Previous work has indicated an aziridinium ion mechanism in the hydrol
ysis of chlorambucil, and the present work on the alkylation of nucleo
philes fully supports this mechanism. This mechanism forms the basis f
or understanding the kinetics of alkylation reactions because their ra
tes are limited by the rate of formation of the aziridinium ion and th
e alkylation reaction competes with the hydrolytic reaction. We have m
easured alpha(N), where alpha(N)(N) is the rate of reaction of the azi
ridinium ion with a nucleophile N relative to its reaction with water
for several nucleophiles that are related to those found in proteins.
The alpha values for hydroxide ion and some other bases are greater th
an 10(3), but the effective values at pH 7.5 are much smaller because
there is little base present. The kinetic equations show that it is ve
ry difficult to alkylate a nucleophile extensively at pH 7.5 before ch
lorambucil has hydrolyzed. Therefore, it is not clear why angiotensin-
converting enzyme is completely inhibited by low concentrations of chl
orambucil. On the other hand, damage to DNA is easily understood.