Chemistry Reference
In-Depth Information
essential antioxidants. It is a sad reflection on our society that much more
time, money and advertising are spent on expensive cosmetic 'remedies' for
ageing than are spent ensuring a healthy diet for all in the population.
Hydrolysis
Hydrolysis, in its widest sense, is the breaking of a chemical bond due to the
reaction of water. This contrasts with
hydration
, which is the addition of
the elements of water to a multiple bond, but with no associated fragmen-
tation of the molecule. A large number of functional groups found in drugs
are prone to hydrolysis on storage (see Figure 8.17), but the most commonly
encountered are esters and amides.
The hydrolysis of esters and amides occurs as a result of nucleophilic
attack on the carbon of the carbonyl group and subsequent cleavage of the
carbon-oxygen or carbon-nitrogen single bond. The carbon of the carbonyl
group is more positive than expected as a result of the high electronegativity
of the adjacent oxygen. The unequal sharing of the bond electrons causes a
polarisation of the bond so that the carbon bears a partial positive charge
(d
), while the oxygen has a partial negative charge (d
).
Hydrolysis reactions occur quite slowly, but, in the presence of acid or
alkali, the rate of the reaction increases and significant decomposition can
occur. It should be remembered that many drugs are amines, which can be
rendered water-soluble by formation of their hydrochloride salt. Salts of
weak bases and strong mineral acids are acidic by partial hydrolysis (see
Chapter 1 if this is not familiar) and the H
formed by hydrolysis of the salt
can catalyse hydrolysis reactions on the drug itself. Similarly, drugs that are
salts of weak acids with strong bases are alkaline in solution and the OH
produced by partial hydrolysis of the salt can act as a catalyst and
bring about decomposition. The mechanisms of acid- and base-catalysed
hydrolysis of esters are shown in Figures 8.18 and 8.19; the mechanisms for
hydrolysis of amides are similar.
Acid-catalysed hydrolysis
The initial protonation on the carbonyl oxygen produces a resonance
stabilised cation; this increases the electrophilicity of the carbonyl group,
making it susceptible to attack by the nucleophilic water (Figure 8.18).
Proton transfer from the water to the alcohol converts the latter into
a better leaving group (G). Incidentally, this mechanism is the reverse of the
mechanism for formation of an ester from an acid and an alcohol under
acidic conditions (esterification).
