Computational and Experimental Investigations of Supramolecular

(Clermont-Ferrand II), 24 aVenue des Landais, 63177 Aubie`re Cedex, France. ReceiVed: March 16, 2007; In Final Form: July 16, 2007. We report the stud...
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J. Phys. Chem. B 2007, 111, 11478-11485

Computational and Experimental Investigations of Supramolecular Assemblies of p-Sulfonatocalix[4]arene Organized by Weak Forces A. Ghoufi, L. Pison, J. P. Morel, N. Morel-Desrosiers, C. Bonal,* and P. Malfreyt Laboratoire de Thermodynamique des Solutions et des Polymeres, UMR CNRS 6003, UniVersite´ Blaise Pascal (Clermont-Ferrand II), 24 aVenue des Landais, 63177 Aubie` re Cedex, France ReceiVed: March 16, 2007; In Final Form: July 16, 2007

We report the study of the supramolecular assemblies formed by the incorporation of quaternary ammonium cations such as Me4N+ or Et4N+ into host-guest assemblies with p-sulfonatocalix[4]arene in the presence of a lanthanide(III) cation in water. We use microcalorimetry to characterize the formation of these supramolecular assemblies. We obtain a molecular description of these assemblies by performing molecular dynamics simulations over a very large period of time. The structures of these supramolecular complexes have been determined and discussed through specific interaction energy contributions. By combining MD simulations and 1NMR spectroscopy, we highlight a specific behavior of the supramolecular assembly with the Me4N+.

1. Introduction The study of host-guest complexation in an aqueous medium is of great importance because it provides an understanding of the chemistry in biological systems. In terms of actual and potential biological applications, the water-soluble p-sulfonated calixarenes have been the focus of considerable interest.1 In fact, they have been registered as antiviral agents,2 blockers of chloride ion channels,3 antithrombic agents,4 as well as inhibitors of lysyl oxidase activity.5 These macrocyclic compounds are also known to be able to form stable and selective complexes with ions and neutral molecules.6,7 A number of studies have been published about the factors controlling the thermodynamic and kinetic stability or selectivity of the resulting complexes.6,7 Depending on the nature of the host, the noncovalent interactions (hydrogen bonding, π-π, CH-π, cation-π, or cation-anion interactions) play a dominant role. Nature has exploited these interactions in biorecognition and biomolecular organization. For example, for the design of an enzyme model,8 the macrocyclic compounds should provide a hydrophobic binding site for the substrate and also should afford hydrogen binding and/ or electrostatic binding sites that are complementary to those of the substrate. Learning from biology, chemists develop highly complex chemical systems from components that interact via noncovalent intermolecular forces. In recent studies, we were interested in gaining an understanding of the complexation behavior of p-sulfonatocalix[n]arene with various organic and inorganic cations.9-11 As a result of our investigation, we obtained a full thermodynamic characterization of the formed complexes. We showed that the organic and inorganic cations bind in very different modes. To consider an association process involving strong electrostatic interactions, we were particularly interested in inorganic cations representative of the lanthanide series (La3+, Nd3+, Sm3+, Eu3+, Gd3+, Dy3+, and Yb3+).9,11 This study is also important in view of the increasing applications of lanthanide macrocyclic complexes.12 The thermodynamic results9,11 obtained by microcalorimetry revealed the formation of 1:1 complexes. For all * To whom correspondence should [email protected].

be

addressed.

E-mail:

lanthanide cations used, the association process is enthalpically unfavored and entropically favored (∆rH° > 0 and T∆rS° . 0) due to the partial desolvation of both the metal cation and the sulfonato groups of the ligand, which form an ionic bond outside of the cavity. We were also concerned by the association between p-sulfonatocalix[4]arene and quaternary ammonium cations (R4N+)9,11 and alkylammonium cations (RNH3+).9,10 This kind of complex is of particular interest from a biological viewpoint in line with the recognition between the neurotransmitter acethylcholine and acethylcholine esterase.13 With these cations, we also found the formation of 1:1 complexes. The process is essentially enthalpy-driven (∆rH° < 0 and T∆rS° < 0 or > 0), the association being governed by the inclusion of the alkyl groups within the cavity and the resulting van der Waals interactions. In fact, the entropy gain due to the desolvation of the species is almost compensated by the strong entropy loss upon inclusion, and as a result, the process is enthalpy-driven. We obtained additional information at a microscopic level using molecular dynamics simulations.14-16 The structures of the complexes determined from MD calculations were fully consistent with those deduced from the analysis of the experimental data. The MD calculations14-16 confirmed that the organic and inorganic cations bind in different modes. The lanthanide cations are located outside of the cavity of the calixarene, forming an outer-sphere complex, while for the R4N+ cations, the alkyl chains are totally or partially included into the cavity of the calixarene. In the case of the quaternary ammonium cations, these calculations also pointed out a correlation between the experimental ∆rH° values and the number of atoms inserted into the cavity of the calixarene. Furthermore, it was shown that the specific behavior of Et4N+, which exhibits remarkably negative enthalpy and entropy of binding, results from the inclusion of the largest number of atoms into the cavity accompanied by an important loss of degrees of freedom. Supramolecular chemistry is concerned with weak noncovalent interactions between two or more molecules. During the last 10 years, a concept of using noncovalent supramolecular interactions to build large molecular structures has emerged.17 Atwood et al.18 pioneered, in the solid state, the use of

10.1021/jp0721245 CCC: $37.00 © 2007 American Chemical Society Published on Web 09/13/2007

Supramolecular Assemblies of p-Sulfonatocalix[4]arene p-sulfonatocalix[4]arene in building-up structures that intercalate or absorb ions and small molecules. In fact, the same macrocycle can serve as a platform to form inorganic/organic clay-like materials that mimic naturally occurring clays. Structures of p-sulfonatocalix[4]arene revealed initially a bilayer arrangement with the calixarenes arranged in an up/down fashion. The bilayer arrangement is comprised of hydrophobic layers of adjacent calixarenes engaged in π-stacking interactions and a hydrophilic domain between these layers containing included water molecules, metal ions, and various organic molecules.19-24 In this context, we aim to investigate the species formed by combining the La3+ cation, p-sulfonatocalix[4]arene (Cal4-), and Me4N+ or Et4N+ cations in aqueous solution. While these systems can be used to gain an understanding of the nature and the strength of the interactions involved in the p-sulfonatocalixarene complexation, the assembly of such multicomponent arrays is of interest in itself. In an attempt to assess whether interactions take place between these various molecules, we initiate this work by microcalorimetry measurements. It is not possible to thermodynamically characterize the formation of these supramolecular assemblies in a reliable way from the direct microcalorimetric experiments using a competition method directly involving Cal4and the two competitor ligands (La+ and R4N+). In such conditions, several contributions must be considered, but it is not possible to evaluate the exact part of them. To simplify the binding model necessary to fit the heat effects, we use an indirect microcalorimetric method. This method takes advantage of involving only one equilibrium, the formation of a complex between the lanthanide cation (La3+) and the complexed organic anion (Cal4- + R4N+) previously prepared by association of Cal4- with R4N+ at a ratio sufficiently high to ensure full complexation. To clarify the results and to associate a microscopic description, we perform molecular simulations. The objectives of MD simulations are twofold; we aim to highlight the formation of supramolecular assemblies of calix[4]arene and to examine, in detail, the structures and the hydration properties of the species formed. For this purpose, we decide to perform MD simulations over a very large period of time (10 ns) compared to that used in previous simulations (1 ns). 1H NMR experiments on the supramolecular assemblies formed from Me4N+ and Et4N+ will provide further support to the description based on MD simulations. The outline of the paper is as follows. Section 2 describes the experimental part. Section 3 contains a description of the potential model and of the computational techniques we have used for the MD simulations. In section 4, we present the results of the MD simulations that we relate to the experimental data. Finally, in section 5, we draw the main conclusions from our work. 2. Experimental Section 2.1. Solutions. The 25,26,27,28-tetrahydroxy-5,11,17,23tetrasulfonic calix[4]arene hydrate was purchased from Acros Organics. The calix[4]arene was decolorized by adsorption on active carbon and dried under vacuum at 353 K. From Karl Fischer titration (Mettler Toledo DL 31), the hydration state of the calixarenes was found to be 16%. LaCl3‚6H2O was bought from Strem Chemicals (purity 99.9%) and was used as received. (CH3)4NBr (Merck, 99%) and (C2H5)4NBr (Fluka, 99%) were dried at 373 K, stored in a desiccator, and used without further purification. Stock solutions of the rare-earth salt, ∼0.1 mol kg-1, were analyzed for cation concentration by titration with Titriplex III (Merck) following classical methods. All of the

J. Phys. Chem. B, Vol. 111, No. 39, 2007 11479 solutions were prepared by weight from triply distilled water. The pKa values reported in the literature25-27 for the macrocycle indicate that, at pH 2, all of the sulfonate groups located on the upper rim are deprotonated. The charge of the macrocycle is then -4. 2.2. 1H NMR. 1H NMR spectra in D2O at 298 K were recorded with a Brucker-Avance 400 MHz spectrometer. The solvent peak (unaffected by the concentration variation of the host and guest) at 4.7 ppm was used as the internal reference. 1H NMR spectra were recorded for a fixed concentration of the tetraalkylammonium cation (about 5 × 10-3 M) in the absence and in the presence of p-sulfonatocalix[4]arene (about 5 × 10-3 M) and in the presence of an increasing amount of La3+ defined by the ratio F ) [calixarene]total/[La3+]total. 2.3. Microcalorimetry. All of the measurements were performed using a multichannel microcalorimeter (LKBThermometric 2277 thermal activity monitor) equipped with a titration-perfusion vessel. Wadso¨ and co-workers28 have thoroughly described this twin thermopile heat-conduction calorimeter and analyzed its performance. The experiments were carried out using a 1 mL glass vessel fitted with a gold stirrer. The vessel was charged with 0.9 mL of calixarene solution (4.0 mmol kg-1) previously complexed with Me4N+ or Et4N+ (10 mmol kg-1). In such conditions and according to the association constants of Cal4- with the organic cations,9 the filling of the calixarene cavity is achieved. A volume of 10 µL of La3+ solution (30 mmol kg-1) was injected in each step using a Lund syringe pump (Thermometric) equipped with a 250 µL Hamilton syringe fitted with a gold cannula. Twenty injections were made for each titration experiment. Static and dynamic calibrations were used; the power values observed upon titration ranged from 30 to 100 µW. Separate dilution experiments were performed under the same conditions. Each experiment was repeated at least twice for reproducibility. Values for the apparent association constant K′ and apparent standard enthalpy of reaction ∆rH′° in a given medium were calculated by using the Digitam 4.1 minimization code (Thermometric). The two series of data obtained for each system were simultaneously used in the regression analysis. 3. Simulation 3.1. Potential Models. The p-sulfonatocalix[4]arene molecule was modeled using the all-atom (AA) version of the Cornell force field AMBER.29 The general potential function is of the form

U)

kb(r - ro)2 + ∑ kθ(θ - θo)2 + ∑ kφ[1 + ∑ bonds angles dihedrals N-1

cos(lφ + δ)] +

N

∑ ∑ i)1 j)i+1

{ [( ) ( ) ] σij

4ij

12

-

rij

∞

σij

6

+

rij qiqj

∑l ′ |r

ij

+ nL|

}

(1)

where kb, kθ, and kφ are the force constants for deformation of bonds, angles, and dihedrals, respectively. The equilibrium values of bond distances and valence angles correspond to ro and θo, respectively. In the dihedral angle term, l is the periodicity, and δ is the phase factor. The last term in eq 1 corresponds to the electrostatic energy of the system where rij ) ri - rj and ri represents the position of the point charge qi. The prime just after the summation term indicates that the sum is performed over all periodic images, n ) (nxLx, nyLy, nzLz)

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Ghoufi et al. (1-4 van der Waals interactions) are reduced by a factor of 0.5.29 The parameters of the sulfonate groups were taken from ref 31. The Lennard-Jones potential parameters for the interactions between unlike atoms were calculated by using the Lorentz-Berthelot mixing rules (quadratic and arithmetic rules for ij and σij parameters, respectively). The water molecules were represented with the TIP3P model.32 The electrostatics interactions were calculated using the Ewald sum method,33,34 with the different contributions given by the following formula

Uelec )

)

1 8πo

(

∞

∑i ∑a ∑j b*a ∑ |n|)0 ∑ ′ |r

qiaqjb + n|

( )|∑ ∑ iajb

erfc(R|riajb +

|

2 k2 exp qia exp(ik‚ria) 2Vo k*0 k2 4R2 i a qiaqib R 1 erf(Rriaib) q2ia (2) 3/2 8πo i a b*a riaib 4π  i a

n|) +

1

∑

1

∑∑∑

∑∑

o

Figure 1. Trajectories of the distances from the com of the calixarene to the com of the tetraethylammonium cation and from the com of the calixarene to the lanthane cation in three different systems (Cal4- + La3+), (Cal4- + Et4N+), and (Cal4- + Et4N+ + La3+).

Figure 2. Distributions of the calixarene-tetraethylammonium cation energy contributions (kJ mol-1) in the insertion complex (Cal4- + Et4N+) and in the supramolecular assembly (Cal4- + Et4N+ + La3+).

TABLE 1: Thermodynamics Parameters Characterizing the Complexation of La3+ in Acidic Aqueous Solution (pH ) 2) at 298.15 Ka host

guest

log K′

∆rG′°

∆rH′°

T∆rS′°

(Cal4- + Me4N+) (Cal4- + Et4N+) Cal4Cal4Cal4-

La3+ La3+ La3+ Me4N+ Et4N+

2.59 2.62 4.23 4.40 4.67

-14.85 -14.94 -24.13 -25.12 -26.72

8.96 5.33 9.21 -26.02 -41.28

23.710 20.27 33.34 -0.94 -14.512

a The ∆rG′°, ∆rH′°, and T∆rS′° thermodynamic properties are given in the molar scale and expressed in kJ mol-1. The experimental thermodynamic properties characterizing the insertion complexes9 of the calixarene with Me4N+ and Et4N+ and the outer-sphere complex9 with La3+ are given for comparison. The number -14.85 means -14.8 ( 0.5.

with nx, ny, and nz integers, and over atoms j, except j ) i if n ) 0. The C-H and O-H covalent bonds were kept at a fixed length by use of the SHAKE algorithm,30 and the aromatic rings were kept planar using six improper torsional potentials. The intermolecular and intramolecular interactions consist of a van der Waals repulsion-dispersion term calculated using the Lennard-Jones (6-12) potential, represented by the penultimate term in eq 1. In the AMBER force field, the nonbonded interactions between atoms separated by exactly three bonds

where n is the lattice vector of a periodic array of MD cell images; a and b denote atoms of molecules i and j, respectively. In the first term of eq 2, when i ) j, the summation discounts any excluded atoms b of atom a. Let us remind that the excluded atoms b of atom a are atoms that are linked through a bond, angle, or torsion to atom a. The third term in eq 2 indicates that the summations run over only the excluded atoms b of atom a in the molecule i; riajb is the distance between the atoms a and b belonging to the two different molecules i and j, and qia and qib represent the charges on atoms a and b, respectively. 3.2. Computational Methodology. Two types of systems were simulated; the system called ME is defined by (Cal4- + Me4N+ + La3+) and consists of one p-sulfonatocalix[4]arene molecule (Cal4-), one tetramethylammonium cation (Me4N+), one lanthane cation (La3+), and 900 waters. In the ET system, Me4N+ is replaced by Et4N+. For clarity, these systems will be called ME and ET throughout this paper, respectively. When the system (Cal4- + Me4N+) was studied, three Na+ cations were added to ensure the electroneutrality in the simulation box. The sodium cations were located in such a way that the Na+‚‚‚Na+ and Na+‚‚‚calixarene distances were larger than the cutoff radius. We checked that these distance criteria were respected during the acquisition phase. The periodic boundary conditions were applied in the three dimensions. The long-range electrostatic interactions were evaluated by the Ewald summation technique. The parameters of this method were R ) 0.2651 (convergence parameter), within a relative error of 10-6, and kmax ) {8 × 8 × 8} (the reciprocal space vectors). The equations of motions were integrated using the Verlet Leapfrog algorithm scheme in the NPT ensemble (P ) 1 atm and T ) 298 K) with 2 fs as the time step. We applied the multiple time step algorithm35 in which two steps of different lengths were used to integrate the equation of motions. With this algorithm, the CPU time was decreased by a factor varying from 3 to 8. The simulations were performed in the NPT ensemble using the Berendsen algorithm36 with coupling constants of 0.1 (temperature) and 0.5 ps (pressure). The Verlet list sphere radius was fixed to 14 Å. A typical run consisted of 500 ps of equilibration followed by a production phase of an additional 10 ns. The acquisition phase extended over a very large period of time. When the ME and ET systems were simulated, the La3+ cation was initially placed so that there were no interaction with both the calixarene and the organic cation. The structural and thermodynamic properties were calculated over 500 000 configurations saved

Supramolecular Assemblies of p-Sulfonatocalix[4]arene

Figure 3. (a) Distributions of the distance between La3+ and the oxygen atoms of the sulfonate groups of the calixarene (left axis) in the insertion complex (Cal4- + Et4N+) (red curves) and in the supramolecular assembly (Cal4- + Et4N+ + La3+) (black curves). The integrations of these distributions are represented by the solid line (right axis). (b) La3+-water oxygen rdfs (left axis) with the corresponding number of water molecules as a function of r (right axis).

during the acquisition phase. The configurations were generated using the parallel version of the DL_POLY_MD package37 by using up to 16 processors at a time. The atomic charges of the macrocycle were fitted to reproduce the molecular electrostatic potential created around the calixarene anion at the HF level with the 6-31G* basis. We used the CHELPG38 procedure as a grid-based method. The quantum ab initio calculations were carried out using the GAMESS package.39 The partial charges on the Me4N+ and Et4N+ cations were taken from the work of Jorgensen and Gao.40 4. Results and Discussions To evidence the formation of supramolecular assemblies, we have performed microcalorimetric experiments. A solution of p-sulfonatocalix[4]arene previously complexed with Me4N+ or Et4N+ was titrated by a solution of La3+. The complex solution was contained in the vessel. The heat effects were fitted from nonlinear least-squares fit using several binding models, and in both cases, only a 1:1 stoichiometry adequately describes the association process. The K′ and ∆rH′° values deduced from these fits are reported in Table 1 with the corresponding ∆rG′° and T∆rS′° values. For relevant comparison, in Table 1, we have also reported the thermodynamic parameters previously obtained for the calorimetric titrations9 of Cal4- with the two quaternary ammonium cations (Me4N+ or Et4N+) and with La3+. It is worth noting that the presence of the quaternary ammonium cation inside of the cavity of the calixarene does

J. Phys. Chem. B, Vol. 111, No. 39, 2007 11481

Figure 4. Equilibrium conformations of (a) the outer-sphere complex (Cal4- + La3+), (b) the supramolecular assembly defined by the (Cal4+ Et4N+ + La3+) system, (c) the supramolecular assembly defined by (Cal4- + Me4N+ + La3+), and (d) the outer-sphere complex (Cal4- + La3+) when the organic cation has left the cavity.

not induce significant effects on the association of Cal4- with La3+. Indeed, the binding process is always characterized by positive entropy and enthalpy changes which are typical of purely ionic binding in water. The binding is entropy-driven, indicating that the inclusion of the organic cations into the host cavity does not change the factors governing the formation of the complexes with La3+. However, the association constants with La3+ in the presence of the quaternary ammonium cation in the cavity of the calixarene are much smaller than the one determined without the quaternary ammonium cation (Table 1). These decreases are related to the less favorable entropic values, the enthalpies changes being on the same order of magnitude. The less favorable entropic values can be explained in part by the fact that the cavity of the calixarene is already desolvated due to the insertion of the organic cation. The microcalorimetric experiments show then the possibility of association of La3+ with Cal4- in the presence of Me4N+ or Et4N+. We focus now on the molecular description of these supramolecular structures by performing MD simulations. In previous paper, from the calculation of the asphericity coefficient, we have shown that the global conformation of the calixarene is spherical.14 Accordingly, we may compare the structure of the calixarene to a sphere whose radius is approximately equal to 5 Å. This value corresponds to that of the root-mean-square radius of gyration of the calixarene. The use of this parameter with additional typical distances such as the center of mass (com) has proved to be efficient to describe the geometrical features of different complexes of the calixarene. Let us consider the results obtained in the ET system. Figure 1 shows the distance from the com of Cal4- to the com of Et4N+ in the ET system and in the insertion complex (Cal4- + Et4N+) as a function of the simulation time. We also added distance

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Ghoufi et al.

Figure 5. Trajectories of the distances from the com of the calixarene to the com of the tetraethylammonium cation and from the com of the calixarene to the lanthane cation in three different systems (Cal4- + La3+), (Cal4- + Me4N+), and (Cal4- + Me4N+ + La3+). The periods of time P1 and P2 discussed throughout the paper are represented in this figure.

from the com of Cal4- to the com of La3+ in the supramolecular structure of ET and in the (Cal4- + La3+) outer-sphere complex. The first peak of the trajectory of the Cal4-‚‚‚La3+ distance in the ET system only shows the initial position of the La3+ cation, which has been chosen in such a way that there are no interactions between La3+ and the macrocycle. After 1.5 ns, Figure 1 exhibits an equilibrium distance of 8.7 Å. Interestingly, the equilibrium Cal4-‚‚‚La3+ distance is larger than that calculated (6.1 Å) in the standard outer-complex where the Et4N+ is not involved. The Cal4-‚‚‚La3+ energy contribution is favorable in the two types of complexes and is in line with the corresponding Cal4-‚‚‚La3+ distance. More exactly, this energy contribution decreases from -72 to -103 kJ mol-1 as the distance decreases from 8.7 to 6.1 Å. Concerning the insertion of the Et4N+ cation, we observe no change in the distance between the organic cation and the calixarene in the two types of complexes. The result is that the insertion of the Et4N+ cation is not perturbed upon the interaction with La3+. This feature is confirmed in Figure 2 by identical distributions of the Cal4-‚‚‚Et4N+ cation energy contribution in the two types of complexes. In the case of the association between R4N+ cations and the calixarene, we recall that Et4N+ leads to the more significant insertion in terms of the number of methylene and methyl groups,14,15 in line with a remarkably negative enthalpy of binding. The number of atoms inside of the cavity is equal to 21 for Et4N+ and 17 for Me4N+, although Et4N+ is only partially inserted in the cavity. These MD results are then consistent with the fact that, in the supramolecular assembly formed, Et4N+ is always included into the calixarene cavity, whereas the lanthanide cation is located outside of the cavity. Simulations also highlight that the insertion of the organic cation does affect the position of the lanthanide cation outside of the cavity and consequently probably changes the structure of the complex in comparison with the (Cal4- + La3+) outer-sphere complex. In order to complete this analysis and to specify the location of La3+ in the supramolecular assembly formed, we show in part a of Figure 3 the distributions of the distance from the lanthanide cation to the oxygen atoms of the four sulfonate groups in the two systems (Cal4- + Et4N+ + La3+) (black

curves) and (Cal4- + La3+) (red curves). We check that the distributions of the La3+‚‚‚O distance calculated in the supramolecular assembly are very different from those resulting from the standard outer-sphere complex. In the case of the latter, the distributions exhibits three peaks between 5 and 12 Å, indicating that the oxygen atoms of the sulfonate group do not perturb the first hydration shell of the La 3+ cation. Concerning the supramolecular assembly formed by the calixarene, Et4N+, and La3+, the La3+‚‚‚O distance distributions show clearly two peaks at a distance of less than 5 Å. The integration of this region gives a mean number of three oxygen atoms of the sulfonate groups. The result is that the first hydration shell of the lanthane cation is then perturbed by these oxygen atoms. Part b of Figure 3 represents the lanthane-water oxygen radial distribution functions (rdfs) in the two types of complexes with the corresponding hydration number. We see that the first hydration shell around La3+ is composed of 10.6 and 7 water molecules in the (Cal4- + La3+) and ET cases, respectively. It means that the first hydration shell of La3+ is constituted by oxygen atoms of both water molecules and sulfonate groups. In the supramolecular assembly formed, La3+ is directly bonded to Cal4- by a sulfonate group, in contrast with that we have previously shown in the outer-sphere complex where only the second hydration shell of La3+ is changed upon the interaction with the macrocycle. The structural features of these complexes can be visualized in Figure 4 through instantaneous equilibrium conformations resulting from our MD simulations. Because the enthalpy change for the binding of the tetraethylammonium cation by the calixarene is much more favorable than that calculated for the binding of the tetramethylammonium9 (Table 1), it is then very interesting to study the supramolecular assembly formed with the calixarene, tetramethylammonium, and lanthane cations. Figure 5 shows the trajectories of the distance from the com of the calixarene to the com of La3+ in the ME system. We add for comparison the trajectories from the com of the macrocycle to the com of La3+ and to the com of Me4N+ in the (Cal4- + Me4N+) and (Cal4+ La3+) systems. We observe in Figure 5 that the mean distance between the calixarene and Me4N+ is 2.92 Å in the insertion complex and that the mean distance between the calixarene and

Supramolecular Assemblies of p-Sulfonatocalix[4]arene

J. Phys. Chem. B, Vol. 111, No. 39, 2007 11483

Figure 6. (a) Cal4-‚‚‚Me4N+ interaction energy (kJ mol-1) as a function of time calculated in the insertion complex (Cal4- + Me4N+) and in the system (Cal4- + Me4N+ + La3+); (b) Cal4-‚‚‚Me4N+ interaction energy, Cal4-‚‚‚Et4N+ interaction energy, and Cal4-‚‚‚H2O interaction energy calculated in the (Cal4- + Me4N+), (Cal4- + Et4N+), and (Cal4- + La3+) systems, respectively.

La3+ cation is 6.2 Å in the outer-sphere complex. The trajectories calculated from the ME system show clearly two typical periods. The periods P1 and P2 cover 1.2 and 0.9 ns, respectively. Although this range of time seems to be short in this figure, we underline that the periods P1 and P2 extend over simulation times that are comparable to those used by the previous MD simulations 14-16 of the insertion and outer-sphere complexes. The first period corresponds to t < 2.5 ns and shows the possible insertion of the tetramethylammonium cation with a lanthane cation sampling a large region above the sulfonate groups with some Cal4-‚‚‚La 3+ distances on the order of 10 Å in the P1 and P2 periods of time (see Figure 5). For these periods, the average distance from the calixarene com to the tetramethylammonium com is 3 ( 1 Å. Figure 6a shows the Cal4-‚‚‚Me4N+ energy contribution as a function of time. This figure confirms both the insertion by favorable energy contribution between the cation and the macrocycle and the leaving process of the organic cation from the cavity in the second period by very weak values of this energy contribution. The second period (t > 2.5 ns) shows that the tetramethylammonium cation leaves the cavity of the calixarene to go back to the bulk. The lanthane cation recovers a position above the sulfonate groups with a distance (6.2 Å) typical of that of an outer-sphere complex. Figure 5 shows that the trajectory of the

La3+‚‚‚calixarene distance calculated in the second period matches very well with that calculated in the outer-sphere complex (Cal4- + La3+). From the energetic viewpoint, we explain the release of the organic cation by representing the trajectories of the average of the calixarene‚‚‚Me4N+ energy contribution in the (Cal4- + Me4N+) system, of the average of the Cal4-‚‚‚.Et4N+ energy contribution in the (Cal4- + Et4N+) system, and of the average of the energy between the calixarene and the water molecules inside of the cavity of the calixarene in the (Cal4- + La3+) system. In this outer-sphere complex, the number of water molecules inside of the cavity is calculated from the integration of the calixarene com-water oxygen rdf up to the value of the radius of gyration of the cavity. These energy contributions are displayed as a function of time in Figure 6b. When the association implies the insertion of the tetramethylammonium and the tetramethylammonium cations, the desolvation of the calixarene cavity is total. From the average value of the energy contributions, ECal4-‚‚‚Me4N+ ) -20.3 kJ mol-1, ECal4-‚‚‚Et4N+ ) -35.6 kJ mol-1, and ECal4-‚‚‚H2O ) -25.6 kJ mol-1, we can see that the release of the tetramethylammonium cation from the calixarene cavity is favorably balanced by the solvation of the cavity by four water molecules, whereas the hypothetical release of the tetraethylammonium, which has not been observed from the MD simulations, could not be

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Ghoufi et al. upfield (1.5 ppm) after addition of the calixarene, showing the insertion of Me4N+ inside of the cavity of the calixarene. In the presence of La3+, the chemical shift evolves from 1.5 to 1.8 ppm, whereas no shift is observed in the case of Et4N+. Furthermore, we observed problems of precipitations when the amount of La+ added increased (F ) 0.6). We did not detect any precipitation during microcalorimetric titrations. This could be explained by the fact that the procedure followed for the 1H NMR experiments requires higher concentrations. Since this was under fast chemical exchange conditions, the observed chemical shift was the population average of the chemical shift of the free and of the complexed tetramethylammonium cation, and the changes in chemical shift may be explained by a partial dissociation of the Me4N+ cation with the calixarene. This dissociation can be viewed through the release of the tetramethylammonium from the calixarene cavity. 5. Conclusions

Figure 7. The 400 MHz 1H NMR spectra in D2O at 25 °C of 5.15 × 10-3 M Et4N+ (a) with no host, (b) with 4.72 × 10-3 M calixarene, (c) with 5.23 × 10-3 M calixarene and 3.72 × 10-3 M La3+, and (d) with 5.44 × 10-3 M calixarene and 7.54 × 10-3 M La3+. The 400 MHz 1H NMR spectra in D2O at 25 °C of 5.42 × 10-3 M Me4N+ (e) with no host, (f) with 5.03 × 10-3 M calixarene, and (g) with 4.54 × 10-3 M calixarene and 3.75 × 10-3 M La3+. The symbol (/) corresponds to the signal of the quaternary ammonium cations.

compensated by the favorable interactions between the calixarene and the water molecules of the cavity. To provide an experimental support to the explanation resulting from the molecular simulations, 1H NMR experiments in D2O at 298 K were performed. The spectrum of the Et4N+ solution without the calixarene and La3+ is given in curve a of Figure 7 and presents two peaks at 1.2 and 3.2 ppm associated with the methyl and methylene groups of Et4N+, respectively. Upon addition of the calixarene, we observe only one peak for each group CH3 and CH2, indicating a fast exchange on the 1H NMR time scale between the free and the complexed Et4N+ (curve b of Figure 7). Furthermore, the proton chemical shifts are shifted upfield, highlighting the inclusion of the organic cation in the cavity of the calixarene. Such observation is in line with our previous experimental and simulation studies.9,14-16 It also appears that whatever the amount of La3+ added into the (Cal4- + Et4N+) complex solution, no shift is detected (curves c and d of Figure 7). This result emphasizes that the environment of the CH3 and CH2 groups is not changed by La3+ and clearly indicates that combining La3+, Cal4-, and Et4N+ stable complexes are formed, with La3+ located outside of the calixarene cavity. As a result, both calorimetric and 1H NMR experiments demonstrate the formation of a supramolecular assembly in excellent agreement with MD simulations. The same approach is taken with Me4N+. The spectrum of the Me4N+ solution without the calixarene and La3+ is represented by curve e of Figure 7. This curve presents a peak at 3.1 ppm related to the methyl group. This peak is shifted

Throughout this paper, we report computational and experimental investigations of supramolecular assemblies of psulfonatocalix[4]arene with both tetraalkylammonium and lanthanide cations organized by weak forces in water. We have performed microcalorimetric measurements and MD simulations of these supramolecular assemblies over a large simulation time of 10 ns. Concerning the supramolecular assembly formed by the calixarene, the tetraethylammonium, and the lanthane cations, we observe that the organic cation is inserted into the calixarene cavity and that the lanthane cation is located outside of the cavity close to a sulfonate group. When the tetramethylammonium cation is involved, we observe both the supramolecular assembly with La3+ interacting with a sulfonate group and the formation of the outer-sphere complex between the calixarene and La3+ after the release of the organic cation from the calixarene cavity. We explain that Me4N+ goes back to the bulk by the fact that the solvation of the calixarene cavity is more favorable at the energetic level than the calixarene‚‚‚ tetramethylammonium interaction energy. The MD simulations led us to perform NMR experiments to confirm the partial release of the organic cation from the calixarene cavity in the (Cal4- + Me4N++ La3+) system. The NMR experiments showing a possible dissociation of the supramolecular assembly are in agreement with the conclusions drawn from the molecular simulations. Acknowledgment. The authors would like to acknowledge the Institut du De´veloppement et des Ressources en Informatique Scientifique IDRIS (CNRS) for a generous allocation of CPU time on parallel computers. The authors are indebted to Y. Israe¨li for fruitful discussions about the NMR experiments. References and Notes (1) Silva, E. D.; Coleman, A. W. Tetrahedron 2003, 59, 7357. (2) Hwang, K. M.; Qi, Y. M.; Liu, S. Y. PCT Int. Appl. WO 92122709, 1992; Harris, S. J. PCT Int. Appl. WO 0244121, 2002. (3) Atwood, J. L.; Bridges, R. J.; Junega, R. K.; Singh, A. K. U.S. Patent 5489612 A, 1996. (4) Hwang, K. M.; Qi, Y. M.; Liu, S. Y.; Choy, W.; Chen, J. U.S. Patent 5441983 A, 1995. (5) Hulmes, D.; Aubert-Foucher, E.; Coleman, A. PCT Int. Appl. WO 2000007585, 2000. (6) Sansone, F.; Segura, M.; Ungaro, R. In Calixarenes 2001; Asfari, Z., Bo¨hmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer Academic Publishers: Dordrecht, The Netherlands, 2001; p 496. (7) Casnati, A.; Sciotto, D.; Arena, G. In Calixarenes 2001; Asfari, Z., Bo¨hmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer Academic Publishers: Dordrecht, The Netherlands, 2001; Chapter 24.

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