DOI: 10.1002/cphc.200600772

133Cs Diffusion NMR Spectroscopy:A Tool for Probing Metal Cation–pInteractions in Water

Diana Cuc,[a] Daniel Canet,[a] Jean-Pierre Morel,[b]

Nicole Morel-Desrosiers,[b] and Pierre Mutzenhardt*[a]

The non-covalent interaction between a cation and a p-system, the so-called cation–p interaction, has attracted muchinterest during the past two decades because it plays an im-portant role in supramolecular chemistry and biology.[1] This in-teraction is basically electrostatic but recent theoretical studieshave shown that induction, dispersion and charge-transfercontributions are also crucial.[2] The interaction energy happensto be strong in the gas phase; however, it is much weaker andfairly specific in aqueous media where the cation is stronglysolvated. As a result, it is difficult to evidence experimentally,without ambiguity, this type of interaction in water.[3] Recently,some of us did overcome the difficulty by using highly sensi-tive microcalorimetry.[4] This technique is a powerful tool formeasuring the thermodynamic parameters that characterize in-teracting molecules because it not only gives the enthalpychanges but also yields the association constants, even in thecase of weak interactions. Although NMR spectroscopy andmore specifically diffusion NMR spectroscopy are widely usedin supramolecular chemistry,[5] it has never been applied tostudy cation–p interactions in water. Herein, we introducecesium diffusion NMR measurement as a possible tool forquantifying the association constant between a cation and ap-system in a homogeneous aqueous phase.

Calixarenes and calixarene-crown ethers, which are com-posed of phenol units connected by ortho-methylene bridges,belong to the most widely studied class of synthetic iono-phores and many reviews list the abundant literature on thesubject.[6] The p-sulfonatocalixarenes, which are largely solublein water and can complex a variety of guests in this solvent,are suitable receptors for the study of cation–p interactions inaqueous media. Some of us did investigate the binding of thep-sulfonatocalix[4]arene (SC4; see Scheme 1) with variousmetal cations in water using microcalorimetry: the monovalentand multivalent ions yielded completely different sets of ther-

modynamic parameters.[4,7] In spiteof an unfavorable enthalpy of reac-tion, the binding of an earth-alkalior lanthanide metal cation is rela-tively strong (K�103–104) due to avery favorable entropy of reactionthat largely controls the bindingprocess.[7] Such a thermodynamicbehavior (DrH8>0 and TDrS8@0) istypically encountered upon forma-tion of an ion pair in water and es-sentially reflects the desolvation of the ions upon binding.[8] Inthis case, it clearly indicates that the di- or trivalent metalcation remains outside the calixarene cavity where it forms anouter-sphere (solvent-mediated) complex with the SO3

�

groups of the calixarene; this was confirmed by molecular dy-namics simulations of the La3+–SC4 complex in water.[9] Insharp contrast, the binding of the alkali metal cations is veryweak (K�10) and enthalpy-driven.[4] Such a thermodynamicbehavior (DrH8<0 and TDrS8<0) does, in this case, indicatethat the monovalent metal cations bind inside the calixarenecavity through cation–p interactions. We now want to investi-gate these inclusion complexes by NMR spectroscopy.

Among the alkali metal ions, cesium is particularly appealingdue to its NMR properties. Only one stable cesium isotope(133Cs) is NMR-active with 100% of natural abundance. It pos-sesses an absolute sensitivity roughly 280 times greater than13C allowing NMR measurements at ion concentration samplesin the millimolar range. Moreover, the 133Cs chemical shift isvery sensitive to the cesium chemical environment and canthus be used to characterize its complexation.[10] Another im-portant property of this cesium isotope is that its quadrupolarmoment is small albeit its spin is 7/2. Therefore, relatively longrelaxation times (longitudinal T1 and transversal T2 relaxationtimes) are observed and should allow us to perform 133Cs diffu-sion NMR experiments. To the best of our knowledge, the useof cesium in diffusion NMR measurements has been scarcelyreported.[11]

1H, 13C and 133Cs NMR spectra of the mixtures were recorded(see the Supporting Information). They reveal that the systemis in fast exchange relative to the chemical shift timescale—only a single “averaged” resonance is detected for all nuclei.The 1H chemical shifts of SC4 were analyzed by the Jobmethod of continuous variations (see Figure SI1 in the Sup-porting Information), which confirmed an assembly with a 1:1ratio formed in solution. Thus, the chemical shifts of SC4 werefitted to a 1:1 binding model using WinEQNMR software.[12] Anassociation constant K=21�9 Lmol�1 was found in goodagreement with microcalorimetry results. It must be empha-sized that the total chemical shift variation is very small,Dd(SC4, aromatic proton)=0.045 ppm. To confirm the forma-tion of a complex in aqueous solution, structural evidence hasto be found. The conformations of calix[4]arenes in solutioncan be deduced from the 13C chemical shift of methylenegroups connecting each pair of aromatic rings.[13] The value of30.975 ppm for free SC4 increases to a maximum of31.005 ppm for mixtures proving a syn-conformation of the

[a] D. Cuc, Prof. D. Canet, Prof. P. MutzenhardtUMR SRSMC 7565, Nancy-Universit#, CNRSM#thodologie RMNFacult# des Sciences et Techniques, BP 23954506 Vandoeuvre-les-Nancy Cedex (France)Fax: (+33)383-684-347E-mail : Pierre.Mutzenhardt@rmn.uhp-nancy.fr

[b] Prof. J.-P. Morel, Prof. N. Morel-DesrosiersLaboratoire de Thermodynamique des Solutions et des Polym:resUMR CNRS 6003, Universit# Blaise Pascal (Clermont-Ferrand II)24 avenue des Landais, 63177 Aubi:re Cedex (France)

Supporting information for this article is available on the WWW underhttp://www.chemphyschem.org or from the author.

Scheme 1. Structure of p-sul-fonatocalix(4)arenes (SC4).

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phenol rings (i.e. a cone conformation). One must recognizethat it is difficult to obtain information proving the formationof an inclusion complex in aqueous solution because the usualNMR techniques based on the nuclear Overhauser effectcannot be applied here. Therefore, we anticipate that the mea-surement of the translational diffusion coefficient can give usthe relevant information. These measurements were performedon SC4 by 1H NMR spectroscopy and, in a more unusual way,on the cesium ion by 133Cs NMR measuremanets (Figure 1). Theapparent diffusion (Cs or SC4) coefficients obtained can be ex-pressed as shown in Equation (1):

Dobs ¼ Xbound � Dbound þ ð1�XboundÞ � Dfree ð1Þ

where Xbound is the fraction of the complex and D is the diffu-sion coefficient.

From the apparent diffusion coefficients measured on thehost (SC4, Figure 2), we observe that the apparent diffusion co-

efficient of SC4 remains constant and close to thevalue of free SC4 molecule (D=3.50�0.05L10�10 m2s�1). This type of evolution is generally metwhen the host molecule is much larger than theguest molecule or in the presence of an inclusioncomplex. A more detailed inspection of the apparentdiffusion coefficients of SC4 shows that they areslightly higher than those of the free form (up to7%). By considering the Stokes–Einstein diffusionequation, this reflects a slight reduction of the hydro-dynamic radius of the diffusing species, and can alsobe considered as an indication for the presence of aninclusion complex. Cesium diffusion coefficients ex-hibit a more significant variation compared withproton chemical shifts. From each measurement(Figure 2), it is possible to calculate directly the frac-tion of the complex, Xbound, using Equation (1). HereDbound was set equal to the free diffusion coefficientof SC4 and Dfree was set equal to the free diffusioncoefficient of cesium. The association constant canbe calculated directly, this constitutes a well-known

advantage compared with the determination by titration tech-niques.[14] A value of K=22�9 Lmol�1 was found which is invery good agreement with the value obtained by proton titra-tion and microcalorimetry techniques. Obviously, the accuracyof the K values depends on the molecular fraction (see theSupporting Information) and it becomes satisfactory when thehost molecule (SC4) is in excess.

In conclusion, we stress that 133Cs pulsed-gradient spin echo(PGSE) diffusion data (D values) are appropriate to recognizeassociation phenomena. It could constitute a valuable tool insupramolecular chemistry and biology to derive associationconstants, in particular when the proton chemical shiftchanges are weak. The combination of 1H and 133Cs NMR tech-niques demonstrates the existence of an inclusion complexwhere association is driven by cation–p interactions.

Experimental Section

25,26,27,28-Tetrahydroxy-5,11,17,23-tetrasulfonatocalix[4]arene(SC4), purchased from ACROS, was decolorized by adsorption onactive carbon, dried under vacuum at 80 8C and used without fur-ther purification. CsCl was bought from Merck (suprapur). All solu-tions were prepared from triply distilled water. D2O (10% v/v) wasused. Details about the samples are given in the Supporting Infor-mation. All the NMR experiments were carried out at 298 K.1H NMR spectra for titration experiments and 13C NMR spectra wererecorded on an Bruker AVANCE 600 MHz operating at 14.1 T fittedwith a 1H/13C/15N triple resonance cryoprobe. 1H and 133Cs diffusionNMR experiments were recorded on an Bruker AVANCE 400 MHzspectrometer operating at 9.4 T and equipped with 1H/13C/BB tripleresonance probe fitted with a 56.3 Gcm�1 Z-gradient coil. Longitu-dinal relaxation times (T1) of cesium were measured using the in-version recovery technique. T1 values range from 11.2 s for freecesium down to 1.5 s for mixtures. Transversal relaxation times (T2)of cesium were measured using the Carr–Purcell–Meiboom–Gill(CPMG) technique. T2 values range from 10.60 s for free cesiumdown to 1.11 s for mixtures. Stimulated echo bipolar longitudinaleddy-current delay (LED) diffusion sequence[15] was used with

Figure 1. 133Cs NMR diffusion data showing the signal decay as a function of the gradientstrength (9.4 T, 52.48 MHz, 298 K) ; ~: mixture ([Cs]=5.53 mm, [SC4]=27.67 mm),D=1.28L10�10 m2 s�1; * : free cesium in a capillary (external reference), [Cs]=33.2 mm,D=1.82L10�9 m2 s�1.

Figure 2. Evolution of the apparent diffusion coefficient of cesium ions (&)and p-sulfonatocalix[4]arene (aromatic proton, *) as a function of the molec-ular fraction in SC4.

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shaped gradient pulses to avoid any misinterpretation due tochemical exchange; a WATERGATE scheme[16] has been used toeliminate the water resonance for proton diffusion measurements.A capillary containing a solution of free cesium was inserted in allsample and serves as a reference for diffusion experiment. For133Cs diffusion NMR spectroscopy (52.45 MHz), a typical diffusion in-terval of 3 s was used with 3 ms gradient pulse lengths; for eachdiffusion experiment at least 16 spectra resulting from a linear var-iation of the gradient amplitude were acquired. The number ofscan (up to 128) was optimized for each sample depending on thecesium concentration. Diffusion coefficients were extracted usingthe Bruker XWINNMR software (version 3.5).

Acknowledgements

Support from the Service de Biophysicochimie des InteractionsMol#culaire (UHP) and Service Commun of RMN (UHP) is ac-knowledged. D.C. is supported by a PhD French ministerial fel-lowship.

Keywords: cation–p interactions · cesium · diffusion · host–guest systems · NMR spectroscopy

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Received: December 20, 2006Published online on February 15, 2007

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