In the Laboratory
1H
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NMR Measurement of the Trans–Cis Photoisomerization of Cinnamic Acid Derivatives Basil Danylec and Magdy N. Iskander* Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia; *
[email protected] Since 1990 more than 3500 articles on photoisomerization have been published (1). The Z–E isomerization is well investigated in many research areas. Examples are in biological activity and selectivity (2), synthesis of novel alkenes (3), and energy computation of transition state and mechanism of Z–E isomerization (4 ). We have utilized the Z–E isomerization of olefins as a useful technique in combinatorial chemistry for developing congeneric chemophores (biologically active ligands). We are currently directing this effort at the synthesis of structural isomers of cinnamic acid derivatives, which are target molecules in our research program for the development of macrophage migration inhibitory factor (MIF) ligands (5). The present measurement of transformation of trans to cis isomers using 1H NMR was virtual validation of the photoisomerization of these olefinic compounds. This experiment has considerable educational merit in the field of Z–E photoisomerization. We therefore recommend the trans–cis photoisomerization of methyl p-hydroxycinnamate (Fig. 1) as an undergraduate laboratory experiment in organic chemistry. Experimental Procedure
Cis Isomerization of the Methyl p-Hydroxy-transcinnamate Methyl p-hydroxy-trans-cinnamate (500 mg, 2.809 mmol) was dissolved in molecular-sieve-dried acetonitrile (150 mL) and the solution was deoxygenated by bubbling nitrogen gas through it for 1 h. The solution was then transferred to an immersion-well photochemical reactor fitted with a water-cooled medium-pressure mercury arc lamp (125 W, Photochemical Reactors Ltd., Reading, Berkshire, UK) and irradiated. Proton NMR Measurements A 7.5-mL aliquot was reduced to dryness under vacuum. The 1H NMR sample was prepared by dissolving the residue in 0.75 mL of 5:1 CDCl3–CD3OD. TMS was added as an internal standard. Spectra were run on a Bruker Advance DRX 300 spectrometer. Methyl p-hydroxy-trans-cinnamate (1) (before irradiation) 1 H NMR (CDCl –CD OD–TMS): δ 3.79 (s, 3H, 3 3 CO2CH3), 6.15 (d, 1H, J2,3 = 15.9 Hz, H-2), 6.83 (d, 2H, J6,5/8,9 = 8.5 Hz, H-6, H-8), 7.41 (d, 2H, H-5, H-9), 7.63 (d, 1H, H-3).
Silylation of the Cis–Trans Methyl p-Hydroxycinnamic Acid Mixture After 2 h of irradiation, a 2:3 mixture of cis–trans methyl p-hydroxycinnamate (1.20 g, 6.74 mmol), imidazole (1.16 g, 17.04 mmol) and tert-butyldimethylsilyl chloride (1.60 g, 10.62 mmol) dissolved in DMF (10 mL) was stirred at room 1000
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Figure 1. Conversion of methyl p-hydroxy-trans-cinnamate (1) to the thermodynamically less stable cis isomer (2).
temperature for 0.5 h. The solvent was distilled off under vacuum and the residue was column chromatographed using silica gel 60, Merck 107734 (50:1 silica–crude product)– toluene to isolate two isomers. Methyl p-(tert-butyldimethylsiloxy)-trans-cinnamate (686 mg) was obtained as a white powder, Rf = .28 (silica gel/toluene). NMR (CDCl3–TMS): δ 0.22 (s, 6H, Si(CH3)2), 0.99 (s, 9H, SiC(CH3)3), 3.79 (s, 3H, CO2CH3), 6.30 (d, 1H, J2,3 = 16.0 Hz, H-2), 6.83 (d, 2H, J6,5/8,9 = 8.4 Hz, H-6, H-8), 7.41 (d, 2H, H-5, H-9), 7.64 (d, 1H, H-3). 1H
Methyl p-(tert-butyldimethylsiloxy)-cis-cinnamate (630 mg) was obtained as a white powder, Rf = .43 (silica gel–toluene). NMR (CDCl3–TMS): δ 0.21 (s, 6H, Si(CH3)2), 0.98 (s, 9H, SiC(CH3)3), 3.72 (s, 3H, CO2CH3), 5.82 (d, 1H, J2,3 = 12.8 Hz, H-2), 6.81 (d, 2H, J6,5/8,9 = 8.4 Hz, H-6, H-8), 6.84 (d, 1H, H-3), 7.63 (d, 2H, H-5, H-9). 1H
Hazards UV light is hazardous to the eyes. Students who have to check the reaction should wear UV glasses. The following are recommended: oberon didynium II blue lenses, Aldrich Z 23,064-2. Chemicals that should be handled with caution are acetonitrile (flammable liquid [75-05-8]), p-hydroxycinnamic acid (irritant [501-98-4]), and tert-butyldimethylsilyl chloride (flammable liquid and corrosive [1000-50-6]). The UV reactor should be placed in a fume hood with a protective sliding door during the course of reaction. Results and Discussion The examination of the reaction course with thin layer chromatography was ineffective, as both isomers demonstrated the same relative mobility on silica gel with a number of eluent systems. 1H NMR spectroscopy was therefore used to monitor the progress of isomerization. Aliquots were taken periodically, and the spectra (Fig. 2) display the progression of the photochemically induced isomerization. This time-course study demonstrated the conversion of the trans isomer (1) to the cis isomer (2), as evidenced by the gradual appearance of the new olefinic proton doublet
Journal of Chemical Education • Vol. 79 No. 8 August 2002 • JChemEd.chem.wisc.edu
In the Laboratory
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Chemical Shift (ppm) Figure 2. Time course study of the photoisomerization of methyl phydroxy-trans-cinnamate (1) as monitored by 300 MHz 1H NMR spectroscopy.
at δ 5.66 ppm with a coupling constant of 12.9 Hz and the disappearance of the trans isomer doublet at δ 6.15 ppm, J = 15.9 Hz. The optimal reaction time appeared to be 6 h. Prolonged irradiation collapsed the olefinic proton signals and there was a concomitant appearance of new up-field signals. These new products were not identified. The plots in Figure 3 highlight the olefinic proton region of interest. Integration or peak height measurement of the cis (5.66 ppm, J = 12.9 Hz) and trans (6.15 ppm, J = 15.9 Hz) signals allowed the determination of the relative amounts of these two materials. These results were verified by reacting the irradiated product mixture with tert-butyldimethylsilyl chloride– imidazole–DMF at room temperature for 0.5 h. This gave a mixture of cis and trans methyl p-(tert-butyldimethylsiloxy)cinnamate, which was conveniently separated using column chromatography (silica gel–toluene, Rf = .43 [cis] and 0.28 [trans]). The relative amounts of the cis and trans isomers recovered were then determined. This exercise can be completed in 3–5 h, depending on the level of the students and the nature of the course. A suggested protocol for this experiment is as follows. In the first hour, students can run the irradiation and check on the formation of cis isomer. The ratio of the two isomers can then be calculated by measuring either the peak height or the corresponding integration of the cis (5.66 ppm, J = 12.9 Hz) and trans (6.15 ppm, J = 15.9 Hz) signals of these two isomers
Figure 3. Time course study demonstrating the appearance of the cis olefinic proton at 5.78 ppm.
(Fig. 3). Amounts of the cis isomer sufficient to carry out the rest of experiment can be obtained in the first hour. Also during this time, students can prepare for the derivatization of the mixture and column chromatography (see the experimental section). Silylation of the irradiated mixture takes 15–30 min, depending on the quantity of the mixture. The last part is the chromatographic separation and identification of the cis and trans isomers in the reaction mixture (see the experimental section). If the photochemical reactor cannot be assembled in the institution’s workshop, a complete reactor can be purchased from Aldrich, Z 25,946-2. W
Supplemental Material
Instructions for students and notes for the instructor are available in this issue of JCE Online. Literature Cited 1. SciFinder Scholar 2000, Release 3.0; American Chemical Society: Washington, DC; see SciFinder Scholar home page, http://www.cas.org/SCIFINDER/SCHOLAR/ (accessed Mar 2002). 2. Dondoni, A; Perrone, D; Turturici, E, J. Chem. Soc., Perkin Trans. 1997, 1, 2389. 3. Liu, R. S. H. Acc. Chem. Res. 2001, 34, 555–562. 4. Garcia-Exposito, E.; Gonzalez-Moreno, R.; Martin-Vila M.; Muray, E.; Rife, J.; Bourdelande, J. L.; Branchadell, V.; Ortuno, R. M. J. Org. Chem. 2000, 65, 6958. 5. Pirrung, M. C.; Chen, J.; Rowley, E. G.; McPhail, A. T. J. Am. Chem. Soc. 1993, 115, 7103.
JChemEd.chem.wisc.edu • Vol. 79 No. 8 August 2002 • Journal of Chemical Education
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