Neutral redox-active hydrogen- and halogen-bonding [2]rotaxanes for the electrochemical sensing of chloride

Article abstract of DOI:10.1039/c4dt02591a

The first examples of redox-active ferrocene-functionalised neutral [2]rotaxanes have been synthesised via chloride anion templation. ¹H NMR spectroscopic titrations reveal that these [2]rotaxane host systems recognize chloride selectively over other halides and oxoanions in highly-competitive aqueous media. By replacing the hydrogen bonding prototriazole units of the rotaxane axle component with iodotriazole halogen bond-donor groups, the degree of chloride selectivity of the [2]rotaxanes is modulated. Electrochemical voltammetric experiments demonstrate that the rotaxanes can sense chloride via cathodic perturbations of the respective rotaxanes' ferrocene-ferrocenium redox-couple upon anion addition.

Full text of DOI:10.1039/c4dt02591a

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Neutral redox-active hydrogen- and
halogen-bonding [2]rotaxanes for the
electrochemical sensing of chloride†
Cite this: Dalton Trans., 2014, 43,
17274
Jason Y. C. Lim,a Matthew J. Cunningham,b Jason J. Davisb and Paul D. Beer*a
The first examples of redox-active ferrocene-functionalised neutral [2]rotaxanes have been synthesised
1
via chloride anion templation. H NMR spectroscopic titrations reveal that these [2]rotaxane host systems
recognize chloride selectively over other halides and oxoanions in highly-competitive aqueous media. By
replacing the hydrogen bonding prototriazole units of the rotaxane axle component with iodotriazole
halogen bond-donor groups, the degree of chloride selectivity of the [2]rotaxanes is modulated. Electro-
chemical voltammetric experiments demonstrate that the rotaxanes can sense chloride via cathodic
perturbations of the respective rotaxanes’ ferrocene–ferrocenium redox-couple upon anion addition.
Received 26th August 2014,
Accepted 2nd October 2014
DOI: 10.1039/c4dt02591a
www.rsc.org/dalton
discoveries that halogen bond-donors can profoundly influ-
Introduction
ence the selectivity of anion recognition,10 the effect of in-
Anions are ubiquitous and their importance in biology and the corporating the halogen bond donor iodotriazole motif into
environment resulting from anthropogenic activities is well the axle component of a redox-active rotaxane on anion recognition
established. This continues to stimulate the growth of anion and subsequent electrochemical sensing is also investigated.
detection and binding in supramolecular chemistry.1–3 While
artificial anion receptors have yet to achieve the remarkable
selectivities found in nature, interlocked host molecules such
Experimental
General
as rotaxanes, more commonly employed for potential mole-
cular machine-like nanotechnological applications,4,5 have
emerged as promising candidates for anion binding and
sensing in recent years.6 Their unique positively-charged three
dimensional topological cavities, containing convergent hydro-
gen bonding and halogen bond donor groups, facilitate the
selective encapsulation of the anionic guest species in highly-
competitive aqueous solvent media.7,8 We have recently
demonstrated that neutral [2]rotaxane host analogues are also
capable of recognizing halide anions, with binding affinities
comparable to charged pyridinium axle component rotaxane
systems.9 The integration of redox-active reporter groups into
interlocked structural frameworks also empowers such systems
to sense anions by means of electrochemical methodologies.6
Herein, we describe the synthesis of a series of unprece-
dented neutral redox-active [2]rotaxanes containing a ferro-
cene-appended macrocycle unit, and demonstrate their ability
to selectively recognise and electrochemically sense chloride in
preference to bromide and oxoanions. Motivated by our earlier
All commercially available chemicals and solvents were used
as received without further purification. All dry solvents were
thoroughly degassed with N2, dried through
a Mbraun
MPSP-800 column and used immediately. Triethylamine was
distilled and stored over potassium hydroxide pellets. De-
ionised water was used in all cases. All tetrabutylammonium
salts used for anion titrations were stored in vacuum desicca-
tors prior to use.
NMR spectra were recorded on Bruker AVIII HD Nanobay
400 MHz, Bruker AVIII 500 MHz and Bruker AVIII 500 MHz
(with 13C cryoprobe) spectrometers. Electrospray ionisation
mass spectrometry (ESI-MS) was performed using the Waters
Micromass LCT and Bruker microTOF spectrometers.
Synthesis
Compounds 3,11 4,12 8,13 9a 14 and 9b 15 were synthesised
according to literature procedures. Procedures for the prepa-
ration of the ferrocene-appended macrocycles 7a–d are
detailed in the ESI.†
5-Ferrocene isophthalamide bis-azide macrocycle precursor
(5). To a vigorously stirred suspension of 5-ferrocenyl iso-
phthalic acid (3) (630 mg, 1.80 mmol) in dry CH2Cl2 (5 mL)
aChemistry Research Laboratory, Department of Chemistry, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, UK. E-mail: paul.beer@chem.ox.ac.uk
bPhysical & Theoretical Chemistry Laboratory, South Parks Road, Oxford, OX1 3TA, UK
†Electronic supplementary information (ESI) available. See DOI: 10.1039/c4dt02591a
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containing catalytic quantities of dimethylformamide was back-extracted with CH2Cl2 (2 × 10 mL). The combined organ-
added oxalyl chloride dropwise (0.46 mL, 5.40 mmol) under ics were dried with MgSO4 and dried in vacuo to give a pale
N2. The reaction was stirred for 2 hours to obtain a clear red green solid. Purification by silica gel chromatography (eluent:
solution, which was evaporated to dryness in vacuo to yield the 4% CH3OH in CH2Cl2) gave the product as a white solid
1
acid chloride as a dark red solid, which was then re-dissolved (350 mg, 71%). H NMR (400 MHz, CDCl3) δ 8.94 (2H, s, pyri-
3
in dry CH2Cl2. This solution was added dropwise to a colour- dine N-oxide ArH), 8.34 (2H, t, J = 6.2 Hz, CONH), 8.12 (1H, s,
less solution of 4 (0.800 g, 3.60 mmol) in dry CH2Cl2 (50 mL) pyridine N-oxide ArH), 7.53 (2H, s, triazoleH), 7.12 (12H, d, 3J =
containing anhydrous triethylamine (1.50 mL, 10.8 mmol) and 8.3 Hz, stopper-ArH), 6.97–7.02 (16H, m, stopper ArH), 6.67
catalytic quantities of N,N-dimethylaminopyridine (DMAP) at (4H, d, 3J = 8.8 Hz, stopper ArH), 4.96 (4H, s, –CH2O), 4.38 (4H,
0 °C. The reaction was allowed to warm up to room tempera- t, 3J = 6.2 Hz, –CH2-triazole), 3.50 (4H, q, 3J = 6.5 Hz,
ture and stirred overnight. After which, the reaction mixture –CH2NHCO), 2.22 (4H, t, 3J = 6.0 Hz, –CH2CH2CH2), 1.21 (54H,
t
was washed successively with 10% HCl (20 mL) and water (2 × s, Bu axle); 13C NMR (100 MHz, CDCl3) δ 162.5, 156.0, 146.4,
20 mL). The combined organics were dried with MgSO4 and 144.0, 140.5, 133.6, 132.4, 130.7, 124.1, 123.5, 113.1, 63.1, 61.5,
the solvent removed in vacuo to form a sticky red-orange 48.5, 37.8, 34.3, 31.4, 29.3; MS (ESI +ve) m/z 1455.8480 ([M +
liquid. Silica gel chromatography (eluent: 6 : 4 EtOAc– Na]+, C93H109N9NaO5, calc. 1455.8510).
1
petroleum ether) gave 5 as an orange solid (602 mg, 45%). H
Bis-iodotriazole axle (10b). Pyridine N-oxide bis-azide 8
4
NMR (400 MHz, CDCl3) δ 8.09 (2H, d, J = 1.6 Hz, ArH), 7.91 (21 mg, 0.061 mmol) and iodoalkyne stopper 9b (81 mg,
4
(1H, d, J = 1.6 Hz, ArH), 6.88 (8H, m, hydroquinone-H), 6.70 0.121 mmol) were dissolved in THF (3 mL) with heating, and
3
3
(2H, br. t, J = 5.2 Hz, CONH), 4.73 (2H, t, J = 1.6 Hz, FcH), allowed to cool to ambient temperature before copper(I) iodide
4.40 (2H, t, 3J = 1.6 Hz, FcH), 4.16 (4H, t, 3J = 4.8 Hz, (1.2 mg, 0.0061 mmol) and TBTA (3.2 mg, 0.0061 mmol) were
3
–OCH2CH2N3), 4.11 (4H, t, J = 5.2 Hz, CONHCH2CH2O), 4.05 added portionwise. The reaction was stirred overnight under
(5H, s, FcH), 3.90 (4H, quart., 3J = 5.2 Hz, CONHCH2), 3.57 N2, following which the reaction mixture was washed with 10%
(4H, t, 3J = 4.8 Hz, –CH2N3); 13C NMR (100 MHz, CDCl3) δ aqueous ammonia (2 × 5 mL) and the aqueous layer back-
167.0, 153.1, 152.8, 141.5, 134.9, 127.5, 122.2, 115.8, 115.6, extracted with chloroform (2 × 10 mL). The combined organic
83.3, 69.9, 69.9, 67.7, 67.3, 66.9, 50.2, 39.8; MS (ESI +ve) m/z layer was dried with MgSO4 and solvent removed to give a pale
781.2137 ([M + Na]+, C38H38FeNaN8O6, calc. 781.2157).
5-Ferrocene isophthalamide bis-amine macrocycle precursor 5% CH3OH in CH2Cl2) gave the product as a white solid
green solid. Silica gel chromatographic purification (eluent:
1
(6). Ferrocene-appended bis-azide macrocycle precursor
5
(61 mg, 60%). H NMR (400 MHz, CDCl3) δ 9.10 (2H, s, pyri-
3
(610 mg, 0.804 mmol) was dissolved in a minimum amount of dine N-oxide ArH), 8.39 (2H, t, J = 5.6 Hz, CONH), 8.35 (1H, s,
3
methanol (ca. 30 mL), and 10% by weight Pd/C (150 mg) was pyridine N-oxide ArH), 7.22 (12H, d, J = 8.4 Hz, stopper ArH),
added portionwise to the orange solution. Hydrazine mono- 7.10–7.06 (16H, m, stopper ArH), 6.82 (4H, d, 3J = 9.2 Hz,
hydrate (0.13 mL, 4.02 mmol) was then added to the vigorously stopper ArH), 4.99 (4H, s, –OCH2), 4.49 (4H, t, 3J = 6.6 Hz,
3
stirred suspension and the reaction heated under reflux for –CH2-iodotriazole), 3.55 (4H, quart., J = 5.6 Hz, –CH2NHCO),
3
t
7 hours. After cooling to ambient temperature, the reaction 2.30 (4H, quint., J = 6.0 Hz, –CH2CH2CH2), 1.29 (54H, s, Bu);
was filtered through celite, and the resulting orange solution 13C NMR (100 MHz, CDCl3) δ 162.5, 156.1, 148.3, 147.7, 144.0,
was dried in vacuo to obtain 6 as an orange solid in quantitat- 140.5, 140.3, 133.7, 132.4, 130.7, 124.1, 113.3, 81.3, 63.1, 61.5,
1
ive yield. H NMR (400 MHz, CDCl3) δ 8.01 (2H, s, ArH), 7.91 48.8, 37.6, 34.3, 31.4, 28.7; MS (ESI +ve) m/z 1706.6375 ([M +
(1H, s, ArH), 6.86 (8H, dd, J = 9.6 Hz, hydroquinone-H), 6.77 Na]+, C93H107I2N9NaO5, calc. 1706.6377).
3
3
(2H, t, J = 5.6 Hz, CONH), 4.73 (2H, s, FcH), 4.39 (2H, s, FcH),
General protocol for synthesis of [2]rotaxanes (1a–e)
4.15 (4H, t, 3J = 4.8 Hz, CONHCH2CH2O), 4.04 (5H, s, FcH),
3
3
3.94 (4H, t, J = 4.8 Hz, OCH2CH2NH2), 3.89 (4H, quart., J = In all cases, the appropriate axle (10a or 10b), bis-amine
4.8 Hz, CONHCH2), 3.06 (4H, t, 3J = 4.8 Hz, CH2NH2); 13C NMR macrocycle precursor 6 and the appropriate isophthalic acid
(100 MHz, CDCl3) δ 167.0, 153.5, 152.7, 141.4, 134.9, 127.4, were used in a 1 : 1 : 1 mole ratio. Firstly, the isophthalic acid
122.2, 115.5, 115.5 (repeat), 83.0, 70.7, 69.7, 69.7 (repeat), 67.3, (1.0 eq.) was suspended in dry CH2Cl2 (2 mL) containing a
66.7, 41.6, 39.8; MS (ESI +ve) m/z 707.2528 ([M + H]+, drop of DMF. Oxalyl chloride (3.0 eq.) was added dropwise and
C38H43FeN4O6, calc. 707.2527).
the reaction was stirred for 4 hours till a clear solution was
Bis-prototriazole axle (10a). Pyridine N-oxide bis-azide 8 obtained. The solvent was removed and the yellow bis-acid
(120 mg, 0.345 mmol), alkyne 9a (375 mg, 0.690 mmol), tris- chloride was thoroughly dried under vacuum before being
[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) (73.0 mg, redissolved in dry CH2Cl2 (5 mL) and taken up in a syringe.
0.138 mmol), diisopropyl-ethylamine (0.18 mL, 1.04 mmol) The appropriate axle, 6, and dry triethylamine (4.0 eq.) were
and
tetrakis(acetonitrile)copper(I)
hexafluorophosphate dissolved in dry CH2Cl2 (30 mL), and the bis-acid chloride
(43.4 mg, 0.138 mmol) were dissolved in CH2Cl2 (20 mL) with solution was added dropwise over 30 minutes. The resulting
slight heating. The resulting reaction mixture was then cooled clear orange reaction mixture was stirred under N2 overnight.
to ambient temperature, and stirred overnight under N2 to give Following which, the organic layer was washed successively
a cloudy green suspension. The reaction was washed with 10% with 1 M citric acid (20 mL), saturated aqueous NaHCO3
aqueous ammonia (3 × 10 mL), and the aqueous layer was (20 mL) and water (10 × 20 mL), before being dried with
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MgSO4. The solvent was removed in vacuo to give an orange d, J = 8.8 Hz, stopper ArH), 6.39 (8H, m, hydroquinone ArH),
solid, which was purified using preparatory thin layer chromato- 5.05 (4H, s, –OCH2 axle), 4.75 (2H, s, FcH), 4.33 (2H, s, FcH),
3
graphy to give the desired [2]rotaxane as an orange solid.
4.25 (4H, t, J = 6.7 Hz, –CH2-triazole axle), 4.00 (5H, s, FcH),
tert-Butyl-functionalised, bis-prototriazole rotaxane (1a). 3.95–3.98 (8H, m, –CH2O macrocycle), 3.72–3.74 (8H, m,
3
Using tert-butyl isophthalic acid (18.8 mg, 0.085 mmol), –CONHCH2 macrocycle), 3.26 (4H, t, J = 6.7 Hz, –CH2NHCO),
t
oxalyl chloride (0.022 mL, 0.26 mmol), axle 10a (124 mg, 2.06 (4H, t, 3J = 6.8 Hz, –CH2CH2CH2 axle), 1.27 (54H, s, Bu
0.085 mmol), bisamine 6 (60 mg, 0.085 mmol) and triethyl- axle); 13C-NMR (125 MHz, CDCl3–d4-MeOD 1 : 1) δ 169.1, 166.9,
amine (0.047 mL, 0.34 mmol) yielded 1a (32 mg, 16%). 1H 163.1, 157.0, 153.7, 153.5, 152.1, 149.2, 145.0, 145.0 (repeat),
NMR (500 MHz, CDCl3–d4-MeOD 1 : 1) δ 8.44 (2H, s, pyridine 124.4, 141.3, 140.4, 135.3, 134.7, 133.6, 133.2, 131.6, 130.5,
t
N-oxide ArH), 8.42 (1H, s, Fc-ArH), 8.39 (1H, s, Bu-ArH), 8.11 128.9, 126.6, 124.9, 124.7, 123.6, 116.0, 114.1, 83.9, 70.6, 70.6
(2H, s, Fc-ArH), 8.10 (1H, s, pyridine N-oxide ArH), 8.10 (2H, s, (repeat), 67.6, 67.5, 64.0, 62.3, 50.0, 40.9, 38.1, 35.0, 32.1, 32.0,
tBu-ArH), 7.82 (2H, s, triazoleH), 7.20 (12H, d, 3J = 8.3 Hz, 30.6, 29.6; MS (ESI +ve) m/z 2292.0956 ([M
+
Na]+,
3
stopper-ArH), 7.05 (16H, m, stopper ArH), 6.80 (4H, d, J = 8.8
Hz, stopper ArH), 6.37 (8H, s, hydroquinone ArH), 5.06 (4H, s,
C
138H152FeN14NaO13, calc. 2292.0905).
Nitro-functionalised, bis-prototriazole rotaxane (1d). 5-Nitro
–OCH2 axle), 4.84 (2H, br. s, FcH), 4.41 (2H, br. s, FcH), 4.21 isophthalic acid (15 mg, 0.070 mmol), oxalyl chloride
3
(4H, t, J = 6.5 Hz, –CH2-triazole axle), 4.10 (5H, s, FcH), 3.97 (0.018 mL, 0.21 mmol), axle 10a (100 mg, 0.070 mmol), bis-
(8H, m, –CH2O macrocycle), 3.73 (8H, m, –CONHCH2 macro- amine 6 (49 mg, 0.070 mmol) and triethylamine (0.040 mL,
1
cycle), 3.26 (4H, t, 3J = 6.5 Hz, –CH2NHCO axle), 2.04 (4H, t, 0.28 mmol) gave 1d (32 mg, 20%). H-NMR (500 MHz, CDCl3–
3J = 6.5 Hz, –CH2CH2CH2 axle), 1.34 (9H, s, tBu macrocycle), 1.27 d4-MeOD 1 : 1) δ 8.97 (1H, s, NO2-ArH), 8.88 (2H, s, NO2-ArH),
t
(54H, s, Bu axle); 13C NMR (125 MHz, CDCl3–d4-MeOD 1 : 1) δ 8.45 (2H, s, pyridine N-oxide ArH), 8.37 (1H, s, Fc-ArH), 8.14
169.1, 168.7, 162.7, 156.6, 153.2, 148.9, 144.7, 142.0, 140.9, (2H, s, Fc-ArH), 8.08 (1H, s, pyridine N-oxide ArH), 7.78 (2H, s,
3
140.0, 134.7, 134.4, 133.1, 132.9, 131.2, 128.9, 128.7, 124.6, triazoleH), 7.19 (12H, d, J = 8.5 Hz, stopper-ArH), 7.05 (16H,
123.1, 115.5, 113.7, 67.1, 63.6, 62.0, 40.8, 37.7, 35.6, 34.8, 31.7, m, stopper ArH), 6.79 (4H, d, 3J = 8.8 Hz, stopper ArH),
31.5, 30.4, 30.2; MS (ESI +ve) m/z 2348.1594 ([M + Na]+, 6.41–6.37 (8H, m, hydroquinone ArH), 5.04 (4H, s, –OCH2
3
C143H161FeN13NaO13, calc. 2348.1613).
axle), 4.74 (2H, s, FcH), 4.33 (2H, s, FcH), 4.25 (4H, t, J = 6.5
Bis-ferrocene functionalised bis-prototriazole rotaxane Hz, –CH2-triazole axle), 4.00 (5H, s, FcH), 3.99 (8H, m, –CH2O
(1b). 5-Ferrocene isophthalic acid (20 mg, 0.057 mmol), oxalyl macrocycle), 3.74 (8H, m, –CONHCH2 macrocycle), 3.26 (4H, t,
3
chloride (0.015 mL, 0.171 mmol), axle 10a (81 mg, 3J = 6.5 Hz, –CH2NHCO), 2.06 (4H, t, J = 6.5 Hz, –CH2CH2CH2
t
0.057 mmol), bisamine 6 (40 mg, 0.057 mmol) and triethyl- axle), 1.26 (54H, s, Bu axle); 13C-NMR (125 MHz, CDCl3–d4-
1
amine (0.032 mL, 0.23 mmol) gave 1b (30 mg, 22%). H NMR MeOD 1 : 1) δ 168.9, 166.5, 162.9, 156.7, 153.5, 153.3, 149.4,
(500 MHz, CDCl3–d4-MeOD 1 : 1) δ 8.41 (2H, s, pyridine 149.0, 144.8, 144.8 (repeated), 142.4, 141.1, 140.2, 136.8,
N-oxide ArH), 8.37 (2H, s, Fc-isophthalamide ArH), 8.14 (4H, s, 135.1, 133.4, 133.0, 131.9, 131.4, 128.7, 126.4, 126.2, 124.7,
Fc-isophthalamide ArH), 8.06 (1H, s, pyridine N-oxide ArH), 124.5, 123.3, 116.2, 115.8, 115.7, 113.8, 83.7, 70.4, 70.3,
3
7.72 (2H, s, triazoleH), 7.19 (12H, d, J = 8.5 Hz, stopper-ArH), 67.3, 63.7, 62.0, 40.9, 40.8, 37.9, 34.8, 31.8, 30.4, 29.4; MS
7.05 (16H, m, stopper ArH), 6.79 (4H, d, 3J = 8.8 Hz, stopper (ESI +ve) m/z 2336.0797 ([M + Na]+, C139H152FeN14NaO15, calc.
ArH), 6.37 (8H, s, hydroquinone ArH), 5.03 (4H, s, –OCH2 axle), 2336.0803).
4.75 (4H, s, FcH), 4.33 (4H, s, FcH), 4.20 (4H, t, 3J = 6.5 Hz,
tert-Butyl-functionalised, bis-iodotriazole rotaxane (1e). tert-
–CH2-triazole axle), 4.01 (10H, s, FcH), 3.97 (8H, m, –CH2O Butyl isophthalic acid (19 mg, 0.085 mmol), oxalyl chloride
macrocycle), 3.74 (8H, m, –CONHCH2 macrocycle), 3.25 (4H, t, (0.022 mL, 0.26 mmol), axle 10b (143 mg, 0.085 mmol), bis-
3
3J = 6.5 Hz, –CH2NHCO), 2.04 (4H, t, J = 6.5 Hz, –CH2CH2CH2 amine 6 (60 mg, 0.085 mmol) and triethylamine (0.047 mL,
t
1
axle), 1.26 (54H, s, Bu axle); 13C NMR (125 MHz, CDCl3–d4- 0.34 mmol) gave 13 (13 mg, 6%). H-NMR (500 MHz, CDCl3–
MeOD 1 : 1) δ 168.7, 162.7, 156.6, 153.2, 148.9, 144.7, 142.0, d4-MeOD 1 : 1) δ 8.48 (2H, s, pyridine N-oxide ArH), 8.38 (1H, s,
141.0, 140.0, 134.9, 133.1, 132.9, 131.3, 128.8, 124.6, 124.2, Fc-ArH), 8.37 (1H, s, Bu-ArH), 8.15 (2H, s, Fc-ArH), 8.14 (1H, s,
t
t
3
123.0, 115.6, 113.7, 83.6, 70.3, 67.3, 63.6, 62.0, 48.5, 40.8, 37.8, pyridine N-oxide ArH), 8.13 (2H, s, Bu-ArH), 7.20 (12H, d, J =
34.8, 31.8, 30.4; MS (ESI +ve) m/z 2475.0965 ([M + Na]+, 8.6 Hz, stopper-ArH), 7.07–7.04 (16H, m, stopper ArH), 6.81
3
C
149H161Fe2N13NaO13, calc. 2475.0928).
(4H, d, J = 8.9 Hz, stopper ArH), 6.40 (8H, m, hydroquinone
Pyridine-functionalised, bis-prototriazole rotaxane (1c). 3,5- ArH), 4.92 (4H, s, –OCH2 axle), 4.76 (2H, s, FcH), 4.37 (2H, s,
3
Pyridine dicarboxylic acid (12 mg, 0.070 mmol), oxalyl chloride FcH), 4.21 (4H, t, J = 7.0 Hz, –CH2-triazole axle), 4.00 (5H, s,
(0.018 mL, 0.21 mmol), axle 10a (100 mg, 0.070 mmol), bis- FcH), 3.97 (8H, m, –CH2O macrocycle), 3.73 (8H, m,
amine 6 (49 mg, 0.070 mmol) and triethylamine (0.040 mL, –CONHCH2 macrocycle), 3.29 (4H, t, 3J = 6.9 Hz, –CH2NHCO
1
3
0.28 mmol) gave 1c (14 mg, 9%). H-NMR (500 MHz, CDCl3– axle), 2.04 (4H, t, J = 6.9 Hz, –CH2CH2CH2 axle), 1.35 (9H, s,
d4-MeOD 1 : 1) δ 9.15 (2H, s, macrocycle pyridine ArH), 8.96 tBu macrocycle), 1.27 (54H, s, Bu axle); 13C-NMR (125 MHz,
t
(1H, s, macrocycle pyridine ArH), 8.45 (2H, s, axle pyridine CDCl3–d4-MeOD 1 : 1) δ 169.3, 168.9, 163.0, 156.9, 153.4, 153.3,
N-oxide ArH), 8.36 (1H, s, Fc-ArH), 8.13 (2H, s, Fc-ArH), 8.07 (1H, 149.1, 148.2, 144.9, 142.2, 141.2, 140.3, 135.1, 134.7, 133.5,
s, pyridine N-oxide ArH), 7.80 (2H, s, triazole-H), 7.19 (12H, d, 133.0, 131.4, 129.0, 128.8, 126.8, 124.8, 123.6, 123.5, 115.8,
3J = 8.5 Hz, stopper-ArH), 7.05 (16H, m, stopper ArH), 6.79 (4H, 114.1, 83.7, 83.0, 70.5, 70.4, 67.5, 67.5 (repeat), 67.4, 63.8, 62.1,
17276 | Dalton Trans., 2014, 43, 17274–17282
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40.8, 38.0, 35.7, 34.9, 31.8, 31.6, 29.9; MS (ESI +ve) m/z N-oxide axle precursor component9 could not be undertaken
2598.9513 ([M + Na]+, C143H159FeI2N13NaO13, calc. 2598.9511).
in chloroform solution.
Hence, a new chloride anion-templated clipping strategy for
neutral rotaxane formation was used. As illustrated in
Scheme 2, the proto- and iodotriazole-linked pyridine N-oxide
axles 10a and 10b were prepared by the CuAAC reaction of pyri-
dine N-oxide bis-azide 8 13 and the alkyne functionalized ter-
phenyl stoppers 9a 14 and 9b 15 respectively. The [2]rotaxanes
were then prepared by condensation of bis-amine 6 with the
appropriate bis-acid chloride derivative in the presence of an
equimolar quantity of stoppered axle 10a or 10b. Removal of
the templating chloride anion (generated in situ from the
amide condensation reactions) from the rotaxane binding
cavity was achieved by repeated washings with water to afford
the charge-neutral [2]rotaxanes 1a–e isolated in yields of up to
22% following purification by preparative thin layer chromato-
graphy. All five rotaxanes were characterised by 1H and 13C
NMR spectroscopy and high resolution electrospray ionisation
mass spectrometry (ESI-MS).
Results and discussion
Synthesis of redox-active [2]rotaxanes
The target redox-active [2]rotaxane host design, shown in
Fig. 1, consists of a pyridine N-oxide axle component inter-
locked with a bis-isophthalamide functionalised macrocycle,
which is functionalized at one of the isophthalamide motifs
with a ferrocene group.
Ferrocene appendage to an isophthalate ester motif was
achieved via Sandmeyer-type coupling involving ferrocenium
and 5-diazonium isophthalate ester,11 as detailed in Scheme 1.
Subsequent ester hydrolysis gave the corresponding 5-ferro-
cene isophthalic acid 3, which, upon reaction with oxalyl chlor-
ide, afforded the bis-acid chloride. Condensation with two
equivalents of amine 4 12 produced the bis-azide macrocycle
precursor 5 in 49% yield. Reduction of 5 using hydrazine
monohydrate with 10% palladium loading on carbon allowed
quantitative conversion to the bis-amine macrocycle precursor
6. The synthesis of the ferrocene-appended macrocycles 7a–d
was achieved under high dilution conditions via amide con-
densation reactions between bis-amine 6 and bis-acid chlor-
ides in yields ranging from 20–37%. However, with the
exception of the tert-butyl functionalised macrocycle 7a, all the
cyclic products unexpectedly displayed poor solubility in low-
polarity halogenated solvents. As a consequence, the pre-
viously reported anion-templated copper catalysed azide–
alkyne cycloaddition (CuAAC) ‘click’ stoppering rotaxane syn-
thesis of a pseudorotaxane assembly containing the pyridine
Evidence for the interlocked nature of the rotaxanes is pro-
1
vided by a comparison of their H-NMR spectra with those of
the free macrocycle and axle components (Fig. 2). Significant
upfield shifts are seen for signals arising from the protons of
the hydroquinones (e and f) of the macrocycle and the pyri-
dine N-oxide of the axle (i.e. m and n). These arise from diag-
nostic aromatic donor–acceptor interactions between the
macrocycle and the axle. Furthermore, distinct downfield
shifts in the macrocycle internal isophthalamide protons a
and b are observed, which arise due to hydrogen bonding
interactions with the oxygen atom of the pyridine N-oxide axle.
Although only one of these protons can interact with the pyri-
dine N-oxide oxygen atom at any one time, there are approxi-
mately equal perturbations of protons a and b for all the
[2]rotaxanes bearing asymmetric macrocycles (1a and 1c–e),
which is indicative of the macrocycle pirouetting around the
axle in a dynamic fashion which is fast on the NMR time-
scale.‡ Finally, numerous through-space interactions were
observed between the macrocycle and axle components of
all rotaxanes in their two-dimensional 1H–1H ROESY spectra
(see ESI†), giving conclusive evidence of their interlocked
nature.
Anion recognition studies
1H NMR titrations. The anion binding properties of the
1
neutral [2]rotaxanes were investigated using H-NMR titration
experiments in the highly competitive solvent mixture
45 : 45 : 10 CDCl3–CD3OD–D2O.
The addition of tetrabutylammonium (TBA) chloride to the
prototriazole-bearing [2]rotaxanes 1a–d caused the proton
signals for macrocycle isophthalamide protons a and b, as
‡Further evidence of this pirouetting motion is provided by the fact that unlike
many pyridinium axle rotaxanes,13,16 no splitting of the hydroquinone 1H-NMR
signals was observed following rotaxane formation, which is indicative of co-
conformational dynamic behaviour being fast on the NMR timescale.
Fig. 1 Structure of target neutral ferrocene (Fc)-appended [2]rotaxanes
1a–e.
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Scheme 1 Synthesis of ferrocene-appended macrocycles.
well as the pyridine N-oxide proton m to undergo significant 1 : 1 stoichiometric association constant values shown in
downfield shifts (Fig. 3). These arise from hydrogen bonding Table 1.§
interactions with the chloride anion residing within the inter-
All the rotaxanes exhibit the selectivity trend of chloride >
locked binding cavity of the rotaxanes. Interestingly, no differ- bromide > iodide, in spite of chloride being the most heavily
ence in the magnitude of perturbation was observed between solvated halide in this aqueous solvent mixture following the
macrocycle protons a and b, suggesting that there is no prefer- Hofmeister series.18 This suggests that the rotaxanes’ inter-
ence for chloride binding at either isophthalamide unit. locked cavity is of complementary size for chloride anion rec-
Similar downfield shifts were observed for the respective rotax- ognition. Interestingly, the halide anion association constants
anes’ axle prototriazole protons as well, confirming their invol- of the prototriazole-[2]rotaxanes 1a–d generally show little vari-
vement in anion binding as a result of the axle wrapping ation regardless of the substituent on the macrocycle isophthal-
around the interlocked cavity bound chloride anion. Upfield amide motif. This indicates that the dynamic nature of these
perturbations of the hydroquinone proton signals e and f are rotaxanes enable the halide to bind at either macrocycle com-
seen, indicating that chloride binding increases the strength ponent isophthalamide anion recognition site.
of aromatic donor–acceptor interactions between the macro-
We have previously demonstrated that introducing halogen
cycle’s electron rich hydroquinone groups and the electron bond donor groups into macrocyclic and interlocked host
deficient pyridine N-oxide axle motif. Analogous titration systems can dramatically influence their anion recognition
experiments with bromide and iodide resulted in similar behaviour.15,19,20 However, Table 1 shows the bis-iodotriazole
perturbations of the respective rotaxanes’ proton signals, [2]rotaxane 1e exhibits the same trend in anion selectivity, i.e.
although they were of smaller magnitude. By contrast, no chloride > bromide > iodide > dihydrogen phosphate, although
significant shifts were observed on addition of dihydrogen it is noteworthy that a large reduction in association constant
phosphate (Fig. 4) and acetate which suggests these oxoanions magnitude is observed for all halides, and a smaller degree of
are not bound by the rotaxanes; presumably they are too chloride selectivity is obtained compared to the prototriazole-
large to be encapsulated by the interlocked host cavity.
WinEQNMR217 analysis of the halide titration data monitoring
§Within experimental error, the same association constant values were deter-
the chemical shift of the internal isophthalamide proton
mined using titration data from monitoring protons a, b, m and those of the axle
of the pyridine N-oxide axle component (Fig. 4) determined prototriazole units.
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Fig. 2 Partial 1H-NMR spectra of (A) proto-triazole axle 10a; (B)
[2]rotaxane 1a; and (C) macrocycle 7a (500 MHz, 1 : 1 CDCl3–CD3OD,
298 K).
Fig. 3 1H-NMR of [2]rotaxane 1a with (A) no TBACl present; (B) 1.0
equivalent of TBACl; (C) 2.0 equivalents of TBACl present (500 MHz,
45 : 45 : 10 CDCl3–CD3OD–D2O, 298 K, [host] = 1.5 mM). Proton labels
follow those in Fig. 2.
Scheme 2 Synthesis of neutral [2]rotaxanes via the amide conden-
sation methodology.
to the Ag/AgNO3 reference electrode as shown in Table 2. As
expected when taking account of the neutral pyridine N-oxide axle
component, their E1/2 values were very similar to that of macro-
cycle 7a, unlike a previously-reported cationic ferrocene-appended
pyridinium axle-based [2]rotaxane.22
bearing rotaxane analogues. This may be a consequence of the
bulky triazole iodine atoms of the axle sterically hindering the
entry of halides into the interlocked binding cleft of 1e, which
decreases the rotaxane’s anion binding affinity.
In the presence of increasing quantities of chloride,
a cathodic shift of the Fc/Fc+ redox couple was observed for
[2]rotaxane 1a (Fig. 5 and Table 3). This is consistent with halide
binding within the rotaxane’s interlocked cavity stabilising the
ferrocenium oxidation state, presumably via a through-bond
mechanism, resulting in an enhanced binding affinity of chlor-
ide.23 A significant cathodic shift of 27 mV was observed in the
presence of 1.0 equivalent of chloride, which increased to
37 mV upon addition of a further 4 equivalents. In contrast,
macrocycle 7a displayed smaller cathodic shifts of 14 mV and
31 mV with 1.0 and 5.0 equivalents of chloride respectively.
Bromide elicited a smaller cathodic shift with [2]rotaxane 1a
compared to chloride (Fig. 6 and Table 3), which can be attrib-
uted to the larger and more charge-diffuse nature of the halide
anion. However, a loss of electrochemical reversibility was
Electrochemical anion sensing. The electrochemical anion
recognition properties of rotaxanes 1a–e and ferrocene-
appended macrocycle 7a were investigated by cyclic voltamme-
try in the electrolyte solution of 0.1 M TBAPF6 in 1 : 1 CH2Cl2–
CH3CN with Ag/AgNO3 reference electrode.21
¶
[2]Rotaxanes 1a–e demonstrated electrochemical quasi-
reversibility of the Fc/Fc+ redox couple (see ESI†), with E1/2
values of between +207 and +219 mV being obtained with respect
¶Prior to utilising the Ag/AgNO3 working electrode, a 1H NMR titration experi-
ment was performed in the presence of TBANO3 and [2]rotaxane 1b (solutions
prepared as described in Section S3). The results obtained indicated that the
nitrate anion does not bind in the cavity of the rotaxanes (see ESI†).
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Table 3 Comparison of the shifts in the Fc/Fc+ redox couple of tetra-
butyl-functionalised macrocycle 7a and [2]rotaxane 1a upon anion
additiona
ΔE1/2 for 7a/mV
ΔE1/2 for 1a/mV
1.0 eq.
5.0 eq.
1.0 eq.
5.0 eq.
Cl−
−14
−9
−31
−27
−16
−19
−34
−37
Br−
−21
−25
b
b
Acetate
H2PO4
−5
−
b
b
b
a Anions added as TBA salts. Electrolyte: 0.1 M TBAPF6 in 1 : 1 CH2Cl2–
CH3CN. Reference electrode: Ag/AgNO3; working electrode: glassy
carbon; counter electrode: platinum. T = 293 K. b Not possible to
determine E1/2 after anion addition due to loss of reversibility and
redox peaks.
Fig. 4 Binding isotherms of anion titrations for [2]rotaxane 1a with
different TBA salts. The chemical shift of the internal isophthalamide
proton of the pyridine N-oxide axle component is plotted as a function
of equivalents of TBA salts added. Identical binding isotherms were
obtained monitoring macrocycle component protons a and b and the
axle prototriazole signal (500 MHz, 45 : 45 : 10 CDCl3–CD3OD–D2O,
298 K, [host] = 1.5 mM).
anions investigated, chloride gave the largest cathodic shift,
which correlates with the rotaxane’s 1H NMR-determined
selectivity trend (Table 1).
Similar magnitudes of chloride anion-induced cathodic per-
turbations for all the prototriazole-bearing[2]rotaxanes 1b–d
were observed (Table 4). In spite of the bis-iodotriazole-
bearing [2]rotaxane 1e exhibiting notably weaker chloride
anion binding than its prototriazole analogues (Table 1), com-
parable cathodic perturbations were observed (Table 4). When
compared with previously-reported charged [2]rotaxane22 and
[2]catenane11 systems bearing the same 5-ferrocene isophthal-
amide motif immediately adjacent to the interlocked anion
binding site on the macrocycle component, it is noteworthy
that the cathodic perturbations observed with chloride are of
similar magnitude to the cathodic shifts exhibited by the
neutral rotaxane systems reported here. This indicates that the
binding enhancement factor (BEF) of this series of neutral
[2]rotaxanes following oxidation of the ferrocene moiety is
dictated by the through-bond communicative distance between
the interlocked binding site and the ferrocene reporter group.
Table 1 Association constants, Ka (M−1), for [2]rotaxanes 1a–e with
various halide anionsa
1a
1b
1c
1d
1e
Cl−
Br−
I−
546(10)
373(15)
138(5)
423(13)
259(20)
120(16)
569(12)
346(16)
124(3)
542(16)
376(13)
149(9)
152(5)
133(5)
81(8)
a Anions added as their TBA salts, temperature = 298 K, solvent:
45 : 45 : 10 CDCl3–CD3OD–D2O, 298 K, values quoted have units of
M−1
. The errors associated with each (<15%) are quoted in
−
parentheses. H2PO4 and acetate did not bind to any of the rotaxanes
investigated.
Table 2 E1/2 values of [2]rotaxanes 1a–e and macrocycle 7aa
1a
1b
1c
1d
1e
7a
E1/2/mV
+211
+212
+207
+212
+219
+204
a Electrolyte: 0.1 M TBAPF6 in 1 : 1 CH2Cl2–CH3CN. Values are reported
with respect to the Ag/AgNO3 reference electrode at T = 293 K.
Conclusions
A series of novel neutral redox-active ferrocene functionalised
[2]rotaxanes have been synthesised via chloride-templated clip-
ping of bis-isophthalamide macrocycles around a pyridine
N-oxide axle component. Following chloride template removal,
1H NMR titration experiments revealed that the rotaxanes
exhibit chloride selectivity over the heavier halides and oxo-
anions such as dihydrogen phosphate and acetate in com-
petitive aqueous solvent media due to host–guest size-
complementarity. Incorporating halogen bond-donors in the
form of iodotriazole units into the rotaxane axle component
diminished the halide anion binding affinity of the rotaxane
which may be rationalised on steric grounds. Electrochemical
voltammetric anion sensing investigations demonstrated the
neutral rotaxane hosts to be capable of detecting chloride via
significant cathodic perturbations of the rotaxanes’ ferrocene/
ferrocenium redox-couple.
observed with the disappearance of the CV reduction wave in
the presence of more than 1.0 equivalent of the oxoanions
acetate and H2PO4−. This suggested that an EC mechanism
was in operation where formation of the ferrocenium moiety
following electrochemical oxidation led to its rapid consump-
tion by reacting with the oxoanions to form an unknown
redox-stable species.k A similar loss of electrochemical reversi-
bility, via an EC pathway, was observed with macrocycle 7a as
well (see ESI†). Notably, Table 3 shows that amongst all the
kFurther evidence of a chemical change to the ferrocene moiety, following the
occurrence of an EC mechanism, was provided when electrochemical reversibil-
ity was not restored upon titrating an excess of chloride anions into the oxo-
anion-1a electrochemical mixture, in spite of the rotaxane’s preference for
binding chloride.
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Fig. 5 (A) CVs of [2]rotaxane 1a in 0.1 M TBAPF6 (1 : 1 CH2Cl2–CH3CN) with increasing equivalents of TBACl added. (B) Plot of the half-wave poten-
tial (E1/2) of 1a in the presence of different aliquots of TBACl. (C) Plot of half-wave potential (E1/2) of 7a with increasing quantities of TBACl added.
Fig. 6 CVs of [2]rotaxane 1a in the presence of increasing aliquots of (A) TBABr; (B) TBA acetate; and (C) TBAH2PO4.
Table 4 Shifts in redox couple of Fc/Fc+ of [2]rotaxanes 1a–e upon
addition of TBACla
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−27
−25
−20
−25
−20
−37
−34
−24
−33
−31
a Electrolyte: 0.1
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Acknowledgements
J.Y.C.L thanks the Agency for Science, Technology and
Research (A*STAR), Singapore, for a postgraduate scholarship.
M. J. C. thanks the European Research Council for funding
under the European Union’s Framework Program (FP7/2007-
2013) ERC Advanced Grant Agreement number 267426.
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