2. ➢ 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 rule and hence it is Aromatic heterocyclic
compound.
➢ Molecular formula: C3N2H4
3. SYNTHESIS
1. Debus Radiszewski synthesis:
❖ This is probably the most important synthesis of imidazoles.
❖ It consists of condensing a dicarbonyl compounds such as
glyoxal, α-keto aldehydes or diketones with an aldehyde in
the presence of ammonia.
❖ Benzil with benzaldehyde and two molecules of ammonia
reacts to yield 2,4,5-triphenylimidazole.
4. SYNTHESIS
2. Dehydrogenation of Imidazolines:
❖ Imidazoles prepared by dehydrogenation of imidazolines in
presence of milder reagent, barium managanate.
❖ Imidazolines obtained from alkyl nitriles and 1,2-
ethanediamine on reaction with BaMnO4 yields 2-
substituted imidazoles.
5. SYNTHESIS
3. From α-Halo ketones:
❖ This reaction involves an interaction between an amidine and
an α-halo ketone.
❖ Phenacyl bromide and benzamidine affords 2,4-
diphenylimidazole.
6. SYNTHESIS
4. From oxazole:
➢ Oxazole undergo ring transformation when
treated with ammonia, formamide,
hydrazine or amines in the presence of
acids.
7. ❖Imidazole is an amphoteric substance.
❖ With acid act as proton acceptor
❖With base act as proton donor
8. 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.
9. i) Nitration
Imidazole on nitration with nitrating mixture- fuming HNO3 &
H2SO4 afford 4(5)-nitroimidazole.
ii) Sulphonation
Imidazole on sulphonation with sulphuric acid afford
imidazole-4(5)-sulphonic acid.
10. 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.
iv) Iodination
Imidazole is iodinated only under alkaline conditions and
produces 2,4,5-triiodoimidazole.
11. iv) Diazo coupling reaction
▪ N-unsubstituted imidazole substituted with activating
substituents (electron releasing) undergo diazo coupling
readily in alkaline medium preferentially at the position 2.
▪ The presence of electron releasing substituents on the
imidazole facilitates diazo coupling, while the electron
withdrawing substituents deactivate the imidazole towards
diazonium ion.
12. 2. Oxidation
Imidazole ring is resistant to oxidation but it is
degraded by hydrogen peroxide and perbenzoic acid.
13. 3. Cycloaddition reaction
Imidazoles undergo addition across the C=C under
photochemical conditions.
Eg: The reactions of imidazoles with benzophenone and
acrylonitrile.
19. ➢ Oxazole is an unsaturated five membered
heterocyclic ring consists of oxygen and nitrogen as
hetero atoms at 1st and 3rd positions.
➢ It follows Huckel rule and hence it is Aromatic
heterocyclic compound.
➢ Molecular formula: C3H3 ON
20. ➢ 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 liquid, b.p-69°C and has an odour
resembling like pyridine.
➢ It is weakly basic.
2-oxazoline 3-oxazoline 4-oxazoline oxazolidine
21. SYNTHESIS
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 or a strong
mineral acid.
23. SYNTHESIS
2. From α-hydroxy ketones:
➢ It is a simple method reported by Bredereck and
Bangert
➢ It involves a reaction between ethyl α-hydroxy
keto succinate and formamide to give
diethyloxazole-4,5-dicarboxylate which is
subsequently hydrolysed and decarboxylated to
oxazole.
26. SYNTHESIS
4. Fischer oxazole synthesis:
❑ Reaction of cyanohydrin with aromatic
aldehyde in presence of anhydrous ether
and dry HCl afford oxazole derivatives.
27. 1. Electrophilic substitution reactions
✓ Oxazole is more reactive towards electrophilic
substitution than thiazole but less than imidazole.
✓ The preferred attack takes place at position -5.
✓ Electrophilic attack, however, occurs readily when
the ring is activated by electron donating
substituents.
✓ The ring positions react in the order 5 > 4 > 2
28. i) Bromination
✓ Bromination in presence of N-bromo succinimide (NBS)
of 2-phenyloxazole results in 5-bromo-2-phenyloxazole.
29. ii) Nitration
✓ Nitration and sulfonation of oxazole itself are difficult because of the
presence of pyridine type nitrogen.
✓ Nitration of 2-phenyloxazole furnishes p-nitrophenyl oxazole.
iii) Sulphonation
30. 2) Diels-Alder reaction
▪ Diel’s-Alder cycloaddition of oxazole (conjugated
diene) and dienophile produces pyridine
derivatives.
31. 3) Oxidation
▪ Oxazole ring is not stable to oxidative conditions and thus is opened by the
action of oxidising agents such as cold potassium permanganate, chromic
acid and Ozone.
▪ 2,4,5-triphenyloxazole affords a quantitative yield of benzoic acid with
chromic acid.
▪ Oxazole is normally stable to the action of hydrogen peroxide.
▪ 4-(2-oxazolyl)pyridine with H2O2 gives the pyridine N-oxide derivative.
32. 4) Reduction
▪ Oxazole on reduction with sodium in ethanol yields
oxazolidines.
▪ 2,5-diphenyloxazole is reduced finally to 2-benzylamino-1-
phenylethanol by lithium aluminium hydride (LiAlH4)
33. 1. Oxaprozin
Oxaprozin is a NSAID used symptomatically treat
inflammation, pain and rheumatoid arthritis.
34. 2. Benoxaprofen, Flunoxaprofen
These are used as analgesic, antipyretic and anti-
inflammatory drugs. It was given to patients with
rheumatoid arthritis and osteoarthritis.
38. ➢ Thiazole is an unsaturated five membered
heterocyclic ring consists of sulphur and nitrogen
as hetero atoms at 1st and 3rd positions.
➢ It follows Huckel rule and hence it is Aromatic
heterocyclic compound.
➢ Molecular formula: C3H3 SN
39. ➢ The Partially reduced thiazoles are called
thiazolines and three types are possible depending on
the position of the double bond.
➢ Thiazole is a colourless liquid, b.p-177°C and has an
odour resembling like pyridine.
➢ It is weakly basic.
2-thiazoline 3-thiazoline 4-thiazoline
40. SYNTHESIS
1. Robinson-Gabriel synthesis:
❖ This synthesis involves heating of acylamino ketone
with phosphorus pentasulphide to give thiazole
derivatives.
❖ The carbonyl group is probably attacked first by P2S5,
the oxygen atom being replaced by sulphur and the
intermediate cyclizes to thiazole.
N-(2-Oxopropyl)acetamide
41. SYNTHESIS
2. Hanstch Thiazole synthesis:
❖ This method involves condensation of an α-
haloketones with thioamides or thiourea to yield
thiazole derivatives.
❖ Eg: Chloroacetaldehyde on condensation with
thioformamide affords thiazole.
42. SYNTHESIS
3. Cook Heilborn synthesis:
❖ This synthesis involves condensation of α-
aminonitrile with carbon disulphide.
43. SYNTHESIS
4. From thioamides :
❖ Thiazole derivatives may obtained by reacting a
thioamide with substituted 2-chloro 2-
chloromethyl)oxiranes.
44. 1. Electrophilic substitution reactions
✓ The electrophilic attack preferably takes place at position- 5
in presence of electron releasing groups.
Bromination
▪ If electron releasing groups are present, then bromination is
easily achieved.
45. Sulphonation
✓ sulphonation of thiazole may be achieved under
drastic conditions in the presence of mercury
sulphate as catalyst to give thiazole-5-sulphonic
acid.
HgSO4
46. 2. Nucleophilic substitution reactions
✓ The C-2 position being susceptible to nucleophilic attack.
✓ The reaction of potassium amide in liq. ammonia with
thiazole affords 2-aminothiazole.
✓ With n-butyllithium, the position-2 is metalated to yield
thiazole-2-lithium.
47. 3. Reduction
✓ Thiazole ring is resistant to the action of many
reducing agents, although Raney Nickel can be
used for desulphurization reactions.
48. 4. Formation of Quaternary ammonium
salts
✓ The quaternization of thiazole takes place at
position-3.
49. 1. Sulphathiazole
➢It is short acting sulphonamide antibiotics
used to treat bacterial infections.
50. 2. Thiabendazole
➢ It is an anthelmintic drug used to treat infections
caused by worms such as threadworm. It may also
be used to treat pinworm, hookworm and
roundworm infections.
51. 3. Niridazole
➢ It is anthelminthic drug used as schistosomicide.
Schistomiasis is helminthic disease caused by certain
flatworms.
52. 4. Famotidine
➢ It is H2 receptor antagonist, used to treat and
prevent ulcers in the stomach and intestines.
