Chemistry Reference
In-Depth Information
Figure 6.9 Metal hydroxides in nitrile hydration (8 and 9) and amide
hydrolysis (9 and 10).
6.5
Leaving-group Activation
Leaving-group activation could be considered to be the reverse of nucleophile activa-
tion. In ester hydrolysis, metal ions can activate the leaving group by coordinating to
the leaving group oxygen and lowering the basicity of the alkoxide [50, 51]. When
strong nucleophiles (e.g. hydroxide or alkoxide) are used to cleave esters with good
leaving groups (e.g. p-nitrophenol or acetate), the reaction takes place rapidly and
the Brønsted coefficient (
lg
) is about 0.3 [52]. In such cases, lowering the basicity
of the leaving group by 10 log units through metal coordination will result in about
a thousand-fold increase in the cleavage reaction rate. When weak nucleophiles (e.g.
acetate or phenoxide) are used to cleave esters with poor leaving groups (e.g. alkoxide),
the reaction is slow and
b
b
lg
approaches 1.0 [52]. In this case, a ten-fold decrease in
basicity of the leaving group will result in a matching increase in the rate of hydrolysis.
In amide hydrolysis, the leaving group amines are generally basic enough to be pro-
tonated at neutral pH (Figure 6.10). Leaving-group activation by metal coordination is
not important for amide hydrolysis since protonated amines are stronger acids (and
better leaving groups) than metal coordinated amines. In general, groups that are ea-
sily protonated will not be activated by metal ions (Figures 6.6 and 6.10).
For the transesterification and hydrolysis of phosphate diesters,
b
lg
ranges from
about 0.67 to 0.76 [53, 54]. Thus, leaving-group activation by metal coordination should
result in a large rate acceleration (~10
7
-10
8
-fold) for both transesterification of RNA
and hydrolysis of DNA. However, it is a challenge to design metal complexes that will
bind well enough to the leaving group oxygen of carboxyl and phosphate esters.
Figure 6.10 Tetrahedral intermediate for amide hydrolysis.
