In the Laboratory edited by
Green Chemistry
Mary M. Kirchhoff ACS Green Chemistry Institute Washington, DC 20036
Greening Wittig Reactions: Solvent–Free Synthesis of Ethyl trans-Cinnamate and trans-3-(9-Anthryl)2-Propenoic Acid Ethyl Ester
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Kim Chi Nguyen and Haim Weizman* Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093; *
[email protected] Green experiments for undergraduate organic chemistry laboratories are of major importance. Besides providing a safer laboratory setting for students and reducing environmental pollution, green chemistry carries an educational message. When a green experiment is presented to students together with its “non-green” alternative, it can inspire students to seek out green chemistry solutions when working in a future scientific career. Green chemistry experiments for organic undergraduate labs have been developed (1, 2); however, expanding the repertoire of reactions is highly desirable. We feel that a useful approach for the development of new green chemistry experiments is to design green alternatives to existing experiments. Good candidates are experiments that have been published in this Journal as they are likely being used in schools and therefore will be easier for instructors to adopt the alternative green procedure. Here we present two examples for using this approach to create solvent-free alternatives for conventional Wittig reactions. The Wittig reaction is widely used to install a double bond in a highly selective manner (3). This reaction is particularly useful in an undergraduate laboratory since it provides an opportunity to discuss the interesting aspects of the reaction mechanism and presents the interpretation of more complicated NMR spectra. A solvent-free Wittig experiment has recently been developed by grinding together an aldehyde, a phosphonium salt, and potassium phosphate (4).
However, this approach gives a mixture of isomers, resulting in modest isolated yields. The following experiments present two additional methods for conducting solvent-free reactions as alternatives to the more common procedures that require methylene chloride or DMF as solvents. The first example is a reaction between a solid phosphorane and liquid aldehyde while the second reaction takes place in a melt. Both reactions are fast, proceed with high yield and excellent stereoselectivity, and their product isolation is simple. The reactions were developed on a microscale although they can be performed on a macroscale as well. Synthesis of Ethyl trans-Cinnamate The synthesis of ethyl trans-cinnamate using a stabilized ylide was published recently (1, Scheme I) (5). The experiment was carried out using methylene chloride as a solvent. Since methylene chloride is a suspected carcinogen, it is beneficial to develop a solvent-free alternative for this experiment. Benzaldehyde and (carbethoxymethylene)triphenylphosphorane are stirred together without solvent for 15 minutes at room temperature. The reaction proceeds in quantitative yield and the product is isolated by diluting the mixture with hexanes and filtering the insoluble triphenylphosphine oxide. The ratio between trans and cis isomers is about 95:5 (based on NMR), similar to what was observed for the reaction in methylene chloride (6). Although the origi-
Scheme I. Synthesis of ethyl cinnamate (top) and trans-3-(9-anthryl)-2-propenoic acid ethyl ester (bottom).
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In the Laboratory Table 1. NMR Data in CDCl3 δHα (ppm)
δHβ (ppm)
Jαβ /Hz
∆δ
1
6.44
7.69
15.9
1.25
2
5.95
6.95
12.3
1.00
3
6.44
8.64
16.0
2.20
Compound
NOTE: See Scheme I for labeling of the hydrogen atoms.
Scheme II. Strong dipole–dipole interactions influence the stereochemical outcome of the Wittig reaction.
nal procedure was carried out at 0 ⬚C, we did not observe any significant difference in the trans兾cis ratio when the reaction was performed at room temperature. Synthesis of trans-3-(9-Anthryl)-2-Propenoic Acid Ethyl Ester This experiment was developed as an alternative to published syntheses of trans-9-(2-phenylethenyl)anthracene (7– 9). The solvent for this reaction is typically methylene chloride or DMF. The alternate reaction takes advantage of the moderate melting point of 9-anthraldehyde (103–105 ⬚C) and the stability of the ylide and is carried out in a melt (Scheme I). Both solids are mixed together and heated until the aldehyde melts. The reaction is stirred for an additional 15 minutes and then is cooled to room temperature. The semisolid is triturated with hexane and the suspension is filtered. Evaporation of the solvent gives oil containing about 5% of the cis isomer. Recrystallization from methanol gives the pure trans isomer, 3, in typical isolated yields of 80–85%. Hazards Hexanes and methanol are flammable liquids. Other reagents are potentially irritants. Discussion The experiments presented here offer additional procedures for performing solvent-free reactions in undergraduate laboratories. Both experiments are simple to set up, have fast kinetics, and require minimal work up. Both reactions can, therefore, be executed side-by-side in one lab period. This allows instructors to demonstrate two methods for accomplishing solvent-free reactions and discuss stereochemistry and NMR as it relates to the Wittig reaction. The experiments reveal the stereochemical outcome of the Wittig reaction of stabilized ylides. It is well established that stabilized ylides give predominantly trans or (E ) alkenes. Interestingly, both reactions demonstrate that the selectivity does not change in the absence of a solvent or at elevated temperatures. The reactions provide an opportunity to discuss recent developments in the understanding of the factors governing the stereoselectivity of the Wittig reaction. Several explanations have been proposed for the observed high selectivity. The Vedejs model (10) suggests that steric interactions in the transition state determine the outcome of the reaction. Nonstabilized ylides form an early transition state— a cis puckered four-membered ring—that relieves the 1,2and 1,3-steric strain. Stabilized ylides have a later planar transition state (resembling the oxaphosphetane) and in the pla120
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nar conformation, a trans orientation is favored to avoid 1,2interaction. Recently it was suggested that dipole–dipole interactions play an important role in determining the structure of the transition state (11). Both reactants, the aldehyde and the ylide, have strong dipole moments. In our case, the dipole is oriented along the carbonyl group in the aldehyde and along the C⫺C bond between the negatively charged ylide and the ester (Scheme II). The strong dipole–dipole interactions impose puckering of the ring in order to orient the dipoles in a favorable anti-parallel manner. Although both cis and trans orientation will allow for such anti-parallel orientation, the bulky substituents will be oriented trans to the ester in order to minimize 1,3-steric interactions. This will lead to the formation of the trans isomer. The proton NMR spectra of the compounds synthesized in these reactions provide an opportunity to discuss several aspects of NMR to students. The spectrum of ethyl cinnamate is a mixture of two isomers where the major product is the trans isomer. This spectrum is an interesting example because the ratio between the two products is 95:5; hence, to an inexperienced eye, the NMR spectrum of the products will appear as a single product that is slightly contaminated. The alkenyl protons of the major product are located at 6.44 and 7.69 ppm. The coupling constant of 15.9 Hz clearly indicates that this is the trans isomer: characteristic vicinal coupling constants of 12–18 Hz for the trans or (E ) isomer compare to 6–12 Hz for the cis or (Z ) isomers (12 ). The alkenyl protons of the minor component are located at 5.95 and 6.95 ppm. In this case the vicinal coupling constant is 12.3 Hz, which falls in the gray area that can indicate either a cis or trans isomer. This example provides a lesson in the difficulties of assigning ambiguous peaks in NMR spectra. If the minor product was the only product isolated from the reaction, it would be difficult to determine which isomer it is based on the coupling constants. Once the major and minor products are identified, the ratio between isomers can be extracted from the integration of the alkenyl protons, which provides a measure of the stereoselectivity of the reaction. An additional intriguing feature of the NMR spectra is the large difference in chemical shifts of the alkenyl protons (Table 1). This difference can be attributed to the β effect of the conjugated ester group. Students can easily draw a resonance structure that places a positive charge on the β carbon, therefore causing deshielding of the attached proton. At this point the students should question this explanation; assuming this, one would expect to have similar chemical shifts for both cis and trans isomers. The students need to realize that while it is possible to write similar resonance structures for the compounds in two dimensions, the molecular structures are three-dimensional. Modeling reveals that ethyl trans-cinnamate adopts a planar conformation while the cis
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In the Laboratory
isomer is twisted due to steric repulsions (see the Supplemental MaterialW). The twisted conformation does not allow for the same degree of overlap between the orbitals as does the planar conformation; therefore, the β effect is less prominent. Another plausible explanation is the effect of the shielding cone of the carbonyl group (13). Comparing the chemical shifts of the anthracene derivative 3 to those corresponding to ethyl trans-cinnamate 1 reveals that the α proton has an identical chemical shift while the β proton is further shifted, almost 1 ppm downfield. Some students will attribute this change to an extended β effect over the larger conjugated system. Again it is important to note that this derivative adopts a conformation where the anthryl residue is orthogonal to the conjugated ester (owing to steric interaction between protons 1 and 8 of the anthryl and the alkenyl proton). Hence the observed shift can not be attributed to extended conjugation. The shift is probably due to the larger ring current of anthracene compared to benzene (and therefore increased deshielding). The students can draw this conclusion by comparing NMR data for vinyl anthracene (where the equivalent proton is located at 7.50 ppm) and styrene (see the Supplemental MaterialW). Therefore the β effect contributes about a 1.6 ppm downfield shift and the ring current contributes a 0.9 ppm shift. Conclusions The two reactions presented here are green alternatives to published procedures of Wittig reactions. Performing solvent-free reactions in undergraduate laboratories reduces health and environmental risks and educates students about the benefits of minimizing solvent usage. The simplicity of the experiments allows them to be performed simultaneously and creates an NMR data set suitable for interpretation. The data provide a basis for an inquiry-based discussion of the stereochemistry of the Wittig reaction and the factors influencing the chemical shifts of alkenyl protons.
Acknowledgment We thank Pfizer La Jolla for financial support. W
Supplemental Material
List of chemicals and equipment, student handout, notes for the instructor, NMR spectra, and computational data are available in this issue of JCE Online. Literature Cited 1. Doxsee, K. M.; Hutchison, J. E. Green Organic Chemistry: Strategies, Tools, and Laboratory Experiments; Thompson Learning: Mason, OH, 2002. 2. Haack, J. A.; Hutchison, J. E.; Kirchhoff, M. M.; Levy, I. J. J. Chem. Educ. 2005, 82, 974. 3. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927. 4. Leung, S. H.; Angel, S. A. J. Chem. Educ. 2004, 81, 1492– 1493. 5. Speed, T. J.; Mclntyre, J. P.; Thamattor, D. M. J. Chem. Educ. 2004, 81, 1355–1356. 6. Speed, T. J.; Mclntyre, J. P.; Thamattor, D. M. J. Chem. Educ. 2004, 81, 1355–1356; see NMR spectrum in the Supplemental Material. 7. Silversmith, E. F. J. Chem. Educ. 1986, 63, 645. 8. Mayo, D. W.; Pike, R. M.; Butcher, S. S. Microscale Organic Laboratory; Wiley: New York, 1986; pp 163–172. 9. Williamson, K. Macroscale and Microscale Organic Experiments, 3rd ed.; Houghton Mifflin: Boston, 1999; pp 464–467. 10. Vedejs, E.; Marth, C. F. J. Am. Chem. Soc. 1988, 110, 3948– 3958. 11. Robiette, R.; Richardson, J.; Aggarwal, V. K.; Harvey J. N. J. Am. Chem. Soc. 2005, 127, 13468–13469. 12. Silverstein, R. M.; Webster, F. X. Spectroscopic Identification of Organic Compounds, 6th ed.; Wiley: New York, 1998; p 212. 13. Shaw, R.; Roane, D.; Nedd, S. J. Chem. Educ. 2002, 79, 67– 69.
edited by
William F. Coleman Wellesley College Wellesley, MA 02481
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