Chemistry Reference
In-Depth Information
6.6
Combining Lewis Acid Activation and Nucleophile Activation
Lewis acid activation (Figure 6.3) and nucleophile activation (Figure 6.8) may be com-
bined with one or more metal complexes to provide large rate accelerations for hydro-
lysis and other organic reactions. While Lewis acid activation alone (Figure 6.4) pro-
vides about 2
10
5
-fold rate acceleration for the hydrolysis of formyl morpholine, a
combination of Lewis acid activation and nucleophile activation (
12
) gives about 4
10
7
-fold rate acceleration for the hydrolysis reaction over the background hydroxide
rate at pH 7 [35]. For acetonitrile, combining Lewis acid activation and nucleophile
activation (
13
) gives about a 10
10
-fold rate acceleration for the hydration reaction
[41]. Thus, the combined activation provides an almost 10
4
-fold greater rate accelera-
tion than Lewis acid activation alone (Figure 6.4). For phosphate diesters, Lewis acid
activation gives a ca. 50-fold rate acceleration for the hydrolysis reaction [55]. The com-
bination of Lewis acid activation and nucleophile activation (
14
) gives about a 10
10
-fold
rate acceleration for the hydrolysis reaction (over the background hydroxide rate at pH
7) [43, 54]. Assuming Lewis acid and nucleophile activations are additive for each re-
action, nucleophile activation alone would provide 2
10
8
-fold
rate accelerations for the hydrolysis of formyl morpholine, acetonitrile and dimethyl
phosphate, respectively. The greater effect of nucleophile activation for phosphate die-
ster hydrolysis may be due in part to the longer P-O (
14
) bonds compared with C-O
(
12
) or C-N (
13
). The longer bond should result in less strain in the four-membered
ring transition state (Figure 6.11).
Interestingly, catalytic turnover can be achieved for the hydration of nitriles with the
Co(
III
) complex (
13
). Hence, fundamental information gained from studying intramo-
lecular model systems (
8
-
11
) that do not give catalytic turnover can be applied to obtain
true catalysts. Lewis acid activation and nucleophile activation can also be combined
using mononuclear Co(
III
) [56], Cu(
II
) [51] or Zn(
II
) [32] complexes to hydrolyze un-
activated esters with catalytic turnover.
The combination of Lewis acid and nucleophile activations in
12
-
14
requires four-
membered ring transition states. Interestingly, the mechanism for carboxypeptidase A
(CPA) catalyzed hydrolysis of peptides also appears to involve joint Lewis acid and
nucleophile activations that lead to the formation of a four-membered ring transition
state. Christianson and Lipscomb [57] have determined the crystal structure (
15
)ofa
ketone bound to CPA. Surprisingly, the ketone is in its hydrated form with both oxy-
gens of the gem-diol bound to the active-site zinc of CPA (Figure 6.12).
10
2
-, 5
10
3
-, and 2
Figure 6.11
Joint Lewis acid activation and nucleophile activation.
