Wittig Reaction Lab Report
Introduction
Discovered by Georg Wittig in 1954, the Wittig reaction is a robust organic synthesis method for preparing stereospecific alkenes. In general, Wittig reactions involve an aldehyde or ketone and a Wittig reagent (triphenylphosphonium ylide) and result in the formation of an alkene product and triphenylphosphine oxide (side product). Stereospecific alkene products can be synthesized by adjusting the reaction reagents and conditions.
In the 60 years since the Wittig reaction was discovered, many articles have expanded upon its mechanism. For example, Bryne, et al.1 describe in a review how our understanding of the Wittig reaction mechanism has changed with new computational and experimental studies. Recent evidence suggests Wittig reactions run in lithium-salt-free conditions occur solely under kinetic control via an oxaphosphetane intermediate. This finding applies to all phosphonium ylides, stabilized or unstabilized, and is contrary to many previously reported mechanisms. …show more content…
The Wittig reaction has been employed to create many novel alkene products. One example is the synthesis of sintenin, a natural ester, as reported by Sharma, et al.2 Many natural esters are biologically active compounds that exhibit anti-microbial, anti-inflammatory, and anti-tumor properties. Sintenin exhibits cytotoxic activity in human tumor cell lines and is currently being researched as a cancer treatment. Organic synthetic methods such as the Wittig reaction are fundamental for developing drugs against cancer, malaria, and other diseases. Scheme 1: Reaction of 2-Nitrobenzaldehyde and Methyl (Triphenylphosphoranylidene) Acetate
Our experiment involved the reaction of 2-nitrobenzaldehyde (1) and methyl (triphenylphosphoranylidene) acetate (2) to form methyl (2E)-3-(2-nitrophenyl) acrylate (3) and triphenylphosphine oxide (4) (side product). As the phosphonium ylide was charge stabilized (by the ester group), the trans alkene was favored. Thus, the general and mechanism schemes only depict the formation of the E isomer.
The mechanism for forming methyl (2E)-3-(2-nitrophenyl) acrylate involved the formation of a four-membered oxaphosphetane intermediate (5) from the reagents. After oxaphosphetane decomposition, methyl (2E)-3-(2-nitrophenyl) acrylate and triphenylphosphine oxide (side product) directly formed. Scheme 2: Mechanism of Methyl (2E)-3-(2-Nitrophenyl) Acrylate Formation
Results and Discussion The Wittig reaction we ran produced 33 mg (0.159 mmol, 31.9% yield) of a tan crystalline product.
Although the yield of our reaction was mediocre, the purity of the sample (as analyzed by 1H and 13C NMR) was poor. There are many factors that may have caused poor purity, of which include reaction incompletion during exposure to microwave radiation, poor mixing, and poor product isolation during column chromatography. As seen in the 1H NMR spectrum, impurity peaks (>10%) corresponding to methyl (triphenylphosphoranylidene) acetate, acetone, ethyl acetate, and hexane were identified. The phosphonium ylide peak indicates that the reaction did not go to completion (leftover starting material). Meanwhile, the acetone, ethyl acetate, and hexane peaks show there was residual solvent in the sample submitted for NMR analysis (compounds were not in reaction scheme). Because acetone, ethyl acetate, and hexane are volatile, we deduced that our evaporation of the final product was
inadequate.
The large number of impurity peaks may explain the inconsistencies in the 1H NMR spectrum. It was difficult to definitively identify peaks in the aryl region due to nonsensical integration values (δ 7.27-7.68 had integration of 353.97). We speculated the large integration to be due to excess impurities (phosphonium ylide, triphenylphosphine oxide, or other aromatic compounds), but we could not definitively identify the impurities causing the response. It was thus not possible to determine the molar ratio of the impurities to pure product in our sample.
We decided which fractions to isolate the alkene product from based on TLC. By TLC, we selected fractions that had a response under UV at Rf ~0.650 (product) but no response under DNPH. DNPH was selected as an indicator because it stains spots yellow only if an aldehyde is present. Coincidentally, the alkene product of interest and 2-nitrobenzaldehyde both had Rf ~0.650; using DNPH allowed us to differentiate between the two compounds and select fractions without the starting aldehyde. Because we only used two of the seven fractions, though, the yield of our reaction was lower than expected.
Despite these shortcomings, we were able to identify that the product we formed had trans stereochemistry. Mechanistically, the Wittig reaction involves the nucleophilic addition of a phosphonium ylide to the electrophilic carbonyl group of an aldehyde or ketone. Because of the Bürgi-Dunitz approach, the betaine must reorient itself so the triphenylphosphine and oxide groups can form the oxaphosphetane intermediate. This intermediate is a relatively unstable and thus quickly decomposes to form the alkene and triphenylphosphine side product. For the most part, the stereospecificity of this reaction can be determined using the R group of the aldehyde. Because the rate of the Wittig reaction is dependent on the stability of the phosphonium ylide, aldehydes with R groups that stabilize the ylide's negative charge (e.g. nitro and ester groups) tend to form the more stable trans alkene in a slow, irreversible manner. Meanwhile, phosphonium ylides that are unstabilized tend form the cis alkene in a fast, reversible manner. Because an ester group stabilized the phosphonium ylide we used, our product was predicted to primarily consist of the E isomer. This was confirmed by determining the coupling constants of the alkene hydrogens (J = 15.7 and 15.8 Hz).
There are several things we could do to improve yield of the alkene product. First, make sure that all of the reactants (aldehyde, phosphonium ylide) react while exposed to microwave radiation. Second, stir the resulting amalgam quickly and thoroughly to further ensure reaction completion. Third, prepare a longer column with more stationary phase (silica gel) to improve isolation resolution. To improve the purity of the final product, we could make sure the reaction goes to completion and evaporate our recrystallized product thoroughly to remove any residual solvent.
In conclusion, our preparation of methyl (2E)-3-(2-nitrophenyl) acrylate had a percent yield of 31.9%. Although we succeeded in creating a stereospecific alkene (trans product), our NMR spectra indicated that the purity of our product was poor. This was attributable to several errors that were best summarized as reaction incompletion, poor isolation during column chromatography, and incomplete evaporation of solvent. Following the improvements delineated above would allow us to prepare more pure product in the future.
Experimental Methyl (2E)-3-(2-Nitrophenyl) Acrylate (3).3 76 mg (0.503 mmol) of 2-nitrobenzaldehyde, 174 mg (0.520 mmol) of methyl (triphenylphosphoranylidene) acetate, and 98 mg silica gel were combined in a 1-dram vial. This mixture was microwaved at 40% power for 2 minutes and stirred until a tan powder formed. The powder was mixed with 0.50 mL mobile phase (50:50 ethyl acetate:hexane) and transferred to a chromatography column with silica gel stationary phase. During isolation, seven 1 mL fractions were collected. Each fraction was analyzed by TLC; fractions 4 and 5 (no DNPH response) were used to recrystallize the product by evaporation. 33 mg (0.159 mmol, 31.9% yield) of tan crystalline product was collected. The product was dissolved in 0.7 mL CDCl3 for NMR analysis. TLC: Rf 0.643 (silica gel, 50:50 ethyl acetate:hexane, UV/DNPH). 1H NMR (300 MHz, CDCl3) δ 8.13 (d, J = 15.7 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 6.37 (d, J = 15.8 Hz), 3.83 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 162.32, 132.62, 132.16, 132.02, 128.57, 128.41, 57.95.
Discovered by Georg Wittig in 1954, the Wittig reaction is a robust organic synthesis method for preparing stereospecific alkenes. In general, Wittig reactions involve an aldehyde or ketone and a Wittig reagent (triphenylphosphonium ylide) and result in the formation of an alkene product and triphenylphosphine oxide (side product). Stereospecific alkene products can be synthesized by adjusting the reaction reagents and conditions.
In the 60 years since the Wittig reaction was discovered, many articles have expanded upon its mechanism. For example, Bryne, et al.1 describe in a review how our understanding of the Wittig reaction mechanism has changed with new computational and experimental studies. Recent evidence suggests Wittig reactions run in lithium-salt-free conditions occur solely under kinetic control via an oxaphosphetane intermediate. This finding applies to all phosphonium ylides, stabilized or unstabilized, and is contrary to many previously reported mechanisms. …show more content…
The Wittig reaction has been employed to create many novel alkene products. One example is the synthesis of sintenin, a natural ester, as reported by Sharma, et al.2 Many natural esters are biologically active compounds that exhibit anti-microbial, anti-inflammatory, and anti-tumor properties. Sintenin exhibits cytotoxic activity in human tumor cell lines and is currently being researched as a cancer treatment. Organic synthetic methods such as the Wittig reaction are fundamental for developing drugs against cancer, malaria, and other diseases. Scheme 1: Reaction of 2-Nitrobenzaldehyde and Methyl (Triphenylphosphoranylidene) Acetate
Our experiment involved the reaction of 2-nitrobenzaldehyde (1) and methyl (triphenylphosphoranylidene) acetate (2) to form methyl (2E)-3-(2-nitrophenyl) acrylate (3) and triphenylphosphine oxide (4) (side product). As the phosphonium ylide was charge stabilized (by the ester group), the trans alkene was favored. Thus, the general and mechanism schemes only depict the formation of the E isomer.
The mechanism for forming methyl (2E)-3-(2-nitrophenyl) acrylate involved the formation of a four-membered oxaphosphetane intermediate (5) from the reagents. After oxaphosphetane decomposition, methyl (2E)-3-(2-nitrophenyl) acrylate and triphenylphosphine oxide (side product) directly formed. Scheme 2: Mechanism of Methyl (2E)-3-(2-Nitrophenyl) Acrylate Formation
Results and Discussion The Wittig reaction we ran produced 33 mg (0.159 mmol, 31.9% yield) of a tan crystalline product.
Although the yield of our reaction was mediocre, the purity of the sample (as analyzed by 1H and 13C NMR) was poor. There are many factors that may have caused poor purity, of which include reaction incompletion during exposure to microwave radiation, poor mixing, and poor product isolation during column chromatography. As seen in the 1H NMR spectrum, impurity peaks (>10%) corresponding to methyl (triphenylphosphoranylidene) acetate, acetone, ethyl acetate, and hexane were identified. The phosphonium ylide peak indicates that the reaction did not go to completion (leftover starting material). Meanwhile, the acetone, ethyl acetate, and hexane peaks show there was residual solvent in the sample submitted for NMR analysis (compounds were not in reaction scheme). Because acetone, ethyl acetate, and hexane are volatile, we deduced that our evaporation of the final product was
inadequate.
The large number of impurity peaks may explain the inconsistencies in the 1H NMR spectrum. It was difficult to definitively identify peaks in the aryl region due to nonsensical integration values (δ 7.27-7.68 had integration of 353.97). We speculated the large integration to be due to excess impurities (phosphonium ylide, triphenylphosphine oxide, or other aromatic compounds), but we could not definitively identify the impurities causing the response. It was thus not possible to determine the molar ratio of the impurities to pure product in our sample.
We decided which fractions to isolate the alkene product from based on TLC. By TLC, we selected fractions that had a response under UV at Rf ~0.650 (product) but no response under DNPH. DNPH was selected as an indicator because it stains spots yellow only if an aldehyde is present. Coincidentally, the alkene product of interest and 2-nitrobenzaldehyde both had Rf ~0.650; using DNPH allowed us to differentiate between the two compounds and select fractions without the starting aldehyde. Because we only used two of the seven fractions, though, the yield of our reaction was lower than expected.
Despite these shortcomings, we were able to identify that the product we formed had trans stereochemistry. Mechanistically, the Wittig reaction involves the nucleophilic addition of a phosphonium ylide to the electrophilic carbonyl group of an aldehyde or ketone. Because of the Bürgi-Dunitz approach, the betaine must reorient itself so the triphenylphosphine and oxide groups can form the oxaphosphetane intermediate. This intermediate is a relatively unstable and thus quickly decomposes to form the alkene and triphenylphosphine side product. For the most part, the stereospecificity of this reaction can be determined using the R group of the aldehyde. Because the rate of the Wittig reaction is dependent on the stability of the phosphonium ylide, aldehydes with R groups that stabilize the ylide's negative charge (e.g. nitro and ester groups) tend to form the more stable trans alkene in a slow, irreversible manner. Meanwhile, phosphonium ylides that are unstabilized tend form the cis alkene in a fast, reversible manner. Because an ester group stabilized the phosphonium ylide we used, our product was predicted to primarily consist of the E isomer. This was confirmed by determining the coupling constants of the alkene hydrogens (J = 15.7 and 15.8 Hz).
There are several things we could do to improve yield of the alkene product. First, make sure that all of the reactants (aldehyde, phosphonium ylide) react while exposed to microwave radiation. Second, stir the resulting amalgam quickly and thoroughly to further ensure reaction completion. Third, prepare a longer column with more stationary phase (silica gel) to improve isolation resolution. To improve the purity of the final product, we could make sure the reaction goes to completion and evaporate our recrystallized product thoroughly to remove any residual solvent.
In conclusion, our preparation of methyl (2E)-3-(2-nitrophenyl) acrylate had a percent yield of 31.9%. Although we succeeded in creating a stereospecific alkene (trans product), our NMR spectra indicated that the purity of our product was poor. This was attributable to several errors that were best summarized as reaction incompletion, poor isolation during column chromatography, and incomplete evaporation of solvent. Following the improvements delineated above would allow us to prepare more pure product in the future.
Experimental Methyl (2E)-3-(2-Nitrophenyl) Acrylate (3).3 76 mg (0.503 mmol) of 2-nitrobenzaldehyde, 174 mg (0.520 mmol) of methyl (triphenylphosphoranylidene) acetate, and 98 mg silica gel were combined in a 1-dram vial. This mixture was microwaved at 40% power for 2 minutes and stirred until a tan powder formed. The powder was mixed with 0.50 mL mobile phase (50:50 ethyl acetate:hexane) and transferred to a chromatography column with silica gel stationary phase. During isolation, seven 1 mL fractions were collected. Each fraction was analyzed by TLC; fractions 4 and 5 (no DNPH response) were used to recrystallize the product by evaporation. 33 mg (0.159 mmol, 31.9% yield) of tan crystalline product was collected. The product was dissolved in 0.7 mL CDCl3 for NMR analysis. TLC: Rf 0.643 (silica gel, 50:50 ethyl acetate:hexane, UV/DNPH). 1H NMR (300 MHz, CDCl3) δ 8.13 (d, J = 15.7 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 6.37 (d, J = 15.8 Hz), 3.83 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 162.32, 132.62, 132.16, 132.02, 128.57, 128.41, 57.95.