Chemistry Reference
In-Depth Information
Basicity of heterocyclic compounds
Many drugs and biologically active compounds contain nitrogen in a hetero-
cyclic ring. While a full discussion of their basicity is beyond the scope
of
this topic, a brief
summary of
factors influencing basicity will be
considered.
In
aliphatic heterocyclic compounds
, the nitrogen atom is part of a
saturated heterocyclic ring and the lone pair of electrons is available for
reaction with protons (e.g. piperidine, Figure 3.19). Compounds of this type
are similar in base strength to their open-chain aliphatic counterparts with
typical p
K
a
values of 8-9.
In
aromatic heterocyclic compounds
, lone pairs on the nitrogen atoms
are involved in interaction with electrons of the aromatic ring. In pyrrole
(Figure 3.19), the lone pair contributes to the aromatic sextet and is not
available for reaction with protons. As a result, pyrrole is a very weak base
with a p
K
a
value so low that it is a negative number.
The six-membered nitrogen heterocycle pyridine (Figure 3.19) is also
a weak base. In the case of pyridine, however, only one electron from the
nitrogen contributes to the aromatic sextet. This leaves an unshared pair of
electrons, which can accept a proton, so that pyridine is measurably basic
with a p
K
a
value of 5.2. This value is similar to that found in aromatic
amines such as aniline (aminobenzene).
Separation of mixtures
It is often the case that pharmaceutical and/or chemical procedures give rise
to mixtures of chemicals. These could arise as a result of incomplete chem-
ical reaction, as in the case of side-reactions and by-products, or when
drugs have to be isolated from complex mixtures of chemicals (e.g. isolation
of a drug metabolite from a blood or urine sample). Knowledge of the
acidity and basicity of drugs is essential if efficient separation is to
be achieved. When a drug molecule ionises, the solubility profile of the
compound changes dramatically. Free acids and bases when they are
unionised tend to dissolve well in non-polar organic solvents such as diethyl
ether, chloroform or ethyl acetate. Upon ionisation, the acid will form an
anion and the base will form a conjugate acid. These will both be more
soluble in aqueous solvents such as water or buffer. This means that acidic
drugs are soluble in organic solvents at low pH (when they are primarily
unionised) and soluble in polar solvents at high pH. Bases, conversely, are
soluble in organic solvents when the pH is high (and the base is unionised)
and are water soluble at low values of pH.
