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)
