In the Laboratory
An Exploration of a Photochemical Pericyclic Reaction Using NMR Data
W
Sara M. Hein Department of Chemistry, Winona State University, Winona, MN 55987
In this experiment, a photochemical [2+2] cycloaddition reaction is investigated. Such reactions often are given as examples on paper, but are rarely investigated by students in the laboratory (1, 2), and very few experiments involving pericyclic reactions have appeared in this Journal (3–10). The photoisomerization of cinnamic acid derivatives has been published as an investigative experiment for a sophomorelevel organic synthesis laboratory (11, 12). Melting points were used to identify the cinnamic acid dimer. This method was preferred because it allowed quick identification of the product with minimal subsequent experimentation. Because sensitive NMR instruments and molecular modeling programs are now available, we have used these valuable tools to characterize synthetic products, including photochemically derived products. Students carry out the photodimerization of trans-cinnamic acid and derivatization of the product. Analysis of the derivatized products and NMR spectroscopy allows students to identify the product of the synthesis. The NMR analysis involves molecular models and the application of coupling constants to determine the product. Once the correct product has been correctly identified, a mechanism can be proposed. This article outlines the significance of both the photochemical and spectroscopic aspects of the photoisomerization of trans-cinnamic acid. Experimental Overview Trans-cinnamic acid is available from several commercial sources (Aldrich Chemical Company and Acros Organics) and has been used in traditional synthetic undergraduate organic laboratory experiments (13–15). The trans isomer is thermodynamically stable. However, when the reagent is exposed to ultraviolet light, it becomes reactive and subsequently dimerizes. The product is first studied by NMR spectroscopy to propose its structure. Then its structure is confirmed through esterification, acetylation, and computer modeling experiments. Each step of the experiment results in 75% yield or better.
promotes one molecule from its ground-state HOMO to its excited-state HOMO, enabling overlap to occur. The objective of this investigation is to determine which one of eleven possible products, including stereoisomers, is formed when trans-cinnamic acid is dimerized. Initial analysis by 1H NMR spectroscopy indicates the product is symmetrical because of the presence of only two resonances representing two different sets of magnetically equivalent nuclei, corresponding to the original alkenyl protons. However, these data also support several possible head-to-tail or head-to-head candidates. Therefore, some previous knowledge about [2+2] cycloaddition reactions and radical stability is required. Suprafacial–suprafacial (same algebraic sign at both ends) and antarafacial–antarafacial (opposite algebraic sign at both ends) orbital symmetries are plausible orientations for cycloaddition. In this experiment, only the head-to-tail, suprafacial–suprafacial product is formed because the antarafacial–antarafacial product is geometrically impossible. Further, dimerization of alkenes can be shown to involve biradical intermediates (17, 18). A biradical intermediate suggests stability is the driving force behind the orientation of the monomers, supporting the head-to-tail configuration. There are only five possible head-to-tail cycloaddition products. Two possible radical intermediates need to be considered: (i) a benzylic radical and (ii) a secondary radical next to the carboxylic acid (Figure 2). The benzylic radical is significantly more stable than the secondary radical, as observed through energy calculations. The biradical transition state has a reasonably long lifetime and the monomers will assume a conformation with the least steric hindrance. In addition,
A
LUMO
B
LUMO
no overlap
bonding overlap
HOMO of ground state
HOMO of excited state
Results and Discussion Ring formation via dimerization of alkenes utilizing [2+2] cycloaddition conditions is well documented (16). These reactions, forbidden thermally because of high activation energies, can be initiated through photochemical means. Theoretically, π orbitals representing ethylene moieties exist as bonding orbitals in the ground state, HOMO (highest occupied molecular orbital). For cycloaddition to occur, overlap must occur between the HOMO and an antibonding orbital, LUMO (lowest unoccupied molecular orbital). This is not possible under ground-state conditions (Figure 1). However, under UV light, trans-cinnamic acid is able to absorb energy that 940
Journal of Chemical Education
•
Figure 1. HOMO and LUMO: (A) before UV irradiation and (B) after irradiation
COOH
COOH
ii
i
Figure 2. Two possible radical intermediates of trans-cinnamic acid.
Vol. 83 No. 6 June 2006
•
www.JCE.DivCHED.org
In the Laboratory
overlap of the p orbitals stabilizes the radicals, which prevents rotation of the carbon–carbon single bond, thereby retaining a geometrical (trans) configuration. The trans configuration of the monomers is confirmed by studying NMR spectra. Two doublet of doublets resonances in the 1H NMR spectrum at 3.78 and 4.25 ppm represent protons on opposite faces of the cyclic portion of the dimer. These are the only two proton resonances that are present aside from those representing the acid and aromatic protons. Further computational analysis supports the trans orientation of the phenyl and acid moieties, narrowing the number of possible dimers to two, as shown in Figure 3. Simple esterification of the two carboxylic acid moieties can be carried out to help students verify the presence of two chemically equivalent groups of cyclobutyl protons. 1H NMR analysis of the esterified dimer reveals a singlet, representing two overlapping methyl groups. This resonance confirms that protons H1 and H1´ and protons H2 and H2´ are magnetically equivalent and not accidentally isochronous. Truxillic acid A and B can then be differentiated. At first glance, truxillic acid A seems more stable and may be presumed to be the correct product of the reaction because of the greater distance between the phenyl and carboxylic acid groups. However, the difference in energy between A and B (4 kcal兾mol) suggests the formation of B, as determined through molecular modeling experiments. Therefore, further analysis is required. Elucidation of the product as truxillic acid A is determined by 1H NMR analysis of the cyclobutyl signals. They exist as doublets of doublets at higher fields (≥ 200 MHz). Splitting patterns at low-field 1H NMR (60–100 MHz), cannot be determined but the product is possible to determine with additional derivatization. Formation of an anhydride and 1H NMR analysis are used to verify the structure. By looking at the two possible truxillic acid structures, it may be presumed that the only possible anhydride can be formed from truxillic acid B because of the proximity of the carboxylic acid groups (Figure 4). However, epimerization of H1 or H1´ in truxillic acid A is possible, which also leads to formation of an anhydride. 1H
H2′
H1′
H
H2 CO2H
Ph
CO2H
H
H1
A
Ph H
Ph
Ph
Ph O
O
O
Ph
Ph
O
O A
It is recommended that this experiment (20) be carried out in conjunction with other laboratory experiments. The first laboratory period involves the preparation of the reaction flask for photodimerization. This requires only 30 minutes, with an additional hour for evaporation. The photodimerization is allowed to proceed for at least two weeks. The dimer is then derivatized by two methods, esterification and acetylation. Esterification requires 1.5–2 hours. Acetylation requires 2–2.5 hours. Subsequent spectroscopic analyses could be carried out concurrently with other procedures to allow each student some instrument time. Each step results in ≈ 75% yield. A high-field NMR spectrometer at 200 MHz or greater is most useful. However, elucidation is also possible with a lower-field instrument. Mechanistic studies could be integrated into a laboratory investigation without a spectrometer if the NMR data are provided to the students. Sun lamps capable of emitting a wavelength of 273 nm are required. Hazards
Experimental
B
Figure 3. Truxillic acids, two possible dimers from cinnamic acid.
O
Experimental Procedure
Trans-cinnamic acid and magnesium sulfate are mild irritants. Tetrahydrofuran, hexanes, and toluene are flammable and can be inhalation hazards. These solvents should be used in the hood. DMSO-d6 and CDCl3 are carcinogens and can be readily absorbed through the skin. Gloves, goggles, and a laboratory coat are recommended. [Editor’s Note: CLIPs are available in J. Chem. Educ. for MgSO4 (2005, 82, 678) and hexane (2001, 78, 587, 1021, 1593).]
CO2H H
CO2H Ph
NMR data from the anhydride derivative are used to differentiate between the two possible structures. The 1H NMR spectrum of anhydride A should reveal three different cyclobutyl resonances with an integration of 1:2:1. The 1H NMR spectrum of the anhydride B would reveal only two separate resonances with a 1:1 ratio. The number of resonances (three) is clear at both high-field and low-field NMR. This supports the original assumption that A is the correct product. Homonuclear decoupling experiments can be carried out to identify the cyclobutyl proton resonances, if desired. The unusual coupling constants observed require homonuclear decoupling experiments to determine the identity of each proton. These coupling constants can be confirmed by several published tables (19).
B
Figure 4. The two possible anhydrides from the truxillic acid structures in Figure 3.
www.JCE.DivCHED.org
•
Cinnamic Acid Dimer Trans-cinnamic acid (1.5 g) is added to a 125-mL Erlenmeyer flask with 2–3 mL of tetrahydrofuran (THF). The acid is dissolved by heating the flask over a steam bath. Once the solution is hot, the flask is rotated to allow the solution to coat the sides and bottom evenly. Excess THF is drained by inverting the flask in a hood for an hour and a cork is added. The inverted flask is then placed in front of a halogen sun lamp (λmax = 273) for 15 days and rotated every 2– 3 days. The white solid is recrystallized in toluene (2.5 g, 85.0%). 1H NMR data are acquired in DMSO-d6.
Vol. 83 No. 6 June 2006
•
Journal of Chemical Education
941
In the Laboratory
Ester Derivative One gram of the isolated dimer, 5 mL of methanol, and 3 drops of sulfuric acid are added to a 25-mL round-bottom flask. The mixture is allowed to reflux for 1.25 hour, cooled, and then 13 mL of water and 13 mL of diethyl ether are added. The aqueous layer is removed and the ether layer washed with saturated NaHCO3 solution. The ether layer is dried over MgSO4, filtered, and evaporated. The solid is recrystallized using hexane (1.05 g, 94.7%). 1H NMR data are acquired in CDCl3. Anhydride Derivative One gram of the isolated dimer, 150 mg of sodium acetate, and 1 mL of acetic anhydride are added to a 10-mL round-bottom flask. The mixture is allowed to reflux for 1.5 hours, cooled, and H2O is added dropwise until the remaining acetic anhydride has been hydrolyzed. Additional H2O is added. The reaction mixture is transferred to a separatory funnel using an additional 10 mL of H2O. The entire reaction mixture is partitioned between water and methylene chloride (5 mL). The organic layer is washed with saturated NaHCO3 solution, dried over MgSO4, filtered, and concentrated to approximately 1 mL. Ice-cold ethanol (2 mL) is added to the mixture to induce crystallization. The solid is recrystallized using hexane (0.86 g, 66.6%). 1H NMR data were acquired in CDCl3. Molecular Modeling Data Molecular modeling calculations were performed using Hyperchem 7. The two structures were studied for geometry optimization. The resulting energies of the truxillic acids were A = ᎑4265 kcal兾mol and B = ᎑4269 kcal兾mol. Radical energies were ᎑2152 kcal兾mol and ᎑2175 kcal兾mol for the carbonyl (ii) and benzylic (i) radicals, respectively. Conclusion This experiment encourages students to determine the product of a cycloaddition reaction based on mechanistic rationale and NMR data. Molecular modeling will support the elucidation process. Although the energy difference in the two possible truxillic acids is minimal (4 kcal兾mol), it can be explained that truxillic acid A is formed because the activation barrier of the HOMO energy transition is less than B. W
Supplemental Material
Instructions for the students and notes for the instructor are available in this issue of JCE Online.
942
Journal of Chemical Education
•
Literature Cited 1. Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic Chemistry, 3rd ed.; HarperCollins: New York, 1987; pp 903–930. 2. March, J. Advanced Organic Chemistry, 4th ed.; John Wiley & Sons: New York, 1992; p 861 and references therein. 3. Martin, W. B.; Kateley, L. J.; Wiser, D. C.; Brumond, C. A. J. Chem. Educ. 2002, 79, 225. 4. Baldwin, J. E.; Leber, P. A.; Lee, T. W. J. Chem. Educ. 2001, 78, 1394. 5. Jaret, R. M.; New, J.; Hurley, R. J. Chem. Educ. 2001, 78, 1262. 6. Ault, Addison. J. Chem. Educ. 2000, 77, 55. 7. Patterson, R. T. J. Chem. Educ. 1999, 76, 1002. 8. Lee, A. W.; So, C. T.; Chan, C. L.; Wu, Y. K. J. Chem. Educ. 1999, 76, 720. 9. Breton, G. W.; Vang, X. J. Chem. Educ. 1998, 75, 81. 10. McDaniel, K. F.; Weekley, R. M. J. Chem. Educ. 1997, 74, 1465. 11. Bell, C. B.; Clark, A. K.; Taber, D. F.; Rodig, O. R. Organic Chemistry Laboratory; Harcourt Brace College: New York, 1997; pp 477–483. 12. Zanger, M.; McKee, J. R. Small Scale Synthesis; Brown: Chicago, 1995; pp 525–527. 13. Mohrig, J. R.; Morrill, T. C.; Hammond, C. N.; Neckers, D. C. Experimental Organic Chemistry; W. H. Freeman and Co.: New York, 1999; pp 84–88. 14. Schoffstall, A. M.; Gaddis, B. A.; Druelinger, M. L. Microscale and Miniscale Organic Chemistry Laboratory Experiments; McGraw-Hill: New York, 2000; pp 405–407. 15. Gilbert, J. C.; Martin, S. F. Experimental Organic Chemistry; Harcourt: Fort Worth, TX, 2002; p 113. 16. March, J. Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th ed.; John Wiley and Sons: New York, 1992; p 861. 17. Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic Chemistry, 3rd ed.; HarperCollins: New York, 1987; p 907. 18. Jones, Maitland, Jr. Organic Chemistry, 3rd ed.; W. W. Norton and Co.: New York, 2005; pp 1135–1136. 19. Pretsch, E. Structure Determination of Organic Compounds: Tables of Spectral Data; Springer: New York, 2000. 20. Adapted procedure from Bell, C. B.; Clark, A. K.; Taber, D. F.; Rodig, O. R. Organic Chemistry Laboratory; Harcourt Brace College: New York, 1997; pp 477–483.
Vol. 83 No. 6 June 2006
•
www.JCE.DivCHED.org
