Phenacetin From Acetaminophen Using a Nucleophilic Attack Mechanism

Introduction

This work aimed to obtain Phenacetin from Acetaminophen using a nucleophilic attack mechanism. Reflux, ice-bath cooling and heating, and vacuum filtration procedures were used to complete the synthesis. Melting point values were instrumentally measured for the final product, and TLC chromatography and IR and NMR spectroscopy were performed to determine the analytical purity of the substance. The percentage yield of the product was 84.3%, which indicates that most of the substance was obtained, and the experiment can be considered a success.

Procedure

This experiment is based on the organic synthesis mechanism of Phenacetin, a drug used for antipyretic and analgesic effects. For this purpose, Acetaminophen (1.5 g) was placed in a 25-mL round-bottom flask entirely in a water bath; stirring was performed using a magnetic stirrer. Sodium hydroxide (4 mL) dissolved in ethyl alcohol was mixed with Acetaminophen and stirred intensively. A reflux device was attached to the flask at 150 °C for fifteen minutes, resulting in an amber coloration of the mixture; the mixture was cooled in a water bath until the liquid phase solidified. Then, pre-prepared bromoethane (0.75 mL) was added to the mixture dropwise, after which second reflux was performed. After cooling, the solid part of the substance was collected by vacuum filtration. In addition, a TLC plate with three points horizontally 1 cm from the bottom edge was used for the solution. On the first point, pure Acetaminophen was applied, on the second, the reaction mixture, and the third was used later. The solid particles were scrubbed after vacuum filtration, added to 4 mL of ethanol in an Erlenmeyer flask, and heated at 100-200 °C, resulting in a clear light brown color. After successive addition of 5 mL of water, the color of the solution changed to murky orange, and after heating to light peachy-amber. After cooling, the crystals of the substance were scrubbed, dissolved in ice water, filtered, and placed on point #3 in a TLC plate to perform chromatography.

Overall Reaction

The Mechanism

The reaction mechanism is based on removing a proton from the hydroxyl group of Acetaminophen with the NaOCH₃ participation (see Figure below). The excess electron density on oxygen attacks the alpha-carbon at the bromoethane by the nucleophilic mechanism, which leads to the displacement of NaBr and the formation of Phenacetin.

Yield of the Product

Final mass: 18.0599 g.

Mass of the vile: 17.1905 g

Mass of the Product: 0.8695 g.

Theoretical Yield:

C₈H₉NO₂ + NaOCH₃ + CH₃CH₂Br → C₁₀H₁₃NO₂ + NaBr + H₂O _{(no balance needed)}

(So, this is limiting reactant)

Hence, the final yield: (0.8695 g)/() = 84.3%