Temperature, Solvent, Proton Transfer and Complexation Effectson the Conformational Flexibility of the Anionic Host

Calix[6]arenesulfonate

Julio Alvarez, Yun Wang, Winston Ong and Angel E. Kaifer*

Center for Supramolecular Science and Department of Chemistry, University of Miami,Coral Gables, FL 33124-0431, USA

Abstract—Calix[6]arenesulfonate is a flexible host that adopts the 1,2,3-alternate conformation in DMSO-d6 solution at roomtemperature, as evidenced by 1H NMR spectroscopic data. This conformational preference is lost at higher temperatures or in thepresence of acid. In aqueous media this calixarene exhibits a very simple proton NMR spectrum, reflecting the fast exchangebetween several conformations. Electrochemical data obtained with electroactive guests (ferrocenemethanol [FcOH], ferro-cenylmethyldimethylammonium [FcN+Me3], and cobaltocenium [Cob+]) indicate that the anionic calixarene host forms complexeswith all of them. The stability of the corresponding complexes increases with the number of positive charges on the guest, but theuncharged forms of the guests are also bound. The affinity between the calixarene and the ferrocene-containing guests decreasessubstantially as the solution goes from neutral (pH 7.0) to acidic (pH 2.6). 1H NMR spectroscopic data in neutral aqueous solutionsuggests that the calixarene (18�) adopts the 1,2,3-alternate conformation as it forms very stable ternary complexes with either twoCob+ or two FcN+Me3 guests, respectively. The complex with FcOH is weaker. Overall, our data demonstrate that the con-formational state of this anionic calixarene host is strongly affected by the nature of the solvent, pH, temperature, as well as by thepresence of appropriate guests in the solution.# 2003 Elsevier Science Ltd. All rights reserved.

Introduction

Ever since these compounds were first reported in 1986by Shinkai and coworkers,1a sulfonated calix[n]areneshave been often viewed as promising water-solublehosts.1b Unlike the extensively studied cyclodextrins,2

sulfonated calixarenes have flexible and often poorlydefined cavities that tend to bind positively chargedspecies. Our group has investigated binding interactionsbetween sulfonated calix[6]arenes and ferrocene deriva-tives.3 Coleman and coworkers4 have reported thecomplexation of basic amino acids by sulfonated calix[n]arenes, with n=4, 5 and 6. Arena et al. have estab-lished that sulfonated calix[4]arenes are good hosts fortrimethylammonium aromatic ions.5 Atwood and co-workers crystallized the sodium salt of calix[6]arene-

sulfonate from neutral aqueous solution and determinedby X-ray diffraction that its solid state conformationwas the 1,2,3-alternate.6 In neutral pH solution two ofthe phenolic OH groups in the lower rim of the calix-arene are deprotonated (this is the reason why we willoften formulate this calixarene with eight negativecharges). Each of these charged phenolates establishesstrong hydrogen bonds with its two neighboring OHgroups, helping rigidify the structure (see Chart 1). Inspite of this important contribution, little has been doneto explore the conformational properties of this calix-arene (18�) and their effect on its binding ability. In thiswork, we report on the pH dependence of the hostproperties of 18� with two ferrocene guests, one of themuncharged (FcOH) and the other positively charged(FcN+Me3, see Chart 1 for structures). We also inves-tigate the complexation of cobaltocenium (Cob+) by18�. Finally, we demonstrate that the conformationalstate and overall flexibility of the host is stronglyaffected by a number of factors including temperature,solvent nature, pH and the presence of appropriateguests.

1472-7862/01/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.PI I : S1472-7862(02 )00061-8

Journal of Supramolecular Chemistry 1 (2001) 269–274

*Corresponding author. Tel.: +1-305-284-3468; fax: +1-305-444-1777 or +1-305-284-4571; e-mail: akaifer@miami.edu

Results and discussion

Solvent, pH and temperature effects on the calixareneconformation

At room temperature the 1H NMR spectrum of 18� (2.0mM in D2O) shows only two rather broad peaks at 7.29(Fig. 1) and 3.76 ppm, corresponding to the calixarene’saromatic and methylene protons, respectively. Theobservation of only two peaks is probably a reflection ofthe flexible nature of this calixarene, which undergoesconformational scrambling at a rate fast enough toaverage all the environments sampled by its methylene

and aromatic protons. An alternative explanation canbe proposed; we can also assume that the calixarenepopulates only the highly symmetric 1,3,5-alternateconformation. In this conformation, the calixarenewould yield a simple 1H NMR spectrum composed oftwo singlets corresponding to the aromatic and themethylene protons. However, this possibility is notconsidered very likely, due to the fact that the highlysymmetric 1,3,5-alternate conformation has never beendetected for this or structurally related calixarenes.6,7

In contrast to the spectral pattern detected in pure D2O,the spectrum of 18� (2 mM) in a 50:50 (v/v) D2O/DMSO-d6 mixture shows three peaks in the aromaticregion (7.28, 7.20 and 6.83 ppm, see Fig. 1) and threesets of peaks [4.13(d), 3.61(s) and 3.18(d)] in the meth-ylene region. These patterns are even better defined (thepeaks are less broadened) if the spectrum is recorded inpure DMSO-d6. These observations are in generalagreement with those made by Shinkai and coworkersin their original report.1 Among all the conformationspossible for calix[6]arenes,8 the 1,2,3-alternate is theonly one consistent with the splitting patterns observedin both the aromatic and methylene regions. However,in the 1,2,3-alternate conformation two of the aromaticsignals would be expected to exhibit meta couplings andappear as doublets. Since the coupling constantsbetween aromatic protons in meta positions is typicallysmall (�2.1 Hz) it is possible that the chemicalexchange processes taking place in the calixarene struc-ture would prevent the observation of this coupling. Inorder to corroborate this hypothesis, we recorded theCOSY spectrum of 18� in DMSO-d6. As shown in Fig-ure 2, no cross peaks were observed in the aromaticregion, while the two doublets in the methylene regionare clearly correlated, as anticipated because of theirlarger coupling constant (�12.8 Hz). Our data suggestthat the observation of meta couplings between aro-matic protons in 18� would require a more pronounced

Chart 1. Structures of the host and the three guests used in this work.

Figure 1. 1H NMR spectra (400MHz) of the aromatic protons of host18� at room temperature (A) in D2O, (B) in D2O–DMSO-d6 (1:1, v/v),and (C) in DMSO-d6.

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slowdown of the processes of interconversion betweenthe calixarene’s aromatic rings. Therefore, we concludethat the presence of 50% or more DMSO in the solutionseems to drive host 18� into the 1,2,3-alternate con-formation and slow the exchange between degenerateconformers so that spectral patterns attributable to thisconformation appear in the 1H NMR spectrum. This isof course in excellent agreement with the X-ray crystalstructure determined by Atwood and coworkers.6

Why do DMSO solvent molecules ‘lock’ 18� in the1,2,3-alternate conformation? Since water competesmore effectively than DMSO for hydrogen bonds, theO–H� �O� hydrogen bonds are stronger in DMSO than inaqueous media, thus keeping the calixarene in this con-formational state. To further explore this issue, we addedDCl to a DMSO-d6 solution of 18� and recorded the 1HNMR spectrum. The results are shown in Figure 3. Theaddition of DCl clearly results in conformational scram-bling and loss of the 1,2,3-alternate conformer’s NMRsignature. This is due to the protonation of the two phe-nolates and subsequent weakening of the hydrogen bond-ing network that rigidifies the calixarene. The effect is fullyreversible and the spectral patterns corresponding to the1,2,3-alternate conformer dominate the spectrum obtainedafter neutralization of the acid with NaOD (Fig. 3).

In pure DMSO it should be possible to induce con-formational scrambling by increasing the temperature.The results of the corresponding series of variable tem-perature experiments are summarized in Figure 4. Asanticipated, increasing the temperature broadens all theproton resonances of the 1,2,3-alternate conformer andeventually leads to the observation of a single aromaticproton and a single methylene proton for the host. Thecoalescence temperature was estimated from theseexperiments to be 67 �C.

Guest complexation studies

All guests selected for this study are electroactive. Bothferrocene derivatives undergo reversible one-electronoxidations to their ferrocenium forms, while cobalt-ocenium can be reversibly reduced to neutral cobalt-ocene. Therefore, a simple way to screen for the possibleformation of stable complexes is to compare the vol-tammetric behavior of the guests in the absence and inthe presence of the host. Figure 5 shows the cyclic vol-tammetric behavior of FcOH in aqueous solution buf-fered at pH 7, in the absence and in the presence of 4equiv of host 18�. Clearly the addition of host has astrong effect on the apparent half-wave potential for theoxidation of the ferrocene derivative, which shifts 120

Figure 2. COSY spectrum (400MHz) of 18� at room temperature in DMSO-d6 solution.

J. Alvarez et al. / Journal of Supramolecular Chemistry 1 (2001) 269–274 271

mV to more negative values. This potential shift clearlyreveals that the calixarene host provides a stronger sta-bilization to the oxidized form of the guest. However,the reduced form is also bound as evidenced by thedecrease observed in the anodic peak current value.Table 1 provides a summary of the pertinent voltam-metric parameters obtained with all three guests inaqueous solutions buffered at pH 2.6 and 7.0. Severalclear trends emerge from the data. First, the presence ofcalixarene 18� at neutral pH has a pronounced effect on

the half-wave potentials and peak currents associatedwith the oxidation of both ferrocene-containing guests.The observed values reveal that both the reduced(ferrocene) and oxidized (ferrocenium) forms of theseguests are bound to the calixarene host. However, thedirection of the host-induced E1/2 shift (to less positivevalues) indicates that the ferrocenium form is morestrongly bound in both cases, probably due to increasedelectrostatic attraction between the host and the guest.The electrochemical parameters follow the same generaltrend in solutions buffered at pH 2.6, but the magnitudeof the calixarene-induced changes is much less pro-nounced. This reveals that the binding interactions ofthe calixarene with both oxidation states of the ferro-cenyl guests are weaker at pH 2.6 than they are at pH

Figure 3. 1H NMR spectrum (400MHz) of the aromatic protons of18� at room temperature in DMSO-d6 (A) before addition of acid orbase, (B) after addition of DCl, and (C) after neutralization of theadded DCl with NaOD.

Figure 4. 1H NMR spectrum (400MHz) of the aromatic protons of18� (2 mM in DMSO-d6) at several temperatures.

Figure 5. Cyclic voltammetric response on a glassy carbon workingelectrode of a 1.0 mM FcOH solution in 0.1M phosphate buffer (pH7) in the absence (continuous line) and in the presence (dotted line) of4 mM calixarene host. Scan rate: 0.1 V/s.

Table 1. Voltammetric parameters for several redox active guests (1.0

mM) in aqueous media at 25 �C in the absence and in the presence of

variable concentrations of calixarene host 18�

Guest [18�]/[Guest]

pH 7.0a pH 2.6b

E1/2

(V)cip

(mA cm�2)dE1/2

(V)cip

(mA cm�2)d

FcOH 0:1 0.234 337 0.227 1841:1 0.175 260 0.215 1854:1 0.114 274 0.191 165

FcN+Me3 0:1 0.446 216 0.441 1751:1 0.342 144 0.411 1705:1 0.331 140 0.393 142

Cob+ 0:1 �1.11e 334e NA NA1:1 �1.23e 150e NA NA4:1 �1.27e 137e NA NA

NA, not accessible as the Cob+/Cob reduction wave cannot berecorded at this pH value due to hydrogen evolution at the electrodesurface.aMedium: 0.1M phosphate buffer.bMedium: 0.1M chloroacetate buffer.cHalf-wave potentials measured against a Ag/AgCl reference elec-trode.dPeak current densities, cathodic for Cob+ and anodic for FcOH andFcN+Me3.eThese values are strongly affected by precipitation of the reduced form(cobaltocene) on the electrode surface. To minimize these problems thehalf-wave potentials were measured by normal pulse voltammetry.

272 J. Alvarez et al. / Journal of Supramolecular Chemistry 1 (2001) 269–274

7.0. At pH 2.6 the calixarene is best formulated as 16�,but the decrease in binding strength appears to be somarked that more than electrostatics (8 vs 6 negativecharges on the host) seems to be at play here (videinfra). The half-wave potential for the reduction ofCob+ also shifts in the same direction (to more negativevalues) upon addition of 18�, suggesting that the oxi-dized form (Cob+) is more strongly complexed than thereduced one (Cob), in general agreement with the dataobtained with the two ferrocenyl guests.

In principle, it should be possible to perform digitalsimulations of the voltammetric data and fit the experi-mental current-potential curves to those simulated usinga model that includes binding equilibria between bothoxidation states of the guest and the host. From theoptimization of the fits, thermodynamic and/or kineticparameters for the binding equilibria should be acces-sible. We did attempt to follow this approach, butquickly realized that the number of parameters to beobtained from the simulations was too large and anyvalues determined in this way would be affected byunacceptably large error margins. Therefore, we decidedto complete our investigation of this host and its com-plexes using 1H NMR spectroscopy.

The chemical shift of the unsubstituted cyclopentadienylring protons of FcOH is strongly affected by the pre-sence of 18� in aqueous solution buffered at pH 7, inexcellent agreement with the electrochemical results.Figure 6A shows the corresponding concentrationdependence. Notice that the chemical shifts do not leveloff even after adding more than 4 equiv of host, sug-gesting the formation of a relatively weak complexbetween FcOH and the calixarene host. By contrast,Figure 6B shows the variation of the chemical shift ofthe Cob+ protons upon additions of 18�. In this case,the chemical shift levels off very quickly after the addi-tion of 0.5 equiv of host, indicating the formation of astrong 2:1 complex (Cob+)2.1

8� in solution. The beha-vior observed with FcN+Me3 is similar to that observedwith Cob+. It is also very illustrative to monitor the 1HNMR spectrum of host 18� as increasing concentrationsof Cob+ are added to the solution. Figure 7 shows theresults of these experiments for both the aromatic andthe methylene protons of the calixarene. Notice that thesingle aromatic peak of the calixarene splits into threeresonances when the concentration of Cob+ guestbecomes approximately twice as large as that of the host(Fig. 7A). Similar data was obtained for the methyleneprotons (Fig. 7B). These results clearly indicate the for-mation of a stable 2:1 complex in which the calixareneadopts a 1,2,3-alternate conformation, rigid enough tobe clearly detected in the time scale of the NMRexperiments. Very fittingly, in this conformation thecalixarene host presents two identical cavities, eachhaving four negative charges. The 2:1 complex is pre-sumably formed by docking of a Cob+ guest againsteach of these two cavities. We have already reportedpreliminary 1H NMR spectroscopic evidence for theformation of a 2:1 complex, (Cob+)2.1

8�, in which thecalixarene adopts a rather rigid 1,2,3-alternate con-formation.9 Similar data (not shown) were obtained

Figure 6. Dependence of the chemical shift of guest protons (at a fixed2 mM concentration in 0.1M phosphate buffer pD 7) on the addedconcentration of calixarene host: (A) data for the protons of theunsubstituted cyclopentadienyl ring of guest FcOH; (B) data for theprotons of the Cob+ guest.

Figure 7. Observed chemical shifts for the protons of host 18� (at afixed 2 mM concentration in 0.1M phosphate buffer pD 7) as a func-tion of increasing concentrations of added Cob+ guest: (A) aromaticprotons; (B) methylene protons.

J. Alvarez et al. / Journal of Supramolecular Chemistry 1 (2001) 269–274 273

with FcN+Me3. Again, the results point to the form-ation of a 2:1 complex, although its overall stability issomewhat lower than that of (Cob+)2.1

8� complex.Finally, additions of the neutral guest FcOH do not lead tothe detection of the spectral signature of the 1,2,3-alternateconformation for 18�, a finding that indicates the lowerstability of the corresponding host–guest complex.

The stability of the (Cob+)2.18� complex in neutral

aqueous media prompted us to investigate its formationin DMSO-d6 solution. The

1H NMR spectrum of 18� inthe presence of 2 equiv of Cob+ is shown at the bottomof Figure 8. Clearly, the spectrum indicates that thecalixarene adopts the 1,2,3,-alternate conformation, asit usually does in DMSO solutions. Strong evidence forthe formation of the complex can be obtained byrecording variable temperature spectral data (Fig. 8).Our results show that the spectral signature of the 1,2,3-alternate conformation gradually disappears as thetemperature increases, eventually leading to the simplerspectrum composed of two singlets (one for the aro-matic and another for the methylene protons). In thepresence of 2 equiv Cob+, the coalescence temperatureis substantially higher (96 �C) than that obtained in theabsence of Cob+ (Fig. 4), reflecting the additional sta-bilization of the 1,2,3-alternate conformer by com-plexation with the Cob+ guests. Similar variabletemperature experiments in the presence of 2 equiv of acationic ferrocene guest (FcN+Me3) afforded a coales-cence temperature of 85 �C (data not shown), whichsupport our previous conclusion on the lower stabilityof the complex between this guest and 18� compared tothat formed with Cob+ as the guest.

Experimental

The calixarene host was prepared as reported by Shinkaiand coworkers.1a The bromide salt of the cationic guestFcN+Me3 was prepared as reported by our group.10

FcOH and Cob+.PF6� were purchased from Aldrich and

used without further purification. All other reagents andsolvents were of the best grade commercially available. 1HNMR spectra were recorded in a Varian VXR-400-S andBruker Avance spectrometers operating at 400MHz.Electrochemical experiments were performed in a BAS 100B/W workstation (Bioanalytical Systems, West Lafayette,IN, USA). A glassy carbon electrode, a Pt counter-electrode and a Ag/AgCl reference electrode were fitted toa single-compartment electrochemical cell. The surface ofthe working electrode was polished with a 0.05-mm alu-mina water slurry on a felt surface and rinsed with purifiedwater before use. The solutions for the electrochemicalexperiments were purged with nitrogen and kept under anitrogen atmosphere throughout the measurements.

Conclusions

The results reported here clearly reveal that the calix-arene host 18� adopts a 1,2,3-alternate conformation insolution under conditions that favor strong O–H� �O�

bonds. In this work, we have demonstrated that the hostmay lose this conformational rigidity and populatefloppier conformational states. Temperature, protontransfer reactions, host–guest complexation reactionsand solvent nature can all be utilized to reversibly controlthe conformational state of this anionic calix[6]arene.

Acknowledgements

The authors acknowledge the generous support of thisresearch from the NSF (to A.E.K. CHE-9982014).

References and notes

1. (a) Shinkai, S.; Mori, S.; Koreishi, H.; Tsubaki, T.; Manabe,O. J. Am. Chem. Soc. 1986, 108, 2409. (b) Casnati, A.; Sciotto,D. In Calixarenes 2001; Asfari, Z., Bohmer, V., Sciotto, D.,Vicens, J., Eds.; Kluwer: Dordrecht, 2001; pp 440–456.2. Connors, K. A. Chem. Rev. 1997, 97, 1325.3. (a) Zhang, L.; Macıas, A.; Lu, T.; Gordon, J. I.; Gokel,G. W.; Kaifer, A. E. J. Chem. Soc., Chem. Commun. 1993,1017. (b) Alvarez, J.; Wang, Y.; Gomez-Kaifer, M.; Kaifer,A. E. Chem. Commun. 1998, 1455.4. Douteau-Guevel, N.; Coleman, A. W.; Morel, J.-P.; Morel-Desrosiers, N. J. Phys. Org. Chem. 1998, 11, 693.5. Arena, G.; Casnati, A.; Contino, A.; Lombardo, G. G.;Sciotto, D.; Ungaro, R. Chem. Eur. J. 1999, 5, 738.6. Atwood, J. L.; Clark, D. L.; Juneja, R. K.; Orr, G. W.;Robinson, K. D.; Vincent, R. L. J. Am. Chem. Soc. 1992, 114,7558.7. We have also determined the crystal structure of a methylatedcalix(6)arene analogue and found that it also adopted the 1,2,3-alternate conformation. See: Castro, R.; Godınez, L. A.; Criss,C. M.; Bott, S. G.; Kaifer, A. E. Chem. Commun. 1997, 935.8. Atsushi, I.; Shinkai, S. Chem. Rev. 1997, 97, 1713.9. Wang, Y.; Alvarez, J.; Kaifer, A. E. Chem. Commun. 1998,1457.10. Isnin, R.; Salam, C.; Kaifer, A. E. J. Org. Chem. 1991, 56, 35.

Figure 8. 1H NMR spectrum (400MHz) of the aromatic protons of18� (2 mM in DMSO-d6) in the presence of 2 equiv of of Cob+ atseveral temperatures.

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