Host Guest Complexation in the Ferrocenyl Alkanethiols Thio β Cyclodextrin Mixed Self-Assembled Monolayers

pubs.acs.org/jpcc Host Guest Complexation in the Ferrocenyl Alkanethiols Thio β Cyclodextrin Mixed Self-Assembled Monolayers Gae lle Filippini, Florent Goujon, Christine Bonal,* and Patrice Malfreyt Clermont Universite, Universite Blaise Pascal, ICCF, UMR CNRS 6296, BP 10448, F-63000 Clermont-Ferrand, France ABSTRACT: A host guest equilibrium involving ferrocenyl alkanethiols thio β-cyclodextrin mixed self-assembled monolayers (FcC n S-/C n S-/β-CD-Au SAMs) is investigated using molecular dynamics (MD) simulations. In this work, we focus on the effects of the alkyl spacer length of the ferrocene adsorbates on the complexation behavior. Our simulations show that the formation of host guest complexes is observed from C 12 chain length Fc-thiols whereas no effect is obtained with shorter alkyl chains (FcC 11 S- Au). Furthermore, we underscore that the presence of the alkyl thiol chains in the ferrocene derivatives largely prevents the deeper insertion of the ferrocene moieties into the β-cd cavity. More details are reported about the impact of the oxidation process on these monolayers. In fact, it appears that Fc + is less inserted into the β-cd cavity than Fc in aqueous solution. Nevertheless, a partial inclusion of the Fc + residue in the cavity of the β-cd is highlighted. In fact, the position of the Fc + into the host cavity allows a spatial location that favors both interactions with water and β-cd. The potential of mean force (PMF) characterizing the association process in aqueous solution confirms a weak association between Fc + and C 5 S-/β-CD-Au SAMs. The effects of both the coadsorbed chains and the positive charge of the electrode surface on the stability of this inclusion complex are also reported. INTRODUCTION β-cyclodextrins (β-cds) are cyclic glucopyranose oligomers possessing a peculiar structure with a hydrophobic inner surface of the molecular cavity and a hydrophilic exterior. This cavity can include some guests of appropriate size to form host guest complexes in aqueous solution. 1 3 Because of these peculiar properties, CDs present applications in various fields such as drug carrier, sensors, cosmetics, food technology, catalysis, and also textiles. 3 7 A dynamic equilibrium controls the association of guest molecules within the cavity of the macrocycle. In fact, the molecular recognition of guests is governed mainly by two key factors. Steric effects are of prime importance because the size of the guest must fit into the cyclodextrin cavity. The second factor is rather thermodynamic since a favorable energetic driving force that pulls the guest into the cavity of the cyclodextrin is required to form a complex. Then expected uses of host guest systems for applications in sensor development or reactive selective catalysts 8 require the immobilization of either the host molecule or the guest molecule on surfaces. Thiolated CDs are able to bind strongly to gold surfaces. Thus, CD-modified gold surfaces have been prepared to obtain self-assembled monolayers (SAMs) 8,9 which exhibit effective binding properties. These monolayers are notably interesting to fix the proteins and other biological guests on surfaces. 7,10 18 Simple structures that are difficult to obtain in another way can be easily obtained from this convenient strategy. 19 In order to design materials with predictable properties, it is fundamental to fully understand how the surface influences the host guest interactions. However, to the best of our knowledge, few investigations have been made in this field. β-cds form 1:1 stoichiometric inclusion compounds with ferrocene (Fc) and its derivatives 20 with binding constants in the range of 10 3 10 4 in aqueous solution. The fact that the ferrocene residues form stable inclusion complexes with β-cds has been widely used to elaborate mediators and molecular sensors 2,21 23 and to assist organic reactions such as asymmetric inductions 24,25 or condensation reactions. 26 It is generally reported that the oxidized positively charged ferricinium ions (Fc + ) are not associated with β-cds. 20,23,27 Then, interaction of Fc + or other metallocenium cations with cyclodextrins is assumed to be negligible. 20,28 30 In the case of ferrocenecarboxylic acid, Evans and co-workers 20 have shown that the association complex Fc-β-CD can only undergo oxidation after the dissociation of the complex (a so-called CE mechanism) in homogeneous solution. Similar results have been obtained for a number of ferrocene derivatives by Kaifer. 23 However, some Fc + -β-cd binding constants obtained from NMR titration were also reported 31 in the literature. For instance, the 1:1 binding constant of the β-cd complex of ferrocenium is equal to 15. 31 In order to elucidate if these complexes can survive to Fc oxidation, we decided to perform molecular simulations experiments. In fact, we have recently demonstrated how molecular dynamics simulations may be used to capture both structural and energetical properties of SAMs. 32 35 In our Received: November 20, 2013 Revised: January 20, 2014 Published: January 22, 2014 2014 American Chemical Society 3102

The Journal of Physical Chemistry C recent papers,36,37 we have shown that computational investigations can be used to obtain quantitative information about supramolecular assemblies using a surface-confined CD. We have studied the formation of a supramolecular system involving ferrocenemethanol and β-cd in both free CD and gold-confined CD conditions. The difference in the association process between homogeneous and heterogeneous conditions has been explained from molecular dynamics simulations. The analysis of the different energy contributions was used to shed more light on the differences observed as a function of the two environments.36,37 In the present study, we specially investigate ferrocenyl alkanethiols-thio β-cd mixed SAMs (FcCnS-/C5S-/β-CD-Au SAMs) using molecular simulations (Figure 1). In fact, the initial configuration. Alkanethiol chains are then grafted to fill the remaining surface using the one-third experimental surface coverage. The system is closed by an additional Au layer, and the remaining volume is filled with water molecules and ions. To reach the experimental concentration of 0.1 M, 2300 water molecules, 4 Na+, and 4 ClO4 are inserted in the simulation box (40.3 39.9 50.0 Å3). In order to model the two-dimensional (2D) periodicity of the system, a large empty space is added after the surface in the z direction, so that neighbor boxes will not interact due to 3D periodic boundary conditions. A comprehensive description of this procedure is given in previous literature.32,38 The system is described by the all-atom version of the Cornell force field AMBER.39 Additional parameters have been used to model Au atoms,40 the ferrocene part,41 sodium cations,42 perchlorate anions,43 and water molecules.44 The reader is redirected to ref 38 for the calculation of the electrostatic interactions in this type of system. The potential of mean force (PMF),45 W(r12), represents the interaction between two particles 1 and 2 kept at a fixed distance r12 from each other when the N 2 particles are averaged over all the configurations. We have used the constraint force method46 to calculate the PMF. The methodology is carefully described in our previous work.36,37 The thermodynamic quantities are obtained by integrating the PMF profile along the separation distance between the βcd and the ferrocenium ion (Fc+)47 49 considering a cylindrical approach.50,51 The association constant K is given by Figure 1. Typical configurations of (a) the simulation cell and (b) the top view of the inclusion complex in FcC12S-/C5S-/β-CD-Au SAM (water molecules and ions are removed for clarity). K= dz πrcyl 2NA exp Wk (Tz) (1) B where NA is the Avogadro number and rcyl is the radius of the cylinder in which the Fc+ can move. The thermodynamic properties of binding are calculated using the following expressions alkanethiols (C5S-) are immobilized on the Au surface to block the intermolecular vacancies between the adsorbed CD molecules. We have studied the structures of the ferrocenyl alkanethiol using various lengths of hydrocarbon chains. The stability of the inclusion complex of gold-confined β-cd with ferrocenyl alkanethiol is evaluated as a function of the hydrocarbon chain length of the monolayers. In our numerical experiments, the ferrocenium is initially inserted into the cavity of the host and the stability of the complexes is observed along the simulation time. In fact, we plan to study if the redoxconverted forms of the guest are still bound to the host. More precisely, we aim at understanding the effect of the redox reaction on the inclusion process and finally at identifying the initial parameters for the formation dissociation of these inclusion compounds. All of these points will be clarified by atomistic simulations. ΔrG = kbt ln K = kbt ln ΔrH = kbt 2 = (2) W (z) dh πrcyl 2NA exp kbt d ln K dt (4) ( dz rcyl 2W (z) exp WkB(Tz) ( dz rcyl 2 exp (3) W (z) kt B ) (5) ) T ΔrS = ΔrH ΔrG COMPUTATIONAL PROCEDURES The system consisted of five layers of a Au(111) surface grafted with one per-6-thio-β-cyclodextrin (β-cd), one ferrocenylalkanethiol chain (FcCnS-) and diluting pentanethiol chains (C5S-) in an aqueous phase containing 0.1 M NaClO4 (see snapshot in Figure 1). In order to investigate the effect of the length of the ferrocenylalkanethiol chain on the association process, we have studied successively the cases of ferrocenylundecanethiol (FcC11S-), ferrocenyldodecanethiol (FcC12S-), ferrocenyltridecanethiol (FcC13S-), and ferrocenylpentadecanethiol (FcC15S-) chains. The β-cd was tethered on the surface through seven grafted points, one on each glycopyranose unit. The ferrocenylalkanethiol chain is grafted close to the β-cd, so that the ferrocene moiety can be included into the cavity in = (6) ( dz rcyl 2W (z) exp WkB(Tz) ( dz rcyl 2 exp WkB(Tz) + kbt ln ) ) (7) dz πrcyl 2NA exp Wk (Tz) B MD simulations of systems in the water phase were run in the constant-nvt ensemble using a time step of 2 fs and a cutoff radius of 15 Å for both dispersive and electrostatic interactions (real part of the Ewald summation). MD simulations of the systems in vacuum are performed in the constant-nve microcanonical ensemble using a cutoff of 18 Å for the 3103

The Journal of Physical Chemistry C Figure 2. z-position of the center of mass of the Fc as a function of the length of the alkyl chains in the Fc derivatives before and after the oxidation in both (a) water and (b) isolated phases. The limit size of the β-cd cavity is given in dotted line for information. Figure 3. Typical configurations showing (a) the release of the FcC11 from the β-cd cavity, (b) the insertion complex in FcC12S-/β-CD-Au SAM (the alkanethiol chains have been removed for clarity), and (c) the tilting of the terminal ferrocene group of the FcC11 into the coadsorbed chains. ferrocene moiety is initially included into the cavity of the host. The stability of the complexes all along the simulation time is estimated. In Figure 2 the z-positions of the center of mass of the Fc derivatives are represented as a function of the alkyl spacer length of the ferrocene adsorbates, before and after oxidation, in both water (Figure 2a) and isolated phases (Figure 2b). The z-axis refers to the direction normal to the surface. We have also evaluated the same position in a system that presents the β-cd host immobilized in SAMs and free Fc, without an alkyl thiolate chain, to observe the formation of the β-cd inclusion complex with the Fc independently of the chain (called C0 in the figure). The dotted line in Figure 2 corresponds to the limit size of the cavity of the β-cd. This limit size is defined by the average z-positions of the oxygen atoms of the β-cd hydroxyl groups. Before oxidation, our results tend to show that β-cd SAM binds all of the guests studied except the FcC11 that is clearly located outside the cavity as shown in Figure 2a. This may be easily interpreted by taking into account the shorter length of electrostatic interactions (standard Coulombic potential). The simulations were run using a modified version of the DL_POLY_MD package,52 running on 12 nodes. A typical run consists of an equilibrium period (1 ns) and a production phase (4 ns). To calculate the potential of mean force, MD simulations were run in the constant-nve microcanonical ensemble at T = 298 K. Each separation distance between host and guest is simulated with an equilibration period of 200 ps and a production of 600 ps. The separation distance between two consecutive simulations is set to 0.2 Å. Up to 60 simulations are done successively to model one PMF curve, giving a total simulated time of 48 ns. RESULTS AND DISCUSSIONS First, the inclusion complexes between ferrocenylalkanethiols and β-cd hosts immobilized in SAMs are studied as a function of the alkyl chain length in the ferrocene derivatives. As explained in Computational Procedures, in all cases the 3104

the ferrocenylundecanethiol derivative (Figure 3a) as compared to the other lengths of the alkyl chains in the ferrocene derivatives. Note that it is rather inconsistent with the results of Frasconi et al. 13 obtained using EC-SPR experiments. They have studied the reorganization and the thickness changes of the SAM due to the redox process, in the presence of β-cd SAM. The influence of hydrocarbon chain length of the monolayers was investigated using ferrocenylhexanethiol (FcC 6 ) and ferrocenylundecanethiol (FcC 11 ). Their results indicate that FcC 6 /βcd SAMs are not inserted into the β-cd cavity. Consequently, the electrons are transferred exclusively by a tunneling process in FcC 6. In the case of FcC 11 /β-cd SAMs, they have obtained a quite different EC-SPR behavior. They assume that the bending of FcC 11 allows the Fc to form an inclusion complex with the β-cd. Hence, the electrons, besides the tunneling process, can also be directly transferred by Fc included in the β-cd cavity. Our simulations indicate that the formation of inclusion complexes is only observed with the C 12 chain length Fc-thiols (Figure 3b) whereas no effect is obtained with shorter alkyl chains such as FcC 11. However, the tilting of the terminal ferrocene group into the coadsorbed chains is clearly evidenced after the release of the FcC 11 from the β-cd cavity (Figure 3c). Consequently, this effect is postulated to be partially responsible to the difference EC-SPR obtained by Frasconi et al. 13 in the case of FcC 11. However, we would like to see additional experimental works on the exact location of the ferrocene group in FcC 11 /β-cd SAMs. With longer ferrocenyl alkyl chains (FcC 12, FcC 13, and FcC 15 ) in aqueous solution, the positions of the Fc derivatives within the cavities are almost the same (Figure 2a). With regard to the free Fc, it is more deeply inserted into the β-cd cavity than the ferrocenylalkanethiols. This deeper insertion is not possible by the presence of alkyl chains of the ferrocene derivatives. After oxidation, the centers of mass of the Fc + samples are in the region slightly above the cavity, as shown in Figure 2a. Additionally, we can observe that the z-positions of the Fc + do not depend on the spacer length of the guest molecule. Here, no release of the included guest molecules upon oxidation is observed even if the simulations highlight that the inclusion of the Fc + is slightly smaller than that obtained for Fc in aqueous solution. However, one should notice that a larger difference of 3.5 Å in the z-position of the Fc + is obtained for C0, indicating a larger partial dissociation of the inclusion complex in this system. Now, if we consider isolated phases before oxidation (Figure 2b), the z-positions of the Fc are similar than that obtained for all host guest complexes in aqueous solution except for C0. In this case, the Fc is less deeply inserted into the β-cd cavity than in water. In addition, no change in the positions of the center of mass of Fc + are observed upon oxidation of Fc into Fc +. This is a significant difference with the behavior described in aqueous solution. These results clearly highlight the role of the water in the localization of the Fc moiety toward the CD cavity. This will be analyzed later. As shown previously, 36,37 the inclusion of the guest molecule into the β-cd cavity controls the binding properties through van der Waals (vdw) interactions. In Figure 4 both the calculated vdw energy contributions involving the ferrocene group and the percentage of the guest molecule inserted into the CD cavity are represented as a function of the length of the alkyl chains in the ferrocene derivatives before and after the oxidation process in water. As expected, the most favorable vdw Figure 4. Correlation between the calculated van der Waals energy contributions of Fc-CD and the percentage of the guest molecule inserted into the β-cd cavity as a function of the length of the ferrocenyl alkyl chains before and after the oxidation process. energy contributions are associated with the largest number of inserted atoms. The number of atoms inserted into the cavity is always greater before rather than after the oxidation of the ferrocene. This is in perfect agreement with the results discussed above. To investigate further the effect of water, we now focus in Figure 5a on both the Lennard-Jones and electrostatic parts of the Fc-CD and Fc-H 2 O energy contributions for the inclusion complexes in FcC 12 S-/C 5 S-/β-CD-Au SAMs before and after oxidation (systems 1 and 2, respectively). For comparison, the same energy contributions have been calculated for a system in which the electrochemical oxidation of the Fc takes place after the total dissociation of the inclusion complex. In this case, the Fc + is located outside the cavity and is immersed into the diluent chains. For this system, a more negative contribution between the Fc + and water is obviously obtained whereas the Fc-CD contribution is negligible, as shown in Figure 5a. We observe that oxidizing system 1 leads to an increase of the Fc- CD contributions mainly due to the electrostatic part since the Lennard-Jones part of this contribution decreases as discussed in Figure 5a. At the same time, the increase of the hydrophilic property of the Fc + also leads to a more favorable Fc H 2 O energy contribution for system 2. In conclusion, we highlight that the change in the z-positions of the Fc + in aqueous solution (Figure 2a) enables more favorable interactions with both water and β-cd. Figure 5b shows spatial distribution functions of both FcC 12 /β-cd SAMs (1) and Fc + C 12 /β-cd SAMs (2). The conformations of the Fc moieties embedded into the cavity reflect a higher order in system (1) whereas in system (2) the cyclopentadienyl ring that is less inserted into the cavity rotates more freely. To understand more deeply the association process in aqueous solution between free Fc + and the grafted β-cd, we report the potential of mean force (PMF) in Figure 6a. The PMF curve has a shape similar to that obtained with the ferrocenemethanol guest (FcOH) and surface-confined CDs. 37 We note as a reminder that in the case of Fc OH the PMF curve shows one deeper free energy local minimum of 40.3 kj mol 1 at d = 0.4 Å. 37 For the free Fc +, a closer look of Figure 6a reveals that the free energy profile exhibits two minima of 10 and 15 kj mol 1 occurring at around 6 and 2 Å, respectively, 3105

Figure 5. (a) Lennard-Jones and electrostatic energy contributions between the ferrocene group and both CD and water in FcC 12 S-/ C 5 S-/β-CD-Au SAMs before (1) and after (2) the oxidation process. As a comparison, these contributions have been also determined for Fc + C 12 outside the cavity (charged out). (b) Spatial distribution functions of the Fc group before (1) and after (2) the oxidation process in FcC 12 S-/C 5 S-/β-CD-Au SAMs. Figure 6. (a) Free energy profile between Fc + and grafted CD as a function of the separation distance between the host and guest. We add for comparison the z-position relative to the surface. (b) Partitioning of the PMF into Fc + H 2 O, Fc + CD, Fc + Alk, and Fc + surface free energy contributions for four different zones. and separated by a small energy barrier. The different free energy contributions of the PMF curve along the reaction pathway are represented in Figure 6b. At larger separation distance, the free energy decreases as Fc + approaches the monolayer surface (coadsorbed chains) leading to the first minimum. This minimum finds its origin in both the Fc + H 2 O and Fc + Alk free energy contributions as shown in zones 1 and 2 of Figure 6b. The free energy barrier of the PMF is caused mainly from an increase of Fc + H 2 O free energy contribution (zone 3). Finally, the Gibbs free energy minimum at 2 Å that it is located at the upper rim of the β-cd is in agreement with the z-positions discussed above (Figure 2). This clearly evidences a weak association in line with the results of standard nonconstraint simulations. Zone 4 of Figure 6b shows that the origin of the association is due to both the favorable Fc + CD energy contribution and to the favorable entropic desolvation process. The association constant and the enthalpy change are obtained by integrating the free energy profile along the host guest separation distance. The thermodynamic parameters are Δ r G = 8.7 kj mol 1, Δ r H = 7.6 kj mol 1, and TΔ r S = 1.1 kj mol 1. Then, the value of K =35is of the same order of magnitude with previous work obtained for the free CD. 31 Finally, even if the stability of the ferrocene complexes is significantly greater than that of the ferrocenium complexes, our results establish unequivocally the weak association between free Fc + and the grafted β-cd. We now focus on the effect of the coadsorbed chains in the z-positions of the Fc + into the β-cd cavity. For this purpose, the z-positions of the free Fc + (C0) as a function of the length of the alkyl thiolate chains are reported in Figure 7a with the configurations of AlkC 5 and AlkC 9 given in Figure 7b. Although we observe more mobility in the z-positions of the cation with longer alkyl thiolate, the positions of the center of mass of the Fc + into the cavity of β-cd SAM are kept unchanged (Figure 7a). This result is surprising. Indeed, the position of the alkane water interface depends on the length of the alkyl thiolate chains. 36 These different distributions of water molecules should induce a change of the positions of the Fc + as explained above. In order to further investigate this effect, we report in Figure 8, the molecular density profiles of the water, the alkylthiolate chains, the Fc + groups and the β-cd along the z-axis normal to the gold surface for the three studied systems. These molecular density profiles are perfectly coincident with those of previous works. 36,37 As expected, the position of the alkane water interface depends on the length of the alkylthiolate chains. However, it is interesting to observe that some water molecules are found within the alkane region in the density profile of water. More precisely, these water molecules are located above the β-cd cavity. As a result, the Fc + H 2 O energy contributions are favorable and very similar in the three systems studied ( 60 kj mol 1 ). This is thoroughly consistent with the position of the Fc + that is unchanged as a function the length of the alkyl thiolate chains (Figure 7a). The electrode surface is positively charged within the potential range where Fc moieties are oxidized (from 0.2 to 0.8 V vs Ag/AgCl). 53,54 To study this effect and the fact that this introduces electrostatic repulsions between the positively charged electrode and ferrocenium cation, we have estimated the charge due to the surface polarization during the ferrocene oxidation process. The monolayer is assimilated to a dielectric material of 7.2 Å in width and of a relative permitivitty ε r = 2.6. This value of permittivity has been used by Rowe and Creager 53 for ferrocenylalkanethiol monolayers. We take the route of 3106

Figure 7. (a) z-positions of the center of mass of the Fc + as a function of the length of the coadsorbed chains. (b) Snapshots of Fc + -C n S-/β-CD-Au SAMs with AlkC5 and AlkC9. Figure 8. (a) Molecular density profiles of the Fc + ion (green), β-cd (red), and water (blue) as a function of the coadsorbed chains (black) along the z-direction. using the same value of ε r even if β-cd is grafted on the surface. The capacitance can be calculated by considering a parallel plate capacitor model using the following expression: C = εε 0 r S l where C is the capacitance, ε 0 is the vacuum permittivity, S is the surface of the metallic plates, and l is the width of the dielectric material. We obtain a surface capacitance of 3.2 μf cm 2 that corresponds to 5.5158 10 7 pf for the electrode surface of 43.2 Å 39.9 Å. The charge of the surface is deduced from q = CU (9) where q is the charge surface and U the surface potential. Using this relation and taking a potential value U = 0.5 V corresponding to that of the redox potential of the ferrocene group, a charge of 1.7213 e is spread over all of the surface. We have performed a simulation with this value of charge for Au in order to observe the effect on the association between Fc + and β-cd. We compare the z coordinate of the Fc + center of mass as a function of the simulation time with that obtained for C = 0 and C = 6.4 μf cm 2. The results are shown in Figure 9. An increased mobility of the Fc + is clearly obtained with a value of 3.2 μf cm 2 for the capacitance. Finally, we observe the release of the Fc + from the CD cavity with twice the value of the capacitance (6.4 μf cm 2 ) leading a smaller dependence (8) Figure 9. Trajectories of the z-position of the center of mass of the Fc + as a function of the capacitance. The limit size of the β-cd cavity is given in dotted line for information. of the positive charge of the electrode surface on the z-positions of the Fc +. CONCLUSION Molecular simulations have been performed to study the host guest equilibrium involving ferrocenyl alkanethiols thio β- cyclodextrin mixed self-assembled monolayers (FcC n S-/C n S-/ β-cd-au SAMs). We have especially focused on the effects of the alkyl spacer length of the ferrocene adsorbates on the complexation behavior. Before oxidation, our results tend to show that β-cd SAM binds to all of the guests studied except the FcC 11 that is clearly located outside the cavity. With longer alkyl chains (FcC 12, FcC 13, and FcC 15 ) in aqueous solution, the positions of the Fc derivatives within the cavity are almost the same. The free Fc is more deeply inserted into the host cavity than the ferrocenylalkanethiols: the alkyl chains of the ferrocene derivatives largely prevent a deeper insertion of the ferrocene moieties into the β-cd cavity. After oxidation, no release of the included guest molecules upon oxidation is observed even if the simulations highlight that the Fc + is lesser inserted into the β-cd than the Fc in aqueous solution. In fact, this change in the z-positions of the Fc + enables more favorable interactions with both water and β- CD. To study more deeply the association process in aqueous solution, the potential of mean force (PMF) between free Fc + and the grafted β-cd has been calculated. The profile decreases 3107

as Fc + approaches the β-cd, leading to a Gibbs free energy minimum of 15 kj.mol 1 at d = 2 Å. This result clearly evidence a weak association. The thermodynamic parameters are Δ r G = 8.7 kj mol 1 (K = 35), Δ r H = 7.6 kj mol 1, and TΔ r S = 1.1 kj mol 1. The effects of both the coadsorbed chains and the positive charge of the electrode surface (due to the potential range where the Fc moieties are oxidized) in the z-positions of the Fc + have also been studied. Although we observe more mobility of the cation with longer alkylthiolate, the positions of the Fc + center of mass into the cavity of the β-cd SAM remain almost unchanged upon the length of the alkyl thiolate chains. With regard to the effect of the positive charge for Au on the association between Fc + and β-cd, a simple plate capacitor model has been used to evaluate the capacitance. Then, the release of the Fc + from the CD cavity is obtained with twice the value of the capacitance (6.4 μf cm 2 ) showing a weak impact of the positive charge of the electrode surface on the z-positions of the Fc +. AUTHOR INFORMATION Corresponding Author *E-mail: Christine.Bonal@univ-bpclermont.fr. Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS This work was supported by a Contrat d Objectifs Partageś of the CNRS, the Universite Blaise Pascal, and the Conseil Reǵional d Auvergne. REFERENCES (1) Rekharsky, M. V.; Inoue, Y. Complexation Thermodynamics of Cyclodextrins. Chem. Rev. 1998, 98, 1875 1917. (2) Szejtli, J. In Comprehensive Supramolecular Chemistry; Atwood, J. L., Davis, J. E. D., Macnicol, D. D., Vo gtle, F., Szejtli, J., Osa, T., Eds.; Pergamon: Oxford, U.K., 1996; Vol. 5. (3) Martin Del Valle, E. M. Cyclodextrins and Their Uses: A Review. Process Biochem. 2004, 39, 1033 1046. (4) Davis, M. E.; Brewster, M. E. Cyclodextrin-Based Pharmaceutics: Past, Present and Future. Nat. Rev. Drug Discovery 2004, 3, 1023 1035. (5) Szejtli, J. Cyclodextrins and Their Inclusion Complexes; Acadeḿiai Kiado: Budapest, Hungary, 1982. (6) Szejtli, J. Cyclodextrin Technology; Kluwer Academic: Dordrecht, The Netherlands, 1988. (7) Villalonga, R.; Cao, R.; Fragoso, A. Supramolecular Chemistry of Cyclodextrins in Enzyme Technology. Chem. Rev. 2007, 107, 3088 3116. (8) Rojas, M. T.; Ko niger, R.; Stoddart, J. F.; Kaifer, A. E. Supported Monolayers Containing Preformed Bonding Sites. Synthesis and Interfacial Binding Properties of a Thiolated β-cd Derivative. J. Am. Chem. Soc. 1995, 117, 336 343. (9) Domi, Y.; Yoshinaga, Y.; Shimatzu, K.; Porter, M. D. Characterization and Optimization of Mixed Thiol-Derivatized β- CD/Pentanethiol Monolayers with High Density Guest-Accessible Cavity. Langmuir 2009, 25, 8094 8100. (10) David, C.; Millot, M. C.; Renard, E.; Se bille, B. Coupling of Antibodies to β-cyclodextrin-coated Gold Surfaces via an Intermediate Adamantyl-Modified Carboxymethylated Dextran Layer. J. Inclusion Phenom. Macrocyclic Chem. 2002, 44, 369 372. (11) Fragoso, A.; Caballero, J.; Almirall, E.; Villalonga, R.; Cao, R. Immobilzation of Adamantane-Modified Cytochrome C at Electrode Surfaces through Supramolecular Interactions. Langmuir 2002, 18, 5051 5054. 3108 (12) Park, I.-K.; von Recum, H. A.; Jiang, S.; Pun, S. H. Supramolecular Assembly of Cyclodextrin-Based Nanoparticles on Solid Surfaces for Gene Delivery. Langmuir 2006, 22, 8478 8484. (13) Frasconi, M.; D Annibale, A.; Favero, G.; Mazzei, F.; Santucci, R.; Ferri, T. Ferrocenyl Alkanethiols-Thio β-cd Mixed Self-Assembled Monolayers: Evidence of Ferrocene Electron Shuttling through the β- CD Cavity. Langmuir 2009, 25, 12937 12944. (14) Frasconi, M.; Mazzei, F. Electrochemical and Surface Plasmon Resonance Characterization of β-cyclodextrin-based Self-Assembled Monolayers and Evaluation of Their Inclusion Complexes with Glucocorticoids. Nanotechnology 2009, 20, 1 8. (15) Fragoso, A.; Ortiz, M.; Sanroma, B.; O Sullivan, C. K. Multilayered Catalytic Biosensor Self-Assembled on Cyclodextrin- Modified Surfaces. J. Incl. Phenom. Macrocycl. Chem. 2011, 69, 355 360. (16) Ling, X. Y.; Reinhoudt, D. N.; Huskens, J. From Supramolecular Chemistry to Nanotechnology: Assembly of 3D Nanostructures. Pure Appl. Chem. 2009, 81, 2225 2233. (17) Frasconi, M.; Mazzei, F. Electrochemically Controlled Assembly and Logic Gates Operations of Gold Nanoparticle Arrays. Langmuir 2012, 28, 3322 3331. (18) Yang, L.; Gomez-Casado, A.; Young, J. F.; Nguyen, H. D.; Cabanas-Daneś, J.; Huskens, J.; Brunsveld, L.; Jonkheijm, P. Reversible and Oriented Immobilization of Ferrocene-Modified Proteins. J. Am. Chem. Soc. 2012, 134, 19199 19206. (19) Ludden, M. J. W.; Reinhoudt, D. N.; Huskens, J. Molecular Printboards: Versatile Platforms for the Creation and Positioning of Supramolecular Assemblies and Materials. J. Chem. Soc. Rev. 2006, 35, 1122 1134. (20) Matsue, T.; Evans, D. H.; Osa, T.; Kobayashi, N. Electron- Transfer Reactions Associated With Host-Guest Complexation, Oxidation of Ferrocene Carboxylic Acid in the Presence of β-cd. J. Am. Chem. Soc. 1985, 25, 8094 8100. (21) He, P.; Ye, J.; Fang, Y.; Suzuki, I.; Osa, T. Voltammetric Responsive Sensors for Organic Compounds Based on Organized Self- Assembled Lipoyl-β-Cyclodextrin Derivative Monolayer on a Gold Electrode. Anal. Chim. Acta 1997, 337, 217 223. (22) Liu, H.; Li, H.; Wing, T.; Sun, K.; Qin, Y.; Qi, D. Amperometric Biosensor Sensitive to Glucose and Lactose Based on Co- Immobilization of Ferrocene, Glucose Oxidase, β-galactosidase and Mutarotase in β-cyclodextrin Polymer. Anal. Chim. Acta 1998, 358, 137 144. (23) Kaifer, A. E. Interplay between Molecular Recognition and Redox Chemistry. Acc. Chem. Res. 1999, 32, 62 71. (24) Kawajiri, Y.; Motohashi, N. J. Strong Asymmetric Induction without Covalent Bond Connection. J. Chem. Soc., Chem. Commun. 1989, 1336 1337. (25) Fornasier, R.; Reniero, F.; Scrimin, P.; Tonellato, U. Asymmetric Reductions by Sodium Borohydride of Ketone-β-Cyclodextrin Complexes. J. Org. Chem. 1985, 50, 3209 3211. (26) Wang, J. T.; Feng, X.; Tang, L. F.; Li, Y. M. Studies on the Reaction of Acetylferrocene with Aromatic Aldehydes in the Presence of β-cyclodextrin. Polyhedron 1996, 15, 2997 2999. (27) Jeon, W. S.; Moon, K.; Park, S. H.; Chun, H.; Ko, Y. H.; Lee, J. Y.; Samal, S.; Selvapalam, N.; Rekharsky, M. V.; Sindelar, V.; Sobransingh, D.; Inoue, Y.; Kaifer, A.; Kim, K. Complexation of Ferrocene Derivatives by the Curcurbit7uril host: A Comparative Study of the Cucurbituril and Cyclodextrin Host Families. J. Am. Chem. Soc. 2005, 127, 12984 12989. (28) Isnin, R.; Salam, C.; Kaifer, A. E. Bimodal Cyclodextrin Complexation of Ferrocene Derivatives Containing n-alkyl Chains of Varying Length. J. Org. Chem. 1991, 56, 35 41. (29) Nielson, R. M.; Lyon, L. A.; Hupp, J. T. Primitive Molecular Recognition Effects in Electron Transfer Processes: Modulation of Trimethylaminomethyl(Ferrocenium/Ferrocene) Self-Exchange Kinetics via Hydrophobic Encapsulation. Inorg. Chem. 1996, 35, 970 973.

(30) Wang, Y.; Mendoza, S.; Kaifer, A. E. The Electrochemical Reduction of Cobaltocenium in the Presence of β-cyclodextrin. Inorg. Chem. 1998, 37, 317 320. (31) Moozyckine, A. U.; Bookham, J. L.; Deary, M. E.; Davies, D. M. Structure and Stability of Cyclodextrin Inclusion Complexes with the Ferrocenium Cation in Aqueous Solution: 1H NMR Studies. J. Chem. Soc., Perkin Trans. 2 2001, 1858 1862. (32) Goujon, F.; Bonal, C.; Limoges, B.; Malfreyt, P. Description of Ferrocenylalkylthiol SAMs on Gold by Molecular Dynamics Simulations. Langmuir 2009, 25, 9164 9172. (33) Goujon, F.; Bonal, C.; Malfreyt, P. Calculation of the Long Range Interactions for Interfacial Properties. Mol. Simul. 2009, 35, 538 546. (34) Goujon, F.; Bonal, C.; Limoges, B.; Malfreyt, P. Molecular Dynamics Description of Grafted Monolayers: Effect of the Surface Coverage. J. Phys. Chem. B 2008, 112, 14221 14229. (35) Goujon, F.; Bonal, C.; Limoges, B.; Malfreyt, P. Molecular Dynamics Simulations of Ferrocene-Terminated Self-Assembled Monolayers. J. Phys. Chem. B 2010, 114, 6447 6454. (36) Filippini, G.; Goujon, F.; Bonal, C.; Malfreyt, P. Environmental Effect on the Redox Properties of SAMs: A Theoretical Investigation of the Nature of the Supporting Electrolyte. Soft Matter 2011, 7, 8961 8968. (37) Filippini, G.; Bonal, C.; Malfreyt, P. Why Is The Association of Supramolecular Assemblies Different in Homogeneous and Heterogeneous Conditions? Phys. Chem. Chem. Phys. 2012, 10122 10124. (38) Goujon, F.; Bonal, C.; Malfreyt, P. Calculation of the Long Range Interactions for Interfacial Properties. Mol. Simul. 2009, 35, 538 546. (39) Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Gould, I. R.; Merz, K. J.; Ferguson, D. M.; Spellmeyer, D. M.; Fox, T.; Caldwell, J. W.; Kollman, P. A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules. J. Am. Chem. Soc. 1995, 117, 5179 5197. (40) Rai, B.; Sathish, P.; Malhotra, C. P.; Pradip; Ayappa, K. G. Molecular Dynamics Simulations of Self-Assembled Alkylthiolate Monolayers on an Au(111) Surface. Langmuir 2004, 20, 3138 3144. (41) Canongia Lopes, J. N.; do Couto, P. C.; Minas da Piedade, M. E. An All-Atom Force Field for Metallocenes. J. Phys. Chem. A 2006, 110, 13850 13856. (42) Aqvist, J. Ion Water Interaction Potentials Derived From Free Energy Perturbation Simulations. J. Phys. Chem. 1990, 94, 8021 8024. (43) Klaḧn, M.; Seduraman, A.; Wu, P. A Force Field for Guanidinium-Based Ionic Liquids That Utilizes the Electron Charge Distribution of the Actual Liquid: A Molecular Simulation Study. J. Phys. Chem. B 2008, 112, 10989 11004. (44) Abascal, J. L. F.; Vega, C. A General Purpose Model for the Condensed Phases of Water: TIP4P/2005. J. Chem. Phys. 2005, 123, 234505 234516. (45) Kirkwood, J. G. Statistical Mechanics of Fluid Solutions. J. Chem. Phys. 1935, 3, 300 313. (46) Ghoufi, A.; Malfreyt, P. Entropy and Enthalpy Calculations from Perturbation and Integration Thermodynamics Methods using Molecular Dynamics Simulations: Applications to the Calculation of Hydration and Association Thermodynamic Properties. Mol. Phys. 2006, 104, 2929 2943. (47) Prue, J. Ion Pairs and Complexes: Free Energies, Enthalpies, and Entropies. J. Chem. Educ. 1969, 46, 12 16. (48) Shoup, D.; Szabo, A. Role of Diffusion in Ligand Binding to Macromolecules and Cell-Bound Receptors. Biophys. J. 1982, 40, 33 39. (49) Ghoufi, A.; Malfreyt, P. Calculation of the Potential of Mean Force From Molecular Dynamics Simulations using Different Methodologies: An Application to the Determination of the Binding Thermodynamic Properties of an Ion-Pair. Mol. Phys. 2006, 104, 3787 3799. (50) Auletta, T.; de Jong, M. R.; Mulder, A.; van Veggel, F. C. J. M.; Huskens, J.; Reinhoudt, D. N.; Zou, S.; Zapotoczny, S.; Scho nherr, H.; Vancso, G. J.; Kuipers, L. α-cyclodextrin Host-Guest Complexes 3109 Probed under Thermodynamic Equilibrium: Thermodynamics and AFM Force Spectroscopy. J. Am. Chem. Soc. 2004, 126, 1577 1584. (51) Yu, Y.; Chipot, C.; Cai, W.; Shao, X. Molecular dynamics study of the inclusion of cholesterol into cyclodextrins. J. Phys. Chem. B 2006, 110, 6372 6378. (52) DL_POLY is a parallel molecular dynamics simulation package developed at the Daresbury Laboratory Project for Computer Simulations under the auspices of the EPSRC for the Collaborative Computational Project for Computer Simulation of Condensed phases (CCP5) and the Advanced Research Computing Group (ARCG) at the Daresbury Laboratory. (53) Creager, S. E.; Rowe, G. K. Solvent and Double-Layer Effects on Redox Reactions in Self-Assembled Monolayers of Ferrocenyl Alkanethiolates on Gold. J. Electroanal. Chem. 1997, 420, 291 299. (54) Yao, X.; Wang, J.; Zhou, F.; Wang, J.; Tao, N. Quantification of Redox-Induced Thickness Changes of 11-Ferrocenylundecanethiol Self-Assembled Monolayers by Electrochemical Surface Plasmon Resonance. J. Phys. Chem. B 2004, 108, 7206 7212.