Selective sodium halide over potassium halide binding and extraction by a heteroditopic halogen bonding [2]catenane

The synthesis and ion-pair binding properties of a heteroditopic [2]catenane receptor exhibiting highly potent and selective recognition of sodium halide salts are described. The receptor design consists of a bidentate halogen bonding donor motif for anion binding, as well as a di(ethylene glycol)-derived cation binding pocket which dramatically enhances metal cation affinity over previously reported homo[2]catenane analogues. 1H NMR cation, anion and ion-pair binding studies reveal significant positive cooperativity between the cation and anion binding events in which cation pre-complexation to the catenane subsequently ‘switches-on’ anion binding. Notably, the heteroditopic catenane displayed impressive selectivity for sodium halide recognition over the corresponding potassium halides. We further demonstrate that the catenane is capable of extracting solid alkali metal salts into organic media. Crucially, the observed solution phase binding selectivity for sodium halides translates to superior functional extraction capabilities of these salts relative to potassium halides, overcoming the comparatively higher lattice enthalpies NaX > KX dictated by the smaller alkali metal sodium cation. This is further exemplified in competitive solid–liquid experiments which revealed the exclusive extraction of sodium halide salts from solid mixtures of sodium and potassium halide salts.

2][23][24][25][26] These favourable binding properties have fuelled the rising prominence of ion-pair receptors in a myriad of applications including salt extraction/solubilisation, [27][28][29][30][31][32][33][34][35][36][37] membrane transport 38,39 and the recognition of biologically-relevant zwitterions. 40,41espite these successes, the design of ion-pair receptors capable of distinguishing chemically-similar ions remains a persistent challenge.3][44] Their shared monocationic nature, spherical geometry and similar ionic radii make selective recognition of these ions a signicant challenge in synthetic receptor systems, 45 a difficulty underscored by the scarcity of heteroditopic ion-pair receptors capable of selectively binding sodium or potassium salts. 35,46,47he demonstrated efficacy of MIM-based receptors to engineer otherwise challenging ion selectivity proles, alongside their modular nature which enables facile incorporation of multiple binding sites, makes them exquisitely suited to function as selective heteroditopic ion-pair receptors.9][50][51][52][53] Prompted by the envisaged utility of MIM-based ion-pair receptors, we previously reported a series of homo [2]catenanes capable of alkali metal halide binding via a di(ethylene glycol)-derived binding site for cation complexation alongside a bis(iodotriazole)benzene halogen bonding donor motif for anion binding. 54While this work highlighted the potential of exploiting the highly pre-organised binding cavities of catenanes to elicit the desired selectivity in sodium and potassium cation binding, the relatively moderate individual cation and anion affinities of these receptors precluded strong ion-pair binding.
Herein we report a heteroditopic hetero [2]catenane (Fig. 1) possessing a modied cation binding site serving to signicantly increase its cation affinity, which in turn leads to a dramatic enhancement in the ion-pair binding affinity of the hetero [2]catenane relative to the homo [2]catenanes.Crucially, the use of di(ethylene glycol) linkers generates a cation binding pocket that exhibits a signicantly closer size complementarity to the smaller sodium cation over the larger potassium cation.Notably, 1 H NMR ion-pair binding studies revealed a preference for binding sodium halide salts over the corresponding potassium halide salts.Importantly, the observed preference for sodium halide binding in the solution phase manifests in superior and exclusive extraction of sodium halide salts, as demonstrated by a series of solid-liquid extraction studies.

Synthesis and characterisation
It was envisaged that the target hetero [2]catenane could be prepared via a cation template-directed strategy [55][56][57][58][59][60][61] in which a sodium ion directs the self-assembly of a pseudo [2]rotaxane complex between the crown ether like di(ethylene)glycolfunctionalised macrocycle 1 and bis(azide) 2. Subjecting the threaded bis(azide) to a copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) macrocyclisation reaction with a bis(iodoalkyne) would concurrently generate the second interlocked macrocycle and the halogen bonding anion binding site.To this end, macrocycle 1, NaBAr F and bis(azide) 2 were pre-complexed in CH 2 Cl 2 for 30 minutes, aer which the bis(iodoalkyne) 3 was added, followed by dropwise addition of Cu(MeCN) 4 PF 6 and tris [(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA).The reaction was allowed to stir at room temperature overnight, then washed with basic EDTA solution and water.Preparative thinlayer chromatographic purication afforded the target hetero [2]catenane 4 in 11% yield, which was characterised by 1 H NMR, 13 C NMR and high-resolution ESI-MS.It is postulated that the low yield is attributed to the competing macrocyclisation reaction to afford non-interlocked 5, which was isolated as the major by-product of the reaction (Scheme 1).
Comparing the 1 H NMR spectrum of [2]catenane 4 in CDCl 3 solution to those of its constituent macrocycles 1 and 5 revealed diagnostic peak shis consistent with an interlocked topology (Fig. 2).The proton resonances arising from macrocycle 1 underwent signicant upeld shis upon formation of the [2]  catenane, attributed to the shielding effect associated with the enforced proximity of these environments to the shielding ring currents of the xylene spacers in 5.No proton signal desymmetrisation of the macrocycles was observed, indicating that under ambient conditions in CDCl 3 the relative coconformational circumrotation of the constituent macrocycles is facile, i.e. fast relative to the NMR timescale.Signicant perturbations were also observed in the signals arising from 5, most notably upeld shis and coalescence of protons H h and H i , indicating that the ethylene glycol region of 5 is threaded through the cavity of 1.

H NMR binding studies
To investigate the potential of the hetero [2]catenane 4 to function as an ion-pair receptor for alkali metal halide salts, 1 H NMR binding studies with sodium and potassium tetrakis[3,5bis(triuoromethyl)phenyl]borate (M I BAr F 4 , where M I = Na + , K + ) were initially undertaken to establish the cation binding ability of 4 in 1 : 1 CD 3 CN/CDCl 3 .
Upon addition of NaBAr F 4 and KBAr F 4 to 4, large perturbations were observed in the ethylene glycol proton resonances of the two constituent macrocycles, as well as the proximal benzylic singlets H g and H 3 , consistent with convergent coordination of the alkali metal cation by the polyether oxygen atoms of both macrocycles (Fig. S7-S8 †).A substantial downeld shi of the xylene protons H 4 from macrocycle 1 was also observed, possibly indicative of a co-conformational rearrangement that rotates these aromatic groups away from the macrocyclic cavity of 5 to accommodate the cation in the binding site, a postulated structure of which is shown in Fig. 3a.
The binding isotherms generated by monitoring the upeld perturbations of ethylene glycol proton H i rapidly approached saturation upon the addition of 1 equiv. of the cation (Fig. S36 †).Fitting the isotherms to a 1 : 1 host-guest stoichiometric binding model using Bindt analysis 62 gave cation association constants of approximately 58 000 M −1 and 28 000 M −1 for Na + and K + respectively, indicating preferential sodium over potassium binding, although the high tting errors (10- 20%) precluded an accurate determination of the Na + > K + binding selectivity (Table 1).Importantly, this represents a signicant enhancement (>10-fold) in cation affinity relative to previously reported homo [2]  highlighting the necessity of the interlocked binding cavity for cation binding.
To further investigate the relative affinities of [2]catenane 4 for sodium and potassium ions, the 1 H NMR cation binding studies were repeated in the more competitive solvent mixture 3 : 1 CD 3 CN/CDCl 3 (Fig. S9-S10 and S37 †), wherein cation binding affinities should be attenuated relative to the 1 : 1 CD 3 CN/CDCl 3 solvent system.In this solvent system the K a (Na + ) value was determined to be approximately 20 000 M −1 , which is signicantly higher (>5-fold) than the corresponding K a (K + ) value (Table 1).This indicates that [2]catenane 4 preferentially binds sodium over potassium, presumably due to more optimal size complementarity between the di(ethylene glycol)-derived binding site and the smaller sodium cation. 57he anion binding affinity of [2]catenane 4 was investigated via analogous 1 H NMR titrations with tetrabutylammonium halide salts (TBAX, where X = Cl, Br, I).In 1 : 1 CD 3 CN/CDCl 3 , the addition of aliquots of TBAX surprisingly resulted in signicant peak broadening and merging (Fig. S11-S13 †).Consequently, the halide association constants of 4 could not be reliably determined in this solvent system.In contrast, the 1 H NMR signals of the [2]catenane host remained sharp in 3 : 1 CD 3 CN/CDCl 3 , which is attributed to the greater solubility of the [2]catenane-anion complex in this solvent system.A signicant downeld perturbation of the internal benzene signal H c was observed, suggesting that halide anion binding occurs via XB interactions with the bis(iodotriazole)benzene donor motif (Fig. S14-S16 †).Bindt 62 analysis of the resulting binding isotherms (Fig. S38 †) unexpectedly revealed that 4 exhibits approximately 2-fold higher halide association constants than its constituent XB macrocycle 5 (Table 2).Whilst initially surprising, since the mechanical bond between crown ether-like macrocycle 1 to macrocycle 5 to form [2]catenane 4 ostensibly  introduces no additional anion binding groups, we tentatively postulate this enhanced halide affinity is attributable to the formation of ancillary CH/X − interactions involving the aromatic spacers of macrocycle 1, which underwent downeld perturbations upon addition of TBA halide salts, and/or coconformational restraints imposed on the XB anion binding motif imposed by the mechanical bond. 63aving established that the binding affinity of 4 for alkali metal cations is sufficient to ensure a high degree of saturation of the receptor in the presence of 1 equiv. of the cation in 1 : 1 CD 3 CN/CDCl 3 , 1 H NMR ion-pair binding studies were conducted by adding aliquots of TBAX salts (X = Cl, Br, I) to a 1 mM solution of 4 containing an equimolar amount of MBAr F 4 (M = Na, K) (Fig. 3a).
Upon addition of Br − and I − , prominent downeld shis of the internal benzene proton H c were observed, which suggest that anion binding remains primarily mediated by XB interactions (Fig. S18, S19, S21 and S22 †).Importantly, the addition of bromide and iodide causes little to no perturbation of the ethylene glycol proton signals, indicating that the cation binding sites of the catenane remain saturated throughout the titration.In contrast, addition of chloride to the receptor-cation complex induces chemical shi perturbations consistent with external ion-pairing and salt recombination (Fig. S17 and S20 †), indicating that despite the high cation affinities of 4, its ion-pair binding ability remains insufficient to overcome the high lattice enthalpies of NaCl and KCl.
In an analogous manner to the anion binding studies, binding isotherms for Br − and I − were constructed by monitoring the downeld shi of H c and subsequently tted to a 1 : 1 host-guest binding model (Fig. S39 and S40 †) to determine apparent anion association constants (K app ) of the monocationic catenane-Na + complexes, assuming near-quantitative pre-complexation of the metal cation to the catenane host.The calculated K app values were in range 10 000-15 000 M −1 in 1 : 1 CD 3 CN/CDCl 3 , demonstrating a dramatic enhancement in the anion binding affinity of [2]catenane 4 in the presence of a co-bound sodium cation.The corresponding K app values of the catenane-K + complex were found to be signicantly lower (Table 3), suggesting a binding preference for sodium halide over potassium halide salts by the [2]catenane receptor.Importantly, the qualitatively similar chemical shi perturbations observed in the NaX and KX titrations, namely a downeld shi of H c and H 4 upon addition of Br − and I − with no significant changes in the ethylene glycol proton signals, indicate that ion-pair binding of KBr and KI by 4 nonetheless remains the dominant process, outcompeting the salt recombination equilibrium.These studies crucially demonstrate strong positive cooperativity between the cation and anion binding events which enables the heteroditopic [2]catenane to act as a potent ion-pair receptor.
In order to quantitatively measure the apparent anion binding constants of the catenane-cation complexes, the ionpair binding studies were repeated in the more competitive solvent system 3 : 1 CD 3 CN/CDCl 3 (Fig. 3b and c).Crucially, the K app values determined for the sodium halide salts were 2 to 5fold higher than the analogous potassium salts (Table 3), indicating that the size-driven selectivity of the [2]catenane 4 for sodium over potassium cations translates to its ion-pair recognition properties.

Solid-state X-ray crystallographic studies
The proposed ion-pair binding mode of 4 was further corroborated by solid-state structural analysis.‡ Slow evaporation of a 1 : 1 CD 3 CN/CDCl 3 solution containing hetero [2]catenane 4 in the presence of NaBAr F 4 and excess TBAI afforded single crystals suitable for analysis by single crystal X-ray diffraction.The solidstate crystal structure revealed a 1 : 1 complex of catenane 4 bound to an NaI ion-pair, in which the guest ions are bound in a host-separated ion-pair binding mode consistent with solution-phase NMR studies (Fig. 4).Notably, the polyether regions of the two interlocked macrocyclic components 1 and 5 are arranged in an orthogonal geometry to form a cation binding pocket.The sodium cation resides within this binding pocket where it is convergently bound by three oxygen atoms each from 1 and 5 to form a six-coordinate distorted octahedral metal centre.In contrast, the iodide anion is located on the periphery of the macrocycle 5 where it forms XB interactions with the bis(iodotriazole)benzene motif, as shown by the I/I − distances (3.4597(7)-3.4820(6)Å, which is 87-98% of the sum of the van der Waals radii of the two atoms).The absence of ancillary CH-X − interactions between macrocycle 1 and the iodide guest in 4$NaI may be due to steric constraints imposed by the formation of a cation binding pocket, which presumably restricts the inter-ring circum-rotation of the catenane.

Solid-liquid extraction studies
The promising ion-pair binding properties of hetero [2]catenane 4 prompted an investigation into its ability to act as an alkali halide salt extractant.To this end, solid-liquid extraction (SLE) studies were undertaken by sonicating a 1 mM CDCl 3 solution of 4 in the presence of a xed excess mass quantity of solid MX (M = Na, K; X = Cl − , Br − , I − ).Large perturbations were observed in the 1 H NMR spectra of 4 post-treatment with NaBr and NaI (Fig. 5c and S45c †).In particular, a dramatic upeld shi of internal benzene proton H c was observed as well as desymmetrisation of the ethylene glycol protons H h/I , which are respectively consistent with anion and cation binding by the [2]catenane.These results indicate complete stoichiometric extraction of both NaX salts, with the post-extraction solution containing only the [2]catenane as the ion-pair bound complex.
In contrast, treatment of 4 with KBr and KI resulted in more complex 1 H NMR spectra which upon closer inspection revealed two sets of proton signals corresponding to two distinct catenane species.In the case of KBr, shown in Fig. 5b, the major set exhibits chemical shis similar to those of the unbound receptor while the minor set resembles the spectrum of the NaBr-bound catenane complexes.These observations suggest incomplete KBr extraction with the bound and unbound catenane complexes in slow exchange.Integration of these signals estimated that 43% of the hetero [2]catenane in solution was present as the ion-pair bound complex.
No signicant signal perturbations were observed upon treatment of 4 with NaCl or KCl (Fig. S47 †), which was attributed to the high lattice enthalpy of alkali metal chloride salts outcompeting ion-pair binding to 4, and is consistent with the observation of salt recombination during titration studies of the catenane-metal complexes with TBACl.
Motivated by the observed superior performance of 4 for sodium bromide/iodide extraction over the corresponding potassium salts, we sought to further investigate the extraction preferences of the catenane receptor via a competitive NaX/KX solid-liquid extraction experiment.To this end, in an analogous procedure to the above-described experiments, a 1 mM CDCl 3 solution of 4 was exposed to a mixture of NaBr/KBr or NaI/KI present in excess.In both cases, this resulted in postextraction spectra identical to those obtained from treatment of the receptor solely with the corresponding sodium halide salt (Fig. 5d and S45d †).Crucially, this provides promising evidence that 4 is capable of preferential sodium halide extraction over the corresponding potassium halide salts.Importantly, this highlights that despite the higher lattice enthalpies of sodium halide over potassium halide salts, dictated by the smaller alkali metal sodium cation, the mechanical bond effect enables sizebased discrimination and thereby achieves selective ion-pair recognition and extraction.

Conclusions
In summary, a heteroditopic [2]catenane ion-pair host system containing an interchain component di(ethylene glycol)-derived cation binding site and a bidentate halogen bonding anion binding site was synthesised via a sodium cation templatedirected approach. 1H NMR cation binding studies revealed a dramatic enhancement in sodium and potassium alkali metal cation affinity relative to a previously reported series of homo [2]  catenanes, as well as considerable sodium over potassium selectivity.The alkali metal halide (MX, X = Br, I) ion-pair binding properties of the catenane were probed by 1 H NMR studies and X-ray crystallography, both of which were consistent with the proposed separated ion-pair binding mode.Ion-pair titrations showed strong binding of alkali metal halide salts with signicant cooperativity between the cation and anion binding events, reected in a signicant 'switch-on' of the catenane's anion affinity upon pre-complexation with a metal cation.Importantly, the catenane was found to bind sodium halide salts 3-5 times more strongly than the corresponding potassium halide salts.Solid-liquid extraction studies highlighted the capability of the catenane to function as an efficient alkali metal halide salt extractant, in which the observed selectivity preference for sodium halide over potassium halide ion-pair binding in solution-state NMR studies impressively translated to superior and exclusive extraction of sodium halide salts from a competitive solid mixture of NaX/KX salts.The potent ion-pair binding capabilities of this heterocatenane receptor, and importantly its ability to discriminate between sodium halide and potassium halide salts, demonstrates the efficacy of exploiting the mechanical bond effect to elicit improved binding affinity and selectivity, which will serve to inform the design of future heteroditopic ion-pair receptors.

Fig. 1
Fig.1Schematic showing the chemical structure (top) and cartoon representation (bottom) of a hetero[2]catenane which functions as a heteroditopic ion-pair receptor capable of potent and selective binding of sodium halides.
Scheme 1 Synthesis of hetero[2]catenane 4 using a sodium cation template-directed strategy.The chemical structures of macrocycle 5 and a previously reported homo[2]catenane 1$XB DEG are shown below.

Fig. 3
Fig. 3 Ion-pair binding studies of hetero[2]catenane 4, including: (a) proposed ion-pair binding mode, showing the pre-complexation of the cation in the di(ethylene glycol)-derived binding cavity, followed by anion binding at the XB donor group.(b) Truncated stacked 1 H NMR spectra of 4 upon progressive addition of TBABr in the presence of 1 eq.NaBAr F 4 .(c) Binding isotherms of 4, showing changes in the chemical shift of H c with increasing equivalents of TBAX salts (X = Br, I) in the presence of 1 eq.MBAr F 4 (M = Na, K).For (b) and (c), [receptor] = 1.0 mM.Solvent = 3 : 1 CD 3 CN/CDCl 3 (v/v).T = 298 K.

Fig. 5
Fig. 5 Solid-liquid extraction studies of alkali metal bromide salts, showing truncated 1 H NMR spectra of: (a) free catenane receptor 4, and postextraction spectra of 4 following treatment with (b) 10 mg KBr; (c) 10 mg NaBr; (d) 5 mg NaBr and 5 mg KBr (CDCl 3 , 298 K, 500 MHz).The inset on the right shows the structure of 4 bound to an MX ion-pair (top) and a schematic illustrating the SLE experiment (bottom).

Table 1
1ation association constants (K a /M −1 ) for[2]catenanes determined by1H NMR titrations a a K a values calculated using Bindt with a 1 : 1 host-guest binding model.Errors are shown in parantheses.All cations added as BAr 4 F− salts.T = 298 K. [Receptor] = 1.0 mM.b Reported in ref. 54. a K a values calculated using Bindt with a 1 : 1 host-guest binding model.Errors are shown in parantheses.All anions added as TBA + salts.Solvent = 3 : 1 CD 3 CN/CDCl 3 .T = 298 K. [Receptor] = 1.0 mM.