Tri-ionizable calix[4]arene ligands: synthesis and lanthanide ion complexation

New proton-ionizable p-tert -butylcalix-4-arene ligands with three N -(X)sulfonyl oxyacetamide groups and one methoxy group on the lower rim capable of forming electroneutral complexes with trivalent lanthanide ions are synthesized. Variation of the electron-withdrawing ability of X (Me, Ph, C 6 H 4 -4-NO 2 , CF 3 ) is used to tune the ligand acidity. Conformations of the ligands in CDCl 3 are investigated by variable temperature NMR spectroscopy. By potentiometric titration, complexation of La 3+ , Eu 3+ , and Yb 3+ by the tri-ionizable complexing agents in MeOH is probed.


Introduction
2][3][4][5][6][7][8][9] By attachment of functional groups to the lower rim of calix [4]arene, new metal ion complexing agents with high selectivity have been discovered.Of special interest in our laboratories are calix [4]arenes with pendent proton-ionizable groups 10,11 since these ligands generally provide stronger binding of cationic species than their neutral analogues.Also when the number of acidic sites in the side arms of the ligand matches the charge on the metal ion an electroneutral complex is formed.For a solvent extraction process, this eliminates the need to transport one or more anions from an aqueous phase into the organic diluent, thereby markedly enhancing metal ion extraction efficiency.This is especially important when highly hydrophilic aqueous phase anions of chloride, nitrate, and sulfate are involved.1] The acidity of the ligand was 'tuned" by variation of the electronwithdrawing ability of X.We now turn our attention to complexing agents for trivalent lanthanide ions.Herein we report the synthesis of tri-ionizable p-tert-butylcalix [4]arene analogues 5-8 (Figure 2) and the initial evaluation of their complexation of selected trivalent lanthanide ions in MeOH by potentiometric titration.In this series of ligands, variation of the electron-withdrawing properties of X should change the acidity.Some conformational flexibility is anticipated due to the small methyl group that is used to cap the fourth phenolic oxygens.

Ligand synthesis
The synthetic route to the tri-ionizable calix [4]arene ligands 5-8 is shown in Scheme 1.
The initial attempt to monomethylate p-tert-butylcalix [4]arene 9 by its reaction with K2CO3 and MeI in MeCN at reflux 13 gave mostly dimethylated product.Subsequently, the monomethyl ether 10 was realized in 60% yield by reaction of 9 with CsF and MeI in DMF at 40 o C. 13 The reported reaction of 10 with K2CO3 and ethyl bromoacetate in MeCN at reflux 14 gave a 50% yield of triester 11.The IR spectrum of 11 showed two different carbonyl absorptions at 1741 and 1758 cm -1 .Basic hydrolysis of triester 11 followed by acidification gave an 80% yield of tri(carboxylic acid) 12. Refluxing 12 with an excess of oxalyl in benzene gave tri(acid chloride) 13, which was used directly in the next step.In the IR spectrum of 13, the carbonyl and O-H stretching absorptions of 12 were replaced by a new carbonyl absorption at 1809 cm -1 .From reactions of tri(acid chloride) 13 with the sodium salts of commercially available sulfonamides in THF, the tri-ionizable calix [4]arene ligands 5-8 were obtained in 52-65% overall yields from tri(carboxylic acid) 12. Structures of new compounds 5-8 and 12 were verified by IR and NMR spectroscopy and confirmed by combustion analysis.
Attachment of groups larger than ethyl to the lower-rim oxygens of calix [4]arenes restricts oxygen-through-the-annulus rotation of the arene units. 14  The 1 H-NMR spectra of ligands 5-8 feature two pairs of doublets for the methylene groups that bridge the arene units (ArCH2Ar) (in 7 at 3.20 and 3.33 ppm for the pseudo equatorial protons and 4.11 and 4.29 ppm for the pseudoaxial protons).A pair of doublets for the diastereotopic protons in the two equivalent OCH2C(O) groups (in 7 at 4.47 and 4.58 ppm) and a singlet for the nonequivalent OCH2C(O) group (in 7 at 4.56 ppm) are also observable.Two nonequivalent N-H groups appears as a pair of broad singlets at 9.60-10.00ppm, except for compound 8 due to the stronger acidic character when X = SO2CF3.
The new tri-ionizable calix [4]arenes are conformationally flexible.When the 1 H-NMR spectrum of compound 6 was taken in CDCl3 at 23 o C, no signal was observed for the OCH3 protons.When the temperature was increased to 45 o C, a broad peak at 3.53 ppm was seen.When the temperature was equal to or below 0 o C, a broad peak emerged at 3.76 ppm.This behavior is interpreted in terms of a cone conformation that interconverts to a partial cone conformation slowly on the NMR time scale at lower temperature but rapidly at higher temperature.The resonances arising from the bridge methylene protons appear as two pairs of doublets at 45 o C in the region of 3.00-4.50ppm.The higher field pair of doublets corresponds to the pseudo-equatorial protons (closer to aromatic rings) and the lower field pair of doublets to the pseudo-axial protons (closer to the ether linkage).The closest pseudo-equatorial protons to the OCH3 group are strongly affected by variations in temperature.At 45 o C, they appeared as a sharp doublet at 3.24 ppm, but when the temperature was decreased the peaks become broader and almost collapse into the other pseudo-equatorial protons peak at -20 o C.This is explained in terms of the conformationally mobile character of the aromatic ring holding the OCH3 group in compound 6.

Complexation of trivalent lanthanides
Since the new ligands 5-8 (Figure 2) behave as acidic ligands (LH3), the first estimation of their binding properties towards some lanthanide ions was obtained potentiometrically.Stability constants βxyz of the complexes, corresponding to the overall equationxLn 3+ + YL 3-+ zH + ↔ LnxLyHz (3x-3y+z)+ (1) were determined in MeOH in the presence of 10 -2 M Et4NCl as the background electrolyte using a competitive method with the protons.The experimental procedure has been previously described in detail. 15n a first step, the acid-base behavior of ligands 5-8 was investigated.Interpretation of the titration curves for ligands 5-7 (Figure 4) confirmed their tri-acidic character leading to the values of the ionization constants, pKa,n, given in Table 1.The pKa,n values for ligands 5 and 6 are nearly the same due to the similarity of the electron-withdrawing abilities of the X groups in the OCH2C(O)NHSO2X side arms. 16Due to stronger electron-withdrawal when X = C6H4-4-NO2 than Me and Ph, the pKa,n values shift appreciably lower.Ligand 8 behaved quite differently.The titration curve showed a drop of potential (i.e., an increase in pH) from the beginning with no inflexion points.We are unable to interpret this behavior at present.Titration curves for ligand 5 in the presence of one equivalent of La 3+ , Eu 3+ and Yb 3+ (Figure 5) and of the three ligands 5-7 in the presence of La 3+ (Figure 4) showed equivalence points near three equivalents of base, consistent with the participation of the three N-(X)sulfonyl carboxamide groups to the complexation and the formation of 1:1 (Ln:L) complexes and possibly the corresponding protonated species.After these equivalences, the shape of the titration curves suggested the formation of methoxy species.The simplest models fitting satisfactorily the experimental data are given in Table 2.However, it must be said that certainly additional methoxy species should form besides the LnL(MeO) -complex, since the fit in this region still has to be improved.The results show no important selectivity of ligand 5 in the series.Lanthanum complexes with ligand 7 are the least stable.This is in agreement with the acidity of this ligand, as shown by linear correlation between log β110 and Σ(pKa,n) (Figure 6) and confirms the predominance of electrostatic interactions in the stability of these complexes.

Experimental Section
General.Reagents were purchased from commercial suppliers and used as received unless otherwise indicated.Tetrahydrofuran (THF) was dried over sodium with benzophenone as an ARKAT USA, Inc.
indicator and distilled immediately before use.Dimethylformamide (DMF), benzene, and acetonitrile were stored over 4 Å molecular sieves.Potassium carbonate and cesium fluoride were activated by heating at 120 o C under oil pump vacuum overnight just before use.Melting points were determined with a Mel-Temp melting point apparatus.Infrared (IR) spectra were recorded with a Perkin-Elmer Model 1600 FT-IR spectrometer on a NaCl plate (film deposited from CH2Cl2 solution) and are reported in wavenumbers (cm -1 ).(12).To triester 11 (1.68 g, 1.83 mmol) in THF (75 mL) was added Me4NOH (80 mL of 7.8 % aq solution) and the mixture was refluxed for 30 h.The THF was evaporated in vacuo and the residue was acidified to pH<1 (8 mL of conc HCl).After extraction with CH2Cl2 (75 mL), the aqueous phase was back-extracted with CH2Cl2 (25 mL).

Potentiometric titrations
The experiments were performed at 25 o C with a combination glass electrode (Mettler U402/S7/120) connected to an automatic titrator (Metrohm 716 DMS Titrino) at 25 °C.The standard filling solution (saturated aq KCl) of the external reference of the combination glass electrode was replaced by a 10 -2 M solution of Et4NCl in MeOH saturated in AgCl.The electrode was calibrated by titration of a 1.0 mM solution of HClO4 with a 10 mM solution of Me4NOH, previously standardized with potassium phthalate.The stability constants of the lanthanide complexes with these ligands were determined by acid-base titration of the ca.1.0 mM ligand solutions containing one equivalent of the metal cation with a concentrated Et4NOH solution.The titration data were interpreted using the programs Sirko 18 and Hyperquad. 19The protonation constants of the L 3-ligands, previously determined from titrations without the metal ions, were held constant during the refinement procedure.The autoprotolysis constant used for the calculations was pKMeOH = 16.7. 20

Figure 4 .
Figure 4. Potentiometric titration curves for ligands 5-7 in MeOH in the absence and presence of La. 3+
Therefore, ligands 5-8 have one mobile arene unit with two possible limiting conformations: cone and partial cone (paco).The broadened signals observed in the 1 H-NMR spectra for the OCH3 group (e.g., at 3.52 ppm in 7) indicate that conformational interconversions are taking place in CDCl3.

Table 2 .
Overall stability constants of some lanthanide complexes in MeOH at 25 ºC