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

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

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