Organic Synthesis Of Heterocyclic Compounds Notes And Mind Maps For CSIR NET Exam

Synthesis and Reactivity of Common Heterocyclic Compounds (O, N, S) – CSIR NET Detailed Notes

Heterocyclic compounds are organic molecules containing at least one heteroatom (O, N, S) in a cyclic ring. They are fundamental in drug design, biochemistry, and material science. Below is an in-depth, structured explanation with proper formatting (subscripts, superscripts, reactions intact) for clear understanding.

1. Five-Membered Heterocycles (One Heteroatom)

(A) Furan (C₄H₄O)

• Aromaticity: 6π-electrons (lone pair on O contributes to conjugation).
• Reactivity: Highly reactive towards electrophiles.

Synthesis Methods:

1. Paal-Knorr Synthesis
   • Reactants: 1,4-Diketone + Acid (H₂SO₄, P₂O₅).
   • Mechanism: Acid-catalyzed cyclodehydration.
   • Example:
   • CH₃-CO-CH₂-CH₂-CO-CH₃ + H⁺ (H₂SO₄) → Furan + 2H₂O
2. From Furfural (Industrial Method)
   • Step 1: Pentose sugar (xylose) → Furfural (acid hydrolysis).
   • Step 2: Furfural → Furan (decarboxylation).
   • C₅H₁₀O₅ (Xylose) → C₅H₄O₂ (Furfural) → C₄H₄O (Furan) + CO₂↑

Reactivity & Reactions:

• Electrophilic Aromatic Substitution (EAS):
  • More reactive than benzene (due to O’s +M effect).
  • Preferred position: C-2 (α-position).
  • Examples:
    • Nitration:
    • Furan + HNO₃ (Ac₂O) → 2-Nitrofuran
    • Friedel-Crafts Acylation:
    • Furan + CH₃COCl (AlCl₃) → 2-Acetylfuran
• Diels-Alder Reaction:
  • Acts as a diene (used in cycloaddition reactions).
  • Example:
  • Furan + Maleic Anhydride → Endo-Adduct (Bicyclic)

(B) Pyrrole (C₄H₄NH)

• Aromaticity: 6π-electrons (lone pair on N participates).
• Reactivity: Highly nucleophilic at C-2.

Synthesis Methods:

1. Paal-Knorr Synthesis
   • Reactants: 1,4-Diketone + NH₃ or RNH₂.
   • Example:
   • CH₃-CO-CH₂-CH₂-CO-CH₃ + NH₃ → Pyrrole + 2H₂O
2. Knorr Pyrrole Synthesis
   • Reactants: α-Aminoketone + β-Ketoester.
   • Example:
   • NH₂-CH₂-CO-CH₃ + CH₃-CO-CH₂-COOEt → Pyrrole-2-carboxylate

Reactivity & Reactions:

• Electrophilic Substitution:
  • Preferred position: C-2 (due to higher electron density).
  • Examples:
    • Vilsmeier-Haack Formylation:
    • Pyrrole + POCl₃ + DMF → Pyrrole-2-carbaldehyde
    • Nitration:
    • Pyrrole + HNO₃ (Ac₂O) → 2-Nitropyrrole
• Acidity of NH Proton:
  • Can be deprotonated (pKa ~17) to form nucleophilic pyrrolyl anion.
  • Example:
  • Pyrrole + NaH → Na⁺[Pyrrolyl]⁻ (Nucleophile)

(C) Thiophene (C₄H₄S)

• Aromaticity: 6π-electrons (S lone pairs contribute weakly).
• Reactivity: More stable than furan, less than benzene.

Synthesis Methods:

1. From Sodium Succinate (Classical Method)
   • Reactants: Sodium succinate + P₂S₅.
   • Example:
   • NaOOC-CH₂-CH₂-COONa + P₂S₅ → Thiophene + Na₂S + H₂O
2. Paal-Knorr Synthesis (Modified)
   • Uses Lawesson’s Reagent (LR) for sulfur insertion.
   • Example:
   • 1,4-Diketone + LR → Thiophene

Reactivity & Reactions:

• Electrophilic Substitution:
  • Preferred position: C-2.
  • Example (Sulfonation):
  • Thiophene + H₂SO₄ → Thiophene-2-sulfonic acid
• Resistance to Oxidation:
  • Unlike furan, thiophene does not cleave with oxidants.

2. Five-Membered Heterocycles (Two Heteroatoms)

(A) Imidazole (C₃H₄N₂)

• Aromaticity: 6π-electrons (both N lone pairs contribute).
• Amphoteric Nature: Can act as acid (NH) or base (N lone pair).

Synthesis Methods:

1. Radziszewski Synthesis
   • Reactants: 1,2-Diketone + Aldehyde + NH₃.
   • Example:
   • CH₃-CO-CO-CH₃ + HCHO + NH₃ → Imidazole

Reactivity & Reactions:

• Electrophilic Substitution:
  • Occurs at C-4/C-5 (electron-rich positions).
• Nucleophilic Substitution:
  • Halogen at C-2 can be displaced by nucleophiles.

(B) Pyrazole (C₃H₄N₂)

• Aromaticity: 6π-electrons.
• Tautomerism: Exists as NH/CH tautomers.

Synthesis Methods:

1. Condensation of Hydrazine with 1,3-Diketones
   • Example:
   • CH₃-CO-CH₂-CO-CH₃ + N₂H₄ → Pyrazole

Reactivity & Reactions:

• Electrophilic Substitution:
  • Occurs at C-4 (less hindered position).

3. Six-Membered Heterocycles (One Heteroatom: Pyridine)

Pyridine (C₅H₅N)

• Aromaticity: 6π-electrons (N lone pair not in conjugation).
• Reactivity: Electrophilic substitution difficult (electron-deficient).

Synthesis Methods:

1. Hantzsch Synthesis
   • Reactants: Aldehyde + β-Ketoester + NH₃.
   • Example:
   • 2CH₃CHO + CH₃COCH₂COOEt + NH₃ → Dihydropyridine → Pyridine (Oxidation)

Reactivity & Reactions:

• Electrophilic Substitution:
  • Occurs at C-3 (meta-position) due to deactivation by N.
• Nucleophilic Substitution:
  • Chichibabin Reaction:
  • Pyridine + NaNH₂ → 2-Aminopyridine

4. Six-Membered Heterocycles (Two Heteroatoms: Pyrimidine)

Pyrimidine (C₄H₄N₂)

• Electron-Deficient: Difficult EAS, favors nucleophilic attack.

Synthesis Methods:

1. Biginelli Reaction
   • Reactants: Urea + β-Ketoester + Aldehyde.
   • Example:
   • NH₂-CO-NH₂ + CH₃COCH₂COOEt + PhCHO → Dihydropyrimidine → Pyrimidine (Oxidation)

Reactivity & Reactions:

• Nucleophilic Substitution:
  • Example:
  • 2-Chloropyrimidine + NH₃ → 2-Aminopyrimidine

Key Takeaways for CSIR NET

Heterocycle	Key Feature	Electrophilic Substitution Position	Important Reaction
Furan	Highly reactive (O +M effect)	C-2 (α)	Diels-Alder, Nitration
Pyrrole	NH acidic, nucleophilic C-2	C-2 (α)	Vilsmeier formylation
Thiophene	Stable, S-resonance	C-2 (α)	Sulfonation
Pyridine	Electron-deficient (N -I effect)	C-3 (meta)	Chichibabin amination
Imidazole	Amphoteric (acid & base)	C-4/C-5	Halogen displacement
Pyrimidine	Very electron-deficient	C-5 (if any)	Nucleophilic substitution (C-2)

End of Notes

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