Isergonic relationship in the acid-catalyzed hydrolysis of carboxylic esters with hydrogen-bonding capability

Article abstract of DOI:10.1002/poc.779

The average value of the enthalpies of activation for the acid-catalyzed hydrolyses of ethyl 2-hydroxypropanoate and five acetate esters with hydrogen bonding capability is 57 ± 7 kJ mol^-1 (p = 0.05). This value is 11 kJ mol^-1 lower than the mean observed for primary and secondary alkyl acetates and ethyl alkanoates, measured in water and in mixtures of water with organic solvent with high water content. The difference is attributed to tighter transition-state complex hydration via hydrogen bonding, relative to reactant ester species. Enthalpy-entropy compensation with an isokinetic temperature of 346 K was found to be valid at p < 0.05, a value typical for solvent-mediated kinetic effects. Copyright

Full text of DOI:10.1002/poc.779

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2004; 17: 567–571
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.779
Isergonic relationship in the acid-catalyzed hydrolysis
of carboxylic esters with hydrogen-bonding capabilityy
Julio F. Mata-Segreda*
School of Chemistry, University of Costa Rica, 2060 Costa Rica
Received 12 May 2003; revised 23 June 2003; accepted 9 September 2003
ABSTRACT: The average value of the enthalpies of activation for the acid-catalyzed hydrolyses of ethyl 2-
hydroxypropanoate and five acetate esters with hydrogen bonding capability is 57 ꢀ 7 kJ molꢁ1 (p ¼ 0.05). This value
is 11 kJ molꢁ1 lower than the mean observed for primary and secondary alkyl acetates and ethyl alkanoates, measured
in water and in mixtures of water with organic solvent with high water content. The difference is attributed to tighter
transition-state complex hydration via hydrogen bonding, relative to reactant ester species. Enthalpy–entropy
compensation with an isokinetic temperature of 346 K was found to be valid at p < 0.05, a value typical for
solvent-mediated kinetic effects. Copyright # 2004 John Wiley & Sons, Ltd.
KEYWORDS: acid-catalyzed ester hydrolysis; hydrophilic esters; hydrogen bonding; activation parameters; enthalpy–
entropy compensation
INTRODUCTION
in simple systems with thermal freedom, as opposed to
the pre-organized nature of enzyme catalytic sites.
Hydrogen bonding to sites other than the reaction
center also seems to play a role in simpler non-enzyme
systems, such as the acid-catalyzed hydrolysis of car-
boxylic esters. Ethyl 2-hydroxypropanoate undergoes
hydrolysis five times faster than ethyl 2-methylpropano-
ate at 25 ꢂC,8 despite the fact that the van der Waals
Enzymes function by lowering transition-state (TS) en-
ergies1 and energetic intermediates2 and also, apparently
by raising reactant-state energy.3 Stabilization of TS
complexes through atomic contacts remote from the
reaction center is known to occur in enzyme catalysis.4
This mechanism affects not only catalysis per se, but also
enzyme selectivity. One such kind of interaction is the
hydrogen bond.5 The pre-organized nature of active sites
is often indicated as the reason for the catalytic efficacy of
these atomic contacts because rate enhancement results
from bringing the reacting species together at the active
site, thus increasing their effective local concentration.
Certain molecular orientations and rotamer distributions
are also favored, that result in reactive positions that
resemble the TS complex. As a net result, there is a
reduction in the entropy cost of these concentration and
orientation effects for TS complex formation. In this way,
any resulting favorable effect on ÁHz contributes to a
greater extent to the reduction of ÁGz.
volume of the 2-propyl group (34.12 cm3 molꢁ1 9
) is
similar to the same molecular parameter for the 1-
hydroxyethyl group (28.49 cm3 molꢁ1).9 An analogous
result is that of ethyl hydroxyacetate (18.27 cm3 molꢁ1 9
)
and ethyl chloroacetate (21.85 cm3 molꢁ1);9 the first
ester being three times more reactive under the same
conditions.8
Hydrogen-bonding capability in the alkyl moiety also
shows the same trend, although to a lesser extent. 2-
Hydroxyethyl acetate and 3-oxabutyl acetate undergo acid
hydrolysis 30% faster than propyl acetate at 25 ꢂC,8 despite
the similarity in the van der Waals volumes of the chains:
28.50, 39.33 and 34.13 cm3 molꢁ1, respectively (van der
Waals volumes calculated from data in Ref. 9).
It is well known that the magnitude of steric hindrance
is associated with solvation processes.10 Therefore, it is
important to address to this basic issue to help understand
quantitative aspects of enzyme selectivity and catalytic
efficiency.
In order to achieve this goal, it was decided to compare
the kinetic behavior of the acid-catalyzed hydrolysis of
esters with hydrogen-bonding capability vs. unfunctio-
nalized alkyl analogs. This experimental model leads to a
straightforward hypothesis: there are stabilizing distant
solvation interactions in the non-enzyme hydrolysis of
Site-mutagenesis experiments have given a clear pic-
ture of the effect of hydrogen bonding to TS complexes,6
ranging from weak bonds to sites remote from the
reaction center, up to much stronger interactions with
the atoms whose bonds undergo either scission or forma-
tion.7 Hence it is useful to establish the minimal amount
of rate acceleration expected from this kind of interaction
*Correspondence to: J. F. Mata-Segreda, School of Chemistry,
University of Costa Rica, 2060 Costa Rica.
E-mail: jmata@cariari.ucr.ac.cr
ySelected paper part of a special issue entitled ‘Biological Applications
of Physical Organic Chemistry dedicated to Prof. William P. Jencks’.
Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2004; 17: 567–571

568
J. F. MATA-SEGREDA
esters capable of hydrogen bonding, despite the thermal
freedom in homogeneous aqueous solution.
Esters with hydrogen-bonding capability undergo acid
hydrolysis at moderately faster rates than their alkyl
analogs. For example, 3-oxabutyl acetate reacts twice
as fast as butyl acetate at 37.0 ꢂC.11,12 One could point to
differences in leaving-group pKa (BuOH, pKa ¼ 16.0;
MeOCH2CH2OH, pKa ¼ 14.84) as a sufficient explana-
tion for this observation, rather than a solvent effect on
TS complex stability. This rationale is overruled when
other polar esters are also compared with 3-oxabutyl
acetate. At 37.0 ꢂC, the relative rates of hydrolysis of
3-oxapentyl acetate (pKa ¼ 15.1), 1,2-ethyl diacetate
(pKa ¼ 15.3), 2-chloroethyl acetate (pKa ¼ 14.31) and
0.98 ꢀ 0.05,12 0.978 and 0.91 ꢀ 0.02,14 respectively.
This shows that a ÁpKa ꢄ 2 yields <10% variation in
k2. Hence the pKa of the leaving group or TS complex
polarity seems not as explanation for the observation,
either.
This paper reports the isobaric activation parameters in
the acid-catalyzed hydrolyses of ethyl 2-hydroxypro-
panoate, 2,3-dihydroxypropyl acetate,11 1,2,3-propyl
triacetate,11 1,2-ethyl diacetate, 3-oxapentyl acetate and
3,6-dioxaoctyl acetate in water solvent, catalyzed by
aqueous Hþ under normal pressure.
RESULTS AND DISCUSSION
Kinetics
acetylcholine
(pKa ¼ 13.9)
are
1.00 ꢀ 0.02,12
The reactions followed the well-established pseudo-
second-order rate law:
HCl
ester þ H2O ꢁ! alcohol þ RCO2H
ð1Þ
d½RCO2Hꢃ=dt ¼ k2½Hþꢃ½esterꢃ
Activation parameters
The observed second-order rate coefficients are listed in
Table 1. They have an average standard deviation of 3%.
Structure exerts no strong effect on the magnitude of
the k2 values, in contrast to alkyl acetates, where the steric
bulk of the alkyl moieties results in a decrease in k2. This
feature had already been reported for the acid-catalyzed
hydrolyses (aqueous H2SO4) of 3-oxaalkyl acetates,12 the
mono-, bi- and triacetates of glycerol11 and 1,2-propyl
diacetate.11
Table 2 gives the isobaric activation parameters. The
activation enthalpies for the acid hydrolyses of unfunc-
tionalized alkyl acetates and ethyl alkanoates have been
found to be fairly constant,8,15 between 65 and
70 kJ molꢁ1. The mean value found in the present study
for esters with hydrogen-bonding capability was
57 ꢀ 7 kJ molꢁ1 (p ¼ 0.05). This 11 kJ molꢁ1 difference
is statistically significant at p < 0.01.
Ethyl 2-hydroxypropanoate has the lowest ÁHz value
in the group. Deletion of this value affords an average
enthalpy of activation of 59 ꢀ 5 kJ molꢁ1 (p ¼ 0.05).
Hence the finding is not an artifact produced by the
Table 1. Second-order specific rates for the hydrolysis of the
esters by aqueous HCl, in water solvent
Temperature
( ꢂC)
104k2
Ester
(sꢁ1 molꢁ1 dm3)
Table 2. Isobaric activation parameters for the acid-
catalyzed hydrolysis of the esters studied, in water solvent
Ethyl 2-hydroxypropanoate
25.0a
30.0
35.0
40.2
45.0
49.8
25.0a
30.0
35.0
40.2
45.0
49.8
27.5
30.7
34.8
39.4
43.1
48.5
30.0
35.0
40.2
45.0
49.8
1.28
1.62 ꢀ 0.02
2.55 ꢀ 0.02
3.2 ꢀ 0.1
ÁHzꢁ1
ÁSz
Ester
(kJ mol
)
(kJ Kꢁ1 molꢁ1
)
4.2 ꢀ 0.2
AcOR/HCl (N ¼ 14a)
AcOEt/Dowex (N ¼ 6b)
AcOEt/HCl
66 ꢀ 2
67 ꢀ 4
68 ꢀ 9
72 ꢀ 3
Variable
Variable
5.8 ꢀ 0.1
1,2 Ethyl diacetate
3-Oxapentyl acetate
0.809
1.26 ꢀ 0.02
1.87 ꢀ 0.02
2.76 ꢀ 0.07
3.98 ꢀ 0.09
5.96 ꢀ 0.08
0.82 ꢀ 0.06
1.22 ꢀ 0.03
1.6 ꢀ 0.1
ꢁ0.092 ꢀ 0.006
AcOEt/Dowex
ꢁ0.077 ꢀ 0.006
z
c
hÁH i ¼ 68 ꢀ 2 kJ molꢁ1
(p ¼ 0.05)
2,3-Dihydroxypropyl acetate/
H2SO4
59 ꢀ 3
ꢁ0.13 ꢀ 0.01
d
d
1,2,3-Propyl triacetate/H2SO4
3-Oxapentyl acetate/HCl
54 ꢀ 1
66 ꢀ 2
ꢁ0.15 ꢀ 0.05
ꢁ0.105 ꢀ 0.008
ꢁ0.16 ꢀ 0.02
ꢁ0.13 ꢀ 0.03
ꢁ0.124 ꢀ 0.007
2.8 ꢀ 0.1
Ethyl 2-hydroxypropanoate/HCl 46 ꢀ 2
3.6 ꢀ 0.2
1,2-Ethyl diacetate/HCl
3,6-Dioxaoctyl acetate/HCl
58 ꢀ 4
59 ꢀ 2
5.1 ꢀ 0.1
z
c
hÁH i ¼ 57 ꢀ 7 kJ molꢁ1
3,6-Dioxaoctyl acetate
1.44 ꢀ 0.03
2.17 ꢀ 0.01
3.2 ꢀ 0.2
(p ¼ 0.05)
a From Refs. 8 and 15.
4.4 ꢀ 0.1
b
From Ref. 28.
6.68 ꢀ 0.08
z
c
hÁH i are given as average values with 95% confidence limits.
d
a From Ref. 8.
From Ref. 11.
Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2004; 17: 567–571

HYDROLYSIS OF HYDROGEN-BONDING ESTERS
569
contribution of that ester, because the difference is still
statistically significant at p < 0.01.
Considerable TS electrostriction is built up in the acid-
catalyzed hydrolysis of unfunctionalized carboxylic est-
ers, as indicated by negative volumes of activation of
molecular hydrogen bonding between the protonated
carbonyl and any of the oxygen acceptors in the alkyl
moiety. The energy of the solvent–solute interactions
would be about the same in both the initial and transition
states. Thus, as a result of this intramolecular stabilizing
interaction, the greater fraction of protonated ester would
be a less complicated explanation for the 11 kJ molꢁ1
decrease in the value of ÁHz. For the case at hand,
intramolecular hydrogen bonding is a proposal difficult
to consider in 55 M water medium for small solute
molecules with no special structural features, such as
the constrained geometries of substituted maleate mono-
anions. It is reasonable that hydrogen bonding by water
decreases the strength of intramolecular bonds.18 Hence
solvent–solute hydrogen bonding is a more probable
interaction. Moreover, if any intramolecular hydrogen
bonding led to increased basicity, ethanolamine would be
a stronger base than ethylamine, and the same would be
expected for the pairs diethanolamine–diethylamine,
triethanolamine–triethylamine and tris(hydroxymethyl)
aminomethane–tert-butylamine. Thermodynamic data
in the literature for the dissociation of these protonated
amines in aqueous solution at 25 ꢂC point in the opposite
direction (ÁpKa values calculated from ÁG ꢂ for the
dissociation of the ammonium ions in aqueous solution
at 25 ꢂC19). The alkylamines are more basic than their
hydroxy analogs by ÁpKa ranging from 1.13 to 2.96.
The above qualitative considerations permit the fol-
lowing argument to be constructed: for this kind of
stabilization mechanism between TS complexes and
solvent molecules, the maximal reduction in energy for
the system is achieved when certain requirements of
intermolecular configuration are met. The geometric
conditions clearly imply a constraint for which the
decrease in energy content will be accompanied by
some degree of entropy loss. Thus, enthalpy–entropy
compensation must exist in the acid-catalyzed hydrolysis
of esters with hydrogen-bonding capability.
around ꢁ9 cm3 mol
,
ꢁ1 16 and entropies of activation in the
range from ꢁ0.08 kJ Kꢁ1 molꢁ1 to ꢁ0.12 kJ Kꢁ1 molꢁ1 15
.
Various pieces of evidence have been adduced to
establish that the acid-catalyzed hydrolysis of esters
involves a tetrahedral addition intermediate. The convin-
cing evidence comes from studies using 18O as a tra-
cer.15,17 Oxygen exchange with the solvent and
hydrolysis occur at comparable rates. This observation
suggests that the intermediate has a lifetime long enough
for the proton transfers required for such isotopic ex-
change to take place.
Kirby offers an excellent discussion on the kinetic
effect of water.15 Plots of log(kobs/[esterHþ]) against
logaH O have slopes close to 2 for ester hydrolyses and
2
for 18O exchange. This is taken as evidence that two
molecules of water are involved in the TS for each
reaction.
The protons of a molecule of water undergoing
addition to the carbonyl group become acidic as bond
formation develops. The role of a second molecule of
water must be to bind one proton from the nucleophile.
Hence an acceptable mechanism involves a molecule of
water acting as a general base to assist the nucleophilic
addition of the other molecule of water to the protonated
ester carbonyl group.
The commonly accepted TS complex core structure
can be represented as shown in Scheme 1. Qualitatively,
this TS complex must be regarded as a hydrophilic
solute that requires a tighter aqueous solvation cavity,
relative to initial ester molecules. Hence esters with
hydrogen-bonding capability (and their TS complexes)
should interact much more strongly with the surrounding
aqueous medium than their more hydrophobic alkyl
analogs. This qualitative argument is supported by
consideration of the hydration enthalpies for a few
solutes such as methanol (ꢁ84 kJ molꢁ1) or formalde-
The validity of isokinetic (isergonic) relationships has
been an ongoing issue for the past four decades. The
strongest critic is, perhaps, Exner.20 He has pointed to
the fact that since both activation entropies and enthalpies
are derived from the same data set, then the two quantities
are statistically dependent. This situation creates the
problem of propagation of uncertainty due to covariance.
Exner further indicated that if an enthalpy–entropy cor-
relation truly exists, the Arrhenius plots of the homo-
logous reactions under study should mutually intersect at
the isokinetic temperature ꢀ. Figure 1 shows that these
four esters comply with Exner’s criterion at a temperature
around 3.2 ꢅ 102 K.
hyde (ꢁ64 kJ molꢁ1
) as compared with ethylene
(ꢁ16 kJ molꢁ1). This structural feature, and the ÁSz and
ÁVz values mentioned above lead to the expectation of
lower activation enthalpies for the case of esters with
hydrogen bonding capability, a claim supported by ex-
periment.
One suggestion was to explore the possibility that these
esters and their TS complexes could be more basic than
their unfunctionalized alkyl analogs, owing to intra-
Since ÁHz and ÁSz are statistically correlated, the
direct linear fitting must be carried out accounting for
the uncertainties in both variables (double-weighted
least-squares fitting). All data pairs have different
degrees of precision (a heteroscedastic data set). As
expected from the result of the first test, the activation
Scheme 1
Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2004; 17: 567–571

570
J. F. MATA-SEGREDA
The average value of ÁSz for the acid-catalyzed hydro-
lysis of the group of esters with hydrogen-bonding cap-
ability studied in this work is ꢁ0.13 ꢀ 0.02 kJ Kꢁ1 molꢁ1
.
It is more negative than the values for the unfunctionalized
analogs ethyl acetate (ꢁ0.092 kJ Kꢁ1 molꢁ1), propyl acet-
ate (ꢁ0.102 kJ Kꢁ1 molꢁ1), 2-propyl acetate (ꢁ0.106 kJ
K
ꢁ1 molꢁ1) or butyl acetate (ꢁ0.109 kJ Kꢁ1 molꢁ1).
Hence any kind of assistance from neighboring groups
seems unlikely in the acid-catalyzed hydrolysis of esters
with hydrogen-bonding capability.
A last point must be added with regard to the ÁHz
values. The activation enthalpies for the acid-catalyzed
hydrolyses of the highly polar (but non-hydrogen-bond-
ing) 2,2,2-trichloroethyl acetate,8 ethyl chloroacetate,8
acetylcholine14 and ethyl 3-(trimethylammonium)pro-
panoate15 are 66, 66, 67 and 67 kJ molꢁ1, values identical
with those observed for the less polar unfunctionalized
alkyl esters. This further observation agrees with our
hypothesis that polarity of the TS complex is not the
general feature that explains the lower ÁHz of the
hydrolysis of esters with hydrogen-bonding capability.
Figure 1. Exner’s test for isokinetic relationship. (a) Ethyl 2-
hydroxypropanoate; (b) ethyl 1,2-diacetate; (c) 3,6-dioxaoc-
tyl acetate; (d) 3-oxapentyl acetate
parameters were found to correlate. The regression
equation with 95% confidence limits is ÁHz
(kJ molꢁ1) ¼ (104 ꢀ 5) þ (363 ꢀ 43)ÁSz (kJ Kꢁ1 molꢁ1
)
(r2 ¼ 0.998). Inclusion of the previously determined para-
meters for 2,3-dihydroxypropyl acetate and 1,2,3-propyl
triacetate11 yields essentially the same result for 95%
confidence limits (r2 ¼ 0.97):
CONCLUSION
z
ÁH ðkJ molꢁ1
Þ
The results of this work support the hypothesis that
hydrogen bonding to atoms remote from the reaction
center contributes to the stabilization of the TS complex
in the acid hydrolysis of esters in aqueous medium.
An 11 kJ molꢁ1 decrease in ÁHz was observed relative
to alkyl-unfunctionalized analogs. The effect is attributed
to stronger TS hydration, relative to reactant ester
specizes. This ꢂÁHz ¼ ꢁ11 kJ molꢁ1 corresponds to
ꢂÁS ¼ ꢁ32 J Kꢁ1 molꢁ1, necessary to meet the solvent
configuration requirements needed to increase the degree
of TS complex solvation in the presence of thermal
freedom.
z
¼ ð103 ꢀ 10Þ þ ð346 ꢀ 80ÞÁS ðkJ Kꢁ1 molꢁ1
Þ
ð2Þ
This isokinetic temperature ꢀ ¼ 346 K is in the range
frequently associated with solvation effects.21
Up to this stage, no discussion has been devoted to
neighboring-group participation by the hydrogen-bonding
oxygen atoms as a mechanistic possibility. In the case of
ethyl 2-hydroxypropanoate, a nucleophilic interaction
could be conceived between the 2-hydroxy group and the
protonated carboxyl, to yield an epoxide-like intermediate.
After departure of the ethoxy-leaving group, the resulting
ꢁ-lactone would rapidly undergo hydrolysis. A similar
effect might also be considered with the oxaalkyl esters
or the esters of glycerol. Acyl compounds certainly un-
dergo intramolecular transfer to adjacent hydroxyl groups
but at rates faster than either hydrolysis or intermolecular
alcoholysis.22,23 The entropies of activation for the cases
where neighboring groups assist in the formation of the
TS are not as negative as the values measured in this work.
For example: (a) The reported value of ÁSz for the
hydrolysis of 2-bromopropanoate at neutral pH to yield
EXPERIMENTAL
All esters were common chemicals from different com-
mercial sources. The reaction mixtures were made by
dissolving 3 cm3 of the ester in 100 cm3 of 0.2 M HCl. The
rates were measured by titration of free acid at suitable
reaction times with NaOH–phenolphthalein in 3.00 cm3
aliquot portions withdrawn from the reaction flask, im-
mersed in a constant-temperature water-bath. In all ex-
periments, >15 data points were collected (>95% of the
total extent of reaction).
The data were fitted to the first-order kinetic scheme
[NaOH] (cm3) ¼ A – B exp(ꢁk1t), by using a non-linear
least-squares computer program in the package ENZFIT-
TER.27 Error limits are standard deviations from the
means obtained from at least three experiments. Second-
order specific rates were obtained by dividing the
observed k1 by the corresponding value of [HCl].
2-hydroxypropanoate is þ37 J Kꢁ1 molꢁ1 24
;
(b) the ami-
nolysis of phenyl 4-(N,N-dimethylamino)butanoate
proceeds with a ÁSz 52 J Kꢁ1 molꢁ1 less negative than the
value for the similar intermolecular reaction between trime-
thylamine and phenyl acetate;22 (c) for the acetolysis of
trans-2-methoxycyclohexyl 4-bromobenzenesulfonate ÁSz
is ꢁ14 J Kꢁ1 molꢁ1 25
;
(d) the saponification of cis-2-hy-
acetate
droxycyclopentyl
proceeds
with
ÁSz ¼ ꢁ32 J Kꢁ1 molꢁ1, which is 96 J Kꢁ1 molꢁ1 less ne-
gative than the measured value for cyclopentyl acetate.26
Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2004; 17: 567–571

HYDROLYSIS OF HYDROGEN-BONDING ESTERS
571
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Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2004; 17: 567–571