A New Class of Halide-Selective Ionophores for Potentiometric Sensors

Dec 8, 2009 - such triazolophane as a halide-selective ionophore in poly(vinyl chloride) (PVC) membrane electrodes. Different membrane compositions we...
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Anal. Chem. 2010, 82, 368–375

Triazolophanes: A New Class of Halide-Selective Ionophores for Potentiometric Sensors Elsayed M. Zahran,† Yuran Hua,‡ Yongjun Li,‡,§ Amar H. Flood,‡ and Leonidas G. Bachas†,* Department of Chemistry, University of Kentucky, Lexington, Kentucky 40506, and Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405 Triazolophanes, cyclic compounds containing 1,2,3-triazole units, are a new class of host molecules that demonstrate strong interactions with halides. These molecules are designed with a preorganized cavity that interacts through hydrogen bonding with spherical anions, such as chloride and bromide. We have explored the use of one such triazolophane as a halide-selective ionophore in poly(vinyl chloride) (PVC) membrane electrodes. Different membrane compositions were evaluated to identify concentrations of the ionophore, plasticizer, and lipophilic additive that give rise to the best chloride and bromide selectivity. The lipophilicity of the plasticizer was found to have a great impact on the electrode response. Additionally, the concentration of the lipophilic additive was found to be critical for optimal response. The utility of a triazolophane-based electrode was demonstrated by quantification of bromide in horse serum samples. The selectivity of anion-selective electrodes is largely dependent on the availability of ionophores that demonstrate selective interaction with the targeted anion. The most successful ionophores for anions include compounds containing strong Lewis acid metal atoms (e.g., tin, indium, cobalt, manganese, and zinc) in the center of a macromolecule,1-3 as for example in metalloporphyrins4,5 and metallophthalocyanines.6,7 The selectivity of such ionophores is mainly controlled by the selective interaction of the central metal and the anion. Further, the multidentate tris(3chlorodimethylstannylpropyl)chlorostannane was used as a phosphate-selective ionophore.8 The strong Lewis acidity of the tin * Corresponding author. E-mail: [email protected]. Phone: +1(859) 257-6350. Fax: +1(859) 323-1069. † University of Kentucky. ‡ Indiana University. § Current Address: Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Organic Solids, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100080, P. R. China. (1) Steed, J. W. Chem. Soc. Rev. 2009, 38, 506–519. (2) Sessler, J. L.; Camiolo, S.; Gale, P. A. Coord. Chem. Rev. 2003, 240, 17– 55. (3) Newcomb, M.; Horner, J. H.; Blanda, M. T.; Squattrito, P. J. J. Am. Chem. Soc. 1989, 111, 6294–6301. (4) Mitchell-Koch, J. T.; Pietrzak, M.; Malinowska, E.; Meyerhoff, M. E. Electroanalysis 2006, 18, 551–557. (5) Qin, Y.; Bakker, E. Anal. Chem. 2004, 76, 4379–4386. (6) Allen, J.; Florido, A.; Young, S. D.; Daunert, S.; Bachas, L. G. Electroanalysis 1995, 7, 710–713. (7) Hassan, S. S. M.; Kelany, A. E.; Al-Mehrezi, S. S. Electroanalysis 2008, 20, 438–443.

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metal atoms dictates the selectivity of the ionophore to the highly hydrophilic phosphate. The use of cyclic ionophores with a geometrically preorganized central cavity is well-established in cation-selective electrodes.9-13 Many of these ionophores interact with spherical cations that fit best within the macromolecular cavity and result in electrodes that have very good selectivity to their primary cations.14-18 Widespread use of cyclic ionophores has not met with similar success in the case of anion-selective electrodes.19-22 Indeed, there is a limited number of reports describing successful anion-selective cyclic ionophores.23-25 A cyclic mercuracarborand ionophore with a well-defined Lewis acidic central cavity has been introduced.23,24 The ionophore was used for the selective determination of chloride in biological samples. Later on, with careful control of the ion fluxes across the membrane, nanomolar iodide detection using the same mercuracarborand has been achieved.25 This cyclic ionophore has exceptional selectivity for chloride against anions found in biological fluids, including salicylate; the latter is a common interferent with the ion-selective electrodes employed (8) Chaniotakis, N. A.; Jurkschat, K.; Ru ¨ hlemann, A. Anal. Chim. Acta 1993, 282, 345–352. (9) Johnson, R. D.; Bachas, L. G. Anal. Bioanal. Chem. 2003, 376, 328–341. (10) Bu ¨ hlmann, P.; Pretsch, E.; Bakker, E. Chem. Rev. 1997, 97, 3083–3132. (11) Gadzekpo, V. P. Y.; Moody, G. J.; Thomas, J. D. R.; Christian, G. D. IonSel. Electrode Rev. 1986, 8, 173–207. (12) Diamond, D.; Svehla, G.; Seward, E. M.; McKervey, M. A. Anal. Chim. Acta 1988, 204, 223–231. (13) Bakker, E. Anal. Chem. 2004, 76, 3285–3298. (14) Kumar, J. A.; Jitendra, R.; Shalabh, J. Int. J. Environ. Anal. Chem 2008, 88, 209–221. (15) Xianshun, Z.; Linhong, W.; Langxing, C.; Fengbo, X.; Qingshan, L.; Xuebing, L.; Xiwen, H.; Zheng-Zhi, Z. Tetrahedron 2002, 58, 2647–2658. (16) Marques de Oliveira, I. A.; Pla-Roca, M.; Escriche, L.; Casabo, J.; Zine, N.; Bausells, J.; Teixidor, F.; Crespo, E.; Errachid, A.; Samitier, J. Electrochim. Acta 2006, 51, 5070–5074. (17) Diamond, D.; Nolan, K. Anal. Chem. 2001, 73, 22A–29A. (18) Suzuki, K.; Sato, K.; Hisamoto, H.; Siswanta, D.; Hayashi, K.; Kasahara, N.; Watanabe, K.; Yamamoto, N.; Sasakura, H. Anal. Chem. 1996, 68, 208– 215. (19) Sathyapalan, A.; Zhou, A.; Kar, T.; Zhou, F.; Su, H. Chem. Commun. 2009, 325–327. (20) Antonisse, M. M. G.; Reinhoudt, D. N. Chem. Commun. 1998, 443–448. (21) Umezawa, Y.; Kataoka, M.; Takami, W.; Kimura, E.; Koike, T.; Nada, H. Anal. Chem. 1988, 60, 2392–2396. (22) Ahlers, B.; Cammann, K.; Warzeska, S.; Kramer, R. Angew. Chem. Int. Ed. 1996, 35, 2141–2143. (23) Johnson, R. D.; Badr, I. H. A.; Diaz, M.; Wedge, T. J.; Hawthorne, M. F.; Bachas, L. G. Electroanalysis 2003, 15, 1244–1250. (24) Badr, I. H. A.; Diaz, M.; Hawthorne, M. F.; Bachas, L. G. Anal. Chem. 1999, 71, 1371–1377. (25) Malon, A.; Radu, A.; Qin, W.; Ceresa, A.; Maj-Zurawska, M.; Bakker, E.; Pretsch, E. Anal. Chem. 2003, 75, 3865–3871. 10.1021/ac902132d  2010 American Chemical Society Published on Web 12/08/2009

Figure 1. (a) Triazolophane and (b) representative model of the interaction of triazolophane with chloride.

in clinical analyzers.26,27 The selectivity of the mercuracarborand ionophore is a result of the strong Lewis acidity of the metal as well as the geometrical limitation of the rigid central cavity. Formation of hydrogen bonds between an anion and a neutral carrier ionophore is another strategy for designing anion-selective ionophores. This strategy is favored for the binding of halides because of their relatively high charge density as compared to other anions. Most of the anion receptors that form hydrogen bonds are based on a combination of NH hydrogen-bonding sites of amide, urea, or thiourea groups.9,28 These groups are arranged in cyclic or acyclic architectures that provide some geometrical selectivity to the target anion.29 The NH groups of some of these ionophores could become protonated, which changes the ionophore to become the charged carrier type, leading to electrodes that demonstrate normal Hofmeister selectivity.30,31 Unlike the NH group, the CH functionality does not get protonated in the membrane system. In CH-based receptors, the strength of anion binding is induced from the preorganization32-34 of the host’s central cavity. A novel class of halide receptors has recently been introduced, triazolophanes (Figure 1), based on CH hydrogen bonding from 1,2,3-triazole units within a preorganized central (26) Lewandowski, R.; Sokalski, T.; Hulanicki, A. Clin. Chem. 1989, 35, 2146. (27) Mori, L.; Waldhuber, S.; Metcalfe, T.; Rauh, J. Clin. Chem. 1997, 43, 1249– 1250. (28) Bondy, C. R.; Loeb, S. J. Coord. Chem. Rev. 2003, 240, 77–99. (29) Prados, P.; Quesada, R. Supramol. Chem. 2008, 20, 201–216. (30) Shishkanova, T. V.; Sykora, D.; Sessler, J. L.; Kral, V. Anal. Chim. Acta 2007, 587, 247–253. (31) Piotrowski, T.; Radecka, H.; Radecki, J.; Depraetere, S.; Dehaen, W, Electroanalysis 2001, 13, 342–346. (32) Cram, D. J. Angew. Chem., Int. Ed. 1988, 27, 1009–1020. (33) Lahiri, S. L.; Thompson, J. L.; Moore, J. S. J. Am. Chem. Soc. 2000, 122, 11315–11319. (34) Tobe, Y.; Utsumi, N.; Kawabata, K.; Nagano, A.; Adachi, K.; Araki, S.; Sonoda, M.; Hirose, K.; Naemura, K. J. Am. Chem. Soc. 2002, 124, 5350– 5364.

cavity.35-38 Triazolophanes have shown good selectivity toward chloride and bromide on the basis of UV and 1H NMR spectroscopic titrations. The preorganization and size of the triazolophane’s macrocyclic structure were found to play an important role in halide recognition selectivity; the triazolophanes showed selective binding with 1:1 complexation stoichiometry to chloride and bromide.36,39 These two anions can fit inside the cavity more snugly compared to the too-small fluoride and toobig iodide. On account of this selectivity and the relatively high binding constant of triazolophane with chloride and bromide in solution phase measurements, we herein evaluated its performance as an ionophore in polymeric membrane anion-selective electrodes. EXPERIMENTAL SECTION Reagents. Most of the chemicals were obtained in the highest purity grade and were used as purchased unless mentioned otherwise. Sodium chloride, potassium chloride, sodium bicarbonate, sodium phosphate dibasic, sodium acetate, and glacial acetic acid were obtained from EMD Chemicals (Gibbstown, NJ). Tridodecylmethylammonium chloride (TDMACl), sodium nitrate, sodium salicylate, sodium bromide, and sodium perchlorate were purchased from Sigma (St. Louis, MO). All the buffers, N[tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid (TES), N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid) (HEPES), 1,3-bis[tris(hydroxymethyl)methylamino]propane (Bis-Tris-pro(35) Li, Y.; Flood, A. H. Angew. Chem. Int. Ed. 2008, 47, 2649–2652. (36) Li, Y.; Flood, A. H. J. Am. Chem. Soc. 2008, 130, 12111–12122. (37) Li, Y.; Pink, M.; Karty, J. A.; Flood, A. H. J. Am. Chem. Soc. 2008, 130, 17293–17295. (38) Li, Y.; Vander Griend, D. A.; Flood, A. H. Supramol. Chem. 2009, 21, 111– 117. (39) Bandyopadhyay, I.; Raghavachari, K.; Flood, A. H. ChemPhysChem 2009, 10, 2535–2540.

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Table 1. Membrane Composition and Response Characteristics of Different Triazolophane-Based Electrodes TDMACl

slope

membrane

triazolophane (wt %)

mol %a

wt %

NPOE (wt %)

I II III IV V VII XIV XV VI VIII IX X

2.0 1.0 2.4 0.0 3.7 3.7 4.5 6.0 2.0 2.0 2.0 2.0

60 60 20 50 60 60 60

0.8 0.5 0.3 2.0 1.3 1.6 1.9 2.5

90 60 5

1.4 0.8 0.1

64.7 65.7 64.8 65.3 63.3 63.1 62.4 61 65.3 64.4

a

PVC (wt %)

Cl- (mV/decade)

Br- (mV/decade)

64.7 65.2

32.5 32.8 32.5 32.7 31.7 31.6 31.2 30.5 32.7 32.2 32.5 32.7

-54.6 -46.4 -32.5 -53.5 -47.9 -55.1 -53.9 -35.4 +23.1 -52.3 -17.8 +32.9

-60.2 -60.3 -57.1 -66.0 -58.2 -61.3 -59.4 -47.5 +23.1 -74.6 -33.9 +32.9

Mole ratio relative to the ionophore.

pane), and 2-(N-morpholino)ethanesulfonic acid (MES) were also obtained from Sigma (St. Louis, MO). 2-Nitrophenyl octyl ether (NPOE), poly(vinyl chloride) (PVC), and bis(2-ethylhexyl) sebacate (DOS), all of Selectophore grade, were obtained from Fluka (Ronkonkoma, NY). Sodium iodide and sodium sulfate were purchased from J. T. Baker (Phillipsburg, NJ). The triazolophane was prepared according to literature methods.35 Enzyme Immunoassay (EIA) tested (negative) serum from a donor New Zealand horse was obtained from Invitrogen (Carlsbad, CA). Deionized water of 18 MΩ (Mili-Q water purification system; Milipore, Bedford, MA) was used throughout the experiments. Membranes and Electrode Preparation. The PVC-based ion-selective electrodes were prepared as described previously.24 The membrane cocktails were prepared by dissolving the specific amounts of the triazolophane, TDMACl, and plasticizer in 1 mL of THF. The different compositions of the membranes used in this study are shown in Table 1. The solution was sonicated for 30 min to ensure complete dissolution of all components, left at rest for 2 h to release any air bubbles, and poured into a 22 mm i.d. glass ring located on a glass slide. The solvent was allowed to evaporate at room temperature overnight, leaving a PVC membrane with a thickness of about 150-200 µm. Small disks of each membrane were punched using a cork borer and mounted onto Philips IS-561 (Gla¨sblaserei Mo¨ller, Zurich, Switzerland) electrode bodies. A solution of 1 × 10-3 M NaCl was used as the internal filling solution. Potentiometric Measurements. All potentiometric measurements were performed at 23 οC, controlled by a Fisher Isotemp Circulator bath (Model 9500), using the following cell assembly: Ag/AgCl|3.0 M KCl|1.0 M CH3COOLi|sample solution|ISE membrane|1 × 10-3 M NaCl|Ag/AgCl. The change in the electrode potential was measured using an eight-channel SC2345 interface (SCC-LP01, National Instruments, Austin, TX). A PCI-6036E multifunction I/O data acquisition device was used to connect the interface to a computer running Lab VIEW 7.0 (National Instruments) software with a custom-designed program for data acquisition and analysis. The pH studies and buffer preparations were performed with the aid of a Fisher Scientific Accumet 915 pH/Ion meter, which was equipped with an Orion pH glass electrode (Beverly, MA). The performance of the triazolophane-based membrane electrode at different pH values (2-12) was determined by adding small aliquots of sodium hydroxide or sulfuric acid to 1 × 10-4 and 1 × 10-2 M 370

DOS (wt %)

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NaCl solutions. The effect of different buffers was evaluated by monitoring the change in the electrode’s potential with incremental additions of the buffer solution to deionized water. The selectivity coefficients were determined by the matched potential method40,41 and the separate solution method.42 The triazolophane-based electrode was used for determination of bromide in 5% (v/v) horse serum solution. RESULTS AND DISCUSSION Triazolophanes (Figure 1) are a new class of anion receptors with a preorganized and rigid central cavity. The size of the cavity provides binding to spherical anions such as halides.35,36 The interaction with halides is based on hydrogen bonding between the eight CH hydrogen atoms of the cavity and the halide anion. The CH of the 1,2,3-triazole moieties is more polarized than that of the phenylene moieties, which in turn dominates the interaction with the encapsulated anion.36 The 1,2,3-triazole unit formed by click chemistry43,44 is often utilized as an amide bond surrogate. It is also known that substitution on the phenylene can increase the affinity to halides.36 The triazolophane displays a planar structure with circular arrangement of the CH hydrogen bond donors, which contributes multiple factors to the selectivity of the receptor: (i) negligible H · · · H interactions between the inner protons, (ii) cooperation of eight hydrogen bonds to compensate for the polarization of anions,39 (iii) favorable formation of 1:1 complexes, with chloride and bromide but not iodide,38 and (iv) the smaller fluoride binds to only half of the macrocycle.36,38,39 Prior UV-vis studies showed a very good binding affinity to chloride and bromide with Ka in the range of 107 M-1 in dichloromethane.36 We hypothesized that the triazolophane with its preorganized central cavity and CH hydrogen bonding to halides is a good candidate as a neutral carrier ionophore for halides. Membranes containing four different concentrations of triazolophane and a constant 60 mol % of TDMACl were evaluated for (40) Gadzekpo, V. P. Y.; Christian, G. D. Anal. Chim. Acta 1984, 164, 279– 282. (41) Umezawa, Y.; Umezawa, K.; Sato, H. Pure Appl. Chem. 1995, 67, 507– 518. (42) Bakker, E.; Pretsch, E.; Bu ¨ hlmann, P. Anal. Chem. 2000, 72, 1127–1133. (43) Rostovtsev, A. V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596–2599. (44) Tornøe, B. C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057–3062.

their response. It is evident (Table 1) that the potentiometric response toward chloride improves from the sub-Nernstian -46.4 mV/decade for membrane II (1 wt % ionophore) to near-Nernstian -54.6 mV/decade for membrane I (2 wt % ionophore). However, 1 wt % ionophore (membrane II) was enough to show a Nernstian response of -60.2 mV/decade toward bromide. A small improvement was observed by further increasing the concentration of the ionophore to 3.7 and 4.5 wt %. Increasing the concentration to 6 wt % presented ionophore solubility problems within the membrane. The nature of the plasticizer influences the dielectric constant9 of the membrane and the mobility10 of the ionophore. Membranes were prepared with two of the most common plasticizers, DOS and NPOE. The dielectric constant of NPOE-plasticized45 and DOS-plasticized46 membranes are 14 and 4.8, respectively. All membranes plasticized with DOS showed a poor response to chloride and bromide (Table 1) and a lower response to highly lipophilic anions in comparison with the NPOE-plasticized membranes. The difference was emphasized when comparing membranes I (-54.6 mV/decade) and IX, which has the same composition as I but used DOS (-17 mV/decade). This result likely arises from the difference in the dielectric constant of the plasticizers. A higher dielectric constant (i.e., membranes with NPOE) increases the polarity and decreases the electrical resistance of the membrane. When using a triazolophane, a pure CH hydrogen-bonding ionophore, the transfer of chloride and bromide to the membrane phase is facilitated by a higher polarity plasticizer in the membrane.46 Similar trends were observed with the hydrogen-bond-forming chloride ionophore, bisthiourea.47 It is well-known that the addition of lipophilic positive sites to neutral carrier based membranes improves the Nernstian response and enhances the permselectivity to anions. These lipophilic positive sites compensate the charge of the anion-ionophore complex at high concentration of the anions, as well as the residual negative charges found to be present in PVC membranes.9,10 They also increase the polarity of the membrane, which enhances the phase transfer of hydrophilic anions. Electrode VI, which has a membrane containing the triazolophane but no additional lipophilic salt, showed a weak cationic response (Table 1). Accordingly, electrodes having six different mole ratios of lipophilic cationic sites (through incorporation of TDMACl in the membrane phase) relative to the ionophore were prepared to improve the permselectivity to anions. The addition of 20 mol % of TDMACl initiates an anionic response (Table 1 and Figure 2) of the triazolophanebased electrode. However, this low percentage is insufficient to achieve a Nernstian response to chloride, although this membrane demonstrated a near-Nernstian response of -57.1 mV/decade for bromide with a detection limit of 8.5 × 10-6 M. On account of the fact that UV and NMR spectroscopic titrations have shown similar complexation affinities of the triazolophane toward chloride and bromide, the difference in potentiometric performance could be attributed to a better phase transfer of the more lipophilic bromide compared to chloride. Subsequently, the amount of TDMACl was increased to 50, 60, and 90 mol % to

improve the chloride response of the membranes (Figure 2). An optimum response of -54.6 mV/decade and detection limit of 5.6 × 10-6 M toward chloride was attained at a ratio of 60 mol % (electrode 1). Changing this ratio from 20 to 60 mol % did not cause a significant effect on the slope of the response to bromide (Figure 3), but the detection limit improved to 6.3 × 10-7 M with a linear range from 2.5 × 10-6 to 1 × 10-1 M. Further increasing the TDMACl ratio to 90 mol % (electrode VIII) resulted in a slight deterioration in the chloride response to -52.3 mV/decade and in a super-Nernstian response of -74.6 mV/decade toward bromide. In this case, the membrane acts as an ionophore-free anion-exchanger electrode, the response theory of which has been described elsewhere.48-50

(45) Eugster, R.; Rosatzin, T.; Rusterholz, B.; Aebersold, B.; Pedrazza, U.; Ru ¨ egg, D.; Schmid, A.; Spichiger, U. E.; Simon, W. Anal. Chim. Acta 1994, 289, 1–13. (46) Sakaki, T.; Harada, T.; Kawahara, Y.; Shinkai, S. J. Inclusion Phenom. Mol. Recog. Chem. 1994, 17, 377–392. (47) Xio, K. P.; Bu ¨ hlmann, P.; Nishizawa, S.; Amemiya, S.; Umezawa, Y. Anal. Chem. 1997, 69, 1038–1044.

(48) Amemiya, S.; Bu ¨ hlmann, P.; Umezawa, Y.; Jagessar, R. C.; Burns, D. H. Anal. Chem. 1999, 71, 1049–1054. (49) Radu, A.; Peper, S.; Bakker, E.; Diamond, D. Electroanalysis 2007, 19, 144– 154. (50) Berrocal, M. J.; Aurelio Cruz, A.; Badr, I. H. A.; Bachas, L. G. Anal. Chem. 2000, 72, 5295–5299.

Figure 2. Chloride potentiometric response of triazolophane-based electrodes containing 2 wt % triazolophane and different mole ratios of TDMACl (relative to ionophore): ([) 0 mol %, (0) 20 mol %, (2) 50 mol %, (b) 60 mol %, and (O) 90 mol %.

Figure 3. Bromide potentiometric response of triazolophane-based electrodes containing 2 wt % triazolophane and different mole ratios of TDMACl (relative to ionophore): ([) 0 mol %, (0) 20 mol %, (2) 50 mol %, (b) 60 mol %, and (O) 90 mol %.

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Figure 4. Effect of pH on potentiometric response of triazolophanebased electrode (2 wt % ionophore and 60 mol % TDMACl in NPOE) in different chloride concentrations: (b) chloride free, ([) 1 mM chloride, and (2) 10 mM chloride. (pH was adjusted with sodium hydroxide and sulfuric acid).

The effect of pH (2-12) on the triazolophane-based electrode was studied by recording the change in the response (Figure 4) as a result of adding very small aliquots of 0.1 M NaOH or H2SO4 to deionized water and 1 and 10 mM NaCl solutions. In the absence of chloride, the triazolophane-based membranes showed a pH dependence with a negative slope of -14.9 mV/ pH across the pH range 3-11. However, with the introduction of 1 and 10 mM NaCl, the electrode response became practically independent of pH over the range of 2-7 with a slight effect at higher pH. The pH response in the absence of chloride can be explained as a response to hydroxide, which is represented by the gradual decrease in the electrode potential with increasing pH. The addition of 1 mM chloride overcame the hydroxide interference, and the electrode potential became stable across the acidic and slightly basic pH ranges; increasing the hydroxide concentration further (pH 8-12) reintroduced the hydroxide interference. On account of the fact that all previously reported complexation experiments involving the triazolophane were performed in an organic solvent (dichloromethane) and that there is no information about the complexation of the triazolophane with the anions of common buffers (acetate, sulfonate, and phosphate), finding an appropriate pH buffer must be determined experimentally. The experiment was performed in two steps: First, the response of the triazolophane-based electrode was measured during the standard addition of various buffers to deionized water. Most of the buffers showed a considerable response upon increasing the buffer concentration to 10 mM, while a moderate effect was shown by the buffers Bis-Tris-propane, HEPES, and TES, adjusted to pH 7 with NaOH. A much smaller response was seen for solutions with MES at pH 5.5 and acetate at pH 4.5. Subsequently, the calibration plots for chloride and bromide were carried out in buffers that demonstrated either a moderate or weak response. The best response (Figure 5) to chloride and bromide was found in water and acetate at pH 4.5. The same slope was found in MES at pH 5.5, but with an elevated detection limit by almost 1 order of magnitude. Weak responses 372

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Figure 5. Chloride potentiometric response of triazolophane-based electrodes containing 2 wt % triazolophane and different mole ratios of TDMACl (relative to ionophore) in different buffers and deionized water: (0) Bis-Tris-propane, pH 7.4; (2) HEPES, pH 7; (∆) phosphate, pH 7; (b) MES, pH 5.5; (O) acetate, pH 4.5; and ([) water. All buffers were prepared in 0.01 M concentration, and the pH was adjusted to the above-mentioned values using NaOH.

were found in the buffers Bis-Tris-propane, HEPES, and phosphate buffer at pH 7. The selectivity pattern of the triazolophane-based selective electrodes was investigated in unbuffered solutions to avoid any contribution from the complexation between the buffer anions and the ionophore.47 The selectivity pattern of the electrodes in which the membrane contained TDMACl but not the triazolophane (electrode IV) was established for comparison purposes. Given that some of the interfering anions do not show a Nernstian response, the selectivity coefficients of the triazolophane-based selective electrode were determined by the matched potential method (MPM).40,41 The calibration plot was constructed for each of the studied anions, and the selectivity coefficients for chloride, pot pot KCl-, J, or bromide, KBr-, J, with respect to different anions were measured at 1 × 10-4 M of the primary ion for the less interfering anions and at 1 × 10-2 M for the highly interfering anions. For meaningful comparison to the physiologically required selectivities, the selectivity coefficients of the anions that showed Nernstian responses were determined using the separate solution method (SSM).42 Tables 2 and 3 show the selectivity of various triazolophane-based electrodes with different concentrations of TDMACl for chloride and bromide, respectively. The content of TDMACl in the membrane was found to have a critical effect on the selectivity pattern of the triazolophane-based electrode. As is evident from Figures 6 and 7, at 20 mol % of TDMACl, electrode III showed enhanced selectivity toward halides over the most lipophilic anions in comparison to the TDMAClbased electrode (electrode IV). Electrode III (Figure 7) showed pot an anti-Hofmeister selectivity toward bromide, e.g., log KBr-, Sal ) -1.54. This high selectivity for bromide shown by the triazolophane-based electrode is consistent with the previously reported high binding constants of the triazolophane with chloride and bromide as measured by NMR and UV spectroscopic titration.35,36 It should be noted that because the triazolophane-based electrode performs favorably at acidic pH buffers,

pot

Table 2. Selectivity Coefficients, log KCl-, J, of Triazolophane-Based Electrodes I, II, III, VIII, and VII Doped with Various Mole Ratios of TDMACl (Relative to the Ionophore) in Comparison with the Anion-Exchanger-Based Membrane, Electrode IV (2 wt % TDMACl) and the Selectivity Required for Physiological Analysis of Chloride I anion

MPMa

ClO4BrSCNSalINO3ClSO42-

5.44 3.50 3.03 2.97 2.70 1.10 0.00 -2.92

II SSMb 2.22 3.02 1.80 0.87 0.00

MPM

III SSM

6.34 3.65 3.22 3.17 3.01 0.97 0.00 -2.81

2.10 3.19 2.05 0.79 0.00

MPM

VIII SSM

4.29 2.90 2.64 1.41 3.56 0.98 0.00 -3.10

MPM

VII SSM

6.99 5.11 4.99 4.91 3.00 2.00 0.00 -1.50

MPM

IV SSM

4.24 3.38 3.58 3.21 2.81 1.35 0.00 -3.98

2.24 2.51 2.24 0.91 0.00

MPM

SSM

7.12 5.20 5.00 4.99 3.10 1.92 0.00 -1.60

1.38 3.75 3.41 2.20 0.00

requiredc NDd 1.52 1.70 0.82 5.52 1.46 0.00 -1.50

a Matched potential method. b Separate solution method was used for anions that showed Nernstian response. c Calculated as explained in the text. d Not determined.

pot

Table 3. Selectivity Coefficients, log KBr-, J, of Triazolophane-Based Electrodes I, II, III, VIII, and VII Doped with Various Mole Ratios of TDMACl (Relative to the Ionophore) in Comparison with the Anion-Exchanger-Based Membrane, Electrode IV (2 wt % TDMACl) and the Selectivity Required for Physiological Analysis of Bromidea I anion

MPM

ClO4ISalSCNNO3BrClSO42-

1.15 -0.48 -0.32 0.40 -1.44 0.00 -2.11 -4.30

a

II SSM -0.40 0.80 -1.40 0.00 -2.22

MPM 1.71 -0.40 -0.31 0.73 -1.71 0.00 -2.32 -4.11

III SSM -0.14 0.99 -1.40 0.00 -2.19

MPM 3.28 0.68 -1.54 -0.27 -1.99 0.00 -3.00 -4.50

VIII SSM

MPM

0.65 -1.65 -0.35 -2.00 0.00

4.61 1.97 4.54 2.78 0.64 0.00 -2.05 -3.90

VII SSM

MPM 1.18 -0.41 -0.48 0.14 -1.45 0.00 -2.41 -4.80

IV SSM 0.01 0.27 -1.32 0.00 -2.24

MPM 4.22 2.43 2.45 2.49 0.80 0.00 -1.56 -3.10

SSM 2.03 2.36 0.85 0.00 -1.38

required ND 4.46 -0.17 0.69 0.46 0.00 -2.80 -2.50

See footnotes for Table 2.

Figure 6. Potentiometric selectivity coefficients of triazolophane-based electrodes containing different mole ratios of TDMACl (relative to ionophore) toward chloride over different anions in comparison with the ion-exchanger-based electrode IV (2 wt % TDMACl, column 5) and the biologically required chloride selectivity (column 6). The required chloride selectivity coefficients to measure Cl- in blood were calculated at 0.01 confidence level based on the minimum blood chloride concentration and the maximum blood concentrations of different anions.

no bicarbonate interference was observed because of the very low bicarbonate equilibrium concentration at that pH. Bromide has been used for a long time as a treatment for patients with epilepsy.51 The determination of bromide is very important for these patients, because it could cause intoxication

at higher concentrations.52,53 Furthermore, bromide poisoning can occur as a result of exposure to brominated hydrocarbons such as halothane and methyl bromide.54 To determine whether the (51) Korinthenberg, R.; Burkart, P.; Woelfle, C.; Moenting, J. S.; Ernst, J. P. J. Child Neurol. 2007, 22, 414–418.

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Figure 7. Potentiometric selectivity coefficients of triazolophane-based electrodes containing different mole ratios of TDMACl (relative to ionophore) toward bromide over different anions in comparison with the ion-exchanger-based electrode IV (2 wt % TDMACl, column 5) and the biologically required bromide selectivity (column 6). The required bromide selectivity coefficients to measure Br- in blood were calculated at 0.01 confidence level based on the minimum therapeutic bromide concentration and the maximum blood concentrations of different anions.

electrodes have the requisite selectivity for the determination of bromide in physiological fluids, the required selectivity coefficients pot of bromide over the physiological background anions, log KBr-, J, were calculated on the basis of the therapeutic concentration of 10-30 mM of bromide54 and the physiological concentrations of key anions: nitrate, 35-40 µM; thiocyanate, 20-30 µM; salicylate, g150 µM; sulfate, 1.0-1.4 mM; and chloride, 98-106 mM.55-57 The selectivity coefficients of the triazolophane-based bromide-selective electrode toward all background anions (Table 3) are less than the physiologically required selectivity calculated at 1% error. This implies that the selectivity of the electrode doped with 20 mol % TDMACl enables the determination of bromide in physiological samples. Subsequently, the triazolophane-based electrode was used to measure the bromide concentration in spiked horse serum samples. The calibration plot for bromide was constructed in a 5% (v/v) serum solution in which the electrode showed a slope of -52 mV/decade with a detection limit of 5 × 10-5 M; the bromide therapeutic concentrations are within the electrode’s measuring range. According to the bromide measurements (Table 4), the bromide recovery is found to be consistent with the clinically allowable percentage (%) of error. This good quantification of bromide in serum is a consequence of the high selectivity of the triazolophane-based electrode over chloride and bicarbonate, the anions having the highest concentration in serum. These two interfering anions limit the application of commercial bromide ISEs in physiological samples, as described in a prior work58 when utilizing bromide-selective electrodes based on a quaternary ammonium salt. (52) Suzuki, S.; Kawakami, K.; Nakamura, F.; Nishimura, S.; Yagi, K.; Seino, M. Epilepsy Res. 1994, 19, 89–97. (53) Heckerling, P. S.; Ammar, K. A. Am. J. Nephrol 1996, 16, 537–539. (54) Hung, Y. M. Hum. Exp. Toxicol. 2003, 22, 459–461. (55) Kage, S.; Kudo, K.; Ikeda, H.; Tsujita, A.; Ikeda, N. J. Chromatogr. B 2005, 817, 335–339. (56) Hutchins, R. S.; Bansal, P.; Molina, P.; Alajarı´n, M.; Vidal, A.; Bachas, L. G. Anal. Chem. 1997, 69, 1273–1278. (57) Di Stasio, E. Biophys. Chem. 2004, 122, 245–252.

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Table 4. Determination of Bromide in Horse Serum Spiked Solutionsa

a

added, mM

average found, mM

recovery, %

10.0 20.0 30.0 50.0

10.2 ± 0.2 19.3 ± 0.4 29.7 ± 1.0 51.0 ± 1.3

102 97 99 102

Data shown are average ± one standard deviation, n ) 3.

In view of the greater biological importance of chloride over bromide,59 additional experiments were performed in order to improve the chloride selectivity by increasing the extent of the TDMACl to enhance the phase transfer of the chloride into the membrane. Figure 6 shows that electrode I (60 mol % TDMACl and 2 wt % triazolophane) has relatively good selectivity for chloride over all interfering anions in comparison to electrode IV, the TDMACl-based membrane. In comparison to the physiological required selectivities, the selectivity pattern of electrode I is good enough for the biological determination of chloride; however, the pot electrode has a log KCl-, Sal ) +2.97, which excludes its application in the analysis of samples that contain therapeutic levels of salicylate (e.g., 500 µM).60 It should be noted, however, that the triazolophane-based electrodes outperform electrodes employed in clinical analyzers, which demonstrate an even worse selectivity toward salicylate, thus, leading to errors when calculating blood electrolyte balance.26,27 Further increasing the extent of TDMACl to 90 mol % (electrode VIII) returns the selectivity back to the normal Hofmeister series, which agrees with many prior reports13 in cases where the lipophilic salt is present in high amounts within the membrane. (58) Katsu, T.; Furuno, K.; Yamashita, S.; Kawasaki, H.; Gomita, Y.; Ohtsuka, Y.; Ohtahara, S. Clin. Chim. Acta 1995, 234, 157–161. (59) Oesch, U.; Ammann, D.; Simon, W. Clin. Chem. 1986, 32, 1448–1459. (60) Matsubayashi, H.; Fastenau, D. R.; McIntyre, J. A. J. Heart Lung Transplant. 2000, 19, 462–468.

indicates the high stability of the triazolophane in the PVC membrane phase.

Figure 8. Response time of the triazolophane-based electrode I containing 2 wt % triazolophane and 60 mol % TDMACl in NPOE.

The response time is an important characteristic of ISEs on account of the fact that it determines their utility in applications such as flow injection and in vivo analysis.61 Response time is defined by the IUPAC as the time between the instant of changing the activity of the primary ion to the first instant at which the rate of change of the measured potential (∆E/∆t) reaches a limiting value.62 The response time was determined from the plot of potential versus time at ∆E/∆t ) -0.1 mV/s (Figure 8). The triazolophane-based electrode I demonstrates a very fast response time of 15 s at low bromide concentrations and less than 10 s at high bromide concentrations. The day-to-day stability was found to be less than ±0.4 mV/decade over the first month. This (61) Bakker, E.; Qin, Y. Anal. Chem. 2006, 78, 3965–3983. (62) Buck, R. P.; Lindner, E. Pure Appl. Chem. 1994, 66, 2527–2536.

CONCLUSIONS A new halide-binding macrocyclic receptor belonging to the triazolophane family was used as a neutral carrier ionophore in poly(vinyl chloride)-based ion-selective electrodes. The ionophore has a preorganized macrocyclic central cavity that binds chloride and bromide through eight hydrogen bonds. Variations in the amount of ionophore, TDMACl, and plasticizer were used to optimize the electrode response. The electrode based on membranes containing 2 wt % triazolophane and 60 mol % TDMACl plasticized with 2-nitrophenyl octyl ether demonstrated a nearNernstian response of -54.6 mV/decade toward chloride with enhanced selectivity in comparison to the ion-exchanger based membrane. The triazolophane-based ion-selective electrode also showed anti-Hofmeister selectivity to bromide with a submicromolar detection limit. This bromide selectivity is sufficient to enable the determination of bromide concentrations at therapeutic levels in a horse serum sample. Future studies will involve tuning the anion selectivity by manipulating the structure of the triazolophane. ACKNOWLEDGMENT The authors acknowledge support from the National Aeronautics and Space Administration (L.G.B.), the Ministry of Higher Education, Egypt (E.M.Z.), and the Chemical Sciences, Geosciences and Biosciences Division, Office of Basic Energy Sciences, Office of Science, US Department of Energy (A.H.F.). Received for review September 22, 2009. Accepted November 21, 2009. AC902132D

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