Chichibabin reaction: practice and mechanism
The strong nucleophile NH₂⁻ attacks pyridine at C2 next to N. The N takes up the negative charge, then a hydride leaves: 2-aminopyridine.
Example
Pyridine is electron-poor and attacked by strong nucleophiles, preferably at C2 next to N. Amide adds and the negative charge sits on N. A hydride is then lost (H₂ escapes) and 2-aminopyridine forms.
Mechanism step by step
- 1
NH₂⁻ adds to C2 of pyridine (the N coordinates to Na⁺); an anionic σ-complex forms with the charge on N.
- 2
A hydride ion is eliminated and reacts with NH₃ or the product to give H₂; the ring is aromatic again.
- 3
Aqueous workup protonates the amide salt to 2-aminopyridine.
Practice tasks
Which product forms, which reagent is needed? After each answer you see the explanation.
Which main product forms?
Background
What is the Chichibabin reaction?
The Chichibabin reaction is the direct amination of pyridine and related nitrogen heterocycles with sodium amide to give 2-aminopyridine. It is the textbook example of a nucleophilic substitution of hydrogen: no halide is replaced, but a hydride. The Russian chemist Aleksei Chichibabin reported it in 1914.
Conditions and how to follow it
Pyridine is heated with sodium amide in a high-boiling inert solvent. The anionic σ-complex turns the mixture deep red and hydrogen is given off; when the gas stops, the reaction is over. Only the aqueous workup turns the sodium salt into free 2-aminopyridine.
Other heterocycles and substituents
Quinoline gives 2-aminoquinoline, isoquinoline reacts at C1 and acridine at C9. If C2 is already substituted, the amide attacks C6; with both positions next to nitrogen blocked, C4 can react. Electron-donating groups slow the reaction because they make the ring less electron-poor.
Side products and limits
With excess sodium amide and at higher temperature a second amination can happen, giving 2,6-diaminopyridine. As a side reaction pyridine rings couple to bipyridines. Because the conditions are hot and strongly basic, many functional groups do not survive.
What 2-aminopyridine is used for
2-Aminopyridine is a building block for drugs, historically for the sulfonamide sulfapyridine and today for compounds such as the anti-inflammatory piroxicam. The Chichibabin reaction has therefore also been used industrially.
Typical mistakes
- C3 is unfavourable for nucleophiles: the negative charge in the intermediate could not be placed on N.
- C4 is possible, but the amide coordinates to the N and therefore preferentially attacks the neighbouring C2.
Often confused with: Nucleophilic substitution of halopyridines · Electrophilic substitution of pyridine
Frequently asked questions
How does pyridine differ from benzene?
N is more electronegative than C and pulls electron density out of the ring: electrophiles react poorly (as with nitrobenzene), nucleophiles readily at C2 and C4. The lone pair on N lies in the ring plane and makes pyridine basic (pKa of pyridinium ≈ 5).
Why is this a special reaction?
Hydride is normally a very poor leaving group. Here regaining aromaticity (and forming H₂) drives the reaction.
What does the Chichibabin reaction give?
Pyridine reacts with sodium amide (NaNH₂) to give 2-aminopyridine. Formally a hydride (H⁻) is replaced by NH₂⁻; the hydride leaves as H₂.
Why does the amide attack position 2?
Attack at position 2 (or 4) puts the negative charge of the intermediate on the electronegative nitrogen, which stabilises it. Position 2 is usually preferred.
What is the Chichibabin reaction of quinoline?
Quinoline is also aminated next to the nitrogen and gives 2-aminoquinoline. Isoquinoline reacts at C1 and acridine at C9.
What conditions does the reaction need?
Classically with sodium amide in a hot inert solvent such as toluene or xylene (about 100 to 150 °C), then aqueous workup. For sensitive heterocycles there is a low-temperature variant with potassium amide in liquid ammonia and an oxidant that takes up the hydride.