Differential and Selective Epoxidation PDF

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1 Differential and Selective Epoxidation Epoxidation of (R)-Carvone by m-CPBA Epoxidation of (R)-Carvone by H2O2/NaOH TA Erik Goebel

Introduction: Epoxidations of (R)-carvone 1 with two different reagents were performed during this experiment. MCPBA and hydrogen peroxide with sodium hydroxide are the two most common reagents used for epoxidation reaction and would produce epoxide but on different locations of 1. “Peroxy acids work well with electron-rich alkenes while alkaline H 2O2 reacts preferentially with electron-deficient” alkenes1. In this reaction, there were two alkene groups in starting material 1, one on the ring and one as a vinyl group. Since the electron richnesses of the two alkenes are different, this would demonstrate the different epoxidation reactions with different reagents. With the formation of epoxide, the chiral centers of the products would be changed, the reactions of the change of chirality would be identified as either diastereoselective or enantioselective. The different selectivities of the reagents are discussed in the Discussion section of this report, and the stereochemistries of products 2 and 3 are determined by gas chromatography. By performing this experiment, the structures and names of the products of the epoxidation reaction with both m-CPBA and alkaline hydrogen peroxide were predicted, carvone-7,8oxide 2 and carvone-1,2-oxide 3. And these two compounds were analyzed with 1H NMR, IR, GC, and MS. The predicted product 2 should be a purple liquid and the predicted product 3 should be a colorless liquid. Results: m-CPBA, carvone-7,8-oxide (2):

2 (R)-carvone 1 was a slightly yellow oil and dichloromethane was a colorless liquid. When stirring in the ice-water bath, the solution turned to foggy white. After 15 minutes of stirring, the solution mixture became clear again and m-CPBA was added, which was in a snowy crystal form. The solution was colorless before m-CPBA was added, after the crystal was added, it didn’t dissolve in the solution mixture at first, and then the solution mixture turned foggy again. After stirring overnights, the solution mixture was white foggy and contained some precipitate. Extraction and washes were performed, and the crude product was clear liquid. After rotate evaporation, the final product was a purple liquid, somewhat oily, with mass of 0.109 g and 99% yield. 1

H NMR, IR, GC, and MS were used to determine the structure and diastereomeric ratio of the product.

From the 1H NMR spectrum of 2, important proton peaks were identified. Refer to Scheme 2 the important values of those proton shifts. The protons of the methyl group on the ring, H c, should have the same shift value, δ 1.77 as the same protons of the starting material 1 because there was no reaction with the alkene of the ring, thus there shouldn’t be any changes of peak shifts of the protons. However, the protons of the methyl group next to the vinyl group, H e, should have different peak shifts, δ 1.31, as the same protons of the starting material because the epoxide was formed on the vinyl group, thus a more electronegative functional group would cause a 1H NMR shift toward the downfield region. When looking at the IR spectrum of 2, the most important acknowledgement made was the conjugated carbonyl stretch.

Because the carbonyl group in both the starting material 1 and product 2 are

conjugated, they should similar stretch positions, 1675 cm -1. And since the vinyl group reacted and formed the epoxide, there is no alkene stretch present in the IR of 2. Gas chromatography and mass spectrometry were also taken in order to determine the diastereometric ratio of the product. From GC, there were two distinctive peaks at 9.026 and 9.04 s, these two peaks

3 were the peaks of the two diastereomers of product 2. The two possible diastereomers of product 2 are drawn below in Scheme 1. Scheme 1. Diastereomers of product 2.

Because m-CPBA reacted with the vinyl group to form the epoxide, only one chiral center changed which resulted to be diastereoselective (more discussed in the Discussion section). The two neighboring peaks at 9.026 and 9.04 s shows the ratio between these two stereoisomers. Because the GC machine could not calculate the percentage between the two compounds, only estimation could be made that the ratio between the two compounds is 0.9:1. The stereoisomer with higher percentage in the product mixture is predicted to be b in Scheme 1 because b is a trans molecule which is less hindered when draw in the chair confirmation. H2O2/NaOH, carvone-1,2-oxide (3): (R)-carvone 1 was a slightly yellow oil and methanol was a colorless liquid. The methanol and 1 solution mixture was cooled in ice-water bath and the solution was colorless. After sodium hydroxide was added, the solution mixture turned creamy yellow. Hydrogen peroxide was then added, and the solution mixture became slightly slushy, but still had the creamy yellow color. The crude product was a creamy slushy solid. After extraction and washes, the product was dried and went under rotate evaporation and the purified product was colorless, with mass of 0.331 g and 60% yield. Like product 2, the 1H NMR, IR, GC, and MS of product 3 was also taken. From the 1H NMR of product 3, important proton peaks were also identified to confirm the structure of 3. Refer to Scheme 3

4 for the 1H NMR shift values. The protons of the methyl group on the ring was shifted downfield because the hydrogen peroxide and sodium hydroxide reacted with the alkene on the ring and formed the epoxide. With the different electronegativity of the neighbor, the protons shifted toward downfield at δ 1.41. But the protons of the methyl group by the vinyl group have the same proton shift, δ 1.71, as the same protons in the starting material 1 because there was no change in the neighboring atoms after the reaction. Also when looking at the IR of 3, clear differences between its IR and the IR of 1 and 2 are the stretches of the carbonyl and the alkene. Because the carbonyl in both the starting material 1 and product 2 are conjugated, they had the stretch around 1675 cm-1. Unlike the carbonyl in 3, it is saturated, which resulted in a shift to 1714 cm-1. Also, in 3, there is an alkene stretch at 1645 cm-1, which was not present in the IR of 2. Gas chromatography and mass spectrometry were also used to determine the stereochemistry of 3. There is only one peak of the product at 8.11 s. The two possible diastereoisomers of 3 are drawn below. Scheme 2. Diastereomers of product 3.

Because there is only one distinctive peak of the product, the assumption could be made that the entire purified product had the same stereochemistry, which concluded in a 100% yield of one of the stereoisomers (more discussed in the Discussion section). And the predicted stereoisomer present is compound d in Scheme 2 because when look at the compound in a flat surface, the epoxide goes into

5 the page while the methyl and vinyl/methyl group go out of the page, gives it less hindered between the epoxide and the vinyl/methyl group. This kind of reaction would be called enantioselective reaction when the reaction chooses one stereochemistry over another. Discussion: In this experiment, two parts were conducted with different reagents to show the different formations of the epoxide products 2 and 3. Analyses of 1H NMR, IR, GC, and MS were done in order to identify the structures and stereochemistries of 2 and 3. Product 2 was a purple liquid and product 3 was a colorless liquid. The yield of 2 was 99% and the yield of 3 was only 60%. The two reagents of the epoxidation reactions, m-CPBA and alkaline hydrogen peroxide, yielded two different stereoisomers. This was because the m-CPBA epoxidation reaction was electrophilic and the alkaline hydrogen peroxide epoxidation reaction was nucleophilic. The different stereochemistries of products 2 and 3 are discussed below. If this experiment was performed again, one change would be keep the crude alkaline hydrogen peroxide product in the refrigerator overnight.

Because purification through silica gel was done

immediately after extraction and washes, keeping it in the refrigerator would possible increase the yield of the reaction. One improvement of this experiment would be better purification methods to increase the yield of product 3. Because this reaction was the epoxidation of 1, epoxides were formed in both reactions on different places of 1. Many evidences on both the 1H NMR and IR spectra showed the formation of the epoxides. For example, by looking at Scheme 3, the 1H NMR data of 1, the protons of the methyl groups, H a and Hb are close to each other at around δ 1.76. After epoxidation, the 1H NMR shift of the protons next to the epoxide would shift toward downfield because of the electronegativity of the epoxide, which would influence the 1H NMR peak values of the protons. Thus, the protons that were effected in 2 were the protons of the methyl group next to the vinyl functional group, H e. Having 1H NMR shift of δ 1.31,

6 1.32, and this would confirm the epoxide formation on the vinyl group. And in product 3, the protons got affected were the protons of the methyl group attached to the ring, H f. By having a 1H NMR shift value of δ 1.41, this showed the formation of the epoxide on the double bond of the ring. Scheme 3. Important 1H NMR shift values of three compounds.

From both the 1H NMR and IR spectra of the two products in each part of the experiment, the chemeoslectivity of the reactions and structures of each product was successfully concluded. The epoxidation of 1 using m-CPBA would yield product 2, and the epoxidation of 1 using hydrogen peroxide and sodium hydroxide would yield product 3. By looking at the IR spectra of the two products 2 and 3, a clear notice would be made of the position of the carbonyl stretches of each product. The carbonyl stretch of 2 is at 1675 cm-1 and the carbonyl stretch of 3 is at 1714 cm-1. The carbonyl stretches of the two products are different because the carbonyl bond in product 2 is conjugated where as in 3 is saturated, thus yield different values of stretches. Also, in 3, there is a alkene stretch, present at 1645 cm-1. But there is no alkene stretch in 2. Mechanisms of the two reactions are drawn below.

Scheme 4. Mechanism of epoxidation of 1 with m-CPBA.

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Scheme 5. Mechanism of epoxidation of 1 with hydrogen peroxide and sodium hydroxide.

The reaction of epoxidation with reagents hydrogen peroxide and sodium hydroxide is a nucleophilic epoxidation reaction. In this case, the nucleophilic epoxidation reaction occurs at alkenes is conjugated with electron withdrawing groups. During this reaction, hydrogen peroxide was the nucleophile and the alkene was the electrophile. The epoxide formed on the ring instead of the vinyl group because the alkene on the ring is electron poor, which would accept an electron pair from the nucleophile hydrogen peroxide. From Scheme 5, the mechanism showed the donation of the electron pair of the hydrogen peroxide anion. There are two possible stereoisomers of 3, but one of them is favored than the other one. Since the GC showed that there is only one of stereoisomers formed, thus this reaction was enantioselective. By looking at the mechanism in Scheme 5, one acknowledge would be made that when the negative charge on the oxygen moves back and form the double bond, and the double bond on the ring would form a

8 single bond with the oxygen of hydrogen peroxide functional group. This would result a downward push on the epoxide while leading the methyl group go out of the page, which would lead to the first type of stereoisomer of product 3 in Scheme 5 or compound d in Scheme 2. Also, this selectivity can be explained with the steric hinderness of the compound. If the stereochemistry of 2 is c in Scheme 2, then the distance between the epoxide and the vinyl/methyl group is shorter than the distance in d. Shorter distance result in more hinderness which would create a less stable molecule, thus the predicted stereoisomer of 2 is d in Scheme 2. Product 2 was formed using the reagent m-CPBA and solvent dichloromethane. The epoxidation with m-CPBA could be described as diastereoselective. A diastereoselective reaction is when changes one of the chiral centers, but preferentially. Which means in the final product, both stereoisomers could be present. Where as an enantioselective reaction is defined as when only one chiral center change was made specifically during the reaction and only one of the stereoisomers could be present. Because during the m-CPBA reaction, the reagent m-CPBA was the electrophile and the vinyl group was the nucleophile. The vinyl group was electron rich thus donates a pair of electrons to m-CPBA and forms the epoxide. When performed GC on product 2, two product peaks showed up which confirmed the theory of diastereoselective reaction. During the epoxidation of 1 with reagent m-CPBA, sodium bisulfite and sodium bicarbonate were used after the reaction was completed. Sodium bisulfite was used because it is a strong reducing agent in organic synthesis, thus sodium bisulfite can reduce and destroy oxidizing agents such as m-CPBA. The use of sodium bicarbonate wash is to neutralize and remove any excess m-CPBA by-product.

Experimental Section:

9 Scheme 6. Reaction scheme of epoxidation of 1 by m-CPBA.

m-CPBA, carvone-7,8-oxide (2): 1 (0.096 g, 0.639 mmol, 1 equiv) was added into a 100 mL round-bottom flask with dichloromethane (4.655 g, 54.810 mmol, 1 equiv). The solution was stirred in an ice-water bath for 15 minutes, and then 7% m-CPBA (0.222 g, 1.286 mmol, 1.5 equiv) was added portionwise. After m-CPBA was added, the flask was stoppered and removed from the ice-water bath, and then stirred at room temperature. The reaction was checked periodically with TLC and then stirred until next class period (from 2/15 to 2/20). After stirring was completed, the reaction was completed. Quenching, extraction and washes took place afterwards. The solution mixture was quenched with 10% sodium bisulfite solution (5 mL) and aqueous saturated sodium bicarbonate solution (5 mL).

The solution mixture was then extracted with

dichloromethane (3 x 5 mL), and the combined organic layers were extracted with aqueous sodium bicarbonate (3 x 5 mL). Finally, the solution mixture was dried over sodium sulfite. After evaporated the solvent in the solution mixture by using rotating evaporator, the isolated and purified final product, 2 (0.109g, 99%), was a purple liquid. 1H NMR (300 MHz, CDCl3) δ 2.71-2.66 (m, 2H), δ 2.61-2.53 (m, 2H), δ 2.45-2.35 (m, 1H), δ 2.30-2.25 (m, 2H), δ 2.21-2.15 (m, 1H), δ 1.77 (s, 3H), δ 1.31-1.32 (d, J = 3 Hz, 3H). IR (neat film, NaCl) 3080 cm-1, 2978 cm-1, 2934 cm-1, 1675 cm-1.

Scheme 7. Reaction scheme of epoxidation of 1 by hydrogen peroxide and sodium hydroxide.

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H2O2/NaOH, carvone-1,2-oxide (3): Compound 1 (0.5 g, 3.328 mmol, 1 equiv) was dissolved with methanol (2.77 g, 86.50 mmol, 1 equiv) in a 100 mL round-bottom flask. The solution mixture was cooled in an ice-water bath for 15 minutes. Then 6M sodium hydroxide solution (5.90 g, 0.01664 mmol, 5 equiv) was added to the solution mixture. Carefully, 30% hydrogen peroxide (1.11 g, 32.63 mmol, 3 equiv) was added dropwise. The solution mixture was then kept cold while monitoring with TLC. When the reaction was completed, confirmed by TLC, it was then diluted with water (30 mL). Extraction and washes were performed. The solution mixture was extracted with diethyl ether (3 x 15 mL) and washed with brine (10 mL). After extraction and washes, the solution mixture was then dried with sodium sulfite and the solvent was removed with rotating evaporator. After the solvent in the solution mixture was evaporated, the crude product was run through a small plug of silica gel with ethyl acetate, and ethyl acetate was then removed with rotating evaporator again. The isolated and purified final product was, 3 (0.331 g, 60%), was a colorless liquid. 1

H NMR (200 MHz, CDCl3) δ 4.79-4.71 (d, J = 16, 2H), δ 3.45-3.44 (d, J = 2, 1H), δ 2.80-2.56 (m, 2H),

δ 2.53-2.33 (m, 1H), δ 2.09-1.83 (m, 2H), δ 1.71 (s, 3H), δ 1.41 (s, 3H). IR (neat film, NaCl) 3080 cm -1, 2979 cm-1, 1714 cm-1, 1645 cm-1. 1

H NMR and IR of 1 were also taken. 1H NMR (200 MHz, CDCl3) δ 4.80-4.75 (d, J = 10, 2H), δ 1.78

(s, 3H), δ 1.75 (s, 3H). IR (neat film, NaCl) 2970 cm-1, 1675 cm-1, 1645 cm-1. (1)

Lai, Y.M.; Mark, Kendrew K. W.; Siu, Yuk-Hong. Journal of Chemical Education. 2006, 83,

1058-1061....