Aromatic Subsitution Reactions- Synthesis of Diazepam

Electrophilic aromatic substitution is the most common reaction of the aromatic compounds.  These reactions begin with the basic reaction of benzene, in which a hydrogen atom is replaced by an electrophile.  An electrophile is electron deficient and readily accepts an electron pair from an electron rich compound.  The same underlying mechanism occurs for every EAS reaction, the only difference is the identity of the electrophile.  The two-step mechanism that occurs is the addition of the electrophile (E⁺) to form a resonance stabilized carbocation and the deprotonation with a base¹.

 

EAS reactions are often used in the synthesis of pharmaceuticals.  The synthesis of diazepam (valium) is a particular example.  Valium is used to treat a wide variety of conditions, anxiety, muscle spasms, and seizures to name a few. 

 

                          ²Synthesis of Diazepam (Valium)

 

In the production of valium (shown above), the starting material is 4-nitrochlorobenzene and phenylacetonitrile.  When treated with NaOH a five membered ring is formed and attached to both molecules, making the new product 5-chloro-2-methylaminobenzophenone.  When treated with (CH₃)₂SO₄ and Fe/HCl 5-chloro-2-methylaminobenzophenone is formed.  The product is treated with an acid chloride and the H on the N is replaced with the electrophile, acetyl chloride.  From there, the final step occurs in which diazepam is formed from the treatment of the product before with hexamine/p-Toluenesulfonic acid (TsOH).

Sources

¹ Smith, Janice G. Organic Chemistry; McGraw Hill Companies, 2011; pp. 642-643.

² Rhodium. Diazepam (Valium) Synthesis.

                http://www.erowid.org/archive/rhodium/chemistry/diazepam

                (Accessed March 4, 2014)