Hydrolysis and retro-aldol cleavage of ethyl threo-2-(1-adamantyl)-3- hydroxybutyrate: Competing reactions

Article abstract of DOI:10.1002/poc.1793

The hydrolysis of ethyl threo-2-(1-adamantyl)-3-hydroxybutyrate (1) and the parent ester ethyl 3-hydroxybutyrate (4) has been studied experimentally and computationally. In the hydrolysis of threo-ester 1 with 2M NaOH, predominantly retro-aldol product was observed, whereas the hydrolyzed product was present in a minor amount. When the reaction is carried out under the same conditions with the parent ester ethyl 3-hydroxybutyrate (4), hydrolyzed product is exclusively observed. The competitive pathways, namely hydrolysis and the retro-aldol reaction for 1 and 4 were investigated using DFT calculations in the both gas and solvent phase. The calculated results in the solvent phase at B3LYP/6-31+G* level revealed that the formation of retro-aldol products is kinetically preferred over the hydrolysis of threo-ester 1 in the presence of a base. However, the parent ester 4 showed that the retro-aldol process is less favored than the hydrolysis process under similar conditions. The steric effect imposed by the bulky adamantyl group to enhance the activation barriers for the hydrolysis of the ethyl threo-2-(1-adamantyl)-3-hydroxybutyrate (1) was further supported by the calculations performed with tert-butyl group at the α-carbon atom of ethyl 3-hydroxybutyrate (7).

Full text of DOI:10.1002/poc.1793

Research Article
Received: 7 October 2009,
Revised: 3 August 2010,
Accepted: 12 August 2010,
Published online in Wiley Online Library: 18 October 2010
(
wileyonlinelibrary.com) DOI 10.1002/poc.1793
Hydrolysis and retro-aldol cleavage of ethyl
threo-2-(1-adamantyl)-3-hydroxybutyrate:
competing reactions
a
ay
b
Bishwajit Ganguly *, Manoj K. Kesharwani , Marija Matkovi c´ ,
b
ay
b
Nikola Basari c´ , Ajeet Singh and Kata Mlinari c´ -Majerski **
The hydrolysis of ethyl threo-2-(1-adamantyl)-3-hydroxybutyrate (1) and the parent ester ethyl 3-hydroxybutyrate (4)
has been studied experimentally and computationally. In the hydrolysis of threo-ester 1 with 2 M NaOH, predomi-
nantly retro-aldol product was observed, whereas the hydrolyzed product was present in a minor amount. When the
reaction is carried out under the same conditions with the parent ester ethyl 3-hydroxybutyrate (4), hydrolyzed
product is exclusively observed. The competitive pathways, namely hydrolysis and the retro-aldol reaction for 1 and 4
were investigated using DFT calculations in the both gas and solvent phase. The calculated results in the solvent phase
at B3LYP/6–31 R G* level revealed that the formation of retro-aldol products is kinetically preferred over the
hydrolysis of threo-ester 1 in the presence of a base. However, the parent ester 4 showed that the retro-aldol process
is less favored than the hydrolysis process under similar conditions. The steric effect imposed by the bulky adamantyl
group to enhance the activation barriers for the hydrolysis of the ethyl threo-2-(1-adamantyl)-3-hydroxybutyrate (1)
was further supported by the calculations performed with tert-butyl group at the a-carbon atom of ethyl
3-hydroxybutyrate (7). Copyright ß 2010 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this paper.
Keywords: ester hydrolysis; retro-aldol; DFT; solvent effect; adamantane
tetrahedral intermediate (first step), followed by a decomposition
INTRODUCTION
ꢀ
of the tetrahedral intermediate to produce RCOO þ R’OH
[
68,69]
The hydrolysis of carboxylic acid esters (RCOOR’) is one of the
most fundamental and thoroughly studied chemical reac-
(second step).
Another less common mode of ester
hydrolysis, BAL2 (base-catalyzed, alkyl-oxygen cleavage, bimole-
[
1–9]
[10–55]
[6–9]
tions.
A variety of experimental and theoretical studies
cular) competes with the BAC2 mode.
The BAL2 mode, which
on ester hydrolysis have provided critical insights into the
fundamental reaction mechanism. Besides extensive interests
within chemistry, the mechanism of base-catalyzed hydrolysis of
leads to the same products as the BAC2 process, is essentially an
[
6–9]
SN2 substitution with a carboxylate leaving group (Scheme 1).
Reaction pathways and energy barriers for the both BAC2 and
AL2 modes of hydrolysis of representative alkyl esters have
been studied in the gas phase and the highest energy barrier
[
6–9,56,57]
esters figures prominently in many biological processes,
B
such as the metabolism of the neurotransmitter acetylcholine
and the degradation of cocaine. Applications include the design
[
58,59]
of transition-state analogs that inhibit acetylcholinesterase
and that elicit anti-cocaine catalytic antibodies.
[
60–63]
The rate of
*
*
a
Correspondence to: B. Ganguly, Analytical Science Discipline, Central Salt and
Marine Chemicals Research Institute (Council of Scientific and Industrial
Research), Bhavnagar, Gujarat 364 002, India.
hydrolysis can have major impact on the metabolism of many
[
64]
drugs and prodrugs. It is known that the hydrolysis rate can be
[
65]
E-mail: ganguly@csmcri.org
controlled by steric effect which is clearly demonstrated in the
[
66,67]
metabolism of some particular drugs.
RCOOR’ þ H O ! RCOOH þ R’OH) involves cleavage of either
the acyl-oxygen or alkyl-oxygen bond.
Ester hydrolysis
´
*
Correspondence to: K. Mlinaric-Majerski, Department of Organic Chemistry
and Biochemistry, Ruper Bo sˇ kovi c´ Institute, Bijeni cˇ ka cesta 54, P.O. Box 180,
Zagreb 10 002, Croatia.
(
2
[
6–9]
The mode of cleavage
E-mail: majerski@irb.hr
may be determined by isotopic labeling and by stereochemical
studies. Both types of cleavage are observed with acid or base
catalysis and the result is a rich array of possible mechanisms. The
base catalyzed hydrolysis of the majority of common alkyl esters
occurs by the attack of the hydroxide ion at the carbonyl carbon.
This mode of hydrolysis has been designated by BAC2 (base
B. Ganguly, M. K. Kesharwani, A. Singh
Analytical Science Discipline, Central Salt and Marine Chemicals Research
Institute (Council of Scientific and Industrial Research), Bhavnagar, Gujarat,
3
64 002, India
b
M. Matkovi c´ , N. Basari c´ , K. Mlinari c´ -Majerski
[
6–9]
Department of Organic Chemistry and Biochemistry, Ruper Bo sˇ kovi c´
Institute, Bijeni cˇ ka cesta 54, Zagreb 10 002, Croatia
catalyzed, acyl oxygen cleavage, bimolecular),
to occur by a two-step mechanism.
and is believed
Generally, this is the
accepted mechanism that consists of the formation of a
[
6–9]
y
These authors have contributed equally in this paper.
J. Phys. Org. Chem. 2011, 24 578–587
Copyright ß 2010 John Wiley & Sons, Ltd.

HYDROLYSIS OF ETHYL-2(1-ADAMANTYL)-3-HYDROXYBUTYRATE
Scheme 2. Reactions of 1 with NaOH
Scheme 3.
Scheme 1. The BAC2, BAL2 of ester hydrolysis and retro-aldol mechanism
calculated for the BAC2 process is always lower than the barrier for
to the best of our knowledge, computational studies on base
catalyzed retro-aldol reactions are scarce in the literature. It is
known that aldol and retro aldol reactions are catalyzed by either
acid or base. The reversibility of the aldol reaction, i.e., an
equilibrium between aldol and carbonyl compounds is one of
the most important characteristics of the aldol reaction.
Conversion of aldol to retro aldol products is catalyzed by a
base to deprotonate the hydroxy group followed by the breaking
[
54]
the B 2 process.
AL
threo-2-(1-Adamantyl)-3-hydroxybutyric acid (2) is an adaman-
[
70]
[71,72]
tyl analog
of the well known 3-hydroxybutyric acid
and
generally one of novel artificial hydrophobic b-hydroxy
[
73,74]
acids.
Hydrophobic properties make it interesting as a
building block in depsipeptide synthesis. Depsipeptides are
heterodetic peptides in which at least one amide bond has been
replaced with an ester bond. These peptide derivatives are
of C—C bond. There are a few reports on theoretical modeling of
[
75]
[87,88]
promising lead compounds for drug discovery. The ester bond
in depsipeptides can be formed by incorporating hydroxy acid
thermal retro-aldol reactions of b-hydroxy esters.
Recently
de novo computational design of breaking of a carbon–carbon
[
76]
into the peptide backbone which makes hydroxy acid crucial
building block for depsipeptide synthesis. Therefore, the
development of methods for synthesis and isolation of novel
bond with retro-aldolases was reported, where four different
[
89]
catalytic motifs were used in a non-natural substrate.
[
77,78]
hydroxy acids is an interesting field in peptide chemistry.
To
incorporate hydroxy acids into more complex peptides and
peptidomimetics, it is important to understand their reactivity.
The reactivity of amino or hydroxy acids in peptide chemistry,
especially considers the possibility of protecting the functional
EXPERIMENTAL
Hydrolysis of ethyl
threo-3-hydroxy-2-(1-adamantyl)butyrate (1)
[
79]
[79]
groups,
the facility of protective groups cleavage
and the
Not all
[
79,80]
[81]
[86]
possibility of making amide
or ester bond.
The corresponding ester 1
(266 mg, 1 mmol) was dissolved
building blocks in peptide chemistry posses the same reactivity
toward introduction of protective group or the formation of
in MeOH (5 ml) and 2 M NaOH (5 ml) was added. The reaction was
stirred at room temperature. At the appropriate time aliquots of
2 ml were taken (Table 1.) and the solvent evaporated. The crude
residue was suspended in CH Cl (35 ml) and washed with water
[
82,83]
peptide bond.
To avoid the formation of by-products,
building blocks in peptide chemistry are used in their protective
forms. Because of the attractively simple methodology for the
esterification of amino acids, this method of carboxyl protection
2
2
[
79]
remains in the practice of peptide synthesis. Ester group is very
[
84]
Table 1. Reactions of 1 with 2 M NaOH in MeOH
often the choice of protection for carboxylic group which gives
importance to the hydrolysis as a method for the deprotection of
Product
[
79,84,85]
b
carboxylic groups.
ratio (%)
a
Ethyl threo-2-(1-adamantyl)-3-hydroxybutyrate (1) was suc-
Entry
Time (h)
Conversion (%)
cessfully used in the preparation of small depsipeptide
3
2
[
86]
fragments. Herein, we report experimental and computational
study of the hydrolysis of ethyl esters 1 in presence of a base.
During the preliminary investigation, we were intrigued by the
finding that the ester 1 yields retro-aldol product 3 predomi-
nantly and hydrolysis was a side reaction (Scheme 2). However,
the parent ester ethyl 3-hydroxybutyrate (4) yields hydrolysis
product 5 only (Scheme 3). These experimental results prompted
us to examine the competitive reaction pathways for esters 1 and
1
2
3
1
4
24
41
55
69
74
79
81
83
26
21
19
17
4
120
100
a
The conversion was determined from the mass of recovered
1
and isolated products 2 and 3.
The product ratio was determined from H NMR spectra of
b
1
4
with the hydroxide ion computationally. It is worthy to note that
isolated mixture of 2 and 3.
the hydrolysis of esters has been extensively studied, however,
J. Phys. Org. Chem. 2011, 24 578–587
Copyright ß 2010 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

B. GANGULY ET AL.
tube. However, due to low resolution and complexity of NMR
spectra, the conversion could be described only qualitatively,
confirming slow hydrolysis of starting compound to the mixture
of products.
Hydrolysis of ethyl 3-hydroxybutyrate (4)
The ester 4 (26.4 mg, 0.2 mmol) was dissolved in MeOH (1ml) and
2
M NaOH (1 ml) was added. The reaction was stirred at room
temperature and monitored by TLC (the used eluent was 5% MeOH
in CH Cl , and spots were visualized by mixture of KMnO
CO :aq.5%NaOH:H
2
2
4
:
K
2
3
2
O¼ 2 g:20 g:5 ml:300 ml. After 5 min the reac-
tion was completed. The reaction was repeated with NaOD/D O in
2
NMRtubeandreactionproduct5identifiedinsituby HNMRspectra.
1
Scheme 4.
Hydrolysis of ethyl (1-adamantyl)acetate (6)
The ester compound 6 (44.9 mg, 0.2 mmol) was dissolved in
MeOH (1 ml) and 2 M NaOH (1 ml) was added. The reaction was
stirred at room temperature. After 1 h the solvent was removed,
(
2 ꢁ 10 ml). The organic phase was dried over anhydrous MgSO
4
.
The solvent was evaporated and the starting compound 1
recovered. The water phase was acidified with 1 M HCl (pH ꢂ 3),
precipitate extracted with diethyl ether (2 ꢁ 25 ml) and dried over
crude residue suspended in CH Cl2 (35 ml) and washed with
2
water (2 ꢁ 10 ml). The organic phase was dried over anhydrous
anhydrous MgSO
4
. The solvent was evaporated and the mixture
MgSO . After solvent evaporation the unreacted compound
4
of products 2 and 3 obtained. The recovered starting compound
6 was recovered. The water phase was acidified with 1 M HCl
1
1
and products 2 and 3 were identified by H NMR. The ratio of
(pH ꢂ 3), precipitate extracted with diethyl ether (2 ꢁ 25 ml) and
1
products 2 and 3 was determined by H NMR and the conversion
dried over anhydrous MgSO . After solvent evaporation
4
of the reaction was determined from the mass balance of isolated
compound 3 was isolated (86%). Unreacted ester 6 and product
3 were identified by H NMR.
1
products. The reaction was repeated with NaOD/D
2
O in NMR
Figure 1. B3LYP/6–31 þ G* calculated relative to gas phase free energies in kcal/mol for BAC2 hydrolysis (solid line) and retro-aldol process (doted line) of
ethyl threo-2-(1-adamantyl)-3-hydroxybutyrate (1). The liberated side products during the formation of intermediate steps are given in italics and the
addition of new species for further process is given in []
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Copyright ß 2010 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2011, 24 578–587

HYDROLYSIS OF ETHYL-2(1-ADAMANTYL)-3-HYDROXYBUTYRATE
Attempts of retro-aldol reaction of
threo-3-hydroxy-2-(1-adamantyl)butyric acid (2)
place initially for 1, which subsequently hydrolyzes to the
corresponding acid 3, while the hydrolysis of 1 and formation
of acid 2, as a minor product is a parallel process.
[
70]
The hydroxy acid 2 (23.9 mg, 0.1 mmol) was dissolved in MeOH
0.5 ml) and 2 M NaOH (0.5 ml) added. The reaction was stirred
at room temperature. After 1 h the solvent was removed and the
To gain a better insight on the competing reactions described
[90–92]
(
herein, density functional calculations (B3LYP/6–31 þ G*)
have been employed to examine the potential energy surface
(PES) for the hydrolysis and retro-aldol processes of 1 and 4. The
potential energy profiles for the hydrolysis and retro-aldol
crude residue suspended in CH Cl2 (20 ml) and washed with
2
water (2 ꢁ 5 ml). The water phase was acidified with 1 M HCl
(
pH ꢂ 3), precipitate extracted with diethyl ether (2 ꢁ 15 ml) and
4
process of 1 in the gas phase are given in Fig. 1. The choice of
B3LYP method in this study is two fold: (i) to compute the results
dried over anhydrous MgSO . After solvent evaporation the acid
2
1
was recovered and identified by H NMR.
[68,69]
with reasonable accuracy;
systems in hands like adamantyl groups within the reasonable
(ii) can be applied to the bulky
computational expenses. B3LYP/6–31 þ G* optimized geome-
COMPUTATIONAL DETAILS
tries involved in hydrolysis of ethyl threo-2-(1-adamantyl)-3-
ꢀ
hydroxybutyrate (1) are given in Fig. 2. The PES of 1 with OH ion
Geometries were fully optimized without any symmetry
[
with the Jaguar
90–92]
showed that the first transition state 1TS1 is 22.9 kcal/mol lower
than isolated reactants (Fig. 1). It has been reported that a first
order saddle point must connect with two local minima
associated with a ‘reactant’ (or an intermediate) and a ‘product’
constraints at B3LYP/6–31 þ G* level,
[
93]
program package. Harmonic force constants were computed
at the optimized geometries to characterize the stationary points
as minima. The calculated number of imaginary frequency (Imag)
at the same level of theory i.e.; energy minimum structures
without imaginary frequencies (NImag ¼ 0), and transition states
with only one imaginary frequency (NImag ¼ 1). The gas phase
energies discussed are computed free energy values. Intrinsic
(
or an intermediate). Hence, a plausible calculated energy barrier
can never be negative. For bimolecular reaction, if the energy of a
transition state is lower than the total energy of the separated
[
94,95]
reaction coordinate (IRC)
calculations were performed on
TSs in order to confirm that TSs did, indeed, lead to the formation
of complex and intermediates of the hydrolysis and retro-aldol
reactions. Solvent calculations were performed using Polarized
[
96-100]
Continuum Solvation Model (PCM)
e ¼ 32.63) as a solvent at same level of theory. Our computed
single-point PCM bulk solvent simulations used the B3LYP/
and methanol
(
6
–31 þ G* optimized equilibrium geometries. For solvent
[101]
calculations Gaussian 03 program was used.
RESULTS AND DISCUSSION
Ethyl threo-2-(1-adamantyl)-3-hydroxybutyrate (1) was prepared
[
86]
by reduction of adamantane substituted ethyl b-ketoester.
In order to obtain threo-2-(1-adamantyl)-3-hydroxybutyric acid
2) the ethyl ester derivative threo-1 was submitted to the base
(
hydrolysis (Scheme 2) and the conversion was monitored by
1
H NMR spectroscopy of isolated products (refer Experimental
section). The conversion of 1 was completed in five days (Table 1),
and 2 and 3 were isolated as minor and major product,
respectively.
To examine the influence of adamantyl group on hydrolysis of
adamantyl-substituted ethyl 3-hydroxybutyrate, such as 1, parent
compound, ethyl 3-hydroxybutyrate (4) was hydrolyzed under
the same conditions (Scheme 3). In the presence of a base, ethyl
3-hydroxybutyrate (4) was completely hydrolyzed in 5 min,
yielding the hydroxy acid 5 as the sole product. Comparing the
hydrolysis process of 1 and 4, it appears that the adamantyl
group facilitates retro-aldol reaction for 1 and suppresses the
formation of acid 2 via hydrolysis. However, it is not clear whether
retro-aldol reaction takes place on hydrolyzed product 2 or on
starting ester 1, leading first to intermediate ethyl (1-adamantyl)
acetate (6) which then hydrolyzes to 3. To gain more insight into
the processes, two additional experiments were performed
(
Scheme 4). The hydrolysis of 6 was very efficient, with conversion
of more than 86% in 1 h. However, when acid 2 was submitted
to the same conditions, retro-aldol reaction did not take place.
These observed results suggest that the retro-aldol reaction takes
Figure 2. B3LYP/6–31 þ G* optimized geometries with important dis-
tances ( A˚ ) involved in BAC2 hydrolysis of ethyl threo-2-(1-adamantyl)
-3-hydroxybutyrate (1). (Gray: carbon; red: oxygen; white: hydrogen)
J. Phys. Org. Chem. 2011, 24 578–587
Copyright ß 2010 John Wiley & Sons, Ltd.
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B. GANGULY ET AL.
reactants, it implies that at least one other stable structure exists
[
between the separated reactants and the transition state.
The calculated free energy of activation is 5.7 kcal/mol from the
tetrahedral intermediate 1INT. The overall potential energy
surface suggests that the second step is the rate-determining
step for the hydrolysis of 1, which is in accord with previous
68,69]
Therefore, we have located the possible complex 1HB between
the reactant and the transition state (1TS1) (Figs 1 and 2).
Transition state 1TS1 further goes to the tetrahedral intermediate
[
68,69]
reports of ester hydrolysis.
exergonic in nature.
The formation of products is
ꢀ
1
INT with the formation of C—O bond between OH ion and the
carbonyl carbon atom. The intermediate 1INT is below 2.7 kcal/
mol with respect to the first transition state 1TS1 (Fig. 1). Further,
four-membered cyclic transition state 1TS2 is formed for the
expulsion of ethoxide ion from the tetrahedral intermediate 1INT.
The competing retro-aldol process for adamantyl-substituted
ester 1 with hydroxide ion has also been computed at the same
level of theory and is shown in Fig. 1 and the stationary points
located for the retro-aldol process are shown in Fig. 3. The
Figure 3. B3LYP/6–31 þ G* optimized geometries with important distances (A) for retro-aldol process of ethyl threo-2-(1-adamantyl)-3-hydroxybutyrate
˚
(1). (Gray: carbon; red: oxygen; white: hydrogen)
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Copyright ß 2010 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2011, 24 578–587

HYDROLYSIS OF ETHYL-2(1-ADAMANTYL)-3-HYDROXYBUTYRATE
abstraction of b-hydroxyl proton of 1 with hydroxide ion leads
to an intermediate 1’INT and the formation of a water molecule.
This process seems to be instantaneous on the potential energy
surface as it lacks the formation of any complex or transition state
while going from reactants to the anionic intermediate 1’INT.
The intermediate 1’INT is 25.4 kcal/mol below the separated
reactants (Fig. 1). The C—C bond cleavage for the expulsion of
acetaldehyde takes place via 1’TS1 with a small free energy
of activation 1.1 kcal/mol yields 1’P and acetaldehyde (Fig. 1).
As mentioned in the experimental studies, the hydrolysis to 3
occurs after the retro-aldol process (Scheme 4). Hence, it is
important to examine the conversion of 1 via the formation of
retro-aldol product 6. In the potential energy surface, we have
computed the transfer of a proton from water to 1’P, which in
turn forms another intermediate 6. This process proceeds via
transition state 1’TS2 with free energy of activation 9.2 kcal/mol
stationary points located on the PES for the hydrolysis and
ꢀ
retro-aldol processes of 1 with OH ion seem to favor the
formation of the later products.
Contrary to 1, the parent ester ethyl 3-hydroxybutyrate
(4) hydrolyzed completely in presence of a base. The reaction
pathways for hydrolysis and retro-aldol reactions of 4 with
hydroxide ion examined in gas phase with B3LYP/6–31 þ G* level
of theory are given in Fig. 4. The calculated stationary points on
ꢀ
the potential energy surface for 4 with OH ion are shown in
Fig. 5. The PES for the hydrolysis of ethyl 3-hydroxybutyrate
(4) with hydroxide is similar to that of 1 (Fig. 4). The calculated
free energy of activation for the first transition state 4TS1 with
respect to 4HB is 1.6 kcal/mol, whereas, the free energy of
activation calculated for the expulsion of ethoxide ion is 6.1 kcal/
[
68,69]
mol with respect to 4INT (Fig. 4).
The retro-aldol process of parent ester 4 with hydroxide ion
is similar to that of ester 1 (Figs 1 and 4). The gas phase optimized
geometries involved in retro-aldol process of 4 are given in Fig. 6.
The formation of anionic intermediate 4’INT after abstraction of
with respect to the complex 1’P.H O (Fig. 1). Water was used as
2
a proton donor instead of methanol due to its higher
[
102]
deprotonation ability.
The formation of 6 with hydroxide
ꢀ
ion is relatively higher in energy presumably due to the instability
b-hydroxy proton with OH ion is 21.9 kcal/mol lower than
ꢀ
associated with OH ion in absence of solvent medium. First step
reactants. The C—C bond cleavage of b-hydroxy ester leads
to the expulsion of acetaldehyde through a small free energy of
activation 1.3 kcal/mol. The proton transfer process has also been
calculated for 4 (Fig. 4). The PES for the hydrolysis and retro-aldol
involves the transition state 6TS1 with free energy of activation
of 7.4 kcal/mol, showing the attack of hydroxide ion on carbonyl
carbon of 6, which in turn leads to another intermediate 6INT.
ꢀ
˚
The C—O distance in 6TS1 and 6INT is 2.41 and 1.49 A,
processes of 4 with OH ion seems to suggest that both
respectively. Second step involves the breaking of another C—O
bond with free energy of activation 4.3 kcal/mol (6TS2). The final
product is more exergonic than the hydrolysis process of 1. The
processes are kinetically comparable. Hence, both hydrolysis
and retro-aldol products should be observed, which is not in
agreement with the experimental observation. To note that the
Figure 4. B3LYP/6–31 þ G* calculated relative to gas phase free energies in kcal/mol for BAC2 hydrolysis (solid line) and retro aldol process (doted line) of
ethyl 3-hydroxybutyrate (4). The liberated side products during the formation of intermediate steps are given in italics and the addition of new species for
further process is given in []
J. Phys. Org. Chem. 2011, 24 578–587
Copyright ß 2010 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

B. GANGULY ET AL.
The hydrolysis and retro-aldol processes of 1 with hydroxide
ion were calculated in methanol using polarized continuum
[
96–100]
model (PCM).
Single-point calculations were performed
using gas phase optimized geometries for each stationary point
at same level of theory. In the case of BAC2 hydrolysis of 1, the
activation barrier for the formation of transition state 1TS1 was
found to be 8.1 kcal/mol. The complex 1HB in methanol was
[
68,69]
found to be higher in energy than the reactants,
suggest that the reaction kinetics of the hydrolysis process is not
which
[
103]
expected to be influenced by the complex 1HB.
The
calculated activation barriers show that the formation of 1TS2
is the rate determining step for the hydrolysis process. The
transition state 1TS2 lies 16.1 kcal/mol above separated reactants
(
is exothermic in nature (Fig. 7). The retro-aldol reaction for 1 with
Fig. 7). The calculated reaction energies show that the hydrolysis
ꢀ
OH ion shows that the formation of intermediate 1’INT is
5
7
1
.0 kcal/mol higher in energy than separated reactants (Fig.
[
104]
).
The transition state 1’TS1 for the C—C bond breaking is
2.9 kcal/mol higher in energy compared to separated reactants.
Subsequently, the activation barrier for the proton transfer
process through the transition state 1’TS2 is 8.0 kcal/mol from
separated reactants (Fig. 7). The retro-aldol product 6 further
undergoes the hydrolysis reaction via two transition states 6TS1
and 6TS2. The formation of 6HB in methanol was found to be
higher in energy than 6 and not considered in this PES. Overall,
the PES for the retro-aldol followed by the hydrolysis process of 1
show that 6TS1 is the rate determining step in the whole process,
which is 1.4 kcal/mol lower than the rate determining step for the
hydrolysis of 1 (Fig. 7). Therefore, the calculated results suggest
that the retro-aldol process is kinetically favored over the
Figure 5. B3LYP/6–31 þ G* optimize geometries with important dis-
˚
tances (A) involved in BAC2 hydrolysis of ethyl 3-hydroxybutyrate (4).
ꢀ
hydrolysis reaction of 1 with OH ion. It is known that retro-aldol
[
105,106]
reactions are reversible in nature.
However, in this case the
subsequent hydrolysis process followed by the retro-aldol makes
it irreversible, which was observed in the experimental product
ratios with time (Table 1).
reactions were carried out in a polar solvent medium and solvent
does play an important role in many reactions. Therefore, the
influence of solvent (methanol in this case) on the potential
energy surfaces of 1 and 4 should also be considered in this
study.
The calculated results showed a different trend for the reaction
of 4 with hydroxide ion in methanol (Fig. 8). The hydrolysis
process was found to be kinetically and thermodynamically
preferred than that of retro-aldol process (Fig. 8). The calculated
ꢀ
activation barrier for the hydrolysis process of 4 with OH ion
is 3.3 kcal/mol lower in energy than the corresponding retro-aldol
reaction. The intermediate product formed due to the expulsion
of acetaldehyde in the initial stage of the retro-aldol process
shows that the preceding transition state 4’TS1 is 0.1 kcal/mol
lower in energy. It might be possible that the complex formation
can take place instead of isolated intermediate products.
The associated complexed form is 3.6 kcal/mol lower in energy
2
than 4’TS1, which, subsequently would go to 4’P.H O (Support-
ing information, Figure S1).
It appears that the bulky adamantyl group enhances
the activation barrier for the hydrolysis of the ethyl
threo-2-(1-adamantyl)-3-hydroxybutyrate (1) through deleter-
ious steric interaction with the nucleophile compared to
parent ester ethyl 3-hydroxybutyrate (4). To corroborate this
observation, we have further calculated the hydrolysis of the
parent ester ethyl 3-hydroxybutyrate substituted with tert-
butyl group (7) at a-carbon atom (Supporting information,
Figure S2). The calculated activation barrier for the hydrolysis
of 7 was found to be 15.9 kcal/mol, which is much higher than
the parent ester 4 (10.6 kcal/mol). It is clear that the bulkiness
of substituents influence the activation barrier for the
hydrolysis of esters.
Figure 6. B3LYP/6–31 þ G* optimize geometries with important dis-
˚
tances (A) for retro-aldol process of ethyl 3-hydroxybutyrate (4).
wileyonlinelibrary.com/journal/poc
Copyright ß 2010 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2011, 24 578–587

HYDROLYSIS OF ETHYL-2(1-ADAMANTYL)-3-HYDROXYBUTYRATE
Figure 7. B3LYP/6–31 þ G* calculated relative electronic energies in kcal/mol for BAC2 hydrolysis (solid line) and retro aldol process (doted line) of ethyl
threo-2-(1-adamantyl)-3-hydroxybutyrate (1) in methanol. The liberated side products during the formation of intermediate steps are given in italics and
the addition of new species for further process is given in []
Figure 8. B3LYP/6–31 þ G* calculated relative electronic energies in kcal/mol for BAC2 hydrolysis (solid line) and retro-aldol process (doted line) of ethyl
3-hydroxybutyrate (4) in methanol. The liberated side products during the formation of intermediate steps are given in italics and the addition of new
species for further process is given in []
of similar bulkiness can cause the same effect on the reaction
pathway which is a presumption yet to be investigated.
Retro-aldol process is kinetically and thermodynamically unfa-
vored in the case of parent ester 4 with hydroxide ion. The role of
solvent is profound to rationalize the experimentally observed
results.
CONCLUSIONS
In the present work, we have showed that the course of a reaction
can be changed with appropriate substituent on the substrate.
The reaction of ethyl threo-2-(1-adamantyl)-3-hydroxybutyrate
(
1) with a base leads toward the formation of retro-aldol as major
products. However, under similar conditions, parent ethyl
-hydroxybutyrate (4) formed hydrolysis product. The computed
3
B3LYP/6–31 þ G* results shed the light on the dramatic change in
Acknowledgements
the course of reaction of 1 and 4 in alkaline medium. The large
activation barrier for the hydrolysis of adamantyl-substituted
esters 1 in methanol leads to 2 as the minor product. The bulky
adamantyl group enhances the steric strain in the system and
increases the barrier for the hydrolysis process, so the reaction
pathway is redirected to energetically more feasible process of
retro-aldol reaction. It is reasonable to presume that other groups
The authors gratefully acknowledge to the Department of
Science and Technology, (DST) New Delhi, India (Grant No.
DST/INT/CROATIA/P8/05), and the Ministry of Science, Education,
& Sports of the Republic of Croatia (Grant No. 098-0982933-2911).
Authors, AS acknowledges to Council of Scientific and Industrial
Research (CSIR), New Delhi and MKK to University Grants
J. Phys. Org. Chem. 2011, 24 578–587
Copyright ß 2010 John Wiley & Sons, Ltd.
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B. GANGULY ET AL.
Commission, New Delhi for award of Fellowships. The authors
also thank the reviewers for their comments and suggestions that
have helped us to improve the paper.
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