The Chichibabin reaction, discovered by A.E. Chichibabin in the early 1900s, allows for the amination of pyridine and its derivatives through nucleophilic aromatic substitution, often yielding 2-aminopyridine and 2-hydroxypyridine. The reaction can be carried out at high temperatures in various inert solvents or at low temperatures in liquid ammonia, with specific conditions affecting the substrate's reactivity. Recent applications include synthesizing mutagenic compounds and optimizing the reaction for high yield and regioselectivity in clinical studies.

1. NAMED REACTIONS IN ORGANIC
SYNTHESIS:CHICHIBABIN REACTION
By
PRUTHVIRAJ K
PRUTHVIRAJ K, MSc

2. Chichibabin Reaction
• In the early 1900s, A.E. Chichibabin reacted pyridine with sodium amide
(NaNH2) in dimethylamine at high temperature (110 °C). After aqueous work-
up, he isolated 2-aminopyridine in 80% yield.1 A decade later, he added
pyridine to powdered KOH at 320 °C, and after aqueous work-up 2-
hydroxypyridine was isolated.2 Similar reactions take place when pyridine or its
derivatives are treated with strong nucleophiles such as alkyl- and aryllithiums
to give 2-alkyl and 2-arylpyridines.11 The direct amination of pyridine and its
derivatives at their electron-deficient positions via nucleophilic aromatic
substitution (SNAr) is known as the Chichibabin reaction. This reaction is
also widely used for the direct introduction of an amino group into the electron-
deficient positions of many azines and azoles (e.g.,quinoline is aminated at C2 &
C4, isoquinoline at C1, acridine at C9, phenanthridine at C6, quinazoline at
C4). Both inter- and intramolecular12-14 versions are available, but
investigations have mainly focused on intermolecular reactions. There are two
procedures for conducting the Chichibabin reaction: A) the reaction is carried
out at high temperature in a solvent that is inert toward NaNH2 (e.g., N,N-
dialkylamines, arenes, mineral oil, etc.) or without any solvent; or B) the
reaction is run at low temperature in liquid ammonia with KNH2 (more soluble
than NaNH2). PRUTHVIRAJ K, MSc

3. • Procedure A proceeds in a heterogeneous medium and the reactions effected under these conditions
show strong dependence on substrate basicity, while procedure B proceeds in a homogeneous
medium and there is no substrate dependence. Frequently, an oxidant such as KNO3 or KMnO4 is
added during procedure B to facilitate the amination by oxidizing the hydride ion (poor leaving group)
in the intermediate ó-complex.9,6 The low temperature conditions make it possible to aminate
substrates such as diazines, triazines, and tetrazines, which are destroyed at high temperatures, but
pyridine itself does not undergo amination in liquid ammonia because it is not sufficiently
electrondeficient.
Mechanism
The Chichibabin reaction is formally the nucleophilic aromatic substitution of hydride ion (H-) by the
amide ion (NH2). In the first step, an adsorption complex is formed with a weak coordination bond
between the nitrogen atom in the heterocycle and the sodium ion (Na+); this coordination increases the
positive charge on the ring. This -complex is then aromatized to the corresponding sodium salt while
hydrogen gas (H2) is evolved (a proton from an amino group reacts with the leaving group hydride ion
PRUTHVIRAJ K, MSc

4. In the laboratory of J.S. Felton, the synthesis of 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-
b]pyridine (PHIP), amutagenic compound isolated from cooked beef, and its 3-methyl isomer
have been accomplished.27 The synthesis of PHIP began with the commercially available 3-
phenylpyridine, which was aminated at the 6-position with sodium amide in toluene by the
Chichibabin reaction in 58% yield.
PRUTHVIRAJ K, MSc

5. • M. Palucki and co-workers synthesized 2-[3-aminopropyl]-5,6,7,8-tetrahydronaphthyridine in large
quantities for clinical studies via a one-pot double Suzuki reaction followed by deprotection and a
highly regioselective intramolecular Chichibabin cyclization.14 This approach was amenable to scale-up
unlike the traditional methods such as the Skraup and Friedländer reactions that involve carbon-
carbon bond forming steps. The Chichibabin reaction was optimized and afforded the desired product
in high yield, excellent regioselectivity, and a significant reduction in reaction time compared to
literature precedent.
PRUTHVIRAJ K, MSc

6. REFERENCES
• STRATEGIC APPLICATIONS OF NAMED REACTIONS IN
ORGANIC SYNTHESIS
By- Laszlo Kurti and Barbara Czako
• REACTIONS, REARRANGEMNTS AND REAGENTS
By- S N Sanyal
PRUTHVIRAJ K, MSc