EXP.NO. 5 Synthesis Of Paracetamol

Paracetamol also known as acetaminophen or APAP, is a medicine used to treat pain and fever.  It is typically used for mild to moderate pain relief.  Evidence for its use to relieve fever in children is mixed .It is often sold in combination with other medications, such as in many cold medications.  In combination with opioid pain medication, paracetamol is also used for severe pain such as cancer pain and pain after surgery .It is typically used either by mouth or rectally, but is also available intravenously .Effects last between 2 and 4 hours. Paracetamol is generally safe at recommended doses.[ Serious skin rashes may rarely occur, and too high a dose can result in liver failure. It appears to be safe during pregnancy and when breastfeeding. In those with liver disease, it may still be used, but in lower doses.  It is classified as a mild analgesic . It does not have significant anti-inflammatory activity and how it works is not entirely clear .Paracetamol was first made in 1877. It is the most commonly used medication for pain and fever in both the United States and Europe. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system .  Paracetamol is available as a generic medication with trade names including Tylenol and Panadol, among others .

Chemical properties Paracetamol molecule polar surface area Paracetamol electrostatic potential map Paracetamol consists of a benzene ring core, substituted by one hydroxyl group and the nitrogen atom of an amide group in the para (1,4) pattern.[The amide group is acetamide (Ethan amide). It is an extensively conjugated system, as the lone pair on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the p orbital on the carbonyl carbon, and the lone pair on the carbonyl oxygen are all conjugated. The presence of two activating groups also make the benzene ring highly reactive toward electrophilic aromatic substitution. As the substituents are ortho, para-directing and para with respect to each other, all positions on the ring are more or less equally activated. The conjugation also greatly reduces the basicity of the oxygen's and the nitrogen, while making the hydroxyl acidic through delocalization of charge developed on the phenoxide anion.

Synthesis of Paracetamol In the laboratory, paracetamol is easily prepared by nitrating phenol with sodium nitrate, separating the desired p-nitro phenol from the ortho- byproduct, and reducing the nitro group with sodium boro hydride. The resultant p-aminophenol is then acetylated with acetic anhydride. In this reaction, phenol is strongly activating, thus the reaction requires only mild conditions nitration The industrial process is analogous, but hydrogenation is used instead of the sodium boro hydride reduction

Mechanism Of Reaction

Paracetamol is made by reacting 4-aminophenol with ethanoic anhydride (more commonly called acetic anhydride). This reaction forms an amide bond and ethanoic acid as a byproduct. When the reaction is complete the paracetamol is then isolated and purified. The synthesis of paracetamol can be broken down into 3 parts: Part 1 – mix the reactants together to form paracetamol. Part 2 – isolate crude paracetamol from the ethanoic acid and unreacted starting materials. Part 3 – purify paracetamol by recrystallisation

Mechanism Of Reaction The lone pair of electrons on the amine of 4-aminophenol attacks the C=O bond of acetic anhydride causing it to break. Nitrogen has a positive charge but regains electrons by losing a proton. The negative charge on the oxygen comes back in to reform the C=O bond. This causes the other C-O bond to break. The result is an amide bond formation and a carboxylic acid by-product.

Procedure 1. Add 2.1 grams of 4-aminophenol into the round-bottomed flask. 2. Using your 25 mL measuring cylinder, measure 18 mL of water and add this to the flask. Add a magnetic follower to the round-bottomed flask. 3. Carefully clamp the flask at the neck and position it in the metal Dry Syn block which should be placed on the stirrer hotplate. Stir the reaction mixture using a magnetic follower. Do not apply heat at this stage . 4-. Assemble the apparatus for reflux as shown in the diagram below. Tip: Do not clamp the condenser

5. Using a Pasteur pipette, measure 3 mL of ethanoic anhydride (also known as acetic anhydride) into a 10 mL measuring cylinder. Add this to your mixture by lifting the condenser and adding directly to the round-bottomed flask. 6. Replace the condenser and switch on the heat to your hotplate (set the dial to about 120°C). Make sure there is water going through your condenser. 7. The reaction is heated at reflux for 15 minutes, stirring continuously. The reaction mixture should become colorless. 8. After refluxing for 15 minutes, switch off the heat and carefully raise the round-bottomed flask away from the Dry Syn block using the boss and clamp. 9. Allow the flask to cool to room temperature. 10. On cooling, crude paracetamol should form in the round-bottomed flask.

11. filter the precipitate (using a Buchner funnel), washing with small amounts of cold, distilled water. 12. After drying, the crude product should be placed in a clean 100cm3 conical flask and recrystallized by heating until it just dissolves in approximately 20ml of water. Cool the flask in ice until crystals of the purified paracetamol appear. Filter the crystals under vacuum, dry in a warm oven and then record the melting point and compare with standard paracetamol tablets (~170oC). Repeat recrystalisation process to achieve a more purer product

Procedure Place 2g of the 4-aminophenol into a 150cm3 conical flask, add 15ml of water and stir the suspension vigorously (magnetic stirrer) for a few minutes. Add 2.2ml of ethanoic anhydride and continue stirring until the suspension dissolves and a precipitate (Paracetamol) eventually forms. After 10 minutes filter the precipitate (using a Buchner funnel), washing with small amounts of cold, distilled water. After drying, the crude product should be placed in a clean 100cm3 conical flask and recrystallized by heating until it just dissolves in approximately 20ml of water. Cool the flask in ice until crystals of the purified paracetamol appear. Filter the crystals under vacuum, dry in a warm oven and then record the melting point and compare with standard paracetamol tablets (~170oC). Repeat recrystalisation process to achieve a more purer product