FIVE-MEMBERED RINGS WITH TWO HETEROATOMS
433
aliphatic amine piperidine (pK a 11.1), we implicated
the higher s character of the pyridine lone pair (sp
2 )
compared with that in piperidine (sp
3 ) to account for
pyridine’s lower basicity (see Section 11.4.1). Even
so, imidazole seems abnormally basic for a compound
with sp
2 -hybridized nitrogen. The enhanced basicity
of imidazole appears to stem from the symmetry
of the conjugate acid, and the resonance stability
conferred by this. The 1,3-relationship allows the two
nitrogen atoms to share the charge equally. Note that
pK a 7.0 means imidazole is 50% protonated in water
(see Section 4.9).
N
N
imidazole
N
N
N
N
H
H
H
N
N
H
H
N
N
pK a 7.0
pK a 14.2
equivalent resonance structures
equivalent resonance structures
Imidazole (pK a 14.2) is also more acidic than pyrrole
(pK a 17.5); this, again, is a feature conferred by
symmetry and the enhanced resonance stabilization
in the conjugate base.
N
N
H
N
O
N
S
H
H
H
pK a 7.0
pK a 0.8
pK a 2.5
Oxazole (pK a 0.8) and thiazole (pK a 2.5) are weak
bases. The basicity of the nitrogen is reduced by the
presence of the other heteroatom. Oxygen and sulfur
provide a stronger electron-withdrawing inductive
effect, compared with nitrogen, but a much weaker
electron-releasing resonance effect.
11.7.2 Tautomerism in imidazoles
A complicating factor in imidazoles is tautomerism.
Imidazole tautomerizes rapidly in solution and consists of two identical tautomers. This becomes a
problem, though, in an unsymmetrically substituted
imidazole, and tautomerism means 4-methylimidazole
is in equilibrium with 5-methylimidazole. Depending upon substituents, one tautomer may predominate. Tautomerism of this kind cannot occur with
N -substituted imidazoles; it is totally dependent upon
the presence of an N–H group. Tautomerism is also
not possible with oxazoles or thiazoles.
N
N
N
N
H
H
identical tautomers of imidazole
N
N
N
N
H
H
non-identical tautomers of methylimidazole;
this compound may be termed 4(5)-methylimidazole
H 3 C
H 3 C
4-methyl-1H-imidazole
5-methyl-1H-imidazole
≡
N
N
H
H 3 C
N
N
CH 3
tautomerism
not possible
Therefore, when we meet structures for the imidazolecontaining amino acid histidine, we may encounter
either of the tautomeric forms shown. Though there
will usually be no indication that tautomers exist, do
not think there is a discrepancy in structures.
CO 2 H
NH 2
N
NH
L-histidine
HN
N
CO 2 H
NH 2
tautomeric forms
of histidine
433
aliphatic amine piperidine (pK a 11.1), we implicated
the higher s character of the pyridine lone pair (sp
2 )
compared with that in piperidine (sp
3 ) to account for
pyridine’s lower basicity (see Section 11.4.1). Even
so, imidazole seems abnormally basic for a compound
with sp
2 -hybridized nitrogen. The enhanced basicity
of imidazole appears to stem from the symmetry
of the conjugate acid, and the resonance stability
conferred by this. The 1,3-relationship allows the two
nitrogen atoms to share the charge equally. Note that
pK a 7.0 means imidazole is 50% protonated in water
(see Section 4.9).
N
N
imidazole
N
N
N
N
H
H
H
N
N
H
H
N
N
pK a 7.0
pK a 14.2
equivalent resonance structures
equivalent resonance structures
Imidazole (pK a 14.2) is also more acidic than pyrrole
(pK a 17.5); this, again, is a feature conferred by
symmetry and the enhanced resonance stabilization
in the conjugate base.
N
N
H
N
O
N
S
H
H
H
pK a 7.0
pK a 0.8
pK a 2.5
Oxazole (pK a 0.8) and thiazole (pK a 2.5) are weak
bases. The basicity of the nitrogen is reduced by the
presence of the other heteroatom. Oxygen and sulfur
provide a stronger electron-withdrawing inductive
effect, compared with nitrogen, but a much weaker
electron-releasing resonance effect.
11.7.2 Tautomerism in imidazoles
A complicating factor in imidazoles is tautomerism.
Imidazole tautomerizes rapidly in solution and consists of two identical tautomers. This becomes a
problem, though, in an unsymmetrically substituted
imidazole, and tautomerism means 4-methylimidazole
is in equilibrium with 5-methylimidazole. Depending upon substituents, one tautomer may predominate. Tautomerism of this kind cannot occur with
N -substituted imidazoles; it is totally dependent upon
the presence of an N–H group. Tautomerism is also
not possible with oxazoles or thiazoles.
N
N
N
N
H
H
identical tautomers of imidazole
N
N
N
N
H
H
non-identical tautomers of methylimidazole;
this compound may be termed 4(5)-methylimidazole
H 3 C
H 3 C
4-methyl-1H-imidazole
5-methyl-1H-imidazole
≡
N
N
H
H 3 C
N
N
CH 3
tautomerism
not possible
Therefore, when we meet structures for the imidazolecontaining amino acid histidine, we may encounter
either of the tautomeric forms shown. Though there
will usually be no indication that tautomers exist, do
not think there is a discrepancy in structures.
CO 2 H
NH 2
N
NH
L-histidine
HN
N
CO 2 H
NH 2
tautomeric forms
of histidine