Student Name Total Synthesis Experiment 344 Honors Nikki Burrmann 5/11/07

Transcription

1 Student Name Total Synthesis Experiment 344 onors Nikki Burrmann 5/11/07

2 2 ABSTRACT Total synthesis is useful in organic chemistry because it allows one to create complex molecules from simple starting materials. In this experiment, the total synthesis of trans-stilbene was performed in two different ways: the first used traditional methods of heating, and the second used microwave radiation to supply energy to the reaction more efficiently. The first reaction in the traditional methods experiment was to synthesize trans-cinnamic acid. The product was verified to be trans-cinnamic acid with a yield of 50.0% and a melting point of C. The second reaction in the traditional methods experiment was to synthesize 2,3-dibromo-3-phenylpropionic acid. The product was verified to be 2,3-dibromo-3-phenylpropionic acid with a yield of 22.7% and a melting point of C. The third reaction was to synthesize trans-1-bromo-2- phenylethene. This reaction was unsuccessful in producing the desired product. The final reaction to synthesize trans-stilbene could not be performed, and the total yield of trans-stilbene was 0.0%. The first reaction in the experiment employing microwave radiation was to synthesize transcinnamic acid. The product was verified to be trans-cinnamic acid with a yield of 99.4% and a melting point of C. The second reaction in the experiment was to synthesize 2,3- dibromo-3-phenylpropionic acid. The product was verified to be 2,3-dibromo-3-phenylpropionic acid with a yield of 39.9% and a melting point of C. The third reaction was to synthesize 1-bromo-2-phenylethene. The reaction successfully produced a 4.55:1 ratio of trans-1- bromo-2-phenylethene: cis-1-bromo-2-phenylethene with a yield of 41.4%. The final reaction was to synthesize trans-stilbene. The product was determined to be a mixture of trans-stilbene and cisstilbene, with a ratio of 1.64 trans:cis, a yield of 160%, and a melting point of C. The total yield of trans-stilbene by microwave heating was 26.3%

3 3 INTRDUCTIN A total synthesis, or multistep synthesis, is the process of performing several different consecutive reactions in order to synthesize the desired product. 1 The goals of total synthesis are to minimize cost, to perform reactions that are environmentally friendly, to develop a scalable synthesis that is applicable in industry, to attain high yields of the desired product, to design a convergent synthesis so as to maximize the final yield given the yield of each reaction, and to use reagents containing a relatively small number of atoms. Due to the multiple reactions involved, it is often useful to employ retrosynthetic analysis when planning a total synthesis. Retrosynthetic analysis is a backward planning procedure of breaking down the desired molecule into successively simpler molecules. nce a retrosynthetic analysis is complete, one must confirm that each of the reactions is feasible in the forward direction and that the stereochemistry is correct. 2 An example of a total synthesis reaction is the synthesis of trans-stilbene from benzaldehyde. This process is shown below in Figure 1. trans-cinnamic acid 2,3-dibromo-3-phenylpropionic acid + B-alanine, pyridine C 2 C 5 5 N- 3 C 2 benzaldehyde malonic acid B K 2 C 3, 2 Pd(Ac) 2, TBA, Na 2 C 3 trans-stilbene Figure 1. The total synthesis of trans-stilbene 1-bromo-2-phenylethene

4 4 In the first reaction, a Knoevenagel condensation is performed with benzaldehyde and malonic acid to produce trans-cinnamic acid. The mechanism of this reaction is shown below in Figure 2. (resonance stabilized) + N 2 2N 3N keto-enol tautomerization +C 2 2N Figure 2. Mechanism for the synthesis of trans-cinnamic acid The E2 elimination of water in the last step, which requires an antiperiplanar geometry between the hydrogen and the group, is what leads to the trans stereochemistry. In this reaction, carbon dioxide gas is released. To prevent overpressure, this reaction must be performed in a vessel open to the air. The mechanism for the synthesis of 2,3-dibromo-3-phenylpropionic acid is shown below in Figure 3.

5 5 C 2 C 2 C 2 Figure 3. Mechanism for the synthesis of 2,3-dibromo-3-phenylpropionic acid ne should note that the bromine source is not elemental bromide, which is quite dangerous. Instead, pyridinium tribromide is used, which liberates molecular bromide in solution. ne may then perform a decarboxylative elimination to produce 1-bromo-2-phenylethene. The mechanism for this reaction, starting from one of the products shown above in Figure 3, is shown below in Figure C 2 Figure 4. Mechanism for the synthesis of 1-bromo-2-phenylethene The E1 reaction creates a carbocation, and one would expect the final trans product to dominate due to sterics. ne can then synthesize trans-stilbene via a Suzuki coupling with phenylboronic acid. A Suzuki coupling is a metal-catalyzed reaction that allows a halide to react with an aryl boronic acid. The mechanism for this reaction is shown below in Figure 5.

6 6 Pd(Ac) 2 Pd Pd B B Pd Figure 5. Mechanism for the synthesis of trans-stilbene Many of the reactions in the total synthesis of trans-stilbene require refluxing or stirring for long periods of time if one uses traditional methods of heating. This is neither an efficient use of time nor does it maximize the yield of product. An alternative to traditional methods of heating is to use microwave radiation to heat the mixture. Microwave heating is advantageous to traditional heating in several ways. First, it allows for shorter reaction times, which increases time efficiency. Also, it makes the reactions green in the following ways: by allowing for shorter reaction times, microwave heating makes it less likely for undesired side reactions to occur. Also, it heats the entire reaction mixture uniformly. This allows one to use the minimal temperature, which lessens product decomposition. Also, it results in higher yields, decreasing the amount of unused reagents. Also, it makes use of safer solvents, such as water. Were solvents such as water to be used in traditional heating methods, problems with solubility would result in decreased yield. Finally, it allows one to safely carry out reactions in a closed system.

7 7 Neither the synthesis of trans-stilbene by traditional methods or by microwave heating meets all of the goals of a total synthesis, although the microwave heating method meets more of these goals. The method of traditional heating is not green, it does not maximize the yield of the target molecule, and it is not convergent. The method of microwave heating is not convergent. METD Synthesis of trans-cinnamic acid, traditional methods Malonic acid ( g) and β-alanine were added to a 25 ml round bottom flask. Benzaldehyde (0.45 ml) was added to the flask using an Eppendorf pipette. Pyridine was added to the flask, and the flask was attached to a reflux apparatus and refluxed for 1.5 hours. The solution was then cooled to room temperature, and poured into a 250 ml flask containing cold water. The solution was acidified with 6M Cl to a p of 2. A solid precipitated out of the solution, and it was collected by vacuum filtration. The crude product was recyrstallized using a solution of 1:1 ethanol:water. The final product was collected by vacuum filtration and dried. The product was weighed, a sample was prepared for 1 NMR, the melting point of the product was measured, and a sample was analyzed by thin film IR. Synthesis of 2,3-dibromo-3-phenylpropionic acid, traditional methods A 25 ml round bottom flask was equipped with a vacuum adapter, which was connected directly to the water aspirator. Trans-cinnamic acid ( g) was added to the flask. Pyridinium tribromide (1.92 g, imprecision due to use of scale in fume hood) was added to the flask, followed by glacial acetic acid. The flask, connected to the vacuum adapter, was stirred for two hours. Then, while the mixture was still being stirred, ice cold water was added to the flask through the vacuum adapter. The flask was placed in an ice bath, and two portions of ice cold water were added to the

8 8 flask. The flask was kept in the ice bath for an additional ten minutes, after which the solid was collected by vacuum filtration. The solid was washed with water. The solid appeared impure, so it was recyrstallized with chloroform. The final product was collected using vacuum filtration. The product was weighed, a sample was prepared for 1 NMR (using d6-acetone as a solvent), the melting point of the product was measured, and a sample was analyzed by thin film IR. Synthesis of 1-bromo-2-phenylethene, traditional methods 2,3-Dibromo-3-phenylpropionic acid ( g), potassium carbonate, and water were combined in a 25 ml round bottom flask. The solution was refluxed vigorously for two hours. The solution was then transferred to a separatory funnel containing dichloromethane. The solution was mixed and the two layers were separated. The aqueous layer was extracted with two portions of dichloromethane. The combined organic layers were washed with saturated sodium chloride and dried with anhydrous magnesium sulfate. The liquid was collected using gravity filtration, and the dichloromethane was then removed from the solution using a steam bath. The product was weighed, and the entire product was diluted with CDCl 3 to be analyzed by 1 NMR. Synthesis of trans-stilbene, traditional methods analysis. This reaction could not be performed because no 1-bromo-2-phenylethene remained after Synthesis of trans-cinnamic acid, microwave heating (performed by Nikki Burrmann) Benzaldehyde (4.0 ml), β-alanine, malonic acid ( g), and pyridine were placed in a 100 ml round bottom flask containing a stir bar. The flask was placed in a microwave cavity, and a short air column and a water condenser were attached to the flask. The open vessel method on the

9 9 microwave (Discover) was used to heat the flask to 110 C for ten minutes at 75 W (Program onors 1 ). The flask was then cooled to 50 C, and the flask contents were poured into a 250 ml beaker containing cold water. 6M Cl was added until the p of the solution was 2. A solid precipitated out, and was collected by vacuum filtration. The solid was recrystallized in 1:1 ethanol: water. The final product was collected using vacuum filtration. The product was weighed, a sample was prepared for 1 NMR, the melting point of the product was measured, and a sample was analyzed by thin film IR. Synthesis of 2,3-dibromo-3-phenylpropionic acid, microwave heating Trans-cinnamic acid from vial 2 ( g) was added to a microwave reaction vessel containing a stir bar. Pyribidium tribromide (1.07 g, imprecision due to using scale in fume hood) and glacial acetic acid were added to the reaction vessel. The vessel was sealed and placed into the microwave cavity. The pressure device was put on top of the reaction vessel, and the microwave (Discover) was programmed to heat the reaction vessel to 100 C for ten minutes at 150 W (Program onors 2 ). The reaction vessel was then cooled to 50 C and the pressure device was removed. The solution in the reaction vessel was transferred to a 50 ml Erlenmeyer flask. The flask was stirred and ice cold water was added to the mixture. The flask was continuously stirred, placed in an ice bath, and two potions of ice cold water were added to the flask. The flask was kept in the ice bath for an additional ten minutes, and then the solid was collected by vacuum filtration. The solid was rinsed with cold water until it was white, after which it was rinsed with cold chloroform. The melting point of the product was measured, the product was weighed, a small sample of the product was dissolved in d6-acetone to be analyzed by 1 NMR, and a small sample of the product was analyzed by thin film IR.

10 10 Synthesis of 1-bromo-2-phenylethene, microwave heating 2,3-Dibromo-3-phenylpropionic acid ( g) was placed in a 10 ml reaction vessel containing a stir bar. Potassium carbonate and water were added to the reaction vessel, the vessel was sealed, and the vessel was placed in the Discover microwave cavity. The pressure device was put on top of the vessel, and the microwave was programmed to heat the solution in the reaction vessel to 100 C for five minutes at 150 W (Program onors 3 ). The reaction vessel was then cooled to below 50 C, and the pressure device was removed. The reaction mixture was then transferred to a 60 ml separatory funnel containing dichloromethane. The solution in the separatory funnel was mixed and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane. The organic layers were combined and washed with saturated sodium bicarbonate and then dried with anhydrous magnesium sulfate. The liquid was collected using gravity filtration, and the dichloromethane was removed using a steam bath. The product was weighed, a sample was prepared for 1 NMR, and a sample was analyzed by thin film IR. Synthesis of trans-stilbene, microwave heating Palladium acetate, phenylboronic acid ( g), sodium carbonate, TBA, 1-bromo-2- phenylethene, and deionized water were added to a 10 ml microwave reaction vessel containing a stir bar. The vessel was sealed and placed in the microwave cavity. The pressure device was put on top of the reaction vessel, and the microwave (Discover) was programmed to heat the reaction vessel to 130 C for five minutes at 150 W (Program onors 4 ). After heating, the reaction vessel was then cooled to below 50 C, and the pressure device was removed. The reaction mixture was transferred to a 60 ml separatory funnel containing diethyl ether. The reaction vessel was rinsed

11 11 with deionized water and diethyl ether, and the contents of the vessel were added to the separatory funnel. After mixing the contents of the separatory funnel, the layers were separated and the organic layer was washed with saturated sodium chloride and then dried with anhydrous magnesium sulfate. The liquid was collected by gravity filtration, and the diethyl ether was removed using a steam bath. The product was weighed, a sample was prepared for 1 NMR, the melting point of the product was measured, and a sample was analyzed by thin film IR. Preparation of a sample for analysis by 1 NMR Unless noted above in the procedure, the solvent used to dilute the sample was CDCl 3. To prepare a sample for 1 NMR, a small sample of the product was diluted with solvent. A Varian xford 300 Mz Spectrometer was used to perform the analysis. IR analysis of a sample. If the sample was liquid, it was placed between two compressed NaCl plates. If the sample was solid, it was dissolved in dichloromethane and placed between two compressed NaCl plates. A uker Vector 22 was used to perform the analysis. Melting point measurement of a sample A MELTEMP was used to measure the melting point of all solids. RESULTS The yields and melting points of the products of each of the reactions are shown below in Table 1. The calculation for the percent yield of the traditional methods synthesis of trans-cinnamic acid can be found on page 76 of the laboratory notebook, for the traditional methods synthesis of 2,3-dibromo-3-phenylpropionic acid on page 78 of the laboratory notebook, and for the traditional

12 12 methods synthesis of 1-bromo-2-phenylethene on page 80 of the laboratory notebook. The percent yield calculation for the microwave heating synthesis of trans-cinnamic acid can be found on page 80 of the laboratory notebook, for the microwave heating synthesis of 2,3-dibromo-3- phenylpropionic acid on page 82 of the laboratory notebook, for the microwave heating synthesis of 1-bromo-2-phenylethene on page 84 of the laboratory notebook, and for the microwave heating synthesis of trans-stilbene on page 86 of the laboratory notebook. Experiment Percent Yield Melting Point of Product ( C) Traditional methods: transcinnamic 50.0% acid synthesis Traditional methods: 2,3-22.7% dibromo-3-phenylpropionic acid synthesis Traditional methods: 1-bromo- 7.84% Not applicable 2-phenylethene synthesis Traditional methods: transstilbene Experiment not performed Experiment not performed synthesis Microwave heating: transcinnamic 99.4% acid synthesis Microwave heating: 2,3-39.9% dibromo-3-phenylpropionic acid synthesis Microwave heating: 1-bromo- 41.4% Not applicable 2-phenylethene synthesis Microwave heating: transstilbene 160% synthesis Total yield of trans-stilbene, 0.0% traditional methods experiment Total yield of trans-stilbene, microwave heating experiment 26.3% Table 1. Yields and melting points of the products of each reaction and the total yields. The 1 NMR and the thin film IR for the product of the traditional methods synthesis of trans-cinnamic acid can be found in Figures 6 and 7, respectively. The 1 NMR and the thin film IR for the product of the traditional methods synthesis of 2,3-dibromo-3-phenylpropionic acid can be found in Figures 8 and 9, respectively. The 1 NMR for the product of the traditional methods

13 13 synthesis of 1-bromo-2-phenylethene can be found in Figure 10. Due to lack of product, no IR could be taken. The traditional method synthesis of trans-stilbene could not be performed. The 1 NMR spectrum for the product of the microwave heating synthesis of transcinnamic acid can be found in Figure 11. The 1 NMR and thin film IR for the product of the microwave heating synthesis of 2,3-dibromo-3-phenylpropionic acid can be found in Figures 12 and 13, respectively. The 1 NMR and thin film IR for the product of the microwave heating synthesis of 1-bromo-2-phenylethene can be found in Figures 14 and 15, respectively. The 1 NMR for the product of the microwave heating synthesis of trans-stilbene can be found in Figures 16 and 17. The thin film IR for the product can be found in Figure 18. The ratio of trans:cis products of 1-bromo-2-phenylethene was found to be 4.55:1 by 1 NMR. This calculation can be found in Figure 13. The ratio of trans:cis products of stilbene was found to be 1.64:1. This calculation can be found in Figure 17. DISCUSSIN The product of the traditional methods synthesis of trans-cinnamic acid was determined to be trans-cinnamic acid by 1 NMR, which can be seen in Figure 6. Small impurities of ethanol and methanol were also identified. The reference 1 NMR spectrum for trans-cinnamic acid can be found in Figure The reference thin film IR spectrum for trans-cinnamic acid can be found in Figure The melting point of the product ( C) is similar to the reference value for trans-cinnamic acid (133 C). 4 The product of the traditional methods synthesis of 2,3-dribromo-3- propionic acid was determined by 1 NMR to be 2,3-dibromo-3-propionic acid (the 1 NMR spectrum of the product can be found in Figure 8). The reference 1 NMR spectrum for 2,3- dibromo-3-propionic acid can be found in Figure No reference thin film IR spectrum could be

14 14 found. owever, the IR spectrum of the product (seen in Figure 9) contains the aromatic C- stretch that would be expected from 2,3-dibromo-3-propionic acid, and it also contains the alkane C- stretch, which confirms that the product was not just the starting trans-cinnamic acid. 6 The melting point of the product ( C) is lower than that of 2,3-dibromo-3-propionic acid (200 C). 5 The cause of this discrepancy is unknown. The product of the synthesis of 1-bromo-2- phenylethene was found by 1 NMR to be a mixture of impurities, including water and hexane (the 1 NMR spectrum of the product can be found in Figure 10.) No aromatic peaks were identified. It is unknown why this reaction failed to produce the desired 1-bromo-2-phenylethene. The product of the synthesis of trans-cinnamic acid by microwave heating was determined by 1 NMR to be trans-cinnamic acid (the 1 NMR spectrum for the product can be found in Figure 11). Impurities of ethanol and acetone were also identified. The reference 1 NMR spectrum for trans-cinnamic acid can be found in Figure No IR spectrum was obtained. The melting point of the product ( C) matches the value for trans-cinnamic acid (133 C). 4 The product of the microwave heating synthesis of 2,3-dibromo-3-propionic acid was determined by 1 NMR to be 2,3-dibromo-3-propionic acid (the 1 NMR of the product can be found in Figure 12). The reference 1 NMR spectrum for 2,3-dibromo-3-propionic acid can be found in Figure No reference thin film IR spectrum could be found. Both aromatic C- stretches and alkane C- stretches were observed in the IR spectrum of the product (seen in Figure 13), which supports the conclusion that the product is 2,3-dibromo-3-propionic acid. 6 The melting point of the product ( C) is close to the reference value for 2,3-dibromo-3-propionic acid (200 C). 5 The product of the synthesis of 1-bromo-2-phenylethene by microwave heating was found to be a mixture of trans-1-bromo-2-phenylethene and cis-1-bromo-2-phenylethene by 1 NMR, with a ratio of 4.55:1 trans:cis. Impurities of ethanol, dichloromethane, water, and acetone were also

15 15 identified. The 1 NMR of the product can be found in Figure 14. The reference spectrum for 1- bromo-2-phenylethene can be found in Figure The reference IR of 1-bromo-2-phenylethene can be found in Figure The product of the synthesis of trans-stilbene by microwave heating was found by 1 NMR to be a mixture of trans-stilbene and cis-stilbene, with a ratio of 1.64:1 trans:cis. The 1 NMR of the product can be found in Figures 16 and 17. Impurities of diethyl ether, water, and hexane were also identified. There are a few observations that do not agree with the assignment of the product as trans and cis-stilbene. First of all, the chemical shifts of the product are not in strong agreement with those of trans and cis-stilbene. The reference 1 NMR spectra of trans-stilbene and cis-stilbene can be found in Figures 24 and 25, respectively. 5 Secondly, this determination required an assignment of peaks that appear to be a doublet to a hydrogen that must be split into a triplet of triplets ( d in Figure 17). Finally, the melting range of the product ( C), although it contains the reference melting point of trans-stilbene (124 C), is very large. 4 This may have been caused by the presence of unreacted phenylboronic acid, which, having a melting point of C, would have made the melting point of the product higher. 4 The reference thin film IR spectra of trans-stilbene and cis-stilbene can be found in Figures 26 and 27, respectively. 3 Also, the yield of the final reaction to synthesize trans-stilbene was 160%. This can be at least partially explained by the presence of a large water impurity. Comparing the ratios of trans-stilbene to cis-stilbene (1.64:1) with that of trans-1-bromo-2- phenylethene to cis-1-bromo-2-phenylethene (4.55:1) produces strange results. ne would expect the ratio of trans:cis to be even higher in the stilbene product. This is because the destabilizing steric effect in the cis product would be much larger for stilbene than for 1-bromo-2-phenylethene. owever, these ratios are similar enough that they could be at least partially be explained by statistical error.

16 16 By comparing the relative yields and purities (as determined by melting point) of the products of the microwave heating syntheses to those of the traditional heating syntheses, the advantages of microwave heating are evident. Each of the microwave heating syntheses produced higher yields than their traditional methods equivalents, and where applicable, the melting point was closer to the reference value in the microwave syntheses than in the traditional heating syntheses. CNCLUSIN Total synthesis is employed by chemists in order to produce complex molecules from relatively simple starting materials. Microwave heating is more useful in total synthesis than traditional heating methods because it is more efficient and more environmentally friendly. In this experiment, the total synthesis of trans-stilbene was performed, first using traditional methods, and then using microwave heating. Total synthesis is useful in organic chemistry because it allows one to create complex molecules from simple starting materials. In this experiment, the total synthesis of trans-stilbene was performed in two different ways: the first used traditional methods of heating, and the second used microwave radiation to supply energy to the reaction more efficiently. The first reaction in the traditional methods experiment was to synthesize trans-cinnamic acid. The product was verified to be trans-cinnamic acid with a yield of 50.0% and a melting point of C. The second reaction in the traditional methods experiment was to synthesize 2,3- dibromo-3-phenylpropionic acid. The product was verified to be 2,3-dibromo-3-phenylpropionic acid with a yield of 22.7% and a melting point of C. The third reaction was to synthesize trans-1-bromo-2-phenylethene. This reaction was unsuccessful in producing the desired product. It is unknown why the reaction failed. The final reaction to synthesize trans-stilbene could not be performed, and the total yield of trans-stilbene was 0.0%.

17 17 The first reaction in the experiment employing microwave radiation was to synthesize transcinnamic acid. The product was verified to be trans-cinnamic acid with a yield of 99.4% and a melting point of C. The second reaction in the experiment was to synthesize 2,3- dibromo-3-phenylpropionic acid. The product was verified to be 2,3-dibromo-3-phenylpropionic acid with a yield of 39.9% and a melting point of C. The third reaction was to synthesize 1-bromo-2-phenylethene. The reaction successfully produced a 4.55:1 ratio of trans-1- bromo-2-phenylethene: cis-1-bromo-2-phenylethene with a yield of 41.4%. The final reaction was to synthesize trans-stilbene. The product was determined to be a mixture of trans-stilbene and cisstilbene, with a ratio of 1.64 trans:cis, a yield of 160%, and a melting point of C. The total yield of trans-stilbene by microwave heating was 26.3%. i 1 Multistep Synthesis of Trans-Stilbene from Benzaldehyde. Chem 344 Spring 2007 Lab Manual. 2 Burrmann, Nikki. Chem 344 Total Synthesis Discussion. April 11, SDBS, 4 Chemfinder, 5 Sigma-Aldrich, 6 Infrared Spectroscopy Regions of Bond Stretching Frequencies for Various Functional Groups, Chem 344 Spring 2007 Lab Manual.