J . Phys. Chem.

1989,93, 3865-3870 3865

Aggregation Behavior of Hydrotropic Compounds in Aqueous Solution

D. Balasubramanian,* V. Srinivas,
Centre f o r Cellular and Molecular Biology, Hyderabad 500 007, India

V. G. Gaikar, and M. M. Sharma

Department of Chemical Technology, University of Bombay, Matunga Road, Bombay 400 019, India
(Received: July 20, 1988; In Final Form: October 18, 1988)

Hydrotropes are a class of compounds that, at high concentrations,enhance the solubility of a variety of hydrophobic compounds
in water. The mechanism of hydrotropy is still incompletely understood. In this paper, we have studied the solution-state
properties in water of the hydrotropes sodium salicylate (NaS), sodium p-toluenesulfonate (NaPTS), sodium xylenesulfonate
(NaXS), sodium cumenesulfonate (NaCS), and sodium butyl monoglycol sulfate (NaBMGS). We find that all these molecules
self-aggregate in aqueous solution to form organized assemblies. It appears that a minimal hydrotropic concentration (MHC)
is essential before hydrotropy can be displayed. We show that hydrotropy is different from salting-in or phase-mixing behavior.
Hydrotropy is a collective molecular phenomenon, exhibited above the MHC. Hydrotropic compounds are seen to be surface
active though somewhat less than classical surfactants. The microenvironmentalfeatures of hydrotrope assemblies are roughly
comparable to those of surfactant micelles: low polarity and a microviscosity of the order of 60 cP. However, there are
notable differencesbetween hydrotrope assemblies and micelles. Solubilizationby the former appears to be higher and somewhat
more selective. The cooperativity displayed by hydrotrope molecules in the aggregation process is low. While hydrotropy
appears above the MHC, it is not strictly analogous to the critical micelle concentration displayed by surfactants.

Over 70 years ago, Neuberg' described the large increase in
the solubility in water of a variety of hydrophobic compounds
brought about by the addition of certain compounds. These
solubility-enhancing molecules were termed hydrotropic agents
or hydrotropes, and the phenomenon itself was named hydrotropy.
Some examples of hydrotropes are sodium benzoate, salicylate,
p-toluenesulfonate, and xylenesulfonate.2 A 2 M solution of the
latter salt in water enhances the solubility of nitrobenzene 50-fold
and that of cresol by a factor of 200 in water.3 Hydrotropy
appears to operate at high concentrations of the hydrotrope in
water; most hydrotropic solutions precipitate the solute (solubi-
lizate) on dilution with water. This is convenient since it allows
the ready recovery of the hydrotrope for reuse.
Despite intermittent attempts over the years, there is no con-
sensus on the mechanism behind hydrotropy. McKee2 suggested
that hydrotropy may be viewed as a salting-in process; he noted
that aqueous solutions of KI, KSCN, and NHISCN are exdlent
solvents for many water-insoluble compounds. Winsor4 suggested
at the same time that the hydrotrope acts as a common solvent
for the hydrophilic and lipophilic compounds present, and thus,
hydrotropy and cosolvency are quite similar. Ueda5 pointed out
that the hydrotrope forms a complex with the solubilizate and also
decreases the activity coefficient of the latter in water, both of
which lead to an increase in solubility. Rath6 was concerned about
the molecular structural features and stacking of hydrotropes while
others had been investigating the possibility of association of these
molecules into aggregates somewhat like what surfactants
Heteroassociation of the solubilizate and the hydrotrope, with a
variety of cohesive factors, has been noted between some drugs
and hydroxybenzoate hydrotropes.12
Saleh's group has been pursuing the association behavior of
hydrotropes and compared them with those of surfactants.I3-l6
(1) Neuberg, C. Biochem. Z . 1916, 76, 107.
(2) McKee, R. H. Ind. Eng. Chem. Ind. Ed. 1946, 38, 382.
(3) Booth, H. S.; Everson, H. E. Ind. Eng. Chem. Ind. Ed. 1948,40, 1491.
(4) Winsor, P. A. Trans. Faraday SOC.1948, 54, 376.
(5) Ueda, S. Chem. Pharm. Bull. 1966, 14, 22.
(6) Rath, H. Tenside 1965, 2, 1.
(7) Mirgorod, Y. A.; Kulibaba, N. S. Kolloidn. Zh. 1979, 41, 461.
(8) Danielsson, I.; Stenius, P. J . Colloid Interface Sci. 1971, 37, 264.
(9) Kostova, N . Z.; Markina, Z . N. Kolloidn. Zh. 1971, 37, 551.
(IO) Schwuger, M. J. Chem.-Ztg. 1972, 96, 248.
( 1 1 ) Lawrence, A. S. C. Nature 1959, 183, 1491.
(12) Poochikian, G. K.; Cradock, J. C. J. Pharm. Sci. 1979, 68, 728.
(13) Badwan, A. A.; El-Khordagui, L. K.; Saleh, A. M.; Khalil, S. A. J.
Pharm. Pharmacol. 1980, 32, 74 p.
(14) Saleh, A. M.; Badwan, A. A.; El-Khordagui, L. K. In?. J . Pharm.
1983, 17, 1 1 5.
Though it appears formally similar, hydrotropy differs from
micellar solubilization of hydrophobic substances in water by
surfactant molecules in its magnitude and perhaps qualitatively
as ~ e 1 1 . l Saleh
~ and El-KhordaguiI6 have given the following
operational definition of hydrotropes. Hydrotropic agents are
freely soluble organic compounds that, at a concentration sufficient
to induce a stack-type aggregation, considerably enhance the
aqueous solubility of organic substances practically insoluble under
normal conditions. These compounds may be anionic, cationic,
or neutral molecules.
This definition requires that hydrotrope molecules aggregate
in a stacklike fashion in solution and solubilize the solute by similar
associative mechanisms. Such a possibility is envisaged with
aromatic hydrotropes like benzoates, hydroxybenzoates, and
substituted benzenesulfonates but not so easily visualized with
aliphatic and alicyclic compounds and inorganic salts that act as
hydrotropes. Two excellent nonaromatic hydrotropes that can
be cited in this connection are sodium n-butyl monoglycol sulfate
and the "Westvaco diacid" [(5-(or 6-)carboxy-4-hexyl-2-cyclo-
hexen-1-y1)octanoic acid] or simply diacid. The diacid has been
studied in some detail by Friberg and associate^"-^^ for its effect
on the destabilization of the lamellar liquid phases obtained in
aqueous dispersions of traditional detergents and related com-
pounds. As they point out, it is the formation of the lamellar liquid
crystalline phase that limits the solubilization of long-chain acids
or alcohols in aqueous micellar solutions. A hydrotrope such as
the diacid is able to disrupt the liquid crystalline structure and
produce a continuous isotropic liquid solubility region, thus en-
hancing the solubility of lipophiles in water. For example, the
solubility of triglycerides in water increases significantly upon
addition of a hydrotrope." A hydrotrope is thus thought to act
by reducing the long-range molecular ordering of an amphiphile
in a lamellar liquid crystal. While the effect of a hydrotrope on
an aqueous surfactant system is highlighted in these studies, the
molecular basis of hydrotrope-water interaction and the basis of
(15) Badwan, A. A.; El-Khordagui, L. K.; Saleh, A. M.; Khalil, S. A. In?.
J . Pharm. 1983, 13, 67.
(16) Saleh, A. M.; El-Khordagui, L. K. Int. J. Pharm. 1985, 24, 231.
(17) Friberg, S . E.; Rydhag, L. J . Am. Oil Chem. SOC.1971, 48, 113.
(18) Cox, J. M.; Friberg, S. E. J . Am. Oil. Chem. SOC.1981, 58, 743.
(19) Flaim, T.; Friberg, S. E.; Force, C. G.; Bell, A. Tenside Deterg. 1983,
20, 4.
(20) Friberg, S. E.; Flaim, T. In StructurelPerformance Relationship in
Surfactants; Rosen, M. J . , Ed.; ACS Symposium Series 253; American
Chemical Society: Washington, DC, 1984; p 107.
(21) Flaim, T.; Friberg, S. E. J. Colloid Interface Sci. 1984, 97, 26.
(22) Friberg, S. E.; Rananavare, S. B.; Osborne, D. W. J. Colloid Interface
Sci. 1986, 109, 487.

0022-3654/89/2093-3865!$01.50/00 1989 American Chemical Society

 ~o~
o+c/ 0
' :N $
3866 The Journal of Physical Chemistry, Vol. 93, No. 9, 1989
SO; No+
NaS CH3 CH3
NaPTS NaXS
NaBMGS
NaCS
Figure 1. Structures of the hydrotropes used in this study.
enhanced solubilization by aqueous solutions of the hydrotrope
alone need to be clarified.
This understanding of the basis of hydrotropy becomes par-
ticularly important since our recent finding that hydrotrope so-
lutions are valuable in enhancing the rates of heterogeneous
chemical reactions, such as the oximation of cyclodecanone, ester
hydrolysis, Cannizarro, and cross-Cannizarro reactions, by 2-3
orders of We have found that some hydrotropes
are able to enhance the solubilities of some aromatic compounds
1000-fold.2s We have also shown that hydrotropes can be suc-
cessfully utilized in the extractive separations and even extractive
distillations of close-boiling ~ u b s t a n c e s .The
~ ~ ~use
~ ~of hydrotropes
in these applications is particularly attractive because of various
factors, such as easy recovery of products and very high selectivity.
At the same time, the problem of emulsification, which is normally
encountered with surfactant solutions, is not faced with hydrotrope
solutions. We have, therefore, studied the solution behavior of
some common hydrotropes in aqueous solution using spectroscopic,
tensiometric, solubility, and kinetic methods. The hydrotropes
studied are sodium salicylate (NaS), sodium p-toluenesulfonate
(NaPTS), sodium xylenesulfonate (NaXS), sodium cumene-
sulfonate (NaCS), and sodium butyl monoglycol sulfate
(NaBMGS), whose chemical structures are shown in Figure 1.
As can be seen, all of these are short-chain amphiphiles and
anionic. While most of them contain the planar benzene ring,
NaBMGS is a short-chain aliphatic sulfate, structurally very
different from the rest. Yet, it is an excellent hydrotrope with
solubilization properties better than some of the others.
Our results suggest that all these hydrotropes self-aggregate
in aqueous solution to form organized assemblies that are rem-
iniscent of surfactant micelles though the cooperativity of asso-
ciation is far less than the latter. It appears that the formation
of an associated structure is a requirement for hydrotropic action
to be displayed, since the increase in solubilization parallels the
association behavior. We have probed some of the microenvi-
ronmental features of the hydrotrope assemblies and compared
them with those of aqueous micelles. To our knowledge, this is
the first detailed report on these aspects of hydrotrope solutions.
Materials and Methods
All the chemicals used were obtained from commercial sources
and were of the highest purity available. NaBMGS was bought
as a 50% solution (from Huls, Germany) and had to be lyophilized
to obtain the solid hydrotrope. NaXS obtained commercially is
(23) Janakiraman, B.; Sharma, M. M. Chem. Eng. Sci. 1985, 40, 2156.
(24) Pandit, A.; Sharma, M . M. Proceedings of World Congress 111 of
Chemical Engineering, Tokyo, Japan, 1986, p 156.
(25) Pandit, A,; Sharma, M. M. Chem. Eng. Sci. 1987, 42, 2517.
(26) Sane, P. V.; Sharma, M. M . Synth. Commun. 1987, 17, 1331.
(27) Gaikar, V. G.;Sharma, M. M. Soluent Extr. fon Exch. 1986, 4, 839.
(28) Gaikar, V. G.; Mahapatra, A,; Sharma, M. M . Sep. Sci. Technol.,
in press.
,/NaPTS
Balasubramanian et al.
d
0.14
J
/
0.0 0.4 0.0 1.2 1.6
[Hydrotrope] -
2.0 2.4 2.8t3
Figure 2. Enhancement in the solubility of FDA in aqueous hydrotrope
solutions at room temperature, as measured by the optical density (OD)
value at 480 nm.
usually a mixture of isomers and was used as such following the
practice in the literature.
Solubilization by the hydrotropes was studied by equilibrating
the solubilizate with the hydrotrope solution of known concen-
tration for several hours in a constant-temperature shaker. The
suspension was centrifuged and the concentration of the solubi-
lizate determined spectrophotometrically with a Hitachi or a
Shimadzu instrument. Solid-liquid alkaline hydrolysis of ethyl
p-nitrobenzoate (EPNB) was carried out in hydrotropic solutions
of NaPTS and NaBMGS, with use of the published procedure.23
The observed enhancements are expressed in terms of 4, which
is the ratio of the volumetric rates in the presence and absence
of the hydrotrope. Surface tension measurements were made with
a White Fischer tensiometer by the platinum ring method.
Fluorescence spectra were obtained with a Hitachi 650-10s
spectrofluorimeter. The excitation wavelengths chosen for
magnesium 8-anilinonaphthalene-1-sulfonate (ANS) and for
diphenylhexatriene (DPH) were 365 and 360 nm, respectively,
and the probe concentrations were in the micromolar range.
Fluorescence polarization measurements were done with DPH,
and the medium microviscositieswere estimated with the simplified
equation applicable for steady-state m e a s ~ r e m e n t and
s ~ ~ the ex-
perimental protocol elaborated earlier.30 Electron spin resonance
(ESR) spectra were run on a Bruker EPR spectrometer in the
X-band. The spin probe used was the sodium salt of 2-(3-
carboxypropyl)-4,4-dimethyl-2-tridecyl-3-oxazolidinyloxy free
radical or more simply called 5-doxy1 stearate. Estimation of the
values of the hyperfine coupling constant (aN) and the reorien-
tational correlation time ( T ~ of
) the spin probe in the various
systems was done with the simplified approach adopted in the case
of solutions and micelles."
Results and Discussion
A . Solubilization by Hydrotropes. Despite the interest in
hydrotropy over all these the only detailed report on
the concentration (and temperature) dependence of hydrotropy
(29) Shinitzky, M.; Barenholz, Y. Eiochim. Eiophys. Acta 1978,515, 367.
(30) Shobha, J.; Balasubramanian, D. Prof.-fndiun Acad. Sci., Chem. Sci.
1987, 98, 469.
(31) Yoshioka, H . J . Am. Chem. Soc. 1979, 101, 28.
(32) McBain, M. E. L.; Hutchinson, E. Solubilization and Related Phe-
nomena; Academic Press: New York, 1955.
(33) Friberg, S.E.; Flaim, D.; Osborne, D. W., personal communication.
Aggregation Behavior of Hydrotropic Compounds The Journal of Physical Chemistry, Vol. 93, No. 9, 1989 3867

PEG (w/v"/o)
IO% 2 0% 3 0%

I
0 15

To- 0 06

t
2 D
2.0- 0 0 10
0.04
t

04 0 8
I
12
I
16
I
2 0
CONCENTRATION (mol/L )
I
2 4
- I
2 8
I
3 2

-
Figure 3. Concentration-dependent enhancement in the solubility of 0.001 I I I I I I I I
0.4 0.8 1.2 1.6 2.0 2.4 2.8 3.2 M
FDA, perylene, and EPNB in aqueous NaBMGS at room temperature.
The concentrations of the solubilizates were measured through their [NoPTS] or [GdSCN]
optical density values (OD) at their absorption band maxima. Figure 4. Increase in the solubility of perylene in water at room tem-
perature, brought about by NaPTS, PEG-6000, and guanidinium thio-
has been by Licht and Wiener." Since insight into the mechanism cyanate.
of hydrotropic action will come about only with more such data,
we have measured the solubilization of several compounds in
aqueous solution by hydrotropes, over a wide range of concen-
trations. Figure 2 presents a representative set. The dye fluor-
escein diacetate (FDA) was chosen here as the solubilizate because
of its negligible solubility in water, its high absorptivity that aids It
an easy and accurate determination of its concentration, its absence
of electric charge, and its low reactivity. The important point that
emerges from Figure 2 is that the solubilization effected by hy-
drotropes is not a linear or monotonic function of their concen-
tration. The profiles of hydrotropy in Figure 2 are sigmoidal,
suggestive of cooperative intermolecular interactions involved in
the solubilization process. Hydrotropy does not seem to be op-
erative below a particular concentration, while above this con-

centration the solubilization rises markedly and levels off to a
plateau. This concentration above which hydrotropy is displayed
may thus be referred to operationally as the minimal hydrotropic
concentration or MHC. As Figure 2 shows, the M H C value
differs from one hydrotrope to another. While further data on
more systems would be necessary to confirm this point, it appears
likely that the M H C of a given hydrotrope is the same toward
several solubilizates. Figure 3 illustrates this point with the hy-
drotrope NaBMGS. Its hydrotropic behavior toward FDA, pe-
rylene, and ethyl p-nitrobenzoate (EPNB) is quite similar; the
three solubilization curves parallel one another, and in each case,
solubilization starts increasing at about the same concentration,
Le., about 0.8 M.
Our observation of a characteristic MHC for hydrotropes leads
some credence to the suggestions made earlier7-I6that hydrotropy
might be similar to micellar solubilization displayed by amphi-
philes. However, this similarity is not total, and there are some
notable differences; we shall discuss these later, but for the mo-
ment, the important point that emerges is that hydrotropy might
involve a cooperative interaction involving hydrotrope molecules.
Additional support for this point comes from a comparison of the
increase in solubility brought about by a hydrotrope with the
salting-in process2 and the increased solubility in the presence of
a cosolvent4 or a phase-mixing agent. Figure 4 compares the
hydrotropy of NaPTS on perylene with the increased solubility
brought about by guanidinium thiocyanate (GdSCN) and by the
addition of poly(ethy1ene glycol) of molecular weight 6000, or
PEG-6000. GdSCN is a salting-in agent35while PEG-6000 is
(34) Licht, W.; Wiener, L. D. Ind. Eng. Chem. 1950, 42, 1538
-
0 I I I I I I I
0 0.2 0 4 0.6 0 8 1.0. I 2 1.4
[NaBMGS]
Figure 5. Comparison of the rate enhancement 6 produced in the alka-
line hydrolysisz3 of EPNB (left-hand side scale, filled circles) and the
solubilization of EPNB (right-hand scale, triangles) as a function of the
concentration of NaBMGS in water at room temperature. 4 refers to
the ratio of the rate in the presence of NaBMGS to that in the absence
of the hydrotrope.
a substance that is soluble in water and in several organic solvents
and is thus a phase-mixing agent that can solubilize hydrophobic
compounds in water.36 GdSCN increases the solubility of perylene
in water only at concentrations greater than 2 M, and the increase
is monotonic and gradual. PEG-6000 also displays a monotonic
increase in its solubilizing ability. In neither case is seen the
sigmoidal pattern observed with NaPTS. It thus appears that
hydrotropy goes beyond miscibility, or c o s ~ l v e n c yor
, ~salting
~ in
and involves some sort of cooperative interactions among the
hydrotrope molecules occurring above the MHC. This point had
not been realized so far in the literature.
B. Reaction Rate Enhancement by Hydrotropes. Janakiraman
and SharmaZ3had found that hydrotropes such as NaPTS are
(35) von Hippel, P.; Schleich, T. In Structure and Stability of Biological
Macromolecules; Timasheff, S . N., Fasman, G. D., Eds.; Marcel Dekker:
New York, 1969.
(36) Balasubramanian, D.; Sukumar, P.; Chandani, B. Tetrahedron Leu.
1979, 3543.
(37) Lindau, G. Naturwissenschaffen 1932,20, 396.
3868 The Journal of Physical Chemistry, Vol. 93, No. 9, 1989 Balasubramanian et al.

-9 0
I NoXS
2 NaPTS

t
3 NOS

4 NoBMGS
-'O

-50
-
\
Dl

m
z
- 3 0 2
Y

- I O

40t 4
-
4
0 01 0 2 C ? 0 4 0 5 0 6 0 7 0 8 09M I I
n 0 2 c3 04 0 5 0 6 c7 0 8 0 9 o
[ Na PTS] CONCENTRATION OF H Y D R O T R O P E . M-
Figure 6. Comparison of the hydrolysis rate enhancement (left-hand side Figure 7. Variation of the surface tension with concentration of several
scale, filled circles) and the solubilization of EPNB (right-hand side scale, hydrotropes in water at room temperature.
squares) as a function of the concentration of NaPTS in water at room
temperature. M for NaPTS, 0.4 M for NaXS, 0.1 M for NaCS, and 0.7 M
for NaBMGS, all at ambient temperature. These values are
able to enhance the rate of alkaline hydrolysis of esters. In light
of our finding that solubility enhancement occurs beyond the
MHC, it becomes of interest to monitor the reaction rate en-
- --
remarkably close to the MHC values determined from the solu-
bilization experiments above (NaS 0.8 M, NaPTS 0.35 M,
NaXS 0.4 M, and NaBMGS 0.8 M) and lend support to
-
hancement as a function of the hydrotrope concentration. Figure
the idea that both of these concentrations of a hydrotrope reflect
5 shows that the reaction rate of alkaline hydrolysis of EPNB does
the onset of the same process, Le., self-aggregation. This would
not show any enhancement (compared to the rate in water) up
also imply that the formation of a self-aggregated assembly is a
to a concentration of 0.8 M NaBMGS. Beyond this concentration,
prerequisite for hydrotropic solubilization to set in (as shown in
the rate increases and becomes 3 times as fast in 1.2 M NaBMGS
Figures 2-4) and hydrotropic enhancement of reaction rates to
as in water. Figure 5 also shows the solubility of EPNB in the
occur (Figures 5 and 6).
hydrotrope solution. As can be seen, the solubility and the hy-
The area occupied at the air-water interface by each of these
drolysis rates go hand in hand, suggesting that enhancement in
hydrotrope molecules was estimated from surface tension mea-
the rate occurs upon increased solubilization. Sequestration of
surements with the Gibbs adsorption isotherm.41 The area per
the EPNB into the hydrotrope medium appears to be a possible
molecule increases in the following order (A2/molecule; all at room
factor in the rate enhancement. The fact that rate enhancement
temperature; error k l % ) : NaS, 44; NaCS, 60; NaPTS, 86;
occurs beyond M H C is noteworthy. In a similar experiment, we
NaXS, 93; and NaBMGS, 155. NaBMGS has a surprisingly
observed that enhancement in the rate of this reaction occurs
large interfacial area, which leads to the likelihood that the
beyond a concentration of 0.4 M NaPTS in water. The solubility
molecule is oriented not erect in the all-trans chain conformation
curve for EPNB in aqueous NaPTS solution overlaps with the
but in the bent form. It would be of interest to verify this pos-
rate enhancement curve, as shown in Figure 6. It would thus
sibility.
seem that the acceleration of reaction rates caused by hydrotropes
The idea of self-aggregation of organic hydrotrope molecules
is related to their solubilization efficiency. This point had in fact
is not new. Both self-aggregation and mixed aggregation have
been anticipated by us earlier.23
been suggested; there is indeed even a model presented for hy-
C. Surface Tensiometry of Hydrotropes. Another common drotrope aggregation into stack-type assemblies,16 with an obli-
statement made about hydrotropes is that they are not surface
a ~ t i v e . ~ , * ~This
~ * -comprehensive
~~ assertion arises in part due gatory planar hydrophobic moiety in each molecule. While most
of the hydrotropes that we have investigated do have the planar
to the fact that a variety of substances, organic or inorganic, have
benzene ring in them, NaBMGS does not, and yet, it behaves in
been classified as hydrotropes and the fact that many of the organic
a manner quite similar to that of the others in all its hydrotropic
compounds used are short-chain aliphatics or benzenoid salts that
properties. It would therefore be worthwhile to study NaBMGS
are assumed not to be surface active. However, in light of the
in greater detail, which we are involved in currently. However,
apparent similarity between hydrotropy and micellar solubilization
the novel and important point that has emerged out of our results
alluded to above, we studied the tensiometric behavior of some
is that hydrotropy is a collective molecular phenomenon and
of these compounds. Figure 7 shows the variation in the surface
requires the presence of noncovalent molecular aggregates.
tension of several hydrotropes with their concentrations in water.
D . Microenvironmental Features of Aggregates. Two mi-
It is seen that the surface tension decreases from 72 dyn/cm for
croenvironmental properties of relevance in the solubilization of
water to a limiting value of around 50-53 dyn/cm for NaS,
molecules into micellar and similar structures are the polarity and
NaPTS, and NaXS, to around 43 dyn/cm for NaCS and 37
the microviscosity (or the fluidity) that the assembly offers to a
dyn/cm for NaBMGS. All of these hydrotropes are indeed surface
molecule that is incorporated in them.42 The fluorescence
active, and some are comparable to micellar amphiphiles (ce- spectrum of the molecule ANS is known to be sensitive to the
tyltrimethylammonium bromide reduces the y value of water to
polarity of the medium it is dissolved in, and this property has
below 40 dyn/cm at concentrations beyond its cmc of 0.9 mM).
been used to estimate the polarities of micellar aggregates of
In any event, the concentration-dependent reduction in the
different sizes and shapes.30 Likewise, the anisotropy of
surface tension is more gradual with hydrotropes in comparison
to the sharper drops encountered with micellar surfactants. The
fluorescence emission of the arene 1,6-diphenylhexatriene (DPH)
data in Figure 7 suggest that each of these hydrotropes self-ag- offers information about their micro~iscosities.~*~~ We have used
gregates beyond a given concentration in water to produce non- these two probes in order to obtain information on hydrotropes.
covalent assemblies; this concentration is 0.65 M for NaS, 0.37 Figure 8 shows that the fluorescence emission wavelength max-
imum (A,) of ANS undergoes a blue shift from 5 15 nm, upon the
addition of NaCS, to reach a limiting value of 455-460 nm beyond
(38) Elworthy, P. H.; Florence, A. T.; Macfarlane, C. B. Solubilization
by Surface Active Agents; Chapman and Hall: London, 1968; pp 170-180.
(39) Thoma, K.; Arning, M. Arch. Pharm. (Weinheim, Ger.) 1976, 309, (41) Shobha, J.; Balasubramanian, D. J . Phys. Chem. 1986, 90, 2800.
865. (42) Singer, L. A. In Solution Behavior of Surfactants; Mittal, K. L.,
(40) Product brochure of Chemische Werke Hiils AG, Sept 1979 Fendler, E. J., Eds.; Plenum Press: New York, 1982; Vol. I , pp 73-112.
Aggregation Behavior of Hydrotropic Compounds The Journal of Physical Chemistry, Vol. 93, No. 9, 1989 3869
r I I I

-
440
0 2 0 4 06 0 8 10
[NaCS],
Figure 8. Variation in the wavelength of the fluorescence spectral band
maximum of the probe ANS with the molarity of NaCS in water.
Conditions: room temperature; ANS concentration 10 pM; excitation
at 365 nm.

a concentration of 0.2 M of the hydrotrope. It is clear that ANS

partitions from water into the hydrotrope aggregate beyond 0.8
M and experiences an environment of reduced polarity therein,
since the emission wavelength of ANS in higher aliphatic alcohols,
e.g., octanol, is around 460 nm3.30Similar results were obtained
for A N S in aqueous solutions of NaBMGS, here again the Y~
shifting to a limiting value above the M H C value of the hydro-
trope.
Next, we solubilized DPH in each of the hydrotrope assemblies 200 400 600 000
and measured its fluorescence anisotropy. The microviscosity of [C],:' UM-
each assembly was estimated from the anisotropy value with use Figure 9. Stern-Volmer quenching behavior of the fluorescence of pe-
of the relation reported by Shinitzky and B a r e n h ~ l z .The~ ~ es- rylene solubilized in 0.2 M sodium dodecanoate (micellar solution), 0.3
timated microviscosity values, at room temperature, of NaPTS, M NaCS, and 1.25 M NaBMGS in water by added CuSO+ Conditions:
NaCS, and NaBMGS are all in the range 0.55-0.65 P, compa- perylene concentration 1 pM; excitation at 406 or 434 nm and emission
rable to those of the micellar aggregates of sodium dodecyl sulfate at 462 nm; room temperature.
(SDS) or of cetyltrimethylammonium bromide (CTAB) in water.M
Thus, these hydrotrope aggregates offer a microenvironment that TABLE I: a N and 7e Values of 5-Doxy1 Stearate in Water and in
is slightly less polar than ionic micelles but of comparable mi- Some Hvdrotrow Solutions'
croviscosity . sample (concn, M) 2 a ~G, lo'%,, s
Another aspect of the microenvironment is the access that a water 34.25 1.6
solubilized or incorporated molecule has to a reagent or an in- NaCS (0.05) 34.5 1.6
teracting partner that is added and confined to the external NaCS (0.3) 34.1 2.2
medium. We chose to solubilize the neutral, symmetric arene NaBMGS (0.12) 36.0 1.3
perylene and to monitor the ability of externally added para- NaBMGS (1.25) 34.5 7.7
magnetic ion Cu2+to quench the aromatic fluorescence. Para- "Spin-label concentration 0.5 mM; room temperature. Sample not
magnetic or spin quenching of fluorescence operates over a distance deaerated.
of 4-6 A only43and is thus an appropriate measure of accessibility
to the fluorophore that is incorporated in the hydrotrope micro- aggregates and membranes.31*" Table I lists the values of aNand
environment. In Figure 9 is plotted the Stern-Volmer quenching 7c of the spin probe in aqueous solutions of the hydrotropes NaCS
by external CuSO, of the fluorescence of perylene solubilized in and NaBMGS at low and high (beyond MHC) concentrations,
the hydrotropes NaCS and NaBMGS above their M H C and in and Figure 10 shows a typical set of ESR spectra. In all these
the micellar solution of sodium dodecanoate. It is seen that the instances, the probe experiences a lowered polarity and increased
hydrotropes protect or shield the perylene molecule from Cu2+ hindrance to motion when the hydrotrope is above its MHC than
quenching better than dodecanoate micelles do and that between when it is below. The reduction in polarity, as reflected by aN,
the two hydrotropes NaBMGS sequesters perylene more effectively is largest in the case of NaBMGS, and it is this hydrotrope that
from the quencher than NaCS. offers the highest hindrance to spin probe motion: the T~ value
Similar results were obtained when the microenvironment of in this case is as high as about 0.7 ns, about 5-fold higher than
these assemblies were probed with the electron spin resonance in water and 2-3-fold higher than in other hydrotrope aggregates.
probe 5-doxy1 stearate. The nitrogen hyperfine coupling constant
aNof such doxy1 probes is sensitive to solvent polarity, with a value Conclusions
of around 17.5 G in water, reducing in value in nonpolar sol- Over the years, a variety of organic compounds and even in-
v e n t ~ . ~ ' *Apart
~ ~ * from
~ ~ .aN,
~ ~which behaves as a polarity in- organic salts have been termed hydrotropes based just on the fact
dicator, the other useful parameter is the reorientational correlation that the solubility of otherwise insoluble compounds in water is
time of motion ( 7 c ) of the probe, which is sensitive to the medium increased in their presence. We have attempted to show in this
viscosity and hence used to study the microviscosity of amphiphile paper that hydrotropy is different in its features from salting-in,
which is displayed by inorganic ions of the chaotropic kind;35*46
(43) Green, J. A.; Singer, L. A.; Parks, J. H. J . Chem. Phys. 1973,58, it also appears different from phase mixing, though the ability
2650. of some hydrotropes to delay the onset of the lamellar liquid
(44)Berliner, L. J. Spin Labelling Academic Press: New York, 1976.
(45)Ellena, J. F.;Archer, S.J.; Dominey, R. N.; Hill, B. D.; Cafiso, D.
S . Biochim. Biophys. Acta 1988,940, 63. (46)Balasubramanian, D.;Mitra, P. J . Phys. Chem. 1979,83, 2724.
3870 The Journal of Physical Chemistry, Vol. 93, No. 9, 1989
0 3 M NaCS
o 12M NaBMGS
b 2 5 M NaBMGS
-
I O gauss
H-
Figure 10. X-band ESR spectra of 5-doxy1 stearate in NaCS and
NaBMGS solutions in water. Room temperature.
crystalline phase in aqueous surfactant system^'^-^^ might be
formally similar to it. Hydrotropic behavior seems to be a col-
lective molecular phenomenon.
While there are several points of resemblance between hy-
drotrope molecules and surfactants (e.g., aggregation, solubilization
of hydrophobic compounds, surface activity, reaction rate en-
hancement), there are some significant differences as well. We
highlight these since one could be easily persuaded to identify
hydrotropes as analogues of micellar amphiphiles, though
Balasubramanian et al.
somewhat less dramatic and efficient. First, hydrotrope solubi-
lization differs from micellar incorporation in some definite ways:
(a) The amount of solubilization is generally higher than that
effected by conventional surfactants, though the latter occasionally
enhance solubilities to very high degree^.^',^^ (b) Not al hy-
drophobes are solubilized by hydrotropes. For example, NaXS
is not able to enhance the solubility in water of aliphatic or alicyclic
hydrocarbons but solubilizes arenes well. Interestingly, the sol-
ubility of p-nitrotoluene in water is not affected by hydrotropes
while those of the ortho and meta isomers are e n h a n ~ e d .Second,
~
the cooperativity displayed by hydrotropes (e.g., Figures 2, 3, and
5-7) in the concentration-dependent variation of their properties
is not as high as in the case of micelles.49 This behavior, plus
th: high values of MHC, suggests that the self-aggregation of
hydrotrope molecules might not be as cooperative as with micellar
surfactants. Any attempt to identify the MHC of a hydrotrope
as analogous to the critical micelle concentration (cmc) of a
micellar surfactant would thus be premature and unwarranted
at this stage. We emphasize this caveat particularly since
MukerjeeS0has shown how apparent cmc values obtained from
breaks in curves like those in Figures 2 or 7 might not represent
micellization but even dimerization or stepwise association. It
would thus be important to estimate the thermodynamic param-
eters of association, the aggregation number, and related param-
eters before a firm conclusion about the nature of hydrotrope
aggregates can be reached. We are currently studying these
aspects in some detail.
Registry No. NaS, 54-21-7; NaPTS, 657-84-1; NaXS, 827-19-0;
NaCS, 15763-16-5; NaBMGS, 67656-24-0; EPNB, 99-77-4; ANS,
18108-68-4; DPH, 1720-32-7; FDA, 596-09-8; CU,7440-50-8; 5-doxyl
stearate, 29545-48-0; perylene, 198-55-0.
(47) McBain, J. W.; McHan, H. J . Am. Chem. SOC.1948, 70, 3838.
(48) It has been shown that micelles of some nonionic poly(ethy1ene gly-
col)-based surfactants show high degrees of selectivity in the extractive sep-
aration of 0- and p-nitrochlorobenzene. The former is solubilized in these
micelles several-hundred-fold better than the latter: Mahapatra, A. Ph.D.
Thesis, University of Bombay, Bombay, India, 1988.
(49) Lindman, B.; Wennerstrom, H. Top. Curr. Chem. 1980, 87, 1 .
(50) Mukerjee, P. J . Pharm. Sci. 1974, 63, 972.