In the Laboratory
Stereospecific Synthesis of the Geometrical Isomers of a Natural Product
W
T. Grove, D. DiLella, and E. Volker* Department of Chemistry, Shepherd University, Shepherdstown, WV 25443; *
[email protected] (Z ) and (E ) isomers of alkenes can differ significantly in their chemical and biological behavior. One of the best known cases is the photochemical isomerization of the retinal-derived portion of rhodopsin. In this process, the steric change associated with the conversion of a (Z ) double bond to the (E ) geometry initiates a nerve signal to the visual cortex of the brain (1). Biosynthesis of alkenes is often selective for one of the geometrical isomers. For example, the sex attractant of the house fly, muscalure, is (Z )-tricos-9-ene. Unsaturated fatty acids from biological sources are usually (Z ) isomers (2). Most texts of organic chemistry introduce several methods for the synthesis of alkenes. These may include bimolecular elimination of an alkyl halide or tosylate, acid-catalyzed dehydration of an alcohol, the Wittig reaction, and the Hofmann elimination. The stereochemistry of the resulting alkenes is usually emphasized in two reactions: (Z ) alkenes result from hydrogenation of alkynes with a Lindlar catalyst and (E ) alkenes result from the reduction of alkynes with elemental sodium or lithium in liquid ammonia. Despite its importance, stereospecific synthesis of geometrical isomers is not a common topic for the introductory organic chemistry laboratory. To address this shortcoming we explored several reactions and found that the Suzuki reaction for the synthesis of (Z )- and (E )-anethole can be performed with excellent results by undergraduates. The reaction can be conducted in one lab period, with isolation and identification performed in a subsequent lab period. Two other, non-stereospecific Pd-catalyzed coupling reactions have recently appeared in this Journal (3, 4). (E )-anethole is the major component of anise oil, which is used as flavoring in cookies and liquors and is also a substitute for licorice root extract in licorice sticks. The desired odor and taste of anise oil is a property of the (E ) compound. The anethole isomers are shown in Figure 1. (E )-anethole has been the subject of four articles that have appeared in this Journal. Garin (5) described the oxidation of anethole to anisic acid. McGahey reported on the stereochemistry of
O
O
(Z )-anethole
(E )-anethole
Figure 1. Isomers of anethole.
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additions to (E )-anethole (6) and LeFevre described the isolation of anethole from anise seeds and the NMR spectra of (E )-anethole (7). Centko and Mohan (8) presented an exercise in NMR and IR spectroscopy based on the epoxidation of anethole. For this experiment, the students are asked to identify the anethole isomer in anise oil. The students need to synthesize both isomers in good purity, isolate, and characterize the products and then compare the data for the isomers with the data for the natural product. For the syntheses of the isomers they use the Suzuki reaction of Pd(0)-catalyzed coupling between an aryl boronic acid and the isomeric vinyl halides (9). To save time the class is split into two groups, one that prepares the (E ) isomer and the other the (Z ) isomer. Once the desired products are synthesized they are analyzed by GC, IR, and NMR. The data from the whole class are available to all students and each can use the results to make his or her own case for the identity of the isomer or isomers in the natural product. The instructor may also ask the students to discuss the variability of the class results. Discussion In general, (E ) acyclic alkenes are more stable than their (Z ) isomers owing to steric effects, as indicated by their relative heats of hydrogenation (1). As a supplement to the experiment, students calculate the energy difference between the isomers using molecular modeling software. They build the models and examine the energy differences and the molecular geometry predicted by molecular mechanics and the semi-empirical methods. They are then asked to explain the calculated conformations in terms of steric repulsion and resonance stabilization, the two oppositely directed factors influencing the conformation of the alkene side chain relative to the benzene ring. Several variations on the experiment described are possible. For example, an instructor who is more interested in comparing different methods for making alkene isomers might chose to compare the Suzuki reaction to another reaction such as the acid-catalyzed dehydration of an alcohol. In another variation, the Suzuki synthesis can be adapted to produce many positional isomers related to anethole by selecting the appropriate aryl boronic acid starting material. For those interested in a larger project, a set of experiments that derives both from the work described here and from the work cited above (5–8) could be done. The experiments could include the isolation of the natural product by steam distillation of anise seeds, the synthesis of an anethole, the spectroscopic analysis of both the extracted and synthesized compounds, and some reactions of anethole. There are many reasons why the Suzuki reaction works well for an introductory organic chemistry laboratory course. It can be performed reliably on the microscale and it pro-
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In the Laboratory
A
B TsO
HO KHSO4
KOt-Bu
+ O
+
heat
O
O
O
major
O
minor
C
O
major
minor
D
Ph + Ph P Ph
I
−
UV 302 nm
1.KOt-Bu 2. O
+
H
O
O
+ O
O
minor
major
O minor
O major
Scheme I. Synthetic routes to anethole: (A) base-induced bimolecular elimination of a tosylate, (B) acid-catalyzed dehydration, (C) Wittig reaction, and (D) photolysis.
duces the target isomer almost exclusively. The products are easily characterized by gas chromatography or other analytical techniques. The starting materials can be purchased at low cost, about $3 per student. Students are exposed to an important member of the large family of recently developed transition-metal catalyzed cross-coupling reactions that includes the Kumada, Negishi, Suzuki, Stille, and Buchwald reactions (10). The Suzuki reaction was recently featured as a cover story in Chem. Eng. News (11) because of its growing importance to industry. The (E ) product dominates in an alkene synthesis if a transition state of the reaction allows for a conformation that minimizes steric hindrance. This is the case in the synthesis of anethole by the base-induced bimolecular elimination of a tosylate (1) or by the acid-catalyzed dehydration of an alcohol (1). On the other hand, mostly (Z ) product is obtained from the Wittig reaction (1). The (Z ) product is also favored if ei-
HO
OH B Br
, THF
(Ph3P)4Pd, KOH O
O
Scheme II. Preparation of (Z )-anethole by the Suzuki reaction.
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ther the (Z ) or (E ) isomer of anethole is photolyzed with 302 nm light (12). The reactions are summarized in Scheme I. In contrast to these stereoselective processes, the stereospecific Suzuki coupling reaction allows the preparation of either the (Z ) or (E ) isomer in high purity. This is possible because the geometry of the vinyl halide starting material is retained in the reaction. The preparation of (Z )anethole is shown in Scheme II. Mechanisms for the Suzuki reaction can be found in the literature (10, 13). Preparation of (Z )-Anethole by the Suzuki Procedure The preparation of (Z )-anethole is described below. The preparation of (E )-anethole is identical with the exception that (E )-1-bromo-1-propene is used in the coupling. Dissolve 84 mg of 3-methoxyphenylboronic acid, 30 mg of tetrakis(triphenylphosphine)palladium(0), and 1.1 mL of 1 M KOH in 2 mL of THF. Next add 178 µL of (Z )-1-bromo1-propene and heat the reaction mixture for 1 h at 60 ⬚C. Add 1 mL of water to the reaction flask and extract the mixture with five 1-mL portions of pentane. Dry the combined extracts over anhydrous sodium sulfate, filter to remove the drying agent, and evaporate the solvent. Dissolve the residue with five 1-mL portions of pentane and filter the solution through a 1-cm silica column to remove polar impurities. Examine the filtrate by GC–MS. If isolation of the product is desired, evaporate the solvent again. Typical student syntheses produce 35–50 mg of colorless oil (43–62% yield, 89–99% in isomeric purity). (Z )anethole has an odor that is different from (E )-anethole. The purity of the sample is analyzed by gas chromatography. For the worked-up samples the chromatograms usually have only
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In the Laboratory
two peaks, one for the desired isomer and a much smaller one for the other isomer. A gas chromatograph equipped with a capillary column can easily resolve the isomers. The NMR spectra of the two isomers are identical except for the vinyl proton region. The 1H NMR spectrum of a given isomer will clearly identify it as anethole but positive identification as (Z ) or (E ) is not conclusive. The coupling constant for two protons in the (Z ) configuration is expected to be in the range 6 to 15 Hz and for the (E ) configuration the coupling constant is 11–18 Hz (14). Because of the overlap in range, the spectra of both isomers are needed for a conclusive identification. The IR spectra of the two isomers are similar but distinguishable. Hazards The boronic acids and the vinyl halides are irritants. Tetrahydrofuran, pentane, and ethyl acetate are flammable solvents and are irritants. Most operations should be done in a fume hood. KOH is highly corrosive and can cause severe damage to eyes and skin. Acknowledgments The authors express their gratitude to Douglas Taber of the University of Delaware for suggesting the Suzuki reaction pathway. Financial support for this work was provided by the WV EPSCoR program, the NASA Space Grant Program, and the John Conard Fund at Shepherd University. Our NMR instrument was obtained with partial support from the National Science Foundation and the IR instrument was purchased with support from the Spectroscopy Society of Pittsburgh. WSupplemental
Material
A student handout and much detailed information for the instructor so that the experiment can be modified to fit
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the instructor’s needs are available in this issue of JCE Online. Complete details and sample data for the chromatography and spectroscopy are provided. Results for some modeling exercises are also provided. Procedures are included for a number of alternative synthetic routes to anethole including the dehydration of 1-(4-methoxyphenyl)-1-propanol. Literature Cited 1. Vollhardt, K. Peter C.; Schore, Neil E. Organic Chemistry, 4th ed.; Freeman: New York, 2003; nerve signal, p 788; base-induced bimolecular elimination of a tosylate, pp 453–456; acidcatalyzed dehydration of an alcohol, pp 457–458; Wittig reaction, pp 747–750; heats of hydrogenation, pp 451–452. 2. Wilkinson, Sophie. Chem. Eng. News 2003, 81 (Sep 22), 33. 3. Harper, Brandy A.; Rainwater, J. Chance; Birdwhistell, Kurt; Knight, D. Andrew. J. Chem. Educ. 2002, 79, 729–731. 4. Callam, Christopher S.; Lowary, Todd L. J. Chem. Educ. 2001, 78, 947–948. 5. Garin, David. J. Chem. Educ. 1980, 57, 138. 6. McGahey, Lawrence. J. Chem. Educ. 1990, 67, 554–555. 7. LeFevre, Joseph W. J. Chem. Educ. 2000, 77, 361–363. 8. Centko, Rebecca S.; Mohan, Ram S. J. Chem. Educ. 2001, 78, 77–79. 9. Organ, Michael G.; Cooper, Jeremy T.; Rogers, Lawrence R.; Soleymanzadeh, Fariba; Paul, Timothy. J. Am. Chem. Soc. 2000, 65, 7959–7970. 10. Miyaura, Norio; Suzuki, Akira. Chem. Rev. 1995, 95, 2457– 2483. 11. Rouhi, A. Maureen. Chem. Eng. News 2004, 82 (Sep 6), 49– 58. 12. Kan, Robert O. Organic Photochemistry; McGraw Hill: New York, 1966; pp 19–21. 13. Matos, Karl; Soderquist, John A. J. Org. Chem. 1998, 63, 461– 470. 14. Pavia, Donald L.; Lampman, Gary M.; Kriz, George S. Introduction to Spectroscopy, 3rd ed.; Harcourt: Philadelphia, 2001; pp 134–137.
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