Chemistry Reference
In-Depth Information
the lone pair of electrons on the nitrogen is available for reaction with
protons. In the case of amides, the carbon-nitrogen bond has significant
double-bond character due to resonance, as shown in Figure 3.10. The lone
pair of electrons on the nitrogen of some drug molecules can be completely
unavailable for reaction with protons. Drugs of this type are so weakly basic
that they actually behave as
acids
in solution. This effect can be illustrated
by considering the compounds below.
O
-
O
R
C
R
C
+
H
2
ยจ
NH
2
Figure 3.10
Resonance effects of the amide group.
Phenylbutazone
Phenylbutazone is a non-steroidal anti-inflammatory drug (or NSAID) that
exerts its anti-inflammatory action through inhibition of the enzyme cyclo-
oxygenase and inhibition of the production of inflammatory mediators
such as prostaglandins. Phenylbutazone, despite containing nitrogen, is a
weak acid with a p
K
a
of 4.4. The acidic hydrogen is on the 4-position of the
pyrazolidinedione ring and upon ionisation the negative charge is delo-
calised onto the adjacent carbonyl groups in a similar manner to that in
warfarin (p
K
a
5.0). See Figure 3.11.
Indometacin
Indometacin is another NSAID with a similar mode of action to that of
phenylbutazone. Indometacin is acidic due to ionisation of the carboxylic
acid group and has a p
K
a
value of 4.5. The nitrogen atom in indometacin is
present as an amide and is essentially neutral. See Figure 3.12.
Barbiturates
Barbiturates are cyclic imides used as hypnotics and (in the case of pheno-
barbital) as anticonvulsants. They are all derivatives of barbituric acid
(which is not pharmacologically active) and differ only in their substituents
on the 5-position of the ring. Barbiturates contain nitrogen atoms, but the
lone pair on the nitrogen is not available for reaction with protons, so barbit-
urates are not basic. Instead, they behave as weak acids in solution
(diprotic actually, though the second ionisation is very weak); the negative
