Binding of carboxylatopillar[5]arene with alkyl and aryl ammonium salts in aqueous medium

Abstract

The complex formation of alkyl ammonium salts by water-soluble carboxylatopillar[5]arene (CP5A) in aqueous medium is reported. p-Xylene diammonium salt and a series of secondary alkyl ammonium salts with various alkyl groups have been prepared and investigated for complex formation. All the ammonium salts exhibit strong host–guest complexation with CP5A under neutral aqueous conditions. ¹H NMR, ¹H DOSY and 2D NOESY NMR experiments have been performed to characterize these inclusion complexes. In this study, the hydrophobic and electrostatic interactions govern the complex formation leading to the formation of pseudorotaxane species. Five pseudo[2]rotaxanes and one pseudo[3]rotaxane were obtained whose association constant values and stoichiometry were evaluated by an NMR titration method. The results indicate the use of ammonium salts as new complimentary synthons for CP5A in aqueous medium, adding to the repertoire of existing recognition motifs such as paraquat and 1,4-bis(pyridinium) derivatives.

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Introduction

Cyclodextrin,¹ calixarene,² crown ether,³ and cucurbituril⁴ have made immense contributions in the field of supramolecular chemistry. In recent years, a new class of macrocycle known by the name of pillar[n]arenes has received much attention owing to its interesting host–guest properties.⁵ The molecular recognition studies with pillar[n]arene hosts are mostly reported in organic media due to the inherent poor solubility of pillar[n]arene analogues in aqueous medium. To combat that, anionic,⁶ cationic⁷ and neutral⁸ water-soluble pillar[n]arenes have been synthesized. Molecular recognition studies in aqueous medium are always fascinating and desirable.

The first water soluble pillar[n]arene reported was anionic carboxylatopillar[5]arene (CP5A) along with its ability to form strong 1 : 1 inclusion complex with paraquat by Ogoshi et al.^6a This success announced the arrival of CP5A as new water soluble host molecule which was subsequently reported to form strong 1 : 1 complex formation with 1,4-bis(pyridinium)butane derivatives in aqueous medium.⁹ Furthermore, CP5A showed strong binding ability towards basic amino acids and lysine metabolites in aqueous medium.¹⁰ Consequently higher homologues of CP5A, carboxylatopillar[6]arene (CP6A),^6b,11 carboxylatopillar[7]arene (CP7A)^6d and carboxylatopillar[9]arene (CP9A),^6e were synthesized and employed for host–guest complex formation with paraquat. Each of CP6A, CP7A and CP9A exhibited extremely strong 1 : 1 complex formation with paraquat. Similarly, for complexation of anionic analytes, cationic water soluble pillar[n]arenes are desirable. The synthesis of first cationic pillar[5]arene was reported by Huang et al. with ten trimethylammonium groups at the upper and lower rims of the pillar[5]arene cavity, which exhibited strong 1 : 1 complex formation with 1-octanesulfonate^7a and moderately strong 1 : 1 complex formation with neutral guests¹² in aqueous medium. In addition, copillar[5]arenes appended with four trimethylammonium groups at the rims, have been synthesized and reported to form strong 1 : 1 complexes with alkyl dicarboxylates in water.^7c Consequently synthesis of the next higher homologue, cationic pillar[6]arene possessing twelve pyridinium groups at both the rims, was reported along with its ability to form strong 1 : 1 complexes with 2-naphthalenesulfonate and 2,6-napthalenedisulfonate in water.^7d Another cationic pillar[6]arene decorated with twelve trimethylammonium groups at both the rims was reported to exhibit strong 1 : 1 complex formation with 2-naphthalenesulfonate.^7e Even neutral water soluble pillar[n]arene analogue, pillar[5]arene decaamine, displayed 1 : 1 host–guest complex formation with linear diacids in aqueous medium which were later transformed to ion pair-stoppered [2]rotaxane.^8a

These molecular recognition studies dished out a wonderful opportunity for the construction of various interesting supramolecular systems in water. For example, supra-amphiphiles based on the host–guest complex of CP7A and an amphiphilic paraquat derivative self-assembled into supramolecular vesicles in water,^6d whereas supra-amphiphile based on an amphiphilic guest bearing 2-naphthalenesulfonate unit formed regular uniform micelles when complexed with cationic pillar[6]arene in aqueous medium.^7e Besides, the morphologies of the supra-amphiphiles were reversibly transformed between vesicles and nanotubes/micelles by application of pH for the host–guest complex of CP6A with amphiphilic guests, which was further utilized as stimuli-responsive material for reversible dispersion of multiwalled carbon nanotubes in water^6b and controlled release of water-soluble dye molecules.¹¹ In addition, CP5A-based nanovalves incorporated into the mechanized silica nanoparticle have been used as stimuli-responsive material for release of the cargo molecules, by lowering the pH ¹³ or adding a competitive binding agent¹⁴ for the CP5A. Moreover, CP5A reportedly acted as a stabilizer for metal nanoparticle synthesis^6c,15 and such hybrid materials have been used for sensing and detection of paraquat^6c and spermine analogues.¹⁵ Likewise, hybrid material based on CP5A functionalized Fe₃O₄ nanoparticle finds use as magnetic solid phase extraction adsorbent for determination of trace pesticides in beverage samples.¹⁶ CP5A was also functionalized on CdTe quantum dots leading to improved chemical and photochemical stability of the nanocrystals.¹⁷ Furthermore, CP5A functioned as an inhibitor of HPV16 L1 pentamer formation due to selective binding to arginine and lysine residues.¹⁸ Additionally, neutral water soluble pillar[5]arene derivative have been reported for targeted drug delivery by Zhao group.¹⁹

The significance of molecular recognition studies of pillar[n]arenes in aqueous medium is underlined by the large number of reports describing its application. Molecular recognition studies of pillar[n]arene hosts with amine based compunds,²⁰ including primary^20g and secondary^20c–f ammonium salts, are scarcely and only reported in organic media. The significance of secondary ammonium salts as guest can be appreciated from the plethora of reports^4a,21,22,23 on host–guest driven interpenetrated structures with crown ethers,²¹ cucurbiturils^4a,22 and calixarenes.²³ Especially, the use of secondary ammonium ions with crown ether has been the cornerstone for the development of rotaxane/catenane-based molecular machines.^3c,24 However, the inability of such complimentary supramolecular synthons to self-assemble in polar solvents like DMSO/water,^21n,25 prompted us to study the binding of secondary ammonium salts by water soluble pillar[n]arenes hosts. The motivation underlying this study is to develop complimentary synthons suitable for fabricating switchable mechanically interlocked molecules (MIM) in aqueous medium,²⁶ the prototype for stimuli responsive molecular switches and machines. Thus we contemplated the use of anionic water soluble pillar[5]arene, CP5A, for the recognition of secondary ammonium salts in aqueous medium.

Host–guest chemistry of pillar[n]arene derivative with secondary ammonium salts in organic media were primarily driven by N–H/π and C–H/π interactions^20c whereas electrostatic and hydrophobic interactions are expected to be dominant in aqueous medium.¹⁰ Herein, we report the host–guest binding of alkyl ammonium salts (G1–G6) with CP5A (Scheme 1) in water. These salts (G1–G6) due to the presence of alkyl chains and/or aromatic moiety would exhibit varying solubility in aqueous medium. The objective of this study is to provide a comprehensive picture of secondary alkyl ammonium salts templated pseudorotaxane formation with CP5A in aqueous medium. Our systematic investigation demonstrated that the salts G1–G5 forms pseudo[2]rotaxane whereas salt G6 forms pseudo[3]rotaxane with CP5A in aqueous medium.

Scheme 1 Cartoon representation of CP5A and alkyl ammonium salts (G1–G6).

Results and discussion

CP5A⊃G1 inclusion complex

We started our investigation with the smallest guest G1 which happens to be water soluble. The host–guest complexation between CP5A and G1 was first examined by ¹H NMR spectroscopy (Fig. 1). The equimolar (10 mM) mixture of G1 and CP5A (Fig. 1b) showed substantial upfield shifts and broadening effects for the G1 protons (H_a–d) compared to free G1 (Fig. 1c), indicating a strong host–guest complex formation. The presence of one set of peaks for CP5A and G1 (Fig. 1b) suggests the host–guest complex formation is in fast exchange on NMR time scale. The downfield shift of aromatic proton H₁ of CP5A (Fig. 1b) compared to free CP5A (Fig. 1a), caused by deshielding gives an additional support for complex formation. Large chemical shifts (Δδ = 0.86 to 1.51 ppm) observed for protons H_a, H_b, H_c and H_d indicate threading of G1 through the cavity of CP5A with ammonium centre close to the carboxylate groups of CP5A giving a pseudorotaxane geometry. Mole ratio plot (Fig. S5†) indicate 1 : 1 stoichiometry for the CP5A⊃G1 complex however the CP5A is not long enough to accommodate G1 completely.

Fig. 1 ¹H NMR spectra (D₂O, 293 K, 400 MHz) of (a) 10 mM CP5A; (b) 10 mM CP5A + 10 mM G1; (c) 10 mM G1.

This implies CP5A residing on either of the two alkyl chains are in equilibrium (Fig. 2) within themselves and with the uncomplexed G1. Moreover, the shuttling of CP5A occurring faster on the NMR time scale. Further evidence for the complex formation was obtained from DOSY NMR experiment which confirms the diffusion coefficients for both CP5A and G1 to be same in D₂O (Fig. S1†). Besides, NOE correlations were observed between aromatic proton H₁ of CP5A and methylene protons H_a–c of G1 confirming a pseudorotaxane geometry (Fig. S2†). NMR titration experiment was performed with constant G1 and varying CP5A concentration (Fig. S3†) to determine the association constants (K_a) of the pseudo[2]rotaxane species. The association constant of CP5A⊃G1 complex in water was calculated to be 5.87(±2.49) × 10³ M⁻¹ using non-linear curve fitting analyses.

Fig. 2 Complexation equilibria involving CP5A and salts (G1–G3) in water.

CP5A⊃G2 inclusion complex

Subsequently the host–guest complexation for partially water soluble guest G2 was investigated. An equimolar (10 mM) mixture of G2 and CP5A was probed by ¹H NMR spectroscopy (Fig. 3b) and similar upfield shits along with broadening were observed for the G2 protons (H_a–f) compared to free G2 (Fig. 3), indicating a strong host–guest complex formation.

Fig. 3 ¹H NMR spectra (D₂O, 293 K, 400 MHz) of (a) 10 mM CP5A; (b) 10 mM CP5A + 10 mM G2; (c) 10 mM G2.

The host–guest complex formation is in fast exchange on NMR time scale. The downfield shift of aromatic proton H₁ of CP5A (Fig. 3b) compared to free CP5A (Fig. 3a), caused by deshielding gives an additional support for complex formation. Surprisingly, the methylene protons H₃ of the rim of CP5A were split into two sets of peaks in a 1 : 1 integration ratio, indicating restricted swinging of the constituent units due to pseudorotaxane geometry formation with G2. As expected, all the methylene protons of G2 showed upfield shifts along with the splitting of H_d,e to H_d (δ = 0.0831 ppm) and H_e (δ = −0.0039 ppm). This suggests the presence of all the methylene groups of G2 inside the cavity with ammonium centre close to the carboxylate groups of CP5A. Again 1 : 1 stoichiometry was obtained from the mole ratio plot (Fig. S10†) for the CP5A⊃G2 complex which means similar complexation equilibrium (Fig. 2) between CP5A and G2. Further evidence for the complex formation was obtained from DOSY NMR experiment, which confirms the diffusion coefficients for an equimolar mixture of CP5A and G2 to be the same in D₂O (Fig. S6†). Moreover, NOE correlations were observed between aromatic proton H₁ of CP5A and methylene protons H_a–c of G2 corroborating a pseudorotaxane geometry (Fig. S7†). NMR titration experiment was done with constant G2 and varying CP5A concentration (Fig. S8†). The titration experiment revealed an association constant value of 2.8(±0.89) × 10⁴ M⁻¹. This hike in K_a value (Table 1) could be explained by the increase in the number of methylene groups resulting in greater hydrophobic effect and C–H/π hydrogen bond interactions.

Table 1 Association constant values^a for guests (G1–G6) complexation with host CP5A at 298 K

Entry	Guest	Association constant (M^−1)
a Association constant values were determined by NMR titration method with constant guest concentrations and varying host concentration.b Association constant value could not be determined due to the limited solubility in aqueous medium.c NMR titration was carried out with constant host concentration and varying guest concentration.
1	G1	(5.87 ± 2.49) × 10^3
2	G2	(2.80 ± 0.89) × 10^4
3	G3	^b
4	G4^c	(2.85 ± 1.88) × 10^3
5	G5	(5.05 ± 0.62) × 10^3
6	G6	K1 = 6.20 ± 1.28 × 10^2
		K2 = 1.65 ± 0.82 × 10^2

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CP5A⊃G3 inclusion complex

Spurred by the successful threading of G1 and G2, water insoluble guest G3 incorporating longer alkyl chain was investigated for host–guest complex formation with CP5A. Reasonably well resolved NMR spectrum could be obtained for G3 by weighing G3 in NMR tube followed by D₂O addition, sonication and occasional heating for long to get a clearer solution which was quickly submitted for NMR recording. Similarly, an equimolar (10 mM) mixture of CP5A and G3 was sonicated with occasional heating to get a clear solution. The recorded ¹H NMR spectrum then showed significant upfield shifts along with broadening effects for G3 (H_b–h) protons compared to free G3 (Fig. 4), indicating a strong host–guest complex formation. The host–guest complex formation is in fast exchange on NMR time scale. The downfield shift of aromatic proton H₁ (Fig. 4b) of CP5A caused by deshielding and splitting of the methylene protons H₃ of CP5A into two sets of peaks, demonstrates the pseudorotaxane formation. The protons of G3 (H_b–h) barring H_a showed upfield shifts along with the splitting of H_c–g to H_c (δ = 0.851 ppm), H_d (δ = 0.403 ppm), H_e,g (δ = −0.119 ppm), and H_f (δ = −0.497 ppm) (Fig. 4b). This implies the presence of the methylene groups CH_2c–h inside the cavity of CP5A while the methylene CH_2a stays out of the cavity. The methylene group CH_2b experiencing small upfield shift (Δδ = 0.131 ppm) and broadening is possibly near the edge of the CP5A cavity. Mole ratio plot and job plot could not be obtained due to the insolubility of the CP5A⊃G3 complex in D₂O over a range of concentration. Heating of the D₂O solution and changing to mixed solvent did not improve the solubility. However, the D₂O solution of CP5A⊃G3 complex became clear on reaching 1.0 equivalent addition of CP5A, as evident from the NMR titration experiment (Fig. S13†). Further addition of CP5A hardly affected the chemical shift of G3 protons, highlighting 1 : 1 stoichiometry for the CP5A⊃G3 complex and similar complexation equilibrium (Fig. 2) between CP5A and G3. Further evidence for the complex formation was obtained from DOSY NMR experiment, which confirms the diffusion coefficients for an equimolar mixture of CP5A and G3 to be the same in D₂O (Fig. S11†). Predictably, NOE correlations were observed between aromatic proton H₁ of CP5A and methylene protons H_d,e,g of G3, corroborating a pseudorotaxane geometry (Fig. S12†). Both the NOE correlation and ¹H NMR spectroscopy are symptomatic of the presence of the methylene group CH_2a of G3 outside the CP5A cavity. Unfortunately, the association constant for CP5A⊃G3 complex could not be determined due to limited solubility in aqueous medium. Moreover CP5A being soluble only in water, these host–guest studies could not be extended in any other solvents.

Fig. 4 ¹H NMR spectra (D₂O, 293 K, 400 MHz) of (a) 10 mM CP5A; (b) 10 mM CP5A + 10 mM G3; (c) 10 mM G3.

CP5A⊃G4 inclusion complex

Increasing chain length of the guests from G1 → G2 → G3 did not alter the stoichiometry of their complexes with CP5A, suggesting repulsive electrostatic interactions between two CP5A units when binding the same ammonium site.²⁷ This motivated us to think of a suitable spacer which could be incorporated between the alkyl groups to minimize/nullify the repulsive interactions of adjacent CP5A units. We hypothesized p-xylene as the suitable spacer which eventually would frame –NH₂⁺CH₂C₆H₄CH₂NH₂⁺– as the central unit of the guest molecules. Therefore, it is imperative to study the host–guest complexation of the p-xylene diammonium chloride (G4) with CP5A. An equimolar (10 mM) mixture of G4 and CP5A was probed by ¹H NMR spectroscopy (Fig. 5). Both aromatic protons (H_a) and benzyl protons (H_b) of G4 could not be observed in the ¹H NMR spectrum indicating remarkable complexation-induced broadening effects. In this case, the guest G4 is probably engulfed by the host CP5A (Fig. 5b). Moreover, the downfield shift of aromatic proton H₁ and broadening of methylene protons H₃ of CP5A compared to free CP5A (Fig. 5) gives an additional evidence for complex formation. Due to the absence of peaks corresponding to the guest G4 in the CP5A⊃G4 complex, ¹H DOSY and ¹H–¹H NOESY could not be recorded. Such remarkable broadening could also be attributed to supramolecular polymer formation at high concentrations.²⁸ Therefore, variable concentration ¹H NMR was done for equimolar mixture of CP5A and G4 (Fig. 6). However the remarkable broadening effect even at low concentrations (Fig. 6d–f) rules out the formation of any polymer at higher concentration (10 mM) and the broadening effect can be attributed solely to the formation of inclusion complexation.

Fig. 5 ¹H NMR spectra (D₂O, 293 K, 400 MHz) of (a) 10 mM CP5A; (b) 10 mM CP5A + 10 mM G4; (c) 10 mM G4.

Fig. 6 ¹H NMR spectra (D₂O, 293 K, 400 MHz) of equimolar mixture of CP5A and G4 at various concentrations (a) 10 mM, (b) 5 mM, (c) 2.5 mM, (d) 1.0 mM, (e) 0.5 mM, (f) 0.1 mM.

NMR titration experiment was done with constant CP5A and varying G4 concentration (Fig. S14†). Mole ratio plot (Fig. S16†) indicates 1 : 1 stoichiometry for the CP5A⊃G4 complex. Non-linear curve fitting analyses revealed an association constant value of 2.85(±1.88) × 10³ M⁻¹ for CP5A⊃G4 complex in water, suggesting a strong host–guest complex.

CP5A⊃G5 inclusion complex

The surprising ability of p-xylene diammonium chloride to form inclusion complex with CP5A would deem p-xylene unfit as spacer. However p-xylene can still be used as spacer, provided CP5A has preference for alkyl over aryl moiety for complex formation. Therefore, we chose the guest G5 and studied host–guest complexation with CP5A. The guest G5 contains an ammonium centre flanked by benzyl moiety and butyl moiety. An equimolar (10 mM) mixture of G5 and CP5A was probed by ¹H NMR spectroscopy (Fig. 7b) and prototypical upfield shifts along with broadening were observed for the G5 methylene and methyl protons (H_a–e) compared to free G5 protons (Fig. 7), indicating a strong host–guest complex formation. Large chemical shifts (Δδ = 1.06 to 1.84 ppm) observed for protons H_a, H_b, H_c and H_d indicate threading of butyl group of G5 through the cavity of CP5A. The benzyl protons H_e showed downfield chemical shift (Δδ = 0.43 ppm) but the phenyl ring protons does not shift at all suggesting that the phenyl ring stays out of the cavity of CP5A. Thus, CP5A binds preferentially the alkyl moiety over the aryl moiety which means p-xylene can be reasonably assumed to act as spacer. This host–guest complex formation is in fast exchange on NMR time scale. The downfield shift of aromatic proton H₁ of CP5A compared to free CP5A (Fig. 7), caused by deshielding also signifies the complex formation.

Fig. 7 ¹H NMR spectra (D₂O, 293 K, 400 MHz) of (a) 10 mM CP5A; (b) 10 mM CP5A + 10 mM G5; (c) 10 mM G5.

Further evidence for the complex formation was obtained from DOSY NMR experiment which confirms the diffusion coefficients for both CP5A and G5 to be same in D₂O (Fig. S17†). Moreover, NOE correlations were observed between aromatic proton H₁ of CP5A and methylene protons H_a, H_c & H_d of G5 confirming a pseudorotaxane geometry (Fig. S18†). NMR titration experiment was done with constant G5 and varying CP5A concentration (Fig. S19†). Mole ratio plot (Fig. S21†) indicates 1 : 1 stoichiometry for the CP5A⊃G5 complex. Non-linear curve fitting analyses revealed an association constant value of 5.05(±0.62) × 10³ M⁻¹ for CP5A⊃G5 complex in water, suggesting a strong host–guest complex.

CP5A⊃G6 inclusion complex

Based on our hypothesized spacer p-xylene, we chose the guest molecule G6 which is expected to form pseudo[3]rotaxane species with CP5A. A 1 : 2 mixture of G6 (10 mM) and CP5A (20 mM) was probed by ¹H NMR spectroscopy (Fig. 8). Both the butyl moiety could not be observed in the ¹H NMR spectrum (Fig. 8b) indicating remarkable complexation-induced broadening effects for the butyl protons H_a–H_d. Similar to G5, the chemical shift of phenyl protons remain unaffected whereas the chemical shift of benzyl protons H_e undergoes downfield shift along with significant broadening. These observed chemical shifts (Fig. 8b) strongly suggests the inclusion of both the butyl groups of G6 into the cavity of CP5A with the phenyl ring staying out of the cavity of CP5A. In this case, the butyl moieties of the guest G6 is probably engulfed by the host CP5A.This encouraging result can only be explained by 1 : 2 stoichiometry of the complex. Further evidence for the complex formation was obtained from DOSY NMR experiment which confirms the diffusion coefficients for both CP5A and G6 to be same in D₂O (Fig. S22†). ¹H–¹H NOESY could not be recorded in this case as the protons of interest H_a–H_d were not observable (Fig. 8b). NMR titration experiment was done with constant G6 and varying CP5A concentration (Fig. S23†). Non-linear curve fitting analyses gave excellent fit for 1 : 2 complexation stoichiometry, corroborating our claim. For G6⊃CP5A₂ complex in water, the association constant values K₁ and K₂ were found out to be 6.20(±1.28) × 10² and 1.65(±0.82) × 10² M⁻¹ respectively, manifesting a strong host–guest complex. Furthermore, mole ratio plot (Fig. S25†) showing 1 : 2 stoichiometry for the G6⊃CP5A₂ complex, leaves no doubt about the formation of pseudo[3]rotaxane species.

Fig. 8 ¹H NMR spectra (D₂O, 293 K, 400 MHz) of (a) 10 mM CP5A; (b) 20 mM CP5A + 10 mM G6; (c) 10 mM G6.

The ability of CP5A to form 2 : 1 complex with guest G6 and not with guests G1–G3, reflects p-xylene as a suitable spacer which effectively eliminates the repulsive interactions between the neighboring CP5A macrocycles. Since guest G4 formed a stable inclusion complex with CP5A, we envisaged that guest G6 may also form 1 : 1 complex with the p-xylene unit being included in the CP5A cavity.²⁹ Despite heating the G6⊃CP5A₂ complex at 373 K with constant stirring for 7 days, the ¹H NMR spectrum does not change. The failure of G6⊃CP5A₂ complex to convert to G6⊃CP5A complex demonstrate that the 1 : 2 complex G6⊃CP5A₂ is both kinetically and thermodynamically stable product. In addition, a look at the association constant values (Table 1) show comparable values for the guests G4 and G1, with G1 having slightly higher association constant value than G4. This is probably due to alkyl chain being the optimum guest for the CP5A cavity.

Conclusion

In conclusion, we have demonstrated pseudo[2]rotaxane and pseudo[3]rotaxane formation in aqueous medium with alkyl ammonium salts as axle and CP5A as wheel component. The high association constant values (K_a ∼ 10³ to 10⁴ M⁻¹) reflect strong affinity of CP5A for dialkylammonium salts. Binding mode for dialkylammonium salt suggests no two units of CP5A can bind to the same ammonium centre unless there is a suitable spacer group in between. We found out that p-xylene unit has the right dimension to function as a suitable spacer and thus by incorporating the spacer group in guest G6, pseudo[3]rotaxane species could be generated. Although CP5A forms 1 : 1 complex with p-xylene diammonium dichloride salt, but with G6 it always binds to the peripheral butyl side chains forming 2 : 1 complex. This represents 2 : 1 complex as both kinetically and thermodynamically stable complex. These complex formations are driven by hydrophobic, electrostatic, C–H/π and hydrogen bond interactions. Present work highlights the use of CP5A as complementary synthon for secondary ammonium salt in aqueous medium. The role of recognition motifs in aqueous medium is of utmost importance for molecular recognition studies and our study provides a new recognition motif for CP5A. This finding will give an impetus for the development of secondary ammonium salt driven interlocked molecules in aqueous medium.

Experimental section

Materials

All reagents and starting materials were bought from commercial suppliers and used without further purification. Host molecule CP5A was prepared according to the reported literature.^6c Guest molecules G1–G4,²⁵ G5 ³⁰ and G6 ²⁹ were prepared according to the reported literature. Anhydrous chloroform (CHCl₃) was obtained from dry distillation of its analytical grade by P₂O₅. Always freshly distilled solvents were used for reactions. Column chromatography was performed on silica gel 60 (Merck 40–60 nm, 60–100 mesh). Deuterated solvents (Cambridge Isotope Laboratories) for NMR spectroscopic analyses were used as received. All ¹H NMR spectra, DOSY spectra and the 2D NOESY spectra were recorded on Bruker 400 MHz spectrometers. All chemical shifts are quoted in ppm. The chemical shifts (δ) in the ¹H NMR spectra are accounted in ppm relative to proton resonance resulting from incomplete deuteration of the solvent D₂O at 4.79 ppm.

NMR titrations

Titration experiments were carried out in D₂O at 298 K on Bruker 400 MHz spectrometers. Generally, fixed concentration of guest was titrated with varying concentration of host solution. Only for guest G4, fixed concentration of host was titrated with varying concentration of guest solution. After each addition of the titrant, the NMR tube has been shaken well for a couple of minutes before recording the ¹H NMR spectrum of the solution. Especially for the initial addition of the titrant, 2–3 readings for the same titrant volume addition has been taken to make sure the solution is saturated. The host and the guest concentrations after each addition have been calculated based on the total volume of the NMR solution. Concentrated solutions of the titrant have been used so that subsequent addition does not alter the volume of the NMR solution to a significant extent for the saturation to reach. From the NMR titration, binding constant and stoichiometry has been determined using non-linear curve fitting analysis and mole ratio plot respectively.

Acknowledgements

S. D. is grateful to UGC, New Delhi for Kothari Postdoctoral Fellowship. PSM thanks the DST, New Delhi, for financial support.

Notes and references

1. (a) J. Szejtli, Chem. Rev., 1998, 98, 1743–1753; (b) A. Harada, Acc. Chem. Res., 2001, 34, 456–464; (c) J. Li and X. J. Loh, Adv. Drug Delivery Rev., 2008, 60, 1000–1017; (d) Y. Chen and Y. Liu, Chem. Soc. Rev., 2010, 39, 495–505; (e) Q. D. Hu, G. P. Tang and P. K. Chu, Acc. Chem. Res., 2014, 47, 2017–2025; (f) A. Harada, Y. Takashima and M. Nakahata, Acc. Chem. Res., 2014, 47, 2128–2140.
2. (a) A. Ikeda and S. Shinkai, Chem. Rev., 1997, 97, 1713–1734; (b) D. S. Guo and Y. Liu, Chem. Soc. Rev., 2012, 41, 5907–5921; (c) S. B. Nimse and T. Kim, Chem. Soc. Rev., 2013, 42, 366–386; (d) D. S. Guo and Y. Liu, Acc. Chem. Res., 2014, 47, 1925–1934; (e) I. Pochorovski and F. Diederich, Acc. Chem. Res., 2014, 47, 2096–2105.
3. (a) Z. Niu and H. W. Gibson, Chem. Rev., 2009, 109, 6024–6046; (b) X. Y. Hu, T. Xiao, C. Lin, F. Huang and L. Wang, Acc. Chem. Res., 2014, 47, 2041–2051; (c) C. J. Bruns and J. F. Stoddart, Acc. Chem. Res., 2014, 47, 2186–2199; (d) M. J. Langton and P. D. Beer, Acc. Chem. Res., 2014, 47, 1935–1949; (e) M. Zhang, X. Yan, F. Huang, Z. Niu and H. W. Gibson, Acc. Chem. Res., 2014, 47, 1995–2005.
4. (a) K. Kim, Chem. Soc. Rev., 2002, 31, 96–107; (b) J. Lagona, P. Mukhopadhyay, S. Chakrabarti and L. Isaacs, Angew. Chem., Int. Ed., 2005, 44, 4844–4870; (c) E. Masson, X. Ling, R. Joseph, L. Kyeremeh-Mensah and X. Lu, RSC Adv., 2012, 2, 1213–1247; (d) L. Isaacs, Acc. Chem. Res., 2014, 47, 2052–2062; (e) A. E. Kaifer, Acc. Chem. Res., 2014, 47, 2160–2167; (f) G. Ghale and W. M. Nau, Acc. Chem. Res., 2014, 47, 2150–2159.
5. (a) M. Xue, Y. Yang, X. Chi, Z. Zhang and F. Huang, Acc. Chem. Res., 2012, 45, 1294–1308; (b) P. J. Cragg and K. Sharma, Chem. Soc. Rev., 2012, 41, 597–607; (c) T. Ogoshi and T.-a. Yamagishi, Eur. J. Org. Chem., 2013, 2961–2975; (d) H. Zhang and Y. Zhao, Chem.–Eur. J., 2013, 19, 16862–16879; (e) C. Li, Chem. Commun., 2014, 50, 12420–12433; (f) T. Ogoshi and T. Yamagishi, Chem. Commun., 2014, 50, 4776–4787; (g) N. L. Strutt, H. Zhang, S. T. Schneebeli and J. F. Stoddart, Acc. Chem. Res., 2014, 47, 2631–2642.
6. (a) T. Ogoshi, M. Hashizume, T. A. Yamagishi and Y. Nakamoto, Chem. Commun., 2010, 46, 3708–3710; (b) G. Yu, M. Xue, Z. Zhang, J. Li, C. Han and F. Huang, J. Am. Chem. Soc., 2012, 134, 13248–13251; (c) H. Li, D.-X. Chen, Y.-L. Sun, Y. B. Zheng, L.-L. Tan, P. S. Weiss and Y.-W. Yang, J. Am. Chem. Soc., 2013, 135, 1570–1576; (d) Z. Li, J. Yang, G. Yu, J. He, Z. Abliz and F. Huang, Org. Lett., 2014, 16, 2066–2069; (e) Z. Li, J. Yang, G. Yu, J. He, Z. Abliz and F. Huang, Chem. Commun., 2014, 50, 2841–2843.
7. (a) Y. Ma, X. Ji, F. Xiang, X. Chi, C. Han, J. He, Z. Abliz, W. Chen and F. Huang, Chem. Commun., 2011, 47, 12340–12342; (b) Y. Yao, M. Xue, X. Chi, Y. Ma, J. He, Z. Abliz and F. Huang, Chem. Commun., 2012, 48, 6505–6507; (c) P. Wei, X. Yan, J. Li, Y. Ma and F. Huang, Chem. Commun., 2013, 49, 1070–1072; (d) W. Chen, Y. Zhang, J. Li, X. Lou, Y. Yu, X. Jia and C. Li, Chem. Commun., 2013, 49, 7956–7958; (e) Y. Ma, J. Yang, J. Li, X. Chi and M. Xue, RSC Adv., 2013, 3, 23953–23956.
8. (a) X. B. Hu, L. Chen, W. Si, Y. Yu and J. L. Hou, Chem. Commun., 2011, 47, 4694–4696; (b) T. Ogoshi, R. Shiga and T. A. Yamagishi, J. Am. Chem. Soc., 2012, 134, 4577–4580; (c) T. Ogoshi, K. Kida and T. A. Yamagishi, J. Am. Chem. Soc., 2012, 134, 20146–20150.
9. C. Li, X. Shu, J. Li, S. Chen, K. Han, M. Xu, B. Hu, Y. Yu and X. Jia, J. Org. Chem., 2011, 76, 8458–8465.
10. C. Li, J. Ma, L. Zhao, Y. Zhang, Y. Yu, X. Shu, J. Li and X. Jia, Chem. Commun., 2013, 49, 1924–1926.
11. G. Yu, X. Zhou, Z. Zhang, C. Han, Z. Mao, C. Gao and F. Huang, J. Am. Chem. Soc., 2012, 134, 19489–19497.
12. Y. Ma, M. Xue, Z. Zhang, X. Chi and F. Huang, Tetrahedron, 2013, 69, 4532–4535.
13. Y. L. Sun, Y. W. Yang, D. X. Chen, G. Wang, Y. Zhou, C. Y. Wang and J. F. Stoddart, Small, 2013, 9, 3224–3229.
14. Y. Zhou, L. L. Tan, Q. L. Li, X. L. Qiu, A. D. Qi, Y. Tao and Y. W. Yang, Chem.–Eur. J., 2014, 20, 2998–3004.
15. Y. Yao, Y. Zhou, J. Dai, S. Yue and M. Xue, Chem. Commun., 2014, 50, 869–871.
16. M. M. Tian, D. X. Chen, Y. L. Sun, Y. W. Yang and Q. Jia, RSC Adv., 2013, 3, 22111–22119.
17. D. X. Chen, Y. L. Sun, Y. Zhang, J. Y. Cui, F. Z. Shen and Y. W. Yang, RSC Adv., 2013, 3, 5765–5768.
18. D. D. Zheng, D. Y. Fu, Y. Wu, Y. L. Sun, L. L. Tan, T. Zhou, S. Q. Ma, X. Zha and Y. W. Yang, Chem. Commun., 2014, 50, 3201–3203.
19. H. Zhang, X. Ma, K. T. Nguyen and Y. Zhao, ACS Nano, 2013, 7, 7853–7863.
20. (a) N. L. Strutt, R. S. Forgan, J. M. Spruell, Y. Y. Botros and J. F. Stoddart, J. Am. Chem. Soc., 2011, 133, 5668–5671; (b) X. Y. Yu, P. Zhang, X. Wu, W. Xia, T. Xiao, J. Jiang, C. Lin and L. Wang, Polym. Chem., 2012, 3, 3060–3063; (c) C. Han, G. Yu, B. Zheng and F. Huang, Org. Lett., 2012, 14, 1712–1715; (d) C. Li, X. Shu, J. Li, J. Fan, Z. Chen, L. Weng and X. Jia, Org. Lett., 2012, 14, 4126–4129; (e) C. Han, Z. Zhang, G. Yu and F. Huang, Chem. Commun., 2012, 48, 9876–9878; (f) C. Han, B. Xia, J. Chen, G. Yu, Z. Zhang, S. Dong, B. Hu, Y. Yu and M. Xue, RSC Adv., 2013, 3, 16089–16094; (g) L. Liu, Y. Chen, L. Wang, H. Meier and D. Cao, Chin. J. Chem., 2013, 31, 624–626.
21. (a) K. C. Leung, F. Aricó, S. J. Cantrill and J. F. Stoddart, J. Am. Chem. Soc., 2005, 127, 5808–5810; (b) H. Hou, K. C. Leung, D. Lanari, A. Nelson, J. F. Stoddart and R. H. Grubbs, J. Am. Chem. Soc., 2006, 128, 15358–15359; (c) B. H. Northrop, F. Aricó, N. Tangchiavang, J. D. Badjić and J. F. Stoddart, Org. Lett., 2006, 8, 3899–3902; (d) E. N. Guidry, J. Li, J. F. Stoddart and R. H. Grubbs, J. Am. Chem. Soc., 2007, 129, 8944–8945; (e) J. Wu, K. C. Leung and J. F. Stoddart, Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 17266–17271; (f) F. Wang, C. Han, C. He, Q. Zhou, J. Zhang, C. Wang, N. Li and F. Huang, J. Am. Chem. Soc., 2008, 130, 11254–11255; (g) L. Fang, M. Hmadeh, J. Wu, M. A. Olson, J. M. Spruell, A. Trabolsi, Y. W. Yang, M. Elhabiri, A. M. Albrecht-Gary and J. F. Stoddart, J. Am. Chem. Soc., 2009, 131, 7126–7134; (h) M. E. Belowich, C. Valente and J. F. Stoddart, Angew. Chem., Int. Ed., 2010, 49, 7208–7212; (i) S. Dong, Y. Luo, X. Yan, B. Zheng, X. Ding, Y. Yu, Z. Ma, Q. Zhao and F. Huang, Angew. Chem., Int. Ed., 2011, 50, 1905–1909; (j) X. Yan, D. Xu, X. Chi, J. Chen, S. Dong, X. Ding, Y. Yu and F. Huang, Adv. Mater., 2012, 24, 362–369; (k) S. Dong, B. Zheng, D. Xu, X. Yan, M. Zhang and F. Huang, Adv. Mater., 2012, 24, 3191–3195; (l) M. Zhang, D. Xu, X. Yan, J. Chen, S. Dong, B. Zheng and F. Huang, Angew. Chem., Int. Ed., 2012, 51, 7011–7015; (m) M. E. Belowich, C. Valente, R. A. Smaldone, D. C. Friedman, J. Thiel, L. Cronin and J. F. Stoddart, J. Am. Chem. Soc., 2012, 134, 5243–5261; (n) S. Dasgupta and J. Wu, Chem. Sci., 2012, 3, 425–432; (o) M. E. Belowich and J. F. Stoddart, Chem. Soc. Rev., 2012, 41, 2003–2024.
22. (a) S. K. Kim, K. M. Park, K. Singha, J. Kim, Y. Ahn, K. Kim and W. J. Kim, Chem. Commun., 2010, 46, 692–694; (b) J. Yin, C. Chi and J. Wu, Org. Biomol. Chem., 2010, 8, 2594–2599.
23. (a) T. Pierro, C. Gaeta, C. Talotta, A. Casapullo and P. Neri, Org. Lett., 2011, 13, 2650–2653; (b) C. Talotta, C. Gaeta, T. Pierro and P. Neri, Org. Lett., 2011, 13, 2098–2101.
24. (a) J. D. Badjic, V. Balzani, A. Credi, S. Silvi and J. F. Stoddart, Science, 2004, 303, 1845–1849; (b) J. D. Badjic, C. M. Ronconi, J. F. Stoddart, V. Balzani, S. Silvi and A. Credi, J. Am. Chem. Soc., 2006, 128, 1489–1499; (c) A. Coskun, M. Banaszak, R. D. Astumian, J. F. Stoddart and B. A. Grzybowski, Chem. Soc. Rev., 2012, 41, 19–30.
25. P. R. Ashton, P. J. Campbell, E. J. T. Chrystal, P. T. Glink, S. Menzer, D. Philp, N. Spencer, J. F. Stoddart, P. A. Tasker and D. J. Williams, Angew. Chem., Int. Ed., 1995, 34, 1865–1869.
26. (a) L. Fang, C. Wang, A. C. Fahrenbach, A. Trabolsi, Y. Y. Botros and J. F. Stoddart, Angew. Chem., Int. Ed., 2011, 50, 1805–1809; (b) H. Li, A. C. Fahrenbach, A. Coskun, Z. Zhu, G. Barin, Y. L. Zhao, Y. Y. Botros, J. P. Sauvage and J. F. Stoddart, Angew. Chem., Int. Ed., 2011, 50, 6782–6788; (c) S. Grunder, P. L. McGrier, A. C. Whalley, M. M. Boyle, C. Stern and J. F. Stoddart, J. Am. Chem. Soc., 2013, 135, 17691–17694.
27. J. Yin, C. Chi and J. Wu, Chem.–Eur. J., 2009, 15, 6050–6057.
28. N. L. Strutt, H. Zhang, M. A. Giesener, J. Lei and J. F. Stoddart, Chem. Commun., 2012, 48, 1647–1649.
29. M. K. Sinha, O. Reany, M. Yefet, M. Botoshansky and E. Keinan, Chem.–Eur. J., 2012, 18, 5589–5605.
30. C. Ghosh, G. B. Manjunath, P. Akkapeddi, V. Yarlagadda, J. Hoque, D. S. Uppu, M. M. Konai and J. Haldar, J. Med. Chem., 2014, 57, 1428–1436.

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Footnotes

† Electronic supplementary information (ESI) available: DOSY spectra, 2D NOESY spectra, ¹H NMR titration, determination of the association constants and job plots. See DOI: 10.1039/c5ra13195b

‡ Present address: Department of Chemistry, National Institute of Technology Patna, Patna-800005, India. E-mail: suvankar@nitp.ac.in

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