4
Bioorganic Chemistry
OH
O
RNH
2
(Amine)
R-OH
(Alcohol)
Coenzyme A
SH
(Thiol)
(Carboxylic acid)
OH
O
(Halogen acid)
HCl
+
N
H
O
R
O
O
R
S-Coenzyme A
O
O
O
O
Cl
O
(a) Amide
(b) Ester
(c) Thioester
(d) Acid anhydride
(e) Acyl halide
Fig. 2
Acyl derivative ranked from greatest hydrolytic stability (highest) to
lowest hydrolytic stability (lowest).
be quantitatively hydrolyzed in a matter
of minutes. This ease of hydrolysis, or
stability, of the compound has profound
biochemical ramiFcations.
It is fairly straightforward to estimate
the relative stability of acyl derivatives.
This stability is roughly proportional to
the p
K
a
of the conjugate acid of the group
attached to the carbonyl carbon (the group
that will be replaced by water); the stronger
the conjugate acid, the less stable towards
hydrolysis the acyl derivative will be. ±or
example, in the case of the amide, the
group attached is RNH. The conjugate acid
of this is RNH
2
or simply an amine. The
p
K
a
of this is very high, on the order of
38. (Note, this is the p
K
a
of the
amine
,
not the p
K
a
of the corresponding ammo-
nium ion.) On the other end of the scale,
if we examine acetyl chloride, the group
attached is Cl. The conjugate acid of this
is HCl or hydrochloric acid. The p
K
a
of
this is on the order of
7. The other acyl
derivatives, esters, thioesters, and acid an-
hydrides, all having attached groups whose
conjugate acid p
K
a
values are intermediate
to these two extremes, are found to be of
intermediate stability (±ig. 2).
What is the reason behind this relation-
ship? One way of looking at it is as follows:
if the p
K
a
of the conjugate acid of the
attached group is high, it means that it is
not very acidic. In other words, the acidic
proton is bound tightly. This tight bind-
ing indicates that the attached group is
capable of donating electrons to produce
effective bond formation, which in turn
reduces the amount of free proton in solu-
tion. When the attached group is attached
to the carbonyl carbon instead, this effec-
tiveness of bond formation is preserved
and is manifested in the bond stability.
±orexamp
le
,cons
iderace
t
icanhydr
ide
from ±ig. 2. This is the condensation
product of two molecules of acetic acid.
It is an effective reagent for adding acetyl
groups to nucleophiles, such as amines.
The conjugate acid of the attached group
would simply be acetic acid, which with
ap
K
a
of 4.5 satisFes the criterion of
being a good leaving group for the reasons
stated above. When the amine attacks the
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