Chemistry Reference
In-Depth Information
Table 6.1 Second-order rate constant (k
OH
) for hydroxide-catalyzed hydrolysis of substrates at 25
8
C.
k
OH
(
M
-1
s
-1
)
Substrate
10
-1
CH
3
C(O)OCH
3
1.5
10
-6
CH
3
C(O)NHCH
3
5.6
10
-6
CH
3
CN
1.6
P(O)(OCH
3
)
3
1.6
10
-4
10
-12
NaOP(O)(OCH
3
)
2
6.8
cleavage) [19] is about the same as typical phosphodiester bonds in DNA and phos-
pholipids [13]. Not surprisingly, nature chose to preserve the genetic material using
the linkage that is by far the most difficult to hydrolyze.
Notably, although the hydroxide rate for methyl acetate hydrolysis is many orders of
magnitude greater than that for N-methyl acetamide, the water rate for ester hydrolysis
(3.16
10
-10
s
-1
at 25
8
C) [20] is only a few times greater than the water rate for typical
peptide hydrolysis (10
-10
s
-1
) [18]. It may seem somewhat surprising that the rates of
hydrolysis of esters at neutral pH are not much greater than those of amides. However,
the leaving group amine in amide hydrolysis is protonated at neutral pH while the
corresponding ether oxygen in ester hydrolysis is not. Thus, amides and esters
have comparable reactivities at neutral pH, but esters are far more reactive than
amides under basic conditions.
As discussed in this chapter, there are three direct modes of activation that metal
ions can provide for hydrolysis reactions, i.e., by Lewis acid, nucleophile and leaving
group. In addition, metal coordinated water molecules can act as general acid catalysts
and metal coordinated hydroxides can act as general base catalysts. We are mainly
concerned with the three direct modes of activation since there is no particular advan-
tage to using metal-based general acids and bases.
6.3
Lewis Acid Activation
Metal ions can increase the electrophilicity of the substrates by direct coordination
(Figure 6.1). Lewis acid activation is important not only for hydrolysis of esters,
amides, nitriles and phosphates [11-15] but also for other organic reactions, including
epoxide opening, aldol condensation, Michael addition, reduction and Diels-Alder
reactions (Figure 6.1). Indeed, chiral Lewis acids have been used as catalysts to carry
out a wide range of stereoselective transformations [21-25]. In all these reactions, the
role of the metal ion is to stabilize the developing negative charge on the coordinated
atom. Often, the coordinated atom is oxygen and thus the role of the metal ion is
mostly oxyanion stabilization.
One way to estimate the relative Lewis acidity of metal ions is by considering the
Brønsted acidity of the metal coordinated water molecules. Table 6.2 lists the pK
a
of
