Ultrasonic detection of hydrophobic interactions: A quantitative approach

Article abstract of DOI:10.1002/poc.1415

Kinetic effects of sonication on ester hydrolysis and tert-butyl chloride solvolysls, studied in ethanol-water binary solvent, are discussed in terms of quantitative relationships between their magnitude and the hydrophobicity of reagents. A number of conclusions were drawn from the observed linear free-energy (LFE) relationships. Independent of reaction mechanism, the decrease in reaction rates with Increasing ethanol content in the solvent is mainly due to hydrophobic stabilization of the ground state. While hydrophobic species can be hidden in the ethanol clusters present in the region X_EtOH > 0.1 5, at lower ethanol contents hydrophobic reagents are weakly solvated and the hydrophobic stabilization can be easily overcome by sonication. Copyright

Full text of DOI:10.1002/poc.1415

Research Article
Received: 18 February 2008,
Revised: 30 April 2008,
Accepted: 29 May 2008,
Published online in Wiley InterScience: 8 July 2008
(
www.interscience.wiley.com) DOI 10.1002/poc.1415
Ultrasonic detection of hydrophobic
interactions: a quantitative approach
a
a
a
b
Ants Tuulmets *, Jaak J a¨ rv , Siim Salmar and Giancarlo Cravotto
Kinetic effects of sonication on ester hydrolysis and tert-butyl chloride solvolysis, studied in ethanol–water binary
solvent, are discussed in terms of quantitative relationships between their magnitude and the hydrophobicity of
reagents. A number of conclusions were drawn from the observed linear free-energy (LFE) relationships. Independent
of reaction mechanism, the decrease in reaction rates with increasing ethanol content in the solvent is mainly due to
hydrophobic stabilization of the ground state. While hydrophobic species can be hidden in the ethanol clusters
present in the region XEtOH > 0.15, at lower ethanol contents hydrophobic reagents are weakly solvated and the
hydrophobic stabilization can be easily overcome by sonication. Copyright ß 2008 John Wiley & Sons, Ltd.
Keywords: ester hydrolysis; hydrophobic interactions; organic–aqueous solutions; sonication effects; solvolysis reactions
about mechanical effects, cavitation induced by sonication can
INTRODUCTION
promote many homogeneous and heterogeneous reactions by
generating free radicals which give rise to chain reactions in
solution.
Hydrophobic effects play an important role in many chemical
processes in aqueous solutions. Two phenomena can be
distinguished: hydrophobic hydration and hydrophobic inter-
action (HI). Hydrophobic hydration denotes how apolar solutes
affect the organization of water molecules in their immediate
vicinity. The HI is the tendency of apolar species to aggregate in
aqueous solutions to reduce their contact surface with water. HI
can lead to pairwise interactions, known as encounter complexes,
to well-defined host–guest complexes, to the formation of small
Sonication studies of solvolysis/hydrolysis reactions in aqueous–
organic binary solvents have brought to light specific solute–
solvent interactions and hydrophobic effects that are not
[
19–23,27–29]
manifested in conventional kinetic investigations.
It
was concluded that in these cases the sonochemical effects may
be related to the perturbation of the molecular structure of the
solvent and, more critically, to the destruction of hydrophobic
solute–solvent interactions.
[
1–5]
clusters of molecules, or to large aggregates.
HI between apolar molecules or apolar parts of molecules in
water are important noncovalent driving forces for inter- and
intramolecular binding and assembly processes, taking place in
However, conclusions drawn so far have been merely
qualitative deductions based on observed sonication effects in
reaction kinetics. In this paper, we show that a quantitative
correlation of kinetic sonication effects with substrate hydro-
phobicity reveals novel details of solvation phenomena and HI in
solutions.
[
1–5]
aqueous chemistry and biochemistry.
In aqueous systems
these interactions can strongly influence chemical equilibria and
[
3–9]
reaction rates.
For example, in the hydrolysis of esters, HIs (the
formation of hydrophobically stabilized encounter complexes or
[
10–14]
clusters with co-solutes) make the ester less reactive.
On
and the benzoin
are dramatically accelerated when carried out
[
15]
the other hand, the Diels–Alder reaction
RESULTS AND DISCUSSION
[
16]
condensation
in water rather than in organic solvents. Such rate enhancements
mostly result from the packing of hydrophobic surfaces of these
reagents in the transition state, whose energy is lowered as
A comprehensive investigation of sonication effects on polar
homogeneous reactions was first performed by Mason’s
[
27,28]
group.
An unexpectedly complicated dependence of the
[
2–5]
hydrocarbon–water contacts are minimized.
effect (kson/k) on the composition of ethanol–water binary
solvent was found for the solvolysis reaction of tert-butyl chloride.
The authors concluded that the application of ultrasound to the
reaction disrupted the binary solvent structure, thus permitting a
Although HI can be studied by a large variety of experimental
and computational techniques, the determination of chemical
[
4,5,17,18]
reactivity has a special position among them.
Indeed, rate
constants can usually be determined with so high a precision,
that small hydrophobic effects can thus be detected.
*
Correspondence to: A. Tuulmets, Institute of Chemistry, University of Tartu,
Jakobi 2, 51014 Tartu, Estonia.
Our contribution to HI studies consists in applying power
ultrasound to kinetic investigation of polar (ionic) homogeneous
reactions in solutions, mainly in ethanol–water binary mix-
E-mail: ants.tuulmets@ut.ee
[
19–23]
a
A. Tuulmets, J. J a¨ rv, S. Salmar
tures.
Institute of Chemistry, University of Tartu, Jakobi 2, 51014 Tartu, Estonia
Ultrasonic acceleration effects on chemical processes are
widely exploited both in the laboratory and industrial prac-
b
G. Cravotto
[
24–26]
tice.
Sonication mostly affects reaction rates, yields, and in
`
Dipartimento di Scienza e Tecnologia del Farmaco, Universita di Torino, Via P.
Giuria 9, I-10125 Torino, Italy
some cases the ratios of reaction products. Besides bringing
J. Phys. Org. Chem. 2008, 21 1002–1006
Copyright ß 2008 John Wiley & Sons, Ltd.

ULTRASONIC DETECTION OF HYDROPHOBIC INTERACTIONS
better solvation of the substrate and resulting in enhanced
reaction rates.
That pioneering work inspired us to extend the investigation to
a mechanistically different reaction, viz. to the hydrolysis of esters.
For the acid-catalyzed hydrolysis of ethyl acetate we observed a
similar dependence of the sonication effect on solvent
[
19,20]
composition.
These results initially led us to think that
sonication effects were merely related to a perturbation of
the solvent system. However, on replacing ethyl acetate with
more hydrophobic esters, we observed a dramatic change in the
dependence of the sonication effect on solvent composition,
which obliged us to revise our early point of view. Solute–solvent
interactions in these complicated systems proved to be
[
20,23]
particularly important in clarifying the matter.
Recent spectroscopic, X-ray diffraction, and mass spectro-
metric investigations have shed light on the structure of
[
30–32]
ethanol–water solutions.
It has been concluded that small
additions of ethanol in the range of 0 < X < 0.08 (X being the
E
E
ethanol molar ratio) exert a strong structure-making effect
accompanied by an increase in the self-association of water.
Further addition of alcohol begins to prevent water from
organizing into 3D structures. Observations suggested that an
ethanol polymer structure evolves and the bulk water structure
breaks down at X > 0.1. In mixtures at X > 0.15 a large number
E
E
of ethanol–water hydrogen bonds are formed at the expense of
water–water bonds. The resulting structure is described by a
cluster model, envisaging a stacked ethanol core and a thin water
[
30–32]
shell.
Figure 1. Linear free-energy relationships between sonication effects for
ester hydrolyses and the hydrophobicity parameter log P. (A) XE ¼ 0.28,
(B) XE ¼ 0.09, and (C) XE ¼ 0.04.
This model allowed a straightforward interpretation of our
results: a hydrophobic reagent could be hidden inside the
clusters and thus made unavailable for the reaction. If ultrasound
is capable of breaking the reagent’s interaction with the
hydrophobic interior of the cluster, it will accelerate the reaction.
Ethyl, n-propyl, and n-butyl acetates were used as probes of the
postulated inclusion of a reagent within clusters. Indeed,
[
36]
In Fig. 1 the LFE relationships
effects are related to the HI of reagents with the solvent system.
Plot 1A represents the relationship at X
show how kinetic sonication
sonication effects measured in the region 0.2 < X
E
< 0.3 matched
E
¼ 0.28 in the region of
in reverse order the hydrophobicity of the esters. n-Butyl acetate
should be the most powerfully held by clusters, and sonication
was found to be least efficient in this case.
To obtain quantitative proof of the above conclusions we
related the sonication effects (Table 1, comprising experimental
data from References
bicity parameter log P, where P is the partition coefficient of the
substrate between 1-octanol and water.
ethanol clusters, providing a convincing quantitative proof of the
conclusions made intuitively. Plots of sonication effects at
X
E
¼ 0.04 and X ¼ 0.09 against hydrophobicity parameters
E
(Fig. 1B, C) also reveal linear relationships. Statistical character-
istics of the correlations are collected in Table 2.
[
20,21,27,33]
) to the Hansch–Leo hydropho-
The observed sonication effect for the hydrolysis of
4-nitrophenyl acetate appeared to be systematically smaller
compared to those for the alkyl ester hydrolyses due to the lower
[
34,35]
Table 1. Sonication effects (kson/k) for the substrates at various molar fractions of ethanol, and the hydrophobicity parameters
kson/k
a
a
a
b
Substrates
0.04 (10)
0.09 (20)
0.25 (45)
Reference
log P
c
c
EtOAc
PrOAc
BuOAc
1.13
1.05
2.43
1.73
1.38
1.09
2.50
[20]
[33]
[20]
[21]
[27]
0.73
1.24
1.78
1.50
2.20
1.59
2.67
1.43
—
1.21
2.24
1.61
1.22
4
-NO -PhOAc
2
tert-BuCl
a
Molar fraction of ethanol in ethanol–water binary mixture. In parentheses w/w% of ethanol.
b
c
[35]
Experimental values from Reference
Interpolated values.
.
J. Phys. Org. Chem. 2008, 21 1002–1006
Copyright ß 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

A. TUULMETS ET AL.
Table 2. Statistical characteristics of correlations between sonication effects for ester hydrolysis, log(kson/k), and hydrophobicity
parameters, log P
a
2
XE
Regression coefficient
Correlation coefficient, R
Standard error
0
0
0
.04
.09
.28
0.357 ꢁ 0.025
0.356 ꢁ 0.123
ꢀ0.209 ꢁ 0.034
0.995
0.807
0.951
0.019
0.095
0.026
a
Molar fraction of ethanol in ethanol–water binary mixture.
sonication intensity used in kinetic measurements (as shown in
the Experimental Section). As we have experimentally found for
effects similar to those shown in Fig. 1 B, C. In other words,
ultrasound appeared to destroy the ester–co-solvent encounter
complexes regardless of the hydrophobicity of these compounds.
For the solvolysis of tert-butyl chloride the points fall away from
[
20]
the ethanol–water solvent system
sonication effect depends insignificantly on the solvent compo-
sition, the equal deviations at different X values can be definitely
that the calorimetric
E
the line in both A and B panels of Fig. 1 (For X
E
¼ 0.04 no
assigned to the difference in the applied sonication intensity.
Indeed, when points for 4-nitrophenyl acetate were shifted
upward by 0.16 log units, they laid equally well on the correlation
lines in all panels of Fig. 1. Some important conclusions follow
from the LFE relationships presented in Fig. 1.
experimental data are available). Although relative sonication
intensities applied in the experiments cannot be estimated, it is
evident that, in comparison with the hydrolysis reactions, at
X
E
¼ 0.28 solvolysis is largely susceptible to sonication, while at
X ¼ 0.09 its rate is little affected by ultrasound.
E
[
23]
Proceeding from the fact that the points for 4-nitrophenyl
acetate and the alkyl acetates lay on common lines in Fig. 1, the
formal LFE test asserts that the mechanism of the sonication
effect is the same for the esters independent of the hydrolysis
reaction mechanism (base-catalyzed vs. acid-catalyzed reactions).
It is certain that sonochemical effects cannot be caused by direct
impact of the acoustic field on the reacting molecules or on the
transition states of reactions since the energy of ultrasound is too
In a recent paper
we extensively discussed the effects of
sonication on the solvolysis reaction in the ethanol–water binary
solvent. We concluded that in this system ethanol causes an
effective hydrophobic stabilization of the ground state of
tert-butyl chloride, leading to a dramatic decrease in the reaction
[
27,28]
rate. Sonication effects
are large and increase with
increasing ethanol content in the binary solvent. However, the
reaction rate observed under ultrasound is only slightly
dependent on solvent composition. This indicates that sonication
suppresses the prevalent hydrophobic ground-state stabilization,
leaving little room for speculation about other medium effects.
Extrapolation of these data to pure water resulted in an almost
negligible sonication effect, in accordance with the highly
[
24,25]
low to alter their electronic, vibrational, or rotational states.
However, as discussed above, ultrasonication can readily disturb
weak solvent–solute interactions, including the hydrophobic
stabilization of reagents. Thus, in light of the sonication effects
one can admit now that independent of the reaction mechanism,
the esters interact similarly with the solvent system. Furthermore,
one can conclude that the regular decrease in the rate of ester
hydrolysis with increasing alcohol content of aqueous binary
solvents is mainly caused by the ground-state hydrophobic
[
37]
destabilized ground state of tert-butyl chloride in water.
According to our LEF tests, the mechanism of ultrasound
interaction with the reacting system might be different for the
solvolysis of tert-butyl chloride and the ester hydrolysis. This can
be inferred from the observed sonication effects for tert-butyl
chloride solvolysis incompatible with the hydrophobicity of the
E
stabilization by the solvent system. In the region X < 0.15 (Fig. 1
B, C) sonication effects vary linearly with the hydrophobicity
parameters; the order of the dependence, however, is the reverse
of that found for the cluster region. This unexpected finding can
be attributed to the weak solvation of esters in this region. While
greater hydrophobicity leads to stronger ground-state stabiliz-
ation, hence to a greater reactivity decrease, ultrasound breaks
down HIs almost entirely, resulting in larger sonication effects for
more hydrophobic esters.
[
35]
reagent in terms of the Hansch–Leo parameter. However, if to
question the tabulated log P value for tert-butyl chloride, equal
shifts of the points in panels A and B of Fig. 1 place them well on
the correlation lines and the same reduced log P value provides a
reasonable sonication effect from the line in panel C.
In Fig. 2 data for an ester hydrolysis and for the solvolysis of
tert-butyl chloride are presented. For the base-catalyzed
[
28]
[21]
Our recent experimental data
corroborate this conclusion
hydrolysis of esters, sonication data for 4-nitrophenyl acetate
straightforwardly. We have began investigating hydrophobic
effects of small amounts of aliphatic alcohols on ester hydrolysis
in water, and started with the neutral hydrolysis of 4-nitrophenyl
chloroacetate, using the spectrophotometric method. This
enabled us to work with a very low ester concentration
are plotted together with the activation enthalpy for the reaction
of structurally similar ethyl 4-hydroxybenzoate.
In the case of the highly hydrophobic esters under
consideration here, the plot of the sonication effect versus
solvent composition shows a reversed trend by comparison with
the corresponding curve of the activation enthalpy. Relatively
great sonication effects and lower values of the activation
enthalpy indicate a weak interaction of the esters with the solvent
ꢀ5
(
10 M) and to avoid resorting to the internal standard used
[
19,20]
in the GLC method (cf. References
).
While the hydrolysis rate, measured in the presence of 1 mol%
of aliphatic alcohols, decreased with increasing hydrophobicity of
the co-solvent, reaction rates under ultrasound were almost the
same, thus providing a dependence of apparent sonication
framework in the region 0.04 < X < 0.15. Further additions of
E
[
32]
ethanol (X
E
> 0.15) lead to formation of clusters,
that are
capable of holding ester molecules more effectively; that leads to
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Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2008, 21 1002–1006

ULTRASONIC DETECTION OF HYDROPHOBIC INTERACTIONS
contents hydrophobic reagents are weakly solvated and
hydrophobic stabilization can be readily suppressed by soni-
cation.
Correlation of kinetic sonication effects with quantitative
hydrophobicity parameters not only affords a better under-
standing of sonication effects on homogeneous polar reactions,
but also opens perspectives for broader investigation into these
solvation phenomena and reaction mechanisms.
EXPERIMENTAL
Data for sonication effects published in former papers were used
in this work. For experimental details corresponding articles
should be addressed. The most important features are the
following:
[
19,20]
Alkyl acetates.
Acid-catalyzed hydrolysis of esters was
followed by gas–liquid chromatography determinations of the
ester concentration in 1 M HCl solutions at 18.3 8C (at 20 8C for
[
33]
propyl acetate ). Sonication was performed with an immersed
titanium horn at 22 kHz. Sonication intensity was 55 W/80 ml.
[
21]
4
-nitrophenyl acetate.
Base catalyzed hydrolysis at pH ¼ 8.0
was followed spectrophotometrically at 20 8C. Sonication was
performed with an immersed quartz horn at 21.1 kHz. Sonication
intensity was 9.4 W/100 ml.
[
33]
4
-nitrophenyl chloroacetate.
Neutral hydrolysis of the ester in
water and in the presence of 1 mol% amounts of alcohols was
followed spectrophotometrically at 20 8C. Sonication was
performed with a cleaning bath at 25 kHz. The sonication
intensity in the reaction cell was 8.1 W/100 ml.
6¼
Figure 2. Sonication effects (kson/k) and activation enthalpies (DH ) in
ethanol–water binary solvents. (A) Base-catalyzed hydrolysis of ethyl
[
27,28]
4
-hydroxybenzoate (data from Reference [38], sonication data for
tert-Butyl chloride.
The solvolysis was followed conductome-
4-nitrophenyl acetate from Reference [21]); (B) solvolysis of tert-
trically at different temperatures. Data for 20 8C are used in this
butylchloride (data from Reference [39], sonication data from
Reference [27]).
work. Sonication was carried out in a cup horn reactor operating
ꢀ2
at 20 kHz with an acoustic intensity of ꢂ1 W cm . The authors
[
28]
believe they worked in the region of stable cavitation.
decreasing sonication effects and increasing activation enthal-
pies. However, in the case of weakly hydrophobic esters the
[
19,20]
sonication effect increases in this region
(cf. Table 1).
Acknowledgements
The sonication effect for tert-butyl chloride increases with the
increase in ethanol content. The increase in sonication effect
reverse to that for highly hydrophobic esters and a parallelism
with the activation enthalpy are obvious for the solvolysis of
tert-butyl chloride providing additional support for discrediting
the log P value of this compound.
This work has been carried out under the auspices of European
Union COST Action D32 and was financially supported by the
Estonian Ministry of Education and Research (Grant
SF0180064s08) and by Estonian Science Foundation (Grant
ETF7498).
CONCLUSIONS
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