Ion-pair recognition of amidinium salts by partially hydrogen-bonded heteroditopic cyclo[6]aramide

Abstract

Convergent heteroditopic cyclo[6]aramide demonstrates efficient ion-pair recognition of amidinium salts in 10% methanolic chloroform (>10⁴ M⁻¹) as confirmed by NMR and conductivity experiments. As predicted by density functional theory (DFT) method simulations, cyclo[6]aramide 1a is able to bind amidinium salts G1–G5 with varying binding affinity in 1 : 1 stoichiometry through hydrogen bonding interactions involving both anion-recognizing amide H-atoms and cation-binding amide carbonyl O-atoms. Particularly, the binding affinities for G1, G2 and G3 are found to decrease with increasing the size of substituents in the amidinium ion in the order of G1 > G2 > G3. Moreover, the association ability for simultaneous binding of cationic and anionic guest species depends considerably on the counterions. Among the four formamidinium salts (Cl⁻, Br⁻, I⁻ and BPh₄⁻) examined, formamidinium chloride is best encapsulated as a contact ion-pair species in the macrocycle. The reduced association constants with increasing the size of counterions in the order of G1 > G6 > G7 > G4 underscore the importance of ion paring in effecting the host–guest interaction. Comparative conductivity studies provide a convenient approach to differentiate between contact and loose ion pairs for these amidinium complexes. This work provides a rare example of binding biologically important types of amidinium cations as ion pairs by a synthetic receptor.

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Introduction

Recognition of amidinium cations by artificial receptors has been a subject of research interest for the last two decades¹ due to their importance in implementing biological functions in DNA-binding and inhibitor drugs. For example, pentamidine isethionate, which contains two amidinium residues, has been widely used for the treatment of pneumocystosis, babesiosis, trypanosomiasis, and leishmaniasis.² However, very few synthetic receptors are available so far for use in binding the amidinium group.^1,3 Among the very limited examples reported up to 2003 and afterwards, only one recognition motif involves the utilization of a highly preorganized multi pyridine-based macrocycle.¹ Therefore, the design and creation of new macrocyclic host–guest systems for amidinium complexation represents a great challenge, particularly when the development of new receptor systems for amidinium ions⁴ has been untouched by supramolecular scientists during the past decade. Furthermore, all artificial receptors are only concerned with complexation of amidinium cation alone, other than binding concomitantly both cationic species and its counteranion, which is widely known as ion-pair recognition. Ion-pair recognition is considered as an efficient approach to enhance binding affinities as shown by salt solubilisation, extraction and membrane transport.⁵ Despite the realization of designed molecules for coordinating zwitterionic amino acids and peptides,⁶ complexation of biologically relevant amidinium ions by synthetic receptors as ion pair in a convergent fashion is still unknown. With widespread use of amidines and their salts,⁷ development of such ion-pair recognition systems may have important implications for medicinal chemistry.

Hydrogen-bonded aromatic amide macrocycles⁸ have received increasing attention because of their interesting host–guest chemistry.⁹ Among them, cyclo[6]aramides, a class of shape-persistent cyclic compounds with amide oxygen atoms inwardly oriented,¹⁰ are of particular interest in their binding affinity towards organic cations. Our recent work has revealed the strong ability of these macrocycles to bind secondary ammonium salts,¹¹ diquat¹² and tropylium.¹³ Their unique host–guest chemistry is also revealed by their capability to specifically discriminate native arginine¹⁴ and to manipulate liquid crystal properties.¹⁵ Interestingly, depletion of partial hydrogen bonds leads to convergent heteroditopic cyclo[6]aramides that have shown high association ability for intimate organic ion pairs.¹⁶ The recent advance of ditopic receptors¹⁷ aroused our intense interest to probe the possibility of binding amidinium salt as ion pair by convergent H-bonded macrocycles. We report herein that heteroditopic cyclo[6]aramide 1a (Fig. 1) is able to recognize a series of amidinium salts G1–G5 with varying binding affinity through hydrogen bonding (H-bonding) interactions. Particularly, G1, G2 and G3 with different steric hindrance in the central carbon of the cation are bound as contact ion pair where the amidinium and chloride are present essentially as one entity as evidenced by NMR and conductivity experiments.

Fig. 1 Chemical structures and proton designations of heteroditopic cyclo[6]aramide 1 and amidinium salt G1–G7. Green and pink represent chloride anion and amidinium cations, respectively.

Results and discussion

Density functional theory (DFT) calculation results

The feasibility of binding a contact ion-pair species amidinium chloride is examined based on density functional theory (DFT) method simulations of the complex system comprising cyclo[6]aramide 1b and amidinium G1, G2. Our computational results on the calculated binding energies reveal that G1 fits well in the cavity of the host molecule (Fig. 2a and S37, ESI†). The chloride anion is engaged in four H-bonds (H, I, J and K), three of which are associated with the anion-binding cleft formed by three H-bond donors from the macrocycle (two amide NH and one aromatic H) with the remaining charge-assisted H-bond formed with the cationic NH group of G1. The ion-pair complexation is further strongly stabilized by four charge-assisted H-bonds (D, E, F, I). With this optimized conformation stabilized by cooperative H-bonding interactions, the amidinium chloride is perfectly engulfed as a contact ion-pair species in the macrocycle. Computer simulations on G2 produce a similar result that shows the acetamidinium chloride stays somewhat above the macrocyclic platform due to the presence of additional methyl substituent (Fig. 2b and S38, ESI†).

Fig. 2 Side (up) and top (down) views of optimized geometry of (a) 1b·G1 and (b) 1b·G2 at the RB3PW91/6-31G (d, p) level; all side chains of 1a are replaced by methyl groups for simplicity (gray = C, white = H, red = O and blue = N). The chloride anion is shown as a CPK model. The dashed green lines indicate intermolecular H-bonds D–K with D = 1.888 Å, E = 1.965 Å, F = 1.889 Å, G = 2.311 Å, H = 2.283 Å, I = 1.982 Å, J = 2.308 Å and K = 2.464 Å; D′ = 1.976 Å, E′ = 1.911 Å, F′ = 2.114 Å, G′ = 2.202 Å, H′ = 2.360 Å, I′ = 2.040 Å, J′ = 2.295 Å and K′ = 2.581 Å.

Ion-pair complexation studies

With the theoretical prediction for the stability of ion-pair complex, ditopic cyclo[6]aramide 1a was synthesized via a multi-step pathway (Scheme S1, ESI†).¹⁶ An acetylene chain was incorporated to improve the solubility of the macrocycle. Since G1 is very hygroscopic and not easy to handle in experiments, guest G2 was tested first for its binding ability with 1a. The first sign of binding with G2 as ion pair came from ¹H NMR experiments. Addition of one equivalent of G2 to a CDCl₃ solution of 1a leads to the downfield shifts in the signals arising from amide and aromatic protons H_j, H_k, H_b and H_g on 1a by 1.39, 0.55, 0.20 and 0.27 ppm, respectively (Fig. 3).

Fig. 3 Partial ¹H NMR spectra of (a) 1.0 mM cyclo[6]aramide 1a; (b) 1.0 mM cyclo[6]aramide 1a·G2 (400 MHz, CDCl₃, 298 K).

This implies that both the cationic and anionic guests are associated primarily with the cavity of this receptor.¹⁸ Particularly, the substantial change of amide proton resonance (Δδ = 1.39 ppm for H_j) relative to other proton resonances strongly suggests the H-bonding interaction of amide hydrogen with chloride anion, and thus its residing in the core of the macrocycle. Moreover, a binding constant of 6.08 × 10³ M⁻¹ in CDCl₃–CD₃OH (v/v, 9 : 1) was obtained by fitting the concentration-dependent change of the chemical shifts of proton 1a-H_d (Fig. 4 and Table 1).

Fig. 4 Partial stacked ¹H NMR spectra of cyclo[6]aramide 1a (1.0 mM) titrated by G2 (0–2.0 equiv.) in (400 MHz, 9 : 1, CDCl₃–CD₃OD, 298 K).

Table 1 Electrical conductivity (σ/μS cm⁻¹)^a,b and association constants (K_a/M⁻¹)^c for complexation of various guests (G1–G7 and TBACl) by 1a at 298 K

Guest	Ion pair	σ/μS cm^−1		Ka^c/M^−1
		Guest^a	Complex^b
a The electrical conductivity σ values were obtained in CDCl3–CD3CN (v/v, 1 : 1).b The electrical conductivity σ values were obtained in CDCl3–CD3CN (v/v, 1 : 1).c The association constant Ka values were obtained by ^1H NMR titration in CDCl3–CD3OD (v/v, 9 : 1).
G1	Contact	63.5	50.3	(5.98 ± 0.89) × 10^4
G2	Contact	69.1	57.2	(6.08 ± 1.72) × 10^3
G3	Contact	77.2	68.5	(4.08 ± 0.73) × 10^3
G4	Loose	333.1	311.8	(2.04 ± 0.48) × 10^3
G5	Loose	351.2	319.4	(5.91 ± 0.60) × 10^3
G6	Contact	67.8	55.6	(1.45 ± 0.58) × 10^4
G7	Contact	78.4	66.8	(5.46 ± 1.49) × 10^3
TBACl	Loose	411.2	392.5	(3.81 ± 0.83) × 10^2

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The involvement of carbonyl oxygen atoms in forming intermolecular hydrogen bonds was corroborated by the infrared experiments of the complex prepared from a mixture of 1a and G1, G2, G3 in a molar ratio 1 : 1. The strong band at 1662 cm⁻¹ of ν(C=O) in 1a shifts to 1648 cm⁻¹ in the complex, revealing a change of 14 cm⁻¹ from vibration of carbonyl oxygen. On the other hand, the band of amidinium N–H vibrations appears at 1699 cm⁻¹ in free G2 and merges into a band at 1705 cm⁻¹ in the complex of 1a·G2 (Fig. 5), suggestive of the interaction of aramide N–H with the oxygen atoms. Similar results were obtained for the complexation of 1a·G1 and 1a·G3 (Fig. S34 and S35, ESI†).

Fig. 5 FT-IR transform infrared spectra of cyclo[6]aramide 1a (a), complex1a·G2 (b) and G2 (c).

Furthermore, results from the high resolution electrospray ionization mass spectrometry (HRESI-MS) show a highly intense fragment ion of [1a + G2 − Cl]⁺ at m/z = 1685.1021 for 1a·G2 in the positive ion mode (Fig. 6a). Importantly, a peak at m/z = 1661.6003, corresponding to [1a + Cl]⁻, is observed in the negative ion mode (Fig. 6b). This result indicates the binding of chloride anion as ion pair in the complex and a 1 : 1 stoichiometry. Similar results were obtained for the ion-pair complexation of G1 (Fig. S30 and S31, ESI†) and G3 (Fig. S32 and S33, ESI†). The method of Job's plot supplied information on the binding stoichiometry of 1a and G2 in solution. The maximum absorbance in UV-vis spectra is observed at 0.5, indicating a macrocycle–ion pair ratio of 1 : 1 in the complex (Fig. 7). In fact, the stoichiometry of all host–guest complexes was found to be 1 : 1 by the Job's plot method (Fig. S5, S17, S21 and S25, ESI†).

Fig. 6 HRESI-MS spectra of an equimolar solution of 1a and G2 in methanol in the positive ion mode (a) and negative ion mode (b).

Fig. 7 Job's plot for the complexation of 1a and G2 in CDCl₃–CD₃OD (v/v, 9 : 1) based on the absorbance at 365 nm, indicating a 1 : 1 stoichiometry. The total concentration is 3 × 10⁻⁴ M.

Evidence in support of chloride ion binding in solution came from the observation that the K_a value (∼10⁴ M⁻¹) obtained by ¹H NMR titrations (Fig. 8) for G1 is larger by over one order of magnitude than the value for G4 (∼10³ M⁻¹) bearing a bulky anion, BPh₄⁻ (Table 1). Thus, the small chloride anion greatly enhances the complexation as compared to a larger anion, indicating its essential contribution to the enhanced cation binding via a positive cooperativity effect. In sharp contrast to G1, TBACl, which shares the same anion but contains a large tetrabutylammonium cation, is bound with a significantly lowered binding constant (∼10² M⁻¹). (Fig. S3–S24, ESI†). The drastic reduction of the binding affinity in the presence of the non-coordinated cationic species TBA or tetramethylammonium,¹⁹ underscores the important cooperative action for ion paring of the formamidinium cation (HC(NH₂)₂⁺) with the chloride to retain its high binding affinity in the recognition process. In addition, replacing the counterions of G1 with halide anions (bromide and iodide) led to G6 and G7 with K_a values in the decreasing order: G1 > G6 > G7 > G4 (Table 1, Fig. S3–S11, ESI†). This indicates that a larger anion tends to screw the anion out of the cavity, which in turn diminishes the binding affinity of the complex. Among the four anions examined above, the smallest anion chloride is mostly likely to be well accommodated in the cavity as ion pair. Results from conductivity study are consistent with ion paring of chloride (vide post). Unfortunately, all attempts to obtain suitable crystals of 1a with amidinium salts failed. However, from 2D ¹H NMR experiments the information on the structure of the complex can be retrieved. The NOESY spectrum of a solution containing an equimolar mixture of 1a·G2 in CDCl₃–CD₃CN (v/v, 1 : 1) shows correlations between the signals attributable to the amidinium ion H¹, H² and aromatic protons H_k, H_g and H_b of 1a (Fig. 9a). Meanwhile, two correlations are observed between the signals of aromatic protons H_b, H_j and methyl proton H³ on the amidinium ion (Fig. 9b). In contrast, no cross-peaks associated with the interaction between exterior aromatic protons of 1a and any protons of G2 are observed (Fig. S36, ESI†). These findings, combined with the facts above, strongly support the residing of both cation and anion as contact ion pair inside the cavity of the host molecule. In addition, the binding affinities are found to decrease with increasing the size of the substituent in the amidinium ion in the order of G1 > G2 > G3, reflecting the decreased steric demands for efficient complexation.

Fig. 8 Partial stacked ¹H NMR spectra of cyclo[6]aramide 1a (1.0 mM) titrated by G1 (0–2.0 equiv.) in (400 MHz, 9 : 1, CDCl₃–CD₃OD, 298 K).

Fig. 9 Expanded 2D NOESY spectra of 1 : 1 complex 1a·G2 showing correlations between aromatic protons of 1a and (a) NH₂ of G2 and (b) CH₃ of G2 (10 mM, 1 : 1, CDCl₃–CD₃CN, 400 MHz, 298 K).

Conductometric studies for the intimacy of ion-pairs

Variation in conductivity of analytes is known to reflect the propensity of host–guest inclusion and ion-pair interaction in solution,²⁰ which can consequently be used to evaluate the intimacy of ion pairs formed by the amidinium ion and the anion. Therefore, conductivity experiments were performed at 5 mM of the host 1a in CHCl₃–CH₃CN (v/v, 1 : 1) for the complexes (Tables 1 and S10, ESI†). Di-n-butylammonium chloride (DBACl) and di-n-butylammonium hexafluorophosphate (DBAH), which are known to be contact ion pair and loose (or separated) ion pair,²¹ respectively, are used as a control. Their conductivity values were determined to be 63.4 and 594.5 μS cm⁻¹ respectively, revealing a tremendous difference in conductivity (Δσ = 531.1 μS cm⁻¹) between the contact and loose ion pairs. Correspondingly, their complexes 1a·DBACl and 1a·DBAH also show a significant difference in conductivity (Δσ = 515.9 μS cm⁻¹). Interestingly, the crystal structure of 1a·DBACl in our previous work reveals contact ion-pair complexation¹⁶ via hydrogen bonding where the distance between one hydrogen of the charge-assisted H-bonds of the di-n-butylammonium cation and the chloride anion measures 2.177 Å. Therefore, the lower conductivity as observed for 1a·DBACl should point to the presence of a highly associated species or a contact ion pair in solution, and conversely, the higher conductivity should correspond to the formation of a loose ion-pair. In these cases, the ion-pair behaviour of the salts and complexes could be well distinguished by the difference of conductivity. It is envisioned that the simultaneous complexation of both amidinium and chloride as contact ion pair by the macrocyclic ditopic receptor would lead to low conductivity. Indeed, upon complexation, G1–G3 offer a conductivity value by ca. five to six-fold lower than G4, and also TBACl, a typical example of loose ion-pair²² (Table 1). These comparative data indicate that amidinium salts with small chloride are bound as contact ion pair in the cavity of 1a, while 1a·G4 having the large anion as the counterion is prone to exist as loose ion pair. The extent to which the anion as contact ion pair is bound inside the cavity is revealed by the increased conductivity with increasing the size of anions in the order of G1 < G6 < G7. Formation of contact ion pair is particularly interesting as this avoids the energetically unfavourable separation of the two ions.²³ Of particular relevance to biological molecules is benzamidinium G3, a structural mimic of arginine and a potent inhibitor.⁴ To the best of our knowledge, implementation of ion-pair recognition of amidinium salts by synthetic receptors is still unknown.

Pentamidine (PAM) isethionate (G5) is a bisamidinium salt that has found extensive use against pneumonia and even for AIDS therapy. Given its structural feature involving two benzamidinium moieties in the molecule, the complexation of PAM by 1a was examined by ¹H NMR spectroscopy. Signals for the aromatic protons H⁷ and H⁸ (Δδ = +0.18 and −0.14 ppm) of G5 undergo downfield shifts in CDCl₃–CD₃OD (v/v, 9 : 1), consistent with its participation in forming the complex with the macrocycle (Fig. S29, ESI†). However, the complex was found to be present in 1 : 1 stoichiometry by both mass spectrometry (MALDI-TOF) (Fig. 10) and the Job's plot method in solution (Fig. 11), and its binding constant with host 1a was found to be (5.91 ± 0.60) × 10³ M⁻¹ (Fig. S26 and S27, ESI†). The close conductivity values between the two complexes 1a·G5 and 1a·G4 (Table 1) indicate that PAM exists as loose ion-pair in solution due to the bulky counterion. The decreased conductivity (Δσ = −31.8 μS cm⁻¹) of 1a·G5 as compared to the free loose ion-pair of G5 is ascribed to the confinement of the cation in the macrocyclic lumen.

Fig. 10 MALDI-TOF spectrum of an equimolar solution CHCl₃–CH₃OH (v/v, 9 : 1) of 1a and G5, showing the presence of 1 : 1 charge-transfer complex [inset: experimental isotope distribution (blue) and computer simulation (red)].

Fig. 11 Job's plot for the complexation of 1a and G5 in CDCl₃–CD₃OD (v/v, 9 : 1) based on the absorbance at 365 nm, indicating a 1 : 1 stoichiometry. The total concentration is 3 × 10⁻⁴ M.

Conclusions

In summary, we have demonstrated a modular system based on convergent heteroditopic cyclo[6]aramide for ion-pair recognition of amidinium chlorides. The association ability for simultaneous binding of cationic and anionic guest species depends considerably on the counterions and the size of amidinium ions. Comparative conductivity studies offer a convenient methodology to discriminate between contact and loose ion pairs for these amidinium complexes. Our findings provide a rare example of ion-pair recognition for formamidinium salts and their kindred compounds by synthetic receptors. Further work may lead to cycloaramide-based receptors for transport, controlled release, and detection of these compounds.

Experimental

Materials and reagents

Compound 1 was synthesised following the reported procedure.¹⁶ Dichloromethane, anhydrous Na₂SO₄ and anhydrous Mg₂SO₄ were purchased from Chengdu Kelong Chemical Factory. CH₂Cl₂ was dried over CaH₂. Column chromatography was carried out using silica gel (300–400 mesh). All other solvents and chemicals used for the synthesis were of reagent grade and used as received. The complex samples for ESI-MS determination were prepared by mixing a CH₃OH solution. Solvents for extraction and chromatography were of reagent grade.

Synthetic procedure of 1a

Pentamer 7 (300 mg, 0.20 mmol) was hydrogenated in the presence of 20% Pd/C (60 mg) in CHCl₃/CH₃OH (80 mL, v/v = 5 : 1) for 10 h at 40 °C. The solution was filtered in darkness as fast as possible followed by immediate removal of the solvent. The reduced diamine 8 was used for the immediate coupling reaction. DMF (5 uL) was added to a suspension of 5-(prop-2-yn-1-yloxy)isophthalic acid 10 (58 mg, 0.20 mmol) and oxalyl chloride (87.5 mg, 0.70 mmol) in CH₂Cl₂. The mixture was stirred for 40 min at room temperature. The solvent was evaporated and the resulting residue was dried in vacuum at room temperature for 30 min. The acid chloride 11 thus obtained was dissolved in CH₂Cl₂ (60 mL) and added dropwise to a mixture of 8 and Et₃N (162 mg, 1.60 mmol) in CH₂Cl₂ (20 mL) at 0 °C. The solution was stirred under N₂ for 7 h. The organic layer was washed with water (20 mL × 3) and dried over anhydrous Na₂SO₄ and filtered. The crude product was purified by chromatography on silica gel (CH₂Cl₂/MeOH = 20 : 1) to provide the product 1a as a white solid (241 mg, 73%). ¹HNMR (400 MHz, CDCl₃, 298 K) (ppm): 10.19 (s, 2H), 9.14 (s, 4H), 9.16 (s, 2H), 9.14 (s, 1H), 8.51 (d, 2H, J = 12 Hz), 8.28 (s, 1H), 8.20 (s, 2H), 7.80 (s, 2H), 7.02 (d, 2H, J = 8 Hz), 6.50 (s, 3H), 4.79 (s, 2H), 4.10 (d, 8H, J = 10 Hz), 3.91 (d, 12H, J = 16 Hz), 2.25 (t, 1H, J = 4 Hz), 1.54–1.26 (m, 74H), 0.94–0.86 (m, 24H); ¹³C NMR (101 MHz, CDCl₃, 298 K): δ 164.55, 163.18, 162.38, 159.92, 159.72, 153.40, 145.87, 135.19, 132.31, 124.98, 124.25, 122.13, 120.92, 118.95, 117.90, 117.81, 112.81, 94.58, 77.22, 72.45, 72.29, 55.89, 55.50, 38.52, 37.86, 31.87, 30.96, 30.35, 30.06, 29.72, 29.72, 29.59, 29.35, 29.08, 28.65, 26.72, 26.38, 23.44, 23.15, 23.09, 22.67, 14.13, 10.35, 10.32; MALDI-TOF MS (m/z) calcd for C₉₇H₁₃₆N₆O₁₅ [M + Na]⁺ 1647.996, found [M + Na]⁺ 1647.900.

Instruments and apparatus

¹H and¹³C NMR spectra were recorded on Bruker AVANCE AV II-400 MHz (¹H: 400 MHz; ¹³C: 100 MHz) (Karlsruhe, Germany). High resolution mass spectra (HR-MS) data were collected by WATERS Q-TOF Premier (California, USA). UV-vis spectra were measured by SHIMADZU UV-2450 (Tokyo, Japan). Chemical shifts are reported in δ values in ppm using tetramethlysilane (TMS). HR-MS data were obtained by WATERS Q-TOF Premier. The geometry optimizations were carried out in gas phase by employing the Gaussian09 program. Fourier transform infrared (FT-IR) data were collected by a Thermo Nicolet NEXUS 670 FT-IR spectrophotometer. MALDI-TOF MS spectra were recorded on Bruker Autoflex III MS spectrometer.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (21172158 and 21572143), the Doctoral Program of the Ministry of Education of China (20130181110023), Open Project of State Key Laboratory of Supramolecular Structure and Materials (SKLSSM201629), and Open Project of State Key Laboratory of Structural Chemistry (20140013) for funding this work.

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Footnote

† Electronic supplementary information (ESI) available: Synthetic procedures, characterization details, titration ¹H NMR spectra and absorption spectral traces. See DOI: 10.1039/c6ra08202e

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