Chemistry, Reactivity, Properties, and Synthesis of Imidazole & Oxazole

Chemistry of Imidazole & Oxazole

Session Objectives

By the end of this session, students will be able to:

• Discuss the various method of synthesis of Imidazole and Oxazole

• Discuss the chemistry, reactivity, properties of Imidazole and Oxazole

Chemistry of Imidazole

• Imidazole is isomeric with pyrazole or azapyrrole

• Also called as glyoxaline, as it was first prepared in 1858 from glyoxal and ammonia

• Imino nitrogen is assigned position-1 while tertiary nitrogen atom position-3

• Imidiazole nucleus is found in number of naturally occurring compounds such as histamine, histidine, pilocarpine and allantoin, purine nucleus, vitamin B12

• Since imidazole also exists in tautomeric forms, either of the nitrogen can bear the hydrogen atom and two nitrogen become indistinguishable

• Numbering becomes rather complex for mono substitution

• For example, 4-methylimidazole is identical with 5-methylimidazole and depending on the position of imino hydrogen compound can be designated

• Such compound is designated as 4(5)-methyl imidazole

Physical properties of Imidazole

• Imidazole is colorless liquid with boiling point 256 0C and is high boiling point among all other five membered heterocyclic compounds

• Shows that hydrogen bonding exists in imidazole ring

• More basic with pka 7.2 than pyridine (pka 5.2)

Molecular Properties of Imidazole

• Shows amphoteric properties and behaves as an acid because it contains pyrrole type amino nitrogen in the ring

• Also forms metallic salts with NaNH2 and RMgX which are extensively hydrolysed by water

• Introduction of alkyl groups increases the basicity, 2-methylimidazole (pka 7.86) and 4(5)-methyl imidazole (pka 7.52)

Synthetic methods of Imidazole

1) Radiszewski Synthesis: most important and common method

• Consists of condensing a dicarbonyl compound such as glyoxal, α-keto aldehydes or α-diketones with aldehyde in the presence of ammonia

• Benzil with benzaldehyde and two molecules of ammonia react to yield 2,4,5-triphenylimidazole

2) Dehydrogenation of imidazolines: can be prepared by dehydrogenation of imidazolines. Milder reagent, barium manganate has been reported by Knapp and coworkers

• Imidazolines obtained from alkyl nitriles and 1,2-ethanediamine on reaction with BaMnO4 yields 2-substituted imidazole

Chemical properties of Imidazole

1) Reaction with acids: imidazole is a mono acidic base and forms crystalline salts with acids

• Also possesses weakly acidic properties (pseudo acidic) and is more acidic than pyrrole

• Forms salts with Grignard reagents or metal ions

 2) Electrophilic substitution:

• Imidazole has increased reactivity toward electrophilic attack and more susceptible than other five membered heterocycles

• From the resonance structures, electrophilic attack is preferred at 4(5) position in imidazole

3) Halogenation: very complex and depends upon type of substrate, reagents and reaction conditions

• Bromination (Br2/CHCl3) yields 2,4,5-tribromoderivative

• Iodination (alkaline conditions) yields 2,4,5-triiodoimidazole

Chemistry of Oxazole

• Oxazole is a 1,3-azole having an oxygen atom and a pyridine type nitrogen atom at 3-position in a five membered ring

• First introduced by Hantzsch in 1887 but was not synthesized until 1947

• Does not occur in nature and does not play any part in fundamental metabolism like imidazole or thiazole

• Partially reduced oxazoles are called oxazolines

• Three types are possible depending on position of double bond

• 2-oxazoline, 3-oxazoline and 4-oxazoline

• Fully saturated system is called oxazolidine- solids

Physical properties of Oxazole

• Oxazole is a liquid with boiling point 69 0C

• Odor resembling that of pyridine

• Miscible with water and many organic solvents

• Weakly basic (pka 0.8)

• Possess a sextet of π-electrons, delocalization is incomplete and has little aromatic character

• Function as dienes in the Diels-Alder reaction and electrophilic substitution is rare

Synthetic methods of Oxazole

1) From ethyl α-hydroxyl keto succinate: Bredereck and Bangert reported a simple method which involves a reaction between ethyl α-hydroxyl keto succinate and formamide to give diethyloxazole-4,5-dicarboxylate and subsequently hydrolysed and decarboxylated to isoxazole

2) Robinson Gabriel synthesis: most common method used for the synthesis of oxazoles

• Involves an α-acylamino ketone which undergoes cyclization and dehydration in the presence of phosphorus pentoxide or strong mineral acid

• Applicable for the synthesis of 2,5-aryloxazoles

Chemical reactions of Oxazole

1) Electrophilic substitution: preferred at 5th position of ring

• Occurs readily when ring is activated with electron donating substituents

• Bromination (NBS) of 2-phenyloxazole results in 5-bromo-2-phenyloxazole

• Nitration and sulfonation of oxazoles are difficult because of presence of pyridine type nitrogen

2) Diels-Alder reaction: behaves similar to furan

• Introduction of second heteroatom does not effect the diene nature of oxazole 

Summary

• Imidazole is isomeric with pyrazole

• Imidazole also exists in tautomeric forms

• High boiling point- Shows that hydrogen bonding exists in imidazole ring

• Shows amphoteric properties and behaves as an acid because it contains pyrrole type amino nitrogen in the ring

• Imidazole has increased reactivity toward electrophilic attack and more susceptible than other five membered heterocycles

• Oxazole is a 1,3-azole having an oxygen atom and a pyridine type nitrogen atom at 3-position in a five membered ring

• Function as dienes in the Diels-Alder reaction and electrophilic substitution is rare

• Electrophilic substitution: preferred at 5th position of ring