CHEM331/333 RBL 6
Nucleophilic Substitution at Carbonyls
(CGW some of chapters 10, 12, Maskill chapter 4, Carey and Sundberg p 465).
1. Tetrahedral intermediates
Nucleophilic substitution at carbonyl carbon with displacement of leaving group X is a common
reaction in synthesis. The reaction is also called 'acyl transfer', since an acyl group (RCO) is being
transferred from X to Nu. The order of reactivity is similar to SN2, with good nucleophiles rapidly
displacing good leaving groups.
O
Nu:
+
R
O
X
R
+
X
Nu
The main difference from SN2 is that a tetrahedral
intermediate is involved because the nucleophile's
filled orbital has to overlap with the unfilled (*)
carbonyl orbital i.e. it has to come from above the
plane of the carbonyl.
Nu
Nu
O
The preferred angle of attack is ~ 110º (the
tetrahedral angle) due to repulsion between
incoming nucleophile and antibonding lobe of *
orbital.
O
Nu
Nu
Nu
2. Two main mechanisms for ester hydrolysis
The two common mechanisms are one for basic hydrolysis called BAc2 (Base-induced, acyl-oxygen
cleavage, bimolecular), and one for acid catalysed hydrolysis AAc2 (Acid-catalysed, acyl-oxygen
cleavage, bimolecular). The 'bimolecular' means that two molecules are involved in the RLS.
OH
R
BAc2
O
O
R'
R
O
O
R
O
O
+
R'
R'OH
OH2
A Ac2
R
R
OH
O
O
O
O
R'
R
R
R'
OH
R'
HO
O
+
R'OH
BAc2
(Base-induced, acyl-oxygen cleavage, bimolecular). Not a base catalysed reaction, since the
hydroxide is used up – the initially formed alkoxide immediately deprotonates the acid to give a
carboxylate.
OH
k1
R
O
R'
k –1
OH
R
R'
k2
O
OH
O
R
R
O
+
+
O
R'H
R'
Evidence for mechanism:
Hindered acids react more slowly, so
reaction likely to be bimolecular.
Kinetics: Rate = kobs[ester][HO–]. Steady
state on tetrahedral intermediate gives
rate
k 1k 2
–
[ester ][HO ]
(k –1 k 2 )
so kobs = k1k2/(k–1 + k2). Since kobs is just a
number, the kinetic expression provides
no evidence for an intermediate – a
simple bimolecular displacement with a
single TS would have the same rate
equation.
Hammett: +ve (probe in R)
Isotopic labelling: There are three oxygens in the tetrahedral intermediate, and these can be
tracked by labelling them with 18O. We will consider two possibilities.
Labelling the OR' group (R') produces labelled alcohol, HR', showing that the O–R' bond
has not been broken (no alkyl–oxygen cleavage).
Labelling the hydroxide by running the reaction in 18OH2 produces labelled carboxylate,
and not labelled alcohol, confirming that the CO–O bond has been broken.
If hydrolysis using labelled hydroxide is stopped before
completion, analysis of remaining unhydrolysed ester
shows that some of the 18O label has got into the ester
carbonyl. This means that the initial tetrahedral
intermediate can equilibrate (via protonation to the
neutral species and deprotonation) with a tetrahedral
intermediate with the charge on the other oxygen
(proton transfers between charged heteroatoms in water
are very fast). Reversion to the ester then introduces the
label. This experiment provides a way of measuring the
relative heights of barriers for forward and backwards
reactions from the tetrahedral intermediate, k -1 and k2.
It turns out that little label normally ends up in
unreacted ester, showing that the forward reaction
usually has the lower barrier (i.e. k2 > k-1). As might be
expected, RCOX with a good leaving group (e.g. X =
OPh) has a higher k2/k–1 ratio than RCOX with a bad
leaving group (e.g. X = NHR, an amide).
OH
R
X
O
R
X
O
OH
R
X
O
O
OH
R
X
OH
AAc2 (Acid-catalysed, acyl-oxygen cleavage, bimolecular). Water is a poor nucleophile, so will only
attack at an appreciable rate if the carbonyl is activated by protonation.
All the steps in acid–catalysed ester hydrolysis are reversible, and the reaction continues until it
reaches equilibrium (the reverse is acid–catalysed ester synthesis). The overall equilibrium constant
for synthesis/hydrolysis of esters is ~ 1, i.e. with equal concentrations of reactants, the reaction
goes about half way starting from either side. For kinetic measurements, only rates in the early
stages of the reaction are analysed, so that back reaction from the ester (k–2) does not have to be
considered.
O
H2O +
R
O
R'
KH+
R
OR'
R
k1
R
O
H
OH
R'
k –1
OH
+ R'OH
OH2
R
R'
OH
OH
OH
k2
R
R
H
R'
OH
+
O
R'H
Evidence for mechanism similar to BAc2:
Hindered acids react more slowly, so
reaction likely to be bimolecular.
Kinetics: Rate = kobs[ester][H3O+]. Steady
state on the tetrahedral intermediate gives
rate
k 1k 2
K [ester ][H 3 O ]
(k –1 k 2 ) H
so kobs = k1k2KH+/(k–1 + k2) assuming the
ester is protonated in a fast preequilibrium
KH+ = [esterH+][H2O]/[ester][H3O+].
Hammett: ~ 0 (probe in R)
Isotopic labelling: As before, 18O labelling shows that the reaction involves acyl-oxygen
cleavage, the tetrahedral intermediates can interconvert rapidly, and k2 and k-1 are of
comparable size. For simplicity we have shown two tetrahedral intermediates - there is also a
third, neutral one, with none of the alcohol/ether groups protonated. This is of lower energy
than the other two, but still in rapid equilibrium with them.
3. Two less common mechanisms for acid hydrolysis of esters
There are two other mechanisms for esters which can give stable cations in strong acid, called AAc1
and AAl1 (the 1 meaning that the slow step is a unimolecular dissociation like SN1). These
mechanisms do not go via tetrahedral intermediates.
AAc1
(Acid-catalysed, acyl-oxygen cleavage, unimolecular). Limited to esters which can ionise to
form a relatively stable acylium ion (the same intermediate as in Friedel-Crafts reactions), or esters
for which the normal AAc2 mechanism is difficult. Protonation on the alcohol oxygen is required to
make it a better leaving group (most of the molecules will in fact be protonated on the more basic
carbonyl oxygen).
R
R
O
H
R'
R'
R
O
R
+
HR'
O
O
HO
HR'
Evidence for mechanism:
Promoted relative to AAc2 by steric
hindrance around carbonyl (example 1
below).
Kinetics: Rate = kobs[ester][H3O+], although a
large excess of acid is usually used so that
the reaction is pseudo-first order, rate =
k'obs[ester].
Hammett: –ve (+, probe in R)
Isotopic labelling: Hydrolysis of R' labelled
ester gives HR', so not alkyl-oxygen
cleavage.
+
Example 1. The ortho-methyls force the ester group out of the plane of the benzene ring, shielding
the carbonyl carbon from attack. Protonation and loss of methanol produces a linear acylium ion
which can then react with a nucleophile e.g. water without it having to get in past the methyls.
O OMe
Me
Me
O OH
Me
Me
Example 2. Acylium ion particularly stable due to resonance. This ester only hydrolyses by A Ac1 in
concentrated acid where the concentration of water is low, otherwise the mechanism is normal
AAc2.
O
OMe
OMe
O
OH
OMe
AAl1 (Acid-induced, alkyl-oxygen cleavage, unimolecular). Occurs when the alcohol portion can
form a stable cation R'+ i.e. From the alcohol's point of view this is an SN1 reaction, with the
protonated ester as a good leaving group. Not an acyl transfer reaction.
R
R'
R
O
R'
R
R
OH
OH
+
R'
H
+
HR'
Common types of ester that hydrolyse by this mechanism are triphenylmethyl (trityl) and tertbutyl esters (example 1 below), used as acid labile protecting groups.
Evidence for the mechanism:
Not sensitive to steric hindrance around
carbonyl.
Kinetics: rate = kobs[ester][H3O+] as before,
promoted by polar ionising solvent (SN1
conditions).
Hammett: small (probe in R)
Isotopic labelling: Hydrolysis of R'
labelled ester gives HO–R', so –R bond
must have broken.
Example 1. tert-Butyl esters can usually be cleaved in the presence of other functional groups by
catalytic amounts of acid. The ester is protonated to a small extent, with the slow step being alkyloxygen cleavage
Example 2. Hydrolysis of a series of substituted ethyl benzoates with electron withdrawing
substituents in concentrated sulphuric acid. This is an unusual situation in which the concentration
of nucleophiles such as water is too low for the normal AAC2 mechanism to be competitive. The
esters start off almost completely protonated in concentrated acid with the slow step generating a
rather unstable ethyl cation. For this particular reaction the mechanism changes to AAc1 (as
mentioned previously) if NO2 is changed to OMe because the acylium ion pathway now becomes
lower in energy (the methyl cation is even more unstable).
Summary of hydrolysis mechanisms
BAc2:
Stoichiometric
+ve (probe in R)
labelling detects tet. intermediate(s)
and acyl-O cleavage.
AAc2:
pre-protonation
~ 0 (probe in R)
labelling detects tet. intermediate(s)
and acyl-O cleavage.
AAc1:
pre-protonation, needs stable acylium ion
- ve (probe in R)
labelling shows acyl-O cleavage
R
O
O
R'
R
O
R
O
O
O
R'
O
R
O
OH
R'
OH
R
O
O
H O
R'
O
R'
O
R
OH
O
R'
R
+
HOR'
R
O
O
R'OH
R'
R
R
+
OH2
R
O
R'
R
AAl1:
pre-protonation, needs stable alkyl cation
~ 0 (probe in R) or + ve in strong acid
labelling shows alkyl-O cleavage
OH
R
O
R'
OH
O
+
R'
O
HO +
R'OH
0
