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 (solubilizate) 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 consensus 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 Neuberg, C. Biochem. Z . 1916, 76, 107. McKee, R. H. Ind. Eng. Chem. Ind. Ed. 1946, 38, 382. Booth, H. S.; Everson, H. E. Ind. Eng. Chem. Ind. Ed. 1948,40, 1491. 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. (1) (2) (3) (4)
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-cyclohexen-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 compounds. 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 enhancing 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
$
3866 The Journal of Physical Chemistry, Vol. 93, No. 9, 1989 ~o~ o+c/
0 '
:N
Balasubramanian et al.
~
SO;
No+
NaPTS
,/
d 0.14 J
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 particularly important since our recent finding that hydrotrope solutions 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 successfully 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 cumenesulfonate (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 reminiscent of surfactant micelles though the cooperativity of association 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 microenvironmental 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.
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 concentration for several hours in a constant-temperature shaker. The suspension was centrifuged and the concentration of the solubilizate 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 experimental 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-(3carboxypropyl)-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) the spin probe in the various tational correlation time ( T ~ of 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 Phenomena; Academic Press: New York, 1955. (33) Friberg, S.E.; Flaim, D.; Osborne, D. W., personal communication.
The Journal of Physical Chemistry, Vol. 93, No. 9, 1989 3867
Aggregation Behavior of Hydrotropic Compounds
PEG (w/v"/o) 2 0%
IO%
I
To-
3 0%
0 15
0 06
2
2.0-
t
D 0
0.04
I
04
0 8
12
-
I
I
I
16
2 0
2 4
CONCENTRATION (mol/L )
I
I
2 8
3 2
Figure 3. Concentration-dependent enhancement in the solubility of FDA, perylene, and EPNB in aqueous NaBMGS at room temperature. The concentrations of the solubilizates were measured through their optical density values (OD) at their absorption band maxima.
has been by Licht and Wiener." Since insight into the mechanism 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 concentrations. Figure 2 presents a representative set. The dye fluorescein diacetate (FDA) was chosen here as the solubilizate because of its negligible solubility in water, its high absorptivity that aids 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 hydrotropes is not a linear or monotonic function of their concentration. 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 operative below a particular concentration, while above this concentration 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 hydrotrope NaBMGS. Its hydrotropic behavior toward FDA, perylene, 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 amphiphiles. However, this similarity is not total, and there are some notable differences; we shall discuss these later, but for the moment, 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 10
t
0.001
I
I
I
1.2
0.8
0.4
I
I
I
2.0
2.4
2.8
or [GdSCN]
[NoPTS]
-
I
1.6
I
3.2 M
Figure 4. Increase in the solubility of perylene in water at room temperature, brought about by NaPTS, PEG-6000, and guanidinium thiocyanate.
It
0
0
I
I
I
I
0.2
0 4
0.6
0 8
[NaBMGS]
I
1.0.
I
I 2
I
1.4
Figure 5. Comparison of the rate enhancement 6 produced in the alkaline 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.
Balasubramanian et al.
3868 The Journal of Physical Chemistry, Vol. 93, No. 9, 1989 -9 0
-'O
I
t
NoXS
2
NaPTS
3
NOS
4
NoBMGS
\
-50
Dl
m
z
- 3 0
2 Y
- I O
0
01
0 2
C ?
0 4
-
0 5
[ Na PTS]
0 6
0 7
0 8
09M
Figure 6. Comparison of the hydrolysis rate enhancement (left-hand side scale, filled circles) and the solubilization of EPNB (right-hand side scale, squares) as a function of the concentration of NaPTS in water at room temperature.
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 enhancement as a function of the hydrotrope concentration. Figure 5 shows that the reaction rate of alkaline hydrolysis of EPNB does not show any enhancement (compared to the rate in water) up to a concentration of 0.8 M NaBMGS. Beyond this concentration, the rate increases and becomes 3 times as fast in 1.2 M NaBMGS as in water. Figure 5 also shows the solubility of EPNB in the hydrotrope solution. As can be seen, the solubility and the hydrolysis rates go hand in hand, suggesting that enhancement in the rate occurs upon increased solubilization. Sequestration of the EPNB into the hydrotrope medium appears to be a possible factor in the rate enhancement. The fact that rate enhancement occurs beyond M H C is noteworthy. In a similar experiment, we observed that enhancement in the rate of this reaction occurs beyond a concentration of 0.4 M NaPTS in water. The solubility curve for EPNB in aqueous NaPTS solution overlaps with the rate enhancement curve, as shown in Figure 6. It would thus seem that the acceleration of reaction rates caused by hydrotropes is related to their solubilization efficiency. This point had in fact been anticipated by us earlier.23 C. Surface Tensiometry of Hydrotropes. Another common statement made about hydrotropes is that they are not surface a ~ t i v e . ~ , * ~This ~ * -comprehensive ~~ assertion arises in part due to the fact that a variety of substances, organic or inorganic, have been classified as hydrotropes and the fact that many of the organic compounds used are short-chain aliphatics or benzenoid salts that are assumed not to be surface active. However, in light of the apparent similarity between hydrotropy and micellar solubilization alluded to above, we studied the tensiometric behavior of some of these compounds. Figure 7 shows the variation in the surface tension of several hydrotropes with their concentrations in water. It is seen that the surface tension decreases from 72 dyn/cm for water to a limiting value of around 50-53 dyn/cm for NaS, NaPTS, and NaXS, to around 43 dyn/cm for NaCS and 37 dyn/cm for NaBMGS. All of these hydrotropes are indeed surface active, and some are comparable to micellar amphiphiles (cetyltrimethylammonium bromide reduces the y value of water to below 40 dyn/cm at concentrations beyond its cmc of 0.9 mM). In any event, the concentration-dependent reduction in the surface tension is more gradual with hydrotropes in comparison to the sharper drops encountered with micellar surfactants. The data in Figure 7 suggest that each of these hydrotropes self-aggregates beyond a given concentration in water to produce noncovalent assemblies; this concentration is 0.65 M for NaS, 0.37 (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, 865. (40) Product brochure of Chemische Werke Hiils AG, Sept 1979
40t
4
I
n
0 2
c3
04
0 5
0 6
c7
0 9
0 8
CONCENTRATION OF H Y D R O T R O P E .
4 I
o
M-
Figure 7. Variation of the surface tension with concentration of several
hydrotropes 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 remarkably close to the MHC values determined from the solubilization experiments above (NaS 0.8 M, NaPTS 0.35 M, 0.8 M) and lend support to NaXS 0.4 M, and NaBMGS the idea that both of these concentrations of a hydrotrope reflect the onset of the same process, Le., self-aggregation. This would also imply that the formation of a self-aggregated assembly is a prerequisite for hydrotropic solubilization to set in (as shown in Figures 2-4) and hydrotropic enhancement of reaction rates to occur (Figures 5 and 6). The area occupied at the air-water interface by each of these hydrotrope molecules was estimated from surface tension measurements with the Gibbs adsorption isotherm.41 The area per molecule increases in the following order (A2/molecule; all at room temperature; error k l % ) : NaS, 44; NaCS, 60; NaPTS, 86; NaXS, 93; and NaBMGS, 155. NaBMGS has a surprisingly large interfacial area, which leads to the likelihood that the molecule is oriented not erect in the all-trans chain conformation but in the bent form. It would be of interest to verify this possibility. The idea of self-aggregation of organic hydrotrope molecules is not new. Both self-aggregation and mixed aggregation have been suggested; there is indeed even a model presented for hydrotrope aggregation into stack-type assemblies,16 with an obligatory planar hydrophobic moiety in each molecule. While most of the hydrotropes that we have investigated do have the planar benzene ring in them, NaBMGS does not, and yet, it behaves in a manner quite similar to that of the others in all its hydrotropic properties. It would therefore be worthwhile to study NaBMGS in greater detail, which we are involved in currently. However, the novel and important point that has emerged out of our results is that hydrotropy is a collective molecular phenomenon and requires the presence of noncovalent molecular aggregates. D . Microenvironmental Features of Aggregates. Two microenvironmental properties of relevance in the solubilization of molecules into micellar and similar structures are the polarity and the microviscosity (or the fluidity) that the assembly offers to a molecule that is incorporated in them.42 The fluorescence spectrum of the molecule ANS is known to be sensitive to the polarity of the medium it is dissolved in, and this property has been used to estimate the polarities of micellar aggregates of different sizes and shapes.30 Likewise, the anisotropy of fluorescence emission of the arene 1,6-diphenylhexatriene (DPH) offers information about their micro~iscosities.~*~~ We have used these two probes in order to obtain information on hydrotropes. Figure 8 shows that the fluorescence emission wavelength maximum (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
-
--
-
(41) Shobha, J.; Balasubramanian, D. J . Phys. Chem. 1986, 90, 2800.
(42) Singer, L. A. In Solution Behavior of Surfactants; Mittal, K. L., 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
440
0 2
0 4
06
[NaCS],
-
0 8
I
I
I
10
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 hydrotrope. Next, we solubilized DPH in each of the hydrotrope assemblies and measured its fluorescence anisotropy. The microviscosity of each assembly was estimated from the anisotropy value with use of the relation reported by Shinitzky and B a r e n h ~ l z .The ~ ~ estimated microviscosity values, at room temperature, of NaPTS, NaCS, and NaBMGS are all in the range 0.55-0.65 P, comparable to those of the micellar aggregates of sodium dodecyl sulfate (SDS) or of cetyltrimethylammonium bromide (CTAB) in water.M Thus, these hydrotrope aggregates offer a microenvironment that is slightly less polar than ionic micelles but of comparable microviscosity . Another aspect of the microenvironment is the access that a solubilized or incorporated molecule has to a reagent or an interacting partner that is added and confined to the external medium. We chose to solubilize the neutral, symmetric arene perylene and to monitor the ability of externally added paramagnetic ion Cu2+to quench the aromatic fluorescence. Paramagnetic or spin quenching of fluorescence operates over a distance of 4-6 A only43and is thus an appropriate measure of accessibility to the fluorophore that is incorporated in the hydrotrope microenvironment. In Figure 9 is plotted the Stern-Volmer quenching by external CuSO, of the fluorescence of perylene solubilized in the hydrotropes NaCS and NaBMGS above their M H C and in the micellar solution of sodium dodecanoate. It is seen that the hydrotropes protect or shield the perylene molecule from Cu2+ quenching better than dodecanoate micelles do and that between the two hydrotropes NaBMGS sequesters perylene more effectively from the quencher than NaCS. Similar results were obtained when the microenvironment of these assemblies were probed with the electron spin resonance probe 5-doxy1 stearate. The nitrogen hyperfine coupling constant aNof such doxy1 probes is sensitive to solvent polarity, with a value of around 17.5 G in water, reducing in value in nonpolar solv e n t ~ . ~ ' *Apart ~ ~ * from ~ ~ .aN, ~ ~which behaves as a polarity indicator, the other useful parameter is the reorientational correlation time of motion ( 7 c ) of the probe, which is sensitive to the medium viscosity and hence used to study the microviscosity of amphiphile (43) Green, J. A.; Singer, L. A.; Parks, J. H. J . Chem. Phys. 1973,58,
2650. (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.
400
200
[C],:'
600
000
UM-
Figure 9. Stern-Volmer quenching behavior of the fluorescence of pe-
rylene solubilized in 0.2 M sodium dodecanoate (micellar solution), 0.3 M NaCS, and 1.25 M NaBMGS in water by added CuSO+ Conditions: perylene concentration 1 pM; excitation at 406 or 434 nm and emission at 462 nm; room temperature. TABLE I: a N and 7e Values of 5-Doxy1 Stearate in Water and in Some Hvdrotrow Solutions' sample (concn, M) water NaCS (0.05) NaCS (0.3) NaBMGS (0.12) NaBMGS (1.25)
2 a ~G, 34.25 34.5 34.1 36.0 34.5
lo'%,,
s
1.6 1.6 2.2 1.3 7.7
"Spin-label concentration 0.5 mM; room temperature. Sample not deaerated. aggregates and membranes.31*" Table I lists the values of aNand 7c of the spin probe in aqueous solutions of the hydrotropes NaCS and NaBMGS at low and high (beyond MHC) concentrations, and Figure 10 shows a typical set of ESR spectra. In all these instances, the probe experiences a lowered polarity and increased hindrance to motion when the hydrotrope is above its MHC than when it is below. The reduction in polarity, as reflected by aN, is largest in the case of NaBMGS, and it is this hydrotrope that offers the highest hindrance to spin probe motion: the T~ value in this case is as high as about 0.7 ns, about 5-fold higher than in water and 2-3-fold higher than in other hydrotrope aggregates.
Conclusions Over the years, a variety of organic compounds and even inorganic salts have been termed hydrotropes based just on the fact that the solubility of otherwise insoluble compounds in water is increased in their presence. We have attempted to show in this paper that hydrotropy is different in its features from salting-in, which is displayed by inorganic ions of the chaotropic kind;35*46 it also appears different from phase mixing, though the ability of some hydrotropes to delay the onset of the lamellar liquid (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
Balasubramanian et al. somewhat less dramatic and efficient. First, hydrotrope solubilization 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 hydrophobes 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 solubility 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 parameters of association, the aggregation number, and related parameters before a firm conclusion about the nature of hydrotrope aggregates can be reached. We are currently studying these aspects in some detail.
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 collective molecular phenomenon. While there are several points of resemblance between hydrotrope molecules and surfactants (e.g., aggregation, solubilization of hydrophobic compounds, surface activity, reaction rate enhancement), 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
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 glycol)-based surfactants show high degrees of selectivity in the extractive separation 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.
