Organic Chemistry - Heterocyclic Compounds - Azoles.pdf

Organic Chemistry Heterocyclic Compounds Five membered rings heterocyclic with two hetero atoms (azoles)| Lec.11 Azoles Contents : General structure of azoles 4 General features 5 Physical properties 8 Imidazole 10 Aromaticity and Basicity Basicity of imidazole compared to pyrrole Tautomeric forms o...

Organic Chemistry Heterocyclic Compounds Five membered rings heterocyclic with two hetero atoms (azoles)| Lec.11 Azoles Contents : General structure of azoles 4 General features 5 Physical properties 8 Imidazole 10 Aromaticity and Basicity Basicity of imidazole compared to pyrrole Tautomeric forms of imidazole Hydrogen bonding of imidazole Preparation of imidazoles Reactions of imidazoles Medicinal uses 12 14 15 16 17 20 27 Azoles Contents : Oxazole 29 Reduced forms of Oxazole 31 Synthesis of Oxazole 32 Azoles General structure of azoles: Azoles General features: Introduction of second heteroatom create azole (nitrogen is one of the heteroatoms). Numbering of the ring start from the heteroatom with higher atomic no. Like pyrrole, furan and thiophene all these rings are aromatics. All the compounds have group C=N- (azomethine , like N in pyridine) which have one unpaired of electrons. Azoles Note: This sign represents azomethine groups in these heterocyclic compounds Azoles 1,3 azole: Imidazole, Oxazole & Thiazole: Five membered ring contains two hetero atoms one of which is nitrogen. The other hetero atoms are N, O & S. All have a characterization of aromatic compounds. Azoles Physical properties: 1- Basicity Imidazole is the most basic compounds pKa= 7.0 Oxazole = 0.8 Thiazole = 2.5 The 1,3 azole are more basic than pyrrole (pKa= -3.8) Imidazole is more basic than pyridine (pKa= 5.2) Azoles 2- Boiling point Imidazole 250-255°C. Oxazole 69-70°C. Thiazole 116- 118°C. 3- Solubility Imidazole soluble in water, oxazole & thiazole springly soluble in water. Imidazole Azoles 1,3 azole: Imidazole: Imidazole is an important nucleus in heterocyclic chemistry. Imidazole is an unsaturated five membered heterocyclic ring consists of two nitrogens as hetero atoms at 1st and 3rd positions. It follows Huckel's rule and hence it is Aromatic heterocyclic compound. Molecular formula: C3N2H4 Azoles 1,3 azole: Imidazole: Aromaticity and Basicity: Azoles Nitrogen atom with pair of electrons-Azoles behave as bases as well as nucleophiles 1,2-azoles are less reactive than 1,3-azoles. Azoles Basicity of imidazole compared to pyrrole: Azoles Tautomeric forms of imidazole: It exists in two equivalent tautomeric forms, because the proton can be located on either of the two nitrogen atoms of Imidazole. Azoles Hydrogen bonding of imidazole: Imidazole is colorless liquid having a high B.P. of 256 0C than all other 5-membered heterocyclic compounds due to the intermolecular H-bonding, where there is linear association of molecules. Azoles Preparation of imidazole: 1. The condensation of a 1,2-dicarbonyl compound with ammonium acetate and an aldehyde results in the formation of an imidazole. Azoles 2. Dehydrogenation of imidazolines in presence of mild reagent; barium manganate (BaMnO4), it is an oxidant. Azoles 3. From Oxazole: Oxazole undergo ring transformation when treated with ammonia, hydrazine or amines in the presence of acids. Azoles Reactions: Imidazole is an amphoteric substance. With acid act as proton acceptor. With base act as proton donor. Azoles Reactions: 1. Electrophilic substitution reactions: Imidazole is more susceptible to electrophilic attack than pyrazole, thiazole, furan or thiophene. Electrophilic attack takes place at 4th or 5th position in imidazole. Electrophilic attack at C-2 involves a canonical form with a highly unfavoured positive nitrogen at position 3. Azoles Electrophilic substitution reactions: i. Nitration Imidazole on nitration with nitrating mixture - fuming HNO3, & H2SO4 afford 4 (5)-nitroimidazole. Azoles ii. Sulphonation Imidazole on sulphonation with sulphuric acid afford imidazole-4 (5)-sulphonic acid. Azoles iii. Bromination Imidazole is brominated very readily in aqueous solution or organic solvent with bromination at the available vacant positions providing 2,4,5-tribromoimidazole. Azoles iv. Iodination Imidazole is iodinated only under alkaline conditions and produces 2,4,5-triiodoimidazole. Azoles 2. Oxidation Imidazole ring is resistant to oxidation but it is degraded by hydrogen peroxide and perbenzoic acid. Azoles Medicinal uses: 1.Metronidazole Anti-amoebic agent for the treatment of amoebic dysentery. 2. Methimazole and carbimazole Antithyroid drugs, used to control hyperthyroidism. Azoles 3. Cimetidine H2 Antagonist-antiulcer drug used for the treatment of gastric and duodenal ulcers. Oxazole Azoles 1,3 azole; Oxazole: Oxazole is an unsaturated five membered heterocyclic ring consists of oxygen and nitrogen as hetero atoms at 1st and 3rd positions. It follows Huckel's rule and hence it is Aromatic heterocyclic compound. Molecular formula: C3H3ON Azoles Reduced forms of Oxazole: Partially reduced oxazoles are called oxazolines and three types are possible depending on the position of the double bond. The fully saturated system of oxazole is oxazolidine. Oxazole is s liquid, b.p:69°C and has an odour resembling lke pyridine. It is weakly basic. Azoles Synthesis of Oxazole: 1. Robinson-Gabriel synthesis: This is most common method used for the preparation of oxazoles. This method involves an α-acylamino ketone which undergoes cyclization and dehydration in the presence of phosphorus pentoxide (P2O5) or a strong mineral acid. Azoles 2. From a-hydroxy ketones: Azoles Example: