Chemistry Reference
In-Depth Information
R
3
N
H
2
O
3
R
3
NH
OH
(3.4)
Water donates the proton and functions as an acid in this reaction. The
equilibrium constant for this reaction is defined as
K
b
and the greater the
value of
K
b
the stronger will be the base.
[R
3
NH
][OH
]
K
b
———--------
(3.5)
[R
3
N]
However, as was discussed in Chapter 1, most of the pharmaceutical
literature refers to the strength of bases in terms of the p
K
a
of the conjugate
acid of the base (R
3
NH
above). In this case,
the higher the value of pK
a
the
stronger is the base
.
Basic drugs are usually administered as their water-soluble salts
(generally the hydrochloride). Care must be taken not to co-administer
anything that will raise the pH of the hydrochloride salt solution in case
precipitation of the less water-soluble free base occurs.
The key point to remember about basicity of amines is the availability
of the lone pair of electrons on the nitrogen atom. If the lone pair is
involved in interactions elsewhere in the molecule, then the amine will not
be basic. This can be illustrated by consideration of the basicity of the local
anaesthetic procaine (see Figure 3.18). The nitrogen of the diethylamino
moiety is present in a tertiary amine. The lone pair of electrons is concen-
trated on the nitrogen atom and is available to accept a proton. This means
that the aliphatic nitrogen can ionise at the pH of human plasma (pH 7.4)
to form the mono-cation of procaine. Conversely, the lone pair of electrons
on the amino group attached to the benzene ring is less available for reac-
tion with protons due to delocalisation into the ring. This delocalisation
increases the electron density of the
ortho
and
para
carbon atoms and
means that the Ar-NH
2
group does not ionise at the pH of blood.
C
2
H
5
N
+ H
2
O
H
2
N
C
2
H
5
O
p
K
a
of N = 2
.
5
p
K
a
of N = 9
.
0
C
2
H
5
+
+ OH
-
N
H
H
2
N
C
2
H
5
O
Figure 3.18
The ionisation of procaine.
