1,3 - Azoles

Heterocyclic compounds, Musab Moahmed (B.Pharm, MSc) 1

1,3-Azoles
• The three 1,3 - azoles, imidazole, thiazole and oxazole, are all very stable
compounds that do not autoxidise.

• The dihydro - and tetrahydro are named imidazoline/imidazolidine,

thiazoline/thiazolidine and oxazoline/oxazolidine.

Heterocyclic compounds, Musab Moahmed (B.Pharm, MSc) 2

1,3 – Azoles: Reactions at Nitrogen
• Protonation:
• 1,3 Azoles form stable salts with strong acids, by protonation of the imine
nitrogen(N – 3) giving imidazolium, thiazolium and oxazolium
salts.

• Imidazole, like water, is both a good donor and a good acceptor of

hydrogen bonds; making intermolecular H-bonds.

Heterocyclic compounds, Musab Moahmed (B.Pharm, MSc) 3

1,3 – Azoles: Reactions at Nitrogen
• Imidazoles with a ring N- hydrogen are subject to tautomerism.

All such tautomeric pairs are inseparable and the convention used to cover
this phenomenon is to write ‘ 4(5) - methylimidazole ’ .

Heterocyclic compounds, Musab Moahmed (B.Pharm, MSc) 4

1,3 – Azoles: Reactions at Nitrogen
• Alkylation at Nitrogen:
• The 1,3 - azoles are quaternised easily at the imine nitrogen with alkyl
halides.
• In the case of imidazoles that have an N- hydrogen, the immediate product
is a protonated N- alkyl – imidazole, which can lose its N- hydrogen to
unreacted imidazole (acting as a base) and react a second time.
• Thus reactions with alkyl halides give mixtures of imidazolium, 1 - alkyl -
imidazolium and 1,3 - dialkyl - imidazolium salts.

Heterocyclic compounds, Musab Moahmed (B.Pharm, MSc) 5

1,3 – Azoles: Reactions at Nitrogen
• Acylation at Nitrogen:
• Acylation of imidazole produces N- acylimidazoles that easily hydrolysed
than N- acyl – pyrroles.

Heterocyclic compounds, Musab Moahmed (B.Pharm, MSc) 6

1,3 – Azoles: Substitution at Carbon (EAS) (HOMW WORK)
• Nitration

• Sulfonation

• Halogenation

• Acylation
• Friedel – Crafts acylations are unknown for the azoles; clearly because of
interaction between the basic nitrogen and the Lewis - acid catalyst. 7
1,3 – Azoles: Reactions with Bases
• Imidazole is appreciably stronger acid than pyrrole (pKa 17.5) because of
the enhanced delocalization of charge, involving both nitrogens in the
imidazolyl anion.
• Salts of imidazoles can be alkylated or acylated on nitrogen.

Heterocyclic compounds, Musab Moahmed (B.Pharm, MSc) 8

1,3 – Azoles: C-Metallation
• The specific deprotonation takes place preferentially at C - 2, or at C - 5 if
the former position is substituted.
• For example, the sequence shown below produces SEM - protected 5 -
substituted imidazoles with retention of a 2 - silyl - substituent if
required.

• The regioselectivity of metal – halogen exchange processes mirrors the C –

H metallations discussed above: thus 2,4 - dibromothiazole reacts at C - 2
firstly.

Heterocyclic compounds, Musab Moahmed (B.Pharm, MSc) 9

1,2 – Azoles: pyrazole

Heterocyclic compounds, Musab Moahmed (B.Pharm, MSc) 10

Pyrazole
• As for imidazole, pyrazoles undergoes rapid tautomerism, involving
switching of hydrogen from one nitrogen to the other.
• Thus substituted pyrazoles are inevitably mixtures, and named similar to
imidazoles : 3(5) – methylpyrazole.
• Also they form intermolecular hydrogen bonding.

Heterocyclic compounds, Musab Moahmed (B.Pharm, MSc) 11

Pyrazole: Addition at Nitrogen
• Protonation:

• Acylation:
• The introduction of an acyl or phenylsulfonyl group onto a pyrazole
nitrogen is usually achieved in the presence of a weak base, such as
pyridine.

Heterocyclic compounds, Musab Moahmed (B.Pharm, MSc) 12

Pyrazole: Substitution at Carbon
• Nitration:
Pyrazole undergo straightforward nitration, at C – 4 giving 4 – nitropyrazole

• Halogenation:
Halogenation of pyrazole gives 4 - monohalo – pyrazoles.

Heterocyclic compounds, Musab Moahmed (B.Pharm, MSc) 13

Pyrazole: Reactions with Bases
• Pyrazole appreciably stronger acid than pyrrole (pKa 17.5), and the same as
that of imidazole.

• N- Alkylations can be conducted in strongly basic conditions and it seems

likely that under these conditions it is the pyrazolyl anion that is
alkylated.

Heterocyclic compounds, Musab Moahmed (B.Pharm, MSc) 14