In the Laboratory
Hetero Diels–Alder Reaction with Aqueous Glyoxylic Acid An Experiment in Organic Synthesis and 2-D NMR Analysis for Advanced Undergraduate Students Jacques Augé and Nadège Lubin-Germain Department of Chemistry, University of Cergy-Pontoise, 95031 Cergy-Pontoise, France
There are few published undergraduate experiments that combine chemical transformation and two-dimensional NMR spectroscopy. The following experiment is addressed to advanced undergraduate students who are trained in organic synthesis and NMR spectroscopy. The experiment can be divided into two parts, but we recommend a time block of eight hours for the full experiment. The first part deals with the hetero Diels–Alder reaction between cyclopentadiene and glyoxylic acid. This is an illustration of the acceleration of organic reactions in aqueous media. The hydrophobic effect (i.e., the entropy-driven aggregation of two nonpolar molecules dissolved in water) (1–3) was suggested as the phenomenon responsible for such an acceleration and the interpretation was extended to the reactions exhibiting a negative volume of activation (4 ). The hetero Diels–Alder reaction is known to be accelerated under pressure, implying a negative volume of activation (5, 6 ) This reaction is indeed facilitated in water (7, 8). The second part deals with the analysis of the products by 1H and 13C spectroscopy. The use of 2-D NMR spectroscopy illustrates the importance of such a technique in the elucidation of a complex chemical structure. This second part is particularly appropriate for an instrumental analysis course and may interest students who are confronted with the interpretation of NMR spectra of different stereoisomers. Experimental Procedure
Preparation of Cyclopentadiene Dicyclopentadiene was placed in a flask adapted with a distillation column and heated to 200 °C to facilitate the retrodimerization. Cyclopentadiene was then distilled (bp 40 °C) and used immediately.1 Cycloaddition The commercially available (from Fluka) aqueous solution of glyoxylic acid (22.5 mL of the 50% aqueous solution; 0.2 mol) was placed in a 250-mL flask, then diluted with 80 mL of water. To this solution were added 2.497 g of cupric sulfate (0.01 mol) and 24 mL (0.38 mol) of freshly distilled cyclopentadiene. The flask was adapted with a refrigerant and the mixture was heated at 60 °C for 3 hours under stirring. After cooling to room temperature, the mixture was extracted with 2 × 25 mL of cyclohexane to remove the excess of cyclopentadiene. The aqueous layer was saturated with sodium chloride and extracted with 5 × 50 mL of ethyl acetate. The combined organic layers were washed with sodium bicarbonate, dried over magnesium sulfate, filtered, and then evaporated, affording an oil. The residue was then taken up in a minimum of ether to induce crystallization (it is sometimes recommended to seed the solution with crystals to more rapidly induce the crystallization). The crystals were
filtered and washed with cold water, affording 6.5 g of the major lactone (1) (mp 63–64 °C). The minor lactone (2), along with uncrystallized lactone 1, remains in the mother liquors.
NMR Spectroscopy NMR spectra were obtained with a Bruker AM 250 instrument operating at a field of 250 and 62.5 MHz for 1H and 13C, respectively. Chemical shifts are reported in ppm downfield from internal TMS. Compound 1: 1H NMR (250 MHz, CDCl3) δ 2.47 (dddd, 1H, J 18, 9. 5, 2.2, and 2.2 Hz), 2.77 (dddd, 1H, J 18, 6, 2.2, and 2.2 Hz), 3.23 (dddd, 1H, J 9.5, 9.5, 6.5, and 6 Hz), 4.75 (d, 1H, J 9.5 Hz), 5.35 (ddd, 1H, J 6.5, 2.2, and 2.2 Hz), 5.94 (dddd, 1H, J 5.5, 2.2, 2.2, and 2.2 Hz), 6.27 (dddd, 1H, J 5.5, 2.2, 2.2 and 2.2 Hz); 13C NMR (62.5 MHz, CDCl3) δ 30.80, 40.52, 69.19, 86.58, 127.5, 141.16, and 177.97. Compound 2: 1H NMR (250 MHz, CDCl3) δ 2.58 (ddddd, 1H, J 17.5, 2, 2, 2, and 2 Hz), 2.77 (dddd, 1H, J 17.5, 7.5, 4.5, and 2 Hz), 3.06 (dddd, 1H, J 7.5, 7.5, 7.5, and 2 Hz), 4.17 (d, 1H, J 7.5), 5.55 (dddd, 1H, J 7.5, 2, 2, and 2 Hz), 5.91 (dddd, 1H, J 5.5, 2, 2, and 2 Hz), 6.10 (dddd, 1H, J 5.5, 4.5, 2 and 2 Hz); 13C NMR (62.5 MHz, CDCl3) δ 36.64, 44.14, 74.37, 87.48, 129.33, 136.75, and 177.67. Results and Discussion
Synthesis Cyclopentadiene is used in excess, but is easily eliminated in the work-up. As cyclopentadiene is only slightly soluble in water (10 mM at 20 °C), a vigorous stirring is essential for a successful reaction. Students must be aware of the fact that the carbonyl functionality of glyoxylic acid in water is
O
+
O CO2H CO2H
H 4
H H H2 4' 3 OH O
H 5
O H
H6
1
7
H 4'
+
H H H2 4 3 OH O
H 5
O H6
H
7
2
Figure 1. Reaction between cyclopentadiene and glyoxylic acid.
JChemEd.chem.wisc.edu • Vol. 75 No. 10 October 1998 • Journal of Chemical Education
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In the Laboratory
H
OH
+
O H
O O
Table 1. Interpretaion of the 1- D and 2- D NMR Spectra of the Lactone 1 Proton δ/ppm J / Hz NOESY Interaction H -5
6.27
J 5, 6 = 5.5
H - 6, H - 4, H - 4′
H-6
5.94
J 6, 7 = 2.2
H -5, H - 7
Figure 2. Rearrangement of the endo transient cycloadduct.
H -7
5.35
J 3, 7 = 6.5
H -2, H -3, H - 6
largely in the hydrated form (9, 10). Despite these drawbacks, the reaction between cyclopentadiene and glyoxylic acid (Fig. 1) proceeded nicely in water (11, 12). Since a large acceleration is observed by the combined use of a Lewis acid as a catalyst and water as the solvent (13), we investigated the effect of copper(II) salts on the reaction. The yield was increased to 63% when the reaction was carried out at 60 °C for 3 hours in the presence of CuCl2, CuSO4, or Cu(NO3)2. The mechanism of the reaction is consistent with a [4+2] hetero Diels–Alder reaction followed by an intramolecular rearrangement according to Figure 2. The endo intermediate gives rise to the major lactone (1); the minor lactone (2) might be derived from the exo intermediate. The NMR spectrum of the residue obtained after work-up allowed us to determine the isomeric ratio (65/35). The major lactone (1) can be isolated by crystallization from ether.
H -2
4.75
J 2, 3 = 9.5
H -3, H -7
H -3
3.23
J 3, 4 = 9.5; J 3, 4′ = 6
H -2, H - 4, H - 7
H - 4′
2.77
J 4, 4′ = 18; J 4′, 5 = 2.2
H - 4, H - 5
H-4
2.47
J 4, 5 = 2.2
H - 3, H - 4′, H - 5
O
O H
H
NMR Spectroscopy The main difference between the NMR spectra of the two isomeric lactones involves the chemical shifts for the protons H-2. The 1H NMR spectrum of one isomer shows a doublet at 4.75 ppm with a coupling constant J2,3 = 9.5 Hz, whereas the signal for the same proton in the other isomer is observed at 4.17 ppm with a coupling constant J2,3 = 7.5 Hz. In order to ascertain the correct structure, a 2-D NMR spectroscopy analysis is required. Students need the NOESY spectra of both lactones (Figs. 3 and 4) to be able to identify them and to interpret all the coupling constants observed in the 1-D spectra. In particular, correlations between H-2 and H3, H-3 and H-7, and even H-2 and H-7 are visible in the phase-sensitive NOESY spectrum for 1 (Fig. 3), whereas for 2, a correlation is only found between H-3 and H-7 and (a very small one) between H-2 and H-3; no interaction between H-2 and H-7 is apparent (Fig. 4). By contrast, crosspeak coupling between H-2 and H-4 is visible in the phasesensitive NOESY spectrum for the lactone 2. These observations allowed us to conclude that in the lactone 1 there is
Figure 3. NOESY spectrum of lactone 1.
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Table 2. Interpretation of the 1- D and 2- D NMR Spectra of the Lactone 2 δ / p p m Proton J / Hz NOESY Interaction H -5
6.10
J 5, 6 = 5.5
H-6
5.91
J 6, 7 = 2
H -5, H - 7
H-7
5.55
J 3, 7 = 7.5
H -3, H - 6
H - 6, H - 4, H - 4′
H -2
4.17
J 2, 3 = 7.5
H -3, H - 4
H-3
3.06
J 3, 4 = 7.5; J 3, 4′ = 2
H -2, H - 4′, H - 7
H - 4′
2.77
J 4, 4′ = 17.5; J 4′, 5 = 4.5
H -3, H -4, H - 5
H-4
2.58
J 4, 5 = 2
H -2, H - 4′, H - 5
a cis relationship between H-2, H-3, and H-7, whereas in the lactone 2 there is a cis relationship between H-2 and H3 and a trans relationship between H-2 and H-7. Tables 1 and 2 give the complete NMR assignments for the lactones 1 and 2. Note 1. If not used immediately, cyclopentadiene must be stored at low temperature, since it is prone to dimerization according to a [4+2] mechanism. Conversely, heating dicyclopentadiene at 200 °C favors the retro Diels–Alder reaction.
Literature Cited 1. Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816–7817. 2. Huque, E. M. J. Chem. Educ. 1989, 66, 581–585. 3. Reichardt, C. Solvents and Solvent Effects in Organic Chemistry; VCH: Weinheim, 1988. 4. Lubineau, A.; Augé, J.; Queneau, Y. Synthesis 1994, 741–760.
Figure 4. NOESY spectrum of lactone 2.
Journal of Chemical Education • Vol. 75 No. 10 October 1998 • JChemEd.chem.wisc.edu
In the Laboratory 5. Matsumoto, K.; Sera, A.; Uchida, T. Synthesis 1985, 1–26. 6. Matsumoto, K.; Sera, A. Synthesis 1985, 999–1027. 7. Grieco, P. A.; Larsen, S. D.; Fobare, W. F. Tetrahedron Lett. 1986, 27, 1975–1978. 8. Lubineau, A.; Augé, J.; Grand, E.; Lubin, N. Tetrahedron 1994, 34, 10265–10276. 9. Chastrette, F.; Bracoud, C.; Chastrette, M.; Mattioda, G.; Christidis, Y. Bull. Soc. Chim. Fr. 1985, 85, 66–74.
10. Sorensen, P. E.; Bruhn, K.; Lindelov, F. Acta Chem. Scand. A 1974, 28, 162–168. 11. Lubineau, A.; Augé, J.; Lubin, N. Tetrahedron Lett. 1991, 32, 7529–7530. 12. MacKeith, R. A.; McCague, R.; Olivo, H. F.; Palmer, C. F.; Roberts, S. M. J. Chem. Soc. Perkin Trans. 1, 1993, 313–314. 13. Engberts, J. B. F. N.; Feringa, B. L.; Keller, E.; Otto, S. Recl. Trav. Chim. Pays-Bas 1996, 115, 457–464.
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