Enhanced anion recognition by ammonium [2]catenane functionalisation of a halogen bonding acyclic receptor

Abstract

Ammonium-dibenzo[24]crown-8 [2]catenane functionalisation of a 3,5-bis-iodotriazole-pyridine motif produces a potent halogen bonding (XB) receptor capable of binding anions in aqueous-acetone solvent mixtures of up to 20% water. Exploiting the kinetically inert nature of the mechanically bonded cationic ammonium [2]catenane substituents, the XB receptor is demonstrated to exhibit superior anion recognition behaviour in comparison to labile sodium cation complexed bis-benzo[15]crown-5 XB and HB triazole-pyridine heteroditopic receptor analogues.

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The continued interest in developing host systems for the molecular recognition of charged species is in no small part due to the pervasiveness of ions in a multitude of fundamental and essential chemical and biological processes.^1,2 The characteristics of counterions have a significant impact on the cation and anion binding affinities of monotopic receptor systems. Consequently, the development of heteroditopic receptors for ion-pair recognition, where favourable proximal cation–anion electrostatic interactions and conformational allosteric cooperativity boost charged guest binding strength, has gained increasing attention in supramolecular host–guest chemistry research for the past few decades.³ Notably, heteroditopic hosts have demonstrated a plethora of potential applications including the extraction and recovery of transition and main-group metals, the solubilisation of inorganic salts in organic media, membrane transport and recognition of biologically-relevant zwitterions.^4–6

Ion-pair recognition is associated with multiple complex equilibria. Strong ion-pairing, particularly in low polarity organic solvents, inhibits the complete dissociation of charged species, and only a fraction of free ions persists in solution.⁷ With heteroditopic receptors, the cation and anion are bound simultaneously, taking advantage of cooperativity between the proximal respective recognition sites. Commonly employed cation binding motifs in heteroditopic host design are crown ethers, and to achieve anion binding, hydrogen bond (HB) donors such as amide, urea and triazole are frequently used.^8–11 During the last decade, the emergence of sigma–hole interactions such as halogen bonding (XB) has demonstrated, in general, their superior anion guest binding capabilities compared to hydrogen bonding (HB) in host design.^12–15

Recently, we reported a series of heteroditopic receptors containing XB donor groups covalently linked to benzo[15]crown-5 motifs, wherein co-bound sodium cation crown ether complexation cooperatively augmented bromide and iodide binding strength.¹⁶ Herein, we present an alternative novel post-mechanical bond synthesis strategy, where a positively charged ammonium [2]catenane motif replaces the crown ether complexed alkali metal cation. Stoddart's pioneering work demonstrating pseudorotaxane assembly between dibenzo[24]crown-8 and the dibenzyl ammonium group, stabilised by strong ion-dipole HB interactions,¹⁷ has led to its extensive employment in the mechanical interlocked molecule (MIM) synthesis of an enormous range of rotaxane and catenane supramolecular architectures.^18–20

A mechanically bonded dibenzo[24]crown-8 dibenzylammonium [2]catenane synthon was employed in the construction of a novel XB 3,5-bis-iodotriazole [2]catenane functionalised pyridyl receptor 1·(PF₆)₂ for anion recognition in aqueous media (Fig. 1a). Extensive ¹H-NMR anion titration investigations demonstrate the superior anion recognition properties of 1·(PF₆)₂ in comparison to bis-sodium cation complexed benzo[15]crown-5 functionalised XB and HB heteroditopic receptor analogues (XB9·2NaPF₆ and HB10·2NaPF₆, respectively). These observations serve to highlight the importance of the kinetically inert nature of the cationic [2]catenane group in enhancing anion binding in competitive aqueous media, as an alternative to a kinetically labile alkali metal cation complexed crown ether.

Fig. 1 Chemical structures of (a) ammonium-dibenzo[24]crown-8 [2]catenane functionalised XB receptor, 1·(PF₆)₂ and (b) XB and HB heteroditopic benzo-15-crown appended analogous receptors containing sodium ion complexed benzo[15]crown-5, XB9·2NaPF₆ and HB10·2NaPF₆, respectively.

In order to prepare azide functionalised ammonium-crown ether [2]catenane synthon 8·PF₆ for subsequent CuAAC click XB reaction, the initial syntheses of azido-dibenzo[24]crown-8 5 and the appropriate bis-alkene ammonium thread 6·PF₆,^21–23 were undertaken using modified procedures (Scheme S1, ESI†). To prepare the macrocycle 5, the bis-tosylate precursor 2 was first prepared from an alkylation reaction of catechol, followed by tosylation. Subsequent macrocyclization was achieved via a potassium cation template ring closing reaction using a modified literature procedure.²⁴ An equimolar solution of the bis-tosylate 2 and 2-nitrocatechol in dry MeCN was refluxed in the presence of KPF₆ and K₂CO₃ to give nitro-functionalised dibenzo[24]crown-8 3 in 87% yield. Reduction of 3 followed by diazotization and a nucleophilic aromatic substitution reaction with NaN₃ gave azido-dibenzo[24]crown-8 5 in 90% yield (Scheme 1).

Scheme 1 Synthesis of azide functionalised dibenzo[24]crown-8, 5.

Qualitative ¹H-NMR spectroscopic studies of pseudorotaxane-complex formation between thread 6·PF₆ and macrocycle 5 were conducted by mixing an equimolar solution of each component in d₂-dichloromethane at room temperature. The ¹H-NMR spectrum of the resulting homogeneous solution showed well resolved signals of both complexed and uncomplexed states, indicating the pseudorotaxane equilibrium was in slow exchange on the NMR timescale (Fig. S17, ESI†). The aromatic proton signals from the threading component 6·PF₆ (H_c and H_b) displayed an upfield shift upon interpenetration, concomitantly with the observation of substantial chemical shift changes of proton signals associated with the macrocyclic component. These evidences all indicate the formation of pseudorotaxane 7·PF₆, in which hydrogen bonding and ammonium cation–dipole (NH⁺–O) interactions, along with π–π interactions stabilise the complexed assembly in d₂-dichloromethane.

The stability of the pseudorotaxane complex assembly allowed for the preparation of the azide appended [2]catenane 8·PF₆via a ring closing metathesis reaction using Grubbs’ 1st-generation catalyst.^25,26 The crude product was purified by preparative silica gel thin-layer chromatography, followed by size exclusion chromatography and anion exchange to afford the azido [2]catenane 8·PF₆ product in 30% yield (Scheme 2). The interlocked nature of catenane 8·PF₆ was confirmed by ¹H–¹H ROESY NMR spectroscopy (Fig. S12, ESI†).

Scheme 2 Synthetic scheme for azide functionalised [2]catenane 8·PF₆via a ring closing metathesis and [2]catenane functionalised XB receptor 1·(PF₆)₂.

The CuAAC reaction of two equivalents of 8·PF₆ with 3,5-bis-iodoethylnylpyridine²⁷ gave the target product 1·(PF₆)₂ in an excellent 85% yield after purification (Scheme 2). The ¹H-NMR spectrum of 1·(PF₆)₂ shows broad proton signals from the pyridyl ring (H_a and H_b) hidden under signals of aromatic crown ether protons with a significant downfield perturbation of aryl protons (H_c, H_d, and H_e) compared to those in the starting material 8·PF₆ (Fig. 2a). Additionally, the methylene proton (H_j, H_k, and H_u–z) resonances of 1·(PF₆)₂ are split into multiple signals whilst the alkyl proton (H_l–s) resonances remain unchanged. Moreover, the HRMS of 1·(PF₆)₂ revealed a signal of m/z = 1185.02467, corresponding to [M-2PF₆⁻]²⁺, in agreement with the theoretical mass spectrum (Fig. 2b and ESI†).

Fig. 2 (a) Comparative truncated ¹H-NMR spectra of 8·PF₆ and 1·(PF₆)₂ in CD₃OD/CDCl₃ (1 : 1 v/v) and (b) HRMS of 1·(PF₆)₂.

The anion recognition properties of 1·(PF₆)₂ were initially investigated by ¹H-NMR spectroscopic titration experiments in the organic solvent mixture 10% d₆-DMSO/CDCl₃. Upon addition of iodide as tetrabutylammonium iodide (TBAI), the chemical shift of the internal pyridyl proton (H_a) displayed downfield perturbations as a function of iodide anion concentration. WinEQNMR2 analysis²⁸ of the titration data determined a 1 : 1 host–guest stoichiometric association constant (K_a) of >10⁴ M⁻¹, while the sodium cation complexed XB receptor XB9·2NaPF₆ reported previously exhibited an apparent K_a of 5660 M⁻¹ for iodide binding in this solvent system.¹⁶ Importantly this initial observation suggested appending a kinetically stable ammonium-crown ether [2]catenane substituent to the XB anion recognition motif significantly enhanced iodide binding affinity in comparison to XB9·2NaPF₆.

Anion binding studies were further undertaken in the more competitive aqueous-organic solvent mixture 5% D₂O/d₆-acetone. Addition of TBAI to 1·(PF₆)₂ resulted in a large downfield perturbation (Δδ = +0.2 ppm, 10 equiv. I⁻) of the internal pyridyl proton signal (H_a) with a concomitant splitting of the resonances arising from the phenyl protons (H_c, H_d, H_e), linked to the iodotriazole motifs. In contrast, the crown ether protons (H_u–z) and the methylene protons adjacent to the ammonium cation group (H_j) showed negligible perturbations, clearly indicating that the halide anion was bound in the XB cleft of the receptor and not interacting directly with the ammonium–crown ether catenane complex (Fig. S18, ESI†).

Although initially only sparingly soluble in the 5% D₂O/d₆-acetone solvent mixture, the addition of two equivalents of NaPF₆ resulted in the dissolution of both XB and HB heteroditopic receptors, indicating respective sodium cation-benzo[15]crown-5 complexation. However, it should be noted that under these experimental conditions, metal cation binding is not quantitative and there remains at equilibrium a significant proportion of un-complexed metal cation and heteroditopic receptor. It is noteworthy that this is not the case with the kinetically inert cationic [2]catenane motif in 1·(PF₆)₂. WinEQNMR2²⁸ and Bindfit analysis²⁹ of the anion titration data monitoring the shifts of the internal pyridyl proton (H_a) determined 1 : 1 stoichiometric anion-host association constants together with apparent association constant data obtained from analogous titrations with XB9·2NaPF₆ and HB10·2NaPF₆ (Table 1). Notably, the catenane functionalised XB receptor 1·(PF₆)₂ bound the heavier halides much more strongly than either XB9·2NaPF₆ or HB10·2NaPF₆, displaying at least over ca. 20-fold and ca. 40-fold enhancement of iodide and bromide binding strength respectively. Impressively, 1·(PF₆)₂ also displayed binding of highly hydrated anions such as Cl⁻ and SO₄²⁻ with K_a values of 44 and 293 M⁻¹ respectively. In 20% D₂O/d₆-acetone, the maximum amount of water content where the host maintained sufficient solubility for ¹H-NMR spectroscopic titration, 1·(PF₆)₂ was still able to bind iodide strongly (K_a = 860 M⁻¹). This observation clearly demonstrates that the combination of mechanically interlocked ammonium cation dibenzo[24]crown-8 containing substituents appended to a XB anion binding scaffold is as an effective novel methodology to achieve anion recognition in highly competitive aqueous solvent mixtures. It is also noteworthy that the superbase property of such ammonium MIM substituents potentially enables the positive charge to be retained even under basic aqueous solvent medium conditions.³⁰

Table 1 Anion association constants of 1·(PF₆)₂ and bis-sodium cation complexed heteroditopic receptors XB9·2NaPF₆ and HB10·2NaPF₆ in 5% D₂O/d₆-acetone, 298 K^a

Anion	Association constant (Ka, M^−1)
	1·(PF6)2	XB9·2NaPF6	HB10·2NaPF6
a K a values obtained by fitting the binding isotherm (monitored chemical shift changes of Ha) to a host–guest 1 : 1 stoichiometric binding model using WinEQNMR2; error(±) is less than 10%; each anion added as its tetrabutylammonium (TBA) salt. b Titrations in the presence of 2 equivalents of sodium cations added as NaPF6. c Titration in 20% D2O/d6-acetone. d Fitting with Bindfit v.05.^29
Cl^−	44	Precipitate	Precipitate
Br^−	5303	273	149
I^−	>10^4, 860^c	455	95
SO4^2−	293^d	Precipitate	Precipitate

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In an effort to compare the halide anion binding properties of the kinetically inert positively charged catenane 1·(PF₆)₂ receptor with a labile ion-pair receptor analogue, the heteroditopic XB bis-dibenzo-24-crown-8 functionalised 3,5-bis-iodopyridyl receptor XB11 was prepared for dibenzyl ammonium (DBA) cation-halide anion ion-pair binding investigation (see ESI† for synthetic details). Unfortunately, the poor solubility of XB11 in common organic solvents, including acetone and acetone/D₂O mixtures, necessitated the ¹H-NMR titration experiments being undertaken in 1 : 1 CD₃CN/CDCl₃. Monitoring perturbations of the receptor's aryl proton H_a in the vicinity of the XB recognition site, Bindfit analysis of the titration data (see ESI,† Table S1) determined the free XB11 receptor binds Br⁻ (K_a = 3640 M⁻¹) much more strongly than I⁻ (K_a = 853 M⁻¹). In the presence of two equivalents of DBA·PF₆ resulting in pseudorotaxane assembly in each of the receptor's dibenzo-24-crown-8 substituents, TBA halide addition caused significant proton shifts, in particular in the aryl proton H_a of the XB recognition site and also induced chemical shift changes of proton signals of aryl protons of DBA⁺. Monitoring the aryl proton H_a proton, Bindfit analysis of the titration data (see ESI,† Table S1) determined 1 : 1 stoichiometric host–guest apparent association constant values for Br⁻ and I⁻ of 779 M⁻¹ and 1752 M⁻¹, respectively, indicating that co-bound secondary ammonium crown ether pseudorotaxane complexation enhances I⁻ binding capability, and by stark contrast attenuates the strength of Br⁻ binding. Tentatively, this may be a consequence of competitive DBA⁺ cation-bromide ion-pairing, which appears to be more significant than DBA⁺ cation-iodide ion-pair association in the mixed organic solvent medium.‡

In conclusion, a novel XB 3,5-bis-iodotriazole-pyridine receptor functionalised with secondary ammonium-dibenzo[24]crown-8 [2]catenane motifs (1·(PF₆)₂), was prepared in high yield via a post-synthetic MIM procedure. The kinetically inert nature of the mechanically interlocked ammonium cations facilitated XB-anion recognition in competitive aqueous-organic solvent mixtures of up to 20% D₂O/d₆-acetone with iodide. Importantly, 1·(PF₆)₂ displayed superior strong and selective anion binding affinity in comparison to labile sodium cation complexed bis-benzo[15]crown-5 XB and HB triazole-pyridine heteroditopic receptor analogues. These observations highlight the potential of exploiting secondary ammonium cation MIM crown ether encapsulation for augmenting anion recognition in competitive aqueous media.

T. B. thanks the Development and Promotion of Science and Technology Talents (DPST) Project, Thailand, for a full student scholarship. Y. C. T. thanks the Croucher Foundation for a scholarship. Authors thank Prof. Chutima Kuhakarn and Natthapat Sawekteeratana from Department of Chemistry, Mahidol University for spectroscopic characterisation of XB11.

Conflicts of interest

There are no conflicts to declare.

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3cc03269h

‡ Quantitative binding data could not be determined from Bindfit analysis of the TBACl titration isotherms.

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