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Lab 10: Williamson Ether Synthesis: Preparation of Phenacetin From Acetaminophen Zeba N. Siddiqui (Partner: Keti Berberi) November 12, 2014

Methods and Background: The goal of this lab is to prepare Phenacetin by the Williamson Ether Synthesis using Acetaminophen and Iodoethane in the presence of a base, Figure 1. Acetaminophen is the active ingredient in Tylenol. The reaction occurs because of the acidity of the phenolic hydrogens which will be deprotonated by potassium carbonate. The product, Phenacetin, then will be purified by recrystallization and then characterized with Thin-Layer Chromatography (TLC), melting point analysis and Infrared (IR) Spectroscopy. Phenacetin is an older analgesic first used for pain relief, like Acetaminophen, and to reduce fevers. It was later banned because it caused cancer and kidney diseases. Table 1 displays the reaction table of the compounds used.

Figure 1 Williamson Ether Synthesis of Acetaminophen to Phenacetin with the use of 2-Butanone and Potassium Carbonate.

Heating under reflux, Figure 2, is defined by a reaction mixture being heated at its boiling point in a flask with a reflux condenser, Figure 3, which allows continuous return of the volatile materials to the flask. In such, no solvent or reaction is removed or lost during the heating. It should also be noted that because the reaction is conducted at higher temperatures, less time is required for the completion of the reaction.

Figure 2 Heating under Reflux

Figure 3 Reflux Condenser

Extraction is the common technique for isolating and purifying a compound. The process of extraction involves transferring a solute from one solvent into another because of the higher solubility in the latter. The two solvents, however, must be immiscible and form two distinct layers; one layer being aqueous the other the organic layer. It is also the method used to separate liquids of different densities. In saying so, the organic layer is denser than the aqueous layer, hence the organic layer is at the bottom while the aqueous layer floats above on top. Separatory funnels, Figure 4, are used to carry out this procedure.

Figure 4 An Illustration of a Separatory Funnel with a separation of Organic Layer and Aqueous Layer (Can be reversed).

Nucleophilic substitution is the substitution of one group for another at a saturated sp3 hybridized carbon. It is usually different functional groups that interconvert with each other, known as

nucleophilic aliphatic substitution. A nucleophile, represented as Nu:, is a nucleus-loving neutral or negatively charged molecule having Lewis base character that attacks the carbon at the opposite end of the leaving group, essentially substituting one group for another. The nucleophile also donates a lone pair of electrons to the carbon to make up for the loss of electrons that the leaving group takes with it. Figure 5 depicts the equation.

Figure 5 Nucleophilic Aliphatic Substitution

Nucleophilic substitution divides into two different types of mechanisms; and these mechanisms are performed depending on the structure of the alkyl group that the leaving group (L) is attached to. One of the mechanisms is a Substitution Nucleophilic Unimolecular Mechanism, or SN1 mechanism for short, Figure 6. This is a two-step reaction in which there is a carbocation intermediate. The carbocation intermediate is formed in one single step and it is the only process occurring at that step. The single rate-determining step, carbocation formation, is the slowest step of the whole reaction. Since the rate-determining step occurs in a single step, it is known as a mechanism unimolecular. SN1 reactions only occur when the alkyl group is tertiary of secondary. This is due to the reason that tertiary and secondary alkyl halides are stable enough to form carbocation intermediates when the leaving group leaves. This corresponds to the fact that more highly substituted carbons can form a more stable carbocation, as the carbocation is stabilized by those substituents.

Figure 6 SN1 Mechanism

The second mechanism is the Substitution Nucleophilic Bimolecular Mechanism, SN2 mechanism, Figure 7. SN2 mechanisms are designated for primary substituted carbons, such as primary alkyl halides. The mechanism is a single-step reaction where there are no carbocation intermediates because the primary alkyl halides are too unstable to form a carbocation intermediate. During single step, the nucleophile attacks the backside of the carbon as the leaving group detaches from that same carbon. Since both of these occur simultaneously in one step, which is also the rate-determining step, it is call a bimolecular substitution.

Figure 7 SN2 Mechanism

Determining whether a substitution reaction is SN1 or SN2 does not only depend on the degree of substitution at that carbon. There are other factors involved, such as steric hindrance. If the carbon has large alkyl groups attached to it, then steric strain is created, making it harder for the nucleophile to attack the carbon on the side opposite of the leaving group via SN2. This is an instance where the SN1 mechanism is favored because it is more stable due to having less steric strain in the molecule. A Rotary Evaporator, Figure 8, solvents are removed under reduced pressure. It is designed for rapid evaporation of solvents without bumping. A variable speed motor is used to rotate the flask containing the solvent being evaporated. While rotation is occurring to the flask, a vacuum is applied and the flask is heated. The rotation spreads a thin film of solution on the inner surface of

the flask. This is to accelerate evaporation which also prevents bumping of the contents within the flask.

Figure 8 Rotator Evaporator

TLC also helps separate mixtures into their individual components. This method is used with smaller sample sizes and utilizes TLC plates. These plates are thin sheets, one side coated with silica gel and the other side layered with aluminum, and example can be found in Figure 4. Drops of the experimental extract, a mixture of the extraction and an authentic sample, and a pure authentic sample are to be placed on the plate and into a mixture of mobile phase composition; the experiment utilizes a 4:1 mixture of Ethyl Acetate/Methylene Chloride. The solvent would rise up if in mobile phase, and stay still if in stationary phase. Polarities are important in determining how well a pure substance separates from a mixture. Silica gel contains an alcohol (OH) functional group making it a polar molecule. As a result, any polar molecule that comes across the silica gel will attach to it and become immobile. On the other hand, if a nonpolar solvent is used, then nonpolar molecules will interact with the nonpolar solvent and travel through the stationary phase, the silica gel. Thus, the more polar the sample is, the slower it will move up the plate; consequently, the less polar, the faster the compound exits the plate. A comparison of the distance traveled by all three spots, authentic sample, co-spot, and authentic product, will be performed, Figure 9.

Figure 9 An example of a Thin Layer Chromatography (TLC)

Pure compounds are homologous samples comprising only of molecules with the same structure. However, possible contamination may still be evident in pure compounds. With these additional impurities, incorrect structural characterizations and would produce false conclusions. The process of recrystallization involves dissolving the solid in an appropriate solvent at an elevated temperature and allowing the crystals to reform on cooling, so that any impurities remain in solution. An alternate method involves melting the solid in the absence of the solvent then allowing the crystals to reform so that the impurities are left in the melt. Almost all solids are more soluble in hot than in cold solvent, something solution crystals take advantage of. For illustrate, if you were to dissolve the solid in hot solvent, an amount insufficient to dissolve the solid in cold solvent, then crystals should form when the hot solution is allowed to cool. The extent of the solid precipitates is dependent upon the solubility difference in the particular solvent at temperatures between the extremes used. The upper extreme is relied upon the boiling points while the lower limit depends on experimental convenience. Impurities observed in the original solid mixture that has dissolved and has remained dissolved after the solution has cooled, isolation and separation of the crystals that have formed should ideally provide pure material. Opposing the above, impurities may not dissolve in the hot solution and would need to be removed by filtration before the solution is cooled. Hypothetically, crystal formation is more pure than the original solid mixture. Often, the solid is not pure after crystallization. Melting point is the method used to identify the purity. To reiterate, the steps to

recrystallization is as the following: selection, dissolution, decoloration, formation, isolation, and drying. Figure 10 depicts recrystallization.

Figure 10 Recrystallization

Melting point is the point where a solid would melt. It is psychical property defined as the temperature at which the phases of a liquid and solid occur in equilibrium without an alteration of temperature. With saying that, the sample would not liquefy at a single temperature point, however, over a temperature range in which the solid begins to melt and then is transformed into a liquid. If the crystalline sample is pure, then it should liquefy over a narrow or sharp range. The start of a solid melting is characterized as a softening, which describes the shrinking of the solid sample. However, it is not always possible to observe this softening, so the use of a range is appropriate. For example, an experimental compound recorded a melt at 115◦C. That would be an improper number, a range is needed at, for example, 114-116◦C. A common method to determine melting point is the use of a capillary tube, found in Figure 11. In this method, an organic solid is placed in the capillary tube. A comparison between the acquired temperature values with the standard values can be found in an index or catalog which will identify an unknown compound.

Figure 11 Capillary Tube

Ethers important compounds consisting of an oxygen atom bound to two R groups. Ethers are commonly found in a natural products such as melatonin and vitamin E. The Williamson Ether Synthesis is a widely used synthetic route to ethers because of simplicity and broad applicability to multiple alcohol and alkyl halide precursors. The reaction proceeds in two steps. The first step is deprotonation of the alcohol by a suitable base to form an alkoxide ion. The second step is an SN2 substitution reaction where the alkoxide acts as the nucleophile and the alkyl halide acts as the electrophile. Figure 12 depicts this synthesis.

Figure 12 Williamson Ether Synthesis

Chemical Name

Formula

Acetaminophe n

C8H9NO2

MW (g/mol ) 151.17

Phenacetin

C10H13NO2

179.22

Potassium Carbonate

K2CO3

138.21

2-Butanone

C2H5CCH3

72.11

BP (◦C) MP (◦C) Density (g/mL) BP: n/a MP: 170 Density: 1.293 BP: decomposes MP: 134 Density: n/a BP: decomposes MP: 891 Density: 2.29 BP: 76.64◦C MP: 86◦C Density: .805

Physical State

Safety Hazards

Solid

Wear Gloves

Solid

Wear Gloves

Solid

Wear Gloves

Liquid

Flammable--Wear Gloves

Table 1 Reaction Table

Experimental Procedures: Williamson Ether Synthesis Procedure. Fist, crush four tablets of 325mg strength Tylenol, which is 1.3g of acetaminophen. Crush with a mortar and pestle and add the resulting powder to a 50mL round-bottom flask, Figure 13.

Figure 13 Mortar and Pestle

Add 2.5g of Potassium Carbonate, 15mL of 2-Butanone, and one boiling stone to the acetaminophen in the round-bottom flask. In the fume hood, add 1mL of iodoethane to the reaction mixture and then assemble a reflux apparatus, Figure 2. Reflux for one hour. After the time has completed, cool the mixture to below the boiling point and vacuum filter, Figure 14, the solids. Wash the solids twice with 5mL of ethyl acetate.

Figure 14 Vacuum Filtration

Next, take a TLC of the reaction. Three spots should be placed. One spot contains the pure acetaminophen, another is the pure reaction mixture, and the last spot, which should be placed in the middle, is the co-spot. The co-spot is the mixture of pure acetaminophen and the reaction mixture. Elute the TLC plate within a 4:1 mixture of ethyl acetate/methylene chloride. Examine under UV lights. Next, transfer the filtrate, from the vacuum filtration, into a separatory funnel. Extract the solution with 20mL of 5% NaOH and then 20mL of water, separately. After, transfer

the cloudy organic layer funnel into a clean Erlenmeyer flask. Dry the layer with the drying agent Sodium Sulfate. Swirl until the product, Phenacetin, is clear. Decant the dried product solution to a 50mL round-bottom flask. Remove the solvent using the rotary evaporation. Next, recrystallize the solid solution using the minimum amount of hot ethanol. Keep in mind to always have the solution and ethanol hot. Once the product has dissolved, remove the solution from the heat and allow it to cool to room temperature. After, place solution in an ice bath. The liquid solution should become a solid. Filter the final product and dry vacuum. Weigh the final product and calculate the percent yield. Finally, characterize the product by another round of TLC, melting point analysis and IR Spectroscopy.

Data Acquisition: Compound

MW (g/mol)

d (g/mL) or M (mmol/mL)

mmol

Equivalents

n/a

Rxn Weight (g) or Volume (mL) 1.3g

Acetaminophe

115.17

8.60

1

n Potassium

138.21

n/a

2.5g

18.10

2.1

Carbonate Iodoethane 2-Butanone

155.97 72.06

1.94 0.805

1.0mL 15mL

21.40 167.60

1.4 19.5

Table 2 Reaction Table for Lab

Relevant Equations and Calculations %Yield = Actual Mass (g) x 100 Predicted Mass (g) Theoretical Mass = Starting Volume x Density x 1 x Reaction x MW Product = # grams 1 mL MW Reaction 1 mol %Error = [Theoretical Value – Experimental Value] x 100 [Theoretical Value] Retention Factor (Rf): Distance Traveled by the Substance (mm)

Distance Traveled by the Solvent (mm)

Limiting Reagent = Acetaminophen Theoretical Mass = 1.3g x

1 mol x 1molx 179.22g = 1.54g 151.17g 1 mol 1 mol

%Yield = 0.12g x 100 = 7.79% 1.54g

%Error = [1.54g – 0.12g] x 100 = 92.21% [1.54] TLC Plate #1: Acetaminophen (Rf): 17 mm = 0.5mm 35 mm Co-Spot (Rf): 17 mm = 0.5mm 35 mm

25 mm = 0.7mm 35 mm

Phenacetin (Rf): 25 mm = 0.7mm 35 mm TLC Plate #2: Phenacetin (Rf): 22 mm = 0.6mm 35 mm

Melting Point (◦C)

Experimental Value ~ 133

Actual Value 134

Table 3 Comparison of Experimental Melting Point and Actual Melting Point

Wavenumber (cm-1) 3073.41 1479.80 1265.28

Functional Group Aromatic Ring Nitrogen Group Ether

Table 4 IR Spectroscopy Peaks

Compound % Yield Rf Value Table 5 Results

Conclusion:

Acetaminophen n/a ~0.5mm

Phenacetin 7.79 % ~0.7mm (TLC #1) ~0.6mm (TLC #2)

The limiting factor, as seen in Relevant Equations and Calculations, is Acetaminophen. Throughout the experiment, Phenacetin was produced. TLC was performed after the first wash and before the extraction to check on the reaction. From here, it was discovered that Acetaminophen is more polar than Phenacetin. Traveling 0.2mm more than Phenacetin, Acetaminophen has a greater affinity towards the stationary phase, while the product was more nonpolar; thus observing a greater affinity towards the mobile phase when compared to Acetaminophen. A second TLC was performed to characterize the final product. In this plate, it was observed that the final product was closely related to the original TLC plate’s spot for the pure reaction mixture. However, the only difference was that in the TLC plate #1, the reaction had an Rf value of approximately 0.7mm while the second was about 0.6mm. This might have been due to remaining impurities, however, I believe it was due to the reaction not being complete enough to continue its travel up the mobile phase. The reaction was stopped to early because of the time crunch of lab. The percent yield obtained was 7.79%. The percent error was 92.21%. The minimum amount of percent yield, and the too high percent error due to a spilling of the reaction mixture. While trying to dry the mixture with the drying agent, a spill of over half the total solution was lost. To explain, the theoretical yield of Acetaminophen was 1.54g. When calculating the percent yield, the equation was 1.54g over the final products weight, which was 0.12g. The 0.12g should have been much higher if not for the loss of the product. To conclude, percent error was not due to left over impurities or other errors in the lab, the reason was a result of a spilling of the product, otherwise, the percent error would have been far less. It should also be understood that the percent error should not be 100% because Phenacetin synthesizes to form Acetaminophen, thus

Acetaminophen breaks down into Phenacetin. Percent yield should also not exceed 100% because of possible impurities not extracted or washed. The experimental melting point was one degree less than the actual melting point. Table 3 expresses the results. The experimental was achieved at approximately 133◦C compared to 134◦C of the actual temperature. The last characterization test was the IR spectroscopy. The final product had peaks to distinguish the functional groups of an aromatic ring, a nitrogen group and an ether. This can be seen in Table 4. These functional groups are appearances of the compound Phenacetin concludes that the reaction did, in fact, occur. Upon the completion of the reaction, it should, however, be noted that the solution often times doe not only contain the desired product, but also unwanted byproducts of the reaction. These compounds have to be removed in the process of isolating the pure product. Extraction and washing is the method used to completely isolate the desired product. Extraction removes the target compound from an impure matrix and washing removes impurities from the target compound. Extraction utilizes 5% NaOH. Thus, NaOH removes the product from any impurities.

Reference: Gilbert, J.C., and Martib, S.M., Experimental Organic Chemistry: A Miniscale and Microscale Approach, 4th Edition, Cengage Learning, Boston, MA, 2006. Landrie, C.L., and McQuade, L.E., Organic Chemistry: Lab Manual and Course Materials, 5th Edition, Hayden-McNeil, LLC, Plymouth, MI, 2016....