The document describes the synthesis of paracetamol from p-aminophenol. It involves reacting p-aminophenol with acetic anhydride which forms an amide bond between the amino group and acetic acid, producing paracetamol. The reaction occurs in three steps - mixing the reactants to form paracetamol, isolating the crude product, and purifying it via recrystallization. The theoretical yield is calculated based on the mole ratios of the reactants and products. The practical yield obtained is 70.82% of the theoretical yield.

1. To synthesis and characterization of
paracetamol
Dr. Pawan Kumar Gupta
Associate Professor
SVKM's Institute of Pharmacy, Dhule, Maharashtra
https://sites.google.com/view/pawanpharma79/about-me?authuser=1

2. Introduction
• Paracetamol or acetaminophen is a very widely used analgesic and antipyretic. It is a relatively safe drug
(toxicity has been observed with very high doses).
• It is typically used for mild to moderate pain relief.
• It is mild analgesic and does not have anti-inflammatory activity
• It is often sold in combination with other medications such as in many cold medications
• It sued for severe pain such as cancer pain and pain after surgery.
• Often taken orally or rectally, but also I. V.
• Effect: last 2hrs and 4 hrs.
• It is safe at recommended dose.
• Serious skin rushes may rarely occur and too high dose can result in liver failure.
• It appears to be safe in pregnancy and breastfeeding women.
• It is on WHO’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.

3. Introduction
• 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.

4. Principle
• 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.
• This reaction is exothermic.
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 by product. 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

5. 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.

6. • REQUIREMENTS
• Round bottom flask
• Measuring cylinder
• Beaker
• Pasteur pipette
• Buchner funnel
• Glass rod
• Filter paper
• Dropper
• Hot plate with magnetic stirrer

7. Chemicals required:
•P-aminophenol
•Acetic anhydride
•Purified water
•Conc. H2SO4
•MeOH

8. Procedure
• 1. Add 3.07 grams of 4-aminophenol into the 50 ml flask and add 18 ml of water into it.
• 2. add 3.5 ml of ethanoic anhydride (also known as acetic anhydride). Add 2-3 drop conc. H2SO4 in the mixture.
• 3. This reaction is exothermic (heat is released after mixing the reactants, and flask become warm.
• 4. Put the flask on hot plate (with magnetic stirrer) and heat the mixture for 1hr (120°C). The reaction mixture
should become colorless.
• 5. Allow the flask to cool slightly before placing it on the bench top
• 6. Now, crystal of the crude product is appeared in the flask. Place the flask on ice-bath for sometime (until
complete crystal is formed)
• 7. Filter the solution using suction pump with the help of Buchner funnel.
• 8. Washing the product with cold water during the filtration
• 9. allow the crude product to dry under vacuum (still attached with suction pump)
• 10. measure the weight of the crude product (3.01 gm)
• 11. Purification: Recrystallization of the crude product with the 50% MeOH in water solution
• 12. Add 25-30 ml of recrystallization solvent into crude product with continuous stirring on hot plate (128
degree C)
• 13. Cool the mixture in ice bath and filter the recrystallized product again and again with the cold water using
suction pump with the help of Buchner funnel.
• 14. Final product is dried under vacuum

9. Calculations
1 mol of the p-aminophenol is equivalent to 1 mol of the paracetamol
C6H7NO
p-aminophenol
Mw: 109.13 C8H9NO2
Paracetamol
Mw 151.16

10. • Theoretical yield:
• 109.13 gm p-aminophenol forms 151.16 gm paracetamol
• 1 gm-------------------------------= 151.16 / 109.13
• X gm------------------------------= (151.16 / 109.13)*x
• Therefore, ___3.07g ___p-aminophenol will form …….? (X) g
paracetamol
• X =(151.16 × __3.07__)/ 109.13 = gm
• Theoretical yield = 4.25 gm
• Practical yield = 3.01 gm

11. Calculations
(3.01/4.25)*100 = 70.82 % yield

12. • https://www.youtube.com/watch?v=xY33L8SqMo4
• Synthesis, TLC, characterization of the product:
• https://www.youtube.com/watch?v=T02vP2s15F8
• Mechanism of Action:
• https://www.youtube.com/watch?v=UkcpOZ7AGBQ
• https://www.youtube.com/watch?v=249FNCSR-Cw
• https://slideplayer.com/slide/15785699/
• https://slideplayer.com/slide/13714086/