excludes structure 5. In the case of 6, the NMR spectra should exhibit signals for the CH=N group (about 8 ppm in the 1H NMR and 150–160 ppm in the 13C NMR) that are not present in the product. These observations are confirmed by the IR spectrum, which shows a sharp absorption at 3382 cm᎑1, with no indication of any other significant bands in the 1600– 1760 cm᎑1 region. The 1H NMR spectrum indicates the presence of protons in the ratio 4:1:1. Four of the proton signals are related to the aromatic system, one is a doublet (5.26 ppm, J = 3.6 Hz), and the other (4.83 ppm) is a broad singlet, possibly too shielded to belong to a phenol group. Finally, the 13C NMR indicates the presence of an unexpected aliphatic CH (75.8 ppm) that is confirmed by the 135-DEPT experiment. To interpret these data, it is necessary to consider the involvement of the phenolic oxygen in the reaction. A reasonable explanation for the outcome could be the formation of diimine 6 (the initially expected product) and its subsequent cyclization by nucleophilic attack of the OH group at the N=CH bonds. This type of cyclization is well documented in the literature (7). In this case, depending on the cyclization mode, structures 7 and 8 can be suggested for the reaction product. Both are 1
Figure 3. 19-Acetylgnaphalin (9). (a) 1H NMR (200 MHz, CDCl3); (b) 13C NMR (50 MHz, CDCl3); (c) 135-DEPT (50 MHz, CDCl3).
fully compatible with the experimental data and justify the multiplicity of the CH signal in the 1H NMR by coupling with the neighboring NH group (Scheme II). However, this time, despite all the information from spectroscopy, it is not possible to decide which of the two structures is correct. This is a situation that an organic chemist has to face sometimes in real life and it exemplifies the limitations of the usual spectroscopic techniques. In this example, the structure of the reaction product was unequivocally determined as the cis-fused benzoxazino-benzoxazine 7 by X-ray crystallographic analysis (6b). H N
O
NH
O
O
NH
heat
O
N
H 7
6 O
O
NH
NH
8
Scheme II
Figure 4. Product obtained in Example 3. (a) 1H NMR (200 MHz, CDCl3); (b) 13C NMR (50 MHz, CDCl3); (c) 135-DEPT (50 MHz, CDCl3).
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Example 3 (Advanced Undergraduate Level) After treatment of 19-acetylgnaphalin (9) (C22H26O7) with KOH in MeOH, a crystalline solid was obtained in quantitative yield (8). The spectroscopic data of 9 and the reaction product are given in Figures 3 and 4. Determine the structure of this compound and propose a mechanistic pathway to explain how it could be formed. Before the discussion and with the help of tables (9), the student should try to make the assignment of the more significant signals in the 13C NMR spectrum of 9 (Fig. 3). 15
O 14 16
13
H
12
O 11
H 2 3
1 4
10 5
9 6
20 8
O Me 17
7
O 18
19
O OCOMe
3. The signals at 62.0 and 48.3 ppm in 9, assignable to carbons C18 and C19, are not present in the reaction product. This points to the opening of the epoxide ring and the loss of a CH2O fragment. 4. Three sp3 quaternary carbons at 61.2 (C4), 54.1 (C5), and 51.6 ppm (C9) are present in the structure of 9, but only one is present in the reaction product (50.1 ppm). If we take the previous conclusions into account this resonance could be assigned to C9.
From these observations, it seems clear that the decalin skeleton and the 3-furyl lactone fragment are still present in the reaction product. The major structural changes have occurred in proximity to the acetoxy group and the oxirane ring (C4, C5, and C6 positions). If we combine all these data with our knowledge of general organic chemistry, we can propose a reasonable explanation for both the structure of the product and the mechanism of the reaction. Initially, we have to account for the loss of the acetyl group during the reaction. This is not difficult to explain, since the transformation takes place in KOH–MeOH. Under these conditions the hydrolysis of the ester group should occur.
9
19-Acetylgnaphalin. IR (KBr): 1748, 1766, 1715, 880 cm᎑1. MS: m/z 402 (M+) 330, 311 (100), 95, 81. Reaction Product. IR (KBr): 1745, 875 cm-1. MS: m/z 312 (M+), 185 (100),134, 96.
Solution At first glance, for a beginner, the 1H NMR spectra in Figures 3 and 4 are discouraging. Even with the structure in hand, just trying to identify the signals of the starting compound seems a difficult task. However, in both 1H NMR spectra, the C8 methyl group at 0.95 ppm, (d, J = 6.5 Hz) in 9 at 1.08 ppm, (d, J = 6.5 Hz) in the reaction product, and the signals of the furan ring (6.3, 7.3, and 7.4 ppm), are easily identifiable. It is also clear that the CH3CO group (1.94 ppm) in 19-acetylgnaphalin is not present in the reaction product. Comparison of the IR data confirms that, for the product, the lactone function (1748 cm᎑1) remains unaltered, but the acetyl (1766 cm᎑1) and keto (1715 cm᎑1) groups originally present in 9 have disappeared. These observations are consistent with the comparative analysis of the M+ peaks in the mass spectra that indicate a loss of 90 units of mass during the reaction. A detailed study of the 13C NMR and the 135-DEPT of both compounds gives the following information about the nature of the final product.
O
O
O
H
H
H O
O O
H
Me
O O
H
Me
KOH/ MeOH 5% RT
Me -CH2O
O
O
O O O
O OAc
9
O
11
10
O
O
O
H
H
H
O
O
O O
H
O
H
Me
O
H
Me
Me
work-up
O
O
H
O
O
O O
15
14
12
H 2O
O
H O
1. The previous conclusions based on the comparison of the IR spectra are corroborated by the presence of the lactone carbonyl carbon (175.5 ppm) and the disappearance of the signals of the acetyl and the keto groups (206.8, 170.8, and 20.8 ppm) in the reaction product. 2. The 13C NMR aromatic region shows the reaction product to possess the four signals of the furan ring (also present in 9), together with other new signals at 147.9, 136.1, 119.7 and 177.0 ppm. With the exception of an sp2 CH (136.1 ppm), all resonances are quaternary carbons. This is confirmed by the 135-DEPT experiment.
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Scheme III
O
H
Me
O HO
13
At that point, it would be reasonable to propose structure 10 as the first intermediate formed under these reaction conditions. The next problem encountered is the explanation for the loss of a CH2O fragment. We can see in intermediate 10
Journal of Chemical Education • Vol. 78 No. 6 June 2001 • JChemEd.chem.wisc.edu
In the Classroom
that a retroaldol cleavage (loss of a CH2O) is likely, leading to enolate 11, which can react further, bringing about the opening of the epoxide ring and the formation of intermediate 12. After protonation in the medium, this could lead to compound 13. Structure 13 does not match the spectra of the reaction product. This is evidenced by the fact that 13 still has a keto group and does not explain the presence of new sp2 signals in the 13C NMR. Therefore an alternative reaction mode for intermediate 12 has to be considered. This is likely to be an attack of the alkoxide in 12 at the carbonyl group. This would yield a dihydrofuran 14 that could undergo protonation and aromatization (loss of water) during workup, leading to 15. The structure of this compound (Montanin A [10], a furanoid diterpene) fits very well with the spectroscopic data and is consistent with the loss of 90 mass units during the process (Scheme III). Conclusion We believe that a more real-life approach in teaching spectroscopic analysis is necessary, particularly in the type of exercises used to illustrate how to extract information from various techniques. We have suggested a classroom discussion for three exercises that obviously can be argued in many other ways. However, it is clear that to establish the structure of a reaction product we have to combine both the spectroscopic data and speculation on the type of transformation involved. It is true that we mostly rely on spectroscopic data when trying to identify an unknown molecule but always after considering in depth all the pieces of information available. If when lecturing we prepare our students to employ their basic knowledge of organic chemistry to support the data provided by the techniques they are learning, they we will be better prepared to make the most of the experiments in the laboratory. Undoubtedly, they will also be more qualified for their future postgraduate courses or industrial jobs. Acknowledgments We want to thank Benjamin Rodriguez and María C. de la Torre (Instituto de Química Orgánica General-CSIC) for providing us with real samples of 19-acetylgnaphalin and Montanin A. We deeply acknowledge W. M. Horspool for his invaluable help in editing the manuscript. Support for this work under grants PB-97-0323 and 2FD97-0314-CO202 from the Dirección General de Enseñanza Superior e Investigación Científica y Técnica (MEC-Spain) and the European Commission is also acknowledged. Note 1. 1H and 13C NMR spectra were obtained in CDCl3 on either a Varian XL-300S or a Bruker 200-AC spectrometer. Chemical shifts are given in ppm relative to TMS (1H, 0.0 ppm) or CDCl3 (13C,
76.9 ppm). IR spectra were recorded on a Perkin-Elmer 781 spectrometer. Mass spectra were obtained on a HP-5989 quadrupole instrument at 70 eV and the m/z values are given in daltons.
Literature Cited 1. See for example: Alexander, C. W.; Asleson, G. L.; Doig, M. T.; Heldrich, F. J. J. Chem. Educ. 1999, 76, 1294–1296. Alexander, C. W.; Asleson, G. L.; Beam, C. F.; Doig, M. T.; Heldrich, F. J.; Studer-Martinez, S. J. Chem. Educ. 1999, 76, 1297–1298. 2. For recent examples of application of spectroscopic analysis in organic laboratory experiments see: (a) Baer, C.; Cornely, K. J. Chem. Educ. 1999, 76, 89–90. (b) Parmentier, L. E.; Lisensky, G. C.; Spencer, B. J. Chem. Educ. 1998, 75, 470–471. (c) Castro, C.; Karney, W. J. Chem. Educ. 1998, 75, 472–474. (d) Hunter, A. D.; Bianconi, L. J.; Dimuzio, S. J.; Braho, D. L. J. Chem. Educ. 1998, 75, 891–893. 3. Some organic spectroscopy workbooks: Duddeck, H.; Dietrich, W. Structure Elucidation by Modern NMR: A Workbook, 3rd ed.; Springer: Berlin, 1999. Lee, T. A. A Beginners Guide to Mass Spectral Interpretation; Wiley: New York, 1998. Pretsch, E.; Clerc, J. T. Spectra Interpretation of Organic Compounds, Wiley/VCH: Weinheim, 1997. Silverstein, M. R.; Webster, F. X. Spectrometric Identification of Organic Compounds, 6th ed.; Wiley: New York, 1997. Field, L. D.; Sternhell, S.; Kalman, J. R. Organic Structures from Spectra, 2nd ed.; Wiley: New York, 1995. Sanders, J. K. M.; Constable, E. C.; Hunter, B. K.; Clive, M. P. Modern NMR Spectroscopy: A Workbook of Chemical Problems, 2nd ed.; Oxford University Press: New York, 1993. Breitmaier, E. Structure Elucidation by NMR in Organic Chemistry: A Practical Guide; Wiley: New York, 1993. 4. Vogel, A. I. Textbook of Practical Organic Chemistry, 5th ed.; ELBS, Longman Scientific: Essex, UK, 1989; p 984. 5. Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic Chemistry, 3rd ed.; Harper and Row: New York, 1987; pp 968–969. 6. (a) Bayer, E. Chem. Ber. 1957, 90, 2325–2338. (b) Tauer, E.; Grellmann, K.-H.; Kaufmann, E.; Noltemeyer, M. Chem. Ber. 1986, 119, 3316–3325. (c) Barluenga, J.; Aznar, F.; Liz, R.; Cabal, M. P.; Cano, F. H.; Foces-Foces, C. Chem. Ber. 1986, 119, 887–899. 7. Valters, R. E.; Fülöp, F.; Korbonits, D. Adv. Heterocycl. Chem. 1995, 64, 251–321. 8. Savona, G.; Paternostro, M.; Piozzi, F. Tetrahedron Lett. 1979, 379–382. 9. Pretsch, E.; Clerc, T.; Seibl, J.; Simon, W. Tables of Spectral Data for Structure Determination of Organic Compounds, 2nd ed.; Springer: New York, 1989. 10. For a detailed 13C NMR study of Montanin A and other furanoid diterpenes from Teucrium species, see: Gacs-Baitz, E.; Kajtar, M.; Papanov, G. Y.; Malakov, P. Y. Heterocycles 1982, 19, 539–550.
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