Paracetamol (acetaminophen) Chemistry Tutorial

Key Concepts

• Paracetamol (acetaminophen) was first synthesized by Joseph von Mering in 1893.
• Paracetamol (acetaminophen) is widely used as an analgesic (pain reliever) and an antipyretic (for reducing fever).
• The systematic IUPAC name for paracetamol (acetaminophen) is N-(4-hydroxyphenyl)ethanamide or N-(4-hydroxyphenyl)acetamide.

  Paracetamol (acetominaphen) is also known as N-acetyl-p-aminophenol.

• Paracetamol (acetaminophen) is sold under the names Panadol®¹ in the UK, Australia and New Zealand and under the name Tylenol®² in the USA.
• Paracetamol (acetaminophen) is an aromatic compound containing an OH (hydroxyl) functional group and a HN-CO-R (amide) functional group.
• Paracetamol (acetaminophen) is a weak acid.
• Paracetamol (acetaminophen) is a white solid with a melting point of 170^oC which is slightly soluble in water.
• Paracetamol (acetaminophen) can be prepared from phenol (hydroxybenzene) in a three step process involving:

  (i) nitration

  (ii) reduction

  (iii) formation of the amide

• Paracetamol (acetaminophen) undergoes hydrolysis in acidic conditions to produce an amine and a carboxylic acid.

Structure of Paracetamol (acetaminophen)

Paracetamol (acetaminophen) contains three functional groups: hydroxyl group (OH) amide group (HN-CO-R) aromatic group (benzene ring)

Properties of Paracetamol (acetaminophen)

Aciditity

Paracetamol (acetaminophen) is a weak acid.

+

H+

The equilibrium position lies very far to the left.
The vast majority of paracetamol molecules in an aqueous solution will be found as the undissociated paracetamol molecules.

At 25^oC, paracetamol (acetaminophen) has a ³K_a = 3.09 x 10^-10

Solubility

It is possible to buy fizzy paracetamol tablets.
In these tablets the paracetamol has been mixed with citric acid (2-hydroxypropane-1,2,3-tricarboxylic acid) and sodium hydrogencarbonate (sodium bicarbonate).
When placed in water, the citric acid and sodium hydrogencarbonate in the tablet react to produce bubbles of carbon dioxide.
The bubbles of carbon dioxide gas help break the tablet up into smaller pieces that are easier to swallow.

Synthesis of Paracetamol (acetaminophen)

Step 1:nitration of phenol

Phenol (hydroxybenzene) will react with sodium nitrate (an oxidizing agent) in the presence of sulfuric acid to produce a mixture of structural isomers of nitrophenol.

	H2SO4 → NaNO3(aq)		+
phenol (hydroxybenzene)		4-nitrophenol (p-nitrophenol) 25% yield		2-nitrophenol (o-nitrophenol) 36% yield

When concentrated sulfuric acid (H₂SO₄) is added to sodium nitrate (NaNO₃) the following reaction occurs:

H₂SO₄ + 2NaNO₃ → Na₂SO₄ + 2HNO₃

Then, in excess sulfuric acid, reactive nitronium ion, NO₂⁺, is produced:

HNO₃ + H₂SO₄ → NO₂⁺ + HSO₄^- + H₂O

The nitronium ion, NO₂⁺, attacks the benzene ring of phenol to produce a mixture of various structural isomers of nitrophenol.

The OH (hydroxyl) functional group of phenol (hydroxybenzene) is said to activate the benzene ring at the 2- and 4- positions. This results in the formation of 2-nitrophenol and 4-nitrophenol.
The 3- and 5- positions of the benzene ring are not activated so 3-nitrophenol and 5-nitrophenol are NOT produced.

4-nitrophenol can be separated from the mixture containing 2-nitrophenol:

• by steam distillation: 2-nitrophenol forms fewer hydrogen bonds with water or other nitrophenol molecules than 4-nitrophenol so it is more volatile in steam than 4-nitrophenol
• or by column chromatography: 2-nitrophenol is less polar than 4-nitrophenol so it has less affinity for silica than 4-nitrophenol.

Step 2: reduction of a nitro group to an amine

In carbon chemistry (organic chemistry) a reduction reaction has occurred if⁴:

• a molecule loses oxygen

  OR

• a molecule gains hydrogen

In the reaction shown below, oxygen is lost from the nitro group of 4-nitrophenol and hydrogen is added to form 4-aminophenol, so the reaction is a reduction reaction:

In the laboratory:				Industrial preparation:
	NaBH4 → Pd/1 M NaOH				H2 → Pt catalyst
4-nitrophenol		4-aminophenol 74% yield		4-nitrophenol		4-aminophenol

A catalyst such as palladium in the laboratory reaction, or platinum in the industrial reaction, is required to provide a surface for the reaction to take place on.
The 4-nitrophenol molecules are held to the surface of the catalyst by weak forces of attraction, which then weakens the strong covalent bonds in the nitro group making it vulnerable to attack by hydrogen.

Step 3: formation of an amide

With the exception of tertiary amines, amines undergo reaction with anhydrides to produce amides.

4-aminophenol, an amine, suspended in water at room temperature readily reacts with ethanoic anhydride (acetic anhydride) to produce a precipitate of the amide paracetamol (acetaminophen) as shown below:

amine	acetic anhydride	amide
	→ room temperature water
4-aminophenol		paracetamol (acetaminophen)

Reactions of Paracetamol (acetaminophen)

Acid Hydrolysis

Hydrolysis (reaction with water) of amides in acidic solution produces an amine and a carboxylic acid.

Hydrolysis of paracetamol (acetaminophen) in acidic solution produces an amine (4-aminophenol) and a carboxylic acid (acetic acid)

amide		amine		carboxylic acid
	H2O/H2SO4 →		+	O ||   H |   HO- C - C -H       | H
paracetamol (acetaminophen)		4-aminophenol		acetic acid (ethanoic acid)