Laboratory Experiment pubs.acs.org/jchemeduc
Epoxidation with Possibilities: Discovering Stereochemistry in Organic Chemistry via Coupling Constants Edward M. Treadwell,* Zhiqing Yan, and Xiao Xiao Department of Chemistry, Eastern Illinois University, 600 Lincoln Avenue, Charleston, Illinois 61920, United States S Supporting Information *
ABSTRACT: A one-day laboratory epoxidation experiment, requiring no purification, is described, wherein the students are given an “unknown” stereoisomer of 3-hexen-1-ol, and use 1H NMR coupling constants to determine the stereochemistry of their product. From this they work backward to determine the stereochemistry of their starting alkene. KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives, Inquiry-Based/Discovery Learning, Addition Reactions, Alkenes, Epoxides, NMR Spectroscopy, Stereochemistry
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laboratory period. Additionally, incorporating TLC analysis to monitor the reaction progress and determine when the reaction was complete was desirable. The pedagogical goals included (1) illustrating the use of coupling constants in 1H NMR spectroscopy to discern stereochemistry; (2) appreciating diastereotopic signals and complex splitting; and (3) recognizing that epoxidation reactions are stereoselective.
ddition reactions to alkenes have been very popular in the organic teaching laboratory repertoire, with epoxidation reactions being one common example. Described reactions have progressed from simple mCPBA epoxidations1 to more advanced experiments that introduce the concepts of regioselectivity,2 stereoselectivity,3 atom economy,4 and green chemistry.5 Previously, we had been using a biphasic dimethyloxirane oxidation of ethyl cinnamate, stilbene, or chalcone, based on published experiments.6 The experiment was subsequently recast into a guided inquiry type of exercise, where the students would not be told the alkene starting material geometry, but use 1H NMR spectral analysis to determine the epoxide product stereochemistry, and, from that, work out the alkene stereochemistry. The practical difficulty here was that only the trans-isomers of the aforementioned alkenes are cheaply available and/or stable, due to the conjugated nature of the substrate; thus, particularly astute students could arrive at the answer from this consideration and “make” the data fit their conclusions, rather than use the data to arrive at a conclusion. Hence, this project was initiated to find a new substrate that would (1) have both the cis- and transisomers commercially available and affordable, (2) undergo the epoxidation reaction and workup in 2 h or less, (3) require little or no purification, and (4) be amendable to 1H NMR spectral analysis to determine the stereochemistry. The second and third requirements were included so that the synthesis and workup part of the experiment could be done in a single © XXXX American Chemical Society and Division of Chemical Education, Inc.
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OVERVIEW OF EXPERIMENT
The epoxidation of 3-hexen-1-ol (Scheme 1)7 was easily carried out in a 3 h lab period (including prelecture), with each student adding their alkene and acetone to a mixed solution of ethyl acetate and sodium bicarbonate (1.05 M) in an Erlenmeyer flask that is placed in an ice bath. An aqueous oxone solution (8.46 mmol KHSO5) is added dropwise via a separatory funnel over 30 min to prepare the dimethyloxirane in situ from acetone. After this, at 15 min intervals, aliquots are spotted versus starting material on TLC plates until the reaction reaches completion. A simple separation of layers, drying of the organic layer, and removal of the solvent via rotory evaporation gives sufficiently pure product for analysis. More detailed procedures can be found in the Supporting Information. Received: August 3, 2016 Revised: March 7, 2017
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DOI: 10.1021/acs.jchemed.6b00587 J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
Laboratory Experiment
Scheme 1. Epoxidation Reaction of 3-Hexen-1-ol
Table 1. Collective Experimental Results and Key Data Rf (starting material)
Rf (product)
av % yields (high−low)
cis (n = 20)
0.39
0.21
50.9 (71.7−16.6)
trans (n = 34)
0.36
0.18
55.6 (87.2−18.8)
3-hexen-1-ol isomer
1
H NMR spectrum epoxide signals 3.19 2.93 2.88 2.79
(td, J = 8.3, 4.4 Hz) (td, J = 6.4, 4.3 Hz) (ddd, J = 6.5, 4.2, 2.4 Hz) (td, J = 5.5, 2.4 Hz)
Figure 1. Representative student 400 MHz 1H NMR spectrum epoxide signals for cis- and trans-3,4-epoxy-1-hexanol.
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HAZARDS The oxone solution is aqueous potassium peroxysulfate, which is a strong oxidizer that can cause fires if mixed directly with organic or combustible materials, and causes burns upon contact with skin, eyes, or lungs. Concentrated sulfuric acid is extremely corrosive (including vapors) including being corrosive to metals. Acetone, both 3-hexen-1-ol isomers, and the epoxide products p-anisaldehyde and ethyl acetate are very flammable and are irritants (especially to the eyes). Ethanol is very flammable, as well as a poison, while hexane is very flammable, damaging to organs, is a severe irritant, can cause drowsiness, and is both a neurotoxin and suspected mutagen. Deuterochloroform is carcinogenic and mutagenic; can cause CNS depression or serious damage to kidney, liver, and heart; and is an irritant.
substrate has been successfully used for three semesters (54 students). Spots for the starting materials and products (visualized using a p-anisaldehyde stain) were sufficiently resolved to make for easy interpretation (Table 1). The typical student yields were between 87% and 17%, with averages of 56% and 51% starting from the trans- and cis-3-hexen-1-ol, respectively.8 The reaction was nearly always complete for the cis-isomer, usually well within 30 min after the last of the oxone solution was added. The trans-isomer was noticeably slower to react, in some cases still not reaching completion after 1 h of stirring. After the initial reaction period, slight heat can be added to the reaction mixture to speed the reaction toward completion. Thus, in some student samples, the starting material was observed in minor to significant amounts, which could be quantified by comparison of the integration ratios of one of the vinylic signals from the starting material to one of the epoxide methine signals in the product. The average amount of residual starting material, however, was only 15%. The presence of unreacted starting material did not hamper the
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RESULTS AND DISCUSSION Both isomers of 3-hexen-1-ol are commercially available in >95% purity for less than $2/mL, and the epoxidation of this B
DOI: 10.1021/acs.jchemed.6b00587 J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
Laboratory Experiment
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constants and identified their epoxide stereochemistry. Of the remaining 20% of the students, the two most prominent mistakes were either simply not interpreting the NMR spectra in their report, or obtaining an erroneous coupling constant by average the distance of all adjacent lines (i.e., not understanding the splitting). Four students had completely erroneous NMR spectrum interpretations due to poorly resolved spectra. Only 65% of the students reported the signals as ddd or td, with the remainder either calling them hextets/heptets or multiplets. A similar number of students (70%) correctly identified their alkene, having missed the concerted and stereoselective nature of the epoxidation reaction. Quite a few of them did not fully appreciate why the epoxide signals were split so heavily, or why the adjacent methylenes were separate signals for 1H each, instead of a 2H quartet, despite previous coverage in lecture. Office hour visits and especially use of a molecular model to show the different environments of the H’s usually eliminated this confusion. A number of students (24%) ignored interpretation of the rest of the NMR spectrum, and while many of them did note the presence of EtOAc or starting material, only 12% reported that this made complete interpretation of the spectrum impossible. No major problems were noted in student analysis of TLC, IR, and GC/MS data, though 15% would either note the reaction went to completion by TLC analysis, despite evidence in IR and NMR spectra that it did not, or note that by TLC analysis there was remaining starting material but that the IR and NMR spectra showed pure product. Overall, the pedagogical goals were satisfied in this experiment, and while the students might not have enjoyed the NMR spectral interpretation, they did understand it and see the use of measuring the magnitude of coupling constants.
H NMR spectral interpretation, as there were no overlapping peaks of interest. A more troublesome interference was observed from residual ethyl acetate solvent present,9,10 as this adds another oxygenated signal in the spectrum as well as a methyl singlet at around 2.0 ppm and a methyl triplet at 1.3 ppm. Both of these interferences, however, can be avoided simply by ensuring the students leave their flask on the rotory evaporator for a sufficiently long time. (The boiling points of the starting materials are sufficiently low that some portion is lost in the rotory evaporator stage.) The 1H NMR spectral analysis was conclusive (see Supporting Information), provided that the samples were shimmed properly and a high-field spectrometer (400 MHz) was used.11 As reported previously in literature studies, the 3J for the cis-epoxide was 4.3 Hz, while the 3J for the trans-epoxide was 2.4 Hz.12 This is in accordance with the generally accepted invocation of the Karplus equation and consideration of the dihedral angle between the two hydrogens. The epoxide methine signals do involve more complex splitting patterns, as the two adjacent methylene hydrogens are diastereotopic, making the signals doublet of doublet of doublets. In practice, for both signals of the cis-isomer and one signal of the transisomer, the two 3JCH(epox)−CH(methylene) values are nearly identical, giving instead a doublet of triplets pattern (Figure 1). The issue of diastereotopicity may be more complicated than some readers wish to delve into, but this is not a problem as the 3 JCH(epox)−3JCH(epox) has the smallest splitting and the students can be instructed just to measure the smallest coupling constants from two lines on each end and arrive at a satisfactory answer. For instructors wishing to introduce additional components and complexity into the experiment, computational programs can be employed to examine conformational analyses, and the possible presence of intramolecular H-bonds, leading to simulations of the 1H NMR spectrum, could be introduced.13 For instructors wishing to incorporate additional spectral analysis into the experiment, the 13C and DEPT spectra are quite clean. Alternatively, IR spectroscopy and/or GC/MS analysis can be included (see Supporting Information for examples of all of these). With regard to the IR spectrum, two advantages of this substrate compared to the aromatic ones mentioned above (ethyl cinnamate, stilbene, and chalcone) were hoped for, first in the ease of collection, in that these products are oils (only the epoxycinnamate is a liquid). Second, the success of the reaction/evidence of the transformation should be more easily apparent, as for the hexenol there is only 1 CC that disappears, while, with the other substrates, the students are looking for the disappearance of a conjugated C C signal amidst remaining aromatic CC stretches. Unfortunately, the CC signal in the trans-isomer is not very prominent. However, careful inspection does reveal the disappearance of the sp2 CH stretch shoulder past 3000 cm−1 in both cases, and is a clear marker for the success or failure of the reaction. Students also analyzed their products by GC/MS, though there are not many fragmentations observable, and it is difficult to determine the stereochemistry from these data. Thus, it is used more of an introduction to the technique rather than for a stand-alone analysis. (Though for those wishing to do so, there is baseline resolution of the two epoxides, allowing for identification by matching of retention times.) Students wrote formal lab reports for this experiment, and the majority (80%) correctly calculated the key coupling
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.6b00587. Student handouts, notes for instructors including list of materials needed, and spectra of the products (PDF, DOCX)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Edward M. Treadwell: 0000-0003-3857-0431 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We would like to acknowledge the 54 students who carried out this experiment, as well as Kraig Wheeler for also adopting this experiment in his section.
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REFERENCES
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R. S.; Mohan, R. S. The discovery-oriented approach to organic chemistry. 4. Epoxidation of p-methoxy-trans-β-methylstyrene: an exercise in NMR and IR spectroscopy for sophomore organic laboratories. J. Chem. Educ. 2001, 78 (1), 77−78. (d) Krishnamurty, H. G.; Jain, N.; Samby, K. Epoxide chemistry: guided inquiry experiment emphasizing structure determination and mechanism. J. Chem. Educ. 2000, 77 (4), 511−513. (2) Mak, K. K. W.; Lai, Y. M.; Siu, Y.-K. Regiospecific epoxidation of carvone: a discovery-oriented experiment for understanding the selectivity and mechanism of epoxidation reactions. J. Chem. Educ. 2006, 83 (7), 1058−1060. (3) (a) Bradley, L. M.; Springer, J. W.; Delate, G. M.; Goodman, A. Epoxidation of geraniol: an advanced organic experiment that illustrates asymmetric synthesis. J. Chem. Educ. 1997, 74 (11), 1336−1338. (b) Burke, A.; Dillon, P.; Martin, K.; Hanks, T. W. Catalytic asymmetric epoxidation using a fructose-derived catalyst. J. Chem. Educ. 2000, 77 (2), 271−272. (c) Hanson, J. Synthesis and use of Jacobsen’s catalyst: enantioselective epoxidation in the introductory organic laboratory. J. Chem. Educ. 2001, 78 (9), 1266−1268. (d) Hii, K. K.; Rzepa, H. S.; Smith, E. H. Asymmetric Epoxidation: A Twinned Laboratory and Molecular Modeling Experiment for Upper-Level Organic Chemistry Students. J. Chem. Educ. 2015, 92 (8), 1385−1389. (e) Harwood, L. M.; Moody, C. J.; Percy, J. M. Experimental Organic Chemistry, Standard and Microscale, 2nd ed.; Blackwell Science Ltd: Oxford, U.K., 1999; pp 455−460. (4) (a) Buglass, A. J.; Waterhouse, J. S. Polymer-supported oxidation reactions. Two contrasting experiments for the undergraduate laboratory. J. Chem. Educ. 1987, 64 (4), 371−372. (b) Cunningham, A. D.; Ham, E. Y.; Vosburg, D. A. Chemoselective Reactions of Citral: Green Syntheses of Natural Perfumes for the Undergraduate Organic Laboratory. J. Chem. Educ. 2011, 88 (3), 322−324. (5) (a) Goodwin, T. E. An asymptotic approach to the development of a green organic chemistry laboratory. J. Chem. Educ. 2004, 81 (4), 1187−1190. (b) Dintzner, M. R.; Kinzie, C. R.; Pulkrabek, K.; Arena, A. F. The Cyclohexanol Cycle and Synthesis of Nylon 6,6: Green Chemistry in the Undergraduate Organic Laboratory. J. Chem. Educ. 2012, 89 (2), 262−264. (6) (a) Broshears, W. C.; Esteb, J. J.; Richter, J.; Wilson, A. M. Simple epoxide formation for the organic laboratory using oxone. J. Chem. Educ. 2004, 81 (7), 1018−1019. (b) Moloney, G. P. Synthesis of 3-(2′methoxy-5′-bromophenyl)-2,3-epoxyphenylpropanone, a novel epoxidated chalcone derivative: an undergraduate organic chemistry experiment. J. Chem. Educ. 1990, 67 (7), 617−618. (7) The epoxidations of both isomers of 3-hexen-1-ol have been reported numerous times in the literature, with a variety of reagents. 1 H NMR spectrum data first reported for cis: Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. Catalytic asymmetric epoxidation and kinetic resolution: modified procedures including in situ derivatization. J. Am. Chem. Soc. 1987, 109 (19), 5765−5780. For trans: Rossiter, B. E.; Sharpless, K. B. Asymmetric epoxidation of homoallylic alcohols. Synthesis of (−)-γ-amino-β-(R)hydroxybutyric acid (GABOB). J. Org. Chem. 1984, 49 (20), 3707− 3711. Data for both isomers, including 13C NMR spectrum and MS data, can be found in Kamata, K.; Hirano, T.; Kuzuya, S.; Mizuno, N. Hydrogen-Bond-Assisted Epoxidation of Homoallylic and Allylic Alcohols with Hydrogen Peroxide Catalyzed by Selenium-Containing Dinuclear Peroxotungstate. J. Am. Chem. Soc. 2009, 131 (20), 6997− 7004. (8) The authors were able to obtain yields of 86.2% and 91.7%, for the cis- and trans-hexenols, respectively. (9) TLC indicates that, for the cis-isomer, even 5 min after the oxone addition is complete, there is more product present than starting material, and after 15 min no starting material is visible. For the transisomer, traces of starting material can still be seen even after 1.5 h. (10) The amount of ethyl acetate present was as high as 50% of epoxide (by integration of 1H NMR spectrum), though 57% of the students saw ethyl acetate amounts of 25% or less. (11) This experiment will most likely not be successful if a lower-field NMR spectrometer (200 MHz or lower) is used, as the resolution will
most likely not allow for observation of all splitting and a clear distinction between the key coupling constants of the epoxides, which differ by only 2 Hz. The difference in shifts of the signals might still make the isomers discernible, though this takes away a significant portion of the analysis. (12) Pavia, D. L.; Lampman, G. M.; Kriz, G. S.; Vyvyan, J. R. Introduction to Spectroscopy, 4th ed.; Brokes/Cole: Belmont, CA, 2009; pp 241−243. (13) This idea was proposed by one of the reviewers, who did investigate this and found it to be illuminating and valid.
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DOI: 10.1021/acs.jchemed.6b00587 J. Chem. Educ. XXXX, XXX, XXX−XXX
