Chalcogen Bond Mediated Enhancement of Cooperative Ion‐Pair Recognition

Abstract A series of heteroditopic receptors containing halogen bond (XB) and unprecedented chalcogen bond (ChB) donors integrated into a 3,5‐bis‐triazole pyridine structure covalently linked to benzo‐15‐crown‐5 ether motifs exhibit remarkable cooperative recognition of halide anions. Multi‐nuclear 1H, 13C, 125Te and 19F NMR, ion pair binding investigations reveal sodium cation–benzo‐crown ether binding dramatically enhances the recognition of bromide and iodide halide anions, with the chalcogen bonding heteroditopic receptor notably displaying the largest enhancement of halide binding strength of over two hundred‐fold, in comparison to the halogen bonding and hydrogen bonding heteroditopic receptor analogues. DFT calculations suggest crown ether sodium cation complexation induces a polarisation of the sigma hole of ChB and XB heteroditopic receptor donors as a significant contribution to the origin of the unique cooperativity exhibited by these systems.


Solution binding studies 1.1 Sodium cation complexation studies
The sodium cation binding properties were studied by addition of two equivalents of NaPF 6 to 1 H-NMR solutions (10% d 6 -DMSO-CDCl 3 ) of each host. In all cases significant downfield perturbations of the phenyl resonances as well as the crown ether ethylene protons were observed indicative of sodium cations binding in each crown ether group ( Figure S1-3). Also perturbations of the respective pyridyl protons (H a and H b ) were observed. To test whether the hexafluorophosphate anion was coordinating to the respective host's anion binding site, analogous titrations with two equivalents of TBAPF 6 were undertaken. No changes in the proton signals associated with the anion binding cleft were seen, confirming that the hexafluorophosphate anion does not participate in anion complexation.

13 C NMR Ion-Pair investigations for 1•XB
Further evidence for the participation of XB in the ion-pair recognition process was obtained by a comparison of 13 C-NMR spectra of 1•XB in the presence of two equivalents of NaPF 6 , and two equivalents of NaI. The chemical shift of the quaternary carbon of the bisiodotriazole motif was significantly perturbed upfield with NaI (Δδ = -2.22 ppm). Iodide anion complexation was also confirmed by the upfield shift of internal pyridyl carbon (Δδ = -1.45 ppm) resulting from the halide anion being located in the bis-iodotriazole XB binding cleft of the receptor ( Figure S4). Figure S4. a) 13 C-NMR spectra of 1•XB, with 2 equivalents of NaPF 6 , with 2 equivalents of NaI in 10% d 6 -DMSO in CDCl 3 (126 MHz, T = 298K) b) Proposed binding mode responsible for halogen bonding induced shift.

125 Te NMR Ion-Pair investigations for 1•ChB
Analogous 125 Te-NMR experiments with 1•ChB were carried out to provide evidence for chalcogen bond formation between the bis-methyltelluro triazole motif and iodide. Addition of two equivalents of NaPF 6 caused an upfield perturbation due to crown ether sodium cation complexation. By contrast, adding two equivalents of NaI induced a downfield shift of the 125 Te signal ( Figure S5).

1 H and 19 F NMR Ion-Pair investigations for 5
The fluorotriazole derivative serves as a non-halogen bond donor group. Qualitative 1 H-NMR spectroscopic experiments, revealed that the addition of 5 equivalents of TBAI to the bis-sodium cation crown ethers complexed fluorotriazole receptor 2.8 did not display any proton resonance perturbations indicating that no halide binding occurs ( Figure S6b). Moreover, the 19 F-NMR spectra also showed no perturbation of the fluorine chemical environment of the fluoro-triazole groups on addition of iodide ( Figure S6c). Figure S6. a) Postulated equilibrium of 5•2NaPF6 in the presence of Ib) Truncated 1 H-NMR spectra and c) Truncated 19 F-NMR spectra of 5 in the presence of 2 equivalents of NaPF 6 and 5 equivalents of TBAI in 10% d 6 -DMSO in CDCl 3 (500 MHz, T = 298K).
In case of uncomplexed hosts titration, solid powder of host was dissolved in a selected solvent to obtain 2 mM of host. Anion solution (250 mM) as the the tetrabutylammonium salts were added in aliquots, the samples thoroughly shaken and spectra recorded. In all cases where association constants were calculated, bound and unbound species were found to be in fast exchange on the NMR timescale. Stability constants were obtained by analysis of the resulting data using the WinEQNMR2328 software.

S1
Benzo-15-crown-5 (1 g, 3.75 mmol) was dissolved in the mixture of CHCl 3 (22 ml) and acetic acid (17 ml) in round bottom flask, and cooled the mixture in an ice bath. Then, a cool solution of 70% HNO 3 (6.4 ml) in acetic acid (5ml) was slowly dropped to the mixture. The reaction was stirred overnight at room temperature. The organic phase was diluted with CHCl 3 and washed with water (50 ml), followed by 5% aqueous solution of Na 2 CO 3 (50 ml). The organic residue was dried over MgSO 4 and removed under vacuum to get yellowish solid (95%).  Figure S11. 1 H NMR spectrum of S1.

1•ChB
Tellurim powder (65 mg, 0.509 mmol) suspended in a minimum of dry THF and the sealed vial cooled to 0⁰C, to which was added a solution of a 1.6M solution of MeLi in diethyl ether (0.27 ml, 0.432 mmol). After the suspension had warmed to room temperature the mixture was sonicated until the formation of a brown suspension was evident and left to stir for 1 hour.

Solid-Liquid extraction experiments
The ability of ion-pair receptors to extract and solubilise salts into organic media is another interesting application of the ditopic host. While a number of alkali metal halide salt HB based systems are known. To the best of our knowledge, exploiting sigma-hole type ion pair receptors in the study of solid-liquid salt extraction is unprecedented.
Solid-liquid extraction studies were carried out by exposing a selected organic solvent solution of each ditopic receptor to an excess of microcrystalline sodium halide salts. After 1 h of sonication at ambient temperature, the solution was filtered and analysed by 1 H-NMR spectroscopy and electrospray mass spectrometry (ESI-MS). Analogous control experiments were conducted to confirm the insolubility of the salt ion the solvent mixture 10% CD 3 CN/CDCl 3 in an analogous fashion as previously reported. [1] The organic solvent mixture of 10% CD 3 CN/CDCl 3 was found to be the most suitable for the extraction studies with NaX (X = Cl, Br, I, NO 3 ) salts. Significant 1 H-NMR chemical shift changes were observed for 1•XB with NaNO 3, NaBr and NaI whilst the signals from the NaCl extraction remained unchanged ( Figure S25). The downfield perturbations of the receptor's internal pyridyl proton H a observed in NaBr and NaI extraction experiments indicated that extraction had occured. High resolution ESI-MS revealed signals corresponding to [1•XB +2Na+X] + where X is Brand I -( Figure S26). With 1•HB, NaBr and NaI extraction solutions revealed the significant 1 H-NMR chemical shift changes, whilst no perturbation of proton resonances were noted with NaCl and NaNO 3 ( Figure S27). The ESI-MS analysis showed signals corresponding to [1•HB +2Na + +X -] + where X is Brand I -( Figure S28). Successful solid-liquid extraction of NaBr and NaI was also seen by 1 H-NMR spectra of 1•ChB ( Figure   S29), however ESI-MS evidence displayed only signals corresponding to [1•ChB +X]where X = Br and I ( Figure S30).

Data collection
Diffraction data for the structures of the complexes 1•HB•2NaI and 1•XB•HCl were collected at 100 K using silicon double crystal monochromated synchrotron radiation (λ = 0.6889 Å) at Diamond Light Source, beamline I19, S1 using a custom-built Crystal Logic diffractometer. Unit cell parameter determination and refinement and raw frame data integration were carried out using the CrysAlisPro S2 package.
Structures were solved by charge-flipping methods using SUPERFLIP S3 and refined by full matrix least squares on F 2 using the CRYSTALS suite. S4 All non-hydrogen atoms were refined with anisotropic displacement parameters. A more detailed discussion of each individual structure is given below, including a description of hydrogen atom treatment for each structure.

Sodium iodide ion-pair complex of the hydrogen-bonding receptor 1•HB•2NaI
Crystals of the complex 1•HB•2NaI suitable for X-ray structural determination were grown by slow evaporation of a chloroform:acetonitrile 9:1 solution of the receptor 1•HB•2NaPF 6 containing two molar equivalents of tetrabutylammonium iodide. The crystals were small and weakly diffracting; despite the use of synchrotoron radiation, the data are of relatively low quality. Consequently, where necessary, geometric restraints to bond lengths and angles were applied to ensure a physically reasonable model and thermal and vibrational restraints were applied to maintain sensible anisotropic displacement parameters. Some positional disorder was identified within the molecular framework of the ditopic ligand 1•HB.
To account for this three of the four triazole groups were modelled over two positions using refined partial occupancies. Comparatively large anisotropic displacement ellipsoids for two of the four benzotriazole groups were also observed, which may indicate further positional disorder within these regions of the structure. Since the quality of the data is insufficient to permit sensible modelling of these regions using two discrete positions for each atom, tight thermal restraints were instead applied. The two iodide counteranions which are not bound within the 3,5-bis-triazole pyridine anion recognition units were modelled over five partially occupied positions. Several partially occupied water molecules are also present within the asymmetric unit. Hydrogen atoms were generally visible in the Fourier difference map. Those attached to carbon atoms were initially positioned geometrically and refined against the data with restraints on bond lengths and angles, after which their positions were used as the basis for a riding model. S5 Most of the hydrogen atoms on the water molecules were not clearly visible in the difference maps and it was not possible to sensibly refine their positions. These hydrogen atoms were inserted at idealised hydrogen bonding positions with O-H distances of 0.9 Å and constrained to ride on the attached oxygen atoms. Figure S31. Thermal ellipsoid representation of the contents of the asymmetric unit for the solid state structure of the complex 1•HB•2NaI. Ellipsoids are shown at the 50% probability level. For clarity, hydrogen atoms have been omitted.

Chloride complex of the protonated halogen-bonding receptor, 1•XB•HCl
X-ray quality crystals of the complex 1•XB•HCl were obtained by slow evaporation of a dichloroethane/acetone solution of the receptor 1•XB. The receptor crystallised as its hydrogen chloride salt, 1•XB•HCl, presumably owing to the presence of a low concentration of hydrogen chloride in the dichloroethane solvent. The crystals were small and weakly diffracting and the data were therefore collected using synchrotron radiation. However, the crystal suffered severe radiation damage during data collection. As a consequence, it was only possible to obtain an incomplete set of low angle data from an initial phi scan. Despite several attempts, we were unable to obtain a more complete set of data. Nevertheless, it was possible to obtain a structure solution, which is presented here solely as a provisional guide to overall conformation and connectivity: while the overall structure is not in doubt, detailed inferences about bond lengths and angles cannot be drawn owing to the low quality of the data. Restraints to the geometries and ellipsoid parameters of all non-hydrogen atoms were applied in order to obtain a sensible refinement. Hydrogen atoms were inserted at calculated positions, refined against the data using soft restraints on bond lengths and angles and then included in the refinement using a riding model. Absent high angle data were removed after consulting the Wilson Plot.
The complex crystallised in the triclinic space group P1. The asymmetric unit contains the protonated ditopic halogen-receptor 1•XB, a chloride counteranion and a partially occupied dichloroethane solvent molecule. The chloride counteranion can be seen to interact with the receptor's N-protonated 5-bis-iodotriazole pyridinium cavity via bidentate C-I·····Clhalogen bonding interactions ( Figure S32). The dichloroethane solvent molecule appears to be involved in four C-H·····Ohydrogen bonding interactions with the oxygen atoms from a proximal crown ether group. The other crown ether group forms close contacts with the Nprotonated pyridinium group from an adjacent molecule, which strongly implies the existence of intermolecular N-H·····Ohydrogen bonding interactions. These interactions link the molecules in an infinite linear chain which is aligned with the crystallographic b axis ( Figure  S33). Although the electron density associated with the N-pyridinium proton could not be observed in the difference map its presence was inferred from the observation of this infinite linear chain, and from the presence of the chloride counteranion.
Selected crystallographic data for the 1•XB•HCl structure are included in Table S1 below but, since the data are not of publication quality, this provisional structure has not been deposited with the Cambridge Crystallographic Data Centre, and full data in cif format are not included. Figure S32. Content of the asymmetric unit for the solid state structure of the complex 1•XB •HCl: the chloride counteranion can be seen to interact with the receptor's N-protonated bisiodotriazole pyridinium cavity via bidentate C-I·····Clhalogen bonding interactions. For clarity, non-polar hydrogen atoms and a partially occupied dichloroethane solvent molecule have been omitted.    (2) 9.2629 (6) b (Å) 23.9836 (7) 14.0190 (9) c (Å) 24.5580 (7) 18.8620 (17)  108.317 (3) 71.859 (7)  96.490 (2) 77.933 (7)  90.532 (2) Figure S35); the average NPA charges at the oxygen atoms of the crown ethers become more negative (Table S4). When a positive point charge of +1.0 is added in place of the calculated position of Na + , the charge polarization in the electronic structures is even more pronounced ( Figure S35). The NPA charges at the oxygen atoms also become more negative while the charges at the X and the Te atoms are evidently more positive (Table S4). That is the binding of the positive charge Na + cation at the crown ether polarizes the electronic structures of the complexes, which enhances the sigma hole bonding interaction.