OIA1012 HETEROCYCLIC COMPOUNDS

Definition of Heterocyclic Compounds

Organic compounds where one or more carbon atoms in a ring are replaced by heteroatoms like nitrogen (N), oxygen (O), or sulfur (S).

Importance of Heterocycles

Found in many pharmaceuticals, vitamins, and biomolecules.

Key components of DNA (purines and pyrimidines).

Types of Heterocycles

Saturated, partially unsaturated, and aromatic.

Saturated Heterocyclic Compounds

Saturated: No double bonds (e.g., tetrahydrofuran).

Partially Unsaturated Heterocyclic Compounds

Partially Unsaturated: Some double bonds (e.g., dihydropyran).

Aromatic Heterocyclic Compounds

Aromatic: Fully conjugated π-electron systems (e.g., pyridine).

Five-Membered Aromatic Heterocycles

Pyrrole (N)

Furan (O)

Thiophene (S)

Six-Membered Aromatic Heterocycles

Pyridine (N)

Pyrylium (O)

Fused Heterocycles

Quinoline & Isoquinoline (benzopyridines).

Indole (benzopyrrole).

Benzimidazole (fused imidazole and benzene).

Trivial Names

Many heterocycles retain their historical names (e.g., furan, thiophene, pyrrole).

Systematic Naming (Hantzsch-Widman System)

Uses prefixes for heteroatoms (e.g., "oxa" for O, "thia" for S, "aza" for N).

Uses suffixes based on ring size (e.g., "-ole" for 5-membered, "-ine" for 6-membered).

Order of Heteroatoms in Naming

Priority: O > S > N > P (descending electronegativity).

Numbering of Heterocycles

Begins at the highest priority heteroatom and proceeds in the direction that gives the lowest numbers to other heteroatoms.

Hückel’s Rule for Aromaticity

A compound is aromatic if it has (4n + 2) π-electrons and a fully conjugated planar ring.

Examples of Aromatic Heterocycles

Pyrrole, furan, thiophene (5-membered, 6 π-electrons).

Pyridine (6-membered, 6 π-electrons).

Pyridine vs. Pyrrole Reactivity

Pyridine: Electrons not involved in π-system → retains basicity.

Pyrrole: Lone pair is part of π-system → reduced basicity.

π-Excessive vs. π-Deficient Heterocycles

π-Excessive: More electron density (e.g., pyrrole, thiophene).

π-Deficient: Electron-deficient (e.g., pyridine, pyrazine).

Electrophilic Substitution in Heterocycles

Pyrrole, furan, and thiophene undergo substitution at C-2 due to resonance stabilization.

Pyridine undergoes substitution at C-3.

Basicity of Heterocycles

Pyridine (pKa = 5.3) is more basic than pyrrole (pKa ≈ -3.8) because pyridine’s lone pair is available for protonation.

Pyrrole Properties

Weak base due to lone pair delocalization.

Darkens upon air exposure due to oxidation.

Found in heme and chlorophyll.

Furan Properties

Highly reactive due to oxygen lone pairs.

Found in sugars (e.g., furanose forms of glucose).

Thiophene Properties

More stable than furan and pyrrole.

Found in some natural products and coal tar.

Azoles (Five-Membered Rings with Two Heteroatoms)

Imidazole: Found in histidine and histamine.

Thiazole: Present in vitamin B1 (thiamine).

Pyridine Uses

Found in nicotine, vitamins (B3), and pharmaceuticals.

Used as a solvent and precursor in drug synthesis.

Pyrimidine & Purine

Pyrimidine: Base structure of uracil, thymine, and cytosine.

Purine: Found in adenine and guanine in DNA.

Quinoline & Isoquinoline

Found in antimalarial drugs (e.g., quinine, chloroquine).

Indole

Found in serotonin and melatonin.

Parent structure of tryptophan and alkaloids.

Benzimidazole

Present in vitamin B12.

Used in antifungal and anthelmintic drugs.

Benzothiophene & Benzofuran

Found in natural products and pharmaceuticals (e.g., raloxifene for osteoporosis).

Benzodiazepines

Include chlordiazepoxide and diazepam (Valium) for anxiety and sedation.

Histamine (Biological Role of Heterocycles)

Involved in immune response and neurotransmission.

Targeted by antihistamines like cimetidine (H2 receptor blocker).

Metronidazole (Nitroimidazole)

Used for bacterial and protozoal infections.

Contains a heterocyclic imidazole ring.

Sumatriptan (Triptan for Migraines)

Contains an indole ring.

Selective serotonin receptor agonist.