Tetrakis(imidazolium) macrocyclic receptors for anion binding

Wallace W. H. Wong, Matthew S. Vickers, Andrew R. Cowley, Rowena L. Paul and Paul D. Beer*
Department of Chemistry, Inorganic Chemistry Laboratory, University of Oxford, South Parks Road, Oxford, OX1 3QR. E-mail: paul.beer@chem.ox.ac.uk

Received 15th July 2005, Accepted 10th October 2005

First published on 31st October 2005


Abstract

New (tetrakis)imidazolium macrocyclic receptor systems of variable cavity size have been synthesised by stepwise alkylation reactions of bis(imidazolium) precursor compounds. Proton NMR titration studies reveal the macrocycles to strongly bind halide and benzoate anions, with two receptor systems displaying notable selectivity for fluoride in competitive acetonitrile–water (9 : 1) solvent media.


1. Introduction

Stimulated by the important role negatively charged species play in biological systems, medicine and the environment, interest in the synthesis of new host molecules designed to recognize and sense anions is ever increasing.1 Positively charged ammonium, guanidinium2 and neutral amide, urea and pyrrole groups3 have all been incorporated into various molecular frameworks to produce receptor systems capable of binding anions of diverse sizes and geometries.

The imidazolium moiety has been recently shown to be an effective motif for complexing anions via favourable electrostatic interactions and hydrogen bonding.4 Although various acyclic imidazolium receptors have been described,5,6 synthetic routes to macrocyclic analogues are rare, especially those containing more than two imidazolium groups.7 We report here the synthesis of novel tetrakis(imidazolium) and benzimidazolium macrocyclic receptor systems which strongly bind halide and benzoate anions, with two receptors exhibiting notable selectively for fluoride anions in highly competitive aqueous–acetonitrile solvent mixtures.

2. Results and discussion

2.1 Syntheses

In an effort to examine the synergy of multiple imidazolium moieties for anion binding, we designed new tetrakis-imidazolium and benzimidazolium macrocyclic receptor systems, which may be considered as calix[4]imidazolium analogues of calix[4]pyrrole.8 Starting with commercially available imidazole and benzimidazole derivatives, a cascade of simple alkylation reactions was employed to synthesise the macrocycles in good yields.

The synthesis of 1,3-bis(N-imidazolyl)propane 1 was achieved by imidazole ring formation starting from commercially avaliable N-(3-aminopropyl)imidazole (Scheme 1).9 The reaction of two equivalents of 1 with 1,3-diiodopropane gave the corresponding imidazole–imidazolium compound 2 in 60% yield. Reaction of 2 with a further equivalent of 1,3-diiodopropane followed by anion exchange with NH4PF6 (aq.) gave the cyclised product 3 in 80% yield (Scheme 1). This remarkably high yield for such a cyclised product suggests the iodide counteranions are playing a significant templating role in macrocycle formation. Indeed, chloride and bromide anions have been shown to exhibit a templation role in the synthesis of bis(imidazolium) macrocycles.10


scheme, filename = b510068b-s1.gif
Scheme 1

An analogous synthetic procedure was used to obtain tetrakis(benzimidazolium) receptors of three different macrocyclic sizes: 6, 9 and 11 (Schemes 2–4). Benzimidazole precursors 4 and 7 were obtained from the alkylation of benzimidazole with 1,3-dibromopropane and 1,4-dibromobutane respectively (Schemes 2 and 3). For the synthesis of the four-fold symmetric receptor 6, two equivalents of 4 were reacted with one equivalent of 1,3-diiodopropane to give 5 in 65% yield (Scheme 2). Precursor 5 was then reacted with a further equivalent of 1,3-diiodopropane to give macrocycle 6 in 31% yield (Scheme 2).


scheme, filename = b510068b-s2.gif
Scheme 2

scheme, filename = b510068b-s3.gif
Scheme 3

scheme, filename = b510068b-s4.gif
Scheme 4

Reaction of two equivalents of 7 with 1,4-diiodobutane afforded 8 in 46% yield. The butyl spaced macrocycle 9 was prepared via reaction of 8 with 1,4-diiodobutane in 28% yield (Scheme 3).

The reaction of 7 with 1,3-diiodopropane gave benzimidazole–benzimidazolium compound 10 and subsequent cyclisation of 10 with a further equivalent of 1,3-diiodopropane afforded receptor 11 in 30% yield after anion exchange with aqueous NH4PF6 (Scheme 4).

For comparison purposes a new acyclic tetrapodal imidazolium receptor was also prepared. The synthesis of the tetrapodal resorcinarene cavitand imidazolium receptor 14 involved a simple alkylation reaction of imidazole with tetra(bromomethyl)resorcinarene cavitand1112 followed by reaction with excess 1-bromohexane and anion exchanged to give the pure product in 37% yield (Scheme 5).


scheme, filename = b510068b-s5.gif
Scheme 5

All four new tetrakis(imidazolium) macrocycles 3, 6, 9, 11 and tetrapodal cavitand imidazolium receptor 14 were characterised by 1H, 13C NMR (Fig. 1) spectroscopy, electrospray mass spectrometry and elemental analysis.


13C NMR spectrum or receptor 9 in CD3CN.
Fig. 1 13C NMR spectrum or receptor 9 in CD3CN.

It is noteworthy that the high field 1H NMR spectra of 6 and 9 reveal a dominant singlet at around 9 ppm for the respective methine (C–H)+ imidazolium proton superimposed upon a much less intense multiplet (Fig. 2 and 3). No evidence of higher oligomers was seen in the electrospray mass spectrum for any of the four macrocycles, only the one plus charged species corresponding to the tetrameric products plus three counter anions with a difference of one mass unit in the respective isotope envelope pattern was observed. This implies the additional multiplet resonances in this methine imidazolium proton region are due to the presence of multiple conformers in solution. Moreover, the 1H NMR spectrum of 6 also displays more than one set of resonances assigned to the aromatic protons of the benzimidazolium moieties (Fig. 2). Resembling the known conformational isomers of calix[4]arenes, in principle these macrocycles may adopt cone, 1,3-alternate, 1,2-alternate and partial cone conformers in solution.12 Variable temperature 1H NMR spectroscopic experiments up to 100 °C in DMSO-d6 solution however, resulted in no significant changes in the NMR spectra of the macrocycles.


1H NMR spectrum of receptor 6 in CD3CN.
Fig. 2 1H NMR spectrum of receptor 6 in CD3CN.

1H NMR spectrum of receptor 9 in CD3CN.
Fig. 3 1H NMR spectrum of receptor 9 in CD3CN.

2.2 X-Ray crystal structures

Bis(benzimidazole) precursor compound 4 and receptor 11 were also characterised by single crystal X-ray crystallography. Crystals of 4 suitable for X-ray structural analysis were grown by the slow diffusion of diethyl ether into a chloroform solution of 4. The crystal system is orthorhombic and the molecule lies on a site with no crystallographic symmetry, but closely approximates to local twofold rotational symmetry (Fig. 4).
Thermal ellipsoid plot of the bis(benzimidazole) precursor 4. Thermal ellipsoids are drawn at the 40% probability level.
Fig. 4 Thermal ellipsoid plot of the bis(benzimidazole) precursor 4. Thermal ellipsoids are drawn at the 40% probability level.

Crystals of 11 suitable for X-ray analysis were grown by the slow evaporation of acetonitrile from a solution of receptor 11 in an acetonitrile–water mixture. The crystal system is triclinic and the macrocyclic tetracation is located on a crystallographic centre of inversion (Fig. 5). Two PF6 ions (related by the inversion centre) lie partly within the macrocyclic ring where the four benzimidazolium moieties are arranged in a cis two up two down 1,2-alternate conformation (Fig. 6).


Thermal ellipsoid plot of the tetrakis(benzimidazolium) receptor 11. Thermal ellipsoids are drawn at the 50% probability level. The four PF6− counter anions and solvent molecules are omitted for clarity.
Fig. 5 Thermal ellipsoid plot of the tetrakis(benzimidazolium) receptor 11. Thermal ellipsoids are drawn at the 50% probability level. The four PF6 counter anions and solvent molecules are omitted for clarity.

Stick representation of receptor 11 in a 1,2-alternate conformation with two counter PF6− anions lying partially within the macrocyclic cavity.
Fig. 6 Stick representation of receptor 11 in a 1,2-alternate conformation with two counter PF6 anions lying partially within the macrocyclic cavity.

2.3 Anion binding studies

The complexation of halide and benzoate anions by the macrocyclic receptors 3, 6, 9, 11 and cavitand 14 was investigated by 1H NMR spectroscopic titration experiments. These anionic guests were chosen for their variety in size, shape and charge density in order to probe the differences in the host–guest binding properties of the receptors. Due to the solubility characteristics of the macrocyclic receptors and their receptor–anion complexes, a highly competitive solvent mixture of acetonitrile-d3 and water (9 : 1) was used throughout.

In all cases the addition of anions caused significant downfield perturbations of the methine (C–H)+ imidazolium proton resonances of each receptor. Interestingly, with receptor 6 the addition of 1 equivalent of TBA fluoride resulted in the methine proton resonances simplifying to a singlet, which implies that anion complexation results in a single conformer in solution (Fig. 7).


The aromatic region of the 1H NMR spectra of receptor 6 upon the addition of 1 equivalent of TBAF to a CD3CN solution.
Fig. 7 The aromatic region of the 1H NMR spectra of receptor 6 upon the addition of 1 equivalent of TBAF to a CD3CN solution.

Monitoring the most intense imidazolium methine (C–H)+ proton resonance produced titration curves and Job plots (refer to the electronic supplementary information) which, after EQNMR,13 a least squares computer fitting program, analysis of the titration binding isotherms (Fig. 8) gave stability constant values displayed in Table 1.

Table 1 Stability constants (K, M−1) for tetrakis(imidazolium) macrocycles with a range of anionsa
 Receptors
Anion3691114
a Solvent = CD3CN–H2O 9 : 1, temperature = 295 K and errors are ± 10%.b Mixed host–guest binding stoichiometry prevented the calculation of a sensible stability constant value.c Precipitation occurred during titration.d The stoichiometry of receptor–benzoate binding is 1 : 2. K1 and K2 are quoted in the table.e Minimal changes observed in the chemical shift of the imidazolium proton.
Fb>104c>104180
Clb1100c71085
Brb1050c50090
I370560900470125
BzOdK1 1800K1 1070K1 1700K1 2700e
K2 470K2 1000K2 940K2 600



1H NMR titration data for the addition of the TBA salt of various halides to a CD3CN–H2O (9 : 1) solution of receptor 6.
Fig. 8 1H NMR titration data for the addition of the TBA salt of various halides to a CD3CN–H2O (9 : 1) solution of receptor 6.

Receptors 6 and 11 form extremely strong and selective 1 : 1 stoichiometric complexes with fluoride, with estimated stability constant values of K >104 M−1. Attempts to repeat the titration experiments with increasing amounts of water unfortunately led to solubility problems. Stoichiometric 1 : 1 complexes were also found with chloride, bromide and iodide anions with a halide selectivity trend of F >> Cl ≈ Br > I for receptor 6 and F >> Cl > Br ≈ I for the larger macrocycle 11 (Table 1).

Presumably these stable halide complexes result from the four imidazolium moieties of 6 and 11 binding the halide anionic guest in a cooperative manner forming strong imidazolium (C–H)+-X hydrogen bonds. The equilibrium geometry of macrocycle 6 with a bound fluoride anion was calculated using Merck Molecular Force Field (MMFF) using the SPARTAN 04 modelling program14 and reveals the fluoride anion to be closely bound within the macrocyclic cavity to each of the benzimidazolium moieties (Fig. 9). Similar equilibrium geometries were calculated for both the larger chloride and bromide anions however, indicating that the pronounced fluoride selectivity exhibited by 6 has little to do with receptor cavity–anion size complementarity. This suggests the more basic character of the fluoride anion dictates the observed selectivity trends with these macrocyclic receptors.


Molecular mechanics model for the 1 : 1 host–guest binding between receptor 6 and fluoride calculated using SPARTAN 04.
Fig. 9 Molecular mechanics model for the 1 : 1 host–guest binding between receptor 6 and fluoride calculated using SPARTAN 04.

It is noteworthy that macrocycle 6 complexes chloride and bromide anions with similar stability (Kca. 1100 M−1). A comparison of the receptor stability constant values with iodide reveals that 9 binds this halide guest anion most strongly, which implies a degree of macrocycle size complementarity.

With receptor 3, a combination of 1 : 1 and 1 : 2 binding stoichiometries were observed with fluoride, chloride and bromide. In a typical titration experiment a steady downfield shift of the imidazolium protons was observed until ca. two equivalents whereupon a large perturbation occurred indicative of a change in binding stoichiometry (Fig. 10). Unfortunately, it was not possible to determine stability constant values from such titration isotherm data.


Titration curve of receptor 3 and TBA Cl monitoring the methine proton in CD3CN–H2O 9 : 1.
Fig. 10 Titration curve of receptor 3 and TBA Cl monitoring the methine proton in CD3CN–H2O 9 : 1.

In contrast to macrocycles 6 and 11, the cavitand receptor 14 only weakly binds halide anions (Table 1) which presumably reflects the tetrapodal receptor's unfavourable cavity size and lack of preorganisation. Indeed, molecular mechanics modelling (SPARTAN 04)14 of the cavitand receptor showed the upper rim appended imidazolium moieties to be highly flexible resulting in the absence of a preorganised binding site.

With the benzoate anion, a binding stoichiometry of 1 : 2 was obtained for all four macrocyclic receptors. The relative size of the carboxylate anion may be responsible for this result. Benzoate being an essentially planar molecule and larger than the halide anions, cannot fit inside the macrocyclic cavities of the receptors. Similar to the hexafluorophosphate anions shown in the solid state structure of 11 (Fig. 6), benzoate anions are likely to reside only partially within the macrocyclic cavity of the receptors and hence the observation of 1 : 2 receptor–benzoate binding stoichiometry. The stability constant values (K2) for the binding of the second benzoate are of significant magnitudes (Table 1). This observation suggests the presence of two independent binding sites for benzoate with these macrocyclic systems which also, taking into account the crystal structure of 11, suggests one benzoate anion may be binding to each side of the receptor. Interestingly, there was no evidence of cavitand receptor 14 binding benzoate in this aqueous–acetonitrile solvent mixture.

3. Conclusions

New (tetrakis)imidazolium macrocyclic receptor systems of various sizes have been prepared via sequential alkylation reactions of bis(imidazolium) precursor derivatives. Proton NMR titration investigations revealed the macrocycles to strongly bind halide anions with two macrocycles 6 and 11 exhibiting pronounced selectivity for binding fluoride in a competitive aqueous–acetonitrile (CD3CN–H2O 9 : 1) solvent media. Evidence for a macrocyclic cavity size effect comes from the largest macrocycle 9 forming the strongest complex with iodide.

All four macrocycles complex the benzoate anion with a 1 : 2 receptor–anion binding stoichiometry. A new tetrapodal cavitand imidazolium receptor was also synthesized and proved to be an inferior anion complexing agent which modelling studies attribute to the absence of a preorganised binding site. This highlights the importance of the preorganised cyclic (tetrakis)imidazolium receptor design for anion recognition efficacy.

4. Experimental

4.1 General details

NMR spectra were recorded on Varian utility 300 and 500 MHz spectrometers. Mass spectrometry was carried out on a Micromass LCT electrospray mass spectrometer (ESMS, cone voltage = 20–50 V, desolvation temp. = 80 °C, source temp. = 60 °C). Elemental analysis was performed at the Inorganic Chemistry Laboratory, Oxford. Crystal data (Table 2) was obtained using Mo Kα radiation on an Enraf–Nonius KappaCCD diffractometer. Crystals were mounted on a glass fibre and cooled rapidly to 150 K in a stream of cold nitrogen using an Oxford Cryosystems CRYOSTREAM unit. Intensity data were processed using the DENZO-SMN package.15 Structures were solved by direct methods using the SIR92 program.16 Full-matrix least-squares refinement was carried out using the CRYSTALS program suite.17 Hydrogen atoms were positioned geometrically after each cycle of refinement. A Chebychev polynomial weighting scheme was applied.

Molecular modelling studies were calculated using Merck Molecular Force Field (MMFF) using the SPARTAN 04 modelling program.14 The molecular models were constructed in three stages using SPARTAN. The geometry of the benzimidazolium moiety was first refined using the basic molecular mechanics refinement in the program. The macrocyclic receptor was constructed by linking the benzimidazolium moieties and then its geometry was refined. The equilibrium geometry of the macrocyclic receptor was calculated using the Merck Molecular Force Field (MMFF). A variety of anions were then inserted into the model of the receptor and, maximising the number of hydrogen bonds, the equilibrium geometry of the receptor plus anion was calculated using MMFF.

MMFF uses a two stage optimisation routine where atoms are allowed to move large distances followed by small distances. The full developmental details of MMFF can be found in reference 18.

Table 2 Crystal data2 and refinement details for compounds 4 and 11
 411
Chemical formulaC17H16N4C46H54F24N10P4
Formula weight276.341326.85
Temperature/K150150
Wavelength/Å0.710730.71073
Crystal systemOrthorhombicTriclinic
Space groupP b c nP[1 with combining macron]
a25.1991(4)9.6741(2)
b8.6736(2)12.6292(2)
c12.6158(2)13.1081(2)
α (deg)9065.7093(10)
β (deg)9071.7542(9)
γ (deg)9083.9297(7)
Cell volume/Å32757.40(9)1385.83(4)
Z81
Calculated density/Mg m−31.3311.590
Absorption coefficient/mm−10.0820.262
F0001168676
Crystal size/mm0.20 × 0.20 × 0.400.10 × 0.10 × 0.32
Description of crystalColourless prismColourless prism
Absorption correctionSemi-empirical from equivalent reflectionsSemi-empirical from equivalent reflections
Transmission coefficients (min, max)0.97, 0.980.92, 0.97
θ range for data collection (deg)5.0 ≤ θ ≤ 27.55.0 ≤ θ ≤ 27.5
Index ranges0 ≤ h ≤ 32, 0 ≤ k ≤ 11, 0 ≤ l ≤ 16−11 ≤ h ≤ 12, −14 ≤ k ≤ 16, 0 ≤ l ≤ 16
Reflections measured1875441262
Unique reflections35646294
Rint0.0450.064
Observed reflections (I > 3σ(I))20213552
Refinement methodFull-matrix least-squares on FFull-matrix least-squares on F
Parameters refined190379
Weighting schemeChebychev 3-term polynomialChebychev 3-term polynomial
Goodness of fit1.12191.1089
R0.03370.0526
wR0.03810.0611
Residual electron density (min, max)/e Å−3−0.18, 0.19−0.49, 0.62


4.2 Syntheses

Imidazole, benzimidazole and the alkylating agents used herein were purchased from Sigma Aldrich whilst 3-aminopropyl imidazole was purchased from Acros Organics and were used without further purification. Tetra(bromomethyl)resorcinarene cavitand 12 was synthesised via a literature procedure.11
1,3-Bis(imidazole)propane 1. N-(3-aminopropyl)imidazole (6.30 g, 0.05 mol) in water (10 mL) was acidified to pH 2 with an aqueous solution of phosphoric acid. Glyoxal (6 mL, 40% aq., 0.05 mol) and formaldehyde (4 mL, 20% aq., 0.05 mol) were added and the reaction mixture was warmed to 95 °C. An aqueous solution of ammonium chloride (2.70 g, 0.05 mol) was added drop wise to the reaction over 1 h. The reaction was heated at 95 °C for a further 15 min and allowed to cool to room temperature before cooling in an ice-water bath. Potassium hydroxide (3.00 g) was dissolved in the cooled reaction mixture and the product was extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous magnesium sulfate. A pale yellow oil was obtained (0.50 g, 6% yield) after the removal of solvent.

1H NMR (CDCl3, 288 K) δ (ppm) = 7.28 (s, 2H, NCHN), 6.88 (s, 2H, NCHCHN), 6.74 (s, 2H, NCHCHN), 3.74 (t, 6.9 Hz, 4H, N–CH2–), 2.10 (quintet, 6.9 Hz, 2H, –CH2–). MS (ESI positive ion, MeOH): m/z 177 (M + H+).

Compound 2. 1,3-Bis(imidazole)propane (0.50 g, 2 eq.) and 1,3-diiodopropane (0.42 g, 1 eq.) were dissolved in dioxane (100 mL) and refluxed for 24 h. The reaction mixture was cooled to room temperature and the precipitate collected by filtration. The light brown solid (0.6 g, 66% yield) was washed with diethyl ether and dried in vacuo.

1H NMR (d6-acetone, 288 K) δ (ppm) = 9.05 (s, 2H, NCHN), 8.89 (s, 2H, NCHN), 7.06–7.95 (m, 8H, NCHCHN), 4.33 (m, 12H, N–CH2–), 2.52 (m, 6H, –CH2–). MS (ESI positive ion, MeOH): m/z 521 [M − I]+.

Receptor 3. Compound 2 (0.20 g, 1 eq.) and 1,3-diiodopropane (0.10 g, 1 eq.) were dissolved in DMF (10 mL) and stirred at 50 °C overnight. The solvent was removed under reduced pressure and the residue was redissolved in methanol (5 mL). A saturated aqueous solution of ammonium hexafluorophosphate (5 mL) was added and heated to boiling. The solvent volume was reduced to ca. 5 mL and the solution was allowed to cool to room temperature. The precipitate was collected and washed with water and methanol followed by diethyl ether. The white solid (0.20 g, 80% yield) was dried under vacuum.

1H NMR (CD3CN, 288 K) δ (ppm) = 8.51 (s, 4H, imidazole), 7.46 (s, 8H, imidazole), 4.23 (t, 7.2 Hz, 16H, N–CH2–), 2.43 (quintet, 7.2 Hz, 8H, –CH2–). 13C NMR (75 MHz, CD3CN, 288 K) δ (ppm) = 136.26 (NCHN), 123.24 (NCHCHN), 46.84 (N–CH2–), 30.22 (CH2). MS (ESI positive ion, MeOH): m/z 363 [M − 2PF6. Anal. calcd for C24H36N8P4F24: C, 28.35; H, 3.54; N, 11.02. Found: C, 28.45; H, 3.51; N, 11.47.

1,3-Bis(benzimidazole)propane 4. Benzimidazole (3.50 g) in THF (50 mL) was added drop wise to a suspension of NaH (60% in mineral oil, 1.20 g) in THF (50 mL) at 0 °C. 1,3-Dibromopropane (3.00 g) was added to the suspension when gas production ceased. The reaction was stirred overnight and filtered. The solvent was removed from the filtrate and redissolved in dichloromethane (100 mL), which was then washed with water (50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed in vacuo to give a pale yellow solid (3.50 g, 85% yield).

1H NMR (CDCl3, 288 K) δ (ppm) = 7.84 (m, 4H, NCHN), 7.29 (m, 6H, ArH), 4.17 (t, 6.6 Hz, 4H, N–CH2–), 2.52 (quintet, 6.6 Hz, 2H, –CH2–). MS (ESI positive ion, MeOH): m/z 277 (M + H+).

Compound 5. 1,3-Bis(benzimidazole)propane 4 (0.50 g, 2 eq.) and 1,3-diiodopropane (0.42 g, 1 eq.) were dissolved in dioxane (100 mL) and refluxed for 24 h. The reaction mixture was cooled to room temperature and the precipitate collected. The light brown solid (0.51 g, 65% yield) was washed with diethyl ether and dried in vacuo.

1H NMR (d6-DMSO, 288 K) δ (ppm) = 9.99 (m, 2H, NCHN), 9.79 (m, 2H, NCHN), 7.18–8.29 (m, 16H, ArH), 4.30–4.73 (m, 12H, N–CH2–), 2.52 (m, 6H, –CH2–). MS (ESI positive ion, MeOH): m/z 721 [M − I]+.

Receptor 6. Compound 5 (0.50 g, 1 eq.) and 1,3-diiodopropane (0.18 g, 1 eq.) were dissolved in DMF (10 mL) and stirred at 50 °C overnight. The solvent was removed under vacuum and the residue was redissolved in methanol (5 mL). A saturated solution of ammonium hexafluorophosphate (5 mL) was added and heated to boiling. The solvent volume was reduced to ca. 10 mL and the solution was allowed to cool to room temperature. The precipitate was collected and washed with water and methanol followed by diethyl ether. The white solid (0.19 g, 31% yield) was dried under vacuum.

1H NMR (CD3CN, 288 K) δ (ppm) = 8.97 (m, 4H, NCHN), 8.01 (m, 2H, ArCH), 7.93 (m, 6H, ArCH), 7.79 (m, 2H, ArCH), 7.74 (m, 6H, ArCH), 4.62 (t, 7.2 Hz, 16H, N–CH2-), 2.65 (quintet, 7.2 Hz, 8H, –CH2–). 13C NMR (75 MHz, CD3CN, 288 K) δ (ppm) = 141.50 (NCHN), 131.97 (ArC), 128.02 (ArCH), 113.92 (ArCH), 44.8 (–NCH2–), 28.8 (CH2). MS (ESI positive ion, MeCN): m/z 1071 [M − PF6]+. Anal. calcd for C40H44N8P4F24.H2O: C, 38.88; H, 3.73; N, 9.08. Found: C, 38.84; H, 3.84; N, 9.06.

1,4-Bis(benzimidazole)butane 7. The procedure for the preparation of 7 was analogous to the synthesis of compound 4 using 1,4-di-bromobutane (3.30 g) was used instead of 1,3-dibromopropane. The product was isolated as a white solid (2.73 g, 66% yield).

1H NMR (CDCl3, 288 K) δ (ppm) = 7.79 (m, 4H, NCHN), 7.29 (m, 6H, ArH), 4.12 (m, 4H, N–CH2–), 1.88 (m, 4H, –CH2–). MS (ESI positive ion, MeOH): m/z 291 (M + H+).

Compound 8. 1,3-Bis(benzimidazole)butane 5 (1.00 g, 2 eq.) and 1,3-diiodobutane (0.53 g, 1 eq.) were dissolved in dioxane (100 mL) and heated under reflux for 24 h. The reaction mixture was cooled to room temperature and the precipitate collected. The light brown solid (1.00 g, 46% yield) was washed with diethyl ether and dried in vacuo.

1H NMR (d6-DMSO, 288 K) δ (ppm) = 9.85 (m, 2H, NCHN), 9.79 (m, 2H, NCHN), 7.18–8.29 (m, 16H, ArH), 4.55 (m, 8H, N–CH2–), 4.31 (m, 4H, N–CH2–), 2.02 (m, 8H, –CH2–), 1.88 (m, 4H, –CH2–). MS (ESI positive ion, MeOH): m/z 763 (M − I)+, 318 (M2+).

Receptor 9. Compound 8 (0.50 g, 1 eq.) and 1,3-diiodobutane (0.18 g, 1 eq.) were dissolved in DMF (10 mL) and stirred at 50 °C overnight. The solvent was removed under reduced pressure and the residue was redissolved in methanol (5 mL). A saturated solution of ammonium hexafluorophosphate (5 mL) was added and heated to boiling. The solvent volume was reduced to ca. 5 mL and the solution was allowed to cool to room temperature. The precipitate was collected and washed with water and methanol followed by diethyl ether. The white solid (0.20 g, 30% yield) was dried under vacuum.

1H NMR (CD3CN, 288 K) δ (ppm) = 8.95 (bs, 4H, NCHN), 7.86 (m, 8H, ArH), 7.69 (m, 8H, ArH), 4.47 (br, 16H, N–CH2–), 2.06 (br, 16H, –CH2–). 13C NMR (75 MHz, CD3CN, 288 K) δ (ppm) = 141.25 (NCHN), 131.95 (ArC), 127.59 (ArCH), 113.94 (ArCH), 47.09 (N–CH2–), 26.15 (–CH2–). MS (ESI positive ion, MeCN): m/z 1127 [M − PF6]+. Anal. calcd for C44H52N8P4F24: C, 41.52; H, 4.12; N, 8.80. Found: C, 41.60; H, 4.10; N, 8.85.

Compound 10. 1,3-Bis(benzimidazole)butane 5 (1.00 g, 2 eq.) and 1,3-diiodopropane (0.53 g, 1 eq.) were dissolved in dioxane (100 mL) and refluxed for 24 h. The reaction mixture was cooled to room temperature and the precipitate collected by filtration. The light brown solid (1.00 g, 46% yield) was washed with diethyl ether and dried in vacuo.

1H NMR (d6-DMSO, 288 K) δ (ppm) = 8.05 (s, 2H, NCHN), 8.00 (s, 2H, NCHN), 7.14–7.82 (m, 16H, ArH), 4.14–4.60 (m, 12H, N–CH2–), 1.88 (br, 2H, –CH2–), 1.75 (br, 8H, –CH2–). MS (ESI positive ion, MeOH): m/z 749 (M − I)+.

Receptor 11. Compound 10 (0.50 g, 1 eq.) and 1,3-diiodopropane (0.18 g, 1 eq.) were dissolved in DMF (10 mL) and stirred at 50 °C overnight. The solvent was removed under vacuum and the pale yellow solid washed with diethyl ether. The solid was subsequently dissolved in the minimum amount of methanol before the addition of a saturated aqueous solution of NH4PF6 (5 mL). The white solid (0.21 g, 94% yield) was collected by filtration and was dried under vacuum.

1H NMR (CD3CN, 288 K) δ (ppm) = 8.86–8.94 (m, 4H, NCHN), 7.90 (m, 8H, ArH), 7.71 (m, 8H, ArH), 4.45–4.62 (br m, 16H, N–CH2–), 2.66 (br m, 4H, propyl CH2), 2.09 (br, 8H, butyl CH2). 13C NMR (75 MHz, CD3CN, 288 K) δ (ppm) = 149.72 (NCHN), 132.00, 131.90 (ArC), 127.73, 127.84 (ArCH), 114.02, 113.80 (ArCH), 47.15 (N–CH2–), 44.70 (N–CH2–), 28.63, 26.07 (–CH2–); MS (ESI positive ion, MeCN): m/z 1099 [M − PF6]+. Anal. calcd for C42H48N8P4F24: C, 40.91; H, 3.97; N, 9.18. Found: C, 40.53; H, 3.89; N, 9.00.

Tetra(bromomethyl)resorcinarene cavitand 12. Tetramethylresorcinarene cavitand11 (7.00 g, 8.02 mmol) and a catalytic amount of AIBN were dissolved in 1,2-dichloroethane (150 mL). NBS (7.00 g, 38.99 mmol) was added portionwise to the solution which was then stirred at 80 °C under N2 for 3 h. Additional NBS (1.00 g) and AIBN (catalytic amount) were added at this stage. The orange solution was then stirred at room temperature for a further 18 h, after which time the solvent was removed under reduced pressure. The resulting solid was stirred in EtOH (150 mL) for 2 h and the resulting precipitate filtered off. This solid was dissolved in CH2Cl2 (20 mL) and layered with EtOH (50 mL) in order to induce crystallisation. The resulting cream crystals were collected and dried in vacuo (8.05 g, 84%).

1H NMR (300 MHz, CDCl3) δ (ppm) = 7.11 (s, 4H, ArH), 6.01 (d, J = 6.6 Hz, 4H, OCH2 [Houter]), 4.75 (t, J = 7.8 Hz, 4H, ArCH), 4.53 (d, J = 6.9 Hz, 4H, OCH2 [Hinner]), 4.40 (s, 8H, CH2Br), 2.17 (m, 8H, ArCHCH2), 1.33 (m, 24H, CH2), 0.89 (t, J = 6.9 Hz, 12H, CH3). Anal. calcd for C56H68Br4O8.½H2O: C, 56.16; H, 5.81; Found: C, 56.06; H, 5.68.

Tetra(imidazolylmethyl)resorcinarene cavitand 13. Tetra(bromomethyl)resorcinarene cavitand 12 (0.10 g, 0.10 mmol) in THF (10 mL) was added dropwise to a suspension of imidazole (25 mg, 0.40 mmol) and NaOH (0.05 g) in THF (50 mL). The mixture was heated under reflux overnight, then the solvent was removed in vacuo. The resulting residue was redissolved in CH2Cl2 (50 mL) and washed with water (2 × 50 mL). The organic layer was dried over anhydrous MgSO4, filtered and a pale yellow powder (0.10 g, yield 96%) was obtained after solvent removal.

1H NMR (300 MHz, CDCl3, 288 K) δ (ppm) = 7.38 (s, 4H, NCHN), 7.16 (s, 4H, ArH), 6.99 (s, 4H, NCHCHN), 6.87 (s, 4H, NCHCHN), 5.90 (d, J = 6.6 Hz, 4H, OCH2 [Houter]), 4.85 (s, 8H, N–CH2), 4.70 (t, J = 7.8 Hz, 4H, ArCH), 4.08 (d, J = 6.9 Hz, 4H, OCH2 [Hinner]), 2.16 (m, 8H, ArCHCH2), 1.34 (m, 24H, CH2), 0.88 (t, J = 6.9 Hz, 12H, CH3). MS (ESI positive ion, MeCN): m/z 1137 [M + H+].

Tetrakisimidazolium resorcinarene cavitand 14. Tetra(imidazolylmethyl)resorcinarene cavitand 13 (0.10 g, 0.10 mmol) and 1-bromohexane (5 mL, excess) in toluene (10 mL) were heated under reflux for 3 d. The solvent was removed under vacuum and the residue redissolved in MeOH (10 mL). Saturated NH4PF6 (aq., 5 mL) was added to the solution and the resulting precipitate was collected by filtration. A pale yellow powder (0.51 g, yield 37%) was obtained on drying in vacuo.

1H NMR (300 MHz, CD3CN, 288 K) δ(ppm) = 8.53 (s, 4H, NCHN), 7.54 (s, 4H, ArH), 7.38 (s, 8H, NCHCHN), 6.23 (d, J = 6.6 Hz, 4H, OCH2 [Houter]), 5.13 (s, 8H, N–CH2), 4.68 (t, J = 7.8 Hz, 4H, ArCH), 4.55 (d, J = 6.9 Hz, 4H, OCH2 [Hinner]), 4.13 (t, J = 6.9 Hz, 8H, hexyl CH2), 2.16 (m, 8H, ArCHCH2), 1.82 (m, 8H, hexyl CH2), 1.38 (m, 24H, CH2), 3.15 (m, 24H, hexyl CH2), 0.89 (m, 24H, CH3). 13C NMR (75 MHz, CD3CN, 288 K) δ (ppm) = 153.2, 139.0, 135.5, 123.5, 122.6, 122.4, 121.0, 99.7, 49.7, 42.9, 37.5, 31.8, 30.7, 29.4, 27.2, 25.3, 22.3, 22.1, 13.4 and 13.2 ppm. MS (ESI positive ion, MeCN): m/z 883 [M − 2PF6]2+, 1912 [M − PF6]+.

4.3 1H NMR titration protocol

1H NMR spectroscopic titration experiments were carried out at ca. 293 K on a 500 MHz Varian Utility Spectrometer. Data were analysed using the computer fitting program EQNMR©. For further details on the workings of the EQNMR computer program please refer to Professor M. J. Hynes.13 To calculate stability constants the binding stoichiometry must be known and the rate of exchange between the complexed and the free receptor must be rapid on the NMR timescale. Therefore the signal is a weighted average of the signals of the two species.

The procedure for 1H NMR titrations was as follows: 1.5 × 10−6 moles of host was dissolved in 500 µL of 9 : 1 CD3CN–H2O (so as to avoid deuterium exchange). 3 × 10−5 moles of TBA anion salt was dissolved in 400 µL of the same solvent corresponding to one equivalent having a volume of 20 µL. A proton NMR of the host was recorded and subsequently aliquots of the anion solution were added to the host (11 × 0.2 eq., 2 × 0.4 eq., 2 × 1 eq., 1 × 2 eq. and 1 × 3 eq.). After each addition of anion, another 1H NMR was recorded.

Acknowledgements

We gratefully acknowledge the EPSRC for studentships (W.W.H.W and M.S.V.).

References

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Footnotes

Electronic supplementary information (ESI) available: Titration data, Job plots, ESMS data. See DOI: 10.1039/b510068b
CCDC reference numbers 283001 and 283002. For crystallographic data in CIF or other electronic format see DOI: 10.1039/b510068b

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