Basai Lab 10 Williamson Ether Synthesis PDF

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Chem 233

Yangbasai Dong

Williamson Ether Synthesis: Preparation of Phenacetin from Acetaminophen Background and methods: Ether is widely used in our daily life, especial in medical field. Therefore, the Williamson Ether Synthesis is a very key process. Diethyl ether was once used as an inhalation anesthetic, but the side effects were unpleasant, and the recovery was often accompanied by nausea and vomiting. Diethyl ether was eventually replaced by halogenated ethers. Enflurane was introduced in the mid-1970s and was eventually replaced by isoflurane. The use of isoflurane is now also declining as the newer generation ethers (sevoflurane and desflurane) are being more heavily used. Inhalation anesthetics are introduced into the body via the lungs and distributed by the circulatory system. They specifically target the nerve endings in the brain. Nerve endings, which are separated by a synaptic gap, transmit signals across the gap by means of small organic compounds called neurotransmitters In this lab, Phenacetin was prepared by the Williamson ether synthesis using acetaminophen and iodoethane in the presence of a base. The phenolic hydrogen is sufficiently acidic to be deprotonated by potassium carbonate to allow the reaction to occur. The product was then purified by recrystallization and characterized by TLC, melting point analysis, and IR spectroscopy.

(Lab Manuel)

For this particular lab, it revolved around ethers. Ethers play a crucial role in organic chemistry. Ethers typically have an oxygen atom in the middle of the structure along with two carbon chains, which are on the sides of the oxygen atom. Reactions that make ethers provide an advantage to modern research because it contains valuable data for creating useful molecules. Compound Acetaminophe

Molar Mass 151.17 g/mol

Density (g/mL) N/A

Mass/Volume 1.3 g

mmol 8.60

Equivalent 1.00

n K2CO3 Iodoethane 2-butane

138.21 g/mol 155.97 g/mol 72.06 g/mol

N/A 1.94 g/mL .805 g/mL

2.5 g 1.0 mL 15 mL

18.1 12.4 167

2.10 1.44 19.4

Chemical Theory and Analytical Techniques: The Williamson ether synthesis is an organic reaction, forming an ether from an organohalide and an alcohol. This reaction occurs in two steps: deprotonation and SN2 reaction. The first step consists of forming an alkoxide ion by the deprotonation of the alcohol by a chosen base. The second step occurs as an SN2 substitution reaction. In the second step, the alkoxide acts as the nucleophile and the alkyl halide acts as the electrophile

(Lab Manuel) In addition, despite the effectiveness of the William ether synthesis, there are certain restrictions to address. The first step is an acid-base reaction and because of the alcohols’ high pka value of 16-18, it does not satisfy the deprotonation requirements for the first step. It is to say that a strong base should be picked because if a very weak base is used, it will not proceed to

the second step of the reaction. Moving along to the second step, the SN2 mechanism, any limitation involved in this step also applies to the Williamson ether synthesis. In this step, the most important decision is the choice of alkyl halide. SN2 reactions work best with sterically unhindered alkyl halides because the nucleophile has to attack the electrophilic carbon at the same time as the carbon-halide is fragmented. It is to say that methyl and primary alkyl halides react more quickly than secondary alkyl halides, and generally, tertiary alkyl halides do not react under this reaction. It should be mentioned that the Williamson reaction often competes with the basecatalyzed elimination of the alkylating agent, and the conditions of the leaving group, as well as the reaction conditions like temperature and solvent can have a strong effect on which is favored. In certain occasions, some structures of the alkylating agent can be prone to elimination. Typically, the Williamson ether synthesis is inefficient when secondary alkyl halides are used and tertiary alkyl halides do not produce ether products. To provide better results in this lab, factors that increase the rate of SN2 should be considered. It is crucial to note that the rate is dependent on two main factors: carbon oxygen bond formation and carbon-halogen bond breakage. The nucleophile will always be an alkoxide and weaker bases make better leaving groups: alkyl iodides > alkyl bromides > alkyl chlorides. Also, the type of solvent, as previously mentioned before, can affect the rate of the reaction. SN2 reactions proceed quicker when polar, aprotic solvents are used because protic solvents hydrogen and solvate the nucleophile which hinders the approach to the electrophile. Known solvents for the Williamson ether synthesis are as follows: dimethyl sulfoxide, dimethyl formamide, acetonitrile, and acetone.

There were various reagents used in this lab: acetaminophen, potassium carbonate, iodoethane, and 2-butanone. A brief discussion of each reagent is fundamental for the understanding of this lab. Acetaminophen was found to be the limiting factor in this lab and it had the major role. Potassium carbonate was used as a drying agent to get rid of unwanted impurities. Because iodide is a good leaving group, iodoethane is an excellent ethylating agent and it was also used as the hydrogen radical promoter. 2-butanone is the precursor to methyl ethyl ketone peroxide, which essentially served as a catalyst for this lab to speed up the chemical process. Moreover, there were additional characterization tests conducted for this lab. A TLC was obtained before and after the Williamson ether synthesis completion to determine whether acetaminophen or phenacetin was more polar, which was based on Rf values. After the competition of the reaction, the melting point of the final product was obtained along with an IR reading. Particularly for the IR reading, it was necessary to see that the OH group disappeared and an ether group was formed, which highly determined the experimental success of this lab In the use of infrared spectroscopy (IR), vibrations caused by the stretching, bending and twisting of the molecule’s bonds is measured. The infrared spectrum is measured in wavenumber in cm-1 where a span from 600 cm-1 to 4000 cm-1 is used for functional groups. Depending on the amount of infrared absorbed in the stretch, bend, or twist, a peak for percent transmittance is obtained. This wavenumber should fall within a certain range of a particular functional group which can be used to identify the presence of that functional group.

(SparkNotes-IR data) Recrystallation is useful for purifying solids where the solid is dissolved in an appropriate solvent at an elevated temperature allowing the crystals to re-form on cooling, so that any impurities remain in the solution. The choice of solvents should allow for reasonable solubility when the solvent is at a high temperature and insoluble when the temperature is decreased. The method to testing the melting point was to pack a few grains of the unknown solid into a testing glass then insert it into the melting point machine. The sample is observed through a magnifier on the machine. The melting point machine would slowly apply more heat to the sample until the sample begins to melt, at which point you would observe the thermometer reading. TLC will be used to analyze the progresse of the reaction. In TLC the stationary phase is bound to a solid support plate, Aluminum with a Silicon coating in this experiment. The plate is placed in a developing chamber with the mobile phase lining the bottom with a small amount of the sample above the mobile phase. A pencil is used to mark the starting point of the sample then again to mark the ending point of the mobile phase and the spots of the separated sample. The TLC uses capillary action to pull both the solvent and the compounds up the plate.

Experimental Procedure: 1. The experiment started by obtaining four tablets of 325 mg strength Tylenol and crushing it by a mortar and a pestle. 2. The resulting powder was added in a 50 mL round bottom-flask. To the acetaminophen, 2.5 g of potassium carbonate, 15 mL of 2-butanone, and one boiling stone was added. The reaction was refluxed for about an hour.

3. After the reflux was complete, the reaction mixture was cooled below its boiling point and the solids were vacuum filtered.

4. The solids were washed 2X with 5 mL of ethyl acetate. Then a TLC was taken before the mixture work up. The TLC contained three lanes: 1.) Pure acetaminophen; 2.) pure acetaminophen + reaction mixture (co-spot); 3.) reaction mixture. 5. The TLC was eluted with 4:1 ethyl acetate: methylene chloride. The TLC was then measured under the UV to circle the spots observed.

6. The filtrate was transferred to a separatory funnel and the solution was extracted with a.) 20 mL of 5% NaOH (aq) and b.) 20 mL of water. 7. The cloudy organic layer was transferred to a clean Erlenmeyer flask and dried using sodium sulfate. 8. The flask was swirled as the sodium sulfate was added and the phenacetin became clear. The dried phenacetin was decanted into a 50 mL round-bottom flask and the solvent was removed using a rotary evaporator. 9. The resulting solid was recrystallized by using a minimum amount of hot ethanol. Once all the phenacetin was dissolved, the solution was removed from the heat and was cooled to room temperature. 10. The final product was filtered and dried with the vacuum apparatus. The final product was weighed and the percent yield was calculated. 11. The final part of the lab was the characterization of the product. It was characterized by TLC, melting point analysis, and IR spectroscopy. 12. For the TLC, a small amount of the solution was mixed with ethyl acetate and the same solvent system was used as the reaction mixture. Finally, the Rf values of all

spots were calculated.

Data Acquisition/Presentation Compound Acetaminophe

Molar Mass 151.17 g/mol

Density (g/mL) N/A

Mass/Volume 1.3 g

mmol 8.60

Equivalent 1.00

n K2CO3 Iodoethane 2-butane

138.21 g/mol 155.97 g/mol 72.06 g/mol

N/A 1.94 g/mL .805 g/mL

2.5 g 1.0 mL 15 mL

18.1 12.4 167

2.10 1.44 19.4

Relevant Equations: Percent Yield = Percent Yield Calculation

Actual Yield Theoretical Yield

x

100

Phenacetin and acetaminophen are in 1:1 mole ratio equivalents for this reaction.

Theoretical yield:

(

( )

)(

)

Starting weight 1mol phenacetin g ∗ ∗ 179.22 =¿ mol 1mol acetaminophen g 151.17 mol

theoretical yield

1.3 g acetaminophen 1 mol phenacetin g ∗( ∗(179.22 =1.54 g phenacetin ( 1mol phenacetin ) ) mol ) 1 mol acetaminophen 151.17 g/mol

Experimental yield = 0.56g phenacetin

Percent yield:

yield ∗100=Percent yield ( experimental theoretical yield ) 0.56 g ∗100=36.36 % yield 1.54 g

TLC data: All points Rf of reactant 0. 24/0.72=0.333 Rf of product 0.27/0.72=0.375 IR spectrum data: Substance

Wavenumber (cm-1)

Functional Group

Phenacetain

3280

N-H stretch

1479-1504.96

C=C (Benzene ring)

Melting Point:

actual melting point: 134ºC Observed melting point of phenacetain: 125-130ºC Data Analysis: The theoretical yield for the reaction was 1.54 g, and the experimental yield was 0.56g. With the theoretical and experimental yield obtained, the percent yield was calculated and found to be 36.36 %. The limiting reagent was acetaminophen because it contained the least number of moles from the starting reagents. There were various human errors involved in this lab. The hydroxyl group located in the acetaminophen compound is more polar, making acetaminophen more polar. Our strip indicated that the co-spot, the product spot, and the reactant spot, all had the same Rf values. This would mean that there is only a little difference in polarity between the products and reactants. The IR should clearly show a lack of hydroxyl group and an appearance of an ether

group, which was the case for this experiment. The ether group was observed to be at 1479and the amide group (N-H bond) was observed at 3280. Conclusion: In this lab, the Williamson ether synthesis was used to convert acetaminophen to phenacetin. The theoretical yield for the reaction was 1.54 g, and the experimental yield was 0.56g. With the theoretical and experimental yield obtained, the percent yield was calculated and found to be 36.36 %. The limiting reagent was acetaminophen because it contained the least number of moles from the starting reagents. There were various human errors involved in this lab. One immediate source of error could have been when the product was emptied out of the round bottom flask. The product could have been stuck to the side of the flask and Excess water used to bring it down could have also affected the product, which would have caused the weight

to increase. Another minor error could have occurred during the vacuum filtration. The product could not have been dried enough, which could have also led to an excess amount of water in the product. In addition, some of the product could have remained in the beaker after recrystallation, which could have caused the dramatic decrease in the final percent yield. After the final product was obtained, some characterizations were taken into account: TLC, melting point, and IR. The Rf values of phenacetin are expected to have a higher Rf value. This is so because phenacetin is slightly less polar than acetaminophen and the only difference between the two molecules is that phenacetin has a ethoxide group while acetaminophen has a hydroxyl group. The hydroxyl group located in the acetaminophen compound is more polar, making acetaminophen more polar. Our strip indicated that the co-spot, the product spot, and the reactant spot, all had the same Rf values. This would mean that there is only a little difference in polarity between the products and reactants.

The melting point. The melting point of the product was observed through the use of a melting point apparatus. The theoretical melting point of phenacetin is 134 degrees Celsius. The phenacetin created through the reaction could be considered fairly pure because the melting point was observed to be close to the theoretical melting point, 125-130 degrees Celsius the slightly lower milting point might be a result of the sample being wet. After the melting point, the IR spectra was observed. It was important to note the diagram that was placed in the introduction part of this lab because it outlined the before and after structure of the compounds involved. From that diagram, it can be seen that an OH functional group is replaced with an ether functional group and everything else from the original compound stayed the same. Because of the change of the OH- group, the IR should clearly show a lack of hydroxyl group and an appearance of an ether group, which was the case for this experiment.

The ether group was observed to be at 1241.58 and the amide group (N-H bond) was observed at 3280. Overall, phenacetin was prepared by the Williamson ether synthesis using acetaminophen and iodoethane in the presence of a base. The phenolic hydrogen is sufficiently acidic to be deprotonated by potassium carbonate to allow the reaction to occur. The product was then purified by recrystallization and characterized by TLC, melting point analysis, and IR spectroscopy. The percentage yield is relatively low. However, by characterization, the purity of my product was high.

Reference(s): Gilbert, J.C., Experimental Organic Chemistry: A Miniscale and Macroscale Approach, Gilbert & Martin, Belmont, 2015, 4th Ed., pp. 55-58, 123-125, 192-202. SparkNotes. Organic Chemistry 1 UV/Vis Spectroscopy. 2015. Retrieved from http://sparkcharts.sparknotes.com/chemistry/organicchemistry1/section13.php McQuade, Lindsey. Organic Chemistry Lab Manual and Course Materials, 2015, 4th Ed.

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