Halogen bonding-enhanced electrochemical halide anion sensing by redox-active ferrocene receptors

Article abstract of DOI:10.1039/c5cc05704c

The first examples of halogen bonding redox-active ferrocene receptors and their anion electrochemical sensing properties are reported. Halogen bonding was found to significantly amplify the magnitude of the receptor's metallocene redox-couple's voltammet

Full text of DOI:10.1039/c5cc05704c

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Halogen bonding-enhanced electrochemical halide
anion sensing by redox-active ferrocene receptors
Cite this: DOI: 10.1039/x0xx00000x
Jason Y.C. Lim,a Matthew J. Cunninghamb Jason J. Davisb and Paul D. Beer*a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
shown to lend itself to superior iodide25 and perrhenate26 anion
The first examples of halogen bonding redox-active ferrocene
receptors and their anion electrochemical sensing properties
are reported. Halogen bonding was found to significantly
amplify the magnitude of the receptor metallocene redox-
couple’s voltammetric response for halide sensing compared
to hydrogen bonding analogues in both acetonitrile and
aqueous-acetonitrile solvent media.
binding in pure water in comparison to HB analogues. Although
anion sensing by XB receptors has been demonstrated via UV-vis27
and fluorescence spectroscopy,28, 29 electrochemical anion sensing by
redox-active XB receptors, to the best of our knowledge, is
unprecedented. Herein, we describe the synthesis of a family of
novel acyclic ferrocene-appended XB donor receptors (Fig. 1), and
importantly,
demonstrate
their
significantly
enhanced
electrochemical anion sensing behaviour in comparison with HB
analogues both in organic and organic-aqueous solvent media.
The ability to detect halides such as chloride and bromide in aqueous
solvent mixtures is crucial in many aspects of medicine, industrial
processes and environmental analyses. For instance, chloride is a key
indicator of fecal contamination in the environment and has vast
applications in industry ranging from antifreezing agents to metal
processing, while bromide is used in sedatives and as an
anticonvulsant in medicine, as well as in the photographic industry.1
As such, artificial halide sensors, which are receptor molecules that
give a detectable optical or electrochemical output signal upon
halide binding, have received much scientific attention in recent
years.2-4 Electrochemical sensors in particular, are especially sought
after due to their innate high sensitivity and facile integration into
applicable devices.5 These receptor molecules typically contain
ferrocene as the redox-active moiety due to its chemical stability,
favourable voltammetric characteristics and large synthetic
repertoire, allowing it to be readily incorporated into a myriad of
molecular architectures.6-12 As a result, ferrocene-containing anion
sensors utilising hydrogen bonding (HB), Coulombic interactions, as
well as Lewis acid and metal coordination have been reported.13-15
Fig. 1. Structures of the redox-active XB receptors and their HB analogues
for electrochemical anion sensing in solution.
The target receptors were designed to have the redox-active
ferrocene motif directly conjugated to XB and HB donor anion
binding sites to facilitate efficient electrochemical reporting.
Receptors 1.XB and 1.HB were prepared using the synthetic
procedure shown in Scheme 1. 3,5-Diiodoaniline was converted to
its diazonium salt and coupled with ferrocene to form 1-ferrocene-
Halogen bonding (XB), a highly-directional attractive non-covalent
interaction between a Lewis-acidic halogen atom and a Lewis base,16
is a recent addition to the toolkit of supramolecular anion binding in
solution. While its utilisation in solid-state crystal engineering and
materials design is well-established,17, 18 its applications in solution-
3,5-diiodobenzene (4). Sonogashira coupling of
4 with two
equivalents of ethynyltrimethylsilane, followed by deprotection of
the terminal trimethylsilyl (TMS) groups afforded the bis-ethyne 5 in
96 % overall yield. Copper(I)-catalysed azide-alkyne cycloaddition
(CuAAC) between 5 and two equivalents of octyl azide gave the bis-
prototriazole derivative 6. Thereafter, capitalising on the acidity of
20
23
phase self-assembly,19,
redox-switching21 and catalysis22,
still
remain in their infancy. We have recently demonstrated that XB
possesses a high degree of covalency,24 a feature that has been
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the triazole functionality,30 regioselective triazole deprotonation of 6 aromatic proton Ha (Fig. 2A), suggesting that anion binding was
was achieved using n-butyllithium. Following quenching with occurring in the binding cavity flanked by the triazoliums moieties.
molecular iodine, 7 was obtained in a good yield of 75 %. Bis- WinEQNMR231 analysis of the titration data determined 1:1
methylation of receptor precursors 6 and 7 with trimethyloxonium stoichiometric association constants summarised in Table 1.
tetrafluoroborate, followed by anion exchange, afforded receptors Notably, both chloride and bromide were bound much more strongly
1.HB and 1.XB respectively as hexafluorophosphate salts.
to the halogen bonding receptor 1.XB than 1.HB, with more than an
order of magnitude enhancement in the association constant
observed in the case of bromide.
Scheme 2. Synthesis of 1,1’-substituted ferrocene receptors. (i) Copper(II)
i
acetate hydrate, Pd(PPh3)2Cl2 (cat.), Pr2NH, ethynyltrimethylsilane, THF,
microwave, 100 oC, 1 h, 68 %; (ii) octyl azide, TBAF, Cu(MeCN)4PF6 (cat.),
TBTA (cat.), NEt3, CH2Cl2, R.T., 2 days, 77 %; (iii) n-BuLi, THF, -78 oC, 1 h
then I2, R.T., 1 h, 90 %; (iv) [Me3O][BF4], CH2Cl2, R.T., 16 h, 3.XB 50 %,
3.HB 59 %.
Scheme 1. Synthesis of dicationic receptors 1.XB and 1.HB. (i) HCl, NaNO2,
0
oC,
1
h
then ferrocene, toluene, 16 h, R.T., 33 %; (ii)
ethynyltrimethylsilane, NEt3, Pd(PPh3)2Cl2 (cat.), CuI (cat.), THF,
microwave, 100 oC, 1 h, 97 %; (iii) K2CO3, MeOH, R.T., 3 h, 96 %; (iv) octyl
azide, Cu(MeCN)4PF6 (cat.), TBTA (cat.), NEt3, CH2Cl2, R.T., 16 h, 85 %;
(v) n-BuLi, THF, -78 oC, 1 h then I2, R.T., 1 h, 75 %; (vi) [Me3O][BF4],
CH2Cl2, R.T., 16 h, 1.XB 76 %, 1.HB 80 %.
The 1,1’-bis-substituted ferrocene receptors 2.XB, 2.HB, 3.XB and
3.HB were synthesised via a similar route starting from 1,1’-
diiodoferrocene (Scheme 2). Following Sonogashira coupling with
two equivalents of ethynyltrimethylsilane, the product 8 was
deprotected in situ with tetrabutylammonium (TBA) fluoride and
reacted immediately with two equivalents of octyl azide to give
2.HB, which was then converted directly to 2.XB with n-
butyllithium and iodine. Dicationic receptors 3.HB and 3.XB, were
prepared via alkylation with trimethyloxonium tetrafluoroborate, and
anion exchanged to the hexafluorophosphate salts.
The anion recognition properties of the dicationic ferrocene-
1
appended receptors were studied via H NMR titration experiments
by adding increasing quantities of Cl- and Br- as their TBA salts to
the receptor solutions (see Supporting Information) ¶. Initial
titrations of 1.HB with Cl- and Br- in d3-acetonitrile determined 1:1
association constants of (909 + 14) M-1 and (404 + 4) M-1
respectively. However, both halides were bound very strongly by
1.XB in the same solvent (Ka > 104 M-1), clearly demonstrating the
1
Fig. 2. Partial H-NMR spectra of (A) dicationic 1.XB in 9:1 CD3CN/ D2O
and (B) neutral 2.XB in CD3CN in the presence of 0 and 10 equivalents of
TBABr (500 MHz, 298 K).
1
1
While H NMR titrations showed that the dicationic receptors 3.XB
superiority of XB for anion recognition in solution. Analogous H
and 3.HB bound both chloride and bromide in 9:1 acetonitrile-D2O,
no binding was observed for the neutral receptors 2.XB and 2.HB in
this solvent mixture. Hence, the titrations for the neutral receptors
were performed in pure acetonitrile instead||. For all 1,1’-substituted
NMR titrations in the more competitive solvent mixture of 9:1
acetonitrile-D2O revealed that the addition of chloride or bromide
caused significant downfield perturbations of the receptor’s internal
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ferrocene receptors (2.XB, 2.HB, 3.XB and 3.HB), addition of all cases, due to the fact that bromide is more charge-diffuse (Table
halides caused a downfield signal shift of the ferrocene protons 2). Most importantly, the XB receptors exhibited significantly larger
immediately adjacent to the triazole/triazolium moieties (Hg in Fig. magnitudes of cathodic shifts in comparison to the HB analogues.
2B) and an upfield shift of Hh. This was clearly indicative that For example with 2.XB, chloride and bromide exhibited cathodic
effective electronic communication of anion binding to the ferrocene shift values of 30 mV and 18 mV respectively, compared with 2.HB
moieties was occurring. Interestingly, despite the rotary flexibility of displaying a small cathodic perturbation of only 6 mV with chloride
the 1,1’-substituted ferrocene motif,32 no desymmetrisation of the 1H and no response at all on addition of bromide. Due to the extensive
NMR spectra were observed upon halide titration, suggesting that aromatic conjugation of the receptors, a through-bond mechanism is
the halide was bound in a cooperative fashion between both likely to account for the communication between the anion binding
triazole/triazolium moieties of each receptor (Fig. 2B). Once again, site and the ferrocene unit.13 As evidenced from X-ray Absorption
the XB receptors bound halides much more strongly than their HB Spectroscopy (XAS) investigations,24 the significant contribution of
analogues. However interestingly, a reversal of halide binding covalency exhibited by halogen bonding-halide interactions in
preference was observed in the aqueous solvent mixture (Table 1). In acyclic and catenane XB receptors may also be responsible for the
acetonitrile, the neutral receptor 2.XB showed a slight preference for enhanced cathodic shift magnitudes observed with the present XB
chloride binding over bromide, due to the higher charge density of ferrocene receptors.
the former guest. However in the presence of water, a distinct
preference for bromide was observed for 3.XB over chloride,
presumably arising from Hofmeister bias where the relatively more
charge-diffuse bromide anion is more poorly hydrated.33
Table 1. Anion association constants (Ka/ M-1)a
Cl-
286 (13)
77 (2)
Br-
1139 (87)
86 (3)
1.XB b
1.HB b
2.XB c
2.HB c
3.XB b
3.HB b
72 (2)
53 (1)
4.0 (0.3)
312 (21)
94 (3)
3.0 (0.3)
1024 (15)
100 (3)
a
1:1 stoichiometric association constants were calculated from 1H NMR
titrations at 298 K using the WinEQNMR2 software31 by monitoring the
following protons: 1.XB and 1.HB – the internal aromatic proton Ha was
monitored; 2.HB and 3.HB – triazole and triazolium protons respectively †;
2.XB and 3.XB – ferrocene proton Hg. Anions were added as their TBA salts.
Errors (+) are given in parentheses and are < 10 %.
b Titrations were performed in 9:1 CD3CN/ D2O. c Titrations were performed
in pure CD3CN as no binding was observed in the presence of water.
Fig. 3. CVs of (A) 1.XB with TBACl; (B) 1.XB with TBABr; (C) 2.XB with
TBACl and (D) 2.XB with TBABr. In all spectra, the CVs at 0 and 10
equivalents of halide are represented by the black and red curves respectively
(potentials compared to the Ag/AgNO3 reference electrode).
The electrochemical anion sensing properties of the ferrocene-
appended receptors were studied by cyclic voltammetry (CV) in an
acetonitrile electrolyte solution of 0.1 M TBAPF6 with a Ag/AgNO3
reference electrode.34
Table 2. Cathodic shifts of the ferrocene/ferrocenium redox couples (ΔE1/2
/
mV) of redox-active receptors upon addition of 10 equivalents of chloride
and bromide in dry acetonitrilea.
Receptors 1.XB, 1.HB, 2.XB and 2.HB displayed electrochemical
quasi-reversibility of the respective ferrocene/ferrocenium redox
couple (see Supporting Information) with E1/2 values of 260, 250,
220 and 160 mV respectively relative to the Ag/AgNO3 electrode in
acetonitrile. Both 1.XB and 2.XB exhibited more anodic E1/2 values
compared to their HB analogues, consistent with the electron-
withdrawing nature of the iodine atoms thermodynamically
disfavouring oxidation of the coupled ferrocene unit. Surprisingly,
receptors 3.XB and 3.HB did not show any evidence of
electrochemical oxidation across the entire potential window
accessible in the electrolyte solution (see Supporting Information).
This could be attributed to the cationic triazolium groups attached
directly to the ferrocene units, causing their oxidation to be so highly
disfavoured that their oxidation potentials lie beyond the accessible
solvent potential window.
ΔE1/2/ mVb
Cl-
-32
-17
-30
-6
Br-
-19
-11
-18
0
1.XB
1.HB
2.XB
2.HB
a
Anions were added as their TBA salts, T = 293 K. Electrolyte: 0.1 M
TBAPF6 in dry acetonitrile.b Error estimated to be + 5 mV.
In order to investigate the effects of water on the redox sensing
capabilities of the XB receptors for chloride and bromide, analogous
CV experiments were undertaken in a 9:1 acetonitrile-water mixture
with 0.1 M TBAPF6 electrolyte. Although no redox response was
observed with the neutral receptors 2.XB and 2.HB in this aqueous
solvent mixture, the dicationic halogen bonding receptor 1.XB was
capable of sensing the halides via modest cathodic shifts of 12 mV
and 15 mV for chloride and bromide anions respectively. In
comparison, the hydrogen bonding dicationic receptor 1.HB displays
a smaller cathodic perturbation of only 6 mV for both halides,
Upon addition of chloride and bromide, cathodic perturbations of the
respective ferrocene/ferrocenium redox couples were observed for
the electrochemically-active receptors (Fig. 3)§. As noted previously
with HB ferrocene-based receptors in general, this arises from halide
anion binding stabilising the ferrocenium oxidation state.13 In
acetonitrile, chloride elicited a larger cathodic shift than bromide in
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11. Q.-Y. Cao, T. Pradhan, S. Kim and J. S. Kim, Org. Lett., 2011, 13
4386-4389.
12. Y. Willener, K. M. Joly, C. J. Moody and J. H. R. Tucker, J. Org.
Chem., 2008, 73, 1225-1233.
,
reflecting the weaker binding of 1.HB with chloride and bromide in
the presence of water compared to 1.XB as shown in Table 1.
In conclusion, we have synthesised the first redox-active XB anion
receptors, and demonstrated that they are capable of
electrochemically sensing chloride and bromide in both acetonitrile
and aqueous acetonitrile solvent media. Most importantly, in all
cases, XB enhanced the recognition and sensitivity of halide
electrochemical sensing as compared with HB, as manifested by
significantly larger cathodic ΔE1/2 perturbations of the respective
receptor’s ferrocene/ferrocenium redox couple. The application of
XB to electrochemical analyte sensing and in device fabrication is
continuing in our laboratories.
13. P. D. Beer, P. A. Gale and G. Z. Chen, Coord. Chem. Rev., 1999,
185–186, 3-36.
14. P. D. Beer and S. R. Bayly, in Anion Sensing, ed. I. Stibor, Springer
Berlin Heidelberg, 2005, vol. 255, ch. 5, pp. 125-162.
15. P. D. Beer, P. A. Gale and G. Z. Chen, J. Chem. Soc., Dalton Trans.,
1999, 1897-1910.
16. T. M. Beale, M. G. Chudzinski, M. G. Sarwar and M. S. Taylor,
Chem. Soc. Rev., 2013, 42, 1667-1680.
17. G. Berger, J. Soubhye and F. Meyer, Polym. Chem., 2015, 6, 3559-
3580.
18. A. Mukherjee, S. Tothadi and G. R. Desiraju, Acc. Chem. Res., 2014,
47, 2514-2524.
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.
19. L. C. Gilday, T. Lang, A. Caballero, P. J. Costa, V. Félix and P. D.
Beer, Angew. Chem. Int. Ed., 2013, 52, 4356-4360.
20. C. J. Serpell, N. L. Kilah, P. J. Costa, V. Félix and P. D. Beer, Angew.
Chem. Int. Ed., 2010, 49, 5322-5326.
21. S. Groni, T. Maby-Raud, C. Fave, M. Branca and B. Schollhorn,
Chem. Commun. , 2014, 50, 14616-14619.
22. F. Kniep, S. H. Jungbauer, Q. Zhang, S. M. Walter, S. Schindler, I.
Schnapperelle, E. Herdtweck and S. M. Huber, Angew. Chem. Int.
Ed., 2013, 52, 7028-7032.
23. S. M. Walter, F. Kniep, E. Herdtweck and S. M. Huber, Angew.
Chem. Int. Ed., 2011, 50, 7187-7191.
Notes and references
a
Chemistry Research Laboratory, Department of Chemistry, University
b
of Oxford, Mansfield Road, Oxford, OX1 3TA (UK). Physical &
24. S. W. Robinson, C. L. Mustoe, N. G. White, A. Brown, A. L.
Thompson, P. Kennepohl and P. D. Beer, J. Am. Chem. Soc., 2015,
137, 499-507.
Theoretical Chemistry Laboratory, South Parks Road, Oxford, OX1 3TA
(UK).
1
¶
The binding of iodide was not investigated by H NMR titrations as it
25. M. J. Langton, S. W. Robinson, I. Marques, V. Félix and P. D. Beer,
is not possible to perform electrochemical anion titrations with the anion
due to its low oxidation potential.
Nat Chem, 2014, 6, 1039-1043.
26. J. Y. C. Lim and P. D. Beer, Chem. Commun. , 2015, 51, 3686-3688.
27. L. C. Gilday, N. G. White and P. D. Beer, Dalton Trans., 2013, 42
15766-15773.
|| Dicationic receptor 3.XB exhibited very strong binding with chloride
and bromide in pure acetonitrile (Ka > 104 M-1).
,
†
Signals for ferrocene protons were not monitored for 2.HB and 3.HB
28. B. R. Mullaney, A. L. Thompson and P. D. Beer, Angew. Chem. Int.
Ed., 2014, 53, 11458-11462.
as their perturbations were too small for reliable association constants to
be obtained.
29. F. Zapata, A. Caballero, N. G. White, T. D. W. Claridge, P. J. Costa,
V. t. Félix and P. D. Beer, J. Am. Chem. Soc., 2012, 134, 11533-
11541.
§ The addition of increasing equivalents of TBA fluoride, dihydrogen
phosphate and sulphate salts to electrochemical acetonitrile solutions of the
receptors led to
a gradual loss of electrochemical reversibility (see
30. R. Tepper, B. Schulze, M. Jäger, C. Friebe, D. H. Scharf, H. Görls
and U. S. Schubert, J. Org. Chem., 2015, 80, 3139-3150.
31. M. J. Hynes, J. Chem. Soc. Dalton Trans., 1993, 311-312.
32. N. H. Evans, C. J. Serpell and P. D. Beer, Chem. Commun. , 2011,
47, 8775-8777.
Supporting Information). The disappearance of both the oxidation and
reduction waves suggested that an EC process was taking place. A similar
loss of reversibility in the presence of these anions was also noted for HB
ferrocene-appended isophthalamide receptors.35
33. H. Wang, C. Li, W. Wang and W. J. Jin, Phys. Chem. Chem. Phys.,
2015, DOI: 10.1039/c5cp03076e.
34. B. Kratochvil, E. Lorah and C. Garber, Anal. Chem., 1969, 41, 1793-
1796.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
35. N. H. Evans and P. D. Beer, Org. Biomol. Chem., 2011, 9, 92-100.
1. L. Chung-Chiun, in Handbook of Chemical and Biological Sensors,
Taylor & Francis, 1996.
2. R. M. Duke, E. B. Veale, F. M. Pfeffer, P. E. Kruger and T.
Gunnlaugsson, Chem. Soc. Rev., 2010, 39, 3936-3953.
3. P. A. Gale and C. Caltagirone, Chem. Soc. Rev., 2015, 44, 4212-
4227.
4. M. J. Langton and P. D. Beer, Acc. Chem. Res., 2014, 47, 1939-1949.
5. N. H. Evans, H. Rahman, A. V. Leontiev, N. D. Greenham, G. A.
Orlowski, Q. Zeng, R. M. J. Jacobs, C. J. Serpell, N. L. Kilah, J. J.
Davis and P. D. Beer, Chem. Sci., 2012, 3, 1080-1089.
6. M. Alfonso, A. Tárraga and P. Molina, Inorg. Chem., 2013, 52, 7487-
7496.
7. M. a. d. C. González, F. Otón, R. A. Orenes, A. Espinosa, A. Tárraga
and P. Molina, Organometallics, 2014, 33, 2837-2852.
8. O. Karagollu, M. Gorur, F. Gode, B. Sennik and F. Yilmaz, Sensors
and Actuators B: Chemical, 2014, 193, 788-798.
9. A. Mulas, Y. Willener, J. Carr-Smith, K. M. Joly, L. Male, C. J.
Moody, S. L. Horswell, H. V. Nguyen and J. H. R. Tucker, Dalton
Trans., 2015, 44, 7268-7275.
10. T. Romero, R. A. Orenes, A. Tárraga and P. Molina,
Organometallics, 2013, 32, 5740-5753.
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