Chemistry Reference
In-Depth Information
Figure 6.27 A3
0
,5
0
-exonuclease model.
b
lg
) is around 0.7. Thus, Lewis acid activation, metal-hydroxide
activation and leaving-group activation could add up to over 10
17
-fold rate acceleration
for DNA hydrolysis. The pseudo-first order rate constant for hydrolysis of a phosphate
diester bond of DNA has been estimated to be about 10
-19
s
-1
at neutral pH and 25
8
C
[13]. A 10
17
-fold rate acceleration for hydrolyzing DNA would reduce the half-life of the
phosphate diester bond from billions of years to about a minute or two.
A remarkable model system (
39
) (Figure 6.27) that combines some of the most sali-
ent features of the polymerase and the exonuclease has been reported [137]. The di-
nuclear metal complex
39
is highly efficient for catalyzing the transesterification of
dimethyl phosphate in methanol. This is an interesting result given the stability of
dimethyl phosphate (Table 6.1). The proposed mechanism for the transesterification
reaction involves two Lewis acid activations, metal-hydroxide activation and leaving-
group activation just as in the proposed mechanism for the exonuclease [Figure
6.26(B)]. Interestingly, the crystal structure of a transition state analog (
40
) for the
transesterification reaction has been obtained (Figure 6.27). Leaving-group activation
is important for the transesterification reaction since metal alkoxides (
35
) cannot be
used to displace rapidly strongly basic alkoxides.
Brønsted coefficient (
6.11
Conclusion
In summary, metal complexes can provide large rate-accelerations for hydrolyzing es-
ters, amides, nitriles, and phosphate mono-, di- and triesters. Combination of Lewis
acid activation and a well-positioned metal hydroxide is all that is required for hydro-
lyzing carboxyl esters, amides and nitriles under mild conditions (neutral pH, ambient
temperature). Dinuclear metal complexes are particularly effective for hydrolyzing
amides and nitriles. Double Lewis acid activation alone is enough for efficient cleavage
of RNA but not for hydrolyzing DNA. Combination of Lewis acid activation, nucleo-
phile activation and leaving-group activation is required to hydrolyze the phosphate
