POC-III UNIT-4

Heterocyclic Compounds

IMPORTANT QUESTIONS

1. Write synthesis, reactions and medicinal use of
   • Pyridine, Basicity of pyridine
   • Imidazole
   • Pyrazole, Thiazole, Oxazole
   • Quinoline + Isoquinoline
2. Write Synthesis and Medicinal use of :-
   • Pyrimidines
   • Purines
   • Their derivatives.

HETEROCYCLIC COMPOUNDS

• These are those organic cyclic compound which contain atleast one different atom than carbon in a ring.
• The atom present in cyclic ring other than 'carbon' is known as 'Heteroatom'.
• Examples: Nitrogen (N), Oxygen (O), Sulphur (S)

1. Write synthesis, reactions and Medicinal use of

PYRIDINE

• It is an unsaturated six membered heterocyclic ring consist of Nitrogen (N) as hetero atom. It is basic in nature.
• Chemical formula $\rightarrow$ $C_5H_5N$

SYNTHESIS (METHODS OF PREPARATION)

1. Hantzsch Pyridine Synthesis: This involve condensation of $\beta$-ketoesters with ammonia & aldehydes.

2. From Acetaldehyde : Pyridine is synthesized by reacting acetaldehyde with formaldehyde and ammonia.

3. From Pyrrole : Pyrrole when heated with methylene dichloride in presence of sodium ethoxide, it formed pyridine.

4. From Acetylene : Pyridine is formed when mixture of acetylene and hydrogen cyanide is passed through red hot tube.

5. From Picolines : Picoline on oxidation with $K_2Cr_2O_7 / H_2SO_4$ gives $\beta$-picolinic acid, which on decarboxylation gives pyridine.

CHEMICAL REACTIONS OF PYRIDINE

1. Reaction with Acids : On protonation, it gives pyridine salts.

2. Electrophilic Substitution Reactions : Preferably substitution takes place at C-3 position, due to high stability of carbocations formed by the attack of electrophile at C-3 Carbon atom.

• Nitration: Pyridine $\xrightarrow{HNO_3 / H_2SO_4 \text{ (573K)}}$ 3-Nitro pyridine

• Sulphonation: Pyridine $\xrightarrow{H_2SO_4 / \text{ (623K)}}$ 3-Sulpho pyridine

• Bromination: Pyridine $\xrightarrow{Br_2 \text{ (573K)}}$ 3-Bromo pyridine

3. Oxidation : Pyridine is oxidized by Hydrogen peroxide to form pyridine-N-Oxide. Pyridine + $H_2O_2$ $\xrightarrow{CH_3COOH, 70^\circ C}$ Pyridine N-Oxide + $H_2O$

4. Nucleophilic Substitution Reactions : Pyridine undergoes nucleophilic substitution reaction at C-2 position. attack on 2nd position gives more stable.

• Pyridine $\xrightarrow{NaNH_2, \text{Liq. } NH_3}$ 2-amino pyridine
• Pyridine $\xrightarrow{KOH, 300^\circ C}$ 2-hydroxy pyridine
• Pyridine $\xrightarrow{LiC_6H_5, 383K}$ 2-phenyl pyridine

5. Reduction :

• Pyridine $\xrightarrow{H_2/Pt \text{ or } Na/C_2H_5OH}$ Piperidine
• Pyridine $\xrightarrow{Na \text{ in Liq. } NH_3 \text{ (Birch reduction)}}$ 1,4-dihydro pyridine
• Pyridine $\xrightarrow{LiAlH_4 \text{ / ether}}$ 1,2-dihydro pyridine

Medicinal uses of Pyridine

Pyridine derivatives are used as a:

• Antiviral agents - Ritonavir (used to treat HIV infections)
• Anti-Inflammatory agents - Indomethacin
• Analgesics - Acetaminophen
• Cardiovascular agents - Nicotinic acid (Niacin)

BASICITY OF PYRIDINE

• Pyridine have molecular formula: $C_5H_5N$
• It contain Nitrogen (N). Nitrogen have 5 valence electrons, which is available for protonation (N) and a lone pair.
• So, Pyridine behaves as a base, because it contain lone pair of electron, so it can donate lone pair.
• Acc. to lewis, Those substances which can donate lone pair of electrons are know as Bases.
• When pyridine is react with acid, it form salts. So it is basic in nature.

Resonance Structure of Pyridine

• Pyridine is weaker base, it has resonance structure which make it stable. So, it is weak basic in nature.
• Pyridine has a ($pK_b$) value of 8.77, which indicates its basic strength.
• It is weaker base than alkylamines but stronger than aniline ($pK_b=9.42$)

Pyridine is more basic than Pyrrole

• Pyridine is a stronger base than pyrrole (or aniline) in which the basicity is reduced by delocalization of N lone pair.
• In pyridine, N does not involved in the resonance and those lone pair of electrons are readily available for reactions.
• In pyrrole, N involved in the resonance (delocalisation) and those lone pair of electrons are not readily available for reactions.

Pyridine is less basic than aliphatic amines

• Pyridine is less basic than aliphatic amines, because pyridine has resonance structure which make it more stable. $\uparrow$ stability = $\downarrow$ Basicity.
• Aliphatic amines has no resonance, so it is less stable. $\downarrow$ Stability = $\uparrow$ Basicity.
• $R-NH_2$ (Aliphatic amines) > Pyridine > Pyrrole

IMIDAZOLE

• Imidazole is a heterocyclic compound with the formula $C_3H_4N_2$.
• It is a five-membered ring structure consisting of three carbon atoms and two nitrogen atoms at non-adjacent positions.

METHOD OF PREPARATION (SYNTHESIS)

1. Debus Method : In this synthesis, dicarbonyl compounds are condensed with aldehydes in presence of ammonia.

Benzil (dicarbonyl compound) + $2NH_3$ + $C_6H_5-CHO$ $\xrightarrow{-3H_2O}$ 2,4,5-triphenyl-1H-Imidazole

2. Dehydrogenation of Imidazoline : Barium mangnate convert imidazolines into imidazole in the presence of sulphur.

Ethylenediamine + R-COOH $\xrightarrow{-H_2O, -NH_3}$ 2-Alkyl-2-Imidazoline $\xrightarrow{BaMnO_4, S}$ 2-alkyl imidazole

3. From $\alpha$-haloketones : $\alpha$-haloketones reacts with amidines to form imidazole.

$C_6H_5-CO-CH_2-Br$ + $HN=CH-NH_2$ $\rightarrow$ 4-phenyl-1H-imidazole

4. From Aminonitrile : Mixture of aldehyde and aminonitrile on condensation gives imidazole.

$R-CHO$ + $R'-CH(NH_2)-CN$ $\rightarrow$ Imidazole derivative

CHEMICAL REACTIONS

1. Electrophilic Substitution reactions : It occurs at C-2, C-4, C-5 position, but at C-4 is more favourable.

• Halogenation: Imidazole $\xrightarrow{Br_2 \text{ or } Cl_2}$ 2,4,5-tribromo imidazole.
• Iodination: Imidazole $\xrightarrow{I_2 + KI}$ 4-Iodo imidazole
• Nitration: Imidazole $\xrightarrow{HNO_3 + H_2SO_4}$ 4-Nitro Imidazole

2. Oxidation : Oxidation of imidazole in presence of $H_2O_2$ leads to ring opening i.e. Oxalamide.

Imidazole + $H_2O_2$ $\rightarrow$ Oxalamide + $CO_2\uparrow$ + $H_2O$

3. Reaction with KOH : When imidazole react with KOH, it gives potassium salt.

Imidazole $\xrightarrow{KOH, -H_2O}$ Potassium salt of imidazole

MEDICINAL USES

• Metronidazole, is an anti-amoebic agent used for the treatment of amoebic dysentry.

• Methimazole & Carbimazole are used as anti-thyroid drugs which is used to control hyperthyroidism.

• Pilocarpine - parasympathomimetic agent used to treat glaucoma.

• Antifungal drugs - Miconazole, ketoconazole.

Write a short note on

1. Pyrazole

• It is a heterocyclic compound with the formula $C_3H_4N_2$.
• It is a five-membered ring structure consisting of three carbon atoms and two nitrogen atoms at adjacent position.

Medicinal Uses

• Used as analgesic (pain relievers) and antipyretic (fever reducers).
• Also used as anti-inflammatory (treat arthritis).
• Antiviral, Anti cancer.

2. Thiazole

• It is a heterocyclic compound with the formula $C_3H_3NS$, consisting of a five-membered ring containing both sulfur and Nitrogen atom.

Medicinal uses

• Used as antibacterial, antifungal, anti-inflammatory, antiviral etc.

3. Oxazole

• It is a heterocyclic compound with the formula $C_3H_3NO$ consisting of a five membered ring containing both oxygen & Nitrogen atom.

• Also used as Antibacterial, antifungal, anti-inflammatory.
• Eg: Oxacillin, Oxazepam.

4. Quinoline

• It is a heterocyclic aromatic compound with the formula $C_9H_7N$, consisting of a fused ring system containing a benzene ring and a pyridine ring.

• Chloroquine (Antimalarial)
• Mefloquine (Antimalarial)
• Ciprofloxacin (Antibacterial medication).

5. Isoquinoline

• It is a heterocyclic aromatic compound with the formula $C_9H_7N$, consisting of a fused ring system containing a benzene ring and a pyridine ring, but with a different ring fusion position than quinoline.

• Papaverine $\rightarrow$ Antispasmodic
• Drotaverine

PYRIMIDINE

• It is a heterocyclic aromatic compound with the formula $C_4H_4N_2$, consisting of a six-membered ring containing two Nitrogen atoms.

SYNTHESIS

1. Gabriel Synthesis

• It Involves reactions between urea and malonic acid to give barbituric acid, which on reaction with $POCl_3$ and Zn dust gives pyrimidine.

2. Whittaker Synthesis

• Reduction of 2,6-dichloropyrimidines by using Pd catalyst.

3. From Alkyl Pyridines

• Methyl pyrimidine $\xrightarrow{[O]}$ pyrimidine carboxylic acid $\xrightarrow[-CO_2]{CaO}$ pyrimidine

Medicinal Uses

• 5-fluorouracil - used as an anti-cancer agent.
• Sulfadoxine - Used as an bacterial agent.
• Barbital - used as sedative and Hypnotic.

PURINES

• These are a class of heterocyclic aromatic compounds. with the formula $C_5H_4N_4$, consisting of a fused ring system containing a pyrimidine ring and an imidazole ring.

METHOD OF PREPARATION / SYNTHESIS

1. Fischer Method : It involves conversion of uric acid into 2,6,8-trichloropurine by reaction with $POCl_3$. Excess of chlorine atoms are removed by reduction with HI to form purines.

2. Traube's Method : Heating of 4,5-diamino pyrimidines with formic acid to give purines.

3. From Formamide :

MEDICINAL USES

• Adenine a component of DNA/RNA
• Guanine a component of DNA/RNA
• Caffeine stimulant and vasodilator
• Mercaptopurines Anticancer medications

DERIVATIVES

• Hypoxanthine
• Xanthine
• Uric acid
• Caffeines etc..