Experimental Thermodynamics and Molecular Mechanics

May 22, 1999 - Jose Manuel Madrid, Marisol Villafruela, Roberto Serrano, and Francisco ... Departamento de Quı´mica Fı´sica, UniVersidad de Alcala...
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J. Phys. Chem. B 1999, 103, 4847-4853

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Experimental Thermodynamics and Molecular Mechanics Calculations of Inclusion Complexes of 9-Methyl Anthracenoate and 1-Methyl Pyrenoate with β-Cyclodextrin Jose Manuel Madrid, Marisol Villafruela, Roberto Serrano, and Francisco Mendicuti* Departamento de Quı´mica Fı´sica, UniVersidad de Alcala´ , 28871 Alcala´ de Henares, Madrid, Spain ReceiVed: September 22, 1998; In Final Form: February 23, 1999

Steady-state fluorescence and molecular mechanics calculations were used to study the inclusion complexes of 9-methyl anthracenoate (MA) and 1-methyl pyrenoate (ΜP) with β-cyclodextrin (βCD). Binding constants of 1:1 complexes at different temperatures were obtained from the analysis of the fluorescence enhancement of the βCD solutions with respect to the MA or MP free chromophores. The thermodynamic parameters ∆H and ∆S were also obtained. Molecular mechanics calculations were applied to study both inclusion processes in vacuo and in the presence of water as a solvent. Complexation is mainly due to nonbonded van der Waals host-βCD interactions. Both MA and MP penetrate only partially into the βCD cavity.

Introduction Cyclodextrins (CDs) are torus-shaped cyclic oligosaccharides formed by glucopyranose units joined by R-(1,4)-linkages. One of the most important characteristics of CDs is the formation of inclusion complexes with a variety of low molecular weight compounds1-3 and polymers.4-11 Complex formation depends on the polarity and size of the guest molecule relative to the inner cavity of the host CD. Stoichiometry, binding constants, and thermodynamics parameters on the complexation can be obtained by using several techniques including fluorescence spectroscopy.12-36 Upon inclusion of a fluorophore, CDs generally enhance the luminescence of the guest molecule by shielding it from quenching and nonradiative decay processes. Molecular mechanics modeling37-47 (MM) and molecular dynamics48,49 (MD) simulations can also be useful to strengthen the understanding of inclusion phenomena of small and large molecules. We recently used steady-state fluorescence and MM calculations to study inclusion complexes of 2-methylnaphthoate (MN) with R-, β-,47,50 and γCDs.51 From the ratio of two bands very sensitive to medium polarity, formation constants of 1:1 complexes at different temperatures were obtained. The estimated formation constants at 25 °C were 200 ( 20, 1965 ( 160, and 213 ( 96 M-1 for R-, β-, and γCDs, respectively. The MN/RCD complexation had a larger negative enthalpy change than the MN/βCD and in turn was larger than MN/γCD complexations. Therefore, the MN/RCD complexation was accompanied by a large entropy decrease, whereas the MN/ βCD and MN/γCD complexations each had smaller absolute values but similar entropy increase. Molecular mechanics (MM) studies on MN and R-, β-,47 and γCD51 inclusion complexes in vacuo and in the presence of water molecules, using the Tripos force field52 supplied with Sybyl 6.2,53 were also conducted. Nonbonded van der Waals interactions between MN and CD were the main forces of complexation. Inclusion processes were also accompanied by an increase in the strain of the CD macroring, which becomes larger as the CD cavity decreases. Structures of minima binding energies indicate that MN totally penetrates into the β- and γCD cavities, but it makes only a slight penetration into the cavity of the RCD. This selective ability to insulate MN from the solvent allows for the explana-

tion of the signs of ∆S upon binding, which is consistent with the fluorescence anisotropy and quenching measurements of these systems. In this work, we report steady-state fluorescence spectroscopy and MM calculations in vacuo, as well as in water, to study the complexation of 9-methyl anthracenoate (MA) and 1-methyl pyrenoate (ΜP) with β-cyclodextrin (βCD). Computational results are used to explain the experimental thermodynamics and to determine the geometry and forces responsible for such complexation. Experimental Part Materials. 9-Methyl anthracenoate (MA) and 1-methyl pyrenoate (ΜP) preparation and purification were described previously by us.54,55 βCD (Aldrich) was purified by double recrystallization from distilled and deionized water (Milli-Q water system). Water was checked for impurities by fluorescence before using. Guest/βCD water solutions were prepared by using saturated MA and MP solutions, which were obtained by keeping an oversatured solution of MA (or MP) in an ultrasonic bath at 60 °C for ∼6 h followed by cooling and double filtration by using 0.45 µm nylon membrane filters (Gelman Sci. Inc.). Guest/βCD water solutions were prepared by weight in their own quartz cuvettes and then sealed with Teflon stoppers. All samples were stirred in their own cuvettes for 48 h before measuring. Concentrations used ranged from 0 to approximately 10 mM. Guest concentration was held constant in all experiments (∼10-5 M). Fluorescence Measurements. Steady-state fluorescence measurements were performed by using an SLM 8100 AMINCO spectrofluorometer equipped with a cooled photomultiplier and a double monochromator in the excitation path. Slit widths were 8 nm for excitation and emission. The temperature equilibration of the cell housing (1 cm path quarz cells) was achieved by using a Techne RB-5 bath and a circulator (Techne TE-8A). Excitation wavelengths were 364 and 359 nm for MA and MP solutions, respectively. Polarizers were set at the magic angle conditions for obtaining emission spectra. All measurements were performed in the range of temperatures from 5 to 45 °C at 10 °C intervals.

10.1021/jp9838240 CCC: $18.00 © 1999 American Chemical Society Published on Web 05/22/1999

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Figure 1. Corrected emission spectra for aqueous solutions of guest and βCD at 25 °C: (a) guest ) MA, λexc) 364 nm, and from bottom to top concentrations of βCD (mM) are 0 (0), 0.08 (1), 0.12 (2), 0.16 (3), 0.20 (4), 0.80 (5), 4.0 (6), 8.0 (7), and 12.0 (8); (b) guest ) MP, λexc) 359 nm, and from bottom to top concentrations of βCD (mM) are 0 (0), 0.86 (1), 1.58 (2), 2.86 (3), 4.98 (4), 6.45 (5), 7.87 (6), and 8.91 (7).

Excitation spectra for MA and MP, which are very similar to absorption spectra, were reported previously.54,55 Figure 1 depicts the corrected emission spectra of MA and MP host molecules in water and in aqueous βCD solutions at different βCD concentrations at 25 °C. Spectra for MA and MA + βCD water solutions depicted on the left side in Figure 1 show a wide single band whose maxima is shifted monotonically to the blue when the βCD concentration is increased from ∼485 nm in the absence of βCD to ∼460 nm at the maximum βCD concentration used in our experiments. Spectra for MP in water, depicted in the group of spectra on the right in Figure 1, show a single band whose maximum is centered at ∼415 nm. As the βCD concentration increases, a new peak appears at ∼392 nm. The intensity of this peak increases monotonically with the βCD concentration. However, the most important characteristic of both groups of spectra is the fluorescence enhancement with the βCD concentration. This fluorescence enhancement associated with the complexation process of a guest chromophore with CDs is usually ascribed mainly to the compartmentalization and shielding of the excited singlet species from quenching and nonradiative decay processes that take place in bulk solution. Over the whole βCD concentration range measured, there is no evidence of a broadening of the MA or MP monomer bands that could indicate the presence of excimer emission in any of the cases. The lack of excimer emission obviously indicates that at least simultaneous inclusion of two host molecules in a βCD can be disregarded. This fluorescence enhancement upon CD addition is quantified by the integrated fluorescence emission ratios I/I0, in the presence and in the absence of βCD as a function of the βCD concentration for both MA and MP as depicted in Figure 2, at different temperatures. The fact that much larger βCD concentrations, more than the limit depicted in Figure 2, are needed to reach constant values of I/I0 for MP than for MA suggests lower binding constants for MP/βCD complexes than for the MA/ βCD ones. Thermodynamic Parameters. For a simple one-to-one guest/ CD complexation, the equilibrium can be written as

guest + CD ) guest/CD

(1)

Substituting the mass balance for guest and CD and assuming that [CD]0 . [guest/CD], the molar fraction of complexed guest

Figure 2. Integrated fluorescence emission ratios I/I0 in the presence (I) and in the absence (I0) of βCD of guest molecules MA (top) and MP (bottom) vs βCD molar concentrations at different temperatures 5 °C (9), 15 °C (b), 25 °C (2), 35 °C (1), and 45 °C ([). Lines are the adjustments of the experimental points to eq 5.

f2 can then be defined as

K[CD]0 [guest/CD] ) [guest]0 1 + K[CD]0

(2)

where the “0” subscript indicates initial concentrations and K the association constant for the 1:1 complexation process outlined by eq 1. The integrated fluorescence emission I can be expressed in terms of molar fractions of uncomplexed (f1) and complexed (f2) forms as

I ) G[kf1Φ0 + f2Φ]

(3)

where G is a constant depending on the chromophore concentration and other instrumental conditions, and Φ0 and Φ are the emission quantum yields of uncomplexed and complexed species, respectively. Furthermore, we can assume not only that the complexed form has a quantum yield different from the uncomplexed one but also that the free guest is affected by interactions with free and complexed CDs.20 A quantum yield change is predicted for free guests in the CD solutions. We designate k as the factor for this quantum yield change. In the absence of CD eq 3 becomes

I0 ) GΦ0 (4)

(4)

With the division of eq 3 by eq 4 and the substitution of eq 2, the following expression can be derived:

I k + (Φ/Φ0)K[CD] ) I0 1 + K[CD]

(5)

A nonlinear regression program56 was used to fit I/I0 experimental data to eq 5 in a reasonable manner. The solid lines depicted in Figure 2 are the results of this adjustment.

Inclusion Complexes with β-Cyclodextrin

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TABLE 1. Equilibrium Constants 10-1K (M-1 Units), as Well as Their Absolute Errors for the Inclusion Complexes MA and MP with βCD at Five Different Temperatures, Determined by Using the Nonlinear Regression Adjustments from Eq 5 guest

5 °C

15 °C

25 °C

35 °C

45 °C

MA MP

50 ( 19 5.7 ( 3.1

34 ( 12 3.5 ( 4.5

19 ( 10 3.4 ( 4.8

25 ( 0.9 2.3 ( 5.4

17 ( 0.9 1.9 ( 5.6

TABLE 2: Variation of Enthalpies, Entropies, and Absolute Errors for the Formation of the 1:1 Complexes of MN, MA, and MP with βCD, Determined by Using the Classical van’t Hoff Plot

Table 1 collects the estimated binding constants K for the 1:1 inclusion complex formation of MA and MP with the βCD at different temperatures. Values of Φ/Φ0 for MA and MP complexation processes are ∼1.8 and ∼7.0, respectively. Factors k are close to 1, ∼1.03, and ∼0.92 for MA and MP complexation processes, respectively, at any temperature. Values of K collected in Table 1 for the MA/βCD and MP/ βCD are accompanied by larger experimental errors than those obtained by measuring intensity ratios of bands sensitive to medium polarity for MN/βCD.50 At 25 °C the binding constants K for both complexes of MA and MP are 187 ( 99 and 34 ( 48 M-1, lower than the ones for MN/βCD of 1965 ( 160 M-1.50 The relatively low association constant of both complexes, especially the MP/βCD, makes it difficult to reach the plateau region in Figure 2 because of solubility problems. This introduces large uncertainties in determining the K values for this complex. However, the stability of the 1:1 inclusion complexes of these three guest molecules with the βCD apparently decreases by a factor of 10 when the size of the chromophore is increased. Any attempt at adjusting the experimental data according to the proper equation to a 1:2 (guest/ CD) stoichiometry resulted in a strongly deviating error between the experimental data and the calculated fitting. Results reported for binding constants for the formation of the 1:1 pyrene/βCD complex exhibit a marked difference, ranging from 7.6 to 277 M-1.18-21,26,57,58 Other authors,21,27,29,59,60 however, found that in addition to a 1:1 pyrene/βCD complex, another one with a 1:2 stoichiometry is also formed at higher βCD concentrations. A single report demonstrates that by use of reversed-phase liquid chromatography, anthracene guests form a 1:1 complex with the βCD, with binding constants in mobile-phase mixtures of methanol water that vary from 373 to 136 M-1.60 The enthalpies and entropies were obtained via the classical van’t Hoff linear plots depicted in Figure 3. This figure also includes data from the MN complex with βCD.50 The thermodynamic parameters ∆H and ∆S are also collected in Table 2. The complexation of MN,50 MA, and MP with the βCD is accompanied by a similar negative enthalpy change being ∆HMN/βCD e ∆HMA/βCD e ∆HMP/βCD. The nearly parallel van’t

∆H, kJ mol-1

∆S, J K-1 mol-1

MNa

-15.1 ( 1.5 -18.1 ( 5.3 -19.1 ( 2.3

+11.8 ( 4.9 -14.5 ( 17.8 -35.8 ( 8.0

MA MP a

Figure 3. van’t Hoff plots of ln K vs T-1 for the formation of MA/ βCD (9) and MP/βCD (b), along with the data of MN/βCD (2) obtained from ref 47.

guest

Data obtained from ref 47.

Hoff lines obtained indicate that the entropy change upon complexation of three esters with a βCD is mainly responsible for the difference of stability of such complexes. ∆S values accompanying MA/βCD and MP/βCD complexations are negative. In a manner similar to the inclusion process of an small guest (MN) into a relative smaller cavity (RCD),50 the complexation of two larger MA and MP guests with βCD, are unfavored entropically. This fact differs from the inclusion process of a smaller guest (MN) into a relatively large cavity such as β- or γCD, which can penetrate into the CD cavities, making the process entropically favored.50,51 Molecular Mechanics Calculations Computer Methods. The calculations in vacuo and in water as a solvent were performed with Sybyl 6.353 and the Tripos force field.54 Computational methods are similar to the ones described previously.47,51 Geometry and charges of βCD and water molecules were obtained by MOPAC,61 and they were also used earlier.47,62 MA and MP geometries and charges were also obtained by MOPAC.61 The potential energy of a molecule was considered as the sum of bond stretching, angle bending, torsional, van der Waals, electrostatics, and out-of-plane interactions. A relative permittivity of 3.5 was used for electrostatics interactions in vacuo and a distance-dependent dielectric constant in the presence of water as solvent. Extended nonbonded cutoff distances were set at 8 Å for van der Waals and electrostatics interactions. Minimization was performed by the simplex algorithm63,64 and the conjugate gradient as a termination method (0.2 and 3.0 for the calculations performed in vacuo and in water, respectively). Aqueous solvation was attempted by using the Molecular Silverware65 algorithm (MS). Periodic boundary conditions were employed using a cubic box with average sides of 32.14 and 32.16 Å for MA/βCD and MP/βCD, respectively. Complexation Process. Schemes and coordinate systems used to define the complexation processes for two MA and MP approaches are depicted in Figure 4. The origin of the Cartesian coordinate system was placed at the center of mass of the oxygens of the primary and secondary hydroxyl groups of the βCD. The y axis passes through the centroids of both sides of the CD torus, as Figure 4 depicts. The yz plane contains one of the glycosidic oxygen atoms. For the complexation process the βCD is kept in this position while the guest molecule approaches by small steps the wider edge of the CD torus along the y axis. The structures generated at each step are then optimized, allowing them to change from the initial conformations. The ester group and the aromatic ring are initially placed perpendicular, and the torsional angles Car-CO-O-CH3 are initially in the trans state (180°) for both MA and MP guests. After optimization the ester group comes slightly closer to planarity with the aromatic ring (∼60 ( 10°). The βCD was constructed, as previously,47,62 in a nondistorted form. The host/guest distance was measured from the origin O to the centroid O′ along the y axis and the orientation of the guest relative to the host by the

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Figure 4. Coordinate system used to define the complexation process and the scheme for the approaches of the guests MA and MP to βCD, which gives the minima Ebinding structures. These approaches are denoted as MA3 and MP4 in the manuscript.

Figure 5. Schemes and nomenclature for different guest-to-host approaches by changing the orientation of MA and MP guests relative to the βCD host.

Madrid et al. θ angle between yz and the aromatic group planes. Besides the guest-to-host approaches depicted in Figure 4, other MA and MP to βCD approaches were considered. Figure 5 depicts different approaches, as well as the notation used for each of them. Different energies and contributions were calculated for each structure generated upon changing the host/guest distance and optimization. Nonbonded βCD/guest interactions, named Ebinding, were obtained as the difference between the potential energy of the guest/CD system and the sum of the potential energies of the isolated guest and βCD molecules in the same structure. Each contribution to the binding energy was calculated in a similar manner. The loss or gain of the guest/CD, CD macroring, or guest potential energies or any of their contributions can be evaluated as the difference of the potential energy of each guest/ CD, CD, or guest, respectively, for the structure corresponding to the minimum Ebinding and the one obtained at large hostguest distance (i.e., Ebinding ≈ 0). The influence of the solvent was obtained by the difference of the total potential energy of the whole system Eguest/CD+water and the energy of water molecules Ewater contained in the solvent box plus the potential energy of the system guest/CD. Complexation in Vacuo. To attain the most favorable path of approach of the guest molecule, 3-D plots of Ebinding vs θ and y coordinate for all the optimized structures were obtained. The procedure was carried out by scanning θ and the coordinate y from 0° to 60° at 5° intervals and from 16 to -2 at 2 Å intervals, respectively. Figure 6 depicts 3-D plots and trajectories that lead to the minimum Ebinding defined by a θmin ) 25° and θmin ) 45° for MA3 and MP4 approaches depicted in Figures 4 and 5. Other guest-to-host approaches depicted in Figure 5 give θmin of 20° for MA1 and MA2, 40° for MP1 and MP2, and 45° for MP3. In the remainder of this work, calculations were performed on the basis of the guest-to-βCD approach where the y coordinate is changed and θ is initially placed at θmin. Figure 7 depicts Ebinding for the optimized structures obtained by changing the y coordinate of each guest molecule from 16 to -2 at 0.5 Å intervals for the trajectory of θmin. The energy of any of the systems studied decreases when the guest approaches the βCD host up to an optimum value of y. Results suggest that the complexation processes are energetically favorable. However, the minimum Ebinding structures are reached for MA3 and MP4 orientations, and they take place at approximately y ) 1.43 and 3.39 Å, respectively, for which an important portion of the MA and MP chromophores are outside

Figure 6. Three-dimensional plot of Ebinding vs θ and the distance (y in Å) between the host and the guest MA (left) and MP (right). The trajectory of θmin is highlighted. The y axis is a 7-fold rotation axis.

Inclusion Complexes with β-Cyclodextrin

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Figure 7. Ebinding vs y coordinate (Å) in vacuo for different schemes of approaching of MA and MP to βCD depicted in Figure 5.

Figure 8. van der Waals (*) and electrostatics (O) contribution to Ebinding (0) vs y coordinate (Å) in water for MA3 (top) and MP4 (bottom). The stars overlay most of the squares.

TABLE 3: EBinding and Selected Components at the Minimum Energy (Subscript min) at the Largest Separation of the Two Components (Subscript ∞) for MA3 and MP4 in Vacuo energy, kcal/mol Ebinding electrostatic part van der Waals part Etot for guest/βCD electrostatic part van der Waals part stretching + bending + torsion Etot for βCD electrostatic part van der Waals part stretching + bending + torsion Etot for guest electrostatic part van der Waals part stretching + bending + torsion

MA3min MA3∞ MP4min MP4∞ -18.8 -0.2 -18.6 110.3 54.9 -29.9 85.3 115.6 55.3 -14.4 74.7 13.5 -0.2 3.1 10.6

-0.0 -0.0 -0.0 125.8 54.0 -10.7 82.5 115.3 54.0 -13.4 74.7 10.4 -0.0 2.8 7.6

-18.9 -0.1 -18.5 107.5 56.4 -30.6 81.7 113.3 54.6 -14.8 73.5 13.2 2.2 2.8 8.2

-0.1 0.0 -0.1 125.8 56.1 -10.5 80.2 115.2 54.0 -13.6 74.8 10.6 2.1 3.2 5.3

the βCD cavity. Ebinding for these structures are very similar, -18.8 and -18.9 kcal/mol, respectively. Table 3 collects data of binding and potential energies for the guest/βCD complex, βCD, and guest and different contributions to the total energy at the minimum and at a host/guest separation of 16 Å, for MA3 and MP4. The van der Waals nonbonded host/guest contributions to Ebinding represent nearly 100% of the complex stabilization. The potential energy of the CD ring, as well as the sum of stretching, bending, and torsional energies upon complexation, does not make any favorable contribution to the stabilization of both complexes. Complexation in Water. As previously,47,51 the simulation used consists of the solvation of each structure generated by changing the coordinate y followed by a minimization (gradient 3.0). Complexation with any of the orientations is energetically favorable, with the most negative Ebinding again obtained for MA3 and MP4. Figure 8 depicts Ebinding and different contributions for the process of inclusion from the optimized structures

Figure 9. Views of the structure of minimum Ebinding in the presence of water for the MA/βCD (left side) and MP/βCD (right side) complexes.

obtained by scanning the y coordinate from +18 to -2 at 1 and 0.25 Å in the vicinity of the lowest binding energies for MA3 and MP4. The most stable structures are reached at y ) 3.32 Å (Ebinding ) -15.6 kcal/mol, θmin ) 29.8°) and at y ) 3.83 Å (Ebinding ) -11.9 kcal/mol, θmin ) 49.4°), respectively. As with calculations in the vacuo, considerable portions of MA and MP are on the exterior of the macrocycle and hence is exposed to the solvent. Figure 9 depicts a view of the MA/ βCD and MP/βCD complexes corresponding to the structures of the minimum binding energies, which is more negative for MA/βCD than for MP/βCD. As Figure 8 depicts, as in vacuo, van der Waals interactions are the most important contribution to the stabilization of the complexes formed in water. The most important components to the total energy are also summarized in Table 4 for both complexes. Most of the total potential energy of the complex is due to the βCD with stretching, bending, and torsion terms as the ones that contribute most to the total CD energy. Complexation, either of MA or MP, is accompanied by an increase in the potential energy of the CD, with the component due to stretching, bending, and torsion as the most important one. Complexation is carried out with a slight distortion of the βCD macroring.

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TABLE 4: EBinding and Selected Components at the Minimum Energy (Subscript min) at the Largest Separation of the Two Components (Subscript ∞) for MA3 and MP4 in Water energy, kcal/mol Ebinding electrostatic part van der Waals part Etot for guest/ βCD electrostatic part van der Waals part stretching + bending + torsion Etot for βCD electrostatic part van der Waals part stretching + bending + torsion Etot for guest electrostatic part van der Waals part stretching + bending + torsion

MA3min MA3∞ MP4min MP4∞ -15.6 -3.0 -12.5 175.3 51.4 9.6 114.3 157.4 52.2 15.1 90.1 33.5 2.3 7.1 24.1

-0.1 -0.0 -0.1 157.3 48.3 13.2 95.8 140.6 46.3 9.6 84.7 16.7 2.0 3.7 11.0

-11.9 -1.3 -10.6 160.7 52.2 -3.2 111.7 146.8 48.8 4.2 93.8 25.7 4.7 3.2 17.8

-0.1 0.0 -0.1 163.3 54.5 13.2 95.6 143.2 49.9 9.8 83.5 20.2 4.6 3.5 12.1

Figure 10. Interaction energy between water and the complex Eguest/CD-water for MA3 (b) and MP4 (O) approaches.

Figure 10 depicts the energy Eguest/CD-water, defined previously, as a function of the y coordinate. Guest-to-CD approaches are accompanied by an increase of this energy, which contributes to destabilize the system for any of the guest/ βCD complexes studied. This fact was observed by us47,51 and others41,48 in the study of other inclusion complexes. Since the minimum Ebinding for MA, MP, and MN47 complexes with βCD are reached at y ) 3.32, 3.86, and 0.15 Å, respectively, MA and MP do not penetrate totally into the βCD cavity, but MN does. The exposure of the guest to the solvent, which is larger for MP than for MA, could justify the experimental sign of the entropy, ∆S < 0 for MA and MP and ∆S > 0 for MN complexation, as well as the decrease of entropy for MP relative to MA. When part of the guest is exposed to the solvent, the positive entropy contribution from loss of its solvent shell is minimized and the loss in the rotational and translational degrees of freedom due to the host-guest association will define the sign of ∆S. Conclusions MA/βCD and MP/βCD complexes with stoichiometry 1:1 are thermodynamically stable. The MP/βCD stability constant at 25 °C is an order of magnitude smaller than the one for MA/ βCD and this one an order of magnitude smaller that the one for MN/βCD. Three complexes show similar negative enthalpy changes upon formation; however, the entropy change decreases with the size of the guest molecule, being negative for both MA and MP complexation and positive for the MN one. This fact reveals that entropy is more important than entalphy in determining the stability of these complexes. Molecular me-

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