In the Laboratory
Epoxidation of Geraniol: An Advanced Organic Experiment that Illustrates Asymmetric Synthesis Lynn M. Bradley, Joseph W. Springer, Gregory M. Delate, and Andrew Goodman Department of Chemistry, The College of New Jersey, P.O. Box 7718, Ewing, NJ 08628-0718 The Sharpless epoxidation reaction is considered one of the most powerful advances in asymmetric organic synthesis (1). It is a classic example of the use of an asymmetric catalyst to provide an enantiomerically enriched mixture of epoxy alcohols. The procedure typically uses titanium(IV) tetraisopropoxide (Ti(OiPr)4) as a catalyst, a peroxide, and dialkyl tartrates to induce asymmetry in the epoxidation reaction of allylic alcohols (see Fig. 1). The experiment described in this paper illustrates the principle of asymmetric epoxidation and enables students to determine enantiomeric product ratios using chiral shift reagents and NMR spectroscopy. To illustrate the difference between the Sharpless asymmetric procedure and the standard epoxidation procedure, geraniol is also epoxidized using 3-chloroperoxybenzoic acid (mCPBA). A comparison of the two epoxidation methods clearly demonstrates that the Sharpless procedure provides not only asymmetric induction in the epoxide products, but also selectivity between the double bonds of geraniol. This multistep reaction sequence offers numerous advantages to the undergraduate organic laboratory. It provides experience with some advanced techniques, such as working under anhydrous conditions, purification of product mixtures by flash chromatography, and chiral NMR shift analysis. It also offers an ideal opportunity for cooperative learning in the laboratory because data exchange is necessary for experimental analysis.
Sharpless Pathway
1. (+)-DET, Ti(OiPr)4
O H
2. TBHP
O
OH
OH
H
(2S, 3S) 1 major isomer
(2R, 3R) 2 minor isomer
OH
H geraniol
mCPBA Pathway
mCPBA, NaHCO3,
O H
CH2Cl2
O
OH
OH
H
(2S, 3S) 1
(2R, 3R) 2
Figure 1. The Sharpless and mCPBA epoxidations of geraniol.
d
c
d
e f
h
c
O
e
O H b
OH a1,a2
g
Epoxy Alcohols (1,2)
1. DMAP, NEt3, Ac2O, CH2Cl2
O f
h
H b
2. H2O, 1 M HCl
OCCH3 a1,a2
i
g
Epoxy Acetates (3,4)
Figure 2. The acetylation reaction and 1H NMR assignments.
Experimental Procedure
Part I. Epoxidation Reactions To Synthesize 2,3-Epoxygeraniol Sharpless Epoxidation Procedure Reaction. Into a 25-mL round-bottom flask is weighed 800 mg (3.88 mmol) of L-(+)-diethyltartrate ((+)-DET). A magnetic stir bar, 960 µL (921 mg, 3.24 mmol) of Ti(OiPr)4 and 10 mL of dry dichloromethane (CH2Cl2 ) are introduced into the flask. A septum is attached to the flask and a nitrogen atmosphere is maintained. The flask and its contents are stirred for 5 min in a {23 °C bath (CCl4 /dry ice).1 With a syringe, geraniol (500 mg, 3.24 mmol) is added to the mixture as a solution in 1 mL of dry CH2 Cl2. Finally, tert-butyl hydroperoxide (TBHP, 1.2 mL, 6.6 mmol, purchased as a 5.0–6.0 M solution in nonane) is added slowly through the septum using a syringe. 2 The resulting solution is allowed to stir for 45 min at {23 °C and the round-bottom flask is capped and stored in a {20 °C freezer until the next laboratory period (but for at least 18 hours). Isolation of Product. The reaction flask is removed from the freezer and placed in a {23 °C bath. Using a syringe, 8.3 mL of 10% tartaric acid solution is added to the flask and the mixture is allowed to stir for 15 min at this temperature. The ice bath is removed and the solution is allowed to stir for 30 additional minutes. The CH 2 Cl2 layer is separated from the top yellow aqueous layer and is washed twice with an equal volume of saturated sodium thiosulfate (Na2S2O 3) solution.3 Finally, the organic layer is washed
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twice with equal volumes of water, dried over anhydrous sodium sulfate (Na2 SO4), and concentrated to give 1.3 g of a cloudy colorless oil.4 Purification of Sharpless Epoxide Isomers by Column Chromatography. An 11- × 300-mm column is packed with a slurry of 7.5 g of 200–400 mesh silica gel in 30% ethyl acetate (EA)/70% petroleum ether (PE). A total of 200 mL of the solvent system is required to both prepare the column and elute the desired epoxide product. The crude epoxide product from above is loaded onto the column and 15 mL of solvent is forced through the column. Fractions are then collected in 5-mL portions. The desired epoxide is eluted in vials 4–11. These fractions are combined and concentrated under vacuum to yield approximately 300 mg (1.76 mol, 55% yield) of enantiomerically enriched 2S, 3Sepoxygeraniol as a clear colorless oil. Thin layer chromatography (TLC): silica gel on aluminum backing, 30% EA/ 70% PE, potassium permanganate (KMnO4 ) dip used to visualize;5 Rf = .50, geraniol; Rf = .31, 2,3-epoxygeraniol (predominant spot); Rf = .19, 6,7-epoxygeraniol. IR (neat, cm{1): 3412 (O–H), 1670 (C=C), 1255 (C–O epoxide stretch). NMR data of 2,3-epoxygeraniol (300 MHz NMR, CDCl3, from Me4Si, refer to Figure 2, compounds 1 and 2, for proton assignments): δ 5.08 (b s, 1H, f proton), 3.82 (dd, 1H, J = 12.1, 4.1, a1 proton), 3.67 (dd, 1H, J = 12.2, 6.7, a2 proton), 2.97 (dd, 1H, J = 6.6, 4.1, b proton), 2.07 (m, 2H, e protons), 1.67, 1.60 (s, 6H, g and h protons), 1.4-1.5 (m, 2H, d protons), 1.29 (s, 3H, c protons).
Journal of Chemical Education • Vol. 74 No. 11 November 1997
In the Laboratory Epoxidation Using mCPBA Reaction. Geraniol (1.00 g, 6.48 mmol) is weighed into a 100-mL round-bottom flask. CH2 Cl2 (25 mL), sodium bicarbonate (NaHCO3, 598 mg, 7.12 mmol), and a magnetic stir bar are introduced into the flask and the mixture is stirred and cooled in a 0 °C ice/water bath. A solution of mCPBA6 (1.76 g, 7.12 mmol, 57–86%—Aldrich, nominal value 70% used for stoichiometry) in 35 mL of CH2Cl2 is added slowly via an addition funnel over a period of 5 min. Almost immediately, a heavy white precipitate forms and the mixture becomes very difficult to stir. The resulting slurry is stirred for 30 min at 0 °C, the ice bath is removed, and the reaction is allowed to stir for 2 hours. Isolation of Product. The mixture is transferred portionwise to a separatory funnel and is washed twice (or until the aqueous layer is basic to pH paper) with an equal volume of saturated sodium carbonate. The entire organic layer is then washed twice with an equal volume of saturated Na 2S2 O 3 solution. The CH 2Cl 2 layer is dried over Na2SO4, filtered, and concentrated to give 1.1 g of a mixture of epoxide products. Purification of Racemic Epoxides by Column Chromatography. A 19- × 300-mm column is packed with a slurry of 25 g of 200–400 mesh silica gel in 30% EA/70% PE. A total of 300 mL of the solvent system is required to both prepare the column and elute the desired epoxide product. The crude epoxide is loaded onto the column and 30 mL of solvent is forced through the column. Fractions are then collected in 12-mL portions; the desired epoxide is eluted in vials 6–9. These fractions are combined and concentrated under vacuum to yield 337 mg (1.98 mmol, 31% yield) of racemic 2, 3-epoxygeraniol as a colorless oil. TLC: silica gel on aluminum backing, 30% EA/70% PE, KMnO4 dip used to visualize; Rf = .50, geraniol; Rf = .31, 2, 3-epoxygeraniol; Rf = .19, 6,7-epoxygeraniol; Rf = .10, 2,3,6,7-diepoxygeraniol (sometimes observed).
Part II. Conversion of 2,3-Epoxygeraniol Enantiomers to Their Corresponding Acetates The procedure is the same as for the epoxidation products from Part I above. Reaction. The purified 2,3-epoxygeraniol from the first part of the experiment (300 mg, 1.76 mmol) is dissolved in 10 mL of CH2Cl2 in a 25-mL round-bottom flask. Dimethylaminopyridine (DMAP, 43 mg, 0.35 mmol) and a magnetic stir bar are added and a rubber septum is attached. Triethylamine (0.5 mL, 3.50 mmol) is added via syringe through the septum and the resulting solution is cooled to 0 °C. Acetic anhydride (Ac2 O, 420 µL, 4.45 mmol) is added dropwise via syringe. Complete conversion to acetate is indicated by TLC after 30 min. Isolation of Products. The reaction mixture is washed with an equal volume of water to hydrolyze the excess Ac2O. The CH2 Cl2 layer is then quickly washed twice with 10 mL of cold 1 M HCl, dried over Na2SO4 , and concentrated to give 350 mg of crude acetate product as a yellow oil. Purification of Acetate Products by Column Chromatography. An 11- × 300-mm column is packed with a slurry of 5.0 g of 200–400 mesh silica gel in 5% EA/95% PE. A total of 100 mL of the solvent system is required to both prepare the column and elute the desired acetate product. The crude acetate from above is loaded onto the column and 10 mL of solvent is forced through the column. Fractions are then collected in 5-mL portions; the desired epoxide is eluted in fractions 4–9. These fractions are combined and concentrated to yield 175 mg (0.824 mmol, 47% yield) of pure acetate product as a clear colorless oil. TLC: silica gel on aluminum backing, 5% EA/95% PE, KMnO4 dip used to visualize;
Rf = .27, desired epoxy acetate. IR (neat, cm{1): 1746 (C=O), 1234 (antisymmetric C–O–C stretch, ester), 1037 (symmetric C–O–C stretch, ester). 1H NMR 2, 3-epoxygeraniol acetate (300 MHz NMR, CDCl3, from Me4Si, refer to Figure 2, compounds 3 and 4, for proton assignments): δ 5.08 (b s, 1H, f proton), 4.32 (dd, 1H, J= 12.2, 4.1, a 1 proton), 4.02 (dd, 1H, J = 12.1, 7.1, a2 proton), 2.99 (dd, 1H, J= 7.1, 4.1, b proton), 2.11 (s, 3H, i), 2.07 (m, 2H, e protons), 1.68, 1.60 (s, 6H, g and h protons), 1.4-1.6 (m, 2H, d protons), 1.31 (s, 3H, c protons).
Part III. Nuclear Magnetic Resonance Chiral Shift Reagent Experiment for Both Purified Acetate Products Preparation of the Substrate Solution. Into a clean, dry vial is weighed 50.0 mg of the purified epoxy acetate. Deuterated chloroform (2750 µL) is added and the solution is mixed well. A 550-µL portion of this solution (contains about 10 mg of substrate) is transferred into a clean, dry NMR tube and capped immediately. The remaining epoxy acetate/ CDCl3 solution is saved in the freezer, in case it is necessary to repeat the experiment at a later time. Preparation of the Chiral Shift Reagent Solution. Europium tris[3(heptafluoropropylhydroxymethylene)-(+)camphorate] (Eu(hfpc)3 , 35.0 mg, 0.029 mmol) is weighed into a clean, dry vial. To this is added 600 µL of CDCl3 and the mixture is stirred to dissolve as much of the solid as possible. This mixture is filtered into another clean, dry vial and capped immediately.7 NMR Experiment. A standard 1H NMR spectrum of the epoxy acetate sample is obtained (Fig. 3). Using an automatic delivery pipet, 50 µL of the Eu(hfpc)3 chiral shift reagent solution is added to the NMR tube. The tube is mixed carefully and the 1H NMR spectrum is obtained. Additional 50-µL increments of the chiral shift reagent solution are added until the epoxide proton originally at 3.0 ppm shifts to about 3.8 ppm and splits. When the two signals are well resolved, they are expanded and integrated to obtain the ratio of enantiomeric products. Results and Discussion The amount of geraniol starting material used for each of the epoxidation procedures reflects the difference in selectivity of the double bonds. In theory, there are three possible epoxide products (ignoring stereochemistry) that can form: (i) the desired 2,3-epoxygeraniol, (ii) 6,7-epoxygeraniol, and (iii) 2,3,6,7-diepoxygeraniol. For the mCPBA epoxidation procedure, an approximately equal amount of the monoepoxide products are formed, indicating a lack of selectivity between the double bonds in geraniol. In addition, a small amount of the diepoxy alcohol also forms during the course of the reaction. It was found that using only a slight excess of mCPBA minimized the amount of the diepoxy alcohol formed while maximizing conversion of geraniol. In the case of the Sharpless epoxidation, only traces of unreacted geraniol and diepoxy alcohols are observed. Also, of the two monoepoxy alcohol products possible, the desired 2,3-epoxygeraniol is formed as the major isomer, thus illustrating the importance of the allylic alcohol in the mechanism of the Sharpless epoxidation. To develop a straightforward experiment using the Sharpless epoxidation procedure, a number of factors had to be evaluated. The choice of a suitable allylic alcohol was of primary concern. To facilitate in product isolation, a molecule large enough to be water insoluble was required. The starting material should not be too reactive under the Sharpless conditions due to the possibility of decomposition of the epoxide product (2). Geraniol satisfied both of these requirements, in addition to illustrating the selectivity dif-
Vol. 74 No. 11 November 1997 • Journal of Chemical Education
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In the Laboratory of peroxides in chemical reactions. Finally, the tartrate ester, tert-butanol, and nonane can be conveniently separated from the epoxy alcohol product using flash chromatography. According to the literature, shift study analysis of the acetate of 2,3-epoxygeraniol can be performed in deuterated benzene with Eu(hfpc)3 by observing the acetate CH3 (4). However, we found that by using CDCl3 as a solvent, the epoxide proton could easily be observed to shift and split without interference from any of the other protons. For the epoxy acetates derived from mCPBA, the addition of 100 µL of chiral shift reagent was sufficient to split the epoxide protons. Integration of the two epoxide protons peaks provides average ratios of 52:48, very close to the expected ratio for a racemic mixture. Analysis of the epoxy acetates derived from the Sharpless reaction clearly indicates that asymmetric epoxidation has occurred. The enantiomeric protons are best resolved when at least 200 µL of chiral shift reagent solution has been added. Students obtained average enantiomeric ratios of 91:9 (2S, 3S: 2R, 3R), quite close to the ratios of 95:5 reported in the literature for the epoxy alcohol isomers (5).
(a)
(b)
Acknowledgments We gratefully acknowledge funding from the National Science Foundation for the purchase of a 300-MHz NMR spectrometer (DUE-9451000), the American Cyanamid Company, and The College of New Jersey. We also thank Georgia Arvanitis for helpful discussions. Notes (c)
Figure 3. (a) 1H NMR spectrum of the pure acetate of 2,3-epoxygeraniol (CDCl3 solvent); (b) 1H NMR chiral shift reagent experiment (Eu(hfpc) 3 ) of the acetate derived from the mCPBA epoxidation procedure (total of 300 µL of shift reagent added); (c) 1H NMR chiral shift reagent experiment (Eu(hfpc) ) of the acetate 3 derived from the Sharpless epoxidation procedure (total of 400 µL of shift reagent added).
ferences between its double bonds. The ratio of titanium to tartrate ligand is crucial to optimize enantioselectivity in the reaction. This experiment used a titanium to ligand ratio of 1:1.2, as has been recommended in later work done on the Sharpless epoxidation procedure (3). The isolation of the epoxide product from the reaction mixture involves the removal of titanium catalyst, excess TBHP, tartrate ester, tert-butanol, and nonane. To remove the titanium catalyst, water-insoluble substrates such as geraniol can be mixed with 10% aqueous tartaric acid solution. Although it is generally recommended to ignore excess TBHP in small scale reactions (
