Pyridine: Structure and Aromatic Properties

Pyridine and Pyridine Derivatives

• Pyridine (C5H5N) is the heterocyclic analogue of benzene (C6H6), derived by substituting -CH= with -N=.
• Pyridine is an aromatic heterocycle, characterized by:
• Stability
• Reacting by substitution
• Deshielded ring H's in the NMR spectrum (δ= 6.8-8.5ppm)

Importance of Pyridine

• Pyridine plays a key role in several biological processes, such as:
• The oxidation/reduction coenzyme NAD
• Pyridoxine (Vitamin B6)
• Pyridine exists in several alkaloids, e.g., nicotine
• It also exists in many synthetic drugs, e.g., Pantoprazole sodium

Resonance of Pyridine

• The N atom has –I effect via σ bond and -M effect via π bond
• Contributing structures:
• • (δ+)
• A, B, C, D, E, and Hybrid structures

Chemical Reactions of Pyridine

• Basic properties:
• Pyridine is basic due to the electron pair on nitrogen (N:)
• Less basic than corresponding aliphatic amines (e.g., piperidine)
• Reactivity:
• Decreased reactivity to SE reactions
• Increased reactivity to SN reactions
• Easier reduction
• Resistance to oxidation reactions
• Increased reactivity of methyl groups at 2-, 4-, and 6-positions

Basic Properties of Pyridine

• Pyridine reacts with acids to give stable salts
• Pyridine is a useful solvent due to:
• Polarity
• Ability to catalyze reactions involving acid elimination
• Miscibility with water and organic solvents
• Alkylation and acylation at nitrogen:
• Formation of quaternary pyridinium salts
• Reaction with percarboxylic acid to form pyridine -N-oxide

Electrophilic Substitution (SE) in Pyridine

• Unreactive to SE reactions due to:
• Electron withdrawing (-M and -I) effects of the ring N
• Destabilization of the intermediate σ-complex by the -I effect of the N atom
• Rapid formation of pyridinium cation, which is resistant to further SE reaction
• Orientation of SE:
• Reaction occurs at position 3- or 5- (β-position) due to the least disfavored σ-complex

Nucleophilic Substitution (SN) in Pyridine

• Favored SN reactions occur at C2, C4, and C6 due to:
• Electron deficiency at these positions
• Stabilization of the intermediate anion by resonance
• Direct Nucleophilic Substitution:
• Reaction with nucleophiles, e.g., Br and NH2

Reaction of Pyridine with Reducing Agents

• Pyridines are easily reduced, e.g., with reducing agents

Reaction of Pyridine with Oxidizing Agents

• Pyridines are resistant to oxidation, but more rapidly oxidized in alkaline media than in acidic solution

Pyridine Derivatives

• Alkyl pyridines:
• Monomethyl pyridines (picolines)
• Dimethylpyridines (lutidines)
• Trimethylpyridines (collidines)
• Pharmaceutical applications:
• Nicotinic acid (Vitamin B3)
• Isonicotinic acid (used in the treatment of tuberculosis)

Synthesis of Pyridine

• Two approaches:
• From 1,5-dicarbonyl compounds
• Hantzsch synthesis (involves the reaction of NH3 with an aldehyde and two molecules of 1,3-dicarbonyl compound)