THE IMPORTANCE OF CONFORMATION OF THE
TETRAHEDRAL INTERMEDIATE IN THE
HYDROLYSIS OF ESTERS AND AMIDES
PIERRE
DESLONGCHAMPS
Département de Chimie, Université de Sherbrooke,
Sherbrooke, Québec, Canada JJK 2R1
ABSTRACT
A new stereoelectronic theory for the cleavage of the tetrahedral intermediate
in the hydrolysis of esters and amides is presented. In this new theory, the pre-
cise conformation of the intermediate hemi-orthoester or hemi-orthoamide
controls the nature of the hydrolysis products. It is postulated that the break-
down of a conformer of a tetrahedral intermediate depends upon the orienta-
tion of the lone pair orbitals of the heteroatoms. Specific cleavage of a carbon—
oxygen or a carbon—nitrogen bond in any conformer is allowed only if the other
two heteroatoms (oxygen or nitrogen) each have an orbital oriented antiperi-
planar to the leaving O-alkyl or N-alkyl group. Experimentally, the oxidation
of acetals by ozone and the acid hydrolysis of a series of cyclic orthoesters
demonstrates clearly that there is indeed a stereoelectronic control in the
cleavage of hemi-orthoesters. Similarly, a study of the basic hydrolysis of a
variety of N,N-dialkylated imidate salts shows that the same stereoelectronic
control is operating in the cleavage of hemi-orthoamides.
It is generally accepted that the most common mechanism for the hydro-
lysis of esters and amides proceeds through the formation of a tetrahedral
intermediate. The conformation of this tetrahedral intermediate (hemi-
orthoester from ester and hemi-orthoamide from amide) has never yet been
considered to be an important parameter in order to obtain a better under-
standing of the hydrolysis reaction'. We wish to report a new stereoelectronic
theory in which the precise conformation of the tetrahedral intermediate
plays a major role.
In this new theory, the nature of the products formed from the hydrolysis
of an ester or amide depends upon the conformation of the tetrahedral hemi-
orthoester or hemi-orthoamide intermediate. It is further postulated that the
breakdown of a tetrahedral conformer depends upon the orientation of the
lone pair orbitals of the heteroatoms. A specific cleavage of a carbon—oxygen
or a carbon—nitrogen bond is allowed only if the other two heteroatoms
(oxygen or nitrogen) of the tetrahedral intermediate each have an orbital
oriented antiperiplanar to the leaving O-alkyl or N-alkyl group.
This new theory originated from our study on the oxidation of acetals to
351
PIERRE DESLONGCHAMPS
esters with ozone2. We will first describe this reaction and then disclose the
theory of stereoelectronic control in the cleavage of hemi-orthoesters3 which
provides an explanation for the formation of products in the ozonolysis of
acetals. We will then furnish independent experimental evidence that specific
cleavage of hemi-orthoesters does indeed take place, based upon a study of
the acid hydrolysis of cyclic mixed orthoesters. Finally, the theory of stereo-
electronic control in the cleavage of hemi-orthoamides will also be presented4.
Our study on the basic hydrolysis of imidate salts will confirm that stereo-
electronic control in the cleavage of hemi-orthoamides does occur.
OZONOLYSIS OF ACETALS
We reported in 1971 that ozone reacts in a completely specific fashion with
the acetal function derived from an aldehyde to give the corresponding ester
and alcohol. This reaction is a general one; the nature of the alkyl groups
/
R—C
+03 -
R—COOR
+ R—OH + °2
HO—R
of the acetal function does not influence the final result, and this reaction
proceeds in essentially quantitative yield. However, we have found that
there is a tremendous difference in the rate of reaction depending on the
nature of the acetal function (Figure 1); cyclic acetals react much faster
(a few minutes at —
78°)
than the acyclic ones (
15 h at —
78°).
The observed
large difference in rates of oxidation of cyclic as compared to acyclic acetals
was the first indication that there was a direct relationship between the con-
formation of the acetal function and its reactivity toward ozone. We believe
that this reaction proceeds via the iisertion of ozone into the C—H bond
of the acetal forming an intermediate such as 1 or 2, which can then break
down to give the reaction products, the ester and the alcohol.
We next investigated the oxidation of acetals where the OR groups were
not identical. It was of interest to examine such substrates because a tetra-
hedral intermediate formed during the oxidation of such unsymmetrical
acetals, could decompose in two different ways. For instance, a substrate such
as 3 (Figure 2) should lead to an intermediate such as 4. Intermediate 4 could
decompose to give the hydroxy-ester 5, or the lactone 6, plus the alcohol. We
found experimentally that ozone reacts smoothly with tetrahydropyranyl
ethers in a completely specific manner, yielding the hydroxy-ester5 exclusively.
No trace of lactone 6 could be detected. Thus, it can be immediately concluded
that if the ozonolysis reaction proceeds through the formation of hemi-
orthoester 4 or its equivalent, this intermediate must decompose in a very
specific manner!
After completing our work on the simple tetrahydropyranyl ethers, the
next logical step was to study this new reaction on tetrahydropyranyl ethers
which possessed a rigid chair conformation. Consequently, the oxidation of
a series of conformationally rigid x- and p3-methyl glycopyranosides was
352
P
R-C
HYDROLYSIS OF ESTERS AND AMIDES
+ 03
1 mm, —
78
Figure 1.
RCj
2
O4,.oEt
4
Figure 2.
1)00Et
+ EtOH
COOCH3
OAc
AcO—J
—OAc
÷——
OAc
CH,OAc
Figure 3.
AcO
0
AcO
H
AcO
AcO
0
CH3
undertaken. We found a very interesting result: the f3
anomers
were smoothly
oxidized by ozone while the
anomers were recovered unchanged. For
example, methyl 2,3,4,6—tetra-O-acetyl4-D-glucopyranoside was converted
353
+ 03
15h, —78
,OCH3
RC\
P—i
RfJ
H
R—COOCH3 + CH3OH
R—COOCH2—CH1--OH
Ac0
PIERRE DESLONGCHAMPS
into methyl 2,3,4,5,6-penta-O-acetyl-gluconate, while the corresponding
anomer was shown to be completely unaffected under the same reaction
conditions (Figure 3).
The preceding results can be summarized in the following way: cyclic
acetals (7) react readily with ozone, while acyclic acetals (10)
react
slowly;
3-glycosides (8) are reactive, but cz-glycosides (9) are inert (Figure 4). These
o
0
RO7
H
o
0
R
CH3'H
8
Figure
4.
results suggested that there was a relationship between the conformation of
the acetal function and its reactivity toward ozone. After viewing models of
the compounds under consideration, we made the following proposal: any
reactive conformer must have on each oxygen atom a lone pair orbital oreiented
antiperiplanar to the C—H bond of the acetal function2. This requirement
was met in the dioxolane acetals (7) and the most stable rotamer of the 3-
glycosides (8). In an cx-glycoside, which can be represented as its favoured
rotamer by structure 9,
the
ring oxygen orbitals are not oriented antiperiplanar
to the C—H bond; it is the ring carbon—oxygen bond which is antiperiplanar.
The lone pair orbitals of the ring oxygen in an x-glycoside (regardless of the
rotamer) are never available, indicating that the oxidation does not proceed
at a detectable rate if only one oxygen has one orbital properly oriented.
Furthermore, acyclic dialkoxy acetals are known6 to exist in one preferred con-
formation (10) which is identical to the favoured rotamer of an cz-glycoside
(9).
This
is quite normal because this conformer is the only one which avoids
the anomeric effect5. Conformer 10 is inert toward ozone. In order to react
with ozone, the dialkoxy acetals must adopt another conformation which has
354
HYDROLYSIS OF ESTERS AND AMIDES
proper orbital orientation. This is possible with the dialkoxy acetals but
impossible with chair-rigid-cx-glycosides. However, any reactive conformer of
the dialkoxy acetal will be present only in a very small amount at equilibrium
because such a conformer has to overcome the anomeric effect which exists
when two lone pair orbitals are in a 1,3-syn-periplanar arrangement.
Consequently, the reaction rate, which is dependent upon the concentration
of the reactive conformer, is going to be low.
It is clear at this stage of our investigation that the postulate of the orienta-
tion of the lone pairs had to be verified in a more rigorous manner. Conse-
quently, we had to consider all the possible gauche conformers that an acetal
function can assume, make rigid chemical models for each of them if possible
and compare their respective reactivity toward ozone.
O
OR'
0
p'—.0 -J 0 pOI
R'- 0c,,
R
R'
R
O)
°c-:
R'
co
R'
R'
Figure
5 shows the nine gauche conformers that are theoretically possible
for an acetal function. Conformers A, B and D have no plane of symmetry.
In fact, conformers A', B' and D' are their respective mirror images, and
therefore chemically equivalent. The, remaining conformers C, E and F
possess a plane of symmetry. Consequently, there are only six conformers
t
A
1,3-syn-periplanar arrangement is equivalent to a 1,3-diaxial arrangement in a six-
membered ring.
355
R'
I
R'
c 0r--.
I
0)
R'
0
c
H
D
c?cL
R'
R'
H
F
E
0
o,
H
0'
Figure 5.
A'
