Solvent effects on the enthalpy and entropy of activation for the hydrolysis of β-lactones

Article abstract of DOI:10.1007/s10953-008-9250-x

The hydrolysis of β-propiolactone and β-butyrolactone in binary water∈+∈dioxane mixtures was investigated by kinetic studies. The following conclusions were reached: First, β-propiolactone is more reactive than β-butyrolactone across the range of water∈+∈dioxane compositions. This observation was rationalized in terms of the electric charge flow caused by the β-butyrolactone's methyl substituent. Second, hydrolysis of these lactones is essentially enthalpy controlled. Third, an increase in the dioxane percentage, which relaxes the intermolecular hydrogen bonds in the ordered structure of water, reduces the enthalpy of activation ΔH ^# and simultaneously increases the entropy of activation ΔS ^#(absolute value) for solvent compositions up to 60% dioxane. Fourth, plotting ΔH ^#/ΔS ^# against the solvent composition yields an N-shaped curve. This results is a consequence of the quadratic and cubic terms appearing in the expressions of ΔH ^# and ΔS ^# as functions of the solvent media composition. Fifth, an ABC classification was set up to characterize the behavior of ΔH ^#/ΔS ^# for the solvolysis of these lactones.

Full text of DOI:10.1007/s10953-008-9250-x

J Solution Chem (2008) 37: 451–457
DOI 10.1007/s10953-008-9250-x
SIMEC’06
Solvent Effects on the Enthalpy and Entropy
of Activation for the Hydrolysis of β-Lactones
José A. Manso · M. Teresa Pérez-Prior · María del Pilar
García-Santos · Emilio Calle · Julio Casado
Received: 20 July 2007 / Accepted: 6 October 2007 / Published online: 15 February 2008
© Springer Science+Business Media, LLC 2008
Abstract The hydrolysis of β-propiolactone and β-butyrolactone in binary water+dioxane
mixtures was investigated by kinetic studies. The following conclusions were reached: First,
β-propiolactone is more reactive than β-butyrolactone across the range of water+dioxane
compositions. This observation was rationalized in terms of the electric charge flow caused
by the β-butyrolactone’s methyl substituent. Second, hydrolysis of these lactones is essen-
tially enthalpy controlled. Third, an increase in the dioxane percentage, which relaxes the
intermolecular hydrogen bonds in the ordered structure of water, reduces the enthalpy of
activation ꢀH# and simultaneously increases the entropy of activation ꢀS#(absolute value)
for solvent compositions up to 60% dioxane. Fourth, plotting ꢀH#/ꢀS# against the sol-
vent composition yields an N-shaped curve. This results is a consequence of the quadratic
and cubic terms appearing in the expressions of ꢀH# and ꢀS# as functions of the solvent
media composition. Fifth, an ABC classification was set up to characterize the behavior of
ꢀH#/ꢀS# for the solvolysis of these lactones.
Keywords Lactones · Mixed solvents · Hydrolysis
1 Introduction
The reactivity in nitrosation reactions of amino acids having an –NH2 group, and its rela-
tionship with the alkylating potential of their products, has been investigated in previous
work [1–3]. Among other conclusions, it was shown that the species formed from the nitro-
sation of these amino acids are the corresponding lactones.
Because some lactones have alkylating reactions with a number of nucleophilic sites in
tissues [4], the reactivity of lactones and its relationship with their carcinogenic activity was
subsequently investigated [5, 6].
J.A. Manso · M.T. Pérez-Prior · M. del Pilar García-Santos · E. Calle · J. Casado (
)
ꢀ
Departamento de Química Física, Universidad de Salamanca, Plaza de la Merced, 37008 Salamanca,
Spain
e-mail: jucali@usal.es

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J Solution Chem (2008) 37: 451–457
Because the behavior of lactones in their hydrolysis reactions is a good indicator of their
reactivity as electrophilic molecules, the hydrolysis of 4-6-membered lactones was investi-
gated in neutral water and in slightly acidic media, and in water +dioxane mixtures [5].
Over a small range of water +dioxane concentrations (water/dioxane ratio not lower than
4/6), an isokinetic ꢀH#/ꢀS# relationship was observed for the hydrolysis of β-propio-
lactone (BPL) and β-butyrolactone (BBL).
Since: (i) At low water + dioxane ratios, plotting ꢀH#/ꢀS# shows a weak but percep-
tible deviation from linearity; (ii) BPL and BBL are potent carcinogenic molecules, with
their behavior in their hydrolysis reactions being an indicator of their reactivity as alkylat-
ing agents [6]; and (iii) previous results [5] have shown that the reactivity of β-lactones
diminishes in water +dioxane mixtures when the percentage of dioxane increases, an in-
vestigation of possible ways of inhibiting the electrophilic capacity of these lactones by
changing the composition of the medium should be of biological interest. The present study
addresses this aim.
2 Experimental
2.1 Materials
β-Propiolactone and β-butyrolactone were obtained from Sigma; dioxane was from Panreac
(Barcelona, Spain). Water was deionized with a MilliQ-Gradient (Millipore).
2.2 Procedures
Hydroxy acids resulting from the hydrolysis of the lactones were used as control species
for monitoring the reaction kinetics. The concentration of hydroxy acid was determined by
titration with NaOH, whose concentration had been standardized by titration with potassium
hydrogen phthalate. In the titration procedure, 1 mL aliquots of the reacting mixture (lactone
and unbuffered CO2-free water) were removed from time to time, added to 9 mL of ice water,
and titrated immediately to a bromothymol blue endpoint (the hydroxy acid pKa values were
in the range 4.5 to 4.7 [7]).
Kinetic runs were performed in triplicate. Temperatures (in the 25 to 35 ◦C range; see
Fig. 1 and Table 1) were kept constant to 0.05◦C using a Lauda-Ecoline RE 120 thermo-
stat.
3 Results and Discussion
The hydrolysis of BPL and BBL (Scheme 1) was investigated at different water +dioxane
volume ratios (from 2:8 up to 10:0).
Experiments performed to determine the influence of changing the lactone concentration
revealed that the reactions are first order with respect to this reagent:
d[HA]
= k[H2O][L] = k1[L]
(1)
dt
where [L] denotes the concentration of lactone, [HA] that of the formed hydroxy acid, and
k1 = k[H2O] is the pseudo-first-order rate constant.

J Solution Chem (2008) 37: 451–457
453
Scheme 1 Hydrolysis of BPL and BBL in neutral media
Figure 1 Integrated form of the pseudo-first-order rate equation (Eq. 1) for hydrolysis of BPL (plot a) and of
BBL (plot b) in 10:0 ("), 8:2 (Q), 6:4 (2), 4:6 (×) and 2:8 (!) water+dioxane mixtures (volume/volume)
−1
◦
where [L] = 0.08 mol·L and t = 35.0 C
o
Figure 1 shows the integrated form of Eq. 1 in terms of the concentration of lactone at
time t, [L]t , and its initial concentration, [L]o, in several water +dioxane mixtures.
Table 1 reports the values of the hydrolysis rate constants for β-propiolactone and β-
butyrolactone in different water +dioxane mixtures. Table 2 shows the values of the activa-
tion parameters for both hydrolysis reactions.
The very similar ꢀS# values found for the hydrolysis of BPL and BBL (Table 2) are
consistent with the analogous geometry of these lactones. These values also show that the
reactivity of these lactones is mainly enthalpy controlled.
The higher ꢀH# value obtained for the hydrolysis of β-butyrolactone must be caused
by the presence of the methyl group as a charge donor on the β-carbon, which causes a
decrease in its electrophilic character. Because, in general terms, substitution of groups on
carbon atoms 2 or 3 in lactones results in a decrease or loss of alkylating potential and
carcinogenicity [8], the steric hindrance of the BBL methyl group must also contribute to
the higher ꢀH# value.
There is a considerable diversity in the behavior of the thermodynamic quantities of ac-
tivation related to solvent composition for the different binary solvent systems. Complex
behavior for ꢀH# that is related to variations in solvent composition has been reported
by Tommila [9] for the hydrolysis of methyl-, ethyl-, and i-propylbenzenesulfonates in
water + acetone and water + dioxane mixtures.

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455
Table 2 Activation parameters as a function of the composition of the medium for the neutral solution
hydrolysis of β-propiolactone and β-butyrolactone
#a
−1
#a
−1
−1
)
Water +dioxane
ꢀH (kJ·mol
)
−ꢀS (J·K ·mol
(volume/volume ratio)
BPL
BBL
BPL
BBL
10/0
9/1
83
–
2
88
85
84
83
82
81
79
82
84
83
77
3
1
1
80
8
78 10
–
89
94
2
1
3
7
3
6
4
4
4
8/2
80
79
76
75
73
78
78
74
73
1
1
3
3
1
1
1
1
1
90
95
3
3
7/3
1
98
6/4
2
1
2
1
1
1
3
107 10
104
110
122
114
111
117
5/5
112
123
109
111
125
130
9
3
3
3
5
2
4/6
3.5/6.5
3/7
2.5/7.5
2/8
140 10
a
Values are given with their standard deviations
#
#
Figure 2 Plot of ꢀS against ꢀH for the hydrolysis of: (a) β-propiolactone and (b) β-butyrolactone in
water +dioxane mixtures. Dashed lines show results obtained previously over a narrower range of composi-
tions
The behavior of ꢀH# and ꢀS# as a function of the solvent composition tends to be
complex. It can be observed (see Fig. 2) that the increase in concentration of dioxane, which
relaxes the intermolecular hydrogen bonds in the ordered structure of water, reduces the
ꢀH# value and simultaneously increases the −ꢀS# value up to 60% dioxane. At higher
percentages of dioxane, an N-shaped type correlation was observed [10].
As depicted in Fig. 2, previous results [5] obtained over a narrower range of compositions
showed a ꢀS#/ꢀH# isokinetic effect. Because the strong effect of dioxane on the kinetic
parameters is a consequence of a strong lactone + water interaction, when the water/dioxane
ratio is not lower than ≈ 4/6 both the enthalpy and entropy tend to be linear functions of the
volume fraction of that solvent mixture, and an isokinetic relationship should result. Figure 2
(dashed lines) shows that this effect indeed occurs [5].

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J Solution Chem (2008) 37: 451–457
Class
Table 3 ABC Classification for the solvolysis of some compounds
◦
Compound
t ( C)
Solvent range
t-Butyl chloride [11]
25.0
50.0
50.0
25.0
60.0
0–90 vol.-% dioxane+H O
A B A
35 60 85 100
2
Ethyl benzenesulfonate [12, 13]
i-Propyl benzenesulfonate [9]
n-Propyl benzenesulfonate [9, 12]
Ethyl bromide [14]
0–95 wt.-% dioxane+H O
A B C A
20 55 90 95 100
2
0–98 wt.-% dioxane+H O
A B A
10 65 95 100
2
0–85 wt.-% Me CO+H O
A C A
25 70 90 100
2
2
0–90 wt.-% Me CO+H O
A C A
35 72 94 100
2
2
When the concentration of the more rapidly moving solvent (water) diminishes, quadratic
and cubic terms appear in the expressions of ꢀH# and ꢀS#. The values of these quantities
are a consequence of the dependence of the Gibbs energy of a solute species on the imme-
diate environment. By including the cubic terms, N-shaped relationships are generated such
as those depicted in Fig. 2 [10].
3.1 ABC classification
When the ꢀS# values are plotted against those of ꢀH# for the hydrolysis of β-propiolactone
and β-butyrolactone in several binary solvent systems (Fig. 2), somewhat complex curves
are obtained. For comparison, it is convenient to use a symbolic terminology to classify
the behavior of the thermodynamic quantities of activation related to the variation of the
solvent [11].
This classification system may be defined with the aid of a plot of ꢀS#/ꢀH# as shown
in Fig. 2. In such plots, arrowheads were placed on the curves to indicate the direction of
increasing mole fraction of the most rapidly moving component of a binary solvent mixture.
In general, this may occur in one of three ways: A, both ꢀH# and ꢀS# increase; B, ꢀH#
decreases while ꢀS# increases; and C, both ꢀH# and ꢀS# decrease.
Figure 2 clearly shows that the plots start in the A class, shift to C, and then back to A.
This leads to a convenient shorthand description of the data: ACA. It is useful to append
subscripts to the letters designating the solvent composition range (as percentages) covered
by each class, in terms of the volume/volume ratio of the most rapidly moving component.
Thus, for the binary water +dioxane solvent system, a complete description of the relative
contributions of ꢀH# and ꢀS# to the hydrolysis rate of β-lactones is given by 20A35C40A100
(N-shaped).
For comparison, Table 3 shows a correlation of the solvolysis rates for different com-
pounds in different binary solvent systems and their ABC classification. A similar type
of behavior is seen between the hydrolysis of β-lactones and the solvolysis of other com-
pounds.
4 Conclusions
Comparison of the results arising from this study of hydrolysis of β-propiolactone and β-
butyrolactone in binary water+ dioxane mixtures results in the following conclusions:
(i) β-Propiolactone is more reactive than β-butyrolactone across the full range of
water +dioxane compositions. This is due to the flow of electric charge caused by
the methyl substituent in β-butyrolactone.

J Solution Chem (2008) 37: 451–457
457
(ii) Hydrolysis of these lactones is essentially enthalpy controlled.
(iii) An increase in the dioxane percentage, which relaxes the intermolecular hydrogen
bonds found in the ordered structure of water, reduces ꢀH# and simultaneously in-
creases ꢀS# (absolute value) up to 60% dioxane.
(iv) The plot of ꢀH#/ꢀS# against the solvent composition is seen to be N-shaped. The
results are a consequence of the quadratic and cubic terms appearing in the expressions
of ꢀH# and ꢀS# as functions of the composition of the medium.
(v) An ABC classification was set up to characterize the behavior of ꢀH#/ꢀS# for the
solvolysis of these lactones.
Acknowledgements The authors thank the Spanish Ministerio de Educación y Ciencia (Project CTQ2004-
05048/BQU), as well as the Spanish Junta de Castilla y León (Grant SA011A05) for supporting the research
reported in this article. J.A.M. and M.T.P.P. also thank the Ministerio de Educación y Ciencia and the Junta
de Castilla y León for Ph.D. grants. Thanks are also given to the valuable comments made by the referees.
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