Question

Propose a synthesis of the drug sulfathiazole from benzene and any necessary amine.

Short answer

Start from benzene, perform nitration, reduction to aniline, protect via acetylation, sulfonation, and cyclization to yield sulfathiazole.

Step-by-step solution

Nitration of Benzene

First, convert benzene to nitrobenzene by carrying out a nitration reaction. Treat benzene with a mixture of concentrated nitric acid (HNO₃) and concentrated sulfuric acid (H₂SO₄) to substitute a nitro group (-NO₂) in the benzene ring, forming nitrobenzene.

Reduction to Aniline

The nitrobenzene is reduced to aniline (phenylamine) by using reducing agents such as tin (Sn) and hydrochloric acid (HCl). This reaction transforms the nitro group into an amino group (-NH₂).

Acetylation of Aniline

Protect the amino group of aniline by acetylating it with acetic anhydride (CH₃CO)₂O, forming acetanilide. This step prevents the undesired reactions of the amine group in subsequent steps.

Sulfonation

Now, introduce a sulfonamide group into the compound. Treat acetanilide with chlorosulfonic acid (ClSO₃H), which will replace one hydrogen atom in the amine's benzene ring with a sulfonamide group (-SO₂Cl).

Cyclization

Reduce the intermediate with ammonium thiocyanate (NH₄SCN), leading to the substitution of the sulfonamide with a thiazole group, forming sulfathiazole as the cyclization completes.

Key concepts

Nitration of Benzene

The very first step in the synthesis of sulfathiazole involves converting benzene to nitrobenzene. This is achieved through a reaction known as nitration. Nitration involves treating benzene with a mixture of concentrated nitric acid, \( \text{HNO}_3 \), and concentrated sulfuric acid, \( \text{H}_2\text{SO}_4 \).
This process substitutes a nitro group, \( -\text{NO}_2 \), into the benzene ring.
This substitution is crucial because it sets the stage for further reactions. Nitration is a fundamental method to introduce nitrogen into aromatic compounds, paving the way for many synthetic pathways.

• Key Reagents: nitric acid and sulfuric acid
• Product Formed: Nitrobenzene
• Importance: Initiates the aromatic transformation

Reduction to Aniline

After forming nitrobenzene in the nitration step, the next transformation is reducing this compound to aniline. This reduction is carried out using reducing agents like tin \(( \text{Sn} )\) and hydrochloric acid \(( \text{HCl} )\).
These reagents work together to convert the nitro group \(( -\text{NO}_2 )\) into an amino group \(( -\text{NH}_2 )\).
Aniline, or phenylamine, is an essential building block in organic synthesis, especially in the creation of dyes, pharmaceuticals, and polymers.

• Key Reagents: Tin and hydrochloric acid
• Product Formed: Aniline
• Importance: Provides the amino functionality required for further reactions

Acetylation of Aniline

Next, the aniline undergoes acetylation to protect the amino group. This is done by reacting aniline with acetic anhydride \(( \text{CH}_3\text{CO})_2\text{O} \).
This reaction produces acetanilide, effectively shielding the amino group from unwanted side reactions in later steps.
Protection strategies like acetylation are crucial in organic chemistry for controlling reactivity and ensuring selectivity in multi-step syntheses.

• Key Reagents: Acetic anhydride
• Product Formed: Acetanilide
• Importance: Prevents unwanted reactions, allowing for a controlled synthesis path

Sulfonation

With acetanilide formed, the route proceeds to introduce a sulfonamide group. Sulfonation involves treating the compound with chlorosulfonic acid \(( \text{ClSO}_3\text{H} )\), which replaces a hydrogen atom in the benzene ring with a sulfonamide group \(( -\text{SO}_2\text{Cl} )\).
This step is vital for setting up the molecular structure needed for later cyclization.
Sulfonation reactions are a backbone in aromatic chemistry for modifying compound solubility and reactivity.

• Key Reagents: Chlorosulfonic acid
• Product Formed: Sulfonamide derivative
• Importance: Modifies functional groups for further chemical transformations

Cyclization Reaction

The final step involves a cyclization reaction to form the desired sulfathiazole. Here, the sulfonamide group interacts with ammonium thiocyanate \(( \text{NH}_4\text{SCN} )\), leading to the substitution with a thiazole ring.
This critical transformation concludes with the attainment of sulfathiazole.
Cyclization is a wonderful tool in organic synthesis that enables ring formation, which is often essential for biological activity in pharmaceuticals.

• Key Reagents: Ammonium thiocyanate
• Product Formed: Sulfathiazole
• Importance: Achieves the final desired complex molecular structure