Williamson Ether Synthesis of Phenacetin

Procedure
The procedure stated in Chem 2120 experiment 6 Williamson Ether Synthesis of Phenacetin laboratory manual was followed without any major changes.
Data and results Compound Amount used MW (g/mol) Moles Stoichiometry/Comments acetaminophen 0.354 g 151.16 2.34 x 10-3 limiting reagent ethyl iodide 0.3mL 155.97 3.75 x 10-3 1.6 equiv 's sodium ethoxide 2.6mL 68.05 3.3 x 10-2 catalyst, reaction solvent crude product obtained: phenacetin 0.32g 179.22 1.78 x 10-3 yield = 76.06%
Recrystallized product: phenacetin 0.16g 179.22 8.92 x 10-4 yield = 38.12%

Table 1-Reagent and yield Data for the synthesis of Phenacetin
Calculations
Crude phenacetin:
Mass of crude phenacetin product = Crude + watch glass mass - Pre-weighed watch glass mass =27.44g-27.12g = 0.32g
Recrystallized phenacetin:
Mass of recrystallized phenacetin product = Crystals + watch glass mass - Pre-weighed watch glass mass = 31.27g-31.11=0.16g

Theoretical yield Acetaminophen:
Moles = = 2.34 x 10-3 yield = {mol product / (mol limiting reagent x 1 mol product / 1 mol reactant)} x 100%) Yield for crude phenacetin obtained = * 100% = 76.06% Yield for recrystallized phenacetin = *100% = 38.12%
For this experiment, acetaminophen was the limiting reagent; hence the crude product gave a yield of 76.06% while the recrystallized product gave a yield of 38.12%.

Physical appearance for products: On addition of acetaminophen to sodium ethoxide there was a brown coloured solution formed. The crude product obtained was observed to have a beige appearance, and the crystals formed where powdery in texture. On the other hand, the pure recrystallized product gave a shiny white colour appearance, with its crystals being needle like in texture.
TLC results:

Legend: i= acetaminophen standard ii= phenacetin standard iii = Recrystallized product

Figure 1: TLC plate with acetaminophen and phenacetin standard, experimental phenacetin spots.

Table2- Qualitative analysis using Chromatography. The Rf values of the standards and re-crystallized sample. The TLC results seen in table 2 above were used to determine the true identity of the experimental product. The standard acetaminophen sample spot had a retention factor value of 0.16, the standard phenacetin sample spot had a retention factor value of 0.27, and the spot done for the crude and re-crystallized product gave a retention factor value of 0.31 and 0.27 respectively. The Mel Temp temperature had a range of 134-1370C and the standard documented melting point for Phenacetin is 133-1360C.
Discussion:
Sodium ethoxide (NaOEt) was used to react with acetaminophen. An alternative procedure would include use of weak base potassium carbonate (K2CO3, pKa = 10.3). K2CO3 is anhydrous, and the Williamson ether synthesis majorly involves the removal of a proton from an alcohol using an SN2 nucleophilic reaction. Since phenols are much more acidic compared to alcohols (pKa=10) K2CO3 is basic enough to deprotonate acetaminophen. When potassium carbonate is present in a solution with acetaminophen it generates the conjugate base of acetaminophen which is powerful enough to pull apart iodoethane. Iodide is left in solution while the CH3CH2 is bonded to acetaminophen and phenacetin is the product. However, Williamson ether synthesis process requires a strong base such as sodium hydride or sodium metal.
Recrystallization requires careful techniques which if not followed properly could lead to loss of recrystallized product. Some loss, resulting from transferring solids from one container to another and leaving a little material behind, cannot be avoided. But it can be ignored by improving the techniques employed in transferring the product. Also, because of the solubility of the solid in the recrystallization solvent, even at low temperatures, any unnecessary prolonged contact with recrystallization solvent, especially if the solvent is not ice-cold will result in loss of product. For that reason, the following problems commonly occur: if too much solvent is added in the recrystallization, a poor or no yield of crystals will result. If the solid is dissolved below the boiling point of the solution, too much solvent will be needed, resulting in a poor yield. In order to obtain optimal results, a minimum of near-boiling solvent should be used for the recrystallization, and a minimum of ice cold solvent should be used for the rinse.
The recrystallized product was considered to be pure due to the fact that, when ran through the TLC plate, an Rf value of 0.27 was obtained which is similar to the Rf value of the standard phenacetin (0.27) that was given in the lab. Acetaminophen produced Rf value of 0.16, its low Rf value is due to its affinity to the stationary phase as its comparatively more polar than phenacetin. Acetaminophen consists of hydroxyl group which is more polar than phenacetin consisting of ethoxide group. This causes acetaminophen to travel much slowly up the column; phenacetin is more soluble and hence travels faster up the column (less affinity to stationary phase) in the mobile phase. When the Mel-Temp apparatus was used to observe the melting point of the recrystallized product, it was discovered that the melting point of the experimental phenacetin (134-137oC) was just a fraction off the literature melting point of phenacetin (133-136 oC), the mel range of the experimental product is narrow same as the literature melting point thus revealing the purity and the identification of the phenacetin product attained in this experiment.

Phenacetin can also be made by the Schotten-Baumann reaction which is an organic reaction used to convert an acyl halide or anhydride to an amide if reacted with an amine and base. In this reaction there is use of added base to drive the equilibrium in the formation of amides from amines and acid chlorides.
The acylation of amines with carboxylic acid chlorides leads to the production of one equivalent acid, which will form a salt with unreacted amine and diminish the yield. The addition of an additional equivalent of base to neutralise this acid is a way to optimise the conditions. Normally, aqueous base is slowly added to the reaction mixture.

References
Schotten-Baumann reaction ~ Name-Reaction.com. (n.d.). Retrieved March 11, 2014, from http://www.name-reaction.com/schotten-baumann-reaction

Drugs from group of esters and amides aromatic carboxylic acids,derivatives of p-aminophenol. (n.d.). Retrieved March 11, 2014, from http://intranet.tdmu.edu.ua/data/kafedra/internal/pharma_2/classes_stud/en/pharm/prov_pharm/ptn/pharmaceutical%20chemistry/3%20course/12%20Pharm.analysis%20of%20esters%20and%20amides%20of%20aromatic%20carboxylic%20acids%20and%20derivatives%20of%20p-aminophenol.htm

References: Schotten-Baumann reaction ~ Name-Reaction.com. (n.d.). Retrieved March 11, 2014, from http://www.name-reaction.com/schotten-baumann-reaction Drugs from group of esters and amides aromatic carboxylic acids,derivatives of p-aminophenol. (n.d.). Retrieved March 11, 2014, from http://intranet.tdmu.edu.ua/data/kafedra/internal/pharma_2/classes_stud/en/pharm/prov_pharm/ptn/pharmaceutical%20chemistry/3%20course/12%20Pharm.analysis%20of%20esters%20and%20amides%20of%20aromatic%20carboxylic%20acids%20and%20derivatives%20of%20p-aminophenol.htm