Synthesis and Reactions of Pyridine: Pyridine is a colorless liquid with a boiling point of 115°C. It has a fishy odor. It was first obtained from bone oil in 1849 and coal tar. Pyridine is mainly used as a solvent and as a base. The lone pair on N-atom is located in an sp2 hybridized orbital and is not involved to maintain aromaticity. The lone pair of electrons are available for protonation and explains the basicity of pyridine. Electron donating substituent at 2 – and 6 – positions enhances the basicity.
Pyridine is considerably more basic than pyrrole and less basic than aliphatic 3° amine.
An alkyl group is an electron-donating group. In aliphatic 3° amine, all the three alkyl groups donate electrons to the N-atom, thereby making lone pair of electrons on N-atom even more easily available for protonation. Hence, pyridine is less basic than aliphatic 3° amine.
Chemical Synthesis of Pyridine
(1) Pyridine is synthesized by reacting acetaldehyde with formaldehyde and ammonia.
(2) Hantzsch synthesis: It is a condensation reaction between an aldehyde, two equivalents of 1, 3-dicarbonyl compound, and ammonia.
(3) From 1,3-dicarbonyl compound and 3-amino acrylate: Unsymmetrically substituted pyridine can be synthesized by the reaction between a 1,3-dicarbonyl compound with 3-amino acrylate.
(4) Guareschi Thorpe Synthesis: Two molecules of aldehydes condense with the keto ester to give substituted pyridine.
(5) Krohnke pyridine synthesis: The α-pyridinium methyl ketone salts react with α, β-unsaturated carbonyl compounds to give 2, 4, 6-trisubstituted pyridines.
(6) Cycloaddition reaction: Various electrocyclic additions have been used to give pyridines as the final products.
(7) Bonnemann Cyclization: It involves trimerization of one part of a nitrile molecule and two parts of acetylene either by heat or by light.
(8) Gattermann – Skita synthesis:
Chemical Reactions of Pyridine
The electronegative nitrogen in the pyridine ring makes the pyridine molecule relatively electron deficient. Hence unlike benzene.
(i) Pyridine does not undergo electrophilic aromatic substitution readily.
(ii) Pyridine is more prone to nucleophilic substitution at positions 2 and 4 and metalation of the ring by strong organometallic bases, and
(iii) Like tertiary amine, pyridine undergoes N – protonation and undergoes oxidation to form N-oxide.
(a) N-Protonation: The lone pair of electrons on the nitrogen atom in pyridine is available for extra bonding. When a pyridine reacts with acids, metallic ions or acyl, sulfonyl, anhydrides, it forms quaternary salts.
(i) Pyridines from crystalline, hygroscopic salts with most protic acids.
(ii) Metallic ions such as aluminum, boron, beryllium, etc. form a complex with basic pyridine.
(iii) Acyl, sulfonyl, or anhydrides readily react with pyridine to form quaternary salts which function as acylating and sulfonating agents.
(iv) Alkyl halides and sulfates readily react with pyridines giving quaternary pyridinium salts.
(v) Pyridine easily reacts with percarboxylic acids to give N-oxides.
(b) Electrophilic Substitution: Benzene readily undergoes electrophilic substitution reactions. In pyridine, an electronegative N-atom creates π-electron deficiency at each C-atom and deactivates the ring towards electrophiles. The protonation of N-atom (acidic reaction condition) further deactivates the ring. Hence, pyridine undergoes electrophilic substitution with extreme difficulty and only under extreme reaction conditions.
(i) Halogenation and nitration:
(ii) Friedel-Crafts Reaction: Pyridine forms a complex with AlCl3 which is highly unreactive. Hence, pyridine does not undergo Friedel-Crafts reactions.
(iii) Mercuration: When pyridine is heated with mercuric acetate at 170-180°C, the salt initially formed undergoes rearrangement to give 3-pyridylmercuriacetate.
(c) Oxidation: Pyridine ring is resistant to oxidation, but the N-atom being highly electron-rich, can easily be oxidized by hydrogen peroxide or various peracids to pyridine-N-oxide.
(d) Reduction: Since pyridine easily reacts with nucleophiles, it may be reduced by nucleophilic reducing agents.
(e) Nucleophilic substitution: Electrophilic substitution is the characteristic reaction of benzene while nucleophilic substitution is the characteristic of pyridine. Nucleophilic substitution takes place at C2 and C4 positions.
(i) Alkylation and arylation: Pyridine reacts with alkyl or aryl lithiums to give a dihydropyridine intermediate which then gets converted into substituted pyridine.
(ii) Amination: Pyridine reacts with sodamide to give 2-aminopyridine. It is called the chichibabin reaction.
Bromopyridines undergo nucleophilic substitution in a palladium phosphine catalyzed reaction.
(iii) Hydroxylation: Pyridinium salts are more reactive than pyridine towards nucleophilic substitution. For example, pyridinium salt reacts with alkaline potassium ferricyanide to give N-substituted 2-pyridones.
Applications in Drug Synthesis
It is present as a core skeleton in sulfapyridine (antibacterial), tripelenamine, mepyramine (antihistaminic), niacin, pyridoxine (vitamin), isoniazid (anti – T. B.), etc.
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