New Insights in Cyclodextrin: Surfactant Mixed Systems from the Use

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J. Phys. Chem. B 2007, 111, 12756-12764

New Insights in Cyclodextrin: Surfactant Mixed Systems from the Use of Neutral and Anionic Cyclodextrin Derivatives L. Garcı´a-Rı´o,*,† M. Me´ ndez,† M. R. Paleo,‡ and F. J. Sardina‡ Departamento de Quı´mica Fı´sica and Departamento de Quı´mica Orga´ nica, Facultad de Quı´mica, UniVersidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain ReceiVed: May 8, 2007; In Final Form: July 26, 2007

The kinetics of the hydrolysis of 4-methoxybenzenesulfonyl chloride (MBSC) have been studied in mixed systems made up of surfactant, sodium dodecyl sulfate (SDS) or tetradecyltrimethylammonium bromide (TTABr), and cyclodextrin, β-CD or SBE-β-CD(Captisol). The use of SBE-β-CD instead of β-CD allowed us to indicate certain characteristics of the mixed cyclodextrin-surfactant system: (a) The percentage of uncomplexed cyclodextrin is higher for SBE-β-CD than for β-CD when we use SDS, but the opposite effect was observed when we use TTABr. This behavior can be explained by taking into account the increase in salinity when we add SBE-β-CD, and the electrostatic forces between the SBE-β-CD and the surfactant that have influence on the complexation. (b) The presence or even the charge of cyclodextrin has no effect on the properties of surfactant micelles once they have been formed; in particular, it does not alter Km s or km, parameters very sensitive to the micellar system structure. Therefore, we can conclude that for surfactants concentrations lower than the micellization point, the charge of cyclodextrin modifies the cyclodextrinsurfactant interactions but once the micelles have been formed there is no interaction between them and the cyclodextrins.

Introduction

SCHEME 1

Cyclodextrins are cyclic oligomers of R-D-glucose linked by R-(1f4) bonds. Natural cyclodextrins are classified as R-, β-, or γ-cyclodextrin according to whether they have six, seven, or eight glucose units, respectively. In water solution they exist as aggregates bound together by a network of hydrogen bond.1 Their importance stems from their ability to form inclusion complexes, which derives from the gross geometrical form of their molecules being a truncated hollow cone able to accommodate small organic molecules of suitable size, shape, and polarity. A commonly used rule of thumb is that R-, β-, and γ-cyclodextrin snugly accommodates benzene, naphthalene, and anthracene, respectively.2 Sulfobutylether-β-cyclodextrin (Captisol or SBE-β-CD, Scheme 1) is a polyanionic β-cyclodextrin derivative with a sodium sulfonate salt separated from the lipophilic cavity by a butyl ether spacer group. The SBE substituents on Captisol enhance complexation by providing an extended hydrophobic cavity and an extremely hydrophilic exterior surface. Mixed cyclodextrin-surfactant systems have been widely studied due to their numerous applications in commercial formulations3,4 and the capacity of cyclodextrin to modulate the physicochemical properties of micellar solutions. These systems offer the possibility of systematically studying the association process because properties of micellar solutions can be modulated by systematic variations of the surfactant structure. As a consequence of the binding process, some properties of the target molecules can dramatically change (e.g., cmc). The presence * Corresponding author. E-mail: [email protected]. † Departamento de Quı´mica Fı´sica. ‡ Departamento de Quı´mica Orga ´ nica.

of CD in solutions of amphiphiles forming micelles or other types of self-assembled aggregates introduces a new equilibrium into the medium that may lead to the dissolution of the selfassembled aggregates.5,6 Inclusion complexes have been characterized by a wide variety of techniques such as conductance,7,8 speed of sound,9,10 NMR,11 fluorescence,12 surfactant selective electrode,13,14 surface tension,15 kinetic methods,16 diffusion coefficient,17 etc. Certain characteristics of cyclodextrin-surfactant mixed systems can be highlighted: (i) At surfactant concentrations lower than the micellization point, a complexation equilibrium between the surfactant and the cyclodextrin is established. As the surfactant concentration increases, the concentration of uncomplexed surfactant monomers in equilibrium with the CD is sufficient for the micellization process to begin. (ii) The

10.1021/jp073510p CCC: $37.00 © 2007 American Chemical Society Published on Web 10/16/2007

New Insights in Cyclodextrin SCHEME 2

critical micelle concentration has been found to shift to higher values in the presence of CD. The critical micelle concentration of a micellar system in the presence of a cyclodextrin is equivalent to the combined concentrations of surfactant monomers complexed to the CD and of free dissolved monomer in equilibrium with the micellized surfactant. (iii) Once the micellization process has begun, interactions will not be established between the CD and the micellar system. Recent results from the study of the enthalpy of transfer of cyclodextrin from water to the aqueous surfactant solutions suggest the existence of interactions between micelles and cyclodextrins in systems using hydrogenated18 and fluorinated19 alkanoates. Quantitative analysis of the postmicellar region indicates that the cyclodextrin-micelle forces are ion-dipole (carboxylate head/hydroxylic group) in nature. However, the existence of this kind of interaction can be questioned on the basis of self-diffusion NMR studies of the host-guest interaction between CD and several surfactants.6,11 The aim of the work described here was to confirm that there is no interaction between the CD and the micellar system, so we studied mixed systems with cationic (TTABr) and anionic (SDS) surfactant and anionic (SBE-β-CD) and neutral (β-CD) cyclodextrins. To study these systems, we use as a chemical probe the hydrolysis of 4-methoxybenzenesulfonyl chloride (MBSC), a molecule whose geometry and polarity is suitable for complex formation with cyclodextrin, Scheme 2. The solvolysis mechanism of MBSC has been previously studied in water and in water:organic solvents mixtures.20 Three mechanisms have been proposed for this reaction: (a) heterolysis of the S-Cl bond to give a planar trigonal intermediate sulfonylium cation which then suffers nucleophilic capture by H2O (or OH-), (b) concerted displacement of Cl- (or its conjugate acid) from the sulfur atom by H2O (or OH-) via a trigonal bipyramidal activated complex, and (c) addition of H2O (or OH-) at the sulfur atom to give a trigonal bipyramidal intermediate from which Cl- departs (with or without prior protonation) following, if necessary, a conformational change to allow the nucleophile to occupy an apical position. As far as the sulfonyl transfers are concerned, there is presently an uneasy consensus that a single mechanism, the concerted bimolecular SN2 process, can account for all the experimental evidence so far available. The SN2 mechanism, however, allows considerable variation in the degree of synchronicity in the bond breaking and making, and does not imply a single invariable transition state structure. Experimental Section SDS, TTABr, MBSC, and β-cyclodextrin were Sigma products of the highest available purity and were used without further purification. Captisol (or SBE-β-CD) was obtained from CyDex. Stocks solutions of MBSC were prepared in acetonitrile due to its low solubility in water. The final acetonitrile concentration in the reaction medium was 1% (v/v). Surfactant-CD systems were prepared by mixing appropriate volumes of stock aqueous solutions of CD and surfactant. Kinetic runs were initiated by injecting a stock solution of MBSC into the mixed system in a 1 cm cuvette. Reaction kinetics were recorded by measuring absorbance due to MBSC at 270 nm in a Cary UV-vis spectrophotometer

J. Phys. Chem. B, Vol. 111, No. 44, 2007 12757 with a cell holder thermostated at (25.0 ( 0.1) °C. The MBSC concentration was always approximately 1.0 × 10-4 M. The absorbance-time data of all kinetic experiments were fitted by first-order integrated equations, and the values of the pseudofirst-order rate constants kobs were reproducible to within 3%. The critical micelle concentration of the mixed systems was obtained kinetically and in some cases by surface tension measurements. The surface tension σ (mN m-1) was measured with a Kruss tensiometer (K9) using the Wilhelmy plates procedure. Results Solvolysis of MBSC in the Presence of Cationic and Anionic Micelles. The influence of the concentration of SDS and TTABr has been studied in a wide interval that includes both the regions prior to the cmc, where the molecules of the surfactant are like monomers dispersed in the solution, and the regions after the cmc where the surfactant molecules are associated to form micelles. The effect of the surfactant concentration, SDS and TTABr, on the pseudo-first-order rate constant, kobs, for the hydrolysis of MBSC is shown in Figures 1and 2, respectively. As can be seen from Figures 1 and 2, the pseudo-first-order rate constant remains practically unchanged on increasing the surfactant concentration up until the cmc. At surfactant concentrations higher than the cmc, a clear decrease in kobs can be observed due to the presence of micellar aggregates. These inhibitions are due to the substrate incorporation into the micelles where the rate of the solvolytic reaction is smaller than in bulk water. The formalism of the micellar pseudophase was applied to obtain a quantitative interpretation of the experimental results. Two well-differentiated environments were considered: water and a micellar pseudophase between which the MBSC is distributed (Scheme 3). By considering that the solvolysis can take place simultaneously in water, kw, and at the micellar pseudofase, km, it is possible to derive the following equation, which relates the observed rate constant with the surfactant concentration.

kobs )

kw + kmKm s [Dn] 1 + Km s [Dn]

(1)

where Km s is the distribution constant of MBSC between the water and the micellar pseudophases, Km s ) [MBSC]m/[MBSC]w[Dn]; [Dn] is the concentration of micellized surfactant,1c [Dn] ) [surfactant]T - cmc; and [surfactant]T is the total concentration of the surfactant. The values of cmc are required to fit eq 1 to the experimental results. The critical micelle concentration can be obtained kinetically as the minimal surfactant concentration necessary to observe an appreciable change in kobs. Obtained values are 7.0 × 10-3 and 2.8 × 10-3 M for SDS and TTABr, respectively. These values are in good agreement with those reported in the literature.1c Fitting the experimental results to eq 1, by a nonlinear regression method, provided the values for the distribution constants of the MBSC between the water and the micellar pseudophase (Km s ) and the rate constant in the micellar pseudophase, km. These values along with the cmc values obtained experimentally are given in Table 1. Lines showed in Figures 1 and 2 correspond to the fit of eq 1 to the experimental data using the parameters in Table 1. The association constant of the MBSC to the micellar system 2 -1 than is higher for the TTABr, Km s ) (3.38 ( 0.16) × 10 M

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Figure 1. Influence of SDS concentration on the pseudo-first-order rate constant kobs (left) and its inverse (right) for the hydrolysis of MBSC at 25.0 °C. Curves represent the fits of eq 1 and its inverse to the experimental data and the dotted line represent the expected behavior if there was no hydrolysis when the substrate is associated with the micelle.

Figure 2. Influence of TTABr concentration on the pseudo-first-order rate constant kobs (left) and its inverse (right) for the hydrolysis of MBSC at 25.0 °C. Curves represent the fits of eq 1 and its inverse to the experimental data and the dotted line represent the expected behavior if there was no hydrolysis when the substrate is associated with the micelle.

SCHEME 3

2 -1 for the SDS, Km s ) (2.27 ( 0.04) × 10 M . As the length of the hydrocarbon chain of the surfactant increases, so does its hydrophobity too and hence the association constant must also increase. Likewise, as the length of the hydrocarbon chain of the surfactant increases, the critical micellar concentration, cmc, decreases. The km values shown in Table 1 are clearly lower than the value obtained in bulk water but if we consider that the solvolysis reaction takes place only in the aqueous medium we should simplify eq 1 to kobs ) kw/(1 + Km s [Dn]), which can be rewritten as a function of its inverse, 1/kobs ) 1/kw + (Km s /kw)[Dn]. This last equation predicts a linear dependence between 1/kobs and [Dn]. As can be seen from Figure 2 (right), there is a curvature in the plot more pronounced for high surfactant concentrations. In fact, the deviation respect to the linear dependence is higher than 500% for [Surf] > 0.1 M, so we need to consider the solvolytic process of substrate associated with the micelle. The results show that kw/km is approximately 100 for SDS micelles and 40 for TTABr micelles. The decrease in km respect to kw is due to the lower polarity of the micelle if we compare

with bulk water. According to this idea, km for TTABr should be lower than for SDS because of the polarity of the TTABr is also lower, as can be seen from the lower cmc and higher Km s values. This behavior has been previously interpreted by Bunton20 and co-workers by taking into account the interactions of the transition state for hydrolysis of sulfonyl chlorides with micellar head-groups. They found k+/k- ) 3 values for the solvolysis of MBSC in SDS and CTAB micelles which is in good agreement with k+/k- ) 2.45 found in the present work for SDS and TTABr. Influence of Cyclodextrins on Solvolysis of MBSC. The influence of β-CD and SBE-β-CD on the rate of solvolysis of MBSC was studied. Figure 3 shows the influence of cyclodextrin concentration on the observed rate constant. As can be observed, addition of cyclodextrin to the reaction media inhibited the hydrolysis of MBSC. The experimental behavior can be explained by considering the mechanistic behavior showed in Scheme 4 where MBSC bind the cyclodextrin and the solvolytic reaction takes place simultaneously in water, kw, and through the CD-MBSC complex, kCD. The dependence of kobs on [CD] is expressed by

kobs )

kw + kCDKCD s [CD] 1 + KCD s [CD]

(2)

where KCD s is the equilibrium binding constant of the substrate to the cyclodextrin, kCD is the rate constant for the reaction in the CD, and kw is the rate constant for the hydrolysis in the aqueous medium.

New Insights in Cyclodextrin

J. Phys. Chem. B, Vol. 111, No. 44, 2007 12759

Figure 3. Influence of β-CD (left) and SBE-β-CD concentration (right) on the pseudo-first-order rate constant, kobs, and its inverse (inset) for the hydrolysis of MBSC at 25.0 °C. Curves represent the fits of eq 2 and its inverse to the experimental data and the dotted lines represents the expected behavior if the inclusion complex formed was unreactive.

TABLE 1: Critical Micelle Concentration Obtained Experimentally and Results Obtained by Fitting Eq 1 to the Experimental Data for the Hydrolysis of MBSC in the Presence of Surfactant surfactant SDS TTABr a

cmca/M

cmc/M

-1 Km s /M

km/s-1

kw/s-1

8.0 × 10-3 3.5 × 10-3

7.0 × 10-3 2.8 × 10-3

(2.27 ( 0.04) × 102 (3.38 ( 0.16) × 102

(6.16 ( 0.33) × 10-5 (1.51 ( 0.11) × 10-4

(6.05 ( 0.02) × 10-3 (6.05 ( 0.02) × 10-3

Reference 1c.

SCHEME 4

The good fit between eq 2 and the experimental data for β-CD and SBE-β-CD, lines in Figure 3, allows us to obtain the parameters listed in Table 2. The solvolytic reaction of the CDMSBC complex is responsible for the curvature in the plot of 1/kobs versus [CD], as eq 2 predicts. In addition, the obtained values of kw are in accordance with the corresponding rate constant obtained from separate experiments in pure water. As in the studies carried out in the presence of micellar surfactants, we should remark the lower values of kCD obtained compared with the values obtained in bulk water (approximately 40 times lower for β-CD and 100 for SBE-β-CD). Nevertheless, these values have to be considered to explain the kinetic behavior observed. In case we neglect kCD eq 2 can be simplified and rewritten as 1/kobs ) 1/kw + (KCD s /kw)[CD], which predicts a linear dependence between 1/kobs and [CD]. The insets in Figure 3 show there is no such lineal dependence. In fact, the deviation is higher than 100% between the experimental behavior and the linear dependence. We also have to consider the differences between the kCD values for β-CD and SBE-β-CD, as well as the differences with respect to kw. The polarity in the β-CD cavity is higher than in the SBE-β-CD, so KCD is higher and kCD is lower. The kCD s values are clearly lower respect to the value obtained in bulk water due to the polarity of the medium. Solvolysis of MBSC in Surfactant/Cyclodextrin Mixed Systems. The mixed systems were investigated by carrying out experiments in which the CD concentration was kept constant and the surfactant concentration was varied from values clearly lower than the cmc to values beyond the micellization point

(see Figure 4 for a cationic surfactant and Figure 5 for an anionic one). Experiments were carried out at three different β-CD concentrations ([β-CD] ) 5.22 × 10-4 M, [β-CD] ) 1.71 × 10-3 M, and [β-CD] ) 7.84 × 10-3 M) and three different SBE-β-CD concentrations ([SBE-β-CD] ) 6.01 × 10-4 M, [SBE-β-CD] ) 1.93 × 10-3 M, and [SBE-β-CD] ) 8.58 × 10-3 M). In all the cases the surfactant concentration (TTABr or SDS) was varied from a value smaller than the cmc, 1 × 10-4 M, to 0.30 M, well above the micellization point. From a qualitative point of view, the observed behavior is the same in all the cases, β-CD and SBE-β-CD, and independent of the head group of the surfactant. The observed rate constant extrapolated to zero surfactant concentration diminishes as the concentration of CD increases. This result is consistent with that found for the β-CD/water and SBE-β-CD/water system and is due to the formation of an inclusion complex in which the reaction rate is smaller than in the aqueous medium. When the CD concentration is kept constant, the value of kobs increases to a maximum as the concentration of surfactant increases. The increase in the observed rate constant is due to the competitive formation of inclusion complexes between the CD and the surfactant. The formation of these inclusion complexes displaces the MBSC toward the aqueous medium, where the rate reaction is higher and, as a consequence, the observed rate constant of the reaction increases. The competitive formation of the CD-surfactant inclusion complexes occurs until the concentration of surfactant monomers reaches the value at which the micellization process begins. Once micelles have been formed, the typical inhibiting effect that they have on the hydrolysis of MBSC is observed. Therefore, the maximum observed in the plot of kobs versus surfactant concentration can be attributed to the micellization point, where the kinetic effects caused by the formation of an inclusion complex between the surfactant and the CD (catalytic effect on kobs) and for the formation of the micelles (inhibitory effect on kobs) are compensated. In an effort to develop a kinetic model, we considered the existence of three simultaneous reaction paths: the reaction of the free substrate in aqueous medium, the reaction of the

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Figure 4. Influence of CD concentration on the observed rate constant for the hydrolysis of MBSC at 25.0 °C in the presence of TTABr surfactant. Left: (green circles) [β-CD] ) 5.22 × 10-4 M; (red circles) [β-CD] ) 1.71 × 10-3 M; (blue circles) [β-CD] ) 7.84 × 10-3 M. Right: (green circles) [SBE-β-CD] ) 6.01 × 10-4 M; (red circles) [SBE-β-CD] ) 1.93 × 10-3 M; (blue circles) [SBE-β-CD] ) 8.58 × 10-3 M.

Figure 5. Influence of CD concentration on the observed rate constant for the hydrolysis of MBSC at 25.0 °C in the presence of SDS surfactant. Left: (green circles) [β-CD] ) 5.22 × 10-4 M; (red circles) [β-CD] ) 1.71 × 10-3 M; (blue circles) [β-CD] ) 7.84 × 10-3 M. Right: (green circles) [SBE-β-CD] ) 6.01 × 10-4 M; (red circles) [SBE-β-CD] ) 1.93 × 10-3 M; (blue circles) [SBE-β-CD] ) 8.58 × 10-3 M.

TABLE 2: Results Obtained by Fitting Eq 2 to the Experimental Data for the Hydrolysis of MBSC in the Presence of Cyclodextrin cyclodextrin β-CD captisol

-1 KCD s /M

kCD/s-1

(1.89 ( 0.01) × (3.04 ( 0.04) × 103 103

SCHEME 5

kw/s-1

(1.43 ( 0.03) × (6.2 ( 0.1) × 10-5

10-4

and there are no interactions of any sort between the CD and the micellar system once the micellization process begins. This mechanistic scheme allows us to derive the following expression for the rate constant:

kobs )

complexed substrate with the CD, and the reaction of the substrate associated with the micelle (see Scheme 5). As we have previously demonstrated,21,22 we can assume that there is uncomplexed cyclodextrin coexisting with the micellar system

(6.05 ( 0.02) × 10-3 (6.05 ( 0.02) × 10-3

m kw + kCDKCD s [CDf] + kmKs [Dn] m 1 + KCD s [CDf] + Ks [Dn]

(3)

To solve eq 3, it is necessary to obtain the concentration of uncomplexed cyclodextrin, [CDf], for each surfactant concentration as well as the values of [Dn]. Two methods can be used to obtain the [CDf] values. Calculation of Uncomplexed CD from a Calibration Procedure. For any surfactant concentration, it is possible to obtain the concentration of uncomplexed cyclodextrin from a calibration curve. The calibration curve can be obtained by regrouping eq 2 and using the values of KCD s , kCD, and kw obtained previously (Table 2).

New Insights in Cyclodextrin

[CDf] )

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kw CD Ks (kobs

kobs - kCD)

(4)

As part of the proposed model for the behavior of mixed surfactant/β-CD systems we consider that the concentration of uncomplexed cyclodextrin in equilibrium with the micellar systems remains constant and equal to the value obtained at the cmcapp. This assumption is based on the fact that the concentration of monomers in equilibrium with the micellar system remains constant once the micelles have been formed and is equal to the value at the micellization point. To calculate the concentration of micellized surfactant, Dn, it is necessary to know the cmc. This value can be obtained kinetically from the plots of kobs versus the surfactant concentration in the presence of cyclodextrin, and is the surfactant concentration at which kobs has a maximum value. In the process of fitting eq 4 to the experimental results, KCD and kCD were s keeping constants and equals to the values obtained in the absence of surfactant, kw the value obtained for the rate constant in pure water and the values associated with the micelle, Km s and km, were fitted. Curves in Figures 4 and 5 correspond to the fit of eq 3 to the experimental results by using the parameters in Tables 3 and 4. Calculation of Free CD from Binding Constants. The concentration of free CD can be obtained by means of a simulation procedure, supposing that the complex formed between the surfactant molecules and the CD has a stoichiometric ratio11,23 of 1:1, as well as for the CD-MBSC complex.The complexation constant for binding of the substrate by CD, KCD s , surfactant molecules by the cyclodextrin, Ks and substrate by the micellar system, Km s , are expressed as

KCD s )

[MBSC-CD] [MBSCw][CDf]

Km s )

[MBSCm] [MBSCw][Dn] [Surf-CD] (5) Ks ) [Surfmon][CDf]

The mass balances for the total concentrations of cyclodextrin, surfactant and substrate

[CDT] ) [CDf] + [MBSC-CD] + [Surf-CD]

(6)

[SurfT] ) [Surfmon] + [Surf-CD] + [Dn]

(7)

[MBSCT] ) [MBSCw] + [MBSC-CD] + [MBSCm]

(8)

are combined with binding constants to give a third-order equation for the concentration of uncomplexed cyclodextrin:

R[CDf]3 + β[CDf]2 + γ[CDf] - [CDT] ) 0

(9)

R ) KsKCD s

(10)

CD β ) Ks + KCD s + KsKs ([SurfT] - [CDT] + [MBSCT]) (11)

γ ) 1 + Ks([SurfT] - [CDT]) + KCD s ([MBSCT] - [CDT]) (12) This equation was solved for different values of Ks allowing us to obtain the concentration of uncomplexed cyclodextrin for each surfactant concentration. Using the [CDf] values and with the [Dn] values, we can fit the experimental kobs values to eq 3. The value of Ks for which we obtain the best root-mean-square deviation (χ2) values in fitting eq 3 to the experimental results

Figure 6. Results of fitting eq 3 to the experimental kobs vs [TTABr] data for [SBE-β-CD] ) 1.93 × 10-3 M using different tentative values of Ks: (green circles) experimental data; (blue line) Ks ) 1 × 104 M-1; (green line) Ks ) 6.2 × 104 M-1; (red line) Ks )1 × 106 M-1.

was taken as optimal as can be seen from Figure 6. The validity of this model was tested by fitting eq 3 to the experimental data by means of a two-tier optimization process in which the optimized variable was KCD s , and the values obtained in the simple systems were taken as constants. As can be seen in Tables 3 and 4 the fitted parameters are indistinguishable by using the calibration method or calculating the concentration of uncomplexed cyclodextrin from the binding constants. A second point to note on analyzing Tables 3 and 4 is that the values of the fitted parameters are independent of the cyclodextrin concentration present in the mixed system. A mean value has been calculated to compare our fitted results with those previously obtained in single systems formed by MBSC/CD and MBSC/surfactant. Discussion The results obtained in the previous section have been analyzed taking into account the competition between two phenomena: Surf-CD complexation with the corresponding MBSC expulsion to aqueous media that increases kobs and, on the other hand, MBSC partition between the aqueous medium, the micellar medium and the uncomplexed cyclodextrin, responsible for the observed kinetic behavior. 1. Influence of Adding Cyclodextrin on the Critical Micelle Concentration. It has generally been assumed that the addition of CD to aqueous surfactant solutions increases the cmc,24 but we obtain different results for SBE-β-CD. In the presence of β-CD, the maximum in the curve kobs vs [Surf] is displaced to higher surfactant concentrations as the CD concentration increases. This effect is due to the complexation of the monomers of the surfactant with the β-CD and the consequent effect in the critical micelle concentration. The presence of SBEβ-CD shows a different behavior. Thus, we can observe that the addition of anionic cyclodextrin produces a decrease in the cmc for small concentrations of SBE-β-CD going from cmc ) 2.8 × 10-3 M in the absence of cyclodextrin to cmc ) 1.0 × 10-3 M when [SBE-β-CD] ) 6.01 × 10-4 M and cmc ) 2.4 × 10-3 M when [SBE-β-CD] ) 1.93 × 10-3 M. Further increases in the cyclodextrin concentration produce an increase in the micellization point. Thus, cmc ) 8.9 × 10-3 M when [SBE-β-CD] ) 8.58 × 10-3 M and is in agreement with the influence of salts on the micellization process.25 The balance between the decrease in the cmc due to the addition of salts

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TABLE 3: Values of the Fitted Parameters, Eq 3, Obtained from the Study of the Influence of TTABr Concentration on kobs for Solvolysis of MBSC in Cyclodextrin:TTABr Mixed Systems at 25.0 °C kCD/s-1

-1 KCD s /M

-1 Km s/M

km/s-1

(1.43 ( 0.03) × 10-4 (1.43 ( 0.03) × 10-4 (1.43 ( 0.03) × 10-4 (1.43 ( 0.03) × 10-4 (1.43 ( 0.03) × 10-4 (1.43 ( 0.03) × 10-4 (1.43 ( 0.03) × 10-4 (6.2 ( 0.1) × 10-5 (6.2 ( 0.1) × 10-5 (6.2 ( 0.1) × 10-5 (6.2 ( 0.1) × 10-5 (6.2 ( 0.1) × 10-5 (6.2 ( 0.1) × 10-5 (6.2 ( 0.1) × 10-5

(1.89 ( 0.01) × 103 (1.8 ( 0.3) × 103 (1.89 ( 0.01) × 103 (1.86 ( 0.08) × 103 (1.89 ( 0.01) × 103 (1.95 ( 0.08) × 103 (1.88 ( 0.05) × 103 (3.04 ( 0.04) × 103 (2.7 ( 0.3) × 103 (3.04 ( 0.04) × 103 (2.8 ( 0.2) × 103 (3.04 ( 0.04) × 103 (3.1 ( 0.1) × 103 (2.9 ( 0.2) × 103

(3.8 ( 0.2) × 102 (3.38 ( 0.16) × 102 (3.7 ( 0.1) × 102 (3.38 ( 0.16) × 102 (3.3 ( 0.2) × 102 (3.38 ( 0.16) × 102 (3.5 ( 0.2) × 102 (2.8 ( 0.1) × 102 (3.38 ( 0.16) × 102 (2.6 ( 0.1) × 102 (3.38 ( 0.16) × 102 (2.1 ( 0.2) × 102 (3.38 ( 0.16) × 102 (2.9 ( 0.5) × 102

(1.4 ( 0.1) × 10-4 (1.51 ( 0.11) × 10-4 (1.59 ( 0.08) × 10-4 (1.51 ( 0.11) × 10-4 (1.3 ( 0.2) × 10-4 (1.51 ( 0.11) × 10-4 (1.5 ( 0. 2) × 10-4 (1.1 ( 0.2) × 10-4 (1.51 ( 0.11) × 10-4 (1.1 ( 0.1) × 10-4 (1.51 ( 0.11) × 10-4 (8 ( 2) × 10-5 (1.51 ( 0.11) × 10-4 (1.2 ( 0.3) × 10-4

[CDT]/M 5.22 × 10-4 5.22 × 10-4 1.71 × 10-3 1.71 × 10-3 7.84 × 10-3 7.84 × 10-3 mean values SBE-β-CDa 6.01 × 10-4 SBE-β-CDb 6.01 × 10-4 SBE-β-CDa 1.93 × 10-3 SBE-β-CDb 1.93 × 10-3 SBE-β-CDa 8.58 × 10-3 SBE-β-CDb 8.58 × 10-3 mean values β-CDa β-CDb β-CDa β-CDb β-CDa β-CDb

a

KS/M-1 (49.5 ( 0.5) × 103 (49.5 ( 0.5) × 103 (49.5 ( 0.5) × 103 (49.5 ( 0.5) × 103 (62 ( 1) × 103 (62 ( 1) × 103 (62 ( 1) × 103 (62 ( 1) × 103

[CDf] obtained by the calibration procedure (eq 4). b [CDf] obtained from the binding constants, eq 9.

TABLE 4: Values of the Fitted Parameters, Eq 3, Obtained from the Study of the Influence of SDS Concentration on kobs for Solvolysis of MBSC in Cyclodextrin-SDS Mixed Systems at 25.0 °C kCD/s-1

-1 KCD s /M

-1 Km s /M

km/s-1

(1.43 ( 0.03) × 10-4 (1.43 ( 0.03) × 10-4 (1.43 ( 0.03) × 10-4 (1.43 ( 0.03) × 10-4 (1.43 ( 0.03) × 10-4 (1.43 ( 0.03) × 10-4 (1.43 ( 0.03) × 10-4 (6.2 ( 0.1) × 10-5 (6.2 ( 0.1) × 10-5 (6.2 ( 0.1) × 10-5 (6.2 ( 0.1) × 10-5 (6.2 ( 0.1) × 10-5 (6.2 ( 0.1) × 10-5 (6.2 ( 0.1) × 10-5

(1.89 ( 0.01) × 103 (1.71 ( 0.09) × 103 (1.89 ( 0.01) × 103 (1.8 ( 0.2) × 103 (1.89 ( 0.01) × 103 (17.7 ( 0.8) × 102 (1.8 ( 0.2) × 103 (3.04 ( 0.04) × 103 (3.49 ( 0.14) × 103 (3.04 ( 0.04) × 103 (3.06 ( 0.10) × 103 (3.04 ( 0.04) × 103 (2.86 ( 0.09) × 103 (3.1 ( 0.2) × 103

216 ( 4 227 ( 4 172 ( 14 227 ( 4 181 ( 10 227 ( 4 205 ( 25 112 ( 6 227 ( 4 206 ( 5 227 ( 4 162 ( 8 227 ( 4 192 ( 47

(5.3 ( 0.4) × 10-5 (6.16 ( 0.33) × 10-5 (4 ( 2) × 10-5 (6.16 ( 0.33) × 10-5 (3 ( 2) × 10-5 (6.16 ( 0.33) × 10-5 (5 ( 1) × 10-5 (5.9 ( 0.6) × 10-5 (6.16 ( 0.33) × 10-5 (5.5 ( 0.5) × 10-5 (6.16 ( 0.33) × 10-5 (2.8 ( 0.9) × 10-5 (6.16 ( 0.33) × 10-5 (5.3 ( 1.3) × 10-5

[CDT]/M 5.22 × 10-4 5.22 × 10-4 1.71 × 10-3 1.71 × 10-3 7.84 × 10-3 7.84 × 10-3 mean values SBE-β-CDa 6.01 × 10-4 SBE-β-CDb 6.01 × 10-4 SBE-β-CDa 1.93 × 10-3 SBE-β-CDb 1.93 × 10-3 SBE-β-CDa 8.58 × 10-3 SBE-β-CDb 8.58 × 10-3 mean values β-CDa β-CDb β-CDa β-CDb β-CDa β-CDb

a

KS/M-1 (23.0 ( 0.5) × 103 (23.0 ( 0.5) × 103 (23.0 ( 0.5) × 103 (23.0 ( 0.5) × 103 (5.2 ( 0.1) × 103 (5.2 ( 0.1) × 103 (5.2 ( 0.1) × 103 (5.2 ( 0.1) × 103

[CDf] obtained by the calibration procedure (eq 4). b [CDf] obtained from the binding constants, eq 9.

TABLE 5: Results Based on the Concentration of Uncomplexed Cyclodextrin in Equilibrium with TTABr Micelles Derived from Eq 11 for Different Concentrations of β-CD and SBE-β-CD [β-CD]/M 5.22 ×

10-4

1.71 ×

10-3

[SBE-β-CD]/M 7.84 ×

10-3

cmcapp/M (kobs)max/s-1 % CDf

3.1 × 10-3 6.00 × 10-3 4.8

4.3 × 10-3 5.83 × 10-3

TTABr 9.0 × 10-3 3.60 × 10-3

cmcapp (kobs)max % CDf

7.7 × 10-3 6.04 × 10-3 2.0

9.0 × 10-3 5.93 × 10-3

SDS 1.2 × 10-2 4.70 × 10-3

and the increase in cmc due to complexation of monomers by cyclodextrin will be the cause of the experimental behavior observed. With the anionic surfactant, SDS, we obtain similar results. The cmc shifts to lower values in the presence of small surfactant concentration, going from cmc ) 7.0 × 10-3 M in the absence of CD to cmc ) 6.5 × 10-3 M when [SBE-β-CD] ) 6.01 × 10-4 M and cmc ) 6.7 × 10-3 M when [SBE-βCD] ) 1.93 × 10-3 M, but the cmc value increases to 1.02 × 10-2 M when [SBE-β-CD] ) 8.58 × 10-3 M, because of the increase in the [Na+]. 2. Evidence of Uncomplexed Cyclodextrin in Equilibrium with the Micellar System. A second aspect that should be remarked is the kobs value in the maximum of the plot kobs versus surfactant concentration. This value is lower than the value obtained in bulk water and is due to the presence of uncomplexed cyclodextrin at the micellization point. As can be seen from Figures 4 and 5, the difference between these values

10-4

6.01 ×

1.93 × 10-3

8.58 × 10-3

1.0 × 10-3 5.68 × 10-3 3.7

2.4 × 10-3 4.97 × 10-3

8.9 × 10-3 2.51 × 10-3

6.5 × 10-3 5.50 × 10-3 8.0

6.7 × 10-3 4.35 × 10-3

1.0 × 10-2 1.90 × 10-3

increases along with the total concentration of cyclodextrin present in the medium. Previous studies carried out in our laboratory26 indicate that the percentage of uncomplexed CD in equilibrium with the micellar system remains constant once the micellization process has begun, thus as the total cyclodextrin increases so does the concentration of uncomplexed cyclodextrin. As we previously described, eq 2 can be rearranged to obtain the values of free cyclodextrin (eq 4). To obtain these values, we used the experiments in which [β-CD]T ) 7.84 × 10-3 M because the differences between kobs in the maximum and kw are more important than in the cases where the concentration of cyclodextrin is lower. For SBE-β-CD we used the experiments in which [SBE-β-CD] ) 1.93 × 10-3 M. The differences between kobs and kw are 20% for TTABr and 40% for SDS. If [SBE-β-CD] ) 6.01 × 10-4 M the difference between these values will be lower and if [SBE-β-CD] )

New Insights in Cyclodextrin 8.58 × 10-3 M the value of kobs in the maximum will be too small, making difficult the determination of %CD free properly. In Table 5 we present the percentage of uncomplexed cyclodextrin obtained from a calibration procedure. These results are in good agreement with those obtained from a simulation process (eq 9). The comparison of the results presented in Table 5 allows us to study the possibility of changes in the %CDfree as the nature of cyclodextrin and surfactant varies. (A) Variation of CDf with the Nature of Surfactant. The %βCD free in equilibrium with SDS micelles (2%) is lower than the %β-CD free in the presence of TTABr micelles (4.8%). Contrary to intuition, an increase in the hydrophobity of the surfactant gives rise to an increase in the percentage of uncomplexed cyclodextrin. Thus, when the chain length of the surfactant increases, its affinity to complex with the CD also increases but simultaneously its tendency to micellize increases. So although both processes are enhanced with the hydrophobic character, the micellization is the predominant factor. It is important to point out that the percentage of uncomplexed β-CD (4.8%) is lower than the 9% value obtained previously[26b] for β-CD:TTABr systems. Previous studies were carried out in the presence of [NaOH] ) 0.16 M, increasing the tendency of TTABr to micellize and increasing the percentage of uncomplexed cyclodextrin. (B) Variation of Uncomplexed CD with the Nature of Cyclodextrin. The percentage of uncomplexed CD in equilibrium with the SDS micelles is lower for the systems formed by β-CD (2%) than by SBE-β-CD (8%) but the opposite behavior is observed when the surfactant is TTABr (4.8% with β-CD and 3.7% with SBE-β-CD). The balance between two processes, an increase in the tendency to micellize due to the added salt and the change in the ability of CD to complex the surfactant, can explain the experimental results. As we have discussed previously, the increase in the [Na+] in the medium produced by the addition of SBE-β-CD shifts the cmc to lower values increasing the percentage of uncomplexed SBE-β-CD. On the other hand, the SBE-β-CD presents a greater tendency toward formation of CD-Surfactant complexes with TTABr than with SDS, as can be seen from the values of association constant of surfactant by cyclodextrin. SBE-β-CD Thus, KSDS ) (5.2 ( 0.1) × 103 M-1 is lower than β-CD KSDS ) (23.0 ( 0.5) × 103 M-1 due to the electrostatic repulsion between the anionic headgroup of SDS and the anionic moiety of the CD. The opposite behavior is observed with TTABr because of the electrostatic attraction established, so SBE-β-CD KTTABr ) (62 ( 1) × 103 M-1 is higher than Kβ-CD TTABr ) (49.5 ( 0.5) × 103 M-1. In the presence of SDS, both the added salt and the lower association constant favors [SBE-β-CD]free > [β-CD]free. In the presence of TTABr, the lower percentage of uncomplexed SBE-β-CD is determined by the higher association constant, which is the predominant factor over the increase in the [Na+]. Therefore, the results obtained show that the change in the charge of cyclodextrin produces also a change in the interactions surfactant-cyclodextrin prior to and at the micellization point. 3. Are There Interations between Cyclodextrin and Micelles? The results obtained clearly show that the interaction cyclodextrin-surfactant depends on the nature of cyclodextrin for surfactant concentrations prior to the micellization point. Our aim is to analyze if this behavior is kept beyond the micellization point, that is, if some kind of interaction exists between the micelle and the cyclodextrin once the micelle has been formed. One should expect a different interaction between SBE-β-CD and TTABr and SDS micelles due to the ionic

J. Phys. Chem. B, Vol. 111, No. 44, 2007 12763

Figure 7. Micellar parameters, Km s y km, obtained from studies without cyclodextrin and in mixed systems.

character of the cyclodextrin. In addition, this interaction should be different from the one between β-CD and the micellar aggregates previously mentioned. To shed light on this question, we analyze the values obtained for the binding constant of MBSC to the micelle, Km s , as well as the micellar rate constant, km, in the presence of both cyclodextrins. These parameters show high sensitivity to the micellar aggregate structure. Thus, Km s is related to the hydrophobic character of the micelle so that the value obtained for TTABr is higher than the one obtained for SDS micelles (see Table 1). On the other hand, km depends on the polarity of the medium, as has been shown from studies carried out in solvent mixtures20 (as an example, the rate constant value is around 700 times less from water to 90% acetonitrilewater). Furthermore, km depends on the micelle surface charge so that the quotient k+/k- results k+/k-) 2.45 comparing TTABr and SDS. Therefore, if there was any interaction between micelles and cyclodextrin, it should be reflected on Km s and km. The results shown in Tables 3 and 4 for the different mixed systems indicate that there is no dependence between Km s and km values and the nature of cyclodextrin as well as its concentration, so we can obtain an average value for these parameters. In addition, we can observe from Figure 7 that these values are essentially the same in the presence or in the absence 2 -1 and k ) of cyclodextrin, thus, Km m s ) (3.38 ( 0.16) × 10 M -4 -1 (1.51 ( 0.11) × 10 s for TTABr micelles and Km s ) (2.27 ( 0.04) × 102 M-1 and km ) (6.16 ( 0.33) × 10-5 s-1 for SDS micelles, obtained in single systems, are compatible with those obtained in mixed systems and support the view that micelles and cyclodextrins coexist without interactions between each other. Conclusions From our study in aqueous mixtures of cyclodextrin and surfactant carried out with anionic and cationic surfactants as well as neutral and anionic cyclodextrins, we can conclude that there is no interaction between them once the micelles have been formed. The anionic character of SBE-β-CD has an important influence over the association constant of SDS and TTABr if we compare with β-CD. Thus, the association constant for SDS increases from (5.2 ( 0.1) × 103 to (23.0 ( 0.5) × 103 M-1 going from SBE-β-CD to β-CD but for TTABr the association constant decreases from (62 ( 1) × 103 to (49.5 ( 0.5) × 103 M-1 from SBE-β-CD to β-CD. However, this electrostatic

12764 J. Phys. Chem. B, Vol. 111, No. 44, 2007 interaction has no effect over the binding constant of MBSC to the micelles, Km s , and the micellar rate constant, km, in the presence of cyclodextrins. Acknowledgment. Financial support from Ministerio de Educacio´n y Ciencia (Spain, Project CTQ2005-04779) and Xunta de Galicia (PGIDT03-PXIC20905PN and PGIDT04TMT209003PR) is gratefully acknowledged. M.M. thanks Ministerio de Educacio´n y Ciencia for a FPU fellowship. Supporting Information Available: Tables showing the observed rate constants for the different surfactant-cyclodextrin mixtures are reported. Figures showing the influence of surfactant concentration on the surface tension of the systems. This material is available free of charge via the Internet at http:// pubs.acs.org. References and Notes (1) (a) Bender, M.; Komiyama, M. Cyclodextrin Chemistry; SpringerVerlag: New York, 1978. (b) Saenger, W. Angew. Chem., Int. Ed. Engl. 1980, 19, 344. (c) Fendler, J. H.; Fendler, E. J. Catalysis in Micellar and Macromolecular Systems; Academic Press: New York, 1975. (d) Coleman, A. W.; Nicolis, I.; Keller, N.; Dalbiez, J. P. J. Incl. Phenom. Mol. Recognit. Chem. 1992, 13, 139. (2) (a) Sanemasa, I.; Akamine, Y. Bull. Chem. Soc. Jpn. 1987, 60, 2059. (b) Fujiki, M.; Deguchi, T.; Sanemasa, I. Bull. Chem. Soc. Jpn. 1988, 61, 1163. (c) Sanemasa, I.; Takuma, T.; Deguchi, T. Bull. Chem. Soc. Jpn. 1989, 62, 3098. (3) Jobe, D. J.; Reinsborough, V. C.; Wetmore, S. C. Langmuir 1995, 11, 2476. (4) Utsuki, T.; Brem, H.; Pitha, J.; Loftsson, T.; Kristmundsdottir, T.; Tyler, B. M.; Olivi, A. J. Controlled Release 1996, 40, 251. (5) Nicolle, G. M.; Merbach, A. E. Chem. Commun. 2004, 854. (6) Valente, A. J. M.; Nilsson, M.; Soderman, O. J. Colloid Interface Sci. 2005, 281, 218. (7) Palepu, R.; Richardson, J. E.; Reinsborough, V. C. Langmuir 1989, 5, 218. (8) Rafati, A. A.; Bagheri, A.; Iloukhani, H.; Zarinehzad, M. J. Mol. Liq. 2004, 116, 37. (9) Junquera, E.; Gonzalez Benito, J.; Pena, L.; Aicart, E. J. Colloid Interface Sci. 1994, 163, 355.

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