Chemistry Reference
In-Depth Information
6.4
Nucleophile Activation
Metal hydroxides are thought to be involved in various hydrolytic metalloenzymes,
including carbonic anhydrase, carboxypeptidase, and nucleases [1-3]. Simple metal
hydroxides are active as nucleophilic catalysts for the hydration of carbon dioxide
and the hydrolysis of acetic anhydride and p-nitrophenyl acetate [31]. The rate of these
reactions is accelerated with increase in basicity of the metal hydroxide. The Brønsted
equation has been used to show the linear relationship between the pK
b
s of the metal
hydroxide and the logarithms of the rate constants for the hydration of carbon dioxide
(
b
nuc
= 0.15) and the hydrolysis of acetic anhydride (
b
nuc
= 0.25) and p-nitrophenyl
acetate (
nuc
) can be used to approximate
the extent of bond formation between the metal hydroxide and the substrate at the
transition state (Figure 6.8). With joint Lewis acid activation and metal hydroxide ac-
tivation, the extent of charge buildup on the carbonyl oxygen (Figure 6.3) should be
related to the extent of bond formation between the metal hydroxide and the substrate
(Figure 6.8).
A metal hydroxide that is well positioned next to the substrate could in principle
provide enormous rate acceleration for the hydrolysis reaction. If the metal hydroxide
is positioned such that the entropic barrier for hydrolysis is eliminated without affect-
ing the enthalpic barrier [44], the effective concentration of the metal hydroxide is ex-
pected to be about 10
8
M
[45]. The local concentration of this nucleophile would be 10
15
(10
8
/10
-7
) times greater than the background hydroxide concentration at neutral pH.
The basicity and nucleophilicity of a metal hydroxide is lower than those of the metal
free hydroxide. For a hydrolysis reaction with a
b
nuc
= 0.35). The Brønsted coefficients (
b
b
nuc
of 0.5, a metal hydroxide with a pK
b
of 7.0 would be about 10
4.4
times less reactive than hydroxide. Thus, a metal hydroxide
that is 10
4.4
times less reactive than hydroxide could still provide over a 10
10
-fold rate
acceleration (over the background hydroxide rate) for the hydrolysis reaction if the
effective molarity of the metal hydroxide is 10
8
M
.In
8
[46],
9
[47]
10
[48] and
11
[49] the well-positioned metal hydroxides provide enormous rate accelerations (10
7
to 10
9
) for hydration of the nitriles and hydrolysis of the amides (Figure 6.9). In gen-
eral, effective molarities of well-positioned intramolecular general base groups are
much lower (~1
M
) than those of intramolecular nucleophiles [45]. Consequently, there
is little advantage to using intramolecular metal hydroxides as general base catalysts
when compared with utilizing external general bases.
Figure 6.8 Metal hydroxide attack.
