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Enzymes are Wonderful Catalysts 33
be illustrated by intramolecular reactions in organic chemistry, which is where
we shall begin the discussion.
3.3 Proximity effects
There are many examples of organic reactions that are intramolecular: that is,
they involve two or more functional groups within the same molecule, rather
than functional groups in diVerent molecules. Intramolecular reactions generally
proceed much more rapidly and under much milder reaction conditions
than their intermolecular counterparts, which makes sense since the two
reacting groups are already ‘in close proximity’ to one another. But how can
can we explain these eVects
A useful concept in quantitating proximity eVects is that of eVective concentration.
In order to deWne the eVective concentration of a participating group
(nucleophile, base, etc.), we compare the rate of the intramolecular reaction
with the rate of the corresponding intermolecular reaction where the reagent
and the participating group are present in separate molecules. The eVective
concentration of the participating group is deWned as the concentration of
reagent present in the intermolecular reaction required to give the same rate
as the intramolecular reaction.
I will illustrate this using data for the rates of hydrolysis of a series of phenyl
esters in aqueous solution at pH 7, given in Figure 3.5. The reference reaction in
this case is the hydrolysis of phenyl acetate catalysed by sodium acetate at the
same pH. Introduction of a carboxylate group into the same molecule as the
ester leads to an enhancement of the rate of ester hydrolysis, which for phenyl
succinate (see Figure 3.5 (3) ) is 23 000-fold faster than phenyl acetate (see
Figure 3.5 (1) ). This remarkable rate acceleration is because the neighbouring
carboxylate group can attack the ester to form a cyclic anhydride intermediate,
shown in Figure 3.6. This intermediate is more reactive than the original ester
group and so hydrolyses rapidly.
Note that the rate acceleration is largest when a Wve-membered anhydride is
formed, since Wve-membered ring formation is kinetically favoured over
six-membered ring formation, which in turn is greatly favoured over three-,
four- and seven-membered ring formation. The eVective concentration can be
worked out by comparing the rates of these intramolecular reactions with the
rates of the intermolecular reaction between phenyl acetate and sodium acetate
in water. For phenyl succinate an eVective concentration of 4 000 m is found, so
the hydrolysis of phenyl succinate proceeds much faster than if phenyl acetate
was surrounded completely by acetate ions! Here we start to see the catalytic
potential of proximity eVects.
In the same series of phenyl esters, if the possible ring size of Wve is
maintained, but a cis- double bond is placed in between the reacting groups,